Marx: Rosen's Emergency Medicine: Concepts and Clinical Practice

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Marx: Rosen's Emergency Medicine: Concepts and Clinical Practice, 6th ed., Copyright © 2006 Mosby, Inc.

ROSEN'S EMERGENCY MEDICINE Concepts and Clinical Practice Sixth Edition

Editor-in-ChiefJohn A. Marx, MD, FAAEM, FACEP Chair and Chief, Department of Emergency Medicine, Carolinas Medical Center, Charlotte, North Carolina; Adjunct Professor, Department of Emergency Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina; Senior EditorsRobert S. Hockberger, MD, FACEP, FAAEM Chair, Department of Emergency Medicine, Harbor–UCLA Medical Center, Torrance, California; Professor of Clinical Medicine, David Geffen School of Medicine at UCLA, Westwood, Los Angeles, California; Ron M. Walls, MD, FAAEM, FACEP, FRCPC Chair, Department of Emergency Medicine, Brigham and Women's Hospital; Associate Professor of Medicine (Emergency Medicine), Harvard Medical School, Boston, Massachusetts; James G. Adams, MD, FACP, FACEP Chair, Department of Emergency Medicine, Northwestern Memorial Hospital; Professor of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois; William G. Barsan, MD Professor and Chair, Department of Emergency Medicine, University of Michigan Medical School, Ann Arbor, Michigan; Michelle H. Biros, MD, MS, FAAEM, FACEP Research Director and Faculty Physician, Department of Emergency Medicine, Hennepin County Medical Center; Professor of Emergency Medicine, University of Minnesota Medical School, Minneapolis, Minnesota; Daniel F. Danzl, MD Professor and Chair, Department of Emergency Medicine, University of Louisville School of Medicine, Louisville, Kentucky; Marianne Gausche-Hill, MD, FACEP, FAAP Professor of Medicine, David Geffen School of Medicine at UCLA; Director of EMS and Pediatric Emergency Medicine Fellowship, Department of Emergency Medicine, Harbor –UCLA Medical Center, Torrance, California; Glenn C. Hamilton, MD, MSM Professor and Chair, Department of Emergency Medicine, Wright State University School of Medicine, Dayton, Ohio; Louis J. Ling, MD, FACEP, FACMT Professor of Emergency Medicine and Pharmacy, Associate Dean for Graduate Medical Education, University of Minnesota Medical School; Associate Medicine Director for Medical Education, Hennepin County Medical Center; Senior Associate Medical Director, Hennepin Regional Poison Center, Minneapolis, Minnesota; Edward J. Newton, MD, FACEP Chair, Department of Emergency Medicine, Los Angeles County and University of Southern California Medical Center; Professor of Clinical Emergency Medicine, University of Southern California Keck School of Medicine, Los Angeles, California;

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Notice Knowledge and best practice in this field are constantly changing. As new research and experience broaden our knowledge, changes in practice, treatment, and drug therapy may become necessary or appropriate. Readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of the practitioner, relying on their own experience and knowledge of the patient, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the Editors and Authors assume any liability for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this book.

Library of Congress Cataloging-in-Publication Data Rosen's emergency medicine : concepts and clinical practice.—6th ed. / editor-in-chief, John A. Marx ; senior editors, Robert S. Hockberger, Ron M. Walls ; editors, James Adams… [et al.] p. ; cm. Includes bibliographical references and index. ISBN 0-323-02845-4 1. Emergency medicine. I. Title: Emergency medicine. II. Marx, John A. III. Hockberger, Robert S. IV. Walls, Ron M. V. Adams, James. VI. Rosen, Peter Emergency medicine. [DNLM: 1. Emergencies. 2. Emergency Medicine. WB 105 E555 2006] RC86.7.E5784 2006 616.02′5—dc22 2005041694

Publisher's Team Acquisitions Editor: Todd Hummel Developmental Editor: Kimberly Cox Publishing Services Manager: Frank Polizzano

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Marx: Rosen's Emergency Medicine: Concepts and Clinical Practice, 6th ed., Copyright © 2006 Mosby, Inc.

REFERENCES 1. Tobin MJ: Current concepts: Mechanical ventilation. N Engl J Med1994;330:1056. 2. Bone RC, Eubanks DH: The basis and basics of mechanical ventilation. Dis Mon1991;37:321. 3. Kacmarek RM, Hess DR: Essentials of Mechanical Ventilation, New York, McGraw-Hill/Appleton & Lange, 2002. 4. Banner MJ, Lampotang S: Mechanical ventilators: Fundamentals. In: Stock MC, Perel A, ed.Handbook of Mechanical Ventilatory Support, 2nd ed. Philadelphia: Lippincott Williams & Wilkins; 1997: 5. Slutsky AS: ACCP Consensus Conference: Mechanical ventilation. Chest1993;104:1833. 6. Irwin RS: Mechanical ventilation. In: Rippe JM, ed.Intensive Care Medicine, 5th ed. Philadelphia: Lippincott Williams & Wilkins; 2003: 7. Rossi A, Polese G, De Sandre G: Respiratory failure in chronic airflow obstruction: Recent advances and therapeutic implications in the critically ill patient. Eur J Med1992;1:349. 8. Shivaram U: Cardiopulmonary responses to continuous positive airway pressure in acute asthma. J Crit Care1993;8:87. 9. IPPB Trial Group : Intermittent positive pressure breathing therapy of chronic obstructive pulmonary disease. Ann Intern Med1983;99:612. 10. Bersten AD: Treatment of severe cardiogenic pulmonary edema with continuous positive airway pressure delivered by face mask. N Engl J Med1991;325:1825. 11. Sullivan MP: Continuous positive airway pressure in the prehospital treatment of acute pulmonary edema. Ann Emerg Med1995;25:129. 12. Pollack CV, Torres M, Alexander L: A feasibility study of the use of bilevel positive airway pressure for respiratory support in the emergency department. Ann Emerg Med1996;27:189. 13. Keenan SP: Effect of noninvasive positive pressure ventilation on mortality in patients admitted with acute respiratory failure: A meta-analysis. Crit Care Med1997;25:1685. 14. Poponick JM, Renston JP, Bennett RP, Emerman CL: Use of a ventilatory system (BiPAP) for acute respiratory failure in the emergency department. Chest1999;116:166. 15. Fernandez MM: Noninvasive mechanical ventilation in status asthmaticus. Intens Care Med2001;27:486. 16. Soroksky A, Stav D, Shpirer I: A pilot prospective, randomized, placebo-controlled trial of bilevel positive airway pressure in acute asthmatic attack. Chest2003;123:1018. 17. Vitacca M: Non-invasive modalities of positive pressure ventilation improve the outcome of acute exacerbations in COPD patients. Intensive Care Med1993;19:450. 18. Carrey Z, Gottfried SB, Levy RD: Ventilatory muscle support in respiratory failure with nasal positive pressure ventilation. Chest1990;97:150. 19. Bott J, Carroll MP, Conway JH: Randomised controlled trial of nasal ventilation in acute ventilatory failure due to chronic obstructive airways disease. Lancet1993;341:1555. 20. Liesching T, Kwok H, Hill NS: Acute applications of noninvasive positive pressure ventilation. Chest 2003;124:699. 21. Freichels TA: Palliative ventilatory support: Use of noninvasive positive pressure ventilation in terminal respiratory insufficiency. Am J Crit Care1994;3:6. 22. Ambrosino N: Physiologic evaluation of pressure support ventilation by nasal mask in patients with stable COPD. Chest1992;101:385. 23. Dreyfuss D, Saumon G: Barotrauma is volutrauma, but which volume is the one responsible?. Intensive Care Med1992;18:139. 24. Manning HL: Peak airway pressure: Why the fuss?. Chest1994;105:242. 25. Tobin MJ, Fahey PJ: Management of the patient who is “fighting the ventilator”. In: Tobin MJ, ed.Principles and Practice of Mechanical Ventilation, New York: McGraw-Hill; 1994: 26. Hill NS: Noninvasive ventilation: Does it work, for whom, and how?. Am Rev Respir Dis1993;147:1050. 27. Honig EG: Chronic obstructive pulmonary disease and asthma. In: Stock MC, Perel A, ed.Handbook of Mechanical Ventilatory Support, 2nd ed. Philadelphia: Lippincott Williams & Wilkins; 1997: 28. Tuxen DV: Permissive hypercapnic ventilation. Am J Respir Crit Care Med1994;150:870. 29. Van der Touw T: Cardiorespiratory consequences of expiratory chest wall compression during mechanical ventilation and severe hyperinflation. Crit Care Med1993;21:1908.

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30. Eichacker PQ: Meta-analysis of acute lung injury and acute respiratory distress syndrome trials with low tidal volumes. Am J Respir Crit Care Med2002;166:1510. 31. Cross AM: Non-invasive ventilation in acute respiratory failure: A randomised comparison of continuous positive airway pressure and bi-level positive airway pressure. Emerg Med J2003;20:531. 32. Antonelli M: A comparison of noninvasive positive-pressure ventilation and conventional mechanical ventilation in patients with acute respiratory failure. N Engl J Med1998;339:429. 33. Meyer TJ, Hill NS: Noninvasive positive pressure ventilation to treat respiratory failure. Ann Intern Med 1994;120:760. 34. Celikel T: Comparison of noninvasive positive pressure ventilation with standard medical therapy in hypercapnic acute respiratory failure. Chest1998;114:1636. 35. Keenan SP: Noninvasive positive pressure ventilation in the setting of severe, acute exacerbations of chronic obstructive pulmonary disease: more effective and less expensive. Crit Care Med2000;28:2094. 36. Wood KA: The use of noninvasive positive pressure ventilation in the emergency department: Results of a randomized clinical trial. Chest1998;113:1339. 37. Wang SH, Wei TS: The outcome of early pressure-controlled inverse ratio ventilation on patients with severe acute respiratory distress syndrome in the surgical intensive care unit. Am J Surg2002;183:151. 38. Sydow M: Long-term effects of two different ventilatory modes on oxygenation in acute lung injury: Comparison of airway pressure release ventilation and volume-controlled inverse ratio ventilation. Am J Respir Crit Care Med1994;149:1550. 39. Derdak S: High-frequency oscillatory ventilation for acute respiratory distress syndrome in adults: A randomized, controlled trial, Multicenter Oscillatory ventilation for Acute respiratory distress syndrome Trial (MOAT). Am J Respir Crit Care Med2002;166:801. 40. Burchardi H: New strategies in mechanical ventilation for acute lung injury. Eur Respir J1996;9:1063. 41. Herridge MS, Slutsky AS, Colditz GA: Has high-frequency ventilation been inappropriately discarded in adult acute respiratory distress syndrome?. Crit Care Med1998;26:2073. 42. Wrigge H: Proportional assist versus pressure support ventilation: Effects on breathing pattern and respiratory work of patients with chronic obstructive pulmonary disease. Intensive Care Med1999;25:790. 43. Pollack CV, Fleisch KB, Dowsey K: Treatment of acute bronchospasm with beta-adrenergic aerosols delivered via a Bi-PAP circuit. Ann Emerg Med1995;26:547.

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Marx: Rosen's Emergency Medicine: Concepts and Clinical Practice, 6th ed., Copyright © 2006 Mosby, Inc.

Chapter 44 – Genitourinary System Robert E. Schneider

PERSPECTIVE Despite the advances in the initial management and treatment of the severely injured patient, confusion remains regarding the recognition and subsequent management of genitourinary trauma. Only main renal vein lacerations or a severely shattered kidney, both of which are rare, portend a rapid death. Thus, most genitourinary injuries pale in comparison to the immediate life threats posed by injuries to the chest and abdomen. Hence, the urinary tract as an anatomically injured system is by necessity relegated to a position of secondary importance. Nevertheless, to maintain excellence and expertise in the overall management of all injured patients, it is mandatory for the emergency physician to have a thorough understanding of the global spectrum of genitourinary injury and how it can affect eventual patient outcome. Genitourinary trauma commonly is a covert entity associated with a wide spectrum of injury. Approximately 10% of all multiply injured patients have some manifestation of genitourinary involvement.[1] Because of its uncommon occurrence and subtle presentation, it is often overlooked in the initial evaluation of the trauma victim. Nevertheless, after the primary survey for life-threatening injuries, Foley catheter placement as part of the secondary survey may disclose the first sign of urinary tract injury. The urinary tract is unique in that diagnostic evaluation is always done in a retrograde fashion; that is, suspicion and elimination of urethral injury before bladder injury before ureteral or renal injury. Adherence to this axiom will permit discovery of virtually any important urinary tract injury, even during the resuscitation of critically injured patients.

Definitions For purposes of investigation and staging of urologic injuries, genitourinary trauma is divided into lower tract (i.e., bladder or urethral injury), upper tract (i.e., renal or ureteral injury), and external genitalia (i.e., penile, scrotal, and testicular injury). Each category is further subdivided on the basis of a blunt or penetrating mechanism of injury.

Historical Perspective The basic tenets of lower urinary tract injury have not changed appreciably in the last 25 years. A thoroughly performed physical examination and the recognition of blood at the urethral meatus or gross hematuria will identify all significant lower urinary tract injuries. Major advances in the identification of significant upper tract genitourinary injuries, their clinical markers, and ultimate staging procedures have come to the forefront over the last 18 years. Before 1985, any trauma patient with any amount of microhematuria was described as “at risk” for genitourinary injury and underwent intravenous pyelography (IVP). This was neither diagnostically definitive nor cost-effective and simply perpetuated the existing confusion and controversy. In 1985, Nicolaisen and colleagues[2] published the first of a series of articles that established guide-lines to identify significant upper tract genitourinary injuries, their markers, and the diagnostic studies that would define the exact extent of these injuries and aid in subsequent patient management. In addition, the advent of ultrasonography and computed tomographic (CT) scanning has greatly simplified the diagnosis and management of external genitalia trauma.

CLINICAL FEATURES Signs and Symptoms The signs and symptoms of genitourinary trauma are varied and nonspecific. Acutely, these signs may include flank, abdominal, rib, back, or scrotal pain; urinary retention; and penile/urethral bleeding. Renovascular hypertension may be the only finding weeks to months after injury.

Physical Examination

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Examination of the torso and pelvis during the secondary survey is the first step in the evaluation for urologic injury. Any evidence of abdominal tenderness should alert the examining physician to the possibility of a bladder rupture in addition to other intra-abdominal injuries. This likelihood increases significantly in the presence of a pelvic fracture. Tenderness elicited by pelvic compression or palpation of the pelvic girdle or pubic symphysis supports the diagnosis of a potential pelvic fracture with possible lower urinary tract injury. Examination of the genitalia can be informative. The emergency physician should look for evidence of hematoma or ecchymosis of the penile shaft, scrotal skin, or perineum. Gross blood at the urethral meatus is diagnostic of a urethral injury and dictates the need for early retrograde urethrography. In circumstances in which emergency surgical exploration for life-threatening injuries is needed, the retrograde urethrogram can be performed in the operating room or after the operative procedure. A Foley catheter should never be introduced when there is suspected urethral trauma without first ensuring urethral integrity by retrograde urethrography. Failure to do this may convert a partial urethral tear into a complete disruption. Careful inspection for blood at the vaginal introitus is particularly important in the female patient known to have a pelvic fracture. A thorough vaginal examination will discern vaginal lacerations or urethral disruption caused by displaced bony pelvic fracture fragments. Unlike male urethral injuries, urethrography is not helpful in suspected female urethral injuries because of the urethra's short length. The inability to pass a Foley catheter in a young premenopausal female patient with a pelvic fracture signifies the potential for urethral injury and subsequent necessity for suprapubic urinary drainage. Successful passage of a Foley catheter in the same type of patient with blood at the vaginal introitus does not exclude urethral injury, and these worrisome physical examination findings must be conveyed to the urologist, who can plan subsequent urethral evaluation.[3] In an older postmenopausal female trauma patient, urethral injury must be distinguished from a superiorly retracted urethral meatus and accompanying meatal stenosis. These preexisting conditions are common in an atrophic vaginal setting, and a 12- or 14-Fr coudé or Foley catheter usually is required for successful bladder access. Rectal examination evaluates sphincter tone, bowel wall integrity, and most important, the position of the prostate. Normally, the posterior lobe of the prostate is palpable and well defined ( Figure 44-1 ). A pelvic fracture may disrupt the puboprostatic ligaments and the prostatomembranous urethra, resulting in significant retropubic venous bleeding. This may produce a large pelvic hematoma that can displace the prostate superiorly, resulting in a boggy, ill-defined mass on rectal examination ( Figure 44-2 ).

Figure 44-1 Anatom y of m ale genitalia.

Figure 44-2 Injury to the posterior (m em branous) urethra. The prostate has been avulsed from the m em branous urethra secondary to fracture of the pelvis. Extravasation occurs above the triangular ligam ent and is periprostatic and perivesical. ((From McAninch JW: In Tanagho EA, McAninch JW [eds]: Sm ith's General Urology, 14th ed. Norwalk, Conn, Appleton & Lange, 1995.)Appleton & Lange)

Foley Catheter In any trauma patient presenting with a major mechanism of injury and the absence of any findings suggestive of urethral injury, a Foley catheter should be passed into the bladder. The initial bladder effluent must be observed by the responsible physician. Because of its importance in dictating subsequent patient evaluation, observation of the initial bladder effluent should optimally not be relegated to any other member of

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the resuscitation team. Any color to the urine other than clear or yellow must be considered a sign of gross hematuria until proved otherwise. The presence of gross hematuria indicates urologic injury. Rarely, severe rhabdomyolysis produces large quantities of urine myoglobin, the gross appearance of which can be confused with gross hematuria. In these cases, urinalysis will document the absence of red blood cells (RBCs) consistent with myoglobinuria. Most significant lower urinary tract injuries will be accompanied by either the presence of a pelvic fracture with blood at the urethral meatus or gross hematuria on Foley catheter placement.[4] Upper tract trauma, however, tends to be more subtle. It is often coincident with nonurologic organ disruption, the bleeding from which can be life-threatening. These events may dictate rapid volume resuscitation that can clear gross hematuria quickly. Moreover, blunt injury to the renovascular pedicle or penetrating ureteral injury may not produce gross or even microscopic hematuria.

LOWER URINARY TRACT Urethral Trauma Anatomy The urogenital diaphragm divides the anterior (bulbous and pendulous) urethra from the posterior (membranous and prostatic) urethra. It is a 1.5 cm fascial layer that lies between the ischial rami. It attaches anteriorly to the symphysis, posteriorly to the perineal body and ischial tuberosity, and laterally to the inferior ischial pubic rami. It is traversed by the membranous urethra. The prostatic urethra is contiguous with the urogenital diaphragm and is attached to the posterior symphysis pubis by the puboprostatic ligaments. A fracture of the pelvis with displacement of the symphysis may result in a laceration or avulsion of the prostatic urethra because of the shearing force on the fixed prostatic and membranous urethra. Injuries to the anterior and posterior urethra are caused by different mechanisms, involve different symptoms, and are treated differently.

Pathophysiology Urethral disruption is the most significant injury that must be identified. Failure to do so may lead to significant morbidity (i.e., converting a partial urethral tear into a complete tear). Urethral manipulation can convert a partial urethral tear into a complete tear, thus precluding accurate assessment of urinary output, and subsequently potentiating the long-term complications of urethral trauma (e.g., urethral stricture formation and urinary incontinence). Pelvic fractures account for most posterior urethral injuries proximal to the urogenital diaphragm (see Figure 44-2 ).[5] Anterior urethral injuries distal to the urogenital diaphragm are most often caused by straddle injuries, falls, gunshot wounds, and self-instrumentation ( Figure 44-3 ).[6]

Figure 44-3 Injury to the bulbous urethra. Left: Mechanism : usually a perineal blow or fall astride an object; crushing of urethra against inferior edge of pubic symphysis. Right: Extravasation of blood and urine enclosed within Colles' fascia. ((From McAninch JW: In Tanagho EA, McAninch JW [eds]: Sm ith's General Urology, 14th ed. Norwalk, Conn, Appleton & Lange, 1995.)Appleton & Lange)

Clinical Features During the secondary survey, examination of the lower abdomen, pelvis, genitalia, and rectum provides both direct and indirect evidence to support or refute urethral injury. Lack of pelvic and suprapubic tenderness; absence of penile, scrotal, or perineal hematoma; and normal findings on rectal examination all support the integrity of the urethra. These physical findings permit the safe passage of a 14- or 16-Fr Foley catheter into the bladder if the patient is unable to void and provide a suitable specimen for evaluation.

Diagnostic Strategies Catheter Placement The following technique for catheter placement assumes a normal urethra and includes the use of sterile technique, proper control of the foreskin, the use of copious amounts of lubricating jelly, and the gentle passage of a 14- or 16-Fr Foley or coudé catheter into the bladder. In all uncircumcised patients, continuous foreskin retraction with a folded 4 × 4 inch gauze pad is necessary to control the foreskin during catheter

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placement ( Figure 44-4 ). Without this maneuver, the foreskin tends to repeatedly reduce itself over the glans penis, which contaminates the field and makes catheterization difficult or impossible. Slight resistance to the advancing catheter should be expected at the urogenital diaphragm secondary to voluntary contraction of the external sphincter. This is more apt to occur in a combative, anxious trauma patient than in a cooperative or unconscious patient. When this occurs, the patient should be reassured and asked to relax the perineum and rectal area while gentle advancing pressure is applied to the catheter. This combined approach allows the catheter to navigate the urogenital diaphragm successfully and pass easily into the bladder. If reassurance and relaxation do not allow easy passage of the catheter, it should be removed and a retrograde urethrogram performed. In all cases, the catheter must be passed to its fullest extent before the balloon can be inflated safely, then withdrawn to the point of catheter balloon approximation with the bladder neck and left to drain. Inflation of the catheter balloon under any other circumstances may result in iatrogenic urethral trauma.

Figure 44-4 A, A norm al uncircum cised m an. B, Foreskin has been retracted and a folded 4 × 4 inch gauge sponge wrapped around it to prevent foreskin reduction during instrumentation.

Successful passage of a Foley catheter precludes a complete urethral disruption. Nonetheless, the possibility of a partial urethral injury not manifested by history, mechanism of injury, presence of meatal blood, or other indirect signs on physical examination may exist. If this injury is suspected initially, a retrograde urethrogram should be obtained. The presence of urethral extravasation together with contrast material filling the bladder is diagnostic of a partial urethral injury ( Figure 44-5 ).[6] Identification of a partial urethral injury would permit one careful attempt at urethral placement of a 12- or 14-Fr Foley or coudé catheter, depending on the size of the patient. If any difficulty is encountered, the catheter should be removed and a urologist consulted. If a partial urethral tear is suspected subsequent to successful passage of a Foley catheter, a small feeding tube can be placed along-side the urethral catheter and a modified retrograde urethrogram performed.[4] In this circumstance, the urethrogram is for documentation and subsequent management purposes only because appropriate therapy has already been instituted (i.e., Foley catheter drainage). Under no circumstances should a successfully placed Foley catheter be removed to perform standard retrograde urethrography.

Figure 44-5 Retrograde urethrogram dem onstrates a partial urethral disruption. Note the elongation of the posterior urethra with filling of the bladder. ((From Spirnak JP: Pelvic fracture and injury to the lower urinary tract. Surg Clin North Am 68:1057, 1988.))

Radiology In all cases of suspected urethral injury, a retrograde urethrogram is the diagnostic procedure of choice.[] Retrograde urethrography is not an emergency and should always follow more critical resuscitative measures. In a patient with a pelvic fracture, the entire retrograde urethrogram should be conducted with the patient in a supine rather than oblique position. Certain authors recommend oblique films for portions of the retrograde urethrogram to enhance urethral definition.[] These views add little information to a good supine study. More

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important, pelvic fractures are often associated with significant retropubic venous bleeding and hematoma formation. Maintenance of this stable hematoma can be crucial in the initial hemodynamic resuscitation of the patient. Any patient movement from the supine to the oblique position has the potential to disrupt the organized hematoma with resultant significant and potentially lethal rebleeding. The entire urethral integrity can be defined with the patient in the supine position throughout the examination, aided by oblique stretching of the penis over the left or right thigh to promote necessary urethral unfolding. A preinjection kidney, ureter, and bladder (KUB) film is first obtained. A simple Christmas tree adapter, a Cooke adapter placed on the end of a 60 mL Toomey syringe, or a Toomey syringe alone is gently passed into the urethral meatus until a snug fit inside the meatus is confirmed ( Figure 44-6 ). Some authors have recommended inflation of a Foley catheter balloon just proximal to the fossa navicularis or the use of other cumbersome adjuncts to facilitate injection of contrast media.[] These techniques should be avoided, however, because they promote leakage of contrast material around the penis, which can simulate extravasation on the urethrogram and promote a spurious examination. Next, 60 mL (or 0.6 mL/kg) of full-strength or half-strength iothalamate meglumine (Conray II) is injected over 30 to 60 seconds. A radiograph is taken during the injection of the last 10 mL of contrast material. Retrograde flow through the urethra and into the bladder without extravasation ensures continuity of the urethra and absence of urethral injury ( Figure 44-7 ). Extravasation of contrast material outside the urethra with concomitant evidence of bladder filling distinguishes a partial urethral injury (see Figure 44-5 ) from a complete urethral disruption in which there will be absence of contrast material inside the bladder ( Figure 44-8 ).[] The latter situation requires immediate urologic consultation for appropriate surgical management. In the interim, if measurement of urinary output is essential, the bladder should be accessed by the suprapubic placement of a peel-away sheath and Foley catheter using the Seldinger technique ( Figure 44-9 ).

Figure 44-6 Christm as tree adapter on the end of a 60 m L syringe has been gently placed inside the fossa navicularis in preparation for retrograde urethrography.

Figure 44-7 Norm al anatom y is dem onstrated by a line drawing (A) and by dynam ic retrograde urethrography (B). Bladder (1), prostatic urethra (2), verum ontanum (3), m em branous urethra (4), position of the urogenital diaphragm (5), bulbous urethra (6), and penile urethra (7). The penile and bulbous urethra together are considered the anterior urethra; the prostatic and m em branous urethra com pose the posterior urethra. ((Adapted from McCallum RW, Colapinto V: Urological Radiology of the Adult Male Lower Urinary Tract. Springfield, Ill, Charles C Thomas, 1976.))

Figure 44-8 Retrograde urethrogram s dem onstrates com plete urethral disruption. Note the absence of bladder filling, a finding diagnostic of com plete disruption. ((From Spirnak JP: Pelvic fracture and injury to the lower urinary tract. Surg Clin North Am 68:1057, 1988.))

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Figure 44-9 Percutaneous placem ent of a suprapubic tube with peel-away sheath introducer. A, An 18-gauge needle is in the bladder. A guidewire is advanced through needle. B, A dilator and peel-away sheath are advanced over the guidewire. C, The dilator and guidewire are rem oved. Through the peel-away sheath, an appropriately sized catheter can be introduced into bladder. D, The balloon is inflated, and the sheath is pulled back and peeled away. ((From O'Brien WM: Percutaneous placem ent of suprapub ic with peel away sheath introducer. J Urol 145:1015, 1991.))

Management During physical examination, urethral injury is suggested by the presence of a pelvic fracture, blood at the urethral meatus, the presence of a high-riding or absent prostate on rectal examination, or evidence of a perineal, scrotal, or penile hematoma. Any one of these latter three findings necessitates a retrograde urethrogram to disclose the anatomy and integrity of the urethra. If these findings are absent or the urethrogram is normal, the urethra is intact and a Foley catheter can be passed into the bladder. If a partial urethral disruption is identified, one careful attempt to pass a 12- or 14-Fr Foley or coudé catheter can be undertaken. If a complete urethral disruption is identified, consultation with a urology specialist and placement of a suprapubic catheter for urinary drainage are necessary.

Bladder Trauma Anatomy When empty, the bladder lies retroperitoneally almost entirely within the bony pelvis. It rests on the pubis and adjacent pelvic floor parts. When full, the bladder can extend up to the level of the umbilicus, where it is most vulnerable to blunt and penetrating trauma. The bladder consists of an inner longitudinal, a middle circular, and an outer longitudinal muscle layer. These three layers constitute the detrusor muscle, which contracts to propel urine out the urethra. Blood is supplied to the bladder by the internal iliac artery and vein. The nerve supply comes from the lumbar and sacral segments of the spinal cord. It includes parasympathetic motor fibers to the detrusor muscle and sensory fibers to the detrusor that give rise to the sensation of fullness and urgency when the detrusor is stretched. The third nerve group, the sympathetic fibers, innervate the blood vessels of the bladder and the bladder neck musculature. The mechanism of injury with bladder trauma is usually severe. This is reflected in the high mortality rate of 22% to 44%.[7] There is a high incidence of associated life-threatening nonurologic injury, the treatment of which always takes precedence. The diagnostic evaluation of the bladder, like the urethra, can be accomplished quickly without elaborate radiographic equipment or can be part of the CT evaluation if other nonurologic injuries are being evaluated.

Pathophysiology Extraperitoneal bladder perforation, intraperitoneal bladder perforation, and a combination of the two are the significant injuries in bladder trauma. Proper classification is critical because treatment options are completely different.[8] Whereas most ruptures occur singly as extraperitoneal or intraperitoneal, their coexistence is being recognized more often as the mechanism for bladder injury becomes better understood. The time-honored explanation for extraperitoneal rupture has been pelvic fracture with subsequent bladder laceration from an errant bony fracture fragment. It has become apparent, however, that extraperitoneal perforation can result from blunt trauma alone and need not require a lacerating fracture bony fragment. Intraperitoneal bladder rupture has been ascribed to blunt lower abdominal trauma in a patient with a full bladder. These blunt forces are directed to the dome of the bladder where the urachus originates during embryonic life. Because of this developmental hiatus, the dome is attenuated and represents the anatomic area most susceptible to rupture from sudden rises in intravesical pressure associated with blunt trauma. The dome also is unique in its isolated peritoneal reflection so that rupture in this area most likely will result in intraperitoneal urinary contamination.

Clinical Features Lower abdominal or suprapubic pain, the inability to urinate, or the presence of blood at the urethral meatus

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may alert the physician to the possibility of lower urinary tract trauma.

Diagnostic Strategies Laboratory Gross hematuria in the initial bladder effluent is indicative of urologic injury. The literature clearly defines gross hematuria alone or in conjunction with a pelvic fracture as the absolute markers for significant bladder injury.[] Grossly clear bladder urine in a trauma patient without a pelvic fracture virtually eliminates the possibility of bladder rupture. The overwhelming majority (98%) of patients with bladder rupture have gross hematuria (JW McAninch, personal communication, 1998). The other 2% are representative of the select group of patients with a pelvic fracture and only microhematuria. Clinical judgment is required when deciding when these patients need a bladder evaluation.

Radiology Conventional retrograde cystography or retrograde CT cystography are the diagnostic procedures of choice for suspected bladder injury.[] It is key that these studies not be done in an antegrade fashion, as such procedures may produce incomplete and spurious findings (e.g., injecting intravenous contrast material, clamping the Foley catheter, and allowing the examination to be dependent on antegrade filling of the bladder from renal excretion of progressively dilute contrast material).

Conventional Retrograde Cystogram. Performance of either conventional or CT retrograde cystography assumes or follows exclusion of urethral trauma and the presence of an indwelling Foley catheter in the bladder. A Toomey syringe alone without its central piston is used for gravity instillation of contrast material ( Figure 44-10 ). Allowing the contrast material to freely infuse from a hanging bottle connected to an indwelling Foley catheter runs the risk of the tubing becoming disconnected with subsequent leakage of contrast material onto the examination table ( Figure 44-11A and B ). This may promote an inaccurate examination that results in an unnecessary operative procedure ( Figure 44-11C ). For patients with a pelvic fracture, it is imperative that they remain supine throughout the examination rather than be repositioned obliquely for selected radiographs. This lessens the potential for rebleeding from an organized retropubic hematoma.

Figure 44-10 Retrograde cystogram . A Toom ey syringe without its central piston is connected to the catheter and held by the exam iner while gravity-instilled contrast m aterial fills the bladder.

Figure 44-11 Spurious retrograde cystogram . This exam ination resulted when the tubing from the contrast bottle becam e disconnected from the Foley catheter after both were placed on the exam ination table, and bladder filling was com pleted without direct supervision. A, Kidney, bladder, ureter (KUB) film. B, Postinfusion KUB film interpreted as intraperitoneal bladder perforation. C, Intraoperative retrograde cystogram showing no evidence of extravasation.

A preliminary KUB or scout film is obtained to provide a baseline evaluation of the pelvis, abdomen, and surrounding bony structures. It will become the film of reference for the post-evacuation radiograph obtained after completion of the cystogram. Potential areas of extravasation on the post-evacuation film will be confirmed when compared with the preliminary KUB film ( Figure 44-12 ). Contrast material should not be instilled into the bladder until the quality and anatomic information on the preliminary KUB film are confirmed.

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Figure 44-12 Retrograde cystogram . A, Prelim inary kidney, bladder, ureter (KUB) film . B, Film of filled bladder. C, Postevacuation film com paring posterior extravasation with the prelim inary KUB film .

Full-strength iothalamate meglumine (Conray II) is instilled under gravity filling to one of three endpoints: (1) 100 mL with immediate fluoroscopic evidence of gross extravasation; (2) a total instillation of 300 to 400 mL in any patient 11 years of age or older; in patients younger than 11 years of age, the correct amount of contrast medium is determined by the formula (age in years + 2) × 30; or (3) the instillation of a lesser amount than 100 mL, which initiates a bladder contraction. This will become evident by the retrograde filling of the Toomey syringe with bladder contents. After a few minutes, the original contrast material can again be instilled to the point of stimulating a bladder contraction, at which time an additional 50 mL of full-strength iothalamate meglumine should be injected slowly but forcefully into the bladder. The Foley catheter should be clamped, and an anteroposterior radiograph should be taken of the filled bladder ( Figure 44-13A and B). A lateral film may help clarify any areas in question ( Figure 44-13C ). After the film of the filled bladder meets standards for quality and detail, the bladder should be completely evacuated into a large basin or, preferably, into an available bedside drainage bag. Any spillage of contrast material onto the pelvic genitalia or examination table may lead to false-positive findings on the postevacuation radiograph. The postevacuation film may disclose evidence of posterior bladder wall or extraperitoneal extravasation not seen on the anteroposterior radiograph of the filled bladder ( Figure 44-14 ).

Figure 44-13 Retrograde cystogram . A, Prelim inary kidney, bladder, ureter (KUB) film . B, Film of filled bladder showing extravasation that could be intraperitoneal, as well as extraperitoneal. C, Film of patient in a lateral position shows no evidence of intraperitoneal extravasation.

Figure 44-14 Retrograde cystogram . A, Film of filled bladder. B, Postevacuation film showing extensive extraperitoneal extravasation.

In cases of extraperitoneal bladder perforation, contrast material will be evident in the area of the pubic symphysis and pelvic outlet ( Figure 44-15 ). With intraperitoneal perforation, contrast material outlines intraperitoneal structures (e.g., loops of bowel, the liver, and spleen) ( Figure 44-16 ).

Figure 44-15 Cystographic appearance of extraperitoneal bladder perforation. A and B, Note the teardrop deform ity caused by extrinsic com pression by the pelvic hem atom a and the flam elike wisps of extravasation confined by the pelvis. The bladder itself

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is elongated by a collection of perivesicular fluid. ((From Spirnak JP: Pelvic fracture and injury to the lower urinary tract. Surg Clin North Am 68:1057, 1988.))

Figure 44-16 Cystographic appearance of intraperitoneal bladder perforation. Cystogram reveals m assive intraperitoneal perforation and extravasation. ((From Spirnak JP: Pelvic fracture and injury to the lower urinary tract. Surg Clin North Am 68:1057, 1988.))

Several studies have documented that false-negative results are associated with the use of less than 300 to 400 mL or an age-appropriate amount of contrast material for cystography.[] This has been seen primarily in penetrating bladder injuries in which the perforation from a small-caliber gunshot wound or a thin blade stab wound can be missed. The anatomically interlacing bladder wall muscle fibers are arranged such that these wounds lend themselves to immediate muscle fiber reapproximation and tenuous sealing of the wound by covering peritoneum and intra-abdominal mesentery. Unless an adequate amount of full-strength contrast material is used to fully distend or even overdistend the bladder, extravasation will not be evident, the injury will be missed, and there will be potential for significant morbidity.

Computed Tomography Retrograde Cystogram. The same anatomic information regarding bladder injury may be obtained using retrograde CT cystography rather than routine plain film radiography.[11] CT cystography is best done in trauma patients who are undergoing CT evaluation for other suspected injuries. In either study, undiluted iothalamate meglumine (Conray II) must first be instilled in a retrograde fashion. Intraperitoneal perforation will be disclosed on helical CT scan by the presence of extravasated contrast material throughout the abdominal cavity (i.e., contrast ascites). Extraperitoneal extravasation will be more difficult to visualize but can be appreciated on images taken through the pelvic area ( Figure 44-17A and B ).

Figure 44-17 Bladder rupture. A, Intraperitoneal rupture shows contrast m aterial extravasated from the bladder outlining loops of bowel in the lower abdom en. B, Extraperitoneal rupture shows contrast m aterial extravasating into the disrupted soft tissue plains of the anterior and left pelvic side wall. ((Courtesy of Charlotte Radiology, Em ergency Radiology Section, Charlotte, North Carolina.))

Management In cases of superficial mucosal bladder lacerations, bladder contusions, or simple bladder hematomas, there will be no evidence of extravasation on retrograde cystography. For these injuries, expectant management with or without Foley catheter drainage is the standard of care.[]

Extraperitoneal Bladder Rupture Extraperitoneal bladder rupture heals spontaneously in most circumstances after simple Foley catheter

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drainage for 7 to 14 days using a 20-Fr or larger Foley catheter.[] Care must be taken to ensure continuous bladder decompression and prevention of catheter occlusion by clot or debris. In a patient with known or suspected infected urine before the traumatic event, consideration must be given both to Foley or suprapubic catheter drainage and to surgical placement of drains in the perivesical space to prevent subsequent abscess formation. Primary surgical repair of extraperitoneal bladder rupture should be considered in any trauma patient whose bladder injury appears to extend into the bladder neck or proximal urethra.[] This is most important in the female trauma patient because the short length of the female urethra lends itself to a higher incidence of urinary incontinence after injury. This can hopefully be reduced by primary surgical repair. Any patient whose other associated nonurologic injuries dictate abdominal exploration is a candidate for primary surgical repair of the extraperitoneal bladder injury provided the bladder laceration is easily accessible and does not require operative exposure through a large, organized, stable retropubic hematoma.[]

Intraperitoneal Bladder Rupture Larger, gaping intraperitoneal bladder perforations will not heal spontaneously and always require operative repair.[6] Without operative intervention for intraperitoneal injury, lower urinary tract contamination will quickly infect initially sterile urine and promote the development of subsequent bacterial peritonitis. Bladder repairs are never emergencies and normally follow operative repair of more urgent life-threatening injuries.

UPPER TRACT TRAUMA Renal Trauma Perspective Renal trauma is a capricious injury that has no known identifiable markers. Mechanisms responsible for significant renal injury almost never affect the kidney alone, but most often disrupt and perforate other vital organs that can be solely responsible for the patients' death and may demand immediate operative intervention. Significant renal injuries define a small subset of the trauma population at large. This by itself promotes diagnostic uncertainty and causes some of these injuries to be overlooked initially. Renal injuries are graded 1 through 5 according to the Organ Injury Scale Committee Guidelines, which identifies most injuries requiring operative intervention.[14]

Complications Development of renovascular hypertension occurs in approximately 1% of cases and is the main complication associated with failed arterial repairs or missed pedicle injuries.[14] When associated with elevated renal vein renin levels, nephrectomy is curative. For these reasons, the issue of whether to actively pursue this diagnosis is debated. An isolated pedicle injury in a young, healthy trauma patient would seem to be the ideal circumstance in which an all-out attempt should be made to reconstruct the renal artery or vein.

Anatomy and Physiology The kidneys are located in the retroperitoneal space, are surrounded by adipose tissue and loose areolar connective tissue, and lie along the lower two thoracic vertebrae and the first four lumbar vertebrae. The left kidney is suspended slightly higher than the right ( Figure 44-18 ). The kidneys are not fixed. They move with the diaphragm and are supported by their renal arteries, veins, and adipose tissue, which is connected to a layer of fibrous tissue called the renal fascia, or Gerota's fascia.

Figure 44-18 Dissection of abdom en showing kidneys and ureters and their relationship to other anatomic features in the retroperitoneal space.

The indented medial border of the kidney is called the hilum. The major renal vessels and ureter make up the renal pedicle and enter and exit at the hilum. The longitudinal section of the kidney ( Figure 44-19 ) shows an outer renal cortex and an inner renal medulla with its columns of Bertin. Each column of Bertin forms a papilla that empties into the renal pelvis. The renal pelvis is a funnel-shaped sac with cup-shaped extensions called calyces, which receive urine from each papilla and are the important decompression areas for varied

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rises in intrapelvic pressure.

Figure 44-19 Longitudinal section of kidney.

The kidneys are perfused by 1200 mL of blood per minute, or 20% to 25% of cardiac output. Of this, 90% goes to the cortex and 10% to the medulla. Reduced blood flow to the kidney, whether from blunt or penetrating injury, causes renin to be released from the juxtaglomerular cells. Renin enters the bloodstream and combines with a plasma protein to form angiotensin. Angiotensin raises blood pressure by causing arteriolar vasoconstriction and acting on the adrenal cortex to augment aldosterone secretion. Aldosterone acts on the renal tubules to promote sodium reabsorption. Water follows passively with subsequent increase in blood volume. These changes increase blood flow to the kidney and other organs. The body requires only one third of normal renal function to sustain life. It is unusual in cases of genitourinary trauma to lose total renal function unless the patient's injured kidney is a solitary kidney, which carries a 1 in 1000 to 1 in 5000 incidence.[15]

Epidemiology Renal trauma represents the most common of all urologic injuries.[2] Blunt renal trauma accounts for 80% to 85% of all renal injuries and is five times more common than penetrating renal trauma.[2] With the increasing prevalence nationwide of gunshot and stab wounds in association with drug-related violence, the proportion of injuries due to penetrating trauma may rise. Blunt mechanisms are seen most often after motor vehicle crashes, domestic violence, and sporting injuries. The pathophysiologic mechanisms include rapid deceleration, displacement, and, rarely, an explosion-type injury of the ureteropelvic junction. Approximately 20% of blunt renal trauma cases are associated with intraperitoneal injury.[2] Penetrating renal trauma is associated with intraperitoneal injury in approximately 80% of cases.[2]

Diagnostic Strategies Laboratory No accurate markers for renal injury exist. In all types of renal trauma, the degree of hematuria is not indicative of the severity or extent of injury. Formerly, a trauma patient who exhibited gross or microscopic hematuria was labeled “at risk” for urologic injury and underwent intravenous pyelography. Experience has shown that most of the identifiable injuries were renal contusions that could be managed expectantly. Moreover, in a significant number of severely traumatized patients, vigorous initial fluid resuscitation precluded satisfactory contrast concentration in the kidney, yielding an incomplete, nondiagnostic initial radiographic examination. In 1989, Mee and associates[16] published the hallmark article that established guidelines for the evaluation and treatment of blunt renal trauma. Their 10-year prospective study clearly established that (1) major renal lacerations represent significant reparable renal injuries; (2) adult patients at risk for having sustained major lacerations have either gross hematuria or microhematuria (≥3 to 5 RBCs/hpf) with shock (systolic blood pressure ≤90 mm Hg) initially in the field or on arrival at an emergency department, or, rarely but importantly, a history of sudden deceleration without hematuria or shock; and (3) intravenous contrast-enhanced CT scan is the procedure of choice in identifying the full extent of urologic injury.[] These guidelines are not applicable for cases of penetrating renal trauma or in children.

Pediatrics. In children, the kidney is the most commonly injured genitourinary organ in blunt abdominal trauma.[18] Additionally, unlike adults, major renal injuries can occur in the presence of microhematuria without shock or even in the presence of a normal urinalysis. Prior meta-analyses defined 50 RBCs/hpf as the microscopic quantity below which imaging could be confidently deleted without missing significant injuries.[19] Current literature supports radiographic investigation based mainly on mechanism of injury and clinical suspicion, because no absolute parameters for excluding significant renal injury exist.[20] As with adults, intravenous

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contrast-enhanced helical CT scanning is the diagnostic imaging technique of choice.

Radiology Intravenous Pyelography. Whether simple, routine IVP is ever indicated in the initial evaluation of suspected renal trauma depends on the institution and the radiologist. At a center that does not have 24-hour availability of radiologists and technicians, bolus infusion IVP with nephrotomography rather than simple IVP is the initial study of choice.[] Bolus infusion denotes the rapid injection of 2 mL of contrast material per kilogram of body weight to a maximum of 150 mL after a preliminary KUB film has been obtained.[15] Immediately on completion of the injection, a postinfusion supine film is obtained, followed by 1-, 2-, and 3-minute supine films, specifically tailoring the study to identify both renal outlines and evidence that contrast is extending down the collecting system of the kidney and ureter to the bladder without extravasation. In fact, most authors propose bolus infusion IVP with nephrotomography as the initial study of choice for uncommonly encountered isolated renal injury, which can be difficult to identify prospectively.[16] In the spectrum of experience with bolus infusion IVP as a diagnostic tool for renal injury, most authors find this study adequate only 60% to 85% of the time.[21] Often, abnormal findings are nonspecific and require more sophisticated studies, such as CT scanning, to identify the full extent of the existing renal injuries. When immediate, life-saving, nonurologic surgical intervention is mandated or an expanding retroperitoneal hematoma with the potential for significant renal injury is encountered in the operating room, a 2 mL/kg intraoperative bolus infusion of contrast and a 10-minute film are recommended to ensure the presence of both kidneys before the retroperitoneum is opened and control of the renal pedicle is attempted. A “single-shot” IVP in the emergency department used as a screening examination before the patient is transported to the operating room is discouraged because of the equally unacceptable incidence of false-positive and false-negative results.[15]

Computed Tomography. An intravenous contrast-enhanced helical CT scan is the diagnostic radiographic procedure of choice in evaluating significant upper tract blunt renal trauma. It is more sensitive and specific than bolus infusion IVP with nephrotomography ( Figure 44-20A-E ).[]

Figure 44-20 A, Renal artery injury. The left kidney dem onstrates alm ost com plete acute devascularization. (Note the right flank hem atom a.) B, Subcapsular hem atom a. Deform ing renal parenchym a on the left. C and D, Renal laceration. These two images are of the sam e patient separated by several m inutes of delay. The wedge-shaped hypodensities in the left kidney on the first scan (C) indicate the lacerations. The delayed scan (D) shows extravasation of contrast material from the lacerated kidney. E, Collecting system injury. Extravasation of contrast m aterial from the lacerated right renal pelvis. (Hypodense areas of the kidney represent contusion.) ((Courtesy of Charlotte Radiology, Em ergency Radiology Section, Charlotte, North Carolina.))

Management Blunt Injury Both an adult blunt trauma patient with microhematuria (≥3 to 5 RBCs/hpf) but no shock (systolic blood pressure ≤90 mm Hg) in the field or in the emergency department and a pediatric blunt trauma patient with 50 RBCs/hpf or fewer and no other coexisting major organ injuries can be confidently discharged from the emergency department if no other complicating nonurologic injuries are present that would dictate observation or hospital admission. Outpatient follow-up with a urologist until the microhematuria has cleared is mandatory to be certain it does not represent another more serious underlying condition.[23] Renal artery avulsions, intimal tears, and renal venous injuries should be considered under the classification of significant injuries. Although only 1% to 2% of all renal injuries involve the renal pedicle, their evaluation and management remain a real dilemma based on the frustrating and dismal experience with pedicle injuries

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from major centers.[24] Experience has shown that even under the most ideal clinical circumstances (i.e., fortuitous early recognition and prompt surgical repair), the salvage rate at best for a life-sustaining functioning kidney approaches only 15% to 20%. Renal vein injuries are more common than renal artery avulsions or intimal tears. Both injuries are often associated with rapid deceleration events. Most venous injuries tend to be partial rather than complete tears, or they involve segmental renal vein branches and therefore often occur in the periphery of the vein (i.e., involving contiguous adrenal or gonadal attachments to the left renal vein rather than at the junction of the main renal vein with the vena cava). As expected, a venous injury can potentially contribute more to a patient's unstable hemodynamic status than an arterial injury. The protective secondary vasospasm following arterial disruption does not occur with venous injuries. Pedicle injuries rarely occur alone. Most often they are associated with other life-threatening, nonurologic injuries that require immediate surgical intervention. This delays their diagnosis and repair for up to 6 to 8 hours, which results in significant warm ischemia time with subsequent low salvageability rates. An intravenous contrast-enhanced helical CT scan will identify most renal artery disruptions, whereas renal vein injuries must be indirectly diagnosed by the presence of a normal-appearing kidney in association with a large hematoma disproportionate to the rest of the radiographic study. Major renal lacerations represent approximately 2% to 4% of all renal injuries, and by definition are associated with renal fractures extending deep into the renal medulla and collecting system ( Figure 44-21 ). They also are readily diagnosed by an intravenous contrast-enhanced helical CT scan. Immediate surgical treatment of these injuries is controversial and depends on the presence or absence of continued renal bleeding, the hemodynamic status of the patient, and the degree of continued urinary extravasation.[25] This injury is in sharp contrast to minor renal lacerations (8-15%) and renal contusions (85-92%) that do not extend into the renal medulla or collecting system, are not associated with extravasation of urine, and heal spontaneously ( Figure 44-22 ). These latter two injuries can be managed expectantly and rarely, if ever, require initial or subsequent operative intervention.[16]

Figure 44-21 Major renal lacerations. A, Deep medullary laceration. B, Laceration into collecting system . ((From Nicolaisen GS, et al: Renal traum a: Re-evaluation of the indications for radiographic assessm ent. J Urol 133:183, 1985.))

Figure 44-22 Minor renal injuries. A, Minor renal laceration. B, Renal contusion. ((From Nicolaisen GS et al: Renal traum a: Re-evaluation of the indications for radiographic assessm ent. J Urol 133:183, 1985.))

Penetrating Injury In cases of penetrating renal trauma, the presence or absence of hematuria is of no consequence in predicting upper urinary tract injury. Rather, the location of the penetrating wound in relation to the urinary tract is the most important determining factor in deciding the need for radiographic investigation. Therefore, the absence of hematuria in a patient with a gunshot or stab wound in proximity to the urinary tract does not eliminate the need for an intravenous contrast-enhanced CT scan as the initial diagnostic examination. Significant injuries to the kidney and ureter occur in penetrating trauma without hematuria.[3] The majority of pene-trating renal and ureteral injuries require surgical intervention.

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Ureteral Trauma Pathophysiology Ureteral injuries are rare. Most are traumatic in origin and tend to occur as a result of shootings or stabbings or during various intra-abdominal or retroperitoneal operations.[26] Penetrating ureteral injuries are twice as common as blunt ureteral injuries. Most are localized in the upper third of the ureter.[27] This diagnosis should be considered when patients seen in the emergency department have a recent history of penetrating trauma, fever, and a palpably tender flank mass. If the ureter is injured by blunt trauma, there are often multiple associated nonurologic injuries. The gastrointestinal tract is injured in more than 50% of cases.[28] In pelvic fractures, the ureter is most likely to be injured as it crosses the pelvic brim. The intimate relationship of the ureter to the pelvis at this point allows it to be crushed, causing a contusion, tear, transection, or puncture by sharp fracture spicules.

Clinical Features The clinical picture of blunt ureteral injuries includes hematuria, flank pain similar to renal colic, and a flank mass. These classic signs are often overlooked initially because of the striking abdominal findings caused by associated nonurologic injuries. Hematuria may be present in association with ureteral contusion or partial ureteral tear but is rarely present in cases of complete ureteral transection. Pain in the lower abdomen, a palpable mass containing blood or urine, chills, fever, urgency, frequency, and pyuria are all symptoms of this injury.

Diagnostic Strategies In a Parkland Memorial Hospital series of 71 penetrating ureteral injuries, 32% of patients had no hematuria, 40% had gross hematuria, and 28% had microscopic hematuria.[29] If the patient survived the original penetrating event, the injury usually manifested itself 10 days later with the appearance of urine at the entrance or exit wounds or on the surgical dressings. If there is no vent for extravasated urine, a retroperitoneal urinoma will develop. If the diaphragm or peritoneum has been violated, the urine may cause an empyema or peritonitis.

Radiology If a ureteral injury is suspected, a contrast-enhanced helical CT scan with delayed films or bolus infusion IVP with delayed films should be done.[30] The clarity of injury identification depends on renal function and the lapsed time from the injury. If the study is performed soon after the injury, extravasation often has a ground-glass or hazy appearance as a result of contrast dilution from fluid resuscitation. If the injury is near the ureteropelvic junction, the contrast may extend peripherally around the kidney, giving the appearance of a lacerated renal pelvis or kidney. If the initial study of delayed films is inconclusive, retrograde pyelography is indicated to delineate a ureteral laceration or avulsion ( Figure 44-23A and B ). The more concentrated contrast used in retrograde pyelography compared with that used with routine IVP and the adjunctive use of fluoroscopy promote rapid identification of ureteral injury. A

B

Figure 44-23 Ureteral injuries. A, Intravenous pyelography (IVP) of patient with upper ureteral injury demonstrating extravasation (arrow). B, Retrograde pyelogram dem onstrating extravasation at the ureteropelvic junction (arrow).C, Retrograde pyelogram dem onstrating extravasation into a urinom a in a patient with delayed diagnosis. ((From Presti JC Jr, Carroll PR, McAninch JW: Ureteral and renal pelvic injuries from external traum a: Diagnosis and m anagem ent. J Traum a 29:370, 1989.))

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Management All ureteral injuries must be repaired surgically. If these injuries are diagnosed early, the kidney and ureter can be saved in most cases. In cases of delayed diagnosis, the rate of nephroureterectomies dramatically increases.[31]

EXTERNAL GENITALIA TRAUMA Penile Trauma Anatomy The penis contains three masses of erectile tissue ( Figure 44-24 ). The two corpora cavernosa constitute the main bulk of the penis and lie in the center of the penis. The corpus spongiosum is smaller, lies on the ventral surface of the penis, encases the urethra, and expands at the penile tip to form the glans penis. The tunica albuginea is a dense fibrous envelope that surrounds the corpus spongiosum and each corpus cavernosum. Blood is supplied through arteries lying in each of the three erectile masses and two dorsal penile arteries. A single dorsal vein drains most of the penis.

Figure 44-24 Cross-sectional view of the penis.

Clinical Features Injuries to the penis range from small lacerations or contusions to skin degloving or amputation. Strangulation injuries of the penis with string or scalp hair tightly encircling the shaft of the penis are seen in children ( Figure 44-25 ). Adolescents as well as adults may have various objects of penile incarceration such as bottles, washers, and metal rings ( Figure 44-26 ). These objects are often used to facilitate masturbation, prevent detumescence, and heighten sexual pleasure. These constricting devices must be identified and removed, a procedure that can test the ingenuity of the most experienced physician. If the strangulation is prolonged or appears to be associated with necrosis, the constricting object must be removed on an emergency basis. Various creative techniques, using saws, metal cutters, or emery wheels, may be necessary to remove some metal objects. Plastic surgery repair of the penis may eventually be needed but should be delayed until penile tissue viability has clarified. Fortunately, each corpora body has a separate blood supply and may be preserved even though the penile skin may slough and require skin grafting.

Figure 44-25 Idiopathic foreskin edema. A, This is the sam e picture that can be seen with penile strangulation injuries in children. B, The edem atous foreskin m ust be retracted proxim ally and distally looking for encircling hair, string, or other objects that m ay lead to vascular comprom ise.

Figure 44-26 A, Self-induced priapism . This patient placed two steel washers (B) around the base of his penis to prolong his erection. Subsequent priapism developed and the incarceration necessitated em ergency intraoperative rem oval with a pneum atic orthopedic drill.

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Pediatrics In small children, penile trauma may be associated with possible child abuse, especially when the explanations given for the event do not match the type of injury and objective physical findings. Examples include bruises that look like pinches, cigarette burns, or an injury reportedly caused by a falling toilet seat in a child who is too small to stand unsupported.

Management Superficial lacerations of penile-scrotal skin may be primarily reapproximated with 4-0 chromic or Vicryl absorbable suture. Patients with degloving penile injuries and scrotal skin loss should be treated by a urologist and plastic surgeon in the operating room with cleansing, debridement, and skin flaps or skin grafts. Traumatic penile amputation can be handled by primary reanastomosis (replantation) or local reshaping of the amputated penis. A recovered amputated distal penis should be placed in a clean plastic bag then immersed in cold saline if available. If the proximal penile stump is hemorrhaging, direct pressure on the bleeding source may promote hemostasis. A circumferentially placed Penrose drain at the base of the penis can be used acutely to control blood loss but should not be used for extended periods. Reanastomosis of a severed penis is possible up to 6 hours after amputation. Beyond this period, local reshaping is recommended. Both a urologist and a plastic surgeon should be involved in the patient's management if reimplantation is considered. Traumatic rupture of the corpus cavernosum, or penile fracture, occurs when the tunica albuginea is torn ( Figure 44-27 ). This usually occurs during vigorous sexual intercourse. The patient may hear a snapping sound and experience localized pain, detumescence, and a slowly progressive penile hematoma. Voiding is possible if the urethra is not injured. Ultrasonography is not diagnostically helpful in this setting. Occasional nonoperative management includes bed rest and ice packs for 24 to 48 hours followed by local heat and a pressure dressing. Most injuries are treated surgically. The penile hematoma is evacuated, the torn penile tunica albuginea is sutured, and a pressure dressing is applied. Of patients with a fractured penis, 10% experience a permanent deformity, suboptimal coitus, or impaired erections, especially if managed nonoperatively.

Figure 44-27 Fracture of the penis. Traum atic rupture of the corpus cavernosum , usually associated with sexual activity, results in a profound penile hem atom a, m ost often requiring operative repair.

Traumatic lymphangitis of the penis is a self-limiting disease usually caused by vigorous or prolonged sexual intercourse or masturbation. It is seen as a translucent, firm, nodular, almost cartilaginous cordlike configuration beginning at the coronal sulcus in the subcutaneous tissue. It may involve one side of the penis or encircle it completely. It is usually not tender and is freely mobile. It is best treated by abstinence from sexual activity and resolves in 2 to 3 weeks. Nonsteroidal anti-inflammatory drugs (NSAIDs) may be of some benefit. Traumatic lymphangitis should not be confused with Peyronie's disease, which is caused by recurring microtrauma leading to the formation of plaquelike fibrosis in the dorsal aspect of the tunica albuginea between the two corpora cavernosa. This fibrotic area causes decreased penile distensibility with subsequent dorsal curvature of the penis leading to painful erections and difficult or unsuccessful vaginal penetration. Reassurance and daily doses of vitamin E (400 IU) are the initial modes of therapy with subsequent urologic follow-up evaluation. Thrombosis and thrombophlebitis of the dorsal vein of the penis are usually associated with a history of direct trauma, idiopathic thrombophlebitis, or thromboangiitis obliterans. The physical findings are much more striking than those of traumatic lymphangitis, and the condition is treated symptomatically with heat and NSAIDs. Most human bites to the penis are acquired during sexual activity and represent a potentially serious polymicrobial infection. With this history and an examination showing localized swelling or generalized edema of the penile shaft with erythema suggestive of cellulitis, an immunocompromised patient should be

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admitted to the hospital for broad-spectrum intravenous antibiotic coverage that is sensitive to both aerobic and anaerobic organisms. Careful observation for the development of bacteremia or septicemia must be part of the management plan. An immunocompetent patient can be treated as an outpatient with cephalexin, NSAIDs, and re-evaluation within 2 to 3 days.

TESTICULAR TRAUMA Clinical Features Testicular injuries are most often caused by a fall or kick, or they are incurred while playing a sport and result in a contusion, laceration, fracture, or dislocation. The symptoms include severe pain, faintness, nausea, vomiting, and occasionally urinary retention secondary to pain. On examination, a tender swollen testicle may be present, but often only a small hematoma is noted. Therefore, anyone with a remote history of testicular trauma should undergo testicular color Doppler ultrasonographic examination, the diagnostic procedure of choice, to evaluate the integrity of the testis.[32] It can disclose testicular disruption, extruded testicular parenchyma, or a fragmented testicle. Loss of the normal homogeneous testicular pattern and the presence of a heterogeneous testicular pattern are diagnostic of testicular injury and require urologic evaluation ( Figure 44-28 ). Benign trauma often acts as the inciting event that discloses testicular torsion or malignancy.

Figure 44-28 Testicular rupture. A, Testicular ultrasonogram dem onstrates the norm al hom ogeneous testicular pattern. B, The heterogeneous pattern of injury, tum or, or disruption.

Management Testicular contusions are treated conservatively with bed rest, ice packs, NSAIDs, and appropriate urologic follow-up evaluation. Testicular dislocation occurs as a result of excessive pressure on the scrotum or thigh. In 80% of cases, the testis lies under the abdominal wall. Associated injuries are common, such as a pelvic fracture, hip dislocation, or cutaneous contusions. On examination, the affected hemiscrotum is swollen and ecchymotic with an absent testis. Operative repair is required for testicular laceration, disruption, or dislocation. Hematoma evacuation, testicular parenchymal debridement, and primary closure of the tunica albuginea are the treatments of choice. Immediate surgery allows earlier resumption of daily activity, a shorter hospital stay, greatly reduced morbidity, and a lower orchiectomy rate. Infrequent dog bites to the scrotum occur most often in children.[33] Careful examination of the scrotal tunica vaginalis will disclose involvement of the intrascrotal contents that dictates operative evaluation and repair. All other bites can be washed out thoroughly and closed primarily with absorbable suture. Prophylactic antibiotics can be administered based on the extent of the bite, subsequent injury, and the patient's immune status.

KEY CONCEPTS {,

Diag nosti c eval uatio n of the urina ry tract is gene rally unde

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rtake n in retro grad e fashi on. That is, susp icion and elimi natio n of ureth ral injur y befor e blad der injur y befor e urete ral or renal injur y. {,

Uret hral injur y is sugg este d by the pres ence of a pelvi c fract ure, bloo d at the ureth ral meat us, the pres ence of a highridin g or abse

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nt prost ate on recta l exa mina tion, or evid ence of a perin eal, scrot al, or penil e hem atom a. {,

Gros s hem aturi a alon e or in conj uncti on with a pelvi c fract ure is the abso lute mark er for signi fican t blad der injur y. Gros sly, clear blad der urine in a trau ma

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patie nt with out a pelvi c fract ure virtu ally elimi nate s the poss ibility of blad der ruptu re. {,

Adult patie nts at risk for majo r renal lacer ation s have gros s hem aturi a or micr ohe matu ria (3-5 RBC s/hpf ) with shoc k (syst olic bloo d pres sure ≥90 mm Hg) initial ly in the field

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or the eme rgen cy depa rtme nt, or, rarel y, a histo ry of sudd en dece lerati on with out hem aturi a or shoc k. Pedi atric patie nts can suffe r majo r renal injuri es with out any hem aturi a. {,

If a urete ral injur y is susp ecte d, a contr ast-e nhan ced helic al CT scan with dela yed

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films or bolu s infus ion IVP with dela yed films shou ld be done . If the initial stud y of dela yed films is inco nclu sive, retro grad e pyel ogra phy is indic ated to delin eate a urete ral lacer ation or avul sion.

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REFERENCES 1. McAninch JW: Injuries to the genitourinary tract. In: Tanagho EA, McAninch JW, ed.General Urology, Norwalk, Conn: Appleton & Lange; 1999: 2. Nicolaisen GS: Renal trauma: Re-evaluation of the indications for radiological assessment. J Urol 1985;133:183. 3. Perry MO, Husmann DA: Urethral injuries in female subjects following pelvic fractures. J Urol 1992;147:139. 4. Corriere JN: Trauma to the lower urinary tract. In: Gillenwater JY, ed.Adult and Pediatric Urology, 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2002: 5. Sandler CM, Goldman SM, Kawashima A: Lower urinary tract trauma. World J Urol1998;16:69. 6. Spirnak JP: Pelvic fracture and injury to the lower urinary tract. Surg Clin North Am1988;68:1057. 7. Cass AS, Luxenberg M: Features of 164 bladder ruptures. J Urol1987;138:743. 8. Vaccaro JP, Brody JM: CT cystography in the evaluation of major bladder trauma. Radiographics 2000;20:1373. 9. Hochberg E, Stone NN: Bladder rupture associated with pelvic fracture due to blunt trauma. Urology 1993;41:531. 10. Schneider RE: Genitourinary trauma. Emerg Med Clin North Am1993;11:137. 11. Deck AJ, Shaves S, Talner L, Porter JR: Computerized tomography cystography for the diagnosis of traumatic bladder rupture. J Urol2000;164:43. 12. Corriere Jr JrJN, Sandler CM: Mechanisms of injury, patterns of extravasation and management of extraperitoneal bladder rupture due to blunt trauma. J Urol1988;139:43. 13. Corriere Jr JrJN, Sandler CM: Bladder rupture from external trauma: Diagnosis and management. World J Urol1999;17:84. 14. Santucci RA, McAninch JW: Diagnosis and management of renal trauma: Past, present, and future. J Am Coll Surg2000;191:443. 15. Morey AF: Single shot intraoperative excretory urography for the immediate evaluation of renal trauma. J Urol1999;161:1088. 16. Mee SL: Radiographic assessment of renal trauma: A ten-year prospective study of patient selection. J Urol1989;141:1095. 17. Bretan PN: Computerized tomographic staging of renal trauma: 85 consecutive cases. J Urol 1986;136:561. 18. Brown SL, Elder JS, Spirnak JP: Are pediatric patients more susceptible to major renal injury from blunt trauma? A comparative study. J Urol1998;160:138. 19. Morey AF, Bruce JE, McAninch JW: Efficacy of radiographic imaging in pediatric blunt renal trauma. J Urol1996;156:2014. 20. Nguyen MM, Das S: Pediatric renal trauma. Urology2002;59:762. 21. Carroll PR, McAninch JW: Staging of renal trauma. Urol Clin North Am1989;16:193. 22. Goldman SM, Sandler CM: Upper urinary tract trauma: Current concepts. World J Urol1998;16:62. 23. Hardeman SW: Blunt urinary tract trauma: Identifying those patients who require radiological diagnostic studies. J Urol1987;138:99. 24. Cass AS, Luxenberg M: Management of renal artery lesions from external trauma. J Urol1987;138:266. 25. Tong YC: Use of hematoma size on CT and calculated average bleeding rate as indications for immediate surgical intervention in blunt renal trauma. J Urol1992;147:984. 26. Campbell EW, Filderman PS, Jacobs SC: Ureteral injury due to blunt and penetrating trauma. Urology 1992;40:216. 27. Rober PE, Smith JB, Pierce JM: Gunshot injuries of the ureter. J Trauma1990;30:83. 28. McAninch JW, Corriere Jr JrJN: Renal and ureteral injuries. In: Gillenwater JY, ed.Adult and Pediatric Urology, 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2002: 29. Brandes SB: Ureteral injuries from penetrating trauma. J Trauma1994;36:766. 30. Presti JC, Carroll PR, McAninch JW: Ureteral and renal pelvic injuries from external trauma: Diagnostic and management. J Trauma1989;29:370. 31. Palmer LS: Penetrating ureteral trauma at an urban trauma center: 10-year experience. Urology

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1999;54:34. 32. Fournier Jr JrGR, Laing FC, McAninch JW: Scrotal ultrasonography and the management of testicle trauma. Urol Clin North Am1989;16:377. 33. Cummings JM, Boullier JA: Scrotal dog bites. J Urol2000;164:57.

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Chapter 45 – Peripheral Vascular Injury Edward J. Newton

PERSPECTIVE Injury to major arteries or veins invariably poses a threat to the viability of the affected limb and even to life. Historically, because of rapid blood loss, injury to major vessels was often quickly fatal in the field. Most patients who survived to reach a hospital had relatively minor limb injuries. However, with the advent of modern Emergency Medical Service systems with advanced extrication methods and rapid transport, more patients with major vascular injury reach the hospital alive.[1] In addition, the incidence of penetrating civilian injuries from interpersonal violence and blunt injuries from motor vehicle–related trauma in the United States has increased dramatically over the past 50 years. Consequently, emergency physicians are frequently confronted with critically ill patients harboring overt or occult vascular injuries. Management of vascular injuries has evolved with advances in diagnostic methods and surgical techniques. Treatment of vascular injuries before and during World War II was simple ligation of the peripheral artery or vein involved. This approach resulted in limb amputation rates ranging from 40% for axillary artery injuries to 72% for popliteal artery injuries. During the Korean War, routine attempts to repair injured arteries decreased the amputation rate for popliteal injuries to 32%.[2] During the Vietnam War, repair of axillary and popliteal artery injuries with routine angiography and improved surgical techniques decreased the amputation rate to as low as 5% and 15%, respectively, which approaches the current rate of amputation for civilian injuries.[] However, extrapolation of high-velocity military wound data to low-velocity civilian gunshot wounds may not be valid, and even lower rates might be expected with civilian wounds. Tremendous progress has been achieved in diagnostic and therapeutic techniques for dealing with peripheral vascular injuries, and several noninvasive diagnostic modalities have emerged as accurate alternatives to surgical exploration or angiography. These techniques are easily used in the emergency department, and the goal of timely detection and repair of serious vascular injuries is achievable in the vast majority of cases.

Epidemiology Throughout the world, the etiology of peripheral vascular injuries is divided almost equally between blunt and penetrating mechanisms.[4] In the United States, 70% to 90% of these injuries are due to penetrating wounds.[] Penetrating wounds are particularly common in inner-city urban areas, although the incidence of low-velocity gunshot wounds has decreased over the past several years.[7] Because of the increased use of percutaneous endovascular diagnostic and therapeutic procedures, the incidence of iatrogenic vascular injuries has increased and accounts for up to a third of all cases in some series.[8] Major venous injuries are present in 13% to 51% of cases, but more than 80% are associated with arterial injury as well.[9] Approximately 90% of patients with vascular injury are male, and most are younger than 40 years.[5]

PRINCIPLES OF DISEASE Pathophysiology Blunt and penetrating types of trauma result in a similar spectrum of vascular injuries, although the mechanisms of injury differ. Even though blunt vascular injuries are less common than penetrating injuries, they are often more severe and more commonly require amputation because of associated injuries to nerves, bone, and soft tissue. Certain mechanisms of injury, such as close-range shotgun wounds and animal bites that crush and lacerate vessels, routinely combine penetrating and blunt mechanisms.

Penetrating Trauma Penetrating trauma from gunshot wounds results in the formation of a temporary cavity within distensible soft tissues with almost immediate recoil of these tissues. The size of the cavity and hence the degree of

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soft tissue injury depend directly on the velocity of the missile, as well as the tumble and yaw of the bullet. Consequently, gunshot wounds can cause direct arterial laceration or transection in addition to vascular injury at some distance from the track of the bullet. The latter injuries tend to be tears in the intima of an artery with subsequent thrombosis that may not become apparent for hours to months after the injury. Stab wounds can cause vascular injury by complete or partial transection of vessels. Partial laceration of an artery may produce few symptoms of arterial insufficiency on initial evaluation but commonly results in delayed complications. The vascular structures at risk can be predicted more reliably with stab wounds than with gunshot wounds by taking into consideration the anatomic location, the depth and direction of the wound, and the implement involved. Shotgun wounds are less common than gunshot or stab wounds and cause injuries varying from minor soft tissue wounds to massive destruction of soft tissue and bone, depending primarily on the range from which the shotgun was fired. The presence of multiple missiles ranging from 9 or 10 (buckshot) to dozens (birdshot) also complicates the evaluation of these injuries because of the many potential sites for vascular injury to occur. In addition, close-range shotgun wounds can cause significant blunt trauma to blood vessels, as well as a higher rate of bone and nerve injury than occurs with gunshot wounds. Migration of pellets proximally through the venous system to the heart or migration through an artery with subsequent distal occlusion has been reported frequently as a delayed complication.

Blunt Trauma Blunt injury involves avulsion forces that can stretch vessels beyond their capacity or direct crushing injury that disrupts the vessel wall. Fracture fragments resulting from blunt extremity trauma can lacerate or entrap vessels. Vascular injury can range from small intimal tears to complete avulsion of arteries and nerves. Open avulsion injury of a limb is particularly severe because the skin is the final structure to tear, and once such tearing occurs, it is inevitable that vessels and nerves will be torn as well.[10] Vascular injury must also be suspected in patients with massive soft tissue avulsion or crush injury, displaced long bone fractures, electrical or lightning injuries, and severe burns, as well as in those with compartment syndrome from trauma or prolonged immobilization as a result of stroke, coma, drug overdose, or other causes.[] Dog bites that are inflicted by large animals, such as those used by law enforcement, are particularly prone to the development of arterial injury and wound complications.[] Collateral circulation may continue to perfuse the limb adequately, but injuries that occur proximal to the collateral branch point or that involve both the main trunk and collateral branches will preclude adequate flow. Distal ischemia results from the inability of tissues to continue aerobic metabolism. Eventually, anaerobic metabolism consumes all substrate, thereby resulting in the accumulation of lactic acid. As ischemia progresses, cellular integrity is lost and irreversible cell death occurs. A vicious cycle of tissue edema and further impairment of the blood supply occurs. When no specific measures are taken to cool the limb, it is said that the limb is undergoing “warm ischemia” at room temperature. Although individuals may vary, 6 hours of complete warm ischemia is generally considered the point at which irreversible nerve and muscle damage begins to occur. After 6 hours of warm ischemia, 10% of patients will have irreversible damage; by 12 hours, 90% will. Artificially cooling the limb to just higher than freezing temperature will reduce the metabolic demands of unperfused tissues and greatly prolong the tissue's tolerance of ischemia. Two main types of vascular injury can result from trauma: occlusive injury (transection, thrombosis, and reversible spasm), in which all effective perfusion distal to the occlusion is lost, and nonocclusive injury (intimal flap, arteriovenous fistula [AVF], and pseudoaneurysm), in which some arterial flow continues past the injury.

Complete Occlusive Injury Transection The most common vascular injury is complete transection in which distal flow is effectively eliminated. Cleanly transected arteries will often retract and undergo spasm so that blood loss is minimized. With longitudinal arterial lacerations and venous injuries, blood loss cannot be limited by this means, and such injuries tend to result in greater blood loss. Pulsatile bleeding may lead to exsanguinating hemorrhage and shock.

Thrombosis Intraluminal thrombosis ( Figure 45-1 ) may occur in an injured artery acutely (within 24 hours) or may be delayed for many months. Acute thrombosis is initiated by stasis resulting from compression of the artery or

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from a disruption in the intima of an artery that becomes a nidus for thrombus formation. As the thrombus propagates, complete occlusion of the vessel can occur. Delayed thrombosis can occur months to years after injury if the injured vessel heals with stricture formation and decreased blood flow distally, followed by stasis and clot formation.

Figure 45-1 Com plete throm bosis of the distal brachial artery after reduction of a posterior elbow dislocation. ((Courtesy of D. Dem etreades, MD.))

Reversible Arterial Spasm The precise cause and incidence of significant reversible arterial spasm after trauma are unknown. In many cases the spasm occurs at some distance from the site of traumatic injury. In response to a traumatic stimulus, segmental narrowing of an artery may occlude the artery and produce distal ischemia. The spasm usually reverses with conservative treatment (topical warm saline or topical nitroglycerin paste), but prolonged spasm may require infusion of vasodilators such as nitroglycerin, lidocaine, or saline.[14] In many series, segmental arterial spasm is the most common arteriographic finding. However, it should never be assumed on clinical grounds that symptoms of ischemia are due to arterial spasm; that diagnosis is based on arteriographic results only.

Nonocclusive Injuries Intimal Flap An intimal flap occurs when there is a break in the intima of a vessel, generally from excessive stretch or concussive forces. Although flow is not altered by small flaps and the associated soft tissue wounds often appear benign initially, these intimal flaps may become a nidus for thrombosis that can occur hours to months after the initial injury. However, most intimal flaps heal spontaneously, and asymptomatic injuries that do not disrupt perfusion of the limb can be treated conservatively.

Pseudoaneurysm A true aneurysm contains all three layers of the vessel wall (intima, media, and adventitia) and rarely is caused by trauma. A pseudoaneurysm is formed when hemorrhage from a vessel is contained by surrounding fascia and the resulting hematoma is gradually encased by a capsule of fibrous tissue, analogous in consistency to the adventitia of a normal vessel ( Figure 45-2 ). Because it is relatively thin walled, rupture of a pseudoaneurysm is a distinct possibility. In addition, because its diameter inevitably expands under arterial pressure over days to months, compression of adjacent tissue may result in neuropathy, venous obstruction with resultant peripheral edema and venous thrombosis, and even erosion into adjacent bone. The cavity of a pseudoaneurysm is in direct communication with the lumen of the vessel, so embolization of mural clots may produce distal arterial occlusion. Patients with pseudoaneurysm are commonly seen months to years later with symptoms of compression neuropathy or peripheral arterial embolism or for investigation of a soft tissue “tumor” that represents the growing aneurysm.

Figure 45-2 Multiple sm all pseudoaneurysm s of the axillary artery after penetrating injury. ((Courtesy of D. Dem etreades, MD.))

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Arteriovenous Fistula An AVF is formed when both the artery and an adjacent vein are injured. Higher-pressure arterial flow is directed into the lower-pressure vein, thereby diverting the blood supply to distal tissues and engorging the distal veins. Because the aperture of the fistula is often relatively narrow and thus results in turbulent flow, a bruit and palpable thrill are common diagnostic findings. Symptoms are primarily those of distal ischemia, but rarely, high-output congestive heart failure may occur when large central vessels are involved. Symptoms are often delayed for months because it takes time for the fistula to mature.

Compartment Syndrome Compartment syndrome is most common after crush injury or a long bone fracture but may also be seen after reperfusion of an ischemic limb. Initially, blood flow is diminished and the injury can be considered nonocclusive. Smaller-caliber vessels are compressed first whereas larger vessels remain relatively patent, so pulses may be palpable until late in the course. If allowed to progress, however, all blood flow may end and the injury is then an occlusive one. Progressive edema elevates tissue pressure above capillary pressure, thus ending arterial flow and initiating a cascade of events that results in compartment syndrome. The risk for this complication is increased when ischemia time is prolonged, in the presence of combined arterial and venous injury, after ligation or repair of a major artery or vein, or in the presence of significant soft tissue injury.[5] After restoration of arterial flow to a previously ischemic limb, a cascade of reperfusion injury has been identified that results from release of oxygen free radicals, lipid peroxidation, and influx of intracellular calcium. These mediators give rise to progressive cellular damage, edema, and necrosis, thereby propagating the vicious cycle that increases compartment pressure.[15] Consequently, frequent reexamination of the limb is indicated to assess compartment pressure after arterial repair.

CLINICAL FEATURES Detection and treatment of vascular injuries must take place within the context of the overall resuscitation of the patient according to established principles of trauma care.[16] If the source of bleeding is readily identifiable, it is compressed with digital pressure. Once control of active bleeding has been achieved in this manner, detection and treatment of other life-threatening injuries can proceed. Peripheral vascular injury can occur coincident with nonvascular life-threatening trauma, which takes higher priority in resuscitating the patient. In other cases, peripheral vascular injury may be the most serious or only injury, and evaluation and management of these injuries can proceed directly. Despite rapid transport to a hospital through a modern Emergency Medical Service, injury to large central arteries and veins is still often fatal, and many of these deaths occur before medical contact. Patients who survive to reach the hospital may have obvious exsanguinating hemorrhage or only very subtle signs of vascular injury. Many patients have no evidence of injury but are considered at risk for vascular injury because of penetrating wounds in close proximity to major neurovascular bundles or because they have sustained high-risk injuries such as posterior knee dislocation. Patients who remain hypotensive after an initial fluid challenge may harbor an occult vascular injury if no other cause is found. In addition, patients with symptoms of intermittent claudication or with unexplained peripheral embolization and a history of previous trauma to the limb should be suspected of having occult arterial injury. Peripheral vascular injury can be divided into three categories by physical examination: hard findings, soft findings, and asymptomatic high-risk wounds based on the mechanism of injury.

Hard Findings of Vascular Injury Most patients have the classic “hard” findings of arterial injury, including pulsatile bleeding, an audible bruit or palpable thrill indicative of an AVF, an expanding or pulsatile hematoma, or any combination of the “five P's” of arterial insufficiency: pain on passive extension of the muscle compartment involved, pulselessness, p aresthesias, pallor, and paralysis. In addition, cyanosis and decreased temperature are common in a poorly perfused extremity, and massive distention of distal superficial veins may indicate an AVF as arterial flow is directed into distensible veins. The incidence of arterial injury in patients with any hard finding is consistently greater than 90%,[17] and the presence of these findings requires either further investigation by emergency angiography or immediate surgical intervention, depending on the duration of warm ischemia and the overall status of the patient.

Soft Findings of Vascular Injury An additional group of patients have “soft findings” of vascular injury, including a palpable but diminished pulse in comparison to the uninjured extremity, isolated peripheral nerve injury, or a large nonpulsatile hematoma.[18] The significance of prolonged capillary refill is controversial; some experts find it to be a reliable sign of vascular injury (when combined with a pulse deficit) and consider delayed capillary refill to be

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a valid soft sign of vascular injury. Others have found this sign to be a nonspecific and unreliable predictor of arterial injury.[] Delayed capillary refill in itself is insufficient to diagnose arterial injury but, in combination with other physical signs, supports the diagnosis. Isolated penetrating injury to a peripheral nerve is commonly associated with vascular injury because of the close proximity of these structures within the neurovascular bundles. Vascular injury occurs in 8% to 45% of cases of penetrating peripheral nerve injury.[19] Conversely, vascular injuries have associated peripheral nerve injury in almost half the cases.[20] It is sometimes difficult to distinguish whether the pain, paresthesias, or paralysis is due to a primary nerve injury or to an associated vascular injury or compartment syndrome. In general, primary nerve injury occurs immediately at the time of injury, whereas vascular neuropathy occurs over minutes to hours after the injury.[21] Up to 35% of patients with “soft” findings of vascular injury have positive angiographic studies, although only a small proportion of these injuries require emergency repair.[17]

High-Risk Injuries The proximity of a penetrating wound to a neurovascular bundle is defined imprecisely. Various definitions include 1 cm, 1 inch, or 5 cm as constituting “proximity.” Certainly, penetrating wounds that occur within 1 cm of a major neurovascular bundle or whose presumed trajectory has crossed such a bundle (“proximity wounds”) are more likely to produce an occult vascular injury. Major neurovascular bundles include large limb arteries proximal to critical branch points, such as the axillary, brachial, common femoral, and popliteal arteries ( Figures 45-3 and 45-4 ).[22] In addition, a substantial minority of patients with high-risk injuries, such as bites from large dogs or other animals, severely displaced fractures, crush injuries, or major joint dislocations (especially knee dislocation), will initially have occult vascular injury that is not detected by physical examination. The risk of missing such injuries is that the traditional 6-hour window of “warm ischemia time” will be exceeded or the patient will experience delayed complications resulting in loss of the limb. For example, patients with intimal flaps may be completely asymptomatic initially but can subsequently be subject to arterial thrombosis. Similarly, pseudoaneurysms progressively enlarge to produce compression of adjacent structures but may be very small and undetectable on initial physical examination. Consequently, many centers routinely perform some ancillary confirmation of arterial patency in these cases.

Figure 45-3 Major arteries of the upper lim b. ((From Snell R, Sm ith M [eds]: Clinical Anatom y for Em ergency Medicine. St Louis, CV Mosb y, 1993.)CV Mosb y)

Figure 45-4 Major arteries of the lower limb. ((From Snell R, Sm ith M [eds]: Clinical Anatom y for Em ergency Medicine. St Louis, CV Mosb y, 1993.)CV Mosb y)

History In patients who achieve and maintain hemodynamic stability, a more comprehensive history can be obtained. Important historical points to note include the exact time and mechanism of the injury. The time of

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injury is important because of the limitations of warm ischemia time noted earlier. The mechanism is of clinical and often forensic importance in that the injury is frequently inflicted during an assault or other violent crime, in the context of domestic violence or physical abuse, or in association with work. Various mechanisms of injury may mandate special reporting and may alter the patient's ultimate disposition. Certain types of injuries, such as crush or bite wounds, are particularly prone to complications. The occupation, avocation, and hand dominance of the patient are pertinent because a more aggressive strategy may be indicated in certain cases. Medical conditions that pose a risk of complications are important to note. Patients who are immunocompromised because of diabetes, acquired immunodeficiency syndrome, asplenia, cancer, or steroid use are at increased risk for infection and impaired wound healing. Patients with previous vascular insufficiency have more tenuous perfusion, are more susceptible to ischemia from elevated compartment pressure, and have a higher incidence of complications.[23] As with most aspects of trauma care, patients whose sensorium is altered by head injury or intoxication, patients with spinal cord injury who cannot perceive pain, and those with significant painful distracting injuries will not reliably be able to report pain or paresthesias suggesting vascular insufficiency, so extra caution must be exercised in these cases.

Physical Examination Physical examination is directed at discovering evidence of local wound complications and distal ischemia suggestive of vascular injury. Palpation of pulses in the affected extremities is the initial step. A comparison of the strength and quality of the pulses between the injured limb and its uninjured counterpart is then made. Isolated detection of a pulse deficit distal to the site of injury is a finding that merits further investigation rather than immediate surgery because palpation of pulses is a relatively inaccurate means of predicting arterial injury. False-positive findings of a pulse deficit may occur because of shock, in which all pulses are diminished, congenital absence of a pulse in one extremity, preexisting vascular disease, or arterial spasm. A false-positive finding of a pulse deficit occurs in 10% to 27% of cases.[] False-negative findings can occur with transmission of the pulse through a “soft clot,” past an intimal flap, or through collateral circulation. Distal pulses can persist in 6% to 42% of patients despite significant arterial injury.[24] Compression of an artery by casts, splints, or dressings may produce a pulseless extremity, and these should be removed if evidence of ischemia occurs.[25] Finally, even though the pulse may be absent, the limb may be well perfused by collateral arterial supply, thus making repair of the arterial injury less compelling. Simultaneous palpation of the injured and unaffected limb can detect relatively small differences in skin temperature that may suggest hypoperfusion. Testing two-point discrimination on the injured and unaffected limbs is similarly an effective means of detecting sensory deficits. Auscultation over the site of injury is an often-ignored examination that may reveal a bruit suggestive of an AVF. A bruit is audible in more than half of patients with an AVF.[26] Repeated examination of the hematoma adjacent to the wound is indicated to determine whether it is expanding or pulsatile. Despite the limitations just noted, reliance on the history and physical examination to triage patients into immediate surgery, angiography, and observation groups has been found to be relatively dependable, with a sensitivity of 92% and a specificity of 95%.[17]

DIAGNOSTIC STRATEGIES The diagnostic strategy for detection of peripheral vascular injury must be tailored to the clinical situation. Patients with clearly evident major arterial injury (e.g., pulsatile hemorrhage from a penetrating wound with a cold, pulseless distal end of the extremity) may require emergency operative intervention without the benefit of any ancillary confirmation of their injury. At times, the use of an intraoperative angiogram may be helpful in delineating the exact location and nature of the injury in patients taken directly to the operating room. However, delaying definitive treatment of an obvious arterial injury that is approaching the 6-hour limit of warm ischemia time to obtain an arteriogram is ill advised.

Plain Radiography Plain radiographs of the affected extremity are indicated to detect fractures, joint penetration, and foreign bodies. With gunshot wounds, the sum of the number of intact bullets seen on x-ray and the number of wounds in the body must be an even number. Failure to locate a bullet can result in unexpected complications. Rarely, bullets or shotgun pellets can migrate distally and produce vascular occlusion or migrate proximally through the venous system to the heart. These emboli are readily detected on plain radiographs.[] Lead bullets retained within a synovial joint can result in systemic absorption and elevated lead levels and should be removed electively.[29]

Pulse Oximetry

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Several relatively simple, noninvasive maneuvers can be performed at the bedside to elicit evidence of arterial injury. The use of pulse oximetry has been suggested as a means of identifying limb ischemia after trauma, but its utility in this setting has not been well studied. Clearly, in the absence of a pulse, no reading can be obtained. As the technology of transcutaneous measurement of physiologic indices advances, measurement of tissue oxygenation by near-infrared spectroscopy to quantify muscle oxyhemoglobin may prove more useful in detecting vascular injury.[]

Hand-Held Doppler An inability to palpate pulses in an injured extremity should be verified by auscultation with a hand-held Doppler unit. Apart from the absence of any signal, arterial injury may be suggested by a change in the usual triphasic quality of the Doppler pulse to a biphasic or monophasic waveform as the pulse is “damped” by partial occlusion. Though more sensitive, auscultation of the pulse by Doppler is subject to the same types of limitations as is palpation of the pulse.

Ankle-Brachial Index and Arterial Pressure Index Determination of the ankle-brachial index (ABI) or the arterial pressure index (API) has been well studied and provides somewhat more accurate information than does physical examination alone. Systolic pressure is measured by inflating a standard blood pressure cuff proximal to the injury and recording hand-held Doppler systolic pressure distal to the injury. The process is repeated on the uninjured limb, and a ratio of injured to uninjured systolic pressure is calculated (API). Generally, a ratio less than 0.90 is considered abnormal and is an indication for further investigation. Unfortunately, there is no consensus on the appropriate cutoff ratio to consider abnormal, and figures ranging from 0.85 to 0.99 are cited in various studies.[] If an API less than 0.90 is used as the cutoff, sensitivity decreases slightly but specificity increases. In one series a cutoff of 0.90 resulted in a false-negative rate of almost 40%. In other studies, an API less than 0.90 yielded a sensitivity of 95%, specificity of 97%, positive predictive value of 100%, and negative predictive value of 96%. [] Using an API cutoff of less than 1 produced a sensitivity of 96% to 100% but included many false-positive results.[] Still, the use of an API ratio less than 0.90 can eliminate a large number of unnecessary angiograms for proximity wounds and increase the diagnostic efficiency of angiography by limiting its use to high-yield cases. Limiting angiography to patients with either an abnormal physical examination (primarily a pulse deficit) or an API less than 0.90 appears to be an effective and safe strategy for detecting arterial injury.[] Patients with an API of 0.90 to 0.99 merit observation for 12 to 24 hours for repeated physical examination and API measurements to detect evolving injury. Exclusive reliance on API to screen for arterial injury has significant limitations. Comparisons cannot be made when both limbs are injured or when severe soft tissue mangling precludes placing a blood pressure tourniquet or locating the artery to be measured with the Doppler unit.[39] As with physical examination, the sensitivity of API is limited when an intimal flap allows near-normal flow or when collateral circulation is sufficient to produce near-normal systolic pressure, as in proximal injuries to the subclavian or iliac vessels. Certain arteries (e.g., the profunda femoris, profunda brachii, and peroneal arteries) normally do not produce palpable pulses, and API is of limited utility in these injuries. Shotgun wounds often have normal APIs despite multiple small arterial wounds; angiography is the preferred diagnostic modality in this group. As with angiography, API cannot detect venous injuries. In spite of the limitations just noted, API has proved effective in screening patients with proximity wounds. The vast majority of injuries missed by API heal spontaneously. Those that do not heal are generally seen within 3 months with hard signs of arterial injury.

Ultrasound The development of relatively small portable ultrasound (US) units has made possible direct visualization of both arterial and venous flow in major vessels. There are several different types of US that can detect vascular injury, and newer, more accurate techniques are being developed rapidly. B-mode (real-time) ultrasound is the most readily available form of US in portable units. It can easily visualize arterial pulsation in major vessels. Loss of pulsation distal to an obstruction or thrombosis is readily apparent. However, B-mode US cannot visualize certain anatomic areas accurately (subclavian and iliac vessels) because of overlying gas and is unreliable in detecting a fresh, relatively nonechogenic thrombosis or hematoma. As blood liquefies within a hematoma, it becomes echolucent and more readily distinguishable from surrounding tissues. Doppler US interprets sound moving toward or away from the transducer as flow. Venous flow is heard as a

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low-pitched hum, whereas arterial flow has a higher-pitched triphasic quality. The combination of B-mode and Doppler US is called duplex US and has enhanced accuracy in examining blood vessels. Duplex scans showing a focal increase in peak systolic velocity suggest partial obstruction of the vessel. However, duplex scanning is slightly less accurate in detecting injuries that do not decrease flow, such as small pseudoaneurysms, AVF, and intimal flaps,[32] and it is technically limited in examining certain anatomic areas such as the profunda femoris and profunda brachii arteries and the iliac and subclavian vessels. Duplex US findings may be subtle, and as with other applications of US, its accuracy is highly operator dependent. Despite these limitations, the sensitivity of duplex US in comparison to angiography ranges from 83% to 100%, with a specificity of 99% to 100% and an accuracy of 96% to 100%.[] Color flow Doppler converts Doppler echoes into quantitated visual signals. Flow toward the transducer is seen as red, and flow away from the transducer is seen as blue. The intensity of the color (the number of pixels on the screen) is proportional to flow through the vessel. Small prospective studies have indicated a high rate of accuracy in detecting arterial injury.[42] Absence of flow is readily apparent, but more subtle injuries, such as intimal flaps and small pseudoaneurysms, are more difficult to identify.[39] In addition, color flow Doppler is more accurate than standard venography in detecting major venous injuries.[45] The overall sensitivity of color flow Doppler in detecting arterial injury is 50% to 90%, with a specificity of 95% to 99%. The sensitivity for detecting injuries requiring surgical repair is significantly higher. The use of intravascular US for examination of abdominal aortic aneurysms has been well documented. Though not yet applicable to smaller peripheral vessels, with further reduction in size of the transducers, this technique may eventually be applicable for peripheral vascular injury as well.

Computed Tomography and Magnetic Resonance Imaging Computed tomography with contrast enhancement has had limited utility in the past, but newer-generation helical computed tomographic angiography scans have proved accurate in several small series, with 100% accuracy when compared with angiography or surgical exploration.[] Magnetic resonance angiography has also been described and is highly accurate, but it has yet to prove clinically useful.[]

Arteriography The policy of routinely exploring proximity wounds greatly improved the preservation of injured limbs in World War II. With the advent of arteriography, it became apparent that many negative wound explorations could be avoided with routine arteriography. In a study using routine arteriography, the negative surgical exploration rate in patients with “soft signs” of arterial injury or with proximity wounds fell from 84% to 2%.[51] As a result, until recently standard contrast angiography has been the gold standard for diagnosing peripheral arterial injury. Beginning in the 1980s, the number of civilian penetrating wounds increased tremendously. Because of high cost, limited availability at all hours, and poor reimbursement rates, the policy of routine arteriography for proximity wounds has been questioned. From a practical perspective, the time required to mobilize the angiography team and perform the study may be several hours, thus making this option less desirable when dealing with the time limitations posed by arterial injury. In addition, arteriography has a small, but measurable complication rate, including allergic reactions to contrast media, renal complications, hematoma formation, and false aneurysm formation at the site of cannulation. Finally, the clinical utility of the information provided by arteriography has become increasingly suspect as more of these injuries are being managed expectantly in recent years. Routine “exclusion” arteriography for proximity wounds detects unsuspected arterial injury in 0% to 21% of cases.[] However, relatively few of these patients require emergency surgery. In a series of 284 patients who underwent routine angiography for proximity wounds, 17% had unsuspected arterial injury detected, but only 1.8% (5 patients) required emergency surgical repair.[53] In other series reporting on a total of 483 patients who underwent angiography for proximity wounds, only one arterial injury that required emergency repair was discovered.[] In the presence of “soft signs” of injury, the yield for angiograms increases to 29% to 35%, but many of these injuries do not require emergency repair and can be detected by noninvasive means.[53] In addition, angiography results in an approximately 5% false-positive and false-negative rate when compared with surgical exploration. Many of the injuries detected on angiography are due to reversible vasospasm or very small intimal defects that generally heal spontaneously. Consequently, angiography for proximity wounds can detect injury in up to 21% of cases but results in acute surgical intervention in only 0% to 4.4% of cases.[] Many centers now successfully manage proximity wounds by repeated physical examination over a 24-hour period and reserve angiography for those with abnormal physical findings or an ABI less than 0.9.[] Angiography is also limited in that it cannot detect major venous injuries, which are increasingly being repaired surgically. The use of angiography is difficult in

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children because of the small caliber of their vessels and a propensity for vasospasm induced by angiography. Consequently, physical examination and noninvasive methods are preferred for detection of vascular injury in young children.[] Digital subtraction angiography (DSA) has been used for detecting vascular injuries as well. DSA has been found to be more accurate than standard angiography for detection of extravasation and has the advantage of requiring the administration of a smaller load of contrast material. However, the field of view is much smaller with DSA than with standard angiography, thus making it technically difficult to study the entire course of a limb artery with DSA. Standard angiography is also more accurate than DSA in detecting intimal flaps and dissection. Emergency center angiography involves the administration of intra-arterial contrast in a single bolus with a single radiograph as a rapid bedside alternative to formal angiography. Although technical difficulties occasionally limit its usefulness, accuracy approaching that of formal angiography can be achieved.[]

TREATMENT Initial treatment is directed at ensuring a patent airway and adequate air exchange before assessing the circulation. Once this is accomplished, active hemorrhage is controlled by direct digital pressure. Blind clamping of a bleeding vessel is not recommended because of the risk of crushing adjacent nerves. The use of tourniquets is similarly discouraged because occlusion of veins results in increased compartment pressure and an increased risk for venous thrombosis.[5] In cases in which proximal and distal control cannot be readily achieved in the emergency department, insertion of a Foley catheter into the wound and inflation of the balloon with sterile water can temporarily tamponade the bleeding. Intravenous lines should not be started in the injured extremity because they may be ineffective in delivering resuscitation fluid and because extravasation from an injured vein may increase compartment pressure. Serial hemoglobin determinations may indicate unexpected blood loss from occult vascular injury. Patients with significant blood loss should have blood typed and crossmatched and may require immediate transfusion for stabilization. Patients with significant vascular injury often remain hypotensive despite such infusion and require further volume infusion or blood transfusion. Moribund patients with multiple severe injuries may require urgent amputation as part of their overall stabilization or extrication from wrecked automobiles. Between 50% and 70% of patients with severely mangled limbs require urgent amputation, especially if they have multisystem trauma. The issue of “hypotensive resuscitation” is controversial with major vascular injuries. A tenuous clot can form in injured arteries and prevent further blood loss as long as the patient remains hypotensive. Once arterial pressure reaches a critical, but variable point, the clot may be expelled and massive blood loss can ensue. Therefore, when the arterial injury is inaccessible for occlusion by direct pressure, the target blood pressure for resuscitation should be lowered to a systolic pressure of approximately 90 mm Hg. Overly aggressive and rapid fluid administration in the field or in the emergency department can produce transient intravascular hypervolemia and may ultimately increase the rate of blood loss. Close monitoring of vital signs and the total volume of fluid infused is indicated in these situations. Once a vascular injury is identified, a specific diagnostic and therapeutic strategy can be developed that is consistent with the severity of the injury, the presence of other injuries, and the resources available.

Major Vascular Injuries Major vascular injuries that compromise the viability of a limb must be repaired within 6 hours to avoid irreversible ischemic neuropathy and myonecrosis.[5] If other life-threatening injuries must be repaired first, a temporary polytetrafluoroethylene (PTFE) vascular shunt can be placed in the operating room to restore perfusion to a limb.[59] These temporary PTFE shunts can be left in place for up to 24 hours before thrombosis begins to occur within the shunt. Major arterial transection or thrombosis is ideally repaired by end-to-end reanastomosis if possible without placing undue tension on the suture line. If a larger segment of the artery is destroyed, interposition of a reverse saphenous vein graft is the preferred technique. PTFE grafts are suitable for grafting larger arteries if necessary, but they tend to occlude when used in smaller arteries (e.g., distal to the femoral or brachial arteries). Before completing the reanastomosis, a Fogarty catheter is passed through both ends of the repair to extract any thrombi that may have formed. The distal circulation is flushed with a dilute 1:10 solution of heparin or enoxaparin to prevent early clot formation.[60] Systemic administration of heparin is usually contraindicated in major trauma patients. Pretreatment with mannitol has been shown to reduce compartment pressure and may decrease the risk for compartment syndrome if given preoperatively.[15] Assessment of distal perfusion and, in particular, compartment pressures is indicated frequently after repair and reperfusion of the limb. The use of broad-spectrum

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antibiotics such as a first-generation cephalosporin is recommended before commencing a vascular repair. A course of hyperbaric oxygen therapy has been shown to increase the rate of primary wound healing in patients with severe crush injuries, but it is not standard clinical practice.[61] Apart from excision of the affected arterial segment and repair of the vessel, less invasive techniques have been developed to manage pseudoaneurysms. Percutaneous embolization with Silastic beads, gel clot emboli, or thrombogenic coils is often successful.[] Placement of an endovascular sleeve can exclude the aneurysm and is also a successful alternative to open repair.[63] Similarly, repair of an AVF can be undertaken through open surgical ligation of the fistulous connection, by endovascular placement of a sleeve to exclude the fistula, or by percutaneous embolization of the fistulous tract.[62]

Late Complications Despite timely optimal repair of arterial injuries, approximately 21% of patients experience delayed complications requiring further surgical intervention, even including delayed amputation. The most common of such complications is delayed thrombosis, which often occurs after many months as stenosis at the repair site progresses. Other complications include intermittent claudication, chronic pain or edema of the limb, and aneurysm formation in the graft.[64]

Venous Injuries Venous injuries may be primarily ligated if the condition of the patient cannot tolerate prolongation of surgery. However, the current trend is to repair major venous injuries if possible, particularly in the lower extremity, because wound healing is improved and the incidence of compartment syndrome, venous thrombosis, pulmonary embolism, and chronic edema is decreased.[65] Extensive venous collaterals in the upper extremity make surgical repair less compelling. The timing of repair of a vascular injury when associated with complex fractures requiring fixation is controversial. Historically, the fracture was repaired first to give a more accurate measurement of limb length and the length of graft required for vascular repair and because of fear that manipulation of long bones during reduction might damage the vascular repair. However, the need for postoperative fasciotomy is higher in these patients than in those who undergo vascular repair first (80% versus 36%).[66] Currently in most centers, vascular repair is prioritized over orthopedic repair.

Minor Vascular Injuries Increasingly, minor, nonocclusive vascular injuries are being treated expectantly. Criteria for observation of vascular injuries include low-velocity missile wounds, intact distal circulation, absence of active hemorrhage, and minimal arterial wall disruption on angiography if performed. Angiographic findings meeting these criteria include intimal flaps extending less than 5 mm and pseudoaneurysms smaller than 5 mm in diameter.[5] Follow-up of these injuries with repeat angiography or US reveals that approximately 85% resolve spontaneously.[53] Patients meeting these criteria can be monitored as outpatients for 3 months with repeat physical examination and US to detect delayed complications. Some authors suggest caution with this policy because of multiple cases in which conservative treatment failed after prolonged delay.[67] Others have reported large series demonstrating the safety of this approach.[] However, almost all pseudoaneurysms ultimately require repair and, once discovered, should be repaired electively. Failure to detect and repair occult arterial injuries in children often results in severe differential limb growth, and thus a more aggressive policy of repairing any arterial injury that causes even a relatively minor decrease in blood flow to a child's growing limb may be justified.

SPECIFIC INJURIES Upper Extremity Subclavian Artery and Vein Subclavian artery injuries represent 1% to 2% of all vascular trauma.[70] Isolated injury to the subclavian vein is more common than isolated arterial injury, but in almost half the cases both the vein and artery are injured. [71] The vast majority (95% to 99%) are penetrating wounds, and because of massive hemorrhage, these injuries are often lethal before arrival at a hospital. Mortality in those who reach the hospital alive averages 15%, but overall mortality as high as 75% has been reported.[] The right subclavian artery arises from the brachiocephalic artery, the left from the arch of the aorta. From their origin, they course posterior and inferior to the clavicles to the outer margins of the first ribs, where they become the axillary artery and vein. The left subclavian rises higher than the right and extends into the root of the neck.[22]

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The clinical manifestation is that of hemorrhagic shock in 77% of cases. Occasionally, unsuspected subclavian vascular injury is discovered at thoracotomy for excessive blood loss from a chest tube.[71] Approximately 60% have an associated pneumothorax or hemothorax, and additional injury to mediastinal and spinal structures is relatively common.[70] Symptoms of limb ischemia may be apparent with absent radial and brachial pulses. However, pulses are completely absent in only 33% of cases because collateral flow from the thyrocervical trunk may provide sufficient perfusion to avoid the symptoms and signs of ischemia.[71] Neurologic deficits in the upper extremity occur in more than half the patients. The most severe of these injuries is disruption of the brachial plexus, which occurs in almost 50% of patients.[71] In a series of 100 cases of subclavian artery injury, the combination of physical examination and chest x-ray findings suggestive of subclavian injury (hemothorax, pneumothorax, apical pleural cap, or wide mediastinum) was 100% sensitive and could have eliminated the need for 69% of the arteriograms obtained. [72] If the patient's clinical condition permits, angiography can provide an accurate diagnosis and can locate the injury precisely. APIs are relatively inaccurate with proximal thoracic outlet injuries because of collateral arterial flow. US techniques are also relatively inaccurate in detecting subclavian injuries because of interference by overlying gas-filled lung tissue. Therefore, in cases in which the clinical diagnosis is equivocal (“soft signs” of injury or proximity wounds), arteriography is required to detect the injury. Immediate proximal and distal control of the subclavian artery is very difficult. An incision along the course of the clavicle is recommended but often needs to be extended to a sternotomy.[74] If primary reanastomosis is not possible, synthetic grafts are usually successful. Blunt subclavian injuries are often associated with clavicular fracture or dislocation. Isolated first rib fracture is rarely combined with vascular injury unless posterior displacement has occurred. However, first rib fracture in association with other major injuries, a wide mediastinum on chest x-ray, an expanding hematoma, an upper extremity pulse deficit, or a brachial plexus injury is accompanied by arterial injury in 24% of cases and merits investigation by angiography.[75] Several cases of shear injury of the subclavian artery have been reported to result from a loose shoulder restraint of a seat belt during a motor vehicle accident. Overall, blunt subclavian artery injuries are more severe than penetrating injuries because of higher rates of mortality, limb amputation, and associated brachial plexus injury.[70] Subclavian vein injuries are even more lethal than those to the artery. In addition to massive blood loss, there is a relatively high risk of massive air embolism, which is frequently fatal in association with penetrating subclavian vein injuries.

Axillary Artery and Vein Injury to the axillary vessels constitutes 3% to 9% of all vascular injuries and is divided nearly equally between penetrating and blunt mechanisms.[3] Forceful reduction of a chronically dislocated shoulder is a common iatrogenic cause of axillary artery injury. The axillary artery courses from the lateral border of the first rib to the inferior border of the teres major muscle, where it becomes the brachial artery. The axillary vein runs medial to the artery. The extensive anastomotic arterial connections around the shoulder joint usually permit good collateral flow,[] and up to half of these patients will have palpable pulses as a result of collateral circulation.[76] Because of the close proximity of the brachial plexus and the axillary vessels, significant denervation of the upper extremity can occur. Near-avulsion injuries resulting in scapulothoracic dissociation invariably produce severe disruption of the brachial plexus and often ultimately result in amputation despite successful vascular repair. There is a high rate of amputation for the combination of axillary vascular and brachial plexus injury, mainly because the presence of a flail limb results in amputation for placement of a prosthesis. In addition, patients with a flail limb have a 40-fold increased rate of suicide.[10]

Brachial Artery The brachial artery continues from the lower border of the teres major muscle and divides into the radial and ulnar arteries at the level of the proximal aspect of the radial head. The median and ulnar nerves and the basilic vein are in close proximity to the brachial artery. The profunda brachii artery is a major branch that arises soon after the origin of the brachial artery and often contributes good collateral flow if the brachial artery is injured distal to this branch point.[] Brachial artery injuries occur as a result of penetrating trauma, humeral shaft fracture, elbow dislocation, or animal bites. They are the most common major vascular injuries in the upper extremity. In 75% of cases, the radial pulse is absent.[24] Repair is indicated in all cases because the amputation rate is high with ligation.

Forearm Arteries

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The radial artery begins in the cubital fossa and runs superficially to the distal end of the radius, where it ultimately joins the deep branch of the ulnar artery to form the deep palmar arch of the hand. The ulnar artery begins in the cubital fossa and runs with the ulnar nerve anterior to the flexor retinaculum, at which point it joins the radial artery to form the superficial palmar arch of the hand.[77] Injuries detected by arteriography or US that are below the bifurcation of the arterial supply in the upper extremity do not need to be repaired unless there are signs of ischemia in the hand; hard signs of arterial injury such as an expanding hematoma, pseudoaneurysm, or AVF; or injury to both the radial and ulnar arteries. Some authors recommend repairing all these injuries because of the risk of intermittent claudication or cold intolerance in patients who have one artery ligated. Certain patients are almost exclusively dependent on the ulnar arterial supply to the hand because of an underdeveloped deep palmar arch. These patients clearly must have ulnar artery injuries repaired. Compartment syndrome in the forearm is common after repair of proximal arteries and veins and may require fasciotomy.

Lower Extremity Iliac Artery and Vein Given the intra-abdominal course of the iliac vessels, virtually all these injuries have associated trauma to the small or large intestine, bladder, solid viscera, or bony pelvis. The common and external iliac arteries are injured with equal frequency and more often than the internal iliac vessels.[78] In moribund patients, an initial “damage control” laparotomy with temporary vascular shunting of the iliac vessels is often necessary as resuscitation continues. Once the patient has overcome lactic acidosis, hypothermia, and coagulopathy, a second definitive repair can be undertaken. Surprisingly, the incidence of infection of synthetic or autologous grafts is rather low despite the high degree of bacterial contamination associated with perforation of a hollow viscus. Distal ischemic complications occur in about a third of repaired iliac arteries, and subsequent amputations are required in up to 18%.[78]

Femoral Artery and Vein The external iliac vessels become the common femoral vessels at the inguinal ligament. After giving off the profunda femoris artery in the femoral triangle, the femoral artery continues as the superficial femoral artery almost vertically to the adductor tubercle of the femur and enters the popliteal fossa as the popliteal artery. There are extensive proximal collaterals around the hip joint, including the gluteal, obturator, and pudendal branches of the iliac artery.[22] Common femoral artery injury occurs as a result of intertrochanteric hip fracture, hip dislocation, and iatrogenic injury from the placement of arterial catheters or from hip replacement surgery. Ligation of the common femoral artery culminates in amputation of the lower extremity in 80% of cases, so repair should be attempted in all cases. Penetrating wounds of the thigh result in femoral artery injury in 6.2% of cases, and up to 40% of these injuries are clinically occult. A medial or anteromedial wound track is present in virtually all these cases, and many centers routinely perform angiography on these wounds.[79]

Popliteal Artery and Vein The popliteal artery gives off the genicular branches in the popliteal fossa and then divides into the anterior and posterior tibial arteries at the lower border of the popliteus muscle. The peroneal artery arises from the posterior tibial artery shortly after its origin. The anterior and posterior tibial arteries and the peroneal artery form the trifurcation of the popliteal artery, and each runs with a corresponding vein and nerve in different compartments of the leg.[22] Popliteal artery injury is relatively common and in most cases is due to blunt trauma. The most common cause is posterior knee dislocation in which bony elements directly lacerate or cause thrombosis of the artery, although displaced fractures of the knee may also result in popliteal artery injury. Anterior knee dislocations may cause excessive stretch on the popliteal vessels that can culminate in arterial thrombosis, but this injury is relatively rare. Overall, knee dislocation results in popliteal artery injury in 25% to 33% of cases.[80] Up to 40% of these injuries may be clinically occult, and diagnosis is delayed in up to 40% of cases,[2] although other series note that more than two hard signs of ischemia occur in 71% to 94%.[] Twenty-five percent of cases have an associated injury to the peroneal and posterior tibial nerves, and in half the cases the knee dislocation may reduce spontaneously so that there may be little evidence of the original trauma, particularly in obtunded patients.[81] Patients showing complete ligamentous disruption of the knee on physical examination should be suspected of having a spontaneously reduced knee dislocation. Hemarthrosis may be absent if the joint capsule is torn because blood can track into the fascial planes of the leg.

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No consensus has been reached on the diagnostic approach to detect popliteal artery injury resulting from knee dislocation. There are three possible strategies, and each has proponents and detractors. The first option is to perform routine arteriography on every case of knee dislocation. The second is to perform arteriography on selected cases in which vascular injury is not certain in spite of the combination of physical signs, abnormal ABI measurement, or findings on noninvasive tests such as color flow Doppler, duplex scan, or computed tomographic angiography. The third option is to rely completely on these physical findings and ABI. If both these findings are normal, advocates of this approach claim 100% negative predictive value for vascular injury that requires surgery.[] The choice of these options is institution specific, but most centers continue to use arteriography in selected cases. Abnormal ABI and US (duplex and color flow Doppler) have been found to be very accurate in detecting popliteal injuries, and many centers reserve arteriography for cases in which noninvasive tests result in equivocal findings. As a general rule, high-energy mechanisms of trauma (e.g., auto versus pedestrian, motor vehicle accident) and posterior knee dislocations are more likely to produce popliteal artery injury than low-energy mechanisms are (e.g., sports injuries), and a more aggressive diagnostic approach (i.e., arteriography) may be warranted in such cases. However, patients with penetrating trauma and more than one hard sign of popliteal artery injury can be taken directly to the operating room for repair because delaying these cases to obtain an angiogram is “superfluous, unnecessary, costly and potentially dangerous.”[87] Patients with blunt trauma can have false-positive hard findings generated by soft tissue swelling and external arterial compression, and these patients should undergo diagnostic testing first to confirm arterial injury. The amputation rate for popliteal injuries was as high as 40% in the past but has currently been reduced to zero in some series with modern diagnostic and repair techniques.[] Most amputations are due to blunt trauma with severe mangling of the extremity or delay in repair exceeding 8 hours of warm ischemia time.[81] Because of the high incidence of compartment syndrome with lower leg injuries, fasciotomy is required in 36% to 62% of cases, and some centers routinely perform fasciotomy in all such cases.[88] Approximately two thirds of patients with popliteal artery injury will have persistent deficits caused by peripheral nerve injury, chronic ischemia, or amputation.

Lower Leg Arteries The popliteal artery divides into three branches, the anterior and posterior tibial and the peroneal arteries at the inferior margin of the popliteal fossa. Injuries below the trifurcation at the knee may need repair if hard signs of arterial injury are apparent in the foot or if two of the three arteries are occluded on angiography.[18] However, vascular injuries in the lower part of the leg are notorious for causing compartment syndrome and need to be monitored closely. Amputation is usually due to a combination of soft tissue, nerve, and bone injuries. If significant injury to all three of these tissues is present, the amputation rate may reach 54%.[] The combination of orthopedic and vascular injury, particularly as a result of crush injury, and shock on initial evaluation culminates in amputation in 35% of cases and should be considered a poor prognostic sign for limb viability.[90]

DISPOSITION Patients with confirmed injury to major vessels, equivocal findings on diagnostic tests, or symptoms of limb ischemia must be admitted to the hospital for further investigation or observation. Consultation with a vascular surgeon is indicated as soon as vascular injury is confirmed and the need for emergency operative repair established. Patients who are unstable because of vascular or other injuries may undergo further investigation or exploration in the operating room. If the treating hospital is incapable of performing vascular surgery or appropriate investigations, transfer to a trauma center should be initiated. Delaying transfer for angiograms of proximity wounds in centers that are incapable of acting on positive results is unwise because it often delays definitive care beyond the safe limits of warm ischemia time.

KEY CONCEPTS {,

The over all cond ition of the patie nt deter mine

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s the exte nt of diag nosti c stud y and stabi lizati on in the eme rgen cy depa rtme nt. Criti cal patie nts may requi re imm ediat e surg ery, whic h shou ld not be dela yed for confi rmat ory stud y of obvi ous vasc ular injur y. {,

Arter ial injur y may be readi ly appa rent or

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clinic ally occu lt. Up to 21% of proxi mity wou nds sho w arteri al injur y on angi ogra phy. Simil arly, vario us US mod alitie s and abno rmal APIs frequ ently dete ct clinic ally inap pare nt vasc ular injuri es. {,

Sym ptom s of arteri al injur y may be dela yed by hour s to mont hs after

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the initial injur y. Late onse t of sym ptom s sugg ests dela yed thro mbo sis, pseu doan eury sm or AVF form ation , com part ment synd rom e, or inter mitte nt clau dicat ion resul ting from sten osis or relia nce on smal l-cali ber colla teral vess els for arteri al perfu sion. {,

Rep erfus ion

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injur y can occu r after resto ratio n of arteri al flow and resul t in com part ment synd rom e. Freq uent reex amin ation of the repe rfuse d limb is indic ated in the post oper ative perio d. {,

Com part ment synd rom e frequ ently deve lops in limb s with arteri al injur y, and fasci

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otom y is often requi red.

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Marx: Rosen's Emergency Medicine: Concepts and Clinical Practice, 6th ed., Copyright © 2006 Mosby, Inc.

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analysis. J Vasc Surg1993;17:116. 34. Hood DB, Weaver FA, Yellin AE: Changing perspectives in the diagnosis of peripheral vascular trauma. Semin Vasc Surg1998;11:255. 35. Nassoura ZE: A reassessment of Doppler pressure indices in the detection of arterial lesions in proximity penetrating injuries of extremities: A prospective study. Am J Emerg Med1996;14:151. 36. Lynch K, Johansen K: Can Doppler pressure measurement replace exclusion arteriography in the diagnosis of occult extremity arterial trauma?. Ann Surg1991;214:737. 37. Gahtan V, Bramson RT, Norman J: The role of emergent arteriography in penetrating limb trauma. Am Surg1994;60:123. 38. Atteberry LR: Changing patterns of arterial injuries associated with fractures and dislocations. J Am Coll Surg1996;183:377. 39. Bergstein JM: Pitfalls in the use of color-flow duplex ultrasound for screening of suspected arterial injuries in penetrated extremities. J Trauma1992;33:395. 40. Fry WR: The success of Duplex ultrasonographic scanning in diagnosis of extremity vascular proximity trauma. Arch Surg1993;128:1368. 41. Kuzniec S: Diagnosis of limbs and neck arterial trauma using duplex ultrasonography. Cardiovasc Surg 1998;6:358. 42. Bynoe RP: Noninvasive diagnosis of vascular trauma by duplex ultrasonography. J Vasc Surg 1991;14:346. 43. Anderson RJ: Reduced dependency on arteriography for penetrating extremity trauma: Influence of wound location and noninvasive vascular studies. J Trauma1990;30:1059. 44. Knudson MM: The role of duplex ultrasound arterial imaging in patients with penetrating extremity trauma. Arch Surg1993;128:1033. 45. Gagne PJ: Proximity penetrating extremity trauma: The role of ultrasound in the detection of occult venous injuries. J Trauma1995;39:1157. 46. Soto JA: Diagnostic performance of helical CT angiography in trauma to large arteries of the extremities. J Comput Assist Tomogr1999;23:188. 47. Nunez Jr JrD: Helical CT of traumatic arterial injuries. AJR Am J Roentgenol1998;170:1621. 48. Busquets AR: Helical computed tomographic angiography for the diagnosis of traumatic arterial injury of the extremities. J Trauma2004;56:625. 49. James CA: Magnetic resonance angiography in trauma. Clin Neurosci1997;4:137. 50. Yaquinto JJ: Arterial injury from penetrating trauma: Evaluation with single-acquisition fat-suppressed MR imaging. AJR Am J Roentgenol1992;158:631. 50. Geuder JW: The role of arteriography in suspected arterial injuries of the extremities. Am Surg 1985;51:893. 51. Reid JDS: Assessment of proximity of a wound to major vascular structures as an indication for arteriography. Arch Surg1988;123:942. 52. Dennis JW: New perspectives on the management of penetrating trauma in proximity to major limb arteries. J Vasc Surg1990;11:85. 53. Weaver FA: Is arterial proximity a valid indication for arteriography in penetrating extremity trauma? A prospective analysis. Arch Surg1990;125:1256. 54. Gillespie DL: Role of arteriography for blunt or penetrating injuries in proximity to major vascular structures: An evolution in management. Ann Vasc Surg1993;7:145. 55. Rose SC, Moore EE: Trauma angiography: The use of clinical findings to improve patient selection and case preparation. J Trauma1988;28:240. 56. De Virgilio C: Noniatrogenic pediatric vascular trauma: A ten year experience at a level I trauma center. Am Surg1997;63:781. 57. Itani KM: Emergency center arteriography. J Trauma1992;32:302. 58. Itani KM: Emergency center arteriography in the evaluation of suspected peripheral vascular injuries in children. J Pediatr Surg1993;28:677. 59. Shah DM: Polytetrafluoroethylene grafts in the rapid reconstruction of acute contaminated peripheral vascular injuries. Am J Surg1989;148:229. 60. Chen LE: Effects of enoxaparin, standard heparin, and streptokinase on the patency of anastomoses in severely crushed arteries. Microsurgery1995;16:661. 61. Bouachour G: Hyperbaric oxygen therapy in the management of crush injuries: A randomized double-blind placebo-controlled trial. J Trauma1996;41:333. 62. Naidoo NM: Angiographic embolization in arterial trauma. Eur J Vasc Surg2000;19:77. 63. Criado E: Endovascular repair of peripheral aneurysms, pseudoaneurysms and arteriovenous fistulas. Ann Vasc Surg1997;11:256. 64. Rich NM: Complications of vascular injury management. Surg Clin North Am2002;82:143. 65. Kuralay E: A quantitative approach to lower extremity vein repair. J Vasc Surg2002;36:1213. 66. McHenry TP: Fractures with major vascular injuries from gunshot wounds: Implications of surgical sequence. J Trauma2002;53:717.

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67. Tufaro A: Adverse outcome of nonoperative management of intimal injuries caused by penetrating trauma. J Vasc Surg1994;20:656. 68. Frykberg ER: Nonoperative observation of clinically occult arterial injuries: A prospective evaluation. Surgery1991;109:856. 69. Dennis JW: Validation of nonoperative management of occult vascular injuries and accuracy of physical examination alone in penetrating extremity trauma: 5- to 10-year follow-up. J Trauma1998;44:243. 70. Cox CS: Blunt versus penetrating subclavian artery injury: Presentation, injury pattern, and outcome. J Trauma1999;46:445. 71. Demetriades D: Penetrating injuries to the subclavian and axillary vessels. J Am Coll Surg1999;188:290. 72. Gasparri MG: Physical examination plus chest radiography in penetrating periclavicular trauma: The appropriate trigger for angiography. J Trauma2000;49:1029. 73. McKinley AG, Carrim ATO, Robbs JV: Management of proximal axillary and subclavian artery injuries. Br J Surg2000;87:175. 74. Degiannis E: Penetrating injuries of the subclavian vessels. Br J Surg1994;81:5246. 75. Gupta A, Jamshidi M, Rubin JR: Traumatic first rib fracture: Is angiography necessary?. Cardiovasc Surg1997;5:48. 76. Gonzalez RP, Falimirski ME: The role of angiography in periclavicular penetrating trauma. Am Surg 1999;65:711.discussion 714 77. Gates JD: Penetrating wounds of the extremities: Methods of identifying arterial injury. Orthop Rev 1994;10(Suppl):2. 78. Woodman G, Croce MA, Fabian TC: Iliac artery ischemia: Analysis of risks for ischemic complications. Am Surg1998;64:833. 79. Shayne PH: A case-controlled study of risk factors that predict femoral arterial injury in penetrating trauma. Ann Emerg Med1994;24:678. 80. Trieman GS: Examination of the patient with knee dislocation: The case for selective arteriography. Arch Surg1992;127:1056. 81. Wascher DC: High-velocity knee dislocation with vascular injury. Clin Sports Med2000;19:457. 82. Mills WJ, Barei DP, McNair P: The value of ankle-brachial index for diagnosing arterial injury after knee dislocation: A prospective study. J Trauma2004;56:1261. 83. Abou-Sayed H, Berger DL: Blunt lower-extremity trauma and popliteal injuries: Revisiting the case for selective arteriography. Arch Surg2002;137:585. 84. Klineberg EO: The role of arteriography in assessing popliteal artery injury in knee dislocations. J Trauma2004;56:786. 85. Miranda FE: Confirmation of the safety of physical examination in the evaluation of knee dislocation for injury of the popliteal artery: A prospective study. J Trauma2002;52:247. 86. Stannard JP: Vascular injuries in knee dislocations: The role of physical examination in determining the need for arteriography. J Bone Joint Surg Am2004;86:910. 87. Frykberg ER: Popliteal vascular injuries. Surg Clin North Am2002;82:67. 88. Pretre R: Lower limb trauma with injury to the popliteal vessels. J Trauma1996;40:595. 89. Grossman MD: Gunshot wounds below the popliteal fossa: A contemporary review. Am Surg 1999;65:360. 90. Rowe VL: Shank vessel injuries. Surg Clin North Am2002;82:91.

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Marx: Rosen's Emergency Medicine: Concepts and Clinical Practice, 6th ed., Copyright © 2006 Mosby, Inc.

Section III - Orthopedic Lesions Chapter 46 – General Principles of Orthopedic Injuries Joel M. Geiderman

MANAGEMENT PRINCIPLES Patients with orthopedic injuries and nontraumatic musculoskeletal disorders compose a large portion of the more than 100 million patients who present annually to U.S. emergency departments. Although only rarely life-threatening, orthopedic injuries may threaten a limb or its function, and accurate early diagnosis and treatment can avert long-term problems. Many of these injuries can and should be treated definitively by the emergency physician. Consultation with an orthopedist should be sought for the treatment of most long bone fractures, open fractures, and flexor tendon injuries and for follow-up of certain patients initially treated in the emergency department. Orthopedic injuries often occur as a result of accidents (industrial or otherwise) and frequently involve young, otherwise healthy, working individuals. Accurate initial diagnosis, treatment, and documentation assume great importance medically and economically. Many problems can be avoided if the following 10 general principles are kept in mind: 1. Most orthopedic injuries can be predicted by knowing the chief complaint, the age of the patient, the mechanism of injury, and an estimate of the amount of energy delivered. 2. A careful history and physical examination predict x-ray findings with a high degree of accuracy. Many fractures were accurately described before the advent of roentgenology ( Table 46-1 ). Table 46-1 -- Common Fracture Names and Their Origins Fracture Eponym

Description

Aviator's

Vertical fracture of the neck of the First described in flyers during World War I. talus with subtalar dislocation and Arises from forced dorsiflexion of the foot in backward displacement of the body flying accidents and in traffic accidents after a head-on collision Intra-articular fracture-dislocation of Considered complicated and unstable. the wrist Requires surgical reduction in most cases. Described by Barton in 1838 before the advent of radiography Oblique intra-articular fracture of Results from high-velocity impact across the the dorsal rim of the distal radius articular surface of the radiocarpal joint, with with displacement of the carpus the wrist in dorsiflexion at the moment of along with the fracture fragment impact Wedge-shaped articular fragment Similar mechanism as dorsal Barton's but with sheared off of volar surface of the wrist in volar flexion at time of injury. Also radius (volar rim fracture), referred to as a reverse Barton's. Much more displaced volarly along with the rare than dorsal Barton's carpus Oblique fracture through base of Usually produced by direct force applied to the the first metacarpal with dislocation end of the metacarpal. Dorsal capsular

Barton's

Dorsal Barton's

Volar Barton's

Bennett's

Comment

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of the radial portion of the articular surface Fracture of the neck of the fourth or fifth metacarpal

structures disrupted by the dislocation. Marked tenderness along medial base of thumb Boxer's Results from striking a clenched fist into an unyielding object, usually during an altercation, or against a wall, out of frustration or anger Bosworth Fracture-dislocation of the ankle Rare injury, produced by a severe external resulting in the fibula being rotation force applied to the foot. Physical entrapped behind the tibia examination reveals foot severely externally rotated in relation to the tibia Chance's Vertebral fracture, usually lumbar, Caused by simultaneous flexion and involving the posterior spinous distraction forces on the spinal column, usually process, pedicles, and vertebral associated with use of lap seatbelts. Anterior body column fails in tension along with the middle and posterior columns. May be misdiagnosed as a compression fracture Chauffeur's Solitary fracture of radial styloid Occurs from tension forces sustained during ulnar deviation and supination of the wrist. Name derives from occurrence in chauffeurs who suffered violent, direct blows to the radius incurred while turning the crank on a car, only to have it snap back, during previous eras Clay shoveler's Fracture of the tip of the spinous First described in Australian clay shovelers process of the sixth or seventh who sustained a fracture of the spinous cervical vertebra process by traction as they lifted heavy loads of clay Colles' Fracture of the distal radius with Most common wrist fracture in adults, dorsal displacement and volar especially in the elderly. Results from fall on an angulation; with or without an ulnar outstretched hand. Also known as silver fork styloid fracture deformity, which accurately describes the gross appearance in the lateral view. First described by Colles in 1814, before the advent of radiography Cotton's Trimalleolar fracture Fracture of the lateral malleolus, the posterior malleolus, and either a fracture of the medial malleolus or a disruption of the deltoid ligament with visible widening of the mortise on ankle radiograph Dashboard Fracture of the posterior rim of the Named for mechanism of injury: a seated fracture acetabulum passenger striking the knee on a dashboard, driving the head of the femur into the acetabulum Dupuytren's Fracture-dislocation of the ankle Results from a similar mechanism as the better known Maisonneuve fracture (i.e., external rotation of the ankle), resulting in either deltoid ligament rupture or medial malleolus fracture, diastasis of the inferior tibiofibular joint, and indirect fracture of the fibular shaft. Maisonneuve was the student of Dupuytren Essex-Lopresti Fracture of radial head with Results from longitudinal (axial) compression dislocation of distal radioulnar joint of the forearm Galeazzi's Fracture of the shaft of the radius Results from fall on outstretched hand, with with dislocation of the distal the wrist in extension and the forearm forcibly radioulnar joint. Ligaments of pronated. Inherently unstable with tendency to inferior radioulnar joint are ruptured redisplace after reduction and head of ulna displaced from ulnar notch of the radius Hangman's Fracture-dislocation of atlas and Results from extreme hyperextension during

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Hume

Jefferson

axis, specifically of pars interarticularis of C2 and disruption of C2–3 junction. Separation occurs between second and third vertebral bodies from anterior to posterior side Fracture of the proximal ulna associated with forward dislocation of the head of the radius Burst fracture of ring of C1, or atlas

abrupt deceleration. Most common cause is the forehead striking the windshield of a car during a collision. A bit of a misnomer in that hanging usually produces death by strangulation rather than cord damage Essentially a high Monteggia injury

Axial loading results in a shattering of the ring of the atlas. Decompressive type of injury. Associated with disruption of transverse ligament; an unstable injury Should not be confused with the more common avulsion fracture of fifth metatarsal styloid, produced by avulsion at the insertion of the peroneus brevis. Jones described the fracture that bears his name in 1902, after suffering the injury himself, while dancing Types I, II, and III (see Chapter 39 ) Rare pull-off injury of the fibular attachment of the anterior tibiofibular ligament Lisfranc, a field surgeon in Napoleon's army, described an amputation performed through the tarsometatarsal joint in a soldier who caught his foot in a stirrup when he fell off his horse. Since then, the joint has borne his name Results from external rotation of the ankle with transmission of forces through syndesmosis; proximally the force is relieved by fracture of the fibula. Described experimentally in 1840, before radiography Resultant pelvic injury is unstable. Described by Malgaigne, based on clinical findings, in 1847

Jones'

Transverse fracture of the metatarsal base, occurring at least 15 mm distal to the proximal end of the bone, distal to the insertion of the peroneus brevis

Le Fort Le Fort-Wagstaffe Lisfranc's

Maxillary fracture Avulsion fracture of the anterior cortex of the lateral malleolus Fracture located around the tarsometatarsal (Lisfranc's) joint, usually associated with dislocation of this joint

Maisonneuve

Fracture of proximal third of fibula associated with rupture of the deltoid ligament or fracture of the medial malleolus and disruption of the syndesmosis Fracture of the ilium near the sacroiliac joint with displacement of the symphysis; or a dislocation of the sacroiliac joint with fracture of both ipsilateral pubic rami Fatigue, or stress, fracture of the Arises from long marches or other repetitive metatarsal use trauma (e.g., marathon running) or less commonly from single stumbling movements Fracture of the junction of the Usually caused by fall on outstretched hand proximal and middle thirds of the along with forced pronation of forearm or by a ulna associated with anterior direct blow on the posterior aspect of the ulna. dislocation of the radial head Reported by Monteggia in 1814 Fracture of either ulna or radius, or Name derived from a citizen's attempt to both protect himself from a police officer's baton or “nightstick” by offering the forearm Closed fracture of the radius at the Named for a series of cases presented at the middle third/distal third junction, Piedmont Orthopaedic Society of Durham, without associated ulnar fracture North Carolina Definitions vary (see comment); The exact fracture Pott described in 1769 is most commonly a bimalleolar uncertain; clearly it referred to a fracture of the fracture or a fracture of the distal lower fibula, usually associated with other fibula, 4–7 cm above the lateral fractures or dislocations about the ankle malleolus Intra-articular fracture at base of Produced by an axial load with the metacarpal metacarpal. Frequently Y-or in partial flexion. Worse prognosis than a

Malgaigne

March

Monteggia's

Nightstick

Piedmont fracture Pott's

Rolando's

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Salter-Harris

Stener

Smith's

Teardrop

Thurston Holland's fragment Tillaux

T-shaped, or may be severely Bennett's fracture and, fortunately, more rare comminuted An epiphyseal fracture occurring in Graded I-V, depending on degree of children or adolescents involvement and/or displacement of epiphysis and metaphysis (see text dealing with Salter-Harris fractures and also Figure 46-1 ) Avulsion of the ulnar corner of the Bony equivalent of rupture of the ulnar base of the proximal phalanx of the collateral ligament, or “gamekeeper's thumb” thumb Extra-articular fracture of the distal Reverse of the Colles' fracture but much more radius with volar displacement of uncommon. Sometimes referred to as a distal fragment “garden spade” deformity. Usually results from fall with force to back of hand. First described by Smith in 1847 Wedge-shaped fracture of the Commonly involves a ligamentous injury and anteroinferior portion of the may produce neurologic injury vertebral body, displaced anteriorly Triangular metaphyseal fragment Described by Thurston Holland in 1929. that accompanies the epiphysis in Commonly hyphenated, although technically it Salter-Harris type II fractures should not be Isolated avulsion fracture of the Occurs in older adolescents (12–15 years old) anterolateral aspect of the distal after the medial parts of the epiphyseal plates tibial epiphysis close, but before the lateral part closes. External rotation force places stress on anterior talofibular ligament. Described by Tillaux in 1872

3. If a fracture is suspected clinically, but x-ray films appear negative, the patient initially should be managed with immobilization as though a fracture were present. 4. Criteria for adequate radiographic studies exist; inadequate studies should not be accepted. 5. X-ray studies should be performed before attempting most reductions except when a delay would be potentially harmful to the patient or in some field situations. 6. Neurovascular competence should be checked and recorded before and after all reductions. 7. Patients must be checked for the ability to ambulate safely before discharge from the emergency department and should not be discharged unless this can be established. 8. Patients should receive explicit aftercare instructions before leaving the emergency department, covering such areas as monitoring for signs of neurovascular compromise or increasing compartment pressure, cast care, weight bearing, crutch use, and an explicit plan and timing for follow-up. 9. In a patient with multiple trauma, noncritical orthopedic injuries should be diagnosed and treated only after other more threatening injuries have been addressed. 10. All orthopedic injuries should be described precisely and according to established conventions.

FRACTURES Fracture Nomenclature Describing orthopedic injuries using precise language according to established convention permits relevant information to be communicated clearly to other parties. Terms commonly used to describe a fracture are listed in Box 46-1 . A fracture is a break in the continuity of bone or cartilage. Clinically a history of loss of function, pain, tenderness, swelling, abnormal motion, and deformity suggests a fracture. X-ray studies are the mainstay of diagnosis and are usually, although not always, confirmatory. At times, special views, radionucleotide bone scans, computed tomography (CT) scans, or magnetic resonance imaging (MRI) studies are necessary to confirm a clinical suspicion. These studies should be considered when the clinical impression is at odds with the findings of routine radiography.

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BOX 46-1 Fracture Description

Identification Ope n vers us clos ed Exac t anat omic locat ion Dire ction of fract ure line Sim ple/c om minu ted Posit ion (disp lace ment , align ment )

Additional Modifiers Complete versus incomplete Involvement of articular surface (%) Avulsion Impaction Depr essi on Com pres sion

Special Situations

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Path ologi c Stre ss

General Descriptors Description of a fracture should begin by stating whether the fracture is closed or open (less desirable terms are simple or compound). In a closed fracture, the skin and soft tissue overlying the fracture site are intact. The fracture is open if it is exposed to the outside environment in any manner. This exposure may be as obscure as a puncture wound or as gross as splintered bone protruding through the skin. It is sometimes difficult to determine whether a small wound in proximity to a fracture actually communicates with that fracture. Some physicians advocate probing such a wound with a blunt sterile swab to establish a relationship; no study has established the safety, benefit, or accuracy of this maneuver. If doubt exists, an open fracture should be assumed to be present. The next item that should be noted in the description of a fracture is the exact anatomic location, including the name of the bone, left or right, and standard reference points, for example, the humeral neck or posterior tibial tubercle. Long bones can be divided into thirds—proximal, middle, or distal—and these thirds or the junction of any two of them (e.g., the junction of the middle and distal third of the tibia) are used to describe fractures. The most descriptive language possible should be used. It is better to say “closed fracture of the right ulnar styloid” than “closed fracture of the right distal ulna” because the former conveys more precise anatomic information. An additional modifier describes the direction of the fracture line in relation to the long axis of the bone in question. A transverse fracture occurs at a right angle to the long axis of the bone ( Figure 46-1A ), whereas an oblique fracture runs oblique to the long axis of the bone ( Figure 46-1B ). A spiral fracture results from a rotational force and encircles the shaft of a long bone in a spiral fashion ( Figure 46-1C ). A fracture in which there are more than two fragments present is termed comminuted ( Figure 46-1D ).

Figure 46-1 Types of fractures. A, Transverse. B, Oblique. C, Spiral. D, Com m inuted.

The position and alignment of the fracture fragments (i.e., their relationship to one another) should be described. Fragments are described relative to their normal position, and any deviation from normal is termed displacement. By convention, the position of the distal fragment is described relative to the proximal one. In Figure 46-2 , there is a dorsal displacement of the fractured radius, and in Figure 46-3 , there is lateral, or valgus, displacement of the distal tibia and fibula.

Figure 46-2 Dorsal displacem ent of distal radius.

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Figure 46-3 Valgus displacem ent of distal tibia and fibula. The distal segm ent is angled away from the m idline of the body.

The terms valgus and varus are sometimes confusing. Valgus denotes a deformity in which the described part is angled away from the midline of the body. Conversely, varus denotes a deformity in which the angulation of the part is toward the midline. Alignment refers to the relationship of the longitudinal axis of one fragment to another; deviation from the normal alignment is termed angulation. The direction of angulation is determined by the direction of the apex of an angle formed by the two fracture fragments ( Figure 46-4 ). This angle is opposite to the direction of displacement of the distal fragment.

Figure 46-4 Volar angulation of fractured radius.

Descriptive Modifiers A fracture is termed complete if it interrupts both cortices of the bone and incomplete if it involves only one. It should be noted whether a fracture extends into and involves an articular surface. Frequently the percentage of articular surface that is involved is estimated; in some cases, the percentage that is involved dictates the need to perform a surgical reduction. In general, it is important that the articular surface be restored to anatomic integrity. Avulsion fracture refers to a bone fragment that is pulled away from its normal position by either the forceful contraction of a muscle ( Figure 46-5A ) or the resistance of a ligament to a force in the opposite direction ( Figure 46-5B ). Impaction refers to the forceful collapse of one fragment of bone into or onto another. In the proximal humerus, this collapse typically occurs in a telescoping manner, particularly in elderly patients, whose bones are soft and brittle. In the tibial plateau, impaction occurs frequently in the form of a depression ( Figure 46-6A and B ), and in the vertebral bodies, impaction frequently occurs in the form of compression ( Figure 46-6C ).

Figure 46-5 Avulsion fractures.

Figure 46-6 A and B, Tibial plateau fracture. C, Vertebral body com pression fracture.

A fracture that occurs through abnormal bone is termed pathologic. A pathologic fracture should be suspected whenever a fracture occurs from seemingly trivial trauma. Diseases that cause structural weakness predisposing to injury include primary or metastatic malignancies, cysts, enchondromata, and giant cell tumors. In addition, osteomalacia, osteogenesis imperfecta, scurvy, rickets, and Paget's disease all weaken bones, making them susceptible to fracture. The term pathologic also is applied to fractures through osteoporotic bone when the demineralization is a result of disease, as in polio. Fractures through osteoporotic bone of the elderly usually are not described as pathologic. When fractures occur in normal bones and a history of “trivial trauma” is elicited, violence or battering should be suspected. Repeated

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low-intensity trauma may lead to resorption of normal bone, resulting in a stress fracture. Other names for this condition are fatigue fracture and march fracture (see Table 46-1 ). Most stress fractures occur in the lower extremities and commonly affect individuals involved in activities such as running, basketball, aerobics, and dancing. The tibia, fibula, metatarsals, navicular, cuneiform, calcaneus, femoral neck, or femoral shaft may be involved.[]

Fracture Eponyms Many fractures were described before the advent of radiography and are described by an eponym rather than the exact bony injury. These eponyms reflect the rich history of orthopedic care and, despite the objections of some, are still commonly used to describe orthopedic injuries (see Table 46-1 ).

Fractures in Children Certain features of children's bones distinguish pediatric fractures from adult fractures. Bones of children are necessarily soft and resilient and sustain numerous incomplete fractures. Greenstick fractures are incomplete angulated fractures of long bones. The resultant bowing of the bone causes an appearance resembling a moist, immature branch that breaks in a similar fashion when bent ( Figure 46-7A ). A torus fracture is another form of incomplete fracture, characterized by a wrinkling or buckling of the cortex. In Greek architecture, a torus is a bump at the base of a column, and these fractures, occurring at the end of long bones, take on such an appearance. These fractures may be extremely subtle on radiographs ( Figure 46-7B ).

Figure 46-7 A, Greenstick fracture of m idshaft of fem ur. B, Torus fracture of distal third of radius.

Another feature of growing long bones that is a frequent source of trouble and confusion is the presence of epiphyses, cartilaginous centers at or near the ends of bone that give rise to growth of the bone. Figure 46-8 is a schematic review of the anatomy of a growing bone. Because cartilage is radiolucent, the cartilaginous portion of an epiphysis is not visualized on radiographs. A tendency exists to consider only the ossified nucleus and to ignore the cartilaginous structure that bridges to the metaphysis. Cartilage is present even before an ossified nucleus is seen. Because the epiphyseal growth plate is represented by a radiolucent line, confusion may exist as to whether a fracture line is present. These complexities in interpreting radiographs in children sometimes, but not always, require comparison x-ray views of the noninjured side. Injuries to the epiphyses may result from either compressive or shearing forces. These injuries are relatively common during childhood as opposed to sprains or shaft fractures and must be considered in children with a “sprained ankle” because of the relative weakness of the cartilaginous growth zone, which separates before stronger ligaments and bones are torn or broken. Epiphyseal injuries should be described according to the Salter-Harris classification ( Table 46-2 ).

Figure 46-8 Anatom y of growing bone.

Table 46-2 -- Salter-Harris Classification

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Desc Diagram riptio n Type Fract I ure exten ds throu gh the epiph yseal plate, result ing in displ acem ent of the epiph ysis (this may appe ar merel y as wide ning of the radiol ucent area repre senti ng the growt h plate)

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Desc Diagram riptio n Type As II abov e; in additi on, a triang ular segm ent of meta physi s is fractu red

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Desc Diagram riptio n Type Fract III ure line runs from the joint surfa ce throu gh epiph yseal plate and epiph ysis

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Desc Diagram riptio n Type Fract IV ure line occur s as in type III, but also pass es throu gh adjac ent meta physi s

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Desc Diagram riptio n Type This V is a crush injury of the epiph ysis; it may be diffic ult to deter mine by x-ray exam inatio n

Type I injuries involve only a slip of the zone of provisional calcification. Comparison radiographs are usually necessary to detect small slips. A child with swelling and tenderness over an epiphysis (e.g., of the lateral ankle) and a negative x-ray should be suspected to have an epiphysis injury, rather than a sprain, because the epiphysis is weaker than the overlying ligaments. Type II injuries are similar to type I injuries, with a fracture extending into the metaphysis. The triangular metaphyseal fragment sometimes is referred to as the Thurston Holland sign (see Table 46-1 ). Type II injuries account for approximately three fourths of all epiphyseal fractures. Because the germinal layer is not involved, growth disturbance usually does not occur with type I and II injuries. Type III injuries are composed of a slip of the growth plate plus a fracture through the epiphysis, involving the articular surface. Because this fracture involves the germinal layer, growth may be disrupted. Anatomic reduction does not eliminate the possibility of growth disturbance. Type IV fractures are similar to type III fractures, with the additional involvement of a metaphyseal fracture. Anatomic reduction is essential and usually requires surgery. Growth disturbance occurs in a high proportion of patients. Type V fractures are crush injuries of the epiphyseal plate, usually produced by a compressive force.[3] This type of injury usually occurs in joints that move in one plane, most commonly the knee and ankle. Because this injury occurs in a radiolucent area, the injury may be difficult to diagnose on x-ray, but it should be suspected by mechanism of injury and pain over the epiphysis. The diagnosis can be established by MRI if hemorrhage or a hematoma is identified within the growth plate immediately after injury.[4] Also reported is loss of MRI signal from the cartilage.[5] Growth arrest, manifest by shortening or angulation, is the rule in this injury. Type V injuries are extremely rare.[6]

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In a study of 410 fractures in children, 16.3% were torus fractures, and 13.9% were epiphyseal injuries.[6] Dislocations and subluxations were rare (3%), and most involved the radial head or the patella. There were no shoulder dislocations. The most common sites were the bones of the distal forearm and the hands (usually the phalanges), each group accounting for 20% of the total. The clavicle was involved 13% of the time; the elbow, 8%; the ankle, foot, and femur, 7% each; and the midforearm, lower leg, and humerus, 4% to 6% each. Another study found an incidence of physeal injury of 18% in 2000 bony injuries in children.[7] The peak age at the time of injury was 12 years in boys and 11 years in girls. In this series, the incidence of injury by category was type I, 8.5%; type II, 73%; type III, 6.5%; type IV, 12%; and type V, 0.5%. The sole Salter-Harris type V injury in this series occurred in the proximal tibia. The most frequent sites of Salter-Harris type III fractures are the phalanges and distal tibia, and most type IV fractures occur in the distal humerus and distal tibia. The overall frequency of growth arrest in all injuries is 1.4%, whereas the frequency of serious complications is less than 0.6%. The prognosis depends more on the location of the fracture than the Salter-Harris classification. The proximal tibia is the most common site for growth disturbance. Because the epiphysis is closer to fusing, the chances of growth disturbance are less; this influences decision making in terms of surgical versus conservative management.

Diagnostic Modalities for Fracture Diagnosis Plain Radiography Plain radiography is the mainstay in diagnosing fractures. In addition to confirming or excluding fractures, other pathologic conditions can be identified. With penetrating trauma, foreign bodies, air, and gas also may be detected. With minor trauma, and when good follow-up monitoring is ensured, it is acceptable to delay x-ray films. Delay cannot be permitted, however, when the suspected injury is one that might be made worse by delayed diagnosis, such as a nondisplaced hip fracture. At least two views perpendicular to each other are mandatory in examining long bones, and an oblique view also is usually obtained. In certain locations, such as the phalanges, oblique views are necessary. If doubt still exists, the clinician should ask for more views in various degrees of obliquity to the other films. A fracture line is most visible when it is parallel to the x-ray beam and is invisible when it is exactly 90 degrees to the beam. The clinician should never accept a study that examines the bone in only one plane. When a long bone is found to be fractured, it is imperative that the bone be viewed radiographically in its entire length. Each film must be examined to ensure that proper technique is used and that no important area is omitted from the film. Overexposed films may fail to reveal an abnormality. Although there is some loss of fine detail on portable films, these are acceptable in unstable patients, in whom the risk of moving the patient does not outweigh the benefit of the more detailed study. Computed (digital) radiography is now in widespread use. An advantage of this technique is the ability to alter the image-processing parameters based on a specific clinical problem after an exposure has been made.[7] Disadvantages are that the spatial resolution of computed radiographs, and especially of computer monitor formats, is less than that of standard screen-film combinations and that minification is often necessary when larger body parts, such as the thoracic spine, lumbar spine, and pelvis, are being examined. Minification also may contribute to reduced accuracy in the diagnosis of subtle, high-frequency chest abnormalities, such as pneumothorax. Despite these considerations, computed radiography seems to be acceptable and does not seem to diminish reader performance significantly.[8] Even with good technique, some fractures are not visible initially and do not appear until the margins of the fracture absorb. Absorption widens the radiolucent line, and a defect appears in 7 to 10 days. At that time, new bone produced beneath the periosteum at the margins of the fracture accentuates the fracture. Accordingly, if a fracture is suspected but not visible at the initial visit, the injury should be treated as a fracture and re-examined clinically and radiographically in 7 to 10 days, and the patient should be informed of the rationale for this regimen. Stress views of joints are used in some instances to evaluate the degree of ligamentous injury. Some authors argue against the use of stress views, citing a risk of injuring further an already traumatized structure, additional radiation exposure to the patient and the technologist, and the possibility that pain may not allow sufficient stress to be applied. For these reasons, stress views should be used judiciously in circumstances when other methods of evaluating ligamentous injuries are not available. Comparison views are useful in selected situations, but should not routinely be performed in all pediatric examinations.[9] If a fracture is definitely present on the affected side, the comparison view exposes the child to radiation and adds expense with no benefit. Similarly, an experienced physician generally is able to read a normal film with

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reasonable certainty. It is rational to use comparison views in instances when radiographs are inconclusive and when the confusion arises specifically out of the need to distinguish between a possible fracture and normal developmental anatomy. Obtaining a wide field of the affected extremity is more useful than routine comparison views for a young child because the child often does not localize the pain well; this is especially true with regard to complaints of knee pain in cases of hip injury or wrist complaints in forearm and elbow injury. Comparison views sometimes are helpful in adults when a question of accessory ossicles or nonfused bones (e.g., bipartite patella) exists because these anomalies are usually bilateral. The bleeding that inevitably accompanies fractures may produce soft tissue swelling and may impinge on or obliterate overlying muscle planes. Fat pads, such as in the elbow, may be displaced. Another useful sign is the fat-fluid level, which may accompany fractures extending into the knee joint. The fat-fluid level is visible, however, only if the cross-table technique is used. The bones themselves should be examined systematically. Normal adult bones possess a smooth unbroken contour. A distinct angle is highly suggestive of a fracture. In an adult, the typical fracture is represented by a lucent line that interrupts the smooth contour and usually extends to the opposite side. Nutrient arteries may be confused with fractures, but have different radiographic characteristics: They are fine, sharply marginated, extend obliquely through the cortex, and are less radiolucent than fractures. Pseudofractures can be created by soft tissue folds, bandages or other overlying material, or a radiographic artifact called the Mach effect. If lucencies extend beyond the bones, the line is highly unlikely to represent a fracture. Anomalous bones and calcified soft tissue likewise may be mistaken for fractures. Avulsions and small fracture fragments have an irregular, uncorticated surface, and a defect in the adjacent bone is present, whereas anomalous ossification centers (accessory ossicles) and sesamoids are characterized by smooth cortical margins. Reference texts are useful in identifying and confirming these anomalies because they tend to occur in predictable locations.[10] Compression fractures are represented by increased density rather than a lucency. Finally, “the most commonly missed fracture is the second fracture.” One must be diligent in searching for a second fracture after discovering the first fracture on a study. In particular, certain paired fractures, such as the distal tibia and proximal fibula, should be sought out.

Special Imaging Techniques Radionucleotide Bone Scanning In the past, radionucleotide bone scanning was used to detect skeletal abnormalities not radiographically evident in children and adults.[11] Occult lesions, especially stress fractures, acute osteomyelitis, and tumors, can be detected on these scans, although there are problems with specificity and sensitivity. This modality has been largely supplanted by CT and MRI and now is seldom used.

Computed Tomography CT is used to confirm suspicious fractures or to define better displacement, alignment, or fragmentation of fractures. It also is useful in trauma to rule out cervical spine fracture when plain films are equivocal and in noncompressive vertebral fractures to assess the number of fragments and their spatial relationship to the spinal canal. A CT scan is used frequently to define the integrity of articular surfaces in the acetabulum, knee, wrist, or ankle and in Salter-Harris type IV fractures.[3]

Magnetic Resonance Imaging MRI constitutes the most advanced noninvasive examination of orthopedic structures, delineating lesions of bone, cartilage, ligaments, and other structures, such as menisci, disks, and epiphyseal structures. MRI is expensive and time-consuming and should be reserved for instances when the diagnosis is in doubt and specific findings would alter the treatment.

Complications of Fractures Infection (Osteomyelitis) Open fractures are treated as true orthopedic emergencies because of the risk of infection; the dreadful nature of the complication of osteomyelitis dictates that no time should be wasted in initiating therapy ( Box 46-2 ). Wounds should be covered with sterile dressings, and parenteral antibiotics should be instituted as early as possible. Currently, suggested therapy includes a first-generation cephalosporin, such as cefazolin, for all open fractures, with the addition of an aminoglycoside for types II and III fractures.[] Although the traditional recommendation has been to obtain culture and sensitivity before starting antibiotics, the usefulness of this approach has not been supported by a controlled study.[14] A retrospective analysis of perioperative cultures in open fractures in children failed to show any value in predicting the identity of subsequent infecting pathogens.[15] It is prudent to omit such cultures.[16] BOX 46-2

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Classification and Emergency Management of Open Fractures

Grades Grade I: Wound 20 mm of initial shortening) also may benefit from early orthopedic referral because these have been associated with a higher incidence of nonunion.[21] Greenstick fractures of the midclavicle are common in children ( Figure 50-13 ). Most of these fractures are nondisplaced and heal uneventfully. Initial radiographs may appear normal despite suggestive clinical findings. In these instances, the arm should be immobilized in a simple sling and the radiographs repeated in 7 to 10 days if symptoms persist.

Figure 50-13 Greenstick fracture of the clavicle (arrow).

Most fractures of the clavicle heal uneventfully and can be followed by a primary care physician. A sling should be worn until repeat radiographs show callus formation and healing across the fracture site. Passive shoulder range-of-motion exercises ( Figure 50-14 ) are encouraged to reduce the risk of adhesive capsulitis. Younger children generally require shorter periods of immobilization (2 to 4 weeks) than adolescents and adults (4 to 8 weeks). Vigorous competitive play should be avoided until the bone healing is solid.

Figure 50-14 Pendular shoulder exercises.

Complications Complications are unusual, with the most common ones being delayed union or nonunion.[] Complications after fractures of the medial third resemble complications associated with posterior sternoclavicular dislocations. Fractures of the middle third have been associated with injuries to the neurovascular bundle and the pleural dome. Articular surface injuries (type III lateral clavicle fractures) can lead to subsequent

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osteoarthritis of the ACJ.

Scapula Pathophysiology Fractures of the scapula are rare injuries, with an annual incidence of 10 to 12 per 100,000 population.[] They account for 1% of all fractures and occur primarily in men 30 to 40 years old.[9] A thick muscle coat and the ability to recoil along the chest wall protect the scapula from direct and indirect trauma. In general, considerable force and energy are required to fracture the scapula. Most fractures result from high-speed vehicular accidents, falls from heights, or crush injuries.[24] Coracoid process fractures are usually avulsive, and glenoid rim fractures are commonly associated with anterior glenohumeral dislocations. An acromial process fracture usually results from a direct blow applied to the top of the shoulder. The most important aspect of scapular fractures is the high incidence (75% to 98%) of associated injuries to the ipsilateral lung, chest wall, and shoulder girdle complex.[] The most common associated orthopedic injuries are fractures of the ribs, proximal humerus, and clavicle. Associated lung injuries include pneumothorax, hemothorax, and pulmonary contusion; these may be seen in a delayed fashion, 2 to 3 days after the initial injury. Associated injuries of the head, spinal cord, brachial plexus, and subclavian or axillary vessels are more significant but less common.[] Fractures of the scapula can be classified according to their anatomic location. In the system proposed by Ada and Miller,[25] type I fractures involve the acromion process, scapular spine, or coracoid process. Type II fractures involve the scapular neck, and type III injuries are intra-articular fractures of the glenoid fossa ( Figure 50-15 ). The most common are type IV fractures, which involve the body of the scapula.[25]

Figure 50-15 Com m inuted type III fracture of the scapular. ((Courtesy of David Nelson, MD.))

Clinical Features In a conscious patient, the shoulder is adducted, and the arm is held close to the body. Any attempts at movement result in significant pain. There may be associated tenderness, crepitus, or hematoma over the fracture site. The clinical findings occasionally mimic those seen with a rotator cuff tear. Hemorrhage into the rotator cuff associated with the scapula fracture can result in spasm and a temporary reflex inhibition of function (pseudorupture).[25] The presence of a scapula fracture mandates a thorough search for associated thoracic, intracranial, orthopedic, and neurovascular injuries.

Diagnostic Strategies The trauma series of shoulder radiographs identifies most fractures, as does careful examination of the scapula on the trauma chest radiograph. The axillary lateral view is especially useful in evaluating fractures of the glenoid fossa and the acromion or coracoid processes.[9] The os acromiale (unfused acromial process epiphysis) is present in 3% of the population and should not be confused with a fracture of the acromion.[7] A comparison film can be useful because the abnormality is present bilaterally in 60% of cases. In many patients, fractures of the scapula initially are overlooked because of the life-threatening nature of the associated injuries.[9]

Management Most fractures, including fractures with severe comminution and displacement, heal rapidly with conservative therapy.[] Initial therapy consists of analgesia and immobilization in a sling to support the ipsilateral upper extremity. Passive shoulder exercises (see Figure 50-14 ) are initiated as soon as discomfort subsides to reduce the risk of adhesive capsulitis. In general, patients require a sling for 2 to 4 weeks.[24]

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Fractures of the body and spine usually require no further therapy. Nondisplaced fractures of the acromion process also respond well to conservative therapy. Displaced acromial fractures that impinge on the glenohumeral joint require surgical management. Rarely the acromion is fractured as part of a superior dislocation of the humeral head. In these instances, an accompanying tear of the rotator cuff is invariably present and requires surgical repair. If the coracoclavicular ligaments remain intact, fractures of the coracoid process respond well to conservative therapy. Severely displaced coracoid fractures with ruptured coracoclavicular ligaments usually require open reduction and internal fixation.[6] Scapular neck and glenoid fossa fractures present the most difficult management issues. Although most of these injuries do well with conservative therapy, open reduction and internal fixation are recommended for severely displaced or angulated fractures.[]

Complications Associated injuries of the ipsilateral lung, chest wall, and shoulder girdle account for most complications after fractures of the scapula. A shear-type brachial plexus injury has been associated with fractures of the acromion process. Neurovascular (brachial plexus, axillary artery) injuries also have been reported with fractures of the coracoid process.[6] Scapular neck, body, or spine fractures that extend into the suprascapular notch can injure the suprascapular nerve.[6] Delayed complications include adhesive capsulitis and rotator cuff dysfunction.[24]

Proximal Humerus Pathophysiology Fractures of the proximal humerus are common and account for 4% of all fractures.[27] A prospective Swedish study reported an incidence of 114 per 100,000 with a mean age of 67 years and a female-to-male ratio of 3:1.[28] These fractures occur primarily in the older population, in whom structural changes associated with aging (osteoporosis) weaken the proximal humerus, predisposing it to injury. Although most of these injuries are minimally displaced and do well with conservative therapy, significantly displaced fractures may require operative intervention. Fractures of the proximal humerus separate along old epiphyseal lines, producing four distinct segments consisting of the articular surface (anatomic neck), greater tuberosity, lesser tuberosity, and humeral shaft (surgical neck). The Neer classification system ( Figure 50-16 ) is based on the relationship of these fracture fragments.[] In this system, a segment is considered displaced if it is angled greater than 45 degrees or separated more than 1cm from the neighboring segment. Because this classification system considers only displacement, the number of fracture lines is irrelevant. There are four major categories of fracture: minimal displacement ( Figure 50-17 ), two-part displacement ( Figure 50-18 ), three-part displacement, and four-part displacement. When present, anterior and posterior dislocations are included as part of the classification. Impaction and head-splitting fractures are classified separately.

Figure 50-16 Neer's classification of proxim al hum eral fractures. ((From Neer CS: Displaced proxim al hum eral fractures: Part 1. Classification and evaluation. J Bone Joint Surg Am 52:1077, 1979.))

Figure 50-17 Three-part m inim ally displaced fracture of the proxim al hum erus.

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Figure 50-18 Anteroposterior (A) and axillary (B) views of a two-part displaced fracture of the proximal hum erus. The degree of displacem ent often is visualized better on the axillary view. ((Courtesy of David Nelson, MD.))

The classic mechanism of injury involves a fall on an outstretched abducted arm. Concurrent pronation limits further abduction and levers the humerus against the acromial process; this produces a fracture or dislocation, depending on the tensile strengths of the bone and surrounding ligaments. Older patients are prone to fracture, whereas younger individuals are apt to dislocate. The combined injury (fracture and dislocation) may be seen in middle-aged individuals. Proximal humerus fractures also may result from a direct blow to the lateral side of the arm or from an axial load transmitted through the elbow. High-energy mechanisms and polytrauma are more common in younger individuals.

Clinical Features The affected arm is held close to the body, and all movements are restricted by pain. Tenderness, hematoma, ecchymosis, deformity, or crepitus may be present over the fracture site. Although usually normal, a thorough neurovascular examination helps identify associated injuries of the axillary nerve, brachial plexus, or axillary artery.

Management Minimally displaced fractures (see Figure 50-17 ) constitute 80% to 85% of all cases. No displacement or angulation is present, and the fracture segments are held together by the capsule, periosteum, and surrounding muscles. Initial treatment consists of adequate analgesia and immobilization with a sling and swathe device. As soon as clinical union is achieved (head and shaft move together), functional exercises are initiated. Initial passive exercises (see Figure 50-14 ) are slowly replaced by more active and resistive exercises. Most nondisplaced fractures heal over 4 to 6 weeks. The treatment of two-part, three-part, and four-part displaced fractures is beyond the scope of this discussion. An orthopedic surgeon should be consulted because many of these injuries require operative repair.[30] Fracture-dislocation injuries also may require an orthopedic surgeon. Care must be used because reductions of these injuries in the emergency department are often unsuccessful and can cause separation of previously undisplaced segments. Closed reduction under x-ray control and general anesthesia may be preferable.[31] Posterior glenohumeral dislocations usually are associated with anteromedial impression fractures of the articular surface. A similar fracture of the posterolateral aspect of the humeral head is present with anterior dislocations (Hill-Sachs deformity). Impression fractures involving less than 20% of the articular surface are usually stable. With more than 20% involvement, the reduction is usually unstable and requires surgical repair.

Complications The most common complication of proximal humeral fractures is adhesive capsulitis (“frozen or stiff shoulder”). This complication can be prevented by the early initiation of a thorough rehabilitation program. Two-part fractures of the articular surface and four-part fractures have a high incidence of avascular necrosis of the humeral head. Repeated forceful attempts at reduction of fracture-dislocations may be associated with subsequent heterotopic bone formation (myositis ossificans). Neurovascular injuries (axillary nerve, brachial plexus, and axillary artery) may be encountered with displaced surgical neck fractures and fracture-dislocations.

Proximal Humeral Epiphysis Pathophysiology Fractures of the proximal humeral epiphysis are uncommon and account for 10% of all shoulder fractures in children.[32] The injury can occur at any age while the epiphysis remains open but is most common in boys

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11 to 17 years old.[33] The most common mechanism of injury involves a fall onto the outstretched hand, and the fracture typically occurs through the zone of hypertrophy in the epiphyseal plate. Injuries can be classified according to their location (Salter system), stability, and degree of displacement.[6]

Clinical Features The patient has the injured arm held tightly against the body by the opposite hand. The area over the proximal humerus is swollen and extremely tender to palpation. Radiographs obtained at 90 degrees to each other confirm the diagnosis. Comparison views may be helpful with minimally displaced fractures.[33]

Management Fractures of the proximal humeral epiphysis should not be taken lightly because the potential for growth disturbance exists even under the most ideal conditions. The active healing process at the site of an epiphyseal injury makes delayed reduction extremely difficult. Early orthopedic consultation should be obtained for all such injuries. Children younger than 6 years old usually have Salter I epiphyseal injuries ( Figure 50-19 ) and can be treated conservatively with sling and swathe immobilization and analgesic agents. Children older than age 6 usually have a Salter II epiphyseal injury. Salter II injuries with greater than 20 degrees of angulation should be reduced.[34] Closed reduction is accomplished by reversing the mechanism of injury. Imperfect reductions are often acceptable because growth and remodeling correct the deformity with time. After reduction, unstable injuries should be immobilized in a shoulder spica cast, whereas stable lesions can be immobilized with a sling and swathe. Fractures of the proximal humeral epiphyses generally heal in 3 to 5 weeks.[34]

Figure 50-19 A Salter I injury of the right proximal hum eral epiphysis. B Norm al left side is included for com parison.

Complications Complications are rare and include malunion, growth plate disturbances, and injuries to the neurovascular bundle. Markedly displaced or angulated fractures are more likely to result in a residual loss of mobility.[32]

Dislocations Sternoclavicular Pathophysiology The SCJ is the least commonly dislocated major joint in the body. Significant forces are required to disrupt the strong ligamentous stabilizers of this joint. The most common causes are motor vehicle accidents and injuries sustained in contact sports, such as rugby or football. The SCJ can dislocate in an anterior or posterior direction. Anterior dislocations, which result from indirect forces, are more common (9:1 ratio).[5] The usual mechanism of injury ( Figure 50-20 ) involves an anterolateral force to the shoulder, followed by backward rolling, which levers the medial clavicle out of its articulation. Posterior dislocations ( Figure 50-21 ) can result from a direct blow to the medial clavicle (30%) or from a posterolateral force to the shoulder followed by inward rolling (70%). Posterior dislocations can be associated with life-threatening injuries within the superior mediastinum. Injuries to the SCJ can be graded into three types.[5] A grade I injury is a mild sprain secondary to stretching of the sternoclavicular and costoclavicular ligaments. A grade II injury is associated with subluxation of the joint (anterior or posterior) secondary to rupture of the sternoclavicular ligament. The costoclavicular ligament remains intact. Complete rupture of the sternoclavicular and costoclavicular ligaments results in a grade III injury (dislocation). In patients younger than age 25, these actually represent Salter Type I injuries because the medial epiphysis of the clavicle has not yet fused.[35]

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Figure 50-20 Mechanism s that produce anterior and posterior displacem ents of the sternoclavicular joint. A When the patient is lying on the ground and a com pression force is applied to the posterolateral aspect of the shoulder, the medial end of the clavicle is displaced posteriorly. B When the lateral compression force is directed from the anterior position, the medial end of the clavicle is dislocated anteriorly. The same m echanism could apply with any type of lateral compression injury of the shoulder. ((From Neer CS, Rockwood CA: Fracture and dislocations of the shoulder. In Rockwood CA, Green DP [eds]: Fractures in Adults, 4th ed. Philadelphia, JB Lippincott, 1984.)JB Lippincott)

Figure 50-21 CT scan shows posterior dislocation of the right sternoclavicular (arrow) joint with com pression of the superior m ediastinum . ((Courtesy of Donald Sauser, MD.))

Clinical Features Clinical suspicion is the most important factor in diagnosing these injuries, and prompt diagnosis is vital because it is associated with a better prognosis. Patients have the injured extremity foreshortened and supported across the trunk by the opposite arm. There is pain with any movement of the upper extremity or lateral compression of the shoulders. The SCJ is mildly swollen and tender to palpation. With an anterior dislocation, the displaced medial end of the clavicle may be palpable. Posterior dislocations are associated with more severe pain, and the neck is often flexed toward the injured side.[5] The clavicular notch of the sternum may be palpable, and there may be complaints of hoarseness, dysphagia, dyspnea, and weakness or paresthesias in the upper extremities. Rarely, airway complications can occur. These patients should be examined thoroughly to identify any injuries to superior mediastinal or intrathoracic structures. When necessary, appropriate consultation should be obtained immediately.

Diagnostic Strategies: Radiology Although the diagnosis of sternoclavicular dislocations can be made clinically, it should be confirmed radiologically. Standard anteroposterior, oblique, and specialized (40-degree cephalic tilt) views are often difficult to interpret because of overlapping rib, sternum, and vertebral shadows. CT is best to visualize these dislocations and associated injuries (see Figure 50-21 ) or MRI.[15] Ultrasound also may be a useful adjunct in some circumstances.[5]

Management Treatment of grade I injuries includes immobilization (simple sling), adequate analgesia, and primary care follow-up. Immobilization generally is maintained (1 to 2 weeks) until full painless motion is restored. Grade II injuries should be immobilized with a sling or soft clavicular (figure-of-eight) splint and referred for orthopedic follow-up. The figure-of-eight splint is preferred because it maintains the clavicle in a more anatomic position. Grade II injuries require a longer course of immobilization (3 to 6 weeks) and are more likely to be associated with persistent pain.[] All grade III injuries should be managed by closed reduction. Anterior dislocations may be reduced in the emergency department after orthopedic consultation and intravenous analgesia ( Figure 50-22 ). A rolled sheet is placed posteriorly between the shoulder blades to elevate both shoulders approximately 5 cm above the table. Traction is applied to the arm in an extended (10- to 15-degree) and abducted (90-degree) position. If reduction does not occur, an assistant can add inward pressure on the medial end of the clavicle. Stable reductions should be maintained in a clavicular splint and referred for orthopedic follow-up.[] Most reductions are unstable. Because the deformity is primarily cosmetic and not functional, the current treatment of choice for recurrent anterior dislocations is benign neglect.

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Figure 50-22 Reduction of dislocated sternoclavicular joints. ((From Sim on RR, Koenigsknecht SJ: Em ergency Orthopedics: The Extrem ities, 2nd ed. Norwalk, Conn, Appleton & Lange, 1987.)Appleton & Lange)

Posterior dislocations are true orthopedic emergencies and should be reduced expeditiously.[5] Ideally, reduction of posterior dislocations should be attempted in the operating room under general anesthesia, although it can be attempted in the emergency department under conscious sedation. Emergency reduction may be required for patients with airway obstruction or vascular compromise. The patient is positioned as described previously, and traction is applied in an extended and abducted position. If traction alone does not reduce the dislocation, concurrent clavicular manipulation may be helpful. The skin is sterilely prepared, and the clavicle shaft is grasped with a sterile towel clip and pulled out anterolaterally. When reduced, these injuries are generally stable and can be immobilized with a clavicular splint. Buckerfield and Castle[36] described an alternate method of reduction for posterior dislocations. In this technique, traction is applied to the adducted arm while both shoulders simultaneously are forced posteriorly using direct pressure. This technique levers the clavicle into place and requires much less force than the traditional abduction-extension method.

Complications Complications of anterior injuries are primarily cosmetic. Twenty-five percent of posterior dislocations may be complicated by life-threatening injuries to intrathoracic and superior mediastinal structures. A potential long-term complication of both is degenerative osteoarthritis.

Acromioclavicular Joint Pathophysiology Injuries of the ACJ occur primarily in men and account for 25% of all dislocations about the shoulder girdle.[28 ] The annual incidence is 15 per 100,000, and most injuries result from participation in contact sports, such as football, rugby, ice hockey, and wrestling.[28] A small percentage of injuries are caused by motor vehicle accidents and falls. The most common mechanism of injury involves a fall or direct blow to the point of the shoulder with the arm adducted. The resultant force drives the scapula downward and medially to produce the injury. The weak acromioclavicular ligaments rupture first. With increasing force, the coracoclavicular ligament ruptures, and the attachments of the deltoid and trapezius muscles are torn from the distal clavicle. The ACJ also can be injured after a fall onto the outstretched hand. In this instance, the force is transmitted to the acromioclavicular ligaments only, and the coracoclavicular ligament, which is relaxed, remains uninjured.[37] The three-part Tossy and Allman classification system is based on the degree of damage sustained by the acromioclavicular and coracoclavicular ligaments ( Figure 50-23 ).[8] Type I injuries are sprains of the acromioclavicular ligaments. Type II injuries are associated with disruption of the acromioclavicular ligaments. The joint space is widened, and the clavicle displaces slightly upward. There are minor tears in the attachments of the deltoid and trapezius muscles, but the coracoclavicular ligament remains intact, and the coracoclavicular distance is maintained. A type III injury is characterized by complete disruption of the acromioclavicular ligaments, coracoclavicular ligament, and muscle attachments. The joint space is widened, and the coracoclavicular distance is increased. The clavicle is displaced upward by the pull of the trapezius, and the shoulder is displaced downward by the effect of gravity. Rockwood modified this three-part classification system by describing three additional types (IV, V, and VI) of ACJ injuries.[35] In type IV and V injuries, the ligamentous and muscle disruptions are similar to the disruptions encountered in type III injuries, but the clavicle displaces either posteriorly into the trapezius (type IV) or superiorly in an exaggerated fashion (type V). In the rare type VI injury, the clavicle displaces inferiorly.

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Figure 50-23 Mechanism of injury and classification of acromioclavicular joint injuries. A The direct force is applied to the point of the shoulder (1); the scapula and attached clavicle are forced downward and m edially; the clavicle approaches the first rib (2). If the force continues, the first rib abuts the clavicle, producing a counterforce (3). Depending on the magnitude of the force, a grade I, II, or III sprain m ay occur. B Grade I sprain. A few fibers of the acromioclavicular ligam ent stretch, and a few tear (1); the acrom ioclavicular joint is stable (2); the coracoclavicular ligam ent is intact (3). C Grade II sprain (subluxation). The capsule and the acrom ioclavicular ligam ent rupture (1); the joint is lax and unstable (2); the end of the clavicle rides upward, usually less than half of the width of the end of the clavicle (3); the coracoclavicular ligam ent rem ains intact (4); the attachm ents to the trapezius and deltoid rem ain intact. D Grade III sprain (dislocation). The capsule and acromioclavicular ligam ents rupture (1); the coracoclavicular ligam ent ruptures (2); the insertions of the trapezius and deltoid tear away (3); the clavicle rides upward (4); the interval between the clavicle and the coracoid process is greatly increased (5). ((From DePalm a AF: Surgery of the Shoulder, 3rd ed. Philadelphia, JB Lippincott, 1983.)JB Lippincott)

Clinical Features Patients should be examined while they are in the sitting or standing position because the supine position can mask ACJ instability. Type I injuries are associated with mild tenderness and swelling over the ACJ margin. No deformity occurs, and a full range of motion is usually possible, although painful. Type II injuries produce moderate pain, and the distal end of the clavicle may lie slightly superior or posterior to the acromion. Patients with type III, IV, V, and VI injuries usually have severe pain and hold the arm tightly adducted to reduce traction stress across the joint. In type III injuries, the shoulder hangs downward, and the clavicle rides high, producing a visible clinical deformity. In type IV injuries, the clavicle may be palpable posteriorly, and in type V injuries, the clavicle may be palpable subcutaneously above the acromion. In type VI injuries, the shoulder assumes a flattened clinical appearance.

Diagnostic Strategies: Radiology The energy settings used for the radiographic trauma series overpenetrate the ACJ. Specific ACJ views that use one third to two thirds less intensity should be ordered. The recommended projections include an anteroposterior view of both joints on a single wide film, an axillary lateral view, and a 15-degree cephalic tilt view.[] The axillary lateral view is useful for identifying associated fractures and posterior dislocation of the clavicle. The normal coracoclavicular distance varies between 11 and 13 mm. A difference of more than 5 mm between the injured and uninjured sides is diagnostic of a complete coracoclavicular disruption. Type I injuries have essentially normal radiographs. Type II injuries show widening of the joint and a slight upward or posterior displacement of the clavicle but a normal coracoclavicular distance. Type III, IV, and V injuries have a widened joint, an increased coracoclavicular distance, and either superior or posterior displacement of the clavicle ( Figure 50-24 ). Historically, stress views of the ACJ have been recommended to differentiate between type II and III injuries. Such views lack efficacy for this purpose, and their routine use is unnecessary.[38]

Figure 50-24 Third-degree sprain of the acrom ioclavicular joint. The coracoclavicular distance measures 18 m m (arrow). ((Courtesy of David Nelson, MD.))

Management Type I and II injuries should be immobilized in a sling for comfort and to protect against further injury. These patients should be referred for follow-up with their primary care physician. When pain has subsided (1 to 3 weeks), the patient can begin range-of-motion and strengthening exercises with a return to sports when pain-free function has been achieved.[8] Type IV, V, and VI injuries require early surgical treatment. The management of type III injuries has changed dramatically since the 1980s. Most studies have concluded that conservative treatment provides equal or, in some cases, better functional results than surgical intervention. In addition, surgical patients have longer recovery times and higher complication rates.[8] The main complications of conservative therapy are the persistence of nuisance symptoms (clicking or pain) and a

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cosmetic deformity. Selected patients who are young, have severe displacement (>2 cm), and perform repetitive overhead activities may be candidates for surgical intervention.[8] Treatment of type III injuries in the emergency department should consist of sling immobilization and early (50 years old? Has there been any recent history of blunt trauma?

Radiculopathy and likely a herniated disk Spinal stenosis Ankylosing spondylitis Osteoporotic fracture, spinal malignancy Fracture

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Questions for Patient

Potential Diagnosis

Do you take long-term corticosteroids? Do you have a history of cancer? Does your pain persist at rest? Has there been persistent pain for >6 weeks? Has there been unexplained weight loss? Is the pain worse at night? Are you immunocompromised? (HIV, alcoholic, diabetes) Have you had fevers or chills? Do you have pain, weakness, or numbness in both legs? Do you have bladder or bowel control problems?

Fracture, spinal infection Spinal metastatic malignancy Spinal malignancy, spinal infection Spinal malignancy Spinal malignancy Spinal malignancy, spinal infection Spinal infection Spinal infection Cauda equina syndrome Cauda equina syndrome

HIV, human immunodeficiency virus.

Uncomplicated Musculoskeletal Back Pain Most patients with back pain can be classified in the category of uncomplicated musculoskeletal back pain after excluding worrisome disease processes. Often, patients are unable to recall an inciting incident. The pain usually is characterized as an “ache” or “spasm” and is localized asymmetrically in the lumbar paraspinous muscle with radiation to the buttock or posterior thigh proximal to the knee. Movement exacerbates the pain, and rest relieves it. There is no associated deficit in sensation, strength, or bowel/bladder sphincter tone by history or examination. The only physical finding may be regional lumbosacral tenderness and a limited range of motion of the lower back. This diagnosis of exclusion is made only after ruling out the more worrisome causes of back pain.

Radiculopathy Approximately 1% of all low back pain patients exhibit signs of lumbar radiculopathy (i.e., nerve root irritation).[35] The most common etiology is a herniated lumbar disk; other causes include spinal stenosis, malignancy, and infection. The most common type of lumbar radiculopathy is sciatica—an L5 or S1 radiculopathy. Patients with sciatica describe their pain as radiating from the low back to the legs, distal to the knee. Such pain is characterized as “shooting,” “lancing,” “sharp,” or “burning.” Associated symptoms include focal numbness or weakness in one of the lower extremities. Exacerbating triggers include sitting, bending, coughing, and straining; relieving factors include lying supine and still. On physical examination, the patient frequently is tender in the sciatic notch. The straight leg raise (SLR) test is a fairly sensitive assessment tool to determine if the patient has sciatica. The SLR test is done with the patient supine and the legs extended. The symptomatic leg is passively raised, while keeping the knee straight. The presence of back pain, which radiates past the knee while the leg is elevated 30 to 70 degrees, suggests an L5 or S1 radiculopathy. If the SLR test results in isolated low back pain without radiation symptoms to the legs, however, it is considered to be a negative finding. A positive SLR test has a sensitivity of 80% but a low specificity of 40%, meaning that a negative result is fairly accurate in ruling out sciatica. Corroborative tests for sciatica include the “bowstring sign” (reproduction of pain with deep palpation in the midline popliteal fossa) and Laségue's sign (reproduction of pain with foot dorsiflexion while the leg is elevated just short of the pain threshold during the SLR test). As an alternative to the SLR test, with the patient in a seated position, the knee can be extended (“flip test”), which also should stretch the sciatic nerve. Reproduction of the pain often causes the patient to lean backward reflexively from the pain, almost “flipping” back into a supine position. A crossed SLR test is done by passively raising the patient's asymptomatic leg, while keeping the knee straight. The presence of pain radiating from the back to the opposite affected leg has a sensitivity of only 25% but a high specificity of 90% for sciatica, meaning that a positive crossed SLR result is almost pathognomonic for sciatica, whereas a negative result is nondiagnostic.[20] A reverse SLR test is performed to detect L3 or L4 radiculopathy. With the patient prone, each hip is

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passively extended. If there is irritation of the L3 or L4 nerve root, pain is elicited. In addition to stressing lumbar nerve roots, a thorough examination of the lower extremities detects subtle findings associated with radiculopathies. This examination includes mapping the distribution of pain and assessing individual nerve root function, specifically strength, sensation, and reflexes. For the sensory examination, the earliest deficit can be detected by examining the most distal aspect of the dermatome. Specifically, light touch and pinprick sensation should be tested in the medial foot (L4), the area between the great and second toe (L5), and the lateral foot (S1) ( Figure 51-2 ).

Figure 51-2 Physical exam ination findings for L3-S1 radiculopathy. The “X” m arks the ideal location to test for sensation for each nerve root. C-SLR, crossed straight leg raise; R-SLR, reverse straight leg raise; SLR, straight leg raise.

Herniated Disk Patients with herniated lumbar disks are usually 30 to 50 years old and often have a long history of recurrent nonradicular low back pain, theoretically from irritation of the outer annular fibers of the disk. When the nucleus pulposus of the disk prolapses through the annulus fibrosus, local nerve root inflammation and radiculopathy result. Coughing, sitting, and any movement in general exacerbate the patient's pain and radiculopathy symptoms. The severity of leg pain from radiculopathy often overshadows the back pain. Sciatica findings have a sensitivity of 95% for lumbar disk herniation, meaning that herniation is extremely unlikely in the absence of sciatica.[20] The physical examination should focus on lower extremity neurologic function and signs of radiculopathy. Weakness of ankle dorsiflexion, great toe extension, ankle plantar flexion, and knee extension have respective specificities of 70%, 70%, 95%, and 99% for lumbar disk herniation.

Spinal Stenosis Patients with spinal stenosis are typically older (mean age 55 years) and constitute only 3% of all low back pain patients.[] The classic history, found in 60% to 75% of patients with spinal stenosis, is one of subacute or chronic pain and lower extremity radiculopathy, which occurs with walking and is relieved with rest and, uniquely, leaning forward.[37] Because these symptoms mimic peripheral vascular claudication symptoms, pain from spinal stenosis is termed pseudoclaudication. Typically, vascular claudication lasts 5 minutes after resting, while pseudoclaudication lasts 10 to 15 minutes.[38] Patients with spinal stenosis have symptom relief with spine flexion and leaning forward because it increases spinal canal diameter and reduces spinal cord tension. Sitting improves the symptoms, in contrast to patients with herniated disks. A typical history involves a patient who walks uphill without pain but develops pain while walking downhill because the back is extended. On physical examination, most patients have a lumbar radiculopathy at one or multiple levels and increased back pain with extension.[37] Classically, patients with spinal stenosis walk with a slight bent-forward position. To help distinguish spinal stenosis from vascular claudication, peripheral pedal pulses and ankle-brachial indices should be checked.

Degenerative Spondylolisthesis Most cases of spondylolisthesis, forward displacement of one vertebral body over another, are caused by degenerative changes. This condition is most prevalent in adults older than age 40 and occurs most commonly at the L4-5 and L5-S1 junction. Two thirds of patients with radiographically documented degenerative spondylolisthesis are asymptomatic.[39] For patients with pain, bending, twisting, and lifting activities aggravate the symptoms. Radiculopathies, spinal stenosis symptoms, or both may coexist. On physical examination, patients may have a loss of lumbar lordosis, a step-off along the midline spine if the spondylolisthesis is severe, tight hamstrings, or a radiculopathy.

Arthropathies Inflammatory arthropathies, such as ankylosing spondylitis, rheumatoid arthritis, and psoriatic arthritis, all are

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associated with subacute and chronic low back pain. All of these patients exhibit a decreased range of spinal flexibility. Commonly with ankylosing spondylitis, patients complain of morning back stiffness and pain relief with exercise. On physical examination, these patients may have nonspecific findings, such as decreased spinal mobility, sacroiliac joint tenderness, and decreased chest expansion.

Red Flag Diagnosis: Fracture In all patients with significant blunt trauma to the back or with minimal trauma in the setting of osteoporosis, fractures of the spinal column must be considered. For patients taking long-term corticosteroids, who are predisposed to early osteoporosis, back pain had a specificity of 99.5% for a spinal fracture in one series.[20] This subpopulation of patients must be assessed for a fracture despite the absence of trauma. On examination, tenderness along the midline spine and paraspinous muscles from concurrent muscle spasm usually can be elicited.

Red Flag Diagnosis: Cauda Equina Syndrome Cauda equina syndrome results from a sudden compression of multiple lumbar and sacral nerve roots. Although it is an extremely rare presentation of back pain, it is a neurosurgical emergency. Usually caused by a massive central disk herniation, other etiologies include a spinal epidural abscess, hematoma, trauma, and malignancy. Patients with cauda equina syndrome present with back pain and multiple-level radiculopathies, often involving both legs. Patients may have difficulty with bladder or bowel function. Diagnostic dilemmas arise because patients can present atypically with equivocal neurologic compromise and only mild-to-moderate pain. The most consistent examination finding in cauda equina syndrome is urinary retention. With a high sensitivity of 90%, it is highly unlikely to have this disease process if the patient's postvoid residual urine volume is less than 100 to 200 mL. Saddle anesthesia, sensory deficit over the buttocks, upper posterior thighs, and perineal area, is frequently an associated finding with a sensitivity of 75%. In 60% to 80% of cases, the rectal examination reveals a decreased sphincter tone.[20]

Red Flag Diagnosis: Spinal Infection Epidural abscess and spondylitis (osteomyelitis of the vertebral bone) are two types of dangerous spinal infections. Patients at higher risk include injection drug users, alcoholics, immunocompromised patients (e.g., patients with human immunodeficiency virus, diabetes mellitus, chronic renal failure, long-term corticosteroid use), the elderly, patients recently sustaining blunt trauma to the back, patients with an indwelling catheter, and patients with a recent bacterial infection. For epidural abscesses, approximately 20% of patients have no comorbidities or risk factors. The most common bacterial culprit is S. aureus, spreading hematogenously from a remote site or from direct extension of a local infection, such as spondylitis or disk space infection. Less common culprits are streptococci strains and enteric gram-negative bacilli. Patient history reveals back pain even at rest and subjective fevers. On physical examination, midline spinal tenderness to percussion at the site of abscess is commonly present. What makes a spinal epidural abscess a diagnostic challenge is the fact that about 50% of the patients have no neurologic deficits, and 50% may be afebrile on initial presentation.[40] Nevertheless, it is essential to diagnose this neurosurgical emergency that entails a mortality as high as 23%.[] For spondylitis, infection often begins as a subtle hematogenous seeding of the disk space, causing diskitis. Subsequent contiguous spread of the disk space infection causes vertebral end plate erosion, leading to spondylitis. Similar to an epidural abscess, the most common bacterial culprit is S. aureus. Less commonly, enteric gram-negative bacilli and Mycobacterium tuberculosis (Pott's disease) are the infectious organisms. Injection drug users also are at risk for Pseudomonas spondylitis. Patient history typically reveals a more indolent course of back pain with subjective fevers. The physical examination findings can range from nonspecific tenderness of the spine to radiculopathy and cauda equina syndrome. Similarly nondiagnostic, the presence of fever has a sensitivity of only 27% to 50% for spondylitis.[20]

Red Flag Diagnosis: Malignancy Vertebral infiltration with a tumor can be caused by either a primary or, more commonly, a metastatic malignancy. These patients are generally older than age 50 and often complain of subacute or chronic back pain, which is worse at night. Risk factors include a history of known cancer (98% specificity), unexplained weight loss (94% specificity), persistent pain despite bed rest (90% specificity), and pain lasting more than 1 month (specificity 81%).[43] On examination, these patients typically have mild-to-moderate spinal tenderness. Examination of the organs most likely to metastasize to bone, including breast, prostate, and lung, may be indicated.

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Referred Back Pain Referred pain is often difficult to differentiate from pain originating from the lumbosacral structures. It is vital, however, to make the distinction. A sudden onset of severe, tearing back pain is classically an aortic dissection. Abdominal pain radiating to the back could be a ruptured abdominal aortic aneurysm in an elderly patient with atherosclerotic disease. Alternatively, abdominal pain radiating to the back could be pancreatitis in a chronic alcoholic. Unilateral paraspinal pain associated with fever and nausea in a young woman could be pyelonephritis. In all such cases, a thorough examination of the abdomen, genitourinary system, and cardiovascular system is essential. Distinguishing the primary cause of the pain radically alters the therapy for the patient.

Functional Back Pain Distinguishing functional pain from “real” pain is often difficult, but several clues can be elicited from the history. A prolonged history of nonanatomic pain complaints, vague pain descriptions without localization, multiple lawsuits over similar problems, and lack of coordinated care for a problem that otherwise seems to dominate the patient's life all suggest that a search for a physical cause would be fruitless. These patients are often thought to have secondary gains for their complaints. On physical examination, maneuvers can be performed to try to detect functional back pain, if a psychological overlay is suspected. The first is performing the SLR test from the sitting instead of the supine position. Seemingly focused on the knee examination, the physician extends the patient's knee; this physiologically reproduces the SLR by stretching the L5 and S1 nerve roots. A positive response includes reproduction of the patient's pain and extension of the back while seated to decrease traction on the sciatic nerve. A positive supine SLR test but a negative sitting SLR test suggests a nonphysiologic cause for the pain. A second sign involves superficial tenderness. Some patients, to impress the physician with their degree of pain, respond dramatically to superficial palpation. This response is atypical for patients with genuine back pain. Nondermatomal sensory loss and widespread nondermatomal pain complaints also are unlikely to be caused by physiologic processes. Third, back pain should not be elicited by pushing down on the patient's scalp against the cervical spine. This maneuver axially loads only the cervical and not the lumbar spine. Fourth, a patient who generally overreacts during the examination is probably not giving a true reflection of the actual discomfort. All of these signs are believed to correlate well with psychopathology but have poor prognostic value. They are suggestive of malingering and functional complaints, but are neither sensitive nor specific enough to rule out organic pathology.[]

Back Pain in the Elderly When the elderly experience back pain, musculoskeletal back pain and disk herniation are less likely the underlying etiology. Instead, spinal stenosis and degenerative spondylolisthesis should be considered. Also, the incidence of more worrisome diagnoses, such as an osteoporotic fracture, spinal infection, and malignancy, is much greater in this patient population. Consequently in these cases, the threshold for further investigation should be much lower.

Back Pain in Children The likelihood of congenital etiologies for back pain, such as leg-length discrepancy and spondylolisthesis, is greater for children compared with adults. Spondylolisthesis is diagnosed most often in patients older than age 10 years, who are involved heavily in sports and complain of low back pain worsened with activity. A history suggesting infection or malignancy in children is similar to that of adults. Radicular symptoms are relatively rare in children. Functional processes are suggested when the pain is present only with certain undesired activities, such as housework or chores.

DIAGNOSTIC STRATEGIES Laboratory Evaluation In the absence of historical and physical findings suggesting “red flag” diagnoses for low back pain, laboratory evaluation is unnecessary. When a patient presents with back pain suggesting a spinal infection or malignancy, however, laboratory studies may help with risk stratification. Specifically, a complete blood cell count, erythrocyte sedimentation rate (ESR), and urinalysis should be obtained. Additional laboratory studies should be tailored to the patient's history and physical examination. Liver function tests and amylase/lipase level may need to be checked for abdominal complaints.

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For a spinal infection, the ESR usually is elevated (>20 mm/hr), whereas the serum white blood cell (WBC) count may or may not be elevated.[46] In one study, 13 of 40 (32%) patients with an epidural abscess had a falsely reassuring WBC count less than 11,000/mL.[41] When patients are diagnosed with a spinal infection, blood cultures should be drawn because a single strain, most commonly S. aureus, can be isolated in 50% to 90% of the cases.[] Performing a lumbar puncture to evaluate the cerebrospinal fluid is unnecessary and is relatively contraindicated because of the risk of seeding the cerebrospinal fluid with bacteria. For a bony malignancy, the ESR also usually is elevated, whereas the WBC may be equivocal. The hematocrit may be low secondary to anemia of chronic disease. Other additional helpful laboratory tests include alkaline phosphatase, prostate-specific antigen concentrations, and serum immunoelectrophoresis and urine testing for light chains (for multiple myeloma).

Radiology Plain Radiograph The utility of “screening” lumbosacral plain radiographs for all patients with acute low back pain is extremely low. Plain radiographs contribute little to patient management in the absence of concerning red flag findings and needlessly expose the patient to irradiation.[48] Most patients with back pain do not need radiographs. Most films are normal, but they also may have incidental findings, which may not be the true cause of the patient's pain. These findings include spondylolisthesis, abnormal spinal curvature, disk space wedging, and degenerative changes.[8] Current indications for radiographs in back pain patients are listed in Box 51-1 . BOX 51-1 Indications for Plain Lumbosacral Films in Patients with Low Back Pain

{,

{,

{,

Age youn ger than 18 or older than 50 year s Any histo ry of mali gnan cy or unex plain ed weig ht loss Any histo ry of fever , imm unoc omp romi se, or injec tion

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{,

{,

{,

drug use Rec ent trau ma, other than simp le lifting Prog ressi ve neur ologi c defic its or other findi ngs cons isten t with caud a equi na synd rom e Prol onge d durat ion of sym ptom s great er than 4 to 6 wee ks

Patients with radiculopathy findings suggesting a herniated disk do not require radiographs. In addition to being radiographically undetectable on plain films, disk herniations resolve with conservative management in most cases. If radiographs are obtained, anteroposterior and lateral views are usually sufficient in the emergency department, although many centers also prefer a coned-down lateral sacral view. Oblique films are not necessary except in children, in whom spondylolysis and spondylolisthesis may be more prevalent.[49] On plain radiographs, spondylolisthesis, vertebral osteomyelitis, and vertebral metastatic disease have classic appearances. Spondylolisthesis ( Figure 51-3 ) is classified into grade 1 through grade 4 based on the severity of the anterior slippage of one vertebral body over another. Grade 1, which is often asymptomatic, involves less than 25% slippage. Grade 2 through grade 4 involve 25% to 50%, 50% to 75%,

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and at least 75% slippage, respectively.

Figure 51-3 Lateral plain radiograph and schematic diagram of grade 2 anterior spondylolisthesis of L5 on S1. Grading is based on the percentage of slippage with 0% to 25%, 25% to 50%, 50% to 75%, and greater than 75% corresponding to grades 1 to 4, respectively.

Spondylitis ( Figure 51-4 ) is characterized by erosion of contiguous vertebral endplates and a shortened disk space height, as best seen on the lateral view. Because the anterior subchondral vertebral bone and disk space are highly vascular, it follows that spondylitis has a predilection in these areas because of the hematogenous spread of infection. With more advanced disease, vertebral bony erosion and collapse may occur.

Figure 51-4 Lateral plain radiograph shows Staphylococcus aureus spondylitis of L3 and L4. There is narrowing of the L3-4 disk space and erosion of the vertebral end plates of L3 and L4 (sm all arrows). Notice the distinct vertebral end plate m argins in unaffected areas (large arrows).

Vertebral metastatic disease ( Figure 51-5 ) can present either as a blastic (hyperdense) or lytic (hypodense) lesion and has a predilection for the vertebral body and pedicles. In contrast to osteomyelitis, the intervertebral disk space is spared.

Figure 51-5 Anteroposterior plain radiograph shows blastic infiltration of m etastatic breast cancer to the pedicles of L3-5 (arrows).

If a red flag diagnosis is of concern, a plain radiograph may rule out a fracture but may not be adequate to rule out other pathologies, such as cauda equina syndrome, spinal infection, and malignancy. For cauda equina syndrome, patients more often have normal or nonspecific plain film findings because the most common etiology is a central disk herniation. For spinal infection and vertebral malignancy, the sensitivity of a plain radiograph is only fair at 82% and 60%.[48] In these cases, the patient subsequently should undergo MRI if there is a high clinical suspicion.

Computed Tomography and Magnetic Resonance Imaging For fractures and bony abnormalities of the vertebral column, computed tomography (CT) is superior to MRI. In the case of a fracture, CT helps to elucidate the integrity of the spinal canal and the risk for spinal cord impingement. For all other red flag diagnoses—cauda equina, spinal infection, and malignancy—MRI is the gold standard test. Its superior tissue resolution, especially of the spinal cord and intervertebral disks, and its ability to perform more accurate sagittal reconstructions make MRI the ideal imaging modality. MRI is able to differentiate subtle soft tissue pathology, such as a spinal epidural abscess ( Figure 51-6 ). There is no

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radiation with MRI, whereas CT exposes the patient to about 4 years' worth of natural background radiation.[ 50]

Figure 51-6 Axial T2-weighted m agnetic resonance im aging of Staphylococcus aureus L2 epidural abscess im pinging the dorsolateral aspect of the spinal canal. CSF, cerebrospinal fluid. (Im age contributed by Dr. Stephen Bretz.)

Although disk herniation is easily visualized on MRI, patients with findings consistent with an uncomplicated disk herniation (i.e., without objective neurologic findings on examination) should not routinely undergo MRI imaging because of the self-limited nature of the disease in most cases. Overimaging patients with lumbar radiculopathy may lead to an overdiagnosis of disk herniations because incidental MRI-documented herniations have been shown to occur in 20% to 30% of asymptomatic individuals. The result may be unnecessary surgical interventions.[]

Special Investigations Unless there is suspicion of a process other than uncomplicated back pain or disk herniation, other investigations are not required. MRI is the definitive test for most conditions. Radionuclide scans have been used for locating suspected malignancy, infectious foci, and occult fractures as in spondylolysis. Nuclear medicine scans are regarded as sensitive but nonspecific.

DIFFERENTIAL CONSIDERATIONS Nonspecific low back pain is in many ways a diagnosis of exclusion. In a typical patient, within the 18- to 50-year age range with acute low back pain and with no radiculopathy, prior malignancy, weight loss, or fever, the diagnosis is almost certainly uncomplicated musculoskeletal back pain. When the patient falls outside of the aforementioned parameters, a wide variety of differential diagnoses must be entertained. Almost anything can cause low back pain. Box 51-2 contains an extensive list of possible diagnoses, but it is useful to look at the most common and most serious causes of low back pain other than musculoskeletal lumbosacral pain. One of the most life-threatening causes of referred back pain is a leaking or ruptured abdominal aortic aneurysm. See appropriate chapters for further discussion of specific problems. BOX 51-2 Differential Diagnosis for Low Back Pain

Localized/Common Unc ompl icate d mus culo skel etal back pain Inter verte bral disk herni ation Spin al sten

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osis Spo ndyl olist hesi s Oste oarth ritis Frac ture

Localized/Uncommon Infection Spo ndylit is Epid ural absc ess Diski tis Herp es zost er

Malignancy Metastatic Brea st Lung Pros tate Kidn ey, thyro id, colo n (less com mon ) Primary Multi ple myel oma Lym pho ma

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Leuk emia Prim ary cord/ extra dural tumo rs Oste oid oste oma Othe r prim ary bone tumo rs

Pediatric Spo ndyl olist hesi s/sp ondy lolysi s Seve re scoli osis Sch euer man n's dise ase

Rheumatologic Anky losin g spon dyliti s Psor iatic arthri tis Poly myal

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gia rheu mati ca Reit er's synd rom e

Vascular Arter iove nous malf orm ation of spin al cord Epid ural hem atom a

Life-Threatening Referred Pain Abdo mina l aorti c aneu rysm

Gastrointestinal System Biliar y path olog y Pan creat itis Pepti c ulcer dise ase Dive

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rticul itis

Genitourinary System Ren al colic Pyel onep hritis Pros tatiti s Cysti tis

Gynecologic System Men strua l cra mps Spo ntan eous abort ion Labo r Ecto pic preg nanc y Pelvi c infla mm atory dise ase End omet riosi s Ovar ian cyst Ovar ian torsi on

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Hematologic System Sickl e cell crisi s

Functional Som atiza tion disor der Depr essi on Fibro sitis Malin gerin g

MANAGEMENT Because most patients with acute low back pain have symptomatic resolution within 4 to 6 weeks, only conservative management is needed. In general, MRI and surgery are reserved for the few patients who have concerning systemic signs and patients with refractory, debilitating back pain. Over the past few decades, the accepted practice has shifted 180 degrees from an overaggressive recommendation for invasive surgical intervention to the minimalistic recommendation of symptomatic pain control and early return to activity. The role of the physician in back pain management is to obtain a correct diagnosis, rule out significant pathology, avoid excessive investigation, provide analgesia, and educate the patient.[52] The management of various etiologies for low back pain is summarized in Figure 51-7 . For fractures and referred pain, refer to the appropriate chapters.

Figure 51-7 Algorithm for m anagem ent of low back pain. The patient's history m ay be concerning for m ore than one red flag diagnosis.

Uncomplicated Musculoskeletal Back Pain Besides a thorough history and physical examination, no further investigations are required for uncomplicated low back pain. Only pain control and patient education are indicated. Aside from an initial parenteral opioid or nonsteroidal anti-inflammatory drug, most patients can be managed with oral nonsteroidal medications.[52] Ibuprofen is an ideal choice because it is inexpensive, and various nonsteroidal anti-inflammatory drugs have been shown to have the same efficacy. It is unclear whether ibuprofen is superior to acetaminophen.[53] Short-term opioids also occasionally are needed for break-through pain in the acute setting. Various other medications have been advocated, including benzodiazepines and other muscle relaxants. Based on the current conflicting literature, these medications probably do not provide a significant

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added benefit, but they do increase the incidence of side effects such as drowsiness and drug dependence.[ 54] There is no role for corticosteroids in the treatment of uncomplicated low back pain. In terms of patient education, one of the outdated practices of back pain management was that physicians convinced patients that they were sick. This was done by overinvestigating, overtreating, putting patients to bed, and taking them off work. It now has been shown convincingly and repeatedly that all of those interventions are excessive. Instead, patients should be educated as to why they are not receiving plain films of their lumbosacral spine or laboratory tests and reassured on the likely benign course of the pain. Most patients can be convinced by education and an explanation of radiation dosing. A typical lumbosacral spine series involves as much gonadal radiation as a chest x-ray every day for 5 or 6 years.[55] Patients also are discouraged from the outdated recommendation of strict bed rest. Compared with patients who are prescribed strict bed rest, patients experience earlier resolution of pain and return to work sooner if they remain active.[4] Patients should be made aware, however, that the back pain has a 66% to 84% likelihood of recurring within 12 months.[11] Other supplemental treatment modalities have been shown to be of debatable efficacy in the management of acute and chronic low back pain. These include acupuncture, physiotherapy, chiropractic manipulation, massage, ultrasound, traction, and transcutaneous nerve stimulation.[]

Lumbar Disk Herniation Similar to patients with uncomplicated low back pain, patients with disk herniations and radiculopathy do not benefit from strict bed rest.[5] In the acute setting, these patients should receive analgesics, but further investigation with laboratory tests and radiographs is not necessary. Most of these patients have symptomatic resolution within 6 weeks with conservative, nonsurgical management.[] Corticosteroid injections into the epidural space have been advocated for sciatica in the belief that this helped relieve some of the inflammation associated with disk herniation. Although this treatment may offer some initial symptom improvement, there is no long-term benefit or reduction in the need for later surgery.[62] The use of systemic steroids in back pain and disk herniation remains controversial. It is difficult to argue their benefit in nonspecific low back pain, but the anti-inflammatory effects make empiric sense in the context of radiculopathy. A large retrospective review showed no definite benefit of systemic steroids in either setting, but the definitive trial is yet to be done.[54] When the pain from disk herniation persists for longer than 4 to 6 weeks, outpatient MRI is indicated. With a documented herniation, these patients benefit from surgical diskectomy. Other indications for surgery include intractable pain and worsening motor or sensory deficit. Although surgical patients tend to have earlier relief of pain compared with nonsurgical patients, the 4- and 10-year results are the same. Microsurgery techniques and laser therapy have not been shown to confer any advantage over conventional techniques.[63]

Spinal Stenosis Patients with spinal stenosis should be managed conservatively with pain medications. In the absence of alarming red flag findings, these patients do not require laboratory or radiographic studies in the emergency department. These patients may be candidates for surgery if they show any of the following conditions: progressive neurologic deficit, progressive reduction in ability to walk secondary to pseudoclaudication, evidence of cauda equina syndrome, or intractable pain. Elective surgical decompression is more controversial. A 10-year longitudinal study showed that no findings predicted which patients would benefit more from surgery versus conservative management.[64] The benefits of surgery also must be weighed against the risks of surgery itself because these patients are usually elderly.

Degenerative Spondylolisthesis Patients with symptomatic degenerative spondylolisthesis are managed conservatively with analgesia and lifestyle changes, which include the avoidance of repetitive bending, heavy lifting, and twisting at the waist. For refractory and severe back pain, patients should undergo outpatient MRI and receive neurosurgical follow-up for possible operative decompression.

Red Flag Diagnosis: Fracture See Chapter 40 , Spinal Injuries.

Red Flag Diagnosis: Cauda Equina Syndrome

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Cauda equina syndrome is a neurosurgical emergency that requires urgent operative decompression to help preserve distal neurologic function. All patients with concerning findings, such as saddle anesthesia or a large postvoid residual volume, require emergent MRI. On average, these patients may have an improved outcome if decompression takes place within 24 hours.[65] Early evidence exists, however, that shows delayed operative decompression under a more controlled setting may be performed without any adverse effects, particularly for patients who have overflow urinary incontinence.[66]

Red Flag Diagnosis: Spinal Infection If a patient's history or physical examination is worrisome for a spinal infection, further investigation is paramount. With a low index of suspicion, a normal serum WBC count, ESR, and lumbosacral plain film can safely rule out infection. If any of these tests are abnormal or if the patient has a moderate to high pretest probability for a spinal infection, the next step is to obtain emergent MRI. Pyogenic spinal infections should be treated with broad-spectrum intravenous antibiotics that cover at least for S. aureus and gram-negative bacilli until blood culture results return. Vancomycin should be added if the patient is at risk for methicillin-resistant S. aureus. For injection drug users, antibiotic coverage for Pseudomonas is necessary. For almost all epidural abscesses, treatment also requires neurosurgical drainage and decompression.

Red Flag Diagnosis: Malignancy An algorithmic guideline to the management of back pain, which is worrisome for malignancy, involves subdividing patients into two categories—patients with and patients without a history of prior cancer. Of cancer patients, 20% to 85% develop spinal metastasis.[] These patients are subdivided further into patients with and patients without evidence of a radiculopathy. Most patients fall into the classification of back pain without a history of cancer and without a radiculopathy. They have a history only suggestive of a malignancy, such as unexplained weight loss or back pain that is worse at night. These patients require further risk stratification with plain radiographs and laboratory tests, including a complete blood cell count and ESR. With normal results, these patients can be referred to their primary care physician for further workup. The physician should not feel completely reassured that malignancy has been ruled out, however, because plain films have a false-negative rate of 10% to 17% for vertebral bone metastasis. This false-negative rate is likely due to the fact that a cancer needs to erode at least 50% of the bone before becoming radiographically apparent.[69] With abnormal results, such as a bony lesion or extremely elevated ESR level (>100 mm/hr), these patients should receive urgent MRI as an outpatient within the next 3 to 7 days. For patients with no known history of cancer but with signs of radiculopathy, the workup also includes a plain radiograph, complete blood cell count, and ESR. If the test results are normal, the patients should be referred to their primary care physician for further evaluation for malignancy and other etiologies for radiculopathy, including spinal stenosis and disk herniation. If the workup shows a bony lesion on plain film or an extremely elevated ESR level (>100 mm/hr), these patients should undergo emergent MRI because (1) the presence of radiculopathy may be an early harbinger of impending spinal cord compression from a mass effect, and (2) it is often difficult to distinguish between a neoplasm from early spondylitis (especially tuberculous osteomyelitis) and an osteoporotic fracture causing a vertebral collapse on plain film.[70] For patients with a history of prior cancer and low back pain, all require MRI either emergently or urgently within 3 to 7 days. In the absence of radiculopathy findings, these patients should undergo outpatient MRI regardless of plain film and laboratory results. Plain radiography is too insensitive to rule out a vertebral neoplastic process definitively. If radiculopathy is present, however, these patients require emergent MRI regardless of plain radiography findings because of the concern for spinal cord compression. According to one study of known cancer patients with back pain and radiculopathy, the risk of epidural spinal cord compression was 25% despite normal films and 88% with films showing vertebral metastasis.[71] For all patients undergoing emergent MRI to evaluate for vertebral malignancy and cauda equina syndrome, dexamethasone should be administered to reduce the potential mass effect. In addition to high-dose corticosteroids, patients with a vertebral neoplasm also may benefit from radiation therapy.

Pediatric Back Pain Management of back pain in children is similar to management for adults and depends on the etiology. Spondylolisthesis is managed by observation, with only 4% to 5% of cases worsening. Progression usually stops as skeletal maturity is achieved in the late teens. Current recommendations are for limited contact

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sports in children with less than 30% to 50% slippage and surgical stabilization for children with slippage greater than 30% to 50%. Treatment becomes more aggressive if the child is symptomatic.[72]

Chronic Back Pain Patients with chronic back pain often are regarded as the most challenging of back pain patients. The cause of chronic back pain is complex and multifactorial and usually requires a multidisciplinary approach for the greatest chance for success. There is little doubt that psychosocial factors, including depression, drug dependence, and financial gain, play a significant role in the behavior of many of these patients, making proper assessment and treatment impossible for the emergency physician. After the emergency physician has made sure that no red flag condition exists, emergency management involves analgesia and follow-up. The main decision usually centers on the use of narcotics, which becomes an individual decision for the physician to make. Patients showing drug-seeking behavior classically are from out of town, have a physician who cannot be contacted, or are “allergic” to all nonopioid medications.

DISPOSITION Almost all patients with uncomplicated back pain can be discharged from the emergency department. In rare circumstances, severe pain or an unacceptable social situation may preclude discharge. For patients who have a red flag diagnosis of cauda equina syndrome or epidural abscess, an immediate neurosurgical consultation is required for emergent surgical decompression. For spondylitis, patients require hospital admission for intravenous antibiotics. For vertebral malignancy, the decision to hospitalize a patient for pain control, high-dose corticosteroids, and radiation therapy should be made in conjunction with a neurosurgeon, oncologist, and radiation therapist. One of the most important aspects in the management of patients with low back pain is the discharge instruction. Not only are clear and simple instructions useful to the patient, but they are also a medicolegal necessity for the physician. Physicians must avoid using medical terms. The discharge instructions should include the following: 1.

2.

3.

4.

Diagnosis: Distinguish between uncomplicated (musculoskeletal) back pain and diskogenic radiculopathy. Activity: Recommend maintaining active mobility as limited only by pain, avoiding heavy lifting until symptoms resolve, and getting back to work early. Reassurance: Educate patients on the likely benign etiology for the pain. Warnings: Instruct patients to return to the emergency department immediately if they have a fever; lose bladder or bowel control; have numbness or tingling around their anus, vagina, or penis; or have new pain or weakness down one or both legs.

Pediatric back pain is subject to the same discharge instructions as that of adults. In patients with pain secondary to spondylolisthesis, activity restrictions should be made in conjunction with an orthopedic surgeon. Emergency department disposition for a patient with chronic back pain is relatively simple: pain management with nonopioids, when possible, and follow-up with a primary care provider. The prognosis is guarded because patients who are off of work for 6 months are usually still off of work after 2 years.[30]

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KEY CONCEPTS {, {, {, {, {,

{,

The key to differentiating between benign and serious pathology in low back pain is a focused and thorough history and physical examination. The absence of sciatica findings practically rules out a lumbar disk herniation. Screening laboratory tests and plain radiographs are not indicated for patients with uncomplicated low back pain or a simple disk herniation. The best treatment for uncomplicated back pain and disk herniation is analgesia and resumption of normal activities—not bed rest. Age younger than 18 or older than 50 years, fever, injection drug use, immunocompromised status, symptoms lasting more than 4 to 6 weeks, night pain, and prior malignancy all are red flag warnings of potentially serious causes of back pain and should be heeded and evaluated accordingly. Bilateral leg pain or weakness, bowel or bladder sphincter problems (especially urinary retention), and saddle anesthesia are worrisome for a cauda equina syndrome a neurosurgical emergency.

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UPPER BACK PAIN PERSPECTIVE Background Thoracic pain is far less common than low back pain. Thoracic pain usually has a musculoskeletal origin, but other more emergent causes must be considered first, including thoracic aortic dissection, pulmonary embolism, and esophageal disease. Compared with lumbar disk herniation, which is fairly common, thoracic disk disease is extremely rare, difficult to diagnose, and difficult to treat.

Epidemiology The actual incidence of thoracic pain is unknown. The incidence of symptomatic thoracic disk disease is low, with estimates at 1 in 1 million.[73] The average age is in the 40s with equal gender distribution. Surgery for thoracic disks comprises less than 4% of all disk operations.[74] Metastases are more common in the thoracic spine than lumbar spine, with 60% to 70% of spinal metastases localizing there.[]

PRINCIPLES OF DISEASE Anatomy and Physiology The thoracic vertebral column can be regarded as an extension of the cervical column with the addition of ribs. There are 12 thoracic vertebrae, connected by the anterior and posterior longitudinal ligaments and the ligamentum flavum, similar to the lumbar vertebrae. Also similarly, intervertebral disks provide elasticity and stability to the thoracic column. The spinal canal diameter remains unchanged through the thoracic and lumbar levels, but at the thoracic level, the space around the spinal cord is smaller compared with the lumbar level. Because lumbar nerve fibers have not yet branched off from the spinal cord, the thoracic cord is thicker than the lumbar cord. Significant neurologic findings may result from minimal spinal canal impingement at the thoracic level.

Pathophysiology Common thoracic soft tissue pain is likely a combination of sprain and muscle inflammation. Similar to the lower back, innervation of the paravertebral area is provided by the sinuvertebral nerve, and any anatomic disruption of surrounding structures results in nonspecific pain. Thoracic disk herniations, which most commonly occur in the midthoracic to lower thoracic spine, cause pain and neurologic symptoms in much the same way as lumbar disks. It is not clear why their presentation is so varied, although a possible cause is a higher number of centrally herniated disks, resulting in much more frequent myelopathic symptoms.[74]

CLINICAL FEATURES Symptoms and Signs History Nondiskogenic thoracic back pain usually presents with paraspinal discomfort. There may or may not be a history of trauma or recent unusual activity preceding the onset of pain. Complaints with thoracic disk herniations are variable at best, but usually are associated with long-standing pain, neurologic symptoms, or both. Pain may be localized to one part of the thoracic vertebrae, it may radiate down to the sacrum, or it may have a radicular component along the ribs. Central disk herniation can present as diffuse abdominal and back pain or burning sensation in the lower extremities. Associated findings may include mild weakness, spasticity, gait disturbance, bowel or bladder dysfunction, or paraplegia. These usually progress until the condition is diagnosed. The average patient with thoracic disk disease is not diagnosed until 20 months after first presentation. Pain from other causes should be sought in the initial assessment. A history of trauma, fever, previous malignancy, cardiovascular disease, or gastrointestinal problems may indicate problems originating outside the thoracic spine and may warrant further investigation.

Physical Examination

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Patients with benign musculoskeletal pain have an unremarkable examination. They may exhibit mild to moderate paraspinal tenderness, pain with motion, and even discomfort from chest wall expansion with respirations, but objective findings are minimal. The physical examination for patients with thoracic disk herniations varies with the location and degree of herniation. Objective findings may range from a normal examination to a loss of posterior column function (position, touch, vibration) or unilateral or bilateral weakness. Gait and sensory abnormalities are common. Hypotonic abdominal reflexes may be present with distal hyperreflexia. A Babinski response may be present. Myelopathy may result in urinary retention. Muscle wasting may be present with chronic symptoms. The possibility of other pathologic conditions should be kept in mind during the physical examination, with appropriate assessment tailored to the presentation and clinical suspicion.

DIAGNOSTIC STRATEGIES Laboratory Evaluation In the face of an unremarkable history and physical examination, the likelihood of useful laboratory re-sults is extremely small. In appropriate clinical circumstances, assessment for malignancy, infection, and inflammation should be undertaken.

Radiology The usefulness of a radiograph is dubious in a patient with atraumatic acute thoracic back pain who has no other preexisting illness or neurologic findings. As a general guide, however, suspicion of other conditions; unexplainable symptoms; extremes of age; concern for trauma, tumor, infection, gastrointestinal pathology, or vascular pathology; or prolonged symptoms should prompt basic radiologic studies and appropriate further investigations. Similar to patients with lower back pain, patients with a history of cancer and upper back pain should undergo plain radiography and possibly MRI to assess for vertebral metastatic disease, especially because metastases have a predilection for the thoracic spine. MRI has become the modality of choice for evaluating a herniated thoracic disk. The incidence of asymptomatic disk herniations seen on MRI is 37%. Most herniated thoracic disks, whether symptomatic or not, have been seen to recede spontaneously.[73]

DIFFERENTIAL CONSIDERATIONS Although muscular back pain is extremely common, Box 51-3 lists the expansive differential diagnosis for thoracic back pain. BOX 51-3 Differential Diagnosis for Thoracic Back Pain

{, {, {, {, {, {, {, {, {, {,

Uncompliated musculoskeletal back pain Spinal cord and nerve root pathology (e.g., disk herniation, tumor, hematoma) Vertebral column disease (e.g., primary and metastatic malignancy and osteomyelitis) Disk infection Primary neurologic disease Degenerative and autoimmune arthropathies Herpes zoster Vascular disease (e.g., thoracic aortic dissection, acute coronary syndrome, pulmonary embolism) Thoracic cavity pathology (e.g., pleuritis, pericarditis, pneumonia, esophageal pathology) Intraperitoneal and retroperitoneal abdominal pathology (e.g., peptic ulcer disease, pancreatitis, hepatobiliary disease)

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MANAGEMENT Commonly, thoracic musculoskeletal pain is managed with analgesia. No studies show that there should be any difference in management compared with musculoskeletal low back pain. Thoracic disk disease is difficult to diagnose and manage. Symptomatic pain management and outpatient follow-up are recommended. Given the limited space in the spinal canal at the thoracic level compared with the lumbar level, spinal cord compression from a herniated disk is more likely at the thoracic level. Any herniated disk that precipitates an acute neurologic deficit warrants MRI and early neurosurgical evaluation.

DISPOSITION Patients with benign back pain in any part of the thoracic vertebral column can be discharged with follow-up by the primary care physician. Patients with a suspected thoracic disk require close outpatient follow-up. Most cases of subjective discomfort resulting from thoracic disks without objective neurologic findings resolve on their own, with one study showing a 77% improvement rate.[73] Although there are no clear guidelines as to when emergent neurosurgical consultation is required for thoracic disk herniation, patients with significant pain or neurologic compromise should be assessed rapidly. Radicular symptoms seem to respond better to surgery than nonradicular findings.

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REFERENCES 1. Ng KG: Automated noninvasive blood pressure measurement. Intensive Care World1995;12:89. 2. De Jong JR, Ros HH, De Lange JJ: Noninvasive continuous blood pressure measurement during anaesthesia: A clinical evaluation of a method commonly used in measuring devices. Int J Clin Monit Comput1995;12:1. 3. Jin X: Decreases in organ blood flows associated with increases in sublingual Pco2 during hemorrhagic shock. J Appl Physiol1998;85:2360. 4. Isenberg SJ: Continuous oxygen monitoring of the conjunctiva in neonates. J Perinatol2002;22:46. 5. Abraham E, Ehrlich H: Conjunctival and transcutaneous oxygen monitoring during resuscitation. Ann Emerg Med1984;13:287. 6. Severinghaus JW: Oximetry: What does it tell you?. ASA Annual Refresher Course Lectures1991;266:1. 7. Tremper KK, Barker SJ: Pulse oximetry. Anaesthesiology1989;70:98. 8. Sinex JE: Pulse oximetry: Principles and limitations. Am J Emerg Med1999;17:59. 9. Cote CJ: Adverse sedation events in pediatrics: A critical incident analysis of contributing factors. Pediatrics2000;105:805. 10. Burillo-Putze G: Transcranial oximetry as a new monitoring method for HEMS (Helicopter EMS). Air Med J2002;21:13. 11. Macnab AJ: The cost-benefit of pulse-oximeter use in the prehospital environment. Prehospital Disaster Med1999;14:245. 12. Ward KR, Yealy DM: End-tidal carbon dioxide monitoring in emergency medicine: Part 1. Basic principles. Acad Emerg Med1998;5:628. 13. Buhre W, Rossaint R: Perioperative management and monitoring in anaesthesia. Lancet2003;29:1839. 14. Wang VJ, Krauss B: Carbon dioxide monitoring in emergency medicine training programs. Pediatr Emerg Care2002;18:251. 15. Schneider RE, Murphy MF: Bag mask ventilation and endotracheal intubation. In: Walls RM, ed.Manual of Emergency Airway Management, 2nd ed. Philadelphia: Lippincott Williams & Wilkins; 2004: 43-69. 16. Cardoso MM: Portable devices used to detect endotracheal intubation during emergency situations: A review. Crit Care Med1998;26:957. 17. Wahba RWM, Tessler MJ: Misleading end-tidal CO2 tensions. Can J Anaesth1996;43:862. 18. Ward KR, Yealy DM: End-tidal carbon dioxide monitoring in emergency medicine: Part 2. Clinical applications. Acad Emerg Med1998;5:637. 19. Ahrens T: End-tidal carbon dioxide measurements as a prognostic indicator of outcome in cardiac arrest. Am J Crit Care2001;10:391. 20. Wayne MA, Levine RL, Miller CC: Use of end-tidal carbon dioxide to predict outcome in prehospital cardiac arrest. Ann Emerg Med1995;25:762. 21. Marik PE: Sublingual capnography: A clinical validation study. Chest2001;120:923. 22. Boswell SA, Scalea TM: Sublingual capnography: An alternative to gastric tonometry for the management of shock resuscitation. AACN Clin Issues2003;14:176. 23. Baron BJ: Diagnostic utility of sublingual Pco2 for detecting hemorrhage in patients with penetrating trauma. Acad Emerg Med2002;9:492. 24. Kolb JC: Blunt trauma in the obstetric patient: monitoring practices in the ED. Am J Emerg Med 2002;20:524. 25. An educational aid to obstetrician-gynecologists: Trauma during pregnancy. ACOG Technical Bulletin 1991;161:1-5.

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KEY CONCEPTS {,

{, {,

Although thoracic disk herniation can result in significant upper back pain, other, more dangerous etiologies must be considered first, such as an aortic dissection, pulmonary embolism, and acute coronary syndrome. The associated neurologic examination with thoracic disk hernations can be extremely variable, ranging from nonspecific paresthesias to significant upper motor neuron weakness. The incidence of vertebral metastatic malignancy is higher in the thoracic spine compared with the lumbar spine.

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Marx: Rosen's Emergency Medicine: Concepts and Clinical Practice, 6th ed., Copyright © 2006 Mosby, Inc.

Chapter 52 – Pelvis A. Adam Cwinn

PERSPECTIVE In evaluating a trauma patient, a pelvic fracture or dislocation indicates the profound magnitude of disruptive energy at the time of injury. Significant pelvic injury alerts the physician to the likelihood of major injury to other body systems, and the pelvic injury itself poses diagnostic and therapeutic challenges.

Epidemiology Mechanisms of injury in pelvic fractures include motor vehicle crash in 57% to 71% of patients, collisions with pedestrians in 13% to 18%, motorcycle crashes in 5% to 9%, falls in 4% to 9%, and crushing forces in 4% to 5%.[] Depending on the size of the study group, the types of pelvic fractures included in the study, and the associated trauma to other body systems, reported mortality figures for pelvic injuries range from 8% to 13% in studies totaling 4621 patients with heterogeneous mechanisms of injury.[] The subsets of patients with high-energy pelvic injuries or open pelvic fracture from these studies have a much higher mortality rate. Pedestrians who are struck by motor vehicles and sustain pelvic trauma have a mortality rate of 23%.[5] Mortality in patients with blunt trauma who have the combination of pelvic ring fractures and hemorrhagic shock is approximately 50%.[] This chapter reviews the pertinent anatomic and radiologic anatomy and discusses pelvic trauma in three broad categories: (1) injury to the pelvic viscera and soft tissues, (2) bony injury, and (3) related hemorrhage. The term pelvic fracture includes fractures and dislocations.

Anatomy The bony pelvis is composed of the right and left innominate bones, the sacrum, and the coccyx ( Figure 52-1 ). The innominate bone is formed by three bones that fuse at the acetabulum: the ilium, the ischium, and the pubis. The bony pelvis provides protection for its visceral contents, serves as attachment points for muscles, and transmits weight from the trunk to the lower limbs. Strong posterior ligaments—the sacrospinous, sacrotuberous, iliolumbar, and anterior and posterior sacroiliac (SI) ligaments—provide considerable mechanical support, and disruption of these ligaments is the major cause of pelvic instability after injury.

Figure 52-1 Pelvic anatom y. A Anterior view of pelvis. B Lateral view of right innom inate bone. 1, Iliac fossa; 2, iliac crest; 3, anterior superior iliac spine; 4, anterior inferior iliac spine; 5, symphysis pubis; 6, body of pubis; 7, superior ram us of pubis; 8, inferior ram us of pubis; 9, ram us of ischium ; 10, ischial tuberosity; 11, obturator foram en; 12, ischial spine; 13, lesser sciatic notch; 14, acetabulum (14a, articular surface; 14b, fossa); 15, sacrum ; 16, anterior sacral foram ina; 17, sacroiliac joint; 18, anterior sacroiliac ligam ent; 19, sacrotuberous ligam ent (sacrum to ischial tuberosity); 20, coccyx; 21, sacrospinous ligam ent; 22, greater trochanter of fem ur; 23, lesser trochanter of fem ur; 24, iliofem oral ligam ent; 25, pubofem oral ligam ent; 26, arcuate line; 27, posterior or fem orosacral arch, through which m ain weight-bearing forces are transm itted; 28, anterior arch.

The main weight-bearing forces are transmitted through the posterior wall of the pelvis, called the posterior arch, which is composed of thick bone and ligaments. The rich network of major arteries, veins, and nerves that course adjacent to the anterior wall of the posterior arch may be injured concomitantly with forces causing bony injuries of this arch.

Vascular Anatomy and Pathophysiology

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Most of the blood supply to the pelvis comes from the left and right internal iliac arteries. The internal iliac arteries course at the level of the SI joints. The various arteries that derive from the internal iliac arteries initially run in close proximity to the posterior pelvic arch and eventually anastomose extensively with each other, forming a rich collateral network. The superior gluteal artery is the largest branch. Because it originates at right angles from the internal iliac artery and has little muscular protection, the superior gluteal artery is commonly injured in fractures of the posterior pelvic arch. The obturator and internal pudendal branches are often injured in fractures involving the pubic rami.[9] The venous system also has many collateral branches and is without valves, allowing bidirectional flow. The veins are arranged in a plexus that adheres closely to the pelvic walls. Because these veins are thin walled, they do not have the ability to constrict in response to damage.[9] This anatomic arrangement of the arteries and veins accounts for the hemorrhage seen with pelvic fractures. Without performing angiography, it is impossible to know clinically if a retroperitoneal hematoma is caused by disruption of major arteries or veins or smaller, unnamed blood vessels. Most pelvic hematomas are venous in origin, however, and are contained and tamponaded retroperitoneally by the intact peritoneum. Normal hemostatic mechanisms contain many hematomas, but some continue to enlarge, producing hemorrhagic shock. The hematoma also may dissect anteriorly to invade the anterior abdominal wall—to the chagrin of the unwary clinician who introduces a scalpel or peritoneal dialysis catheter. A retroperitoneal hematoma also may rupture through the peritoneum into the abdominal cavity, causing a loss of the tamponade effect. Hemorrhage from pelvic fractures results from lacerations of the rich vascular network supplying the pelvis and collects in the retroperitoneal space, but considerable bleeding also may occur from the marrow at the fracture sites.[9] Coagulopathy is another cause of persistent retroperitoneal bleeding and should be considered when the patient does not respond to fluid and blood replacement.

Neurologic Anatomy and Pathophysiology The cauda equina course through the sacral spinal canal and exit through the sacral neural foramina to form the lumbar and sacral plexus. Injury to the posterior bony pelvis and sacrum may result in neurologic deficits in the lower extremities and autonomic dysfunction involving the bowel, bladder, and genitalia.

CLINICAL FEATURES Prehospital Care Paramedics should recognize mechanisms of injury that may result in severe trauma to the pelvis, such as an automobile striking the pelvis of a pedestrian or heavy objects crushing the pelvis. On-scene times should be kept as short as possible in cases of severe pelvis injury. Paramedics should consider immobilizing the fractured pelvis using commercial pelvic binding devices or by wrapping the pelvis with a sheet and binding the legs together in cases of prolonged transit times of patients in shock with severe pelvis injury.[10]

History and Physical Examination As priorities permit, the emergency physician should obtain the following history: the mechanism of injury, location and radiation of pain, whether gross hematuria was present if voiding occurred after the injury, last menstrual period, and possibility of pregnancy. On inspection, rotation of the iliac crests indicates a serious pelvic fracture. Leg-length discrepancy may suggest a hip injury or cephalad migration of an unstable hemipelvis. The presence of tenderness on palpation of the sacrum and SI joints in patients with a Glasgow Coma Scale score of 12 or more is an important and reliable sign of injury to the posterior pelvis ring.[11] The integrity of the pelvic ring can be tested clinically by gentle lateral compression and distraction of the iliac crests and gentle inward compression of the symphysis pubis. Extensive movement of fracture fragments should be avoided when any instability is detected. Pain with axial percussion through the bottom of the foot may localize a hip injury or pelvic fracture site. Care must be exercised so that fractures are not displaced further by these maneuvers, which potentially could exacerbate pelvic fracture–related hemorrhage. Careful inspection of the skin and skin folds is necessary to identify open fractures. Perineal ecchymosis or hematoma may be observed, and in cases when many hours have elapsed since the injury, ecchymosis on the abdomen (Cullen's sign) or flanks (Grey Turner's sign) from retroperitoneal hemorrhage may be present. The penis should be milked to examine for blood at the meatus. The digital rectal examination should evaluate sensation, sphincter tone, position and consistency of the prostate, presence of a presacral hematoma, bony contour of the sacrum and coccyx, mucosal penetration of bony spicules, and presence of frank or occult blood. In the setting of a pelvic fracture, female patients should undergo a vaginal examination

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to diagnose an open fracture. Digital rectal and vaginal examinations must be performed carefully, especially in an unconscious patient who cannot localize pain, because it is possible to create an open fracture iatrogenically through the vaginal or rectal wall. The examiner should be mindful when performing these examinations that bony spicules can cause injury to self. Extravasated urine may be detected in the scrotum or the subcutaneous tissues of the penis, vulva, or abdominal wall. The presence and quality of pulses in the lower limb should be assessed, as should sensation, strength, and deep tendon reflexes.

Visceral and Soft Tissue Injuries Open Pelvic Fractures and Deep Perineal Laceration An open pelvic fracture is present when there is direct communication between the fracture site and a skin, rectal, or vaginal wound.[12] These are potentially lethal injuries, especially if the open nature is not recognized, with early mortality resulting from hemorrhage in the acute phase and sepsis and multiorgan failure in the delayed phase.[13] Even after introduction of an aggressive patient treatment protocol, the overall mortality rate of open pelvic fractures is 30% in several series and 78% in the subgroup of patients older than age 40.[] The patient must be rolled on his or her side and the skin over the posterior pelvis and gluteal area inspected carefully for wounds. Some fractures are open only by virtue of a bone spicule penetrating the vagina or rectum, but these must be identified by careful digital rectal and vaginal examinations. Hemorrhage from a large open laceration may be treated by external packing and application of a pressure dressing or packing followed by application of the pneumatic antishock garment.[] A perineal laceration should be inspected but not probed, for fear of disturbing hemostasis and introducing infection. The perineal wounds require aggressive operative debridement and irrigation, and in cases in which the rectum is violated, a diverting colostomy is required.[]

Urologic Injury The overall incidence of bladder or urethral disruption associated with pelvic fracture ranges from 7% to 25%. More than 80% of patients with lower urinary tract injury after blunt trauma have a pelvic fracture, however.[18] The length and tethered anatomy of the male urethra make it vulnerable to rupture in association with high-energy pelvic injuries. Urethral rupture in women with pelvic fractures is less common, but does occur.[19] Although there does not seem to be a significant relationship between the type of pelvic fracture and the type of bladder injury, fractures adjacent to or involving the symphysis pubis are associated most often with urologic injuries.[20] In 103 patients with pelvic fractures in whom cystography was performed, all patients with bladder rupture had fractures of the anterior pelvic arch.[21] It formerly was recommended that a pelvic fracture associated with gross or microscopic hematuria mandated cystourethrography; however, several studies show that microscopic hematuria is not associated with significant urologic injury in these patients.[] Urethrography and cystography are unnecessary in the absence of gross hematuria or clinical suspicion of bladder or urethral rupture.[] Blood at the urethral meatus necessitates a retrograde urethrogram followed by a cystogram. Gross hematuria is investigated by a combination of urethrography, intravenous pyelography, cystography, and computed tomography (CT). The sequence and types of examinations are individualized for each patient. Male sexual dysfunction is a recognized complication of pelvic trauma. The incidence of impotence associated with urethral rupture is significant. In the absence of urethral injury, impotence still may occur secondary to neurovascular disruption associated with the pelvic fracture.[24]

Neurologic Injury Neurologic injury occurs commonly in patients with pelvic ring fractures that have vertical sacral fractures as a component and with transverse fractures at or above the S3 level. Among patients with vertical fractures that involve the foramina, 28% have associated neurologic deficits. In patients with fractures medial to the foramina involving the spinal canal, 56% have neurologic deficits.[25] Autopsy and clinical studies performed on patients with pelvic fractures have documented disruptions by traction and compressive forces at many levels along the neural pathway: within the sacral spinal canal, within the neural foramina, distally in the roots and divisions that form the sacral and lumbar plexus, and to the various nerves derived from these plexus.[25 ]

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Cauda equina syndrome and various plexopathies and radiculopathies may occur as follows. Injury to the L5 root may cause weakness of muscles in the anterior tibial compartment and sensory deficits in the dorsum of the foot and lateral calf. Injury to S1 and S2 roots may cause weakness of hip extension, knee flexion, and plantar flexion and sensory deficits on the posterior aspect of the leg, sole and lateral foot, and genitalia. Injury to S2-5 roots and distal afferent, efferent, and autonomic fibers causes sensory deficits in the perineum, sexual dysfunction, and bowel and bladder dysfunction. Cauda equina syndrome may be fully or partially present with sacral fractures: There is hyperesthesia and later anesthesia in a saddle-shaped distribution in the groin; weakness of ankle plantar flexion, hamstrings, and gluteus muscles; and decreased or absent ankle jerk. With involvement of the lower sacral roots, a neurogenic bladder with overflow incontinence, motor and sensory deficits in the lower extremities, anal sphincter dysfunction, and sexual dysfunction may occur. All patients with neurologic deficits from sacral fractures require orthopedic or neurosurgical consultation.

Gynecologic Injury Vaginal bleeding may result from uterine or vaginal wall laceration secondary to deceleration forces or crush injury or, in a pregnant woman, secondary to abruptio placentae or uterine perforation. Most gynecologic injuries associated with pelvic fracture occur in pregnant patients; however, the nongravid uterus and the fallopian tube or ovary also may be injured.[] Dyspareunia may occur as a late sequela of pelvic fracture.[28] Sexual dysfunction in women also is reported as a sequela of pelvic fracture.[29] Gynecologic consultation is indicated when there is injury to the female reproductive tract in association with a pelvic fracture.

Thoracic Aorta There is a well-documented association between pelvic fracture and injury to the thoracic aorta.[30] This is presumably the result of the enormous forces required to produce either injury. In particular, anteroposterior compression fractures are associated with an eight times greater incidence of aortic rupture than is seen in the overall blunt trauma population.[30]

Penetrating Pelvic Trauma Because of the complex anatomy of the viscera, blood vessels, and nerves within the pelvis, penetrating trauma to this area presents a major challenge to the physician. Overall mortality in this group of patients has been reported to be 6% to 12%, but the mortality of patients in shock is 50%.[] At surgery, vascular injuries singly and in combination were found to involve the aorta; common iliac artery; and external, internal, and common iliac veins. Injuries to genitourinary structures and hollow viscera were common, and a particular concern was fecal contamination from colorectal injury. When present, the finding of blood on digital rectal examination is an important clue that rectal injury has occurred. Emergent surgical consultation is required in all cases of penetrating pelvic trauma.

DIAGNOSTIC STRATEGIES Radiology Routine radiographs of the pelvis are not necessary in asymptomatic, awake, alert blunt trauma patients who have a normal physical examination of the pelvis.[] The physician should obtain an anteroposterior plain radiograph of the pelvis early in the resuscitation phase, however, on all victims of severe blunt trauma who are symptomatic or have a compromised ability to perceive pain. Some sacral fractures and SI joint disruptions may not be well visualized on the anteroposterior view. In hemodynamically stable patients, two additional views—the inlet and outlet (tangential) projections—are often necessary to show these injuries. The anteroposterior, inlet, and outlet views identify virtually all clinically important bony injuries.[36]

Anteroposterior View The anteroposterior view of the pelvis identifies most pelvic fractures and dislocations but often does not show the degree of bony displacement. On the anteroposterior view, the symphysis pubis is normally no more than 5 mm wide, and a small (1 or 2 mm) vertical offset of the left and right pubic rami is normal.[37] Overlapping at the symphysis pubis is abnormal and is the result of a severe crushing injury. Normally the SI joint is approximately 2 to 4 mm wide.[37] On the anteroposterior view, the physician may judge the degree of pelvic rotation caused by technique and positioning by the presence of asymmetry in the size and shape of the left and right obturator foramina and iliac wings. Diastasis of the SI joint also causes an asymmetric appearance of the obturator foramina and the iliac wings: If there is displacement into external rotation, the affected iliac wing appears broader, and the anterior iliac spine appears more prominent.[37] Avulsion fracture of the fifth lumbar transverse process by

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the iliolumbar ligament often accompanies an SI joint disruption or a vertical sacral fracture and is a valuable clue to posterior arch injuries.[37]

Inlet View The inlet projection is obtained with the x-ray beam angled from the head toward the feet at 60 degrees to the plate such that it is perpendicular to the pelvic inlet ( Figure 52-2 ).[16] This view shows posterior and cephalic displacement of the fractures of the posterior arch, widening of the SI joint, and inward displacement of the anterior arch.

Figure 52-2 The inlet view. A Inlet x-ray projection of pelvis. 1, Beam is angled 60 degrees to plate. This view is possible with a portable m achine. B and C Inlet of pelvis is well shown in this radiograph of a unilateral vertical shear fracture with cephalad and posterior displacem ent of the left hem ipelvis (Tile type C1). 1, Norm al sacral ala on the right side; 2, left sacral ala is indistinct because of a vertical fracture, and the cephalad and posterior displacem ent of this hem ipelvis is shown by this inlet projection; 3, ischial spine on the left is partially obscured by bowel gas, but it is located m ore cephalad com pared with the right spine because of cephalad displacem ent of the left hem ipelvis; 4, fractured left superior pubic ram us with displacem ent cephalad; 5, on the inlet view, we are looking through the superior and inferior pubic ram i, which are superim posed so that the obturator foram ina are not seen.

Outlet View The opposite view is the outlet projection, in which the beam is at 30 degrees of cephalic angulation to the plate and is roughly perpendicular to the long axis of the sacrum. It is useful for showing sacral fractures and disruptions of the SI joints.[16] The inlet and outlet projections are performed by angling the beam, and they do not require the patient to be moved.

Computed Tomography Although anteroposterior, inlet, and outlet series detect most pelvic fractures and provide the necessary details for accurate classification,[36] CT has an important role in the planning of orthopedic treatment and the diagnosis of associated visceral injuries and hemorrhage. CT shows whether injuries to the posterior arch are impacted or unstable, or whether there is rotational deformity. CT has the added advantage of rapidly acquiring detailed information on the pelvic fracture and can be reconstructed from other studies, such as abdominopelvic CT scan. Because CT provides detailed information on injury to abdominal and pelvic visceral structures as well as the pelvic fracture, in many centers it has largely replaced plain radiography for suspected pelvic fracture in a hemodynamically stable patient.

Evaluation of Hemorrhage A high percentage of patients with retroperitoneal hemorrhage from pelvic fracture also have active intraperitoneal hemorrhage from coincident organ injury. In a hypovolemic patient with pelvic fracture, it is important to establish early on whether there is hemorrhage within the abdominal cavity necessitating laparotomy. Diagnostic strategies for evaluation of pelvic fracture–associated hemorrhage include diagnostic peritoneal lavage, ultrasound, and CT. Regardless of the modality of evaluation, it is crucial to avoid unnecessary laparotomy because of the higher mortality rate for hemodynamically unstable patients with pelvic fractures who undergo a negative abdominal exploration.

Diagnostic Peritoneal Lavage Diagnostic peritoneal lavage (DPL) is a widely accepted, rapid, and accurate means of establishing the presence of intra-abdominal hemorrhage. It has been largely supplanted in many centers by ultrasound, which is less invasive, and with CT in stable patients. Nevertheless, DPL is an important and effective tool to assist with difficult triage decisions in the trauma patient.[38] A pelvic fracture presents a special situation for DPL and requires an alteration in the technique and an understanding of the variables that can confound the result. DPL is safe and accurate in the presence of a pelvic fracture, provided that the fully open technique is employed (i.e., the peritoneum is entered under direct visual control).[39] If this requirement is met, the false-positive and false-negative rates are each 0.7%, which is comparable to the rates reported for DPL in

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patients without pelvic fractures.[39] Using the fully open technique prevents the operator from blindly entering a retroperitoneal hematoma that may have dissected into the anterior abdominal wall. The DPL may be performed in the infraumbilical location in most patients; however, the supraumbilical location should be employed if any of the following conditions are present: prior abdominal scars, time delay since the injury of more than 1 hour, or a hematoma encountered during the procedure.[39] DPL is useful in establishing the priorities for laparotomy, external fixation, and angiography in a hemodynamically unstable patient with major pelvic fractures, depending on whether the aspirate is negative or positive ( Figure 52-3 ).

Figure 52-3 Algorithm for initial m anagem ent of hem odynam ically unstable pelvic fractures. 10,45 Note: Ultrasound is in wide use in this setting, but its accuracy specifically in the presence of pelvic fracture–related hem orrhage has not been studied.

A negative peritoneal aspirate indicates that the peritoneal cavity is not a major source of bleeding or a significant contributor to hemorrhagic shock. Assuming that external and thoracic sources of blood loss have been eliminated as causes of hemodynamic instability, a negative DPL in a patient with a major pelvic fracture is evidence of the presence of a large retroperitoneal hematoma. Angiography with therapeutic embolization and mechanical fracture stabilization should be pursued aggressively. Gross aspiration of blood indicates possible major intra-abdominal hemorrhage. Immediate laparotomy is recommended for hemodynamically unstable patients with pelvic fractures.[] The lavage that is positive by cell count criteria alone is a special situation. If these patients are hemodynamically unstable, angiography with therapeutic embolization and external pelvis fixation should be performed before laparotomy.[]

Ultrasound (FAST) Focused assessment with sonography for trauma (FAST) is widely used to identify free intraperitoneal fluid rapidly in the trauma patient. The accuracy and safety of the FAST technique in evaluating patients with serious pelvic fractures who are hemodynamically unstable have not been published. Nevertheless, a positive FAST study that shows free fluid is widely used as a triage point to decide on laparotomy in a hemodynamically unstable patient with pelvic fracture. Important caveats relating to FAST in patients with pelvic fractures should be kept in mind. First, it is impossible to evaluate the retroperitoneum with diagnostic ultrasound. Second, there is a significant incidence of false-negative diagnostic ultrasound in patients with pelvic fractures.[42]

Computed Tomography If the patient is hemodynamically stable, CT of the abdomen may be undertaken to evaluate intraperitoneal and retroperitoneal injury. Additional cuts through the pelvis show the degree of displacement and rotation at the sites of pelvic fracture. CT scan with intravenous contrast often can distinguish a stable hematoma from ongoing bleeding from pelvic arteries.[43] The presence or absence of extravasated intravenous contrast material on CT scan of the pelvis is useful in predicting which patients will require therapeutic angiography.[] These comments on CT apply to a hemodynamically stable patient with pelvic injury; however, in a critically ill unstable patient, the value of FAST or DPL in quickly establishing treatment priorities should not be underestimated.

MANAGEMENT General Management Attempts should be made to stabilize the patient hemodynamically with crystalloid infusion. Transfusion of blood products should be initiated without delay in the presence of hypotension and a severe pelvic fracture.[ 10] Lower limb intravenous sites should be avoided in patients with severe pelvic fractures because the infused products may be delivered to the retroperitoneal space.[41] Wrapping the pelvis tightly with a sheet and securing this with towel clips or the use of a pelvic binder to splint the fracture temporarily and tamponade pelvic bleeding is recommended.[] Because many patients with severe pelvic fractures have concomitant injuries to other body systems, the potential need for and timing of laparotomy, angiography,

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and skeletal fixation must be considered early in the course of resuscitation. Figure 52-3 is an algorithmic representation of the investigation and resuscitation of a patient with pelvic injury.

Injury to Bone Classification Multiple classification schemes for pelvic fractures have been proposed. This chapter uses Tile's classification ( Box 52-1 ).[16] Tile's classification is based on the concepts of high-energy and low-energy forces, the mechanism of injury, and the biomechanical factors that together determine the need for external and internal fixation and predict the likelihood of serious hemorrhage and associated injuries. The biomechanical factors include the direction of forces applied to the pelvis, the concepts of rotational instability and vertical instability, and the importance of injury to the strong posterior ligaments of the pelvis.[] Fractures of the acetabulum are classified separately from other pelvic injuries. The terms unstable fracture (referring to mechanical stability) and unstable patient (referring to hemodynamic status) should not be confused, although a cause-and-effect relationship often exists. BOX 52-1 Tile's Classification of Pelvic Fractures

Type A—Stable pelvic ring injury A1— Avul sion fract ures of the inno mina te bone A2— Stabl e iliac wing fract ures or stabl e mini mall y displ aced ring fract ures A3— Tran sver se fract ures of the cocc yx

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and sacr um Type B—Partially stable pelvic ring injury (rotationally unstable, vertically stable) B1— Ope n book injur y— unila teral B2— Later al com pres sion injur y B3— Bilat eral type B injuri es Type C— Unstable pelvic ring injury (vertical shear) (rotationally and vertically unstable) C1 — Unila teral C2 — Bilat eral, one side type B, one side type C C3 — Bilat eral type C

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lesio ns From Tile M: Fractures of the Pelvis and Acetabulum, 2nd ed., Baltimore, Williams & Wilkins, 1995.

Low-Energy Fractures (Tile Type A) Stable Pelvic Ring Injury Fractures of individual bones without involvement of the pelvic ring represent one third of all pelvic fractures. In general, these are stable injuries that heal well with rest and analgesic drugs for pain control ( Figure 52-4 ).[16]

Figure 52-4 Fractures of individual pelvic bones. 1, Avulsion of anterosuperior iliac spine; 2, avulsion of anteroinferior iliac spine; 3, avulsion of ischial tuberosity; 4, fracture of superior pubic ram us; 5, fracture of inferior pubic ram us; 6, fracture of ischial ram us; 7, fracture of iliac wing; 8, transverse fracture of sacrum ; 9, fracture of coccyx.

Avulsion Fractures—Tile Type A1. Avulsion fractures (see Figure 52-4 ) usually occur during athletic activities and are the result of a sudden, forceful muscular contraction or excessive muscle stretch. They are seen more commonly in older children and teenagers before closure of the corresponding physis occurs; adults may have the same symptoms from ligamentous injury at these sites without radiographic abnormality. The ischial tuberosity may be avulsed during strenuous contraction of the hamstrings ( Figure 52-5 ). There is pain on palpation of the involved tuberosity, and this pain is increased by flexion of the hip with the knee in extension (hamstrings stretched), but not with the knee flexed (hamstrings relaxed). Ischial tuberosity avulsion also may cause chronic discomfort with no history of acute injury.

Figure 52-5 A and B Radiograph and interpretive drawing. 1, Avulsion of ischial tuberosity through epiphysis; 2, normal ischial epiphysis.

A portion of the iliac crest epiphysis may be avulsed by contraction of the abdominal muscles. Similarly, the anterior superior iliac spine may be avulsed by forcible contraction of the sartorius muscle. Forceful contraction of the rectus femoris (as in kicking a ball) can result in the less common injury of anterior inferior iliac spine avulsion; however, this radiographic finding must be distinguished from a normal variant, the os acetabuli, which is a secondary center of ossification at the superolateral margin of the acetabulum.[37] Clinical examination is similar in these injuries and reveals local pain, swelling, and limitation of motion. The conservative treatment of all these avulsion injuries is analgesia and bed rest in a position that avoids tension on the affected muscles. Orthopedic consultation is advised for follow-up care. Surgical treatment rarely is required.[48]

Stable, Minimally Displaced Fractures of the Pelvic Ring—Tile Type A2 The normal pelvis is not totally rigid because of the slight mobility at the SI joints and symphysis pubis and the inherent elasticity of bone. A single break in the ring is possible. Nevertheless, the pelvis is not totally

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forgiving, and identification of a single break in the ring should prompt a search for a second disruption.

Iliac Wing Fracture—Tile Type A2-1. Isolated fracture of the iliac wing was described by Duverney in 1751 and now bears his name. It is caused by direct trauma to the iliac crest, usually by lateral compression forces. Although displacement is usually minimal because of the arrangement of the muscle attachments of the abdominal wall, orthopedic consultation is recommended. The fracture may extend into the acetabulum, altering the treatment and prognosis. Severely displaced fractures of the iliac wing require open reduction and internal fixation.[16]

Stable Undisplaced or Minimally Displaced Fractures of the Pelvic Ring— Tile Type A2-2. An isolated fracture of the superior or inferior pubic ramus is the most common pelvic fracture. These fractures are stable and do not displace. They are common fractures in elderly people after a fall and must be considered in the evaluation of an acutely painful hip. Fracture of the body of the ischium is a rare injury that may result from a fall in the sitting position. These fractures around the obturator foramen are treated conservatively with bed rest, analgesia, and early mobilization. Fracture of the superior and inferior pubic rami on the same side is a commonly encountered injury after a fall or vehicular crash. These are generally stable fractures and are treated conservatively. The presence of significant displacement at the fracture site is an important finding and always indicates a second disruption elsewhere in the pelvic ring that must be diagnosed. Even in the absence of displacement, fractures of both rami on the same side may be associated with an unrecognized impaction fracture of the posterior pelvis. If the patient complains of pain in the posterior pelvis or if the radiograph is at all suspicious, further imaging is required. After a ramus fracture, some patients may complain of hip or SI pain despite plain radiographs of these areas that appear normal; these patients subsequently may develop symptoms and request re-evaluation. A study of patients who sustained apparently isolated pubic ramus fractures from simple falls showed increased uptake of radionuclides on bone scans in the acetabulum and SI joint, suggesting that occult bony or ligamentous injury accounted for the complaints of pain.[49] When such patients are evaluated, repeat plain radiographs should be performed. If radiographs are normal, symptomatic treatment, rest, and close follow-up can be prescribed. Radionuclide bone scan can be considered if confirmation of occult posterior injury is required. Stress fractures of the pelvis rarely have been reported with vigorous athletic or military training and in the last trimester of pregnancy.[] Pathologic fracture related to neoplasm, Paget's disease, or dietary osteomalacia is included in the differential diagnosis. Diagnosis of stress fractures is based on the clinical evaluation and can be confirmed by radionuclide bone scan if necessary.

Four-Pillar Anterior Ring Injuries—Tile Type A2-3. Also termed a straddle fracture, four-pillar injuries refer to fractures of both pubic rami on both sides of the symphysis pubis, causing the so-called butterfly segment ( Figure 52-6 ). The injury is produced by a direct blow with a straddle mechanism. Four-pillar injuries also commonly are associated with lateral compression or vertical shear forces, in which case there are concomitant injuries to the posterior pelvic arch, and the injury would be classified as a Tile type B or C. A CT scan of the pelvis is required in cases of four-pillar injuries to detect and classify precisely the posterior arch injury and plan orthopedic treatment.[16] The genitourinary tract frequently is injured concomitantly with this type of pelvic fracture and must be evaluated carefully (see Figure 52-6 ).

Figure 52-6 Four-pillar (straddle) fracture (Tile type A2-3). A and B Partial inlet view of pelvis shows straddle fracture. 1 and 2, Marked com m inution of left pubic bone and com m inuted right superior and inferior ram i. This partial inlet projection shows displacem ent of fragm ents into the pelvis, which is not evident on the anteroposterior view of the sam e patient in C and D. A true inlet projection and com puted tom ography scan (not available) would provide further inform ation about the posterior arch, which is injured frequently in straddle fractures and always should be imaged (see text). C and D Postvoid cystogram of the sam e patient with anteroposterior pelvis. 1, Fractures of pubic ram i are seen again, but do not appear to be as displaced compared

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with A and B because this projection is an anteroposterior view: Even m inor degrees of angulation of the x-ray beam can change the appearance of pelvic fracture displacem ent; 2, extravascular contrast indicates bladder rupture; 3, left acetabular fracture is seen in this projection but not in B because of the difference in projection. The acetabular fracture disrupts the ilioischial line (see also Figure 52-10) and is a posterior column fracture.

Transverse Fractures of the Coccyx and Sacrum—Tile Type A3 Coccygeal Fracture—Tile Type A3-1. Patients may present to the emergency department for evaluation of pain after direct trauma to the coccyx. The mechanism of injury is frequently a fall in the sitting position or a kick. Fracture and injury also may occur during parturition. Physical examination reveals local tenderness to palpation in the gluteal crease, with pain and, sometimes, abnormal motion of the coccyx during palpation on digital rectal examination. Normally the tip of the coccyx moves 30 degrees anteriorly and 1 cm laterally.[51] Displacement also is diagnosed on rectal examination, but attempts at reduction are not recommended. Radiographic confirmation of a coccygeal fracture is not always necessary. Displaced fractures often are seen on the lateral view, but the diagnosis is evident on rectal examination. Undisplaced fractures may be difficult to show radiographically. The physician must decide whether the knowledge gleaned from x-ray studies would alter the therapy to a degree that warrants radiation exposure to the pelvis, especially considering that most of these fractures occur in women. Treatment of coccygeal fracture consists of bed rest, stool softeners, analgesia, and sitz baths to relieve muscle spasm. As activity is increased, maneuvers that may minimize discomfort include using an inflatable rubber donut cushion, alternate sitting on the side of each buttock, slouching to displace body weight more proximally, and sitting on a hard chair rather than a soft one (sinking into a soft chair may distribute weight onto the coccyx).[51] Because of muscle action on the fragment, healing is slow and patients must be cautioned that discomfort may be prolonged. In the case of persistent severe disability, an orthopedic consultation is indicated for considerations of local steroid injection or possible coccygectomy.[52] Other causes of coccydynia (besides fracture) include trauma during parturition; faulty posture; midline disk herniations (caused by nonsegmental referral of pain from irritation of the dura); lumbar facet arthropathy; compression of the first, fourth, and fifth sacral roots; neuralgia from sacral plexopathy or sacrococcygeal neuropathy; infections; and local tumors.[51]

Sacral Fractures Several classification systems have been proposed for fractures of the sacrum and share a distinction between transverse and vertical fractures: The transverse fractures do not involve the pelvic ring, but vertical fractures of the sacrum do.[] The neurologic complication rate secondary to vertical sacral fractures and transverse fractures above the S4 level has been reported to be 21% to 34%[]; however, transverse fractures at or below S4 are unlikely to be accompanied by neurologic injury.[53] Orthopedic or neurosurgical consultation is warranted in all cases of sacral fracture.

Transverse Sacral Fracture—Tile Type A3-2 (Undisplaced), A3-3 (Displaced). An upper sacral transverse fracture is the result of a flexion injury, such as being struck on the lower back by a heavy load while bending over, or by direct forces to the sacrum, as in a fall from a great height.[53] The patient complains of pain in the buttocks, perirectal area, and posterior thighs. There may be local pain, swelling, and bruising overlying the sacrum, and on gentle bimanual rectal examination, severe pain, abnormal motion, and palpable hematoma may be elicited. Radiographically the fracture may be difficult to visualize on anteroposterior and lateral projections, in which case an outlet view may be helpful. Neurologic injuries also are common, with upper transverse sacral fractures necessitating careful clinical evaluation of sacral nerve root function. A lower sacral transverse fracture results from direct trauma to the area. Nerve injury is uncommon with this type of fracture.[53] The comments on general physical findings for upper transverse fracture are applicable here. Attempts at reduction of displaced sacral fractures bimanually through the rectum are discouraged because the injury may be converted to a contaminated open fracture, or an existing presacral hematoma may be enlarged. Surgery is commonly necessary for fractures associated with neurologic dysfunction.[] Simple lower transverse fractures with no associated injury are managed with bed rest and analgesia.

Vertical Sacral Fracture—Tile Type C1-3.

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Vertical sacral fractures are seen only as a component of high-energy fractures. Vertical fractures are classified further into three groups according to whether the fracture line extends lateral to the sacral foramina, through the foramina, or medial to them, involving the central spinal canal.[25] The diagnosis of this fracture on radiographs hinges on careful examination of the symmetrical cortical lines that are normally present at the superior margins of the sacral foramina on the anteroposterior view. Disruption, distortion, or asymmetry of these lines is an important marker of sacral fractures.[37]

High-Energy Fractures (Tile Types B and C) Transmission of high-energy forces to the pelvis causes injury to the posterior, weight-bearing arch resulting in double breaks in the pelvic ring. These are mechanically unstable fractures by definition, although the degree of instability varies with the pattern of the fractures. Because of the large amount of force required to produce these injuries, they commonly are associated with intraperitoneal injuries, retroperitoneal hemorrhage, and injuries to other body systems. A patient with a double break in the pelvic ring must be considered to be critically injured. Malgaigne first described these serious double-break fractures in 1859, defining the pattern of multiple fractures that included both pubic rami plus a constellation of posterior arch injuries on the same side. The term Malgaigne fracture is mentioned for its historical relevance; the newer classification allows for more precise descriptions of the injuries. The following discussion of high-energy injuries uses the Tile classification, which is based on the biomechanical concept that stability of the pelvis depends on an intact posterior weight-bearing arch whose tensile strength derives from the thick SI, sacrotuberous, and sacrospinous ligaments.[16] Important radiographic clues to the presence of serious posterior arch fractures are listed in Box 52-2 . BOX 52-2 Radiographic Clues to Posterior Arch Fractures

{,

Avul sion of L5 trans vers e proc ess[* ]

{,

Avul sion of ischi al spin e[*]

{,

Avul sion of lowe r later al lip of the sacr um (sac rotub erou s

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{,

{,

liga ment )[*] Displ ace ment at the site of a pubi c ram us fract ure Asy mm etry or lack of defin ition of bone corte x at supe rior aspe ct of the sacr al fora mina

* Always indicates m echanical instability.

Tile Type B: Partially Stable Pelvic Ring Injury (Rotationally Unstable but Vertically Stable) Open-Book—Tile Type B1 (Unilateral) and B3 (Bilateral). Severe anteroposterior compression forces result in disruption at or near the symphysis pubis. As the forces continue in the anteroposterior vector, external rotation of the hemipelvis occurs, and the anterior SI ligament and sacrospinous ligaments rupture. The SI joint rotates open as a hinge supported by the intact posterior SI ligament, and the resulting injury is aptly described as an open-book fracture.[16] The other ligaments also remain intact; the injury is rotationally unstable but vertically stable.[16] When diastasis of the pubic symphysis is greater than 2.5 cm on the anteroposterior radiograph, the posterior injury is usually evident (most often SI diastasis, but occasionally sacral or iliac fracture) ( Figure 52-7 ).[16] CT of open-book fractures shows the anterior part of the SI joint to be widened, but the posterior portion to be normal; however, if the injurious forces continue, they may separate the hemipelvis, and the SI joint is seen as widely separated on the plain anteroposterior radiograph and the CT scan.[16] The anteroposterior radiograph may be misleading in suggesting a pure open-book fracture in cases with symphysis disruptions greater than 2.5 cm. These cases commonly are associated with severe type C vertical shear fractures, and careful clinical and CT assessment for vertical instability is essential to classify the fracture properly and plan treatment.[16]

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Figure 52-7 A and B Interpretive drawing and radiograph. Severe unilateral open-book fracture (Tile type B1) from anteroposterior com pression forces that is also open (com pound). 1, Separated pubic sym physis with asym m etry of hem ipelvis; 2, norm al sacroiliac joint; 3, separated sacroiliac joint; 4, cystogram with displacem ent and abnorm ally elongated shape of bladder caused by retroperitoneal hematom a associated with separated left sacroiliac joint, which has pushed the bladder to the right; 5, extravasated contrast into perineum from urethral rupture; 6, soft tissue air indicating an open fracture.

These same forces also may injure the neurologic and vascular structures at the posterior arch; the overall volume of the pelvis is increased in the open-book injury, allowing the expansion of a retroperitoneal hematoma. In several studies of patients with major pelvic ring disruptions, patients with severe grades of anteroposterior compression injuries have the highest crystalloid and blood requirements.[]

Lateral Compression Injury—Tile Type B2. Severe forces applied sideways through the pelvis cause inward rotation of the hemipelvis and reduce the pelvic volume by causing the following lesions. In the anterior arch, the possibilities are double rami fractures on the same side as the posterior injury (Tile type B2-1); double rami fractures on the opposite side of the posterior injury, the so-called bucket-handle fracture (Tile type B2-2); or an overriding symphysis pubis. In the posterior arch, the possibilities are impacted vertical fracture through the sacrum, anterior crush of the SI joint with intact posterior ligaments, or an impacted posterior complex with disrupted posterior ligaments and severe rotational instability ( Figure 52-8 ).[16] Compared with anteroposterior compression and vertical shear fractures, lateral compression fractures are associated with the least requirement for fluid replacement in general.[55]

Figure 52-8 Lateral com pression fracture (Tile type B2). A and B Anteroposterior view of the pelvis. 1, Norm al sacral foram inal lines on the left; 2, sacral foram inal lines on the right are indistinct and do not m irror the norm al side, indicating the subtle second break in the pelvic ring; 3 and 4, fractures of the superior and inferior pubic ram i are overriding and displaced, indicating the lateral com pression forces (there m ust be a second break in the pelvic ring); 5, normal sacroiliac joints. C and D Com puted tom ography scan of sam e pelvis. 1, Norm al sacroiliac joints; 2, com pression fracture of the sacrum through the foram en corresponding to the loss of definition of the foram inal lines in A and B.

Tile Type C: Unstable Pelvic Ring Injury (Rotationally Unstable and Vertically Unstable) Vertical Shear. The forces transmitted through the pelvis causing the injury in type C fractures have sheared through the posterior ligamentous complex, tearing them completely, and across the bony trabecular pattern, causing that hemipelvis to displace posteriorly and possibly cephalad.[47] This is a mechanically unstable pelvic injury and doubly so if vertical shear occurs on each side of the sacrum ( Figure 52-9 ). Type C fractures may be unilateral (C1), bilateral (C3), or a combination of a type C on one side and a type B on the other (classified as C2). Anteriorly the symphysis pubis or two to four pubic rami may be disrupted. Posteriorly there is gross displacement and instability through the sacrum, the SI joint, or the ileum.[]

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Figure 52-9 A and B Vertical shear fractures bilaterally (Tile type C3). At first glance, the pelvis appears normal because of the sm ooth, uninterrupted arcuate line, but careful interpretation reveals the extremely critical nature of the injuries: 1, Fractures through the sacrum —note loss of definition and sym m etry of sacral foram ina indicating vertical fractures through both sides of the sacrum (see com puted tom ography scan in D). 2, Transverse process fragment from right L5 (iliolum bar ligam ent attachm ent) is pathognom onic for a vertical shear fracture through the right sacrum. 3, Transverse process fragm ent from left L5, pathognom onic for a vertical shear fracture through the left sacrum . 4, Both hem ipelves are dislocated cephalad because of the double-ring fractures through each side of the sacrum . This dislocation explains why the L5 transverse processes appear so close to the iliac crests (the body of L5 is obscured because of rotational dislocation of the central free sacral fragm ent posteriorly and because of technique). 5, Norm al sacroiliac joints. C and D Com puted tom ography scan of sam e pelvis. 1, Bilateral com m inuted fractures of sacrum with lateral displacem ent of both hem ipelves; 2, norm al sacroiliac joints.

Avulsion of the ischial spine, the lower lateral lip of the sacrum, or the transverse process of the fifth lumbar vertebra (sites of insertion of ligaments) (see Figure 52-9 and Box 52-2 ) are important clues to the presence of vertical shear fractures.[47] The vertical shearing forces that act on the bone also act on the rich vascular network and nerve plexus that are directly adjacent to the bone. This activity accounts for the major hemorrhage and neurologic injuries associated with vertical shear fractures.

Implications of High-Energy Pelvic Injuries The implications of these injuries reach far beyond the issue of mechanical stability of the pelvis. The mortality rate for patients with vertical shear fractures was 25% and for anteroposterior compression fractures was 14% to 26% in a series totaling almost 2900 patients.[] High-energy fractures also are associated with major blood transfusion requirements, with one series reporting an average of 14.8 U in the anteroposterior compression group, 9.2 U in the vertical shear group, and 3.6 U in the lateral compression group.[55] These serious fractures attest to the large magnitude of force at the time of injury. They mandate an aggressive search for associated trauma to other body regions and a timely use of blood products, especially in elderly patients. Orthopedic consultation should be obtained early in the care of these patients because surgical stabilization of the pelvis can reduce the amount of retroperitoneal bleeding and late sequelae.

Acetabular Fractures Many pelvic fractures in adults involve the acetabulum. The force of injury can be transmitted to the acetabulum through the femur (e.g., striking the dashboard in an automobile crash) or laterally through the side of the hip. On physical examination, hip pain with reproduction of these forces (percussing the sole of the foot and the greater trochanter) is a helpful finding. Tile has a widely accepted separate classification for acetabular fractures ( Box 52-3 ). These four types may occur in combination with each other or in association with a femoral head dislocation or fractures of the pelvic ring. The radiographic anatomy of the acetabulum is explained in Figure 52-10 . BOX 52-3 Acetabular Fractures

{,

{,

Post erior lip fract ure Cent ral or trans vers e fract

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{,

{,

ure Ante rior colu mn fract ure Post erior colu mn fract ure

Figure 52-10 Schem atic drawing of radiographic anatom y of acetabulum in anteroposterior pelvis projection. a, Arcuate (iliopubic) line. b, Ilioischial line. c, Radiographic U or teardrop caused by superim position of parasagittal surface of ileum onto anteroinferior portion of acetabulum. d, Acetabular roof. e, Anterior lip of acetabulum . f, Posterior lip of acetabulum . ((Redrawn from Rogers LF, Novy SB, Harris NF: Occult central fractures of the acetab ulum . AJR Am J Roentgenol 124:98, 1975.))

The posterior lip fracture is the first and the most common form of acetabular fracture and usually is associated with posterior dislocation of the femoral head.[16] The second fracture is the central or transverse fracture. On the anteroposterior view of the pelvis, the fracture line crosses the acetabulum horizontally or obliquely and usually is seen clearly (see Figure 52-6D ). Three separate centers of ossification join within the acetabulum to form the innominate bone. This junction, called the triradiate cartilage, is seen as a Y-shaped lucency in the acetabulum until solid bony union occurs around age 20. On radiographs, this normal anatomic feature may be mistaken for a central fracture, although true fractures also can occur through the triradiate cartilage. Comparison views with the uninjured side may be helpful in difficult cases. The third fracture type involves the anterior, or iliopubic, column, which is formed by bone extending from the ilium to the pubis. The fracture disrupts the arcuate line, and the iliopubic column and radiographic U are usually displaced medially, but the ilioischial line remains intact ( Figure 52-11 ; see Figure 52-10 ). In the case of central dislocation, the femoral head also is displaced medially.

Figure 52-11 A and B Interpretive drawing and radiograph. Acetabular fracture from lateral com pression forces in the third trim ester. 1, The fetus (cranium punctured by acetabular bone); 2, medial dislocation of fem oral head with acetabular fracture; 3, arcuate line (see Figure 52-10) disrupted with medial displacem ent of anterior (iliopubic) colum n; 4, ilioischial colum n fragm ent; 5, left superior and inferior pubic ram i fractures. Note: Fetal assessm ent and m anagem ent would take precedence in this case over m aternal m echanical skeletal dysfunction.

The fourth fracture type involves the posterior or ilioischial column, which is the bone extending from the ilium to the ischium. The entire posterior column becomes separated from the pelvis: The fracture line begins at the sciatic notch, traverses the acetabulum, and ends near the ischiopubic junction. In cases in which the acetabular component is not displaced, it may be difficult to diagnose a posterior column fracture

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on the anteroposterior radiograph. Two helpful radiographic clues are discontinuity of the ilioischial line and separation of the ilioischial line from the radiographic U. CT scan of the acetabulum is the most sensitive imaging modality for further delineation of an acetabular fracture. If CT is not readily available, the external and internal plain film oblique views, also called the Judet views, are useful for imaging the acetabulum and both columns. After a fall, some patients may complain of extreme hip pain and inability to bear weight despite normal anteroposterior pelvis and lateral hip radiographs. An occult acetabular fracture should be considered in this situation, and further imaging should be pursued.

Hemorrhage Mortality in patients with blunt trauma who have the combination of pelvic ring fractures and hemorrhagic shock is approximately 50%.[] In the emergency department phase of the care of patients with pelvic fractures, the goals in terms of hemorrhage are as indicated in Box 52-4 . Blood transfusion is essential treatment, particularly for a patient with anteroposterior compression or vertical shear fracture who is hypotensive and has not responded well to crystalloid infusion. Either of the following simple findings on the anteroposterior view of the pelvis is predictive of the need for major blood transfusions: (1) an open-book fracture or (2) displacement of 0.5 cm or more at any fracture site in the pelvic ring.[56] BOX 52-4 Pelvic Fracture–Related Hemorrhage: Goals in the Emergency Department

1.

Res usci tatio n: Rec ogni ze the patie nt who is in hem orrh agic shoc k, and initiat e bloo d trans fusio n early in the resu scita tion.

2.

Rec ogni tion: Reali ze that

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3.

patie nts with post erior arch injuri es may have a retro perit onea l hem atom a contr ibuti ng to their hypo vole mic state . Eval uati on: Ident ify the patie nt who, in addit ion to a poss ible retro perit onea l hem atom a, has intraabdo mina l blee ding that nece ssita tes lapar otom

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4.

5.

y. Stab ilizat ion: Mini mize mov eme nt of bone at the fract ure sites so as not to distu rb the hem ostat ic proc esse s. Emb oliza tion: Und ersta nd the role and timin g of angi ogra phy in man agin g the patie nt.

In addition to blood transfusion, two important therapeutic modalities for control of hemorrhage are mechanical stabilization of the pelvis and angiographic embolization. There has been some debate as to which of these modalities should take precedence, and this has been predicated on institutional availability. As a general rule, angiography with therapeutic embolization of bleeding arteries is more effective than and takes precedence over external fixation.[]

Mechanical Stabilization External Fixation Acute application of an external fixator has not been proved to decrease morbidity or mortality in a prospective study; however, there is evidence that this technique improves clinical outcome by limiting hemorrhage and restoring mechanical integrity.[57] Many experts believe that this is the preferred method of

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stabilizing the anterior arch of the pelvis to prevent movement at pelvic fracture sites and attendant bleeding.[ 16] Application of the fixator is time-consuming, however, and should not delay more definitive treatment of pelvic or other injuries. In many centers with a multispecialty trauma service, indications for and rapid access to external fixation are predetermined by protocol, which mandates orthopedic consultation as soon as a high-energy pelvic injury is identified. From a mechanical point of view, lower grades of anteroposterior and lateral compression fractures can be treated definitively by the external fixator.[16] In vertically unstable fractures and anteroposterior compression fractures with unstable posterior elements, the external fixator can assist in the correction of external or internal rotation, but does not provide definitive stabilization of the important vertical displacement. Its use in these injuries is as a temporizing measure initially or as an adjunct to traction or open reduction and internal fixation.[] The external fixator must be constructed and applied with consideration of the biomechanical properties of the fracture. Most fixators can be constructed to allow convenient surgical access to the abdomen and groin. The antishock pelvic clamp is a device that can be applied rapidly by the orthopedic surgeon in the emergency department to externally stabilize the posterior pelvic arch on an emergency basis.[] The mechanical design of this and similar devices and standards of practice in the use of these devices are evolving.

Open Reduction and Internal Fixation Indications and modalities of open reduction and internal fixation, either acute or delayed, vary depending on the patient's other injuries, the timing of other surgeries, and the surgeon's preference.[]

Angiography and Embolization The techniques of arteriography and venography have been investigated for their usefulness in managing hemorrhage associated with pelvic fractures. Most commonly, the source of retroperitoneal hemorrhage with pelvic fractures is the venous plexus or smaller veins; however, venography is not useful in managing these patients because even when venous bleeding points are localized, embolization is ineffective because of the extensive anastomoses and valveless collateral flow. In contrast, arteriography is a major diagnostic and therapeutic modality for a patient with severe pelvic hemorrhage from arterial sources. The arteriogram is performed with the contrast material injected through the femoral artery on the least-injured side or via the upper extremity. The examination starts above the level of the aortic bifurcation and proceeds to selective branches of the internal iliac (hypogastric) artery.[7] Transcatheter embolization using thrombogenic coils, foam, or spherules is employed to stop the hemorrhage from the branches of the internal iliac artery ( Figure 52-12 ). In one study, the average blood requirement per patient in the 48 hours or less before embolization was 32 U, but it decreased to 5 U in the 48 hours after embolization.[62]

Figure 52-12 Unilateral open-book fracture (Tile type B1) from anteroposterior com pression forces—pre-em bolization angiogram s. Despite external fixation and control of nonpelvic sources of bleeding, this patient required ongoing blood transfusion. A and B Angiography showed bleeding from a branch of the right iliolumbar artery (1). Extravasated dye reflects bleeding only at the instant of photograph; actual hematom a would be quite large. After em bolizing this artery, the opposite side was exam ined (B and C). On this side, arterial hem orrhage from the left internal pudendal artery (2) was identified and em bolized (postem bolization film s are not included because of space considerations). 3, Marked diastasis of sym physis pubis; 4, right sacroiliac joint diastasis; 5, fracture of inferior pubic ram us; 6, external fixator. ((Angiogram s courtesy of R.L. Desm arais, MD, and P. Rasuli, MD.))

Angiography is indicated when hypovolemia persists in a patient with a major pelvic fracture, despite control of hemorrhage from other sources. Recommended criteria for angiography are (1) more than 4 U of blood transfused for pelvic bleeding in less than 24 hours, (2) more than 6 U of blood transfused for pelvic bleeding in less than 48 hours, (3) large pelvic hematoma seen on CT scan, (4) hemodynamic instability and negative DPL or negative FAST, and (5) large and expanding retroperitoneal hematoma seen at the time of

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laparotomy.[63] Additionally, extravasated contrast blush at the time of contrast-enhanced CT is a marker of the need for angiography.[] The timing of angiography is individualized for each patient depending on priorities for treatment of concomitant injuries. While setting these priorities, physicians should remember that posterior arch disruptions are associated with the most severe hemorrhage; angiography should be considered at an early stage for these patients. Some patients require surgery for treatment of other injuries before undergoing angiography; others proceed directly to the angiography suite from the emergency department. A logistical delay often occurs in mobilizing the angiography team, so this intervention must be anticipated as early as possible. The transfer of the patient to the angiography suite also requires orchestrating the necessary personnel and equipment to care for the critically injured patient there.

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KEY CONCEPTS {,

{,

{,

{,

{,

{,

The most serious high-energy pelvic injuries are anteroposterior compression fractures (open book) and vertical shear fractures. High-energy pelvic injuries can be diagnosed using anteroposterior, inlet, and outlet views. When the patient is hemodynamically stable, a CT scan should be obtained to identify associated injuries to viscera, to identify a retroperitoneal hematoma, and to plan definitive orthopedic care. The emergency physician should anticipate the need for large amounts of blood products. Concomitant injuries to the aortic arch, diaphragm, solid viscera, and genitourinary tract are common. Careful examination of the skin in the perineum and buttocks and digital rectal and vaginal examinations are necessary to diagnose open fractures because these have the highest mortality rates.

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{,

{,

{,

Trauma hospitals should have institutional guidelines and mechanisms to access angiography and external fixation. The combination of posterior arch fracture plus a hypotensive patient is potentially lethal, with a mortality rate of approximately 50%. Aggressive resuscitation with blood products is recommended. Decisions regarding the need for angiographic transcatheter embolization and external pelvic fixation must be made early in the course of care. Open-book fractures and displacement at any fracture site of more than 0.5 cm are predictors for major blood transfusion requirements.

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Marx: Rosen's Emergency Medicine: Concepts and Clinical Practice, 6th ed., Copyright © 2006 Mosby, Inc.

REFERENCES 1. Dalal SA: Pelvic fracture in multiple trauma: Classification by mechanism is key to pattern of organ injury, resuscitative requirements and outcome. J Trauma1989;29:981. 2. Poole GV, Ward EF: Causes of mortality in patients with pelvic fractures. Orthopedics1994;17:691. 3. Pohlemann T: Pelvic fractures: Epidemiology, therapy and long term outcome: Overview of the multicenter study of the pelvis study group. Unfallchirurg1996;99:160. 4. Gansslen A: Epidemiology of pelvic ring injuries. Injury1996;27(Suppl 1):S-A13. 5. Eastridge BJ, Burgess AR: Pedestrian pelvic fractures: 5 year experience of a major urban trauma center. J Trauma1997;42:695. 6. Eastridge BJ: The importance of fracture pattern in guiding therapeutic decision making in patients with hemorrhagic shock and pelvic ring disruptions. J Trauma2002;53:446. 7. O'Neill PA: Angiographic findings in pelvic fractures. Clin Orthop1996;329:60. 8. Starr AJ: Pelvic ring disruptions: Prediction of associated injuries, transfusion requirement, pelvic arteriography, complications and mortality. J Orthop Trauma2002;16:553. 9. Maull KL, Sachatello CR: Current management of pelvic fractures: A combined surgical-angiographic approach to hemorrhage. South Med J1976;69:1285. 10. Biffl WL: Evolution of a multidisciplinary clinical pathway for the management of unstable patients with pelvic fractures. Ann Surg2001;233:843. 11. McCormick JP, Morgan SJ, Smith WD: Clinical effectiveness of the physical examination in diagnosis of posterior pelvic ring injuries. J Orthop Trauma2003;17:257. 12. Brenneman FD: Long-term outcomes in open pelvic fractures. J Trauma1997;42:773. 13. Jones AL: Open pelvic fractures: A multicenter retrospective analysis. Orthop Clin North Am 1997;28:345. 14. Birolini D: Open pelviperineal trauma. J Trauma1990;30:492. 15. Hanson P, Milne J, Chapman M: Open fractures of the pelvis. J Bone Joint Surg1991;73B:325. 16. Tile M: Fractures of the Pelvis and Acetabulum, 2nd ed. Baltimore, Williams & Wilkins, 1995. 17. Davidson BS: Pelvic fractures associated with open perineal wounds: A survivable injury. J Trauma 1993;35:36. 18. Watnik NF, Coburn M, Goldberger M: Urologic injuries in pelvic ring disruptions. Clin Orthop1996;329:37. 19. Diekmann-Guiroy B, Young D: Female urethral injury secondary to blunt pelvic trauma. Ann Emerg Med 1991;20:1376. 20. Cass AS: The multiple injured patient with bladder trauma. J Trauma1984;24:731. 21. Hochberg E, Stone NN: Bladder rupture associated with pelvic fracture due to blunt trauma. Urology 1993;41:531. 22. Fallon B, Wendt JC, Hawtrey CE: Urological injury and assessment in patients with fractured pelvis. J Urol1984;131:712. 23. Antoci JP: Bladder and urethral injuries in patients with pelvic fractures. J Urol1982;128:25. 24. Ellison M, Timberlake GA, Kerstein MD: Impotence following pelvic fracture. J Trauma1988;28:695. 25. Denis F, Davis S, Comfort T: Sacral fractures: An important problem. Clin Orthop1988;227:67. 26. Smith J: Avulsion of the nongravid uterus due to pelvic fracture. South Med J1989;82:70. 27. Doman AN, Hoekstra DV: Pelvic fracture associated with severe intra-abdominal gynecologic injury. J Trauma1988;28:118. 28. Wilkes RA, Seymour N: Dyspareunia due to exostosis formation after pelvic fracture. Br J Obstet Gynaecol1993;100:1050. 29. Kiely N, Williams N: Sexual dysfunction in women following pelvic fractures with sacro-iliac disruption. Injury1996;27:45. 30. Ochsner MG: Associated aortic rupture-pelvic fracture: An alert for orthopedic and general surgeons. J Trauma1992;33:429. 31. Duncan AO: Management of transpelvic gunshot wounds. J Trauma1989;29:1335. 32. Malangoni MA: The management of penetrating pelvic trauma. Am Surg1990;56:61. 33. Civil ID: Routine pelvic radiography in severe blunt trauma: Is it necessary?. Ann Emerg Med 1988;17:488.

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34. Salvino SK: Routine pelvic x-ray studies in awake blunt trauma patients: A sensible policy?. J Trauma 1992;33:413. 35. Koury HI, Peschiera JL, Welling RE: Selective use of pelvic roentgenograms in blunt trauma patients. J Trauma1993;34:236. 36. Resnick CS: Diagnosis of pelvic fractures in patients with acute pelvic trauma: Efficacy of plain radiographs. AJR Am J Roentgenol1992;158:109. 37. Rogers LF, Bradd FJ, Kennedy W: Radiology of Skeletal Trauma, New York, Churchill Livingstone, 1992. 38. Nagy KK: Experience with over 2500 diagnostic peritoneal lavages. Injury2000;31:479. 39. Mendez C, Gubler KD, Maier RV: Diagnostic accuracy of peritoneal lavage in patients with pelvic fractures. Arch Surg1994;129:477. 40. Moreno C: Hemorrhage associated with major pelvic fracture: A multispecialty challenge. J Trauma 1986;26:987. 41. Mucha P, Welch TJ: Hemorrhage in major pelvic fractures. Surg Clin North Am1988;68:757. 42. Ballard RB: An algorithm to reduce the incidence of false-negative FAST examinations in patients at high risk for occult injury. J Am Coll Surg1999;189:145. 43. Cerva DS: Detection of bleeding in patients with major pelvic fractures: Value of contrast enhanced CT. AJR Am J Roentgenol1996;166:131. 44. Stephen DJ: Early detection of arterial bleeding in acute pelvic trauma. J Trauma1999;47:638. 45. Miller PR: External fixation or arteriogram in bleeding pelvic fracture. J Trauma2003;54:437. 46. Routt MLC: Circumferential pelvic antishock sheeting: A temporary resuscitation aid. J Orthop Trauma 2002;16:45. 47. Tile M: Pelvic ring fractures: Should they be fixed?. J Bone Joint Surg1988;70B:1. 48. Lynch SA, Renstrom AFH: Groin injuries in sport: Treatment strategies. Sports Med1999;28:137. 49. Gertzbein SD, Chenoweth DR: Occult injuries of the pelvic ring. Clin Orthop1977;128:202. 50. Pavlov H: Roentgen examination of groin and hip pain in the athlete. Clin Sports Med1987;6:829. 51. Traycoff RB, Crayton H, Dodson R: Sacrococcygeal pain syndromes: Diagnosis and treatment. Orthopedics1989;12:1373. 52. Wray CC, Easom S, Hoskinson J: Coccydynia: Aetiology and treatment. J Bone Joint Surg 1991;73B:335. 53. Gibbons KJ, Soloniuk DS, Razazk N: Neurologic injury and patterns of sacral fractures. J Neurosurg 1990;72:889. 54. Schied DK, Tile M, Kellam JF: Open reduction internal fixation of pelvic ring fractures. J Orthop Trauma 1991;5:226. 55. Burgess AR: Pelvic ring disruptions: Effective classification system and treatment protocols. J Trauma 1990;30:848. 56. Cryer HM: Pelvic fracture classification: Correlation with hemorrhage. J Trauma1988;28:973. 57. Wolinsky PR: Assessment and management of pelvic fracture in the hemodynamically unstable patient. Orthop Clin North Am1997;28:321. 58. Kellam JF: The role of external fixation in pelvic disruptions. Clin Orthop1989;241:66. 59. Ganz R, Krushell RJ, Jakob RP: The antishock pelvic clamp. Clin Orthop1991;267:71. 60. Heini PF, Witt J, Ganz R: The pelvic C-clamp for the emergency treatment of unstable pelvic ring injuries: A report on clinical experience of 30 cases. Injury1996;27(Suppl 1):S-A38. 61. Gruen GS: The acute management of hemodynamically unstable multiple trauma patients with pelvic ring fractures. J Trauma1994;36:706. 62. Matalon TSA: Hemorrhage with pelvic fractures: Efficacy of transcatheter embolization. AJR Am J Roentgenol1979;133:859. 63. Henry SM, Tornetta P, Scalea TM: Damage control for devastating pelvic and extremity injuries. Surg Clin North Am1997;77:879.

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Marx: Rosen's Emergency Medicine: Concepts and Clinical Practice, 6th ed., Copyright © 2006 Mosby, Inc.

Chapter 53 – Femur and Hip Michael A. Gibbs Edward J. Newton James F. Fiechtl

PERSPECTIVE Background Ancient Egyptian and Greek drawings depict a lame person afflicted with hip deformities ambulating with a cane. The first available written description of a hip fracture was by the 16th century French surgeon Ambroise Paré.[1] In 1850, Von Langenbeck was the first to attempt repair of a hip fracture with a nail for internal fixation. Later, Davis used ordinary wood screws in an attempt to aid the healing of femoral neck fractures.[2] With the advent of radiography in the 19th century, the types of fractures and dislocations became easily identifiable, thus allowing discussion and investigation of management strategies, classification systems, and prognosis.

Epidemiology Both age and gender are important predisposing factors for specific injury patterns and pathologic conditions occurring in the hip, femur, and thigh. As a whole, the elderly segment of society almost universally suffers from some type of hip pathology. Osteoarthritis of the hip may severely limit one's ability to perform activities of daily living. Approximately 6 million women in the United States suffer from osteoporosis, and an additional 17 million have osteopenia, both of which predispose to hip fracture.[3] During the late 1990s, approximately 250,000 patients a year sought treatment in emergency departments after sustaining a hip fracture.[4] As baby boomers mature, the number of hip fractures is expected to reach half a million a year by 2050.[5] Eighty percent of femoral neck fractures occur in men. The average age of patients with femoral neck fractures is 72 years for men and 77 years for women.[6] On average, intertrochanteric fractures occur 10 to 12 years later than those of the femoral neck, and women are afflicted eight times more often than men.[7] Overall, three quarters of all hip fractures occur in postmenopausal women older than 50 years.[3] Perthes' disease (avascular necrosis [AVN] of the femoral head) is four times more common in boys than girls and occurs between 3 and 12 years of age. Slipped capital femoral epiphysis (SCFE) is twice as common in boys and peaks at 13 years of age for boys and 11 years for girls in association with the onset of puberty.

PRINCIPLES OF DISEASE Anatomy of the Hip and Femur Skeletal Anatomy The femoral head is firmly seated in the acetabulum, which is reinforced by labral cartilage. The welldeveloped capsule, overlying ligaments, and proximal musculature of the lower extremity add strength to the joint ( Figure 53-1 ). The nearly spherical femoral head articulates with the acetabular cup in a variation of the “ball-and-socket” joint.

Figure 53-1 The ligam ents of the hip com bine to form a tough joint capsule as seen in both anterior (A) and posterior (B)

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views.

The femur is the longest and strongest bone in the human body and is routinely subjected to substantial forces produced during powerful muscle contraction and weight transmission. In an anatomic position, the two femurs extend obliquely from the pelvis medially to the knee and bring the legs closer to the midline, where they can best support the body. Structurally, the femoral neck serves as an oblique strut between the pelvis (the horizontal beam) and the shaft of the femur (the vertical beam) ( Figure 53-2 ). The length, angle, and narrow circumference of the femoral neck permit substantial range of motion at the hip, but these same characteristics subject the neck to incredible shearing forces. A fracture results when these forces exceed the strength of the bone. The intertrochanteric line, an oblique line connecting the greater and lesser trochanter, marks the junction of the femoral neck and its shaft.

Figure 53-2 Bony architecture of proxim al end of the fem ur.

The bone in the femoral head, neck, and intertrochanteric region is predominantly cancellous. This type of structural bone is less resistant to forces produced by torsion than is solid bone. Distal to the intertrochanteric region, the femur is composed predominantly of cortical bone. The subtrochanteric region extends from the superior aspect of the lesser trochanter distally to the center of the isthmus of the femoral shaft. The shaft is a nearly cylindrical tubular structure that flares posteriorly along the linea aspera (rough line) where the fascia inserts. The shaft becomes predominantly cortical and requires greater force to cause failure. The distal metaphysis widens into the condyles at the knee. As the cortex widens and thins, the stress forces increase at the supracondylar region.

Musculature The musculature of the hip and thigh is the largest and most powerful in the human body. The muscles in this region of the body are located within three different compartments, each containing associated nerves and vessels ( Table 53-1 ). The muscles are also grouped according to their primary action at the hip. Knowledge of the major muscle actions offers insight into the injury patterns and deformities commonly seen ( Figure 53-3 ). Table 53-1 -- Contents Found within the Compartments of the Thigh Compartme Muscles nt

Nerves

Vessels

Anterior

Quadriceps femoris, sartorius, iliacus, psoas, pectineus

Lateral femoral cutaneous

Femoral artery and vein

Medial

Gracilis, adductor longus and magnus, obturator externus

Obturator

Profundus femoris artery, obturator artery and vein

Posterior

Biceps femoris, semitendinosus, semimembranosus, adductor magnus

Sciatic, posterior femoral cutaneous

Profundus femoris branches

Figure 53-3 A and B, Anatom ic illustration of the m ajor m uscles acting about the hip and thigh.

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Vascular Anatomy Arterial Supply The arterial supply to the femoral head arises from three sources ( Figure 53-4 ). The major source is the ascending cervical arteries as they branch off the extracapsular ring and run along the femoral neck beneath the synovium. Some blood is supplied to the femoral head from the second source, which is within the marrow spaces as intraosseous cervical vessels. A third and dubious source is from the foveal artery as it lies within the ligamentum teres.

Figure 53-4 The arterial blood supply of the femoral neck and head is provided to varying degrees by three sources: the ascending cervical arteries, the arterial branches within the m arrow (not illustrated), and the dubious foveal artery within the ligam entum teres.

As the external iliac artery passes beneath the inguinal ligament, it forms the common femoral artery.[8] At this point the artery is located midway between the anterior superior spine of the ilium and the symphysis pubis. Approximately 3 to 4 cm distal to the inguinal ligament, the common femoral artery branches to form the superficial and deep femoral arteries. The larger superficial femoral artery passes along the anteromedial aspect of the thigh and terminates at the junction of the middle and lower thirds of the thigh. Here, the superficial femoral artery passes through the adductor hiatus and forms the popliteal artery. The deep femoral artery runs posterolateral to the superficial femoral artery, supplies the hamstrings, and terminates in the distal third of the thigh as small branches piercing the belly of the adductor magnus. These perforating branches are an additional site of potential injury. The abundant blood supply of the thigh aids in healing fractures of the femoral shaft.

Venous System In the proximal two thirds of the thigh, the common and superficial femoral veins lie adjacent to the common and superficial femoral arteries. At the inguinal ligament, the common femoral vein is posterior and medial to the common femoral artery and moves to the lateral position as it passes distally. The deep femoral vein and the greater saphenous vein are the two main tributaries to the common and superficial femoral veins. The deep femoral vein and artery run parallel as the vein joins the superficial femoral vein just distal to the inguinal ligament. The greater saphenous vein arises in the dorsum of the foot and ascends anterior to the medial malleolus. This vein is relatively superficial as it passes up the medial aspect of the leg to join the common femoral vein distal to the inguinal ligament.[8]

Nerves The femoral and sciatic nerves are the major nerves within the thigh. The femoral nerve is the largest branch of the lumbar plexus; it passes under the inguinal ligament lateral to the femoral artery and divides into anterior and posterior branches soon after entering the thigh. The sensory divisions of the anterior branch, the intermediate and medial cutaneous nerves, supply sensation to the anteromedial aspect of the thigh. The motor division of the anterior branch innervates the pectineus and sartorius muscles. The posterior femoral branch forms the saphenous nerve, which supplies sensation to the skin along the medial aspect of the lower part of the leg. The posterior branch also supplies motor function to the muscles of the quadriceps femoris group.[8] The sciatic nerve is the largest peripheral nerve in the body. It arises from the sacral plexus, the fourth and fifth lumbar nerve roots, and the first, second, and third sacral nerve roots. The sciatic nerve exits the pelvis through the greater sciatic foramen and travels through the posterior of the thigh; it extends from the inferior border of the piriformis to the distal third of the thigh. The sciatic nerve gives off articular branches that supply the hip joint. In the thigh, muscular branches innervate the adductor magnus and hamstring muscles. Just proximal to the popliteal fossa, the sciatic nerve divides and forms the tibial and common peroneal nerves.[8]

Pathophysiology Fractures of the Femur and Hip

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The pathophysiology of femur and hip fractures is discussed in the description of individual fractures. The vast majority of hip fractures occur in elderly patients with preexisting bone disease after relatively low-energy trauma, usually a ground-level fall. Major trauma such as motor vehicle crashes or falls from significant heights is responsible for the majority of fractures in young, otherwise healthy individuals.

Osteoarthritis of the Hip and Osteoporosis of the Femur As the population ages, a greater percentage of the population will suffer with the chronic pain associated with degenerative osteoarthritis of the hip. Disability often results from persistent pain and limited physical mobility. The progression of osteoarthritis can be demonstrated with serial radiographs of the affected hip ( Figure 53-5 ).

Figure 53-5 Radiographic evidence for the developm ent of osteoporosis or degenerative joint disease of the hip is dem onstrated with serial radiographs in the sam e patient over several years. A, The sym ptom s are initially m ore dram atic than the radiographic findings of increased sclerosis along the weight-bearing surface of the superior acetabulum . B, The joint space is lost. C, Erosion of the head and acetabular surfaces and reactive bony cystic changes develop.

Osteoporosis is the leading cause of hip fracture. The pathophysiology of osteoporosis is not completely understood, but there are strong associations with hormonal changes related to aging, genetic predisposition, vitamin D deficiency, lack of physical activity, and smoking.[9] Severe osteoporosis and hip fractures are most common in elderly white women. Radiography of the head of the femur can quantify the degree of osteoporosis, even in the nonfractured hip. The trabeculae of the femoral head and neck strengthen the bone and support the large mechanical forces produced across the hip joint. Singh and colleagues introduced a grading system involving the trabecular patterns of the proximal end of the femur that is useful in evaluating the degree of osteoporosis ( Figure 53-6 ).[10] The Singh score for the degree of osteoporosis uses five trabecular groups found within the head, neck, and proximal end of the femur of nondiseased bone. A healthy femur has all five of these groups represented on a plain anteroposterior (AP) radiograph. As osteoporosis begins and then progresses, the groups disappear one at a time in a predictable pattern. A

B

Figure 53-6 Singh score used to quantify the degree of osteoporosis as it develops. Six grades are differentiated by the presence or absence of trabecular groups. A, Grade VI. All normal trabecular groups are visible, and the upper end of the fem ur is occupied by cancellous bone. B, Grade V. The structures of the principal tensile and principal com pressive trabeculae are accentuated. Ward's triangle appears prom inent. C, Grade IV. The principal tensile trabeculae are m arkedly reduced but can still be traced from the lateral cortex to the upper part of the femoral neck. D, Grade III. A break in the continuity of the principal tensile trabeculae opposite the greater trochanter indicates definite osteoporosis. E, Grade II. Only the principal compressive trabeculae are prom inent; the others have been com pletely resorbed. F, Grade I. Even the principal compressive trabeculae are markedly reduced in num ber and are not prom inent. ((From Singh M, Nagrath AR, Maini PS: Changes in trab ecular patterns of the upper end of the fem ur as an index of osteoporosis. J Bone Joint Surg Am 52:457, 1970.))

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Avascular Necrosis Epidemiology and Pathophysiology When a patient has an increasingly painful hip, buttocks, thigh, or knee and no history of recent trauma, AVN of the femoral head should be considered. AVN has been referred to as aseptic necrosis, ischemic necrosis, and osteonecrosis. It is the result of ischemic bone death of the femoral head after compromise of its blood supply. AVN occurs bilaterally in 52% of patients. It is common in relatively young patients, the mean age being 37 years.[11] Although the specific cause is unknown in 20% of cases, known atraumatic causes include chronic corticosteroid therapy, chronic alcoholism, hemoglobinopathy (e.g., sickle cell anemia), dysbarism, and chronic pancreatitis.[11] Traumatic AVN is a subacute manifestation after hip dislocation or femoral neck fracture. It is more common in males and African Americans. The incidence of AVN as a subacute complication of hip dislocation can reach 40%. Its development is clearly related to both the initial degree of trauma and the amount of time that the femoral head remains out of joint. Reduction of the hip within 6 to 12 hours after dislocation significantly decreases the incidence of AVN.[12] For this reason, hip dislocation should be considered one of the few orthopedic emergencies. The emergency physician must be able to reduce the hip if there is any delay in orthopedic consultation. Even with optimal treatment, femoral neck fractures are complicated by AVN in 11% to 19% of cases ( Figure 53-7 ). Apart from direct injury to the key arteries supplying the femoral head, a second factor contributing to the development of AVN is its location within a joint. For all practical purposes, femoral neck fractures are effectively intra-articular fractures. Acutely, bleeding from the fracture site may cause high intracapsular pressure and a tamponade effect on the femoral head, thus further impairing the blood supply.[ 13] In addition, if the bony fragments are not impacted, synovial fluid will lyse the blood clot. Such lysis prevents the development of capillary buds and the scaffolding needed for osseous repair. These factors all contribute to make AVN of the femoral head a common complication.

Figure 53-7 Even with optim um treatm ent of fem oral neck fractures, avascular necrosis of the fem oral head still m ay occur as happened in the patient shown. The fracture was treated by open reduction and internal fixation with a sliding com pression screw and plate to m aintain alignm ent of the fracture while allowing loading across the site.

Intertrochanteric fractures are located in an area of rich blood supply provided by an extracapsular arterial supply. AVN therefore rarely complicates these fractures.

Classification Four stages are used in classifying the progression of AVN. Ischemia of the femoral head, regardless of cause, produces an increase in intramedullary pressure and results in bone death. Reactive bone growth, edema, and fibrosis result ( Box 53-1 ). BOX 53-1 Classification of Avascular Necrosis of the Femoral Head

Stag Isch e I: emia caus es incre ased pres sure, ede ma, and

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fibro sis. New bone form ation mas ks chan ges on plain film; com pute d tomo grap hy is requi red. Stag Addit e II: ional bone grow th appe ars as mottl ed dens ity and luce ncy. The femo ral head main tains its nor mal cont our. Stag Stru e III: ctura l colla pse of the head . “The cres cent sign” is

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pres ent. Stag Seve e IV: re colla pse of the femo ral head , irreg ular dens ities. From Harris JH, Harris WH, Novelline RA: The Radiology of Emergency Medicine, 3rd ed. Baltimore, Williams & Wilkins, 1993.

Calcifying Lesions of the Femur and Hip Myositis Ossificans Epidemiology and Pathophysiology Myositis ossificans (heterotrophic ossification) is pathologic bone formation at a site where bone is not normally found. Traumatic myositis ossificans results from a direct blow or occurs after a fracture. The thigh and hip muscles are most commonly involved. The incidence of myositis ossificans is approximately 2% after closed treatment of hip dislocation but rises to 34% when open reduction is required. These lesions are clinically significant in only 10% to 20% of cases.[14] Bleeding into the muscle after trauma produces a local hematoma with subsequent new bone formation within the hematoma. This inappropriate response may also result from repeated minor trauma for unknown reasons. Within a few weeks, a firm and often painful mass develops in the affected muscles. This lesion matures over a 12-month period.[15] Radiographically, myositis ossificans appears as irregularly shaped masses of heterogeneous bone in the soft tissues around the joint or along fascial planes. Its appearance may simulate primary bone neoplasm, especially when the periosteum is involved. Osteosarcoma and periosteal osteogenic sarcoma should be considered in the differential diagnosis. The ossific mass is often palpable and may limit motion, depending on its location. Operative removal of a mature lesion may be indicated if the lesion is near a joint or is causing permanent impairment ( Figure 53-8 ). A

B

Figure 53-8 Myositis ossificans of the proxim al end of the fem ur. A, Lesion seen along the lateral cortex of the proxim al fem oral shaft. B, Sagittal m agnetic resonance im aging (MRI) views identify calcification within the lateral m usculature of the proxim al end of the fem ur. C, Sam e lesion on an MRI axial view dem onstrating the extent of the lesion.

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Calcifying Peritendinitis and Bursitis Calcification surrounding tendons and bursae or occurring in the joint capsule is referred to as calcific bursitis or calcifying peritendinitis. The cause of these lesions is unknown but may be similar to that of myositis ossificans. There is no relationship between the radiographic findings and acute symptoms. Calcific bursitis is uncommon, but when it does occur, it most frequently affects the trochanteric bursa of the hip ( Figure 53-9 ). The bursal calcification is seen on radiographs as an amorphous, poorly marginated line that is clearly separate from the cortex of the femur.

Figure 53-9 Calcific trochanteric bursitis. Faint calcification (arrow) in the region of the trochanteric bursa is noted along the lateral cortex of the greater trochanter. ((From Harris JH, Harris WH, Novelline RA: The Radiology of Emergency Medicine, 3rd ed. Baltim ore, William s & Wilkins, 1993.)William s & Wilkins)

Neoplastic Disease in the Hip Benign neoplasms of the femur may produce pain severe enough to justify a visit to the emergency department. The most common of these neoplasms is osteoid osteoma. A solitary osteochondroma may be manifested as a large, bothersome mass. Primary malignant neoplasm is also common in the femur and may be osteoblastic or osteolytic. Solitary osteochondroma ( Figure 53-10 ), osteoid osteoma ( Figure 53-11 ), and metastatic lesions are relatively frequent in the femur. Primary malignant neoplasms may be localized (e.g., chondrosarcoma) or generalized (e.g., multiple myeloma).

Figure 53-10 Classic radiographic appearance of a solitary osteochondrom a of the fem ur as seen in the anteroposterior (A) and frog-leg lateral (B) views. This lesion is a cartilage-capped bony excrescence typically arising from the cortex of long tubular bones. ((From Harris JH, Harris WH, Novelline RA: The Radiology of Emergency Medicine, 3rd ed. Baltimore, William s & Wilkins, 1993.)William s & Wilkins)

Figure 53-11 Osteoid osteom a of the fem ur (closed arrow).A, A large focal area of greater density than that of the surrounding fem ur represents both cortical and endosteal proliferation. The new cortical bone is smooth and sharply delineated, indicative of a nonaggressive process. The open arrow represents a bone island. B, A frontal tomogram dem onstrates an oval central radiolucent nidus (closed arrow). ((From Harris JH, Harris WH, Novelline RA: The Radiology of Emergency Medicine, 3rd ed. Baltim ore, William s & Wilkins, 1993.)William s & Wilkins)

CLINICAL FEATURES History

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Age and gender are predisposing factors for certain injuries. A detailed description of any antecedent trauma or other precipitating events is often helpful. With trauma, details of the mechanism of injury may aid in predicting injury patterns. With stress fractures, an alteration in physical activity or exercise routine provides a clue to the diagnosis. Systemic illnesses or known metabolic disorders should be noted. Any past steroid use is important to know because it predisposes patients to AVN in the femoral head. There is a linear relationship between the cumulative steroid dose and the incidence and severity of osteoporosis and hip fracture.[16] Past cancer, irradiation, and chemotherapy are clues to pathologic fractures. A review of systems should include information that may help in ascertaining the cause of atypical groin pain. Pain here may be the result of nephrolithiasis, pelvic inflammation, infection or tumor, inguinal and femoral hernia, or adenopathy from genital or cutaneous infection. A history of low back pain may suggest radiculopathy as the cause of the patient's pain. Elderly patients with a hip fracture sustained in a fall at home may be unable to summon help for hours to days. They often have severe dehydration, electrolyte abnormalities, rhabdomyolysis, and renal insufficiency and require a thorough evaluation of these metabolic parameters before considering surgery.[17] In addition, the reason for the fall should be determined if possible because it may reveal other comorbid conditions (e.g., syncope, cardiac dysrhythmias, polypharmacy, alcoholism). Elderly patients may have additional painful injuries sustained in a fall, most commonly fracture of a vertebral body or wrist. A high suspicion for cervical spine and intracranial injuries must also be maintained. Young patients with a hip fracture as a result of high-energy mechanisms have concomitant injuries in 40% to 75% of cases.[12]

Physical Examination Management principles for injuries of the hip and femur are the same as those for trauma elsewhere. Hypotension is a problem commonly encountered during the initial resuscitation of a multitrauma patient; however, hemorrhagic shock from an isolated femoral fracture must be a diagnosis of exclusion. Although up to 3 L of blood may be lost into the thigh with a femoral shaft fracture and subsequent hypotension may result, cardiac, pulmonary, intra-abdominal, and pelvic trauma must first be considered and excluded. Hypotension, neurovascular compromise, or suspicion of multiple injury requires transfer to a trauma center after the patient has initially been stabilized in the emergency department. After other life-threatening conditions have been addressed, the injured extremity should be carefully evaluated. Visual inspection will reveal any pallor, ecchymosis, asymmetry, or deformity. Abrasions, lacerations, or open wounds are critical because their presence alters the management of concomitant fractures. The position that the leg assumes offers a clue to what may be found radiographically. In the presence of a displaced femoral neck fracture, the leg classically assumes the position of external rotation, abduction, and slight shortening. In intertrochanteric fractures, the leg is found in internal rotation with mild shortening. Shortening or a limb length discrepancy is found with fractures, dislocations, and osteoarthritis. Undisplaced fractures, including stress fractures, will not produce limb shortening or rotation but will be painful on passive range of motion, particularly internal and external rotation. These fractures will also prevent the patient from being able to perform a straight leg raise. In patients with obvious deformities, range of motion should be deferred until after radiographs. Systematic examination will reveal any tenderness or warmth. Active and passive range of motion and muscle strength, though offering important information, are often limited by pain. Detailed neurovascular assessment is vital. Femoral nerve and arterial injury often occurs with subtrochanteric and femoral shaft fractures or anterior hip dislocation. The sciatic nerve can be injured with a hip fracture or posterior hip dislocation. Neurologic examination includes light touch and pinprick sensation. Femoral, popliteal, dorsalis pedis, and posterior tibial pulses are assessed. Comparative blood pressures obtained by Doppler examination in the injured and uninjured extremities may be useful in diagnosing occult femoral arterial injuries. The ankle-brachial index offers useful information regarding arterial injury or insufficiency. An index less than 0.9 strongly suggests arterial injury or stenosis.[18]

DIAGNOSTIC STRATEGIES Radiographic Anatomy and Evaluation The normal radiographic and skeletal anatomy is familiar to emergency medicine physicians ( Figure 53-12 ). One common inaccuracy merits clarification: the soft tissue linear radiolucencies superolateral and inferomedial to the femoral head and neck do not represent the hip capsule as is commonly believed. Instead, they represent the fat within the fascial plane covering the gluteus minimus superiorly and the tendon of the iliopsoas muscle inferiorly.[19] Comparison of these lines on the symptomatic side with those on the unaffected side should not be used to determine whether an effusion of the hip is present.

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Figure 53-12 A, Norm al adult hip. The superior arrow indicates fatty tissue covering the gluteus minim us; the inferior arrow indicates the edge of the iliopsoas m uscle shadow. These m uscles lie im m ediately on the capsule of the hip joint. The sm all concavity in the center of the fem oral head is for the attachm ent of the ligam entum teres. B, Cross-table lateral view of the hip dem onstrating the norm al relationship of the fem oral head to the neck. The asterisk indicates the ischial tuberosity. ((From Harris JH, Harris WH, Novelline RA: The Radiology of Emergency Medicine, 3rd ed. Baltimore, William s & Wilkins, 1993.)William s & Wilkins)

True AP and lateral radiographs of the femur are usually adequate for the evaluation of potential fractures. The femur should be in as much internal rotation as possible. The fracture line may be very subtle, particularly with femoral neck fractures. The authors have found three methods useful in identifying inconspicuous fractures. The use of Shenton's line is described in the section on hip dislocations (see Figure 53-24 ). Lowell[20] described a second method, which is illustrated in Figure 53-16 . When searching for a fracture of the femoral neck, both the medial and lateral cortical margins of the femoral head and neck must be carefully examined for the normal S and reverse S curves found on nonfractured hips. The convex outline of a normal femoral head smoothly joins the concave outline of the femoral neck when in anatomic position. This produces an S and reverse S curve regardless of the angle of the x-ray. A fracture produces a tangential or sharp angle indicative of disruption of the normal anatomic relationship. A third method, useful in the evaluation of seemingly unremarkable hip films, is to trace the trabecular groups as they pass from the femoral shaft to the femoral head. These lines will be disrupted as they pass through the fracture site, and such disruption often provides the only subtle clue. If a fracture is found, radiographs of the knee should be taken as well. It is a basic orthopedic principle to image the joint above and below any fracture.[18]

Figure 53-24 Shenton's line is a sm ooth curved line drawn along the superior border of the obturator foram en and m edial aspect of the fem oral m etaphysis. Disruption of this line should raise suspicion of a fem oral neck fracture or hip dislocation.

Figure 53-16 Lowell20 described the normal anatom ic x-ray appearance of the fem oral head as a sm ooth S and reverse S lines drawn above. The concave outline of the femoral neck m eets the convex outline of the fem oral head in all views. Any tangential angle suggests a fracture.

Occult Hip Fracture If radiographs do not show a fracture, the patient must be observed while ambulating. An inability to ambulate heightens the suspicion of occult fracture. Approximately 5% of all hip fractures are radiographically “occult” on plain films. Failure to detect these injuries results in increased mortality, risk of

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subsequent displacement of the fracture, and a higher incidence of AVN.[21] It also affects patients' disposition, in keeping with the admonition “If they can't walk, they can't go home.” When a painful hip prevents ambulation and plain films do not reveal a fracture, magnetic resonance imaging (MRI) should be performed.[22] In addition, elderly patients with unexplained chronic hip pain for more than 3 weeks may harbor an occult fracture even if they continue to ambulate. T1-weighted MRI reveals a fracture that was imperceptible at the time of injury with 100% accuracy and has been found to be cost-effective when compared with other strategies.[21] Its use allows either earlier operative repair or physical therapy and immediate mobilization. Bone scans have been useful in these patients, yet such scans lack adequate sensitivity. To identify most occult fractures, the scan must be delayed 72 hours after the injury. These 3 days of bed rest and hospitalization while awaiting a bone scan are costly and not without risk (e.g., formation of deep venous thrombosis) ( Figure 53-13 ).

Figure 53-13 A, The patient com plained of hip pain and could not ambulate. Initial radiographs failed to dem onstrate a fracture. B, A radionuclide bone scan 72 hours after the fall provided no evidence of a fracture. C, A m agnetic resonance im age obtained 24 hours after the fall shows an altered signal in the intertrochanteric area, indicative of an acute fracture. (B and C, From Rockwood JC Jr, Green DP, Bucholz RW [eds]: Rockwood and Green's Fractures in Adults, vol 2, 4th ed. Philadelphia, JB Lippincott, 1996).

MANAGEMENT Patients with traumatic fracture of the hip or femur should have blood typed and crossmatched for administration of at least 2 U of blood. Hemodynamic instability may result from dehydration and blood loss of up to 3 U into the fracture site. The potential for significant blood loss and the multiple common associated injuries are important justifications for this recommendation. Currently, treatment of these fractures is hemiarthroplasty or open reduction and internal fixation for femoral neck fractures. Internal fixation with a sliding compression screw is generally used to treat intertrochanteric fractures. The goal is to promote immediate postoperative mobilization. It has become widely accepted that the risks of surgery in elderly patients are minimal when compared with the risks of prolonged bed rest, deep venous thrombosis, pulmonary embolism, pneumonia, and urosepsis from an indwelling Foley catheter. If possible, the repair is conducted under spinal anesthesia to decrease the operative risk. Care of an elderly patient with a hip fracture is a multidisciplinary effort and often requires coordination between the emergency physician, orthopedist, internist, neurologist, and cardiologist to stabilize the patient before surgery. Operative repair should be performed as soon as possible after the patient is resuscitated and is in optimal preoperative condition.

Traction and Immobilization Prehospital personnel often place a Hare splint or similar device that applies traction to the leg before transport if they suspect a femoral fracture. Although such management may provide pain relief and limit blood loss, great care must be given to the proper use of these devices. Prolonged traction during the assessment and management of other injuries can cause or worsen serious neurovascular injury in the thigh. The traction used in the field for transport will produce potentially damaging tension on the nerve and artery. The femoral and sciatic nerves are much more likely to be injured from traction or during surgery than they are from a femoral fracture.[23] Maintaining the leg in flexion at the hip reduces intracapsular pressure, whereas extension of the leg increases pressure and potential for ischemic necrosis of the femoral head. For these reasons, traction should be discontinued once the patient arrives in the emergency department. There are some contraindications to the use of traction. Providers should be instructed that traction should not be applied to any open fracture that has exposed bone. Such reduction pulls grossly contaminated bone fragments back into the wound before adequate debridement can be undertaken in the operating room. Traction should not be used in patients with any suggestion of neurologic involvement because it may worsen the injury. The injured extremity should be immobilized without traction when moving the patient. The leg may be supported in a position of comfort with a pillow placed under the thigh.

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Open Fracture Care By definition, an open fracture is any in which a break in the integrity of the skin and soft tissue allows communication with the fracture and its hematoma. Any wound or break in the skin in proximity must be considered to communicate with the fracture. Open fractures are divided into the three categories ( Table 53-2 ), the third of which may be subdivided according to the amount of nerve, arterial, or periosteal injury present. A bone piercing from the inside outward often causes only a small wound. The contaminated bone tip then slips deceptively back into the soft tissue; therefore, any break in the integrity of the skin makes the fracture an open one. Open wounds should be irrigated and then covered with sterile saline-moistened gauze. Table 53-2 -- Classification of Open Fractures Wound size Soft tissue damage

Type I

Type II

1 cm and 10 cm Extensive muscle devitalization. Nerve and arterial involvement often classified as type IIIb Mechanism of injury Bone edge pierces Variable High-energy shotgun, outward high-velocity gunshots From Morris JM, Blickenstaff LP: Fatigue Fractures. Springfield, Ill, Charles C Thomas, 1967. Type I: endosteal or periosteal callus without a definite fracture line on plain radiographs; type II: a definite fracture is identified on plain radiographs, but no displacement; type III: the fracture is displaced. *

Any shotgun wound, high-velocity gunshot wound, segm ental fracture, farm yard injury, vascular injury, or crush injury is classified as type III, regardless of wound size.

For all type I open fractures, a first-generation cephalosporin should be administered intravenously. Types II and III require additional gram-negative coverage because of the amount of devitalized tissue and increased gram-negative skin flora found in the groin.[24] This additional coverage could be provided by an aminoglycoside such as gentamicin or tobramycin. The use of perioperative first-generation cephalosporins has been shown to reduce postoperative infection even in closed fractures that are to undergo surgery.[18] Great care should be taken to identify tetanus-prone wounds so that appropriate prophylaxis can be provided with penicillin and tetanus immune globulin when indicated.

Compartment Syndrome Because of its larger volume, compartment syndrome within the thigh is far less common than in the lower part of the leg. A large amount of bleeding into the compartment is required before the pressure rises above capillary perfusion pressure. It is difficult to clinically differentiate the expected swelling after an injury from early compartment syndrome. Clinical examination and the use of direct compartment pressure measurements can detect the development of compartment syndrome at an early stage.

Pain Management Systemic Analgesia It is well known that control of pain in emergency departments is often inadequate.[25] There may be greater reluctance to administer adequate doses of analgesics in the elderly because of possible respiratory depression. Nevertheless, pain control should be a high priority during the initial management period.

Femoral Nerve Block Femoral nerve blocks have been used to treat femoral shaft fractures for more than 50 years.[26] Despite proven effectiveness and a low complication rate, this technique has not been widely embraced by emergency physicians or surgeons.[27] Femoral nerve block is invaluable as an adjunct or alternative to systemic analgesics in those at risk for hypotensive side effects. For obvious reasons, careful neurovascular examination and consultation with the orthopedic surgeon involved should be carried out and documented before performing the procedure.

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If a long-acting anesthetic such as bupivacaine is used, the expected onset of analgesia is 15 to 30 minutes, and its duration is 6 to 8 hours.[28]

Hip Arthroplasty Background and Epidemiology Sir John Charnley first described the modern form of total hip arthroplasty (THA) in 1961. Despite many changes in both the design and materials used, Charnley's essential design has been established as the standard.[29] The incidence of THA in the United States rose from 65,000 per year in 1982 to more than 120,000 per year by the mid-1990s.[30] Women account for 62% of THA in the United States. The most common indication for THA is joint failure resulting from severe osteoarthritis. Other indications include rheumatoid arthritis, certain types of hip fracture, AVN, and certain tumors. Arthritis associated with Paget's disease, trauma, ankylosing spondylitis, and juvenile rheumatoid arthritis are also relative indications for total or partial hip arthroplasty.

Outcomes and Complications THA provides an immediate, substantial improvement in pain, functional ability, and overall quality of life. A 10-year follow-up of patient outcomes, including gait, perception of pain, physical mobility, sleep patterns, and energy scores, showed positive results in more than 90% of cases.[31] Despite the tremendous success of THA, there are numerous complications, aseptic loosening of the prosthesis being the most common. Other complications include component wear, infection, surrounding femoral fractures, and deep venous thrombosis. Postoperative dislocation of the femoral component occurs in 3% of patients. Generally, flexion past 90 degrees, adduction, and internal rotation place the hip at risk for dislocation. This combination can occur when patients bend at the waist (e.g., to sit on a normal low toilet or to get out of a chair) or cross their legs ( Figure 53-14 ).[32]

Figure 53-14 Dislocation of the fem oral prosthesis in a patient with a total hip arthroplasty. The fem oral head often becom es caught on the rim of the acetabular cup, thereby preventing reduction. Reduction may disrupt or dislocate the acetabular cup.

SPECIFIC INJURY PATTERNS Fractures of the Hip and Femur Avulsion Fractures The pain of avulsion injuries of the hip may be manifested as referred pain to the thigh and is most common in adolescents and young adult athletes. The muscular origin of this type of injury commonly involves the pelvic apophyses. Avulsion at the site of the growth plate is the result of sudden, maximal muscular exertion. It may occur with rapid acceleration or sudden changes in speed or direction. The athlete classically experiences a sudden piercing pain at the site of injury, describes a “snapping” or “popping” feeling, and frequently falls to the ground because of the intensity of this pain. Avulsion at the anterior superior iliac spine involves the separation of a thin piece of bone as the sartorius muscle suddenly contracts. The anterior inferior spine is avulsed by the rectus femoris, and the hamstring group may pull off the ischial tuberosity ( Figure 53-15 ).

Figure 53-15 Avulsion of the anterior inferior iliac spine by the rectus femoris produced a fracture.

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Proximal Femoral Fractures Classification Systems Fractures of the proximal end of the femur have been classified on the basis of their relationship to the hip capsule (e.g., intracapsular and extracapsular), geographic location (neck, trochanteric, intertrochanteric, subtrochanteric, and shaft fractures), and degree of displacement. A working knowledge of the classification system allows the emergency physician to communicate with the consulting orthopedist regarding the fracture's pattern, stability, and treatment options.

Femoral Neck Fractures Pathophysiology Many now refer to femoral neck fractures as insufficiency fractures in acknowledgment of the major role played by osteoporosis. Age-related bone loss is believed to be the most important factor in determining the incidence of femoral neck fractures.[33] The theory that these fractures result from primary skeletal pathology is supported by the fact that minimal or no injury is associated with most of these fractures. Pathologic fractures from metastatic carcinoma are well described.

Classification. Fractures of the femoral neck were originally divided by location into either subcapital or transcervical types. The subcapital fracture line lies just under the dome of the femoral head's articular surface. Although several classification systems were used to describe these fractures, they have been abandoned because of poor inter-rater reliability and limited clinical utility. Currently, femoral neck fractures should be classified as either nondisplaced or displaced fractures. Fifteen percent to 20% of all femoral neck fractures are nondisplaced fractures. The fracture line may often be very subtle. Techniques described for detection of subtle fracture lines may be useful for this reason. Evaluation of the continuity of the subcapital cortical lines, search for an indistinct broad band of increased subcapital density, and identification of the S and reverse S curves ( Figure 53-16 ) will lead to the correct diagnosis in most cases. In impacted femoral neck fractures, the neck cortex is driven into the cancellous femoral head. Bony impaction lends a certain inherent stability ( Figure 53-17 ). Because of this inherent stability, two different approaches have been advocated: early ambulation and internal fixation. AVN, the most common complication, occurs in 20% of patients regardless of the type of management.[23] The prognosis for nondisplaced fractures is excellent; 96% of patients heal without complication. Without impaction, a nondisplaced femoral neck fracture possesses no inherent stability and will become displaced without internal fixation.

Figure 53-17 A, Subtle nondisplaced im pacted fem oral neck fracture (Garden type I). Use of Lowell's S curves aids in identification. B, A nondisplaced fem oral neck fracture (Garden type II) possesses no stability without im paction. C, The sam e fracture after treatm ent with a sliding com pression screw and side plate.

On initial evaluation, a patient with a displaced fracture of the femoral neck lies with the limb externally rotated, abducted, and slightly shortened. The diagnosis is confirmed with plain hip films ( Figure 53-18 ). To avoid further disruption of the blood supply to the femoral head, range of motion should be deferred unless radiographs fail to reveal a fracture. In all displaced femoral neck fractures, the femoral head is rendered largely avascular, and subsequent signs of AVN and collapse may occur over the ensuing several years.

Figure 53-18 The num ber of parts that the fracture produced classifies intertrochanteric fractures. A, Two-part fractures have one part connected to the fem oral head and a second part attached to the shaft. B, The greater or lesser trochanter is also

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fractured with three-part fractures. A greater degree of instability is produced because the attached muscles continue to act on the fractured trochanter. C, Four-part intertrochanteric fractures involve both trochanters.

Treatment of these displaced fractures is either open reduction with internal fixation or hemiarthroplasty ( Box 53-2 ). BOX 53-2 Relative Indications for Hemiarthroplasty as Treatment of Displaced Femoral Neck Fractures

Parki nson 's dise ase Hem iplegi a or other neur ologi c dise ase Path ologi c fract ure or Pag et's dise ase Olde r than 70 (phy siolo gic age) Blind ness Seve re oste open ia Poor healt h that woul d prev ent a seco nd

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oper ation From Rockwood JL Jr, Green DP, Bucholz RW (eds): Rockwood and Green's Fractures in Adults, vol 2, 4th ed. Philadelphia JB Lippincott, 1996.

Outcome and Complications The mortality rate during the first year after a femoral neck fracture is 14%, as compared with 9% for the control population. Factors affecting mortality include age, male sex, psychiatric illness, end-stage renal disease, and congestive heart failure.[34] Institutionalized patients have a death rate three times higher.[35] Complications can be minimized by early reduction, stable internal fixation, and early ambulation. AVN and nonunion are the two major complications of femoral neck fractures. AVN is the most common complication, despite optimal treatment, because of the complex arterial anatomy. Deep infection in the form of osteomyelitis or septic arthritis is more common with femoral neck fractures because the fracture line extends into the joint. The rate of infection has been dramatically reduced with the use of perioperative antibiotics. Pulmonary embolism is another significant complication and is the leading cause of death 7 days after fracture in all orthopedic patients.

Intertrochanteric Fracture Anatomy The fracture line of intertrochanteric fractures extends between the greater and lesser trochanter of the femur. They are considered extracapsular fractures. The fracture line extends through cancellous bone and has an excellent blood supply. The hip's short external rotators remain attached to the proximal femoral neck, and the internal rotators are attached to the distal end of the femur, thus explaining the position that the leg assumes with this fracture.

Pathophysiology An intertrochanteric fracture in younger adults is usually the result of high-speed accidents or high-energy trauma, such as falls from heights. The elderly may sustain this injury during a fall from any height. The fracture lines are the result of both direct and indirect forces. The direct forces act along the axis of the femur and on the greater trochanter as it strikes the ground. Indirect forces are produced as the iliopsoas pulls the lesser trochanter and the abductors pull the greater trochanter; these forces often cause fractures at the site of insertion.

Classification A large number of classification systems for intertrochanteric fractures have been proposed to predict the possibility of achieving and maintaining stable reduction.[36] An oft-used system, and one sufficient for our use, designates the fracture according to the number of separate bone fragments produced (see Figure 53-18 ).

Management Intertrochanteric fractures carry particular pitfalls for the emergency physician. Great care must be taken to address the entire patient and not focus on the fracture alone. Hemodynamic instability may result from dehydration and blood loss of up to 3 U into the fracture site.[37] Poor nutrition before the fall, chronic diuretic use, and decreased oral intake in patients who have to wait until they are found contribute to the level of dehydration. Up to 70% of these patients are under-resuscitated.[17] Associated distal radial, proximal humeral, and rib fractures and compression fractures of the lumbar and thoracic spine are often overlooked because the femoral fracture distracts the attention of both the patient and physician. Spinal compression fractures most commonly involve T12 and L1. A substantial majority of intertrochanteric fractures require some type of internal fixation. Such fixation allows rapid mobilization, decreased hospital length of stay, reduced mortality, and improved function.[18] The procedure should be performed on an urgent, not an emergency basis. Although the patient's other medical conditions are unlikely to improve significantly, mortality is increased when the patient is taken to the operating room on the day of injury. If delayed longer than 48 hours, however, a 10-fold increase in mortality has been reported.

Outcomes Intertrochanteric fractures have an associated mortality rate of 10% to 30% in the first year. Life expectancy

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returns to normal in those who survive that year. Survival is most commonly related to the patient's age and preexisting medical conditions. Additional risks associated with operative treatment include mechanical failure (1% to 16%), implant migration (2% to 10%), and infection (2% to 8%).[] Mechanical failure and nonunion are much more common in unstable fractures and those that were not adequately reduced. Approximately only half of patients sustaining these fractures are able to eventually regain their original level of ambulation.

Pathologic Intertrochanteric Fractures Aggressive treatment of patients who have pathologic intertrochanteric fractures or impending fractures is indicated if their life expectancy is more than a few months. Such treatment with subsequent radiation therapy improves the patient's quality of life, decreases pain, and improves mobility.

Isolated Fracture of the Greater or Lesser Trochanter Fractures of the greater or lesser trochanter are rare. They occur in women more than in men and are the result of a fall directly onto the trochanter or avulsion by the iliopsoas muscle. There may be a comminuted fracture involving only part of the greater trochanter or more subtle impaction of the lateral cortex. If avulsed, the fragments are displaced superiorly and posteriorly ( Figure 53-19 ).[18]

Figure 53-19 Isolated fracture of the greater trochanter. Note that the trochanter is displaced in the typical posterior and superior direction.

Treatment consists of pain control and early mobilization with crutches; weight bearing is allowed as tolerated by pain. Outpatient management of this injury is possible with a satisfactory social situation. The prognosis is good, and healing is generally excellent.

Subtrochanteric Fracture Anatomy and Pathophysiology Subtrochanteric fractures occur between the lesser trochanter and the proximal 5 cm of the femoral shaft. They may accompany intertrochanteric fractures. The subtrochanteric region is composed almost entirely of cortical bone, which lacks the vascularity important to new bone growth and repair. When fractured, it is more likely to be comminuted than bone with a higher cancellous content. Additionally, the majority of the biomechanical forces of the femur are transmitted down the curved medial cortex of the femoral shaft. If this cortex is disrupted, the metal hardware undergoes the majority of the stress. This mechanism accounts for the increased incidence of hardware failure when the medial cortex is largely involved. These fractures are characteristically deformed because of the unbalanced muscle forces. The attachments of the iliopsoas, gluteal, and external rotator muscles consistently produce flexion, abduction, and external rotation of the proximal fragment.

Epidemiology Subtrochanteric fractures account for 11% of all fractures of the proximal end of the femur. Although 10% of these fractures are caused by gunshots, the mechanism of injury is usually direct blunt trauma.[40] They occur in a bimodal distribution. The first group consists of elderly patients after a fall. The fracture occurs through an area of weakened cortical bone. Pathologic fractures from metastatic lesions, Paget's disease, renal osteodystrophy, osteogenesis imperfecta, and osteomalacia are well recognized in this area. A second distribution of these fractures occurs in victims of extreme high-energy trauma. In this group of patients, the subtrochanteric fracture is rarely an isolated injury because of the tremendous force required to produce it. Associated thoracic and abdominal injuries are common and must be aggressively sought to adequately manage the patient. Thirty percent to 50% of patients with subtrochanteric fractures have associated fractures of the pelvis, spine, or other long bones. Stress fractures can occur in this region but are extremely uncommon.

Classification

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A variety of classification systems for these fractures have been proposed, although none are widely accepted.[36] From a practical standpoint, it is best to define and describe these fractures by location (proximal or distal), angle (transverse, oblique), and the presence of comminution ( Figure 53-20 ).

Figure 53-20 Variants of subtrochanteric fractures. A, Short oblique fracture. B, Short oblique fracture with com m inution. C, Long oblique fracture. D, Long oblique fracture with comm inution. E, High transverse fracture. F, Low transverse fracture.

Management Hemodynamic instability may result from blood loss of up to 3 U into the fracture site.[37] Although such blood loss can lead to hypovolemic shock, other causes of hypotension in a trauma patient must be investigated. Open fractures are rare and, when present, accompany significant soft tissue injury. Vascular and neurologic injuries are also uncommon. Definitive management of subtrochanteric fractures is a complex issue. Maintaining limb length and controlling rotation are difficult. Open reduction with internal fixation is generally the treatment of choice. However, in the rare case with severe comminution or an open, grossly contaminated fracture, nonoperative management may be preferable.[41] Children younger than 10 years may also be treated nonoperatively. The amount of remodeling and growth stimulation that occurs in children of this age usually ensures good results without internal fixation.

Outcomes The bone in the subtrochanteric region is largely cortical and relatively avascular when compared with the cancellous intertrochanteric region. It logically follows that healing is comparatively slow. Comminution is common and increases the likelihood of nonunion. Because of ample muscle coverage in this area, delayed union, nonunion, and hardware failure are rare. Comminuted and distal subtrochanteric fractures have a worse prognosis. Complications include fat embolism and the adverse effects of prolonged immobilization in the elderly. The reported mortality rate from subtrochanteric fractures ranges from 12.2% to 20.8%.[42] The violent force and common associated injuries contribute to the high mortality of patients who sustain these fractures.

Femoral Shaft Fractures Pathophysiology Femoral shaft fractures are common injuries in young adults after high-energy trauma. As is the case with other femoral cortical fractures, considerable violent force is required to produce a fracture in a normal shaft. Automobile and motorcycle accidents, falls, and pedestrian accidents account for the majority of femoral shaft fractures. The femoral shaft usually fails under tensile strain, and a transverse fracture results. Higher forces produce varying degrees of segmentation or comminution. Open fractures of the femoral shaft are less frequent and are often the result of a gunshot wound. Pathologic fractures occur from a torsional stress that produces a spiral fracture.[43]

Classification There is no commonly accepted or easily remembered classification for femoral shaft fractures. Location and geometry of the fracture line should be used to describe these fractures. Transverse, oblique, spiral, wedge, and comminuted are useful terms for describing these fractures.

Clinical Features Patients often arrive in the emergency department with the injured extremity immobilized by traction devices, which should be removed while maintaining immobilization of the limb. Neurovascular injuries are rarely associated with closed femoral shaft fractures.[44] Significant hemorrhage into the thigh can occur with a femoral shaft fracture, just as it can with intertrochanteric and subtrochanteric fractures. Injuries commonly

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occurring in the presence of femoral shaft fractures include hip fractures, fracture-dislocations, femoral neck fractures, supracondylar femoral fractures, and patellar fractures.[45] Almost half of femoral shaft fractures have associated ligamentous damage in the knee. If the patient has a femoral fracture, pain often prevents adequate evaluation of knee stability. Any attempt to evaluate the stability of the knee acutely will result in additional pain and hemorrhage without providing useful reliable information.

Management Internal fixation with intramedullary rods has been demonstrated to shorten both hospitalization and total disability time with most femoral shaft fractures. The vast majority of femoral shaft fractures heal well in time, regardless of the mode of treatment. Severely comminuted fractures are more likely to be treated by closed reduction.

Fractures with Minimal or No Trauma Most patients who arrive in the emergency department with hip or thigh pain will provide a clear history of a traumatic event. Hip or knee pain in the young, in athletes, and in the elderly deserves investigation, even when minimal or no trauma has been reported. This patient population commonly has occult hip pathology and occasionally femoral pathology. Although senile osteoporosis is the leading cause of femoral neck fractures after minor trauma, pathologic fractures of the femur may result from metastatic, metabolic, or endocrinologic disease.[46] The incidence of fracture in patients with hyperthyroidism is 12%.[47]

Outcomes Patients sustaining a femoral shaft fracture have close to a 100% union rate, and most are able to return to work after approximately 6 months. Nonunion is relatively uncommon and occurs in about 1% of patients. Even a minor degree of limb shortening or malalignment leads to posttraumatic arthritis.[48] Refracture is a rare occurrence that occurs at two times during the healing process. The leg can refracture during early healing and callus formation or during the brief period after the hardware is removed. After the hardware is removed, the unsupported bone is required to bear the entire weight of axial loading and is at risk for refracture.

Stress Fractures Biomechanics Stress fracture of the femoral neck was first reported in 1905 by Blecher.[49] Stress fractures occur when normal bone is repeatedly subject to submaximal forces. This recurring stress stimulates the bones to remodel and strengthen. In a stress fracture, osteoblasts are unable to lay down new bone and remodel fast enough, so the bone fails. Stress fractures can also occur in diseased bone when it is subjected to repeated minimal stress.[50]

Clinical Features The symptoms of a stress fracture of the femoral neck are often so subtle that they may be mistaken for muscle strain or an overuse injury. Early symptoms frequently include morning stiffness and aching in the hip on the first steps after a period of rest. The pain gradually increases during prolonged exercise and may reach the point at which bearing weight becomes impossible. Pain is felt in the groin or along the medial aspect of the thigh toward the knee. On examination, an obvious, painful limp is present. This painful or antalgic gait is characterized by shortening of the stance phase of the injured extremity. There is no obvious external rotation or shortening of the leg, only minor discomfort with active or passive motion, except at the extremes of flexion and internal rotation. Tenderness is minimal because of the large amount of soft tissue coverage at the femoral neck.

Diagnostic Strategies Radiographs are helpful if they demonstrate a fracture, but they are often negative until 10 to 14 days after the injury.[18] Endosteal or subperiosteal callus develops during this period and indicates the fracture site. In addition to the standard AP and lateral views of the hip, oblique views may delineate the fracture line. Close attention should be paid to the trabecular fibers of the femoral neck. Often, a stress fracture can be identified as an isolated disruption of either the compressive (medial aspect of the femoral neck) or the tensile (lateral aspect of the femoral neck) trabecular fibers. If a fracture is suspected clinically, negative radiographs should be followed by MRI or computed tomography (CT).[22] If a fracture is found, the other hip should be extensively evaluated because of the significant incidence of bilateral stress fractures.

Classification and Management

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Stress fractures are commonly separated into three classes. This division is used to guide management of stress fractures of the femoral shaft. A type I stress fracture is treated in the hospital with strict bed rest until the pain has subsided and the hip has full range of motion. Because of the tremendous disability associated with displaced fractures, types II and III are internally fixed.[5]

Other Causes of Pain Other considerations in the diagnosis of atraumatic pain of the hip and thigh are listed in Box 53-3 . BOX 53-3 Differential Diagnosis of a Painful Hip without Fracture

Refe rred pain (lum bar spin e, hip, or knee ) Avas cular necr osis of the femo ral head Deg ener ative joint dise ase or oste oarth ritis Hern iatio n of a lumb ar disk Diski tis Toxi c syno vitis of the hip Septi c

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arthri tis Burs itis Tend oniti s Liga ment ous injuri es of the knee or hip Occ ult fract ure Slipp ed capit al femo ral epip hysi s Pert hes' dise ase Tum or (lym pho ma) Dee p veno us thro mbo sis Arter ial insuf ficie ncy Oste omy elitis

Dislocations and Fracture-Dislocations of the Hip and Femur Injury Patterns Epidemiologists have identified injury patterns in victims according to the mechanism of injury.[51] Pedestrians who are struck by a car have head, chest, pelvic, arm, and femur injuries. Motorcyclists tend to sustain pelvic and ipsilateral leg injuries. A person who stumbles and falls seldom has major associated injuries. Each will be discussed in the following sections.

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Hip Dislocations Dislocations and fracture-dislocations of the hip are two of the few true orthopedic emergencies. The hip joint possesses impressive inherent strength and stability; thus, considerable force is required to produce these injuries. With this understanding, a hip dislocation serves as a “red flag” for multisystem injury and should prompt a diligent search for other occult injuries. Serious associated injuries are found in up to 95% of patients with a dislocated hip.[] Knee fractures, ligamentous injuries, and dislocations are present in up to 30% of patients sustaining a hip dislocation.[54] It is highly recommended that in the presence of this type of injury, patients be evaluated as major trauma victims.

Mechanism and Biomechanics Traumatic hip dislocations occur primarily in patients sustaining severe multisystem trauma, most often as a result of high-speed motor vehicle crashes. Failure to use seat belts is a significant risk factor. Other less common mechanisms include falls, sports injuries, and pedestrians struck by automobiles. Posterior dislocations are almost always the result of motor vehicle crashes. A seated vehicle occupant typically has the hip adducted, flexed, and internally rotated at the time of impact. As the knee strikes the dashboard, the force is transmitted through the femoral shaft to the femoral head. With sufficient force, the femoral head dislocates posteriorly. Anterior dislocations result from forceful extension, abduction, and external rotation of the femoral head. These forces lever the head up out of the acetabular cup. Such dislocation most often occurs after a motor vehicle crash when the occupant has the hip abducted and externally rotated at the time of impact. It may also result from a fall or sports injury when the hip is forcefully hyperextended.

Classification The relationship of the femoral head to the acetabulum is used to classify dislocations into anterior, posterior, central, and inferior types. A fracture-dislocation refers to an associated fracture of the acetabulum or femoral head. Posterior dislocations ( Figure 53-21 ) account for 80% to 90% of cases. Anterior dislocations ( Figure 53-22 ) are seen in 10% to 15% of patients. In anterior dislocations, the femoral head may dislocate medially toward the obturator foramen (obturator dislocation) ( Figure 53-23 ) or laterally toward the pubis (pubic dislocation). Central dislocations, which occur in 2% to 4% of cases, are not true dislocations because the entire femoral head is forced centrally through a comminuted fracture of the acetabulum. Inferior dislocation (luxatio erecta) of the hip is a very rare condition that occurs almost exclusively in children younger than 7 years.

Figure 53-21 In a posterior dislocation the hip is internally rotated and the lesser trochanter is superimposed on the fem oral shaft. Failure to visualize the lesser trochanter on the anteroposterior projection identifies a posterior dislocation.

Figure 53-22 In an anterior dislocation the hip is externally rotated, and the lesser trochanter appears in profile. The hip is further from the x-ray cassette than the unaffected side and may appear larger because of the beam 's projection.

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Figure 53-23 Radiograph of obturator dislocation.

Clinical Features. The position of the injured extremity may provide valuable clues when evaluating a hip dislocation. A patient with a posterior dislocation typically holds the hip flexed, adducted, and internally rotated. The knee of the affected extremity rests on the opposite thigh. The extremity is generally shortened, and the greater trochanter and buttock may be unusually prominent. In contrast, a patient with an anterior dislocation holds the hip in abduction, slight flexion, and external rotation. However, these physical findings may be absent in patients with an associated ipsilateral femoral shaft fracture. The neurovascular examination should focus on the sciatic nerve and femoral vessels. Sciatic palsy is present in about 10% of patients with hip dislocation and most commonly involves the peroneal nerve branch. The femoral vessels and nerve are particularly prone to injury after an anterior dislocation.

Diagnostic Strategies Radiologic investigation begins with an AP view of the pelvis. This view alone will identify the majority of hip dislocations. An AP pelvis film should be obtained in all trauma patients with the aforementioned deformities. The AP radiograph should include the entire pelvis and the proximal third of the femur to allow comparison of both hips. When a dislocation is found or suspected, a lateral view of the hip will provide additional definition of the injury. Although most hip dislocations are seen clearly with these two views, several more subtle radiographic signs may assist physicians in making a confident diagnosis. The first indicator involves the position of the lesser trochanter. Because a posteriorly dislocated hip is internally rotated, the lesser trochanter is superimposed on the femoral shaft and is not seen on the AP projection. In contrast, an anteriorly dislocated hip is externally rotated and the lesser trochanter appears in profile. The second clue is found in the size of the femoral head. Because a posteriorly dislocated hip is closer to the x-ray cassette than the unaffected side is, it appears smaller. The converse is true in anterior dislocations, where the hip is farther from the x-ray cassette than the contralateral side is and thus appears larger. The third finding relates to the integrity of Shenton's line ( Figure 53-24 ). This line is a smooth, curved line drawn along the superior border of the obturator foramen and medial aspect of the femoral metaphysis. Disruption of this line should raise suspicion of a femoral neck fracture or hip dislocation.[] An obvious dislocation may distract the physician from a search for concomitant fractures. Examination of the trabecular pattern can identify associated fractures of the acetabulum and femoral head, neck, or shaft. It is especially important to identify acetabular fractures before closed reduction is attempted because intra-articular bone fragments may interfere with effective reduction. Oblique radiographs (Judet views) or CT will help visualize the acetabulum and precisely define the injury.[57]

Management Hip dislocations are true orthopedic emergencies, and reduction should be performed as soon as possible. The earlier the reduction, the better the results. The incidence of AVN, traumatic arthritis, permanent sciatic nerve palsy, and joint instability logarithmically increases with the length of time that the hip remains dislocated[]; therefore, prompt anatomic reduction should be attempted. The timing and method of reduction are dependent on the overall condition of the patient, the type of dislocation, and the presence or absence of associated fractures. In cases of simple dislocation, closed reduction should be attempted first. Although some physicians recommend that this procedure be performed under general anesthesia, this delay and its associated increase in the rate of AVN are not warranted when conscious sedation in the emergency department is readily available. If the emergency physician chooses to attempt closed reduction, the principles of conscious sedation and monitoring should be followed. The primary contraindication to closed reduction is the presence of a femoral neck fracture. Other relative contraindications include coexistent fractures in the dislocated extremity because of an inability to apply traction to the limb. Techniques of closed reduction are described in the next section.

Reduction Techniques The Stimson technique and the Allis technique are the methods most commonly used for reduction of posterior hip dislocations ( Figure 53-25 ).[18] The Stimson technique ( Figure 53-26 ) uses the weight of the limb and the force of gravity to reduce the dislocation and is relatively atraumatic. Although the Stimson

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technique is generally effective, placing an acutely and often multiply injured trauma patient in the prone position to perform the procedure may be a challenge. Adequate radiographic clearance of the spine has usually not yet been accomplished, and the administration of sedatives and analgesics in a prone patient has inherent risks. The Stimson technique is performed as follows: {,

The patient is placed prone with the leg hanging over the edge of the bed. The hip and knee are flexed at 90 degrees

Figure 53-25 Radiograph of posterior dislocation identified by loss of the lesser trochanter on the anteroposterior view.

Figure 53-26 Stim son's technique for hip reduction. See the text for a description of this m ethod.

{, {, {,

{,

An assistant stabilizes the pelvis The operator applies steady downward traction in line with the femur The femoral head is gently rotated and the assistant pushes the greater trochanter anteriorly toward the acetabulum Once reduction is achieved, the hip is brought to the extended position while traction is maintained

In a patient who cannot assume the prone position, the Allis technique should be used ( Figure 53-27 ). This technique is usually effective for obturator dislocations. It is perhaps the most commonly used method for hip reductions in the emergency department and is performed as follows: {,

The patient is placed in the supine position, and the pelvis is stabilized by an assistant

Figure 53-27 The Allis technique for hip reduction. See the text for a description of this

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m ethod.

{,

With the knee flexed, the operator applies steady traction in line with the deformity The hip is slowly brought to 90 degrees of flexion while steady upward traction and gentle rotation are applied The assistant pushes the greater trochanter forward toward the acetabulum Once reduction is achieved, the hip is brought to the extended position while traction is maintained

{,

{,

{,

Other recently described techniques for closed reduction of posterior hip dislocations include the Rochester method[60] and the traction-countertraction technique.[61] Closed reduction of a pubic dislocation can be quite difficult. The anterior position of the femoral head will resist flexion and thus makes the Allis technique impossible. We recommend reduction with the following maneuvers: {, {, {,

The patient is placed in the supine position Longitudinal traction is applied in line with the deformity The hip is hyperextended and internally rotated as an assistant applies downward pressure on the femoral head

Although prompt anatomic reduction is clearly desirable, multiple attempts at reduction in the emergency department should be avoided. Difficulty with reduction is usually the result of incarceration of a tendon, capsular structure, or an unrecognized osteochondral fragment that is blocking reduction. In the case of an irreducible dislocation, closed reduction under general anesthesia or open reduction is often required.

Postreduction Management After closed reduction, the hip should be tested for stability, which is accomplished by gently placing it through a full range of motion to see whether it will redislocate. An AP radiograph of the pelvis should be obtained to verify the adequacy of reduction. The radiograph should be carefully inspected to verify that the femoral head is in the acetabulum, the shaft of the femur is in neutral position, Shenton's line is intact, and the profile of the lesser trochanter is well visualized. The intra-articular space should be symmetrical and, when measured, the same depth as the unaffected joint. Asymmetry signals an entrapped intra-articular fragment and is an indication for CT scanning ( Figure 53-28 ).

Figure 53-28 A, A fracture through the fem oral head is seen with this anterior hip dislocation. B, Incom plete reduction is identified by exam ination of the joint space. This space should be the sam e width as the unaffected joint. Asym m etry signals an entrapped intraarticular fragm ent, which should be verified by com puted tom ography.

In general, fracture-dislocations should be reduced by closed reduction under general anesthesia or by open

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reduction. Attempted closed reduction of a fracture-dislocation by an emergency physician is not recommended in view of the rate of complications and associated medicolegal risk.

Outcomes The precarious blood supply to the femoral head is particularly important with regard to the long-term consequence of hip dislocations. The development of AVN of the femoral head has been reported in 1% to 17% of dislocations. Reduction after 24 hours is correlated with a higher incidence of AVN of the femoral head and posttraumatic arthritis.[58] Other risk factors for the development of AVN include the total dislocation time, the severity of the injury, the number of reduction attempts, and patient comorbid conditions.

Fracture-Dislocation of the Femoral Head Epidemiology and Mechanism. A small subset of hip dislocations are associated with fractures of the femoral head ( Figure 53-29A ). Femoral head fracture occurs in 22% to 77% of anterior hip dislocations and in 10% to 16% of posterior hip dislocations.[62] These injuries are almost always the result of high-speed vehicular trauma. Because of the tremendous force required to produce this injury pattern, coexistent multisystem trauma is the rule.

Figure 53-29 A, Anterior hip dislocation is identified as the lesser trochanter is brought into profile. Note a fracture of the lateral aspect of the greater trochanter. B, A postreduction radiograph demonstrates adequate reduction with symm etrical joint spaces.

When a femoral head fracture and hip dislocation coexist, patients assume the position typical of the dislocation. Hip mobility is markedly reduced and pain is usually severe. After initial stabilization, the involved extremity should be carefully examined for associated fractures of the femoral shaft and knee. The neurovascular examination should assess for femoral or sciatic injury. Radiographs should be evaluated carefully for any femoral head fracture in all patients with hip dislocations. The fracture of the femoral head can be subtle. These fractures may be detected by following the curve of the dislocated head and the acetabular cup to search for a small fragment that may otherwise be overlooked. Known or suspected injuries can be further defined by CT or MRI.[62] In most cases, satisfactory results can be obtained by closed reduction (see Figure 53-29B ).[57] Several authors recommend obtaining a CT scan of the hip before closed reduction to further define the injury and locate fracture fragments.[57] If the hip cannot be reduced by manipulation or if there is an unsatisfactory reduction of the femoral head fragment, open reduction will be required.

Dislocation of Hip Prosthetics An increasing number of patients have undergone hip arthroplasty. In addition to those performed as treatment of femoral neck fractures, nearly 200,000 patients undergo elective primary THA each year.[63] Postoperative dislocation of the prosthesis is a common complication that occurs in 1.5% to 3% of patients.[] Although most dislocations take place within 3 months of surgery, “late dislocations” have been reported up to 10 years after the operative procedure; such dislocations can result from major trauma or from trivial events (e.g., rising from a seated position). Posterior dislocations account for 75% to 90% of cases (see Figure 53-14 ).[53] Reduction techniques for prosthetic hip dislocations are identical to those described earlier. Consultation with an orthopedic surgeon is essential for safe reduction and development of a long-term treatment plan for the patient. Reduction of the prosthesis does not carry the same urgency as reduction of a dislocated hip because there is no risk for the development of AVN once the femoral head has been replaced. However, traction on the sciatic nerve can occur and makes early reduction more compelling. In addition, the reduction itself carries the unique dangers of loosening of the components, fracturing of the surrounding bone, and movement of the acetabular cup; reduction is best deferred to an orthopedic consultant.

Soft Tissue Injuries Soft tissues may be subject to muscle or tendon strain or contusions from misuse, overuse, or accidental

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trauma. Rupture, hemorrhage, or myositis ossificans may develop in muscles.[65]

Muscular Injury Strenuous exercise in a poorly conditioned person, sudden exertion, and direct trauma may all traumatize soft tissues. Cold temperature, vascular or infectious disease, fatigue, and poor training are known predisposing conditions for this injury.[66] Infectious predisposing diseases include trichinosis, tuberculosis, and typhoid fever. A detailed classification system of muscular injuries has been devised, but it is of little clinical significance for the emergency physician. Classification of complete and partial tears is reasonable and of greater clinical utility. Partial tears are reversible injuries that are aggravated by movement or tension. Mild spasm, swelling, ecchymosis, and tenderness cause minor loss of function and strength. Complete tears produce a palpable depression, and the torn muscle edge is also often palpable. Severe spasm, swelling, ecchymosis, tenderness, and loss of muscle function occur. In significant muscle strains, radiographs are needed to evaluate the possibility of an accompanying bony avulsion injury. Initial management of incomplete tears traditionally includes the local application of ice for the first 48 hours, followed by heat. Compressive wraps cause distal venostasis with the potential for distal venous clot formation and do not significantly decrease recovery time. Nonsteroidal anti-inflammatory agents and sufficient analgesics are important for recovery and patient satisfaction. Muscle relaxants may be useful when the injury is accompanied by muscular spasm. In general, complete rest of the affected muscle should be maintained with the recommendation of “weight bearing as pain tolerated.” This progressive muscle loading can be started within 3 to 5 days. Any significant injury should be referred for physical therapy. A complete muscle tear is a serious condition. Consultation plus follow-up with an orthopedic surgeon or sports medicine specialist is vital for these patients.

Sports Injury Patterns Athletes commonly experience muscular injury from accidents and overtraining. The two most common injuries involve the hamstrings and the quadriceps.

The Hamstrings Hamstring muscle strains are common in sports involving running and sudden acceleration. The injury is accompanied by sudden, intense pain in the posterior of the thigh. Any active or passive motion at the hip is poorly tolerated because of the intense pain that movement causes. Crutches and toe-touch weight bearing are recommended until the patient is evaluated by a physician trained in sports medicine. Toe-touch weight bearing refers to walking with crutches while the toes of the injured extremity rest on the ground without placing any weight on it. Appropriate weight-training programs have been shown to speed rehabilitation of this injury.[65] Complete recovery from a hamstring muscle strain may take weeks to months.

The Quadriceps. The quadriceps is the most common muscular group to sustain complete tears. This injury occurs when the muscles are contracted suddenly against the body's weight, such as may occur when an athlete slips or stumbles and attempts to avoid a fall. Ambulation is significantly affected. There is pain with active and passive knee extension. In significant tears, the patient is able to neither actively extend the knee nor maintain its extension against gravity. A depression just proximal to the superior pole of the patella suggests a complete tear. A complete tear of the quadriceps most often requires surgical repair and extensive rehabilitation.

Iliopsoas Strain. Gymnasts and dancers are the most likely group of athletes to experience an injury to the iliopsoas as a result of sudden forceful hip flexion against resistance. Severe pain is often experienced in the groin, thigh, or low back region. Severe intra-abdominal pain is common at the muscle origin and may dominate the clinical picture. Examination reveals groin tenderness and pain with active hip flexion. Radiographs of the femur should be obtained to identify an avulsion fracture of the lesser trochanter. CT will frequently demonstrate a large hematoma. Bed rest with partial flexion at the knee and hip is generally required for 7 to 10 days. With severe strains, symptoms may persist for 2 to 3 months.

Hip Adductor Strain.

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Injury to the hip adductors occurs as the thigh is forcefully abducted, such as in a straddle injury. The patient complains of pain in the groin, the pubic region, and the medial proximal aspect of the thigh. Abduction and adduction are often limited because of pain. Swelling and skin discoloration confirm the tear. If the tear is complete, a defect in the muscle may be felt along the medial aspect of the thigh near the groin.

Gluteus Muscle Strain. The gluteus muscles may be injured with vigorous or forced hip extension as is seen in track-and-field jumping events. The pain is typically less severe than that associated with injuries to other muscle groups. The hip is tender when extended or abducted.

Tendon Injuries. Clinically, tendon strains tend to have a more insidious onset than muscle strains do. These strains may occur at the attachment of the muscles to the superior or inferior pubic ramus, the pubic symphysis, the ischium, and the femur. A groin pull is the layman's term referring to an injury to the tendons of the hip adductors. The injury usually involves only the adductor longus, yet the adductor magnus and brevis and the pectineus are often involved as well.[66] It commonly occurs in skaters and cross-country skiers when an accidental stress abducts the thigh during a powerful contraction of the adductors. These muscles may also be injured from overuse in an unconditioned patient. Local pain is noted at the inferior pubic ramus and the ischial tuberosity. Extension, abduction, and adduction of the hip are painful. The pain may radiate to the back of the thigh. Pain over the greater trochanter may represent tendon strain of the attachments of the gluteus medius, gluteus minimus, tensor fasciae latae, or piriformis. Pain is aggravated by resisted abduction. Tenderness in the groin and painful hip movement suggest a strain of the iliopsoas tendon at its attachment to the lesser trochanter. Trochanteric bursitis, peritendinitis, AVN, neoplasm, and other causes should be considered. Treatment of a tendon strain is similar to that for other soft tissue injuries. The use of crutches with weight bearing as tolerated by pain is helpful for the first 2 weeks. Opioid analgesics and a short course of anti-inflammatory agents should be given. Complete tendon disruption frequently requires surgical repair.

Vascular Injuries Hip dislocations and the various types of femoral fractures may have an associated arterial injury. The vessel may be partially lacerated, completely severed, or thrombosed. Lack of distal arterial flow may also represent a stretched vessel in spasm. The superficial femoral artery is most commonly injured with trauma to the hip and thigh. The common and the deep femoral arteries are less frequently injured. In the acute setting, penetrating trauma is the usual mechanism of injury. Arterial injury with femoral shaft fractures is rare and occurs in less than 2% of the cases reported.[67] Anterior- and superior-type dislocations may produce femoral artery injury.[18] Comparative examination of blood pressure, the ankle-brachial index, and Doppler pulses in the injured and uninjured extremity is critical if arterial injury is suspected. The need for ancillary studies in the evaluation of extremity trauma for vascular injury is somewhat controversial and dependent on the institution.[68] Diagnostic evaluation must not delay surgical exploration when clinical signs and symptoms of vascular injury are obvious.[69] Early restoration of blood flow is essential to prevent ischemic damage to the leg.

Neurologic Injury Trauma, infectious agents, and degenerative disease may all injure peripheral nerves. In trauma, nerves may be injured by a blunt object that causes a contusion, by a sharp penetrating object that produces a partial or complete tear, or by the stretch of a missile as it passes in proximity. Nerves are particularly vulnerable to prolonged ischemia, which can lead to necrosis. Compression of the nerve from a hematoma or a dislocated femoral head may also appear as a neurapraxia manifested by transient loss of conductivity. The femoral and sciatic nerves are rarely injured with femoral shaft fractures because they are encased in muscles throughout the length of the thigh. Treatment of neurovascular compromise and a hip dislocation or a displaced femoral fracture is immediate reduction to ensure limb viability. Reduction should be accomplished before transfer to another facility whenever possible.

Femoral Nerve

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When the femoral nerve is injured, the iliac and femoral arteries are commonly involved because of their anatomic proximity. If injured, the femoral nerve is most often traumatized in penetrating trauma of the pelvis, groin, or thigh. Femoral neuropathy can occasionally result from compression by a hematoma within the abdominal wall or the iliopsoas as a complication of hemophilia, anticoagulant therapy, or trauma.[70] The motor deficit in complete femoral neuropathy is manifested as marked weakness of knee extension. The patient is able to walk on level ground, yet has extreme difficulty walking up stairs or an incline. Patients cannot rise from a sitting position because of significant proximal muscle weakness. The sensory deficit varies, but is localized along the anterior aspect of the thigh and medial lower aspect of the leg. The most reliable spot for testing a sensory deficit is just superior and medial to the patella. The deep tendon reflex of the knee will be diminished or absent. If a traumatic neuropathy is suspected, immediate orthopedic consultation should be obtained. Nerve exploration and repair are generally preferred for penetrating trauma and when direct impingement on the nerve by bone fragments or hematoma is suspected. Surgical exploration and drainage of a hematoma that is impinging on the femoral nerve are appropriate. Progressive nontraumatic neuropathies require urgent neurologic consultation. When a chronic neuropathy exists, atrophy of the anterior aspect of the thigh will already have developed. The motor deficits have been discussed previously.

Sciatic Nerve Sciatic injury is rare with femoral fractures, but it may develop as a result of the traction used to stabilize the fracture during the initial management period. Complete traumatic injury may result from a deep penetrating wound in the hip, thigh, or buttock. Sciatic nerve palsy from both inadvertent injection into the nerve and intraneural or extraneural hemorrhage in patients taking anticoagulants has been described. Posterior hip dislocations and fracture-dislocations produce sciatic neurapraxia in 10% to 14% of these injuries.[] Patients with complete sciatic neuropathy have paralysis of the hamstring muscles and all muscles below the knee. With partial injury, a peroneal palsy with weakness of the extensor hallucis longus muscle is the most sensitive clinical sign. There is sensory loss below the knee and along the posterior of the thigh. The deep tendon reflex at the ankle is absent or diminished. Sciatic injury from posterior dislocations often consists of only transient loss of conductivity, particularly in its motor fibers. Unfortunately, the other injury patterns to the sciatic nerve carry the worst prognosis of all peripheral nerve injuries. The prognosis is poorest when the injury is proximal and complete. Even with optimal repair, recovery is often inadequate. Sciatic neuropathy is a disabling problem. Obvious atrophy of the lower part of the leg and foot develops, followed by ulceration of the sole of the foot and infection. A below-the-knee amputation is frequently necessary in these cases.

SPECIAL PEDIATRIC CONSIDERATIONS Anatomy Development of the femoral head and neck with its growth plates and two primary ossification centers is illustrated in Figure 53-30 . A significant proportion of the pediatric hip is radiopaque cartilage and developing new bone. For this reason, almost any type of trauma in this location carries the potential for premature growth arrest. Understanding that large portions of the pediatric hip are radiolucent will dissuade the tendency to focus attention on the ossified elements.

Figure 53-30 Developm ent of the fem oral head and neck with its growth plates and two prim ary ossification centers.

Hip Dislocation The incidence of hip fractures and dislocations is increasing in young patients, often as a result of high-energy trauma. Up to 50% of children with a hip dislocation will also have fractures elsewhere. In small children, dislocation of the hip is more common than femoral neck fractures. The force required to dislocate a pediatric hip is much less than that required in an adult because the acetabulum is less completely developed than in adults. Seemingly negligible trauma, such as tripping or a minor fall, may dislocate the femoral head in a young child. In a school-age child, athletic injuries are the major cause of traumatic hip

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dislocation. In the teenage years, motor vehicle accidents predominate as the cause of hip dislocations.

Femoral Fractures Unlike adults, the vast majority of pediatric hip fractures do not result from high-energy violent trauma. These fractures are usually the result of falling from heights, jumping out of a swing, being struck by a car, or having a bicycle accident. Child abuse must also be considered. Whereas a car commonly strikes an adult at the tibial level, a smaller child is most often hit at the level of the hip, which results in a fracture there. The classic Salter-Harris division of fractures in the pediatric population is not used in the hip. The Delbet classification is a well-accepted system used for pediatric femoral fractures.[72] This system separates fractures through the physis and the transcervical, cervicotrochanteric, and intertrochanteric regions ( Figure 53-31 ).

Figure 53-31 Pediatric proxim al fem oral fractures are classified by a system that separates fractures in the physis (A) the transcervical area (B), the cervicotrochanteric area (C), and the intertrochanteric region (D). ((From Canale ST, Beaty JH: Fractures of the pelvis. In Rockwood JC Jr, Green DP, Bucholz RW [eds]: Rockwood and Green's Fractures in Children, vol 3, 5th ed. Philadelphia, JB Lippincott, 2001, pp 883-911.)JB Lippincott)

Spiral Shaft Fractures If seemingly trivial trauma has resulted in a spiral femoral shaft fracture in a child, child abuse and pathologic fracture must be considered.[] Common causes of pathologic fracture include unicameral bone cysts, fibrous dysplasia, osteogenesis imperfecta, and malignancy.[]

Management Femoral fractures in children are so rare that most orthopedists treat only three or four in a career.[72] Although these pediatric injuries are extremely rare, their complications are significant. Unlike an adult, a child's femur has growth potential, and any disruption carries the possibility of lifetime disability. Treatment of femoral shaft fractures in adults is aimed at prevention of the complications of prolonged immobilization. Unlike adults, children tolerate bed rest well, which allows more treatment options. The primary goal in children is prevention of the many complications common with femoral fractures. Premature closure of the physeal plate results in a valgus deformity of the hip. AVN, malunion, nonunion, and limb length discrepancy are all complications frequently seen with pediatric femoral fractures. For all these reasons, referral to a pediatric orthopedist is recommended.[72]

The Child with a Limp A child who comes to the emergency department with a limp is a diagnostic challenge. Both life-threatening and benign disease processes can produce a limp. When the child is too young to give an adequate history, the etiology becomes more elusive. The attending physician should inquire about the chronology of the symptoms, the child's development (i.e., social milestones, weight gain, physical development), and diet. Associated illness and a family history may be helpful. Though challenging, the history and physical examination, combined with appropriate diagnostic modalities, will allow discovery of the cause in most patients. An important point to remember in the pediatric population is that the knee is a common site for referred hip pain. Proper follow-up is crucial to avoid additional morbidity in these children.

Evaluation of the Child's Gait Gait is a learned, complex combination of motions produced through coordination of the musculoskeletal, peripheral, and central nervous systems. A limp is produced by anything that alters this process and can be divided into categories according to the underlying abnormality. Pain, muscle weakness, structural alteration, peripheral sensory deficit, and cerebellar or vestibular imbalance are major categories. A limp caused by pain is referred to as an “antalgic” gait. Conditions that disturb the biomechanics of the hip or cause the child pain may affect any of the elements of gait. Other conditions such as cerebellar pathology or disease of the

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knee or foot are discussed in their appropriate sections.

Etiology of the Limp Inflammation and Infection Inflammation of the articular surface, the intraarticular synovium, or the joint capsule creates pain. Weight bearing increases the pain. The child limps in an attempt to limit the proportion of time that the affected hip bears the body's weight. Toxic synovitis is a common nonbacterial inflammatory clinical entity that can cause a limp. Little is known about its etiology. It develops most frequently in boys between 3 and 10 years of age. Clinically, the synovitis is manifested as pain in the hip or knee. An antalgic gait is present with minimal systemic symptoms. There is restriction of hip motion and associated muscle spasm, and the child will often refuse to bear weight on the hip. As the disease progresses, the joint capsule is increasingly stretched and intraarticular pressure rises. The potential volume of the joint capsule is largest with the hip flexed, abducted, and externally rotated. The child prefers to lie in this position as the capsule begins to bulge to minimize the tension and intra-articular pressure. The diagnosis of toxic synovitis must be one of exclusion of more serious diseases that mimic it. Acute joint inflammation and pain may be associated with juvenile rheumatic arthritis, systemic lupus erythematosus, Perthes' disease, septic arthritis, and tuberculous arthritis. Ultrasound of the hip joint will detect an effusion in 78% of cases of toxic synovitis but cannot distinguish this condition from septic arthritis.[76] Joint aspiration may be required when the diagnosis is in doubt. Distinguishing between toxic synovitis and septic arthritis can be a diagnostic dilemma. Recent work has illustrated four key predictors: temperature higher than 38.5° C in the preceding week, non–weight bearing (refusal or inability to bear weight even with support), erythrocyte sedimentation rate higher than 40 mm/hr, and a white blood cell count greater than 12,000 cells/mL. These four predictors were developed in a retrospective study and then validated in a prospective study.[] Based on the validation study, the probability of septic arthritis was 2% for zero predictors, 9.5% for one predictor, 35% for two predictors, 73% for three predictors, and 93% for four predictors.[79] These predictors should be used in conjunction with clinical assessment. Acute bacterial infections of the hip and femur require early identification and intervention to minimize their subsequent morbidity and disability.[79] Unfortunately, the diagnosis is often missed initially because the child may appear relatively nontoxic in the early phases of infection. Signs and symptoms of systemic illness usually accompany infection of the femur or hip. Fever, malaise, decreased oral intake, a limp, or refusal to bear any weight is common.[80] Whereas osteomyelitis most commonly develops in the metaphysis in adults, the physeal region is often the infected site in children. Pyarthrosis (septic arthritis) may result from hematogenous seeding or direct extension of osteomyelitis. The hip and the knee are the most common infected joints. The causative agent in osteomyelitis and pyarthrosis is nearly always a gram-positive organism, usually Staphylococcus. The incidence of Haemophilus influenzae infection has fallen as a direct result of its addition to the childhood immunization regimen. Neonates, asplenic children, and children with sickle cell anemia are at risk for infection with gram-negative organisms. Salmonella is also more often seen in sickle cell patients with osteomyelitis. Viral and rickettsial diseases (e.g., Lyme disease) have been known to be present in subacute cases.[81]

Radiographic Evaluation Identification of acute osteomyelitis by plain radiographs is difficult until 2 to 3 weeks after infection. Pyarthrosis may be manifested by widening of the space between the femoral head and the acetabular roof and bulging of the joint capsule and surrounding soft tissues. This is seen as a change in the contour of the gluteus minimus and iliopsoas fat stripes ( Figure 53-32 ). Care should be taken to distinguish the normal shadow of the muscles and the joint capsule as described earlier in this chapter (see Figure 53-12 ). Plain radiographs are seldom useful in the initial identification of infection because visualization of a joint effusion has low sensitivity for pyarthrosis. Bone scan, MRI, CT, and ultrasound-guided joint aspiration are appropriate to diagnose a septic joint.

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Figure 53-32 Prom inence of the soft tissue shadows about the right hip, including bulging of the obturator internus muscle and its aponeurosis (open arrows), indicates distention of the joint capsule. The opposite hip shows the norm al soft tissue shadows indicated by the closed arrows. ((From Harris JH, Harris WH, Novelline RA: The Radiology of Emergency Medicine, 3rd ed. Baltim ore, William s & Wilkins, 1993.)William s & Wilkins)

The inflammatory process involved in the immune system's attempt to eradicate the intruder also begins to destroy the body's own articular surface. Even with treatment, most children experience some arthritic disability.[82]

Slipped Capital Femoral Epiphysis Anatomy The capital femoral epiphysis appears during the first year of life. The epiphysis of the greater trochanter appears by the age of 5 and the lesser trochanter during the 13th year of life. All these structures unite during the 18th through 20th years. The anatomic relationship has been compared with a scoop of ice cream sitting on a cone. This relationship remains symmetrical on both AP and lateral radiographs ( Figure 53-33 ). Asymmetry in any view represents either SCFE or a subcapital fracture ( Figures 53-34 and 53-35 ).

Figure 53-33 An anteroposterior radiograph of a 10-year-old boy demonstrates the norm al anatom ic relationship of the capital fem oral epiphysis, the proximal physis, the apophysis of the lesser trochanter, and the triradiate synchondrosis.

Figure 53-34 Frank slipped capital fem oral epiphysis. The capital fem oral epiphysis is displaced m edially, inferiorly, and posteriorly. The inhom ogeneity of the fem oral neck is consistent with early avascular necrosis. ((From Harris JH, Harris WH, Novelline RA: The Radiology of Em ergency Medicine, 3rd ed. Baltimore, William s & Wilkins, 1993.)William s & Wilkins)

Figure 53-35 Right slipped capital femoral epiphysis. A, The slippage appears m inim al and m ay be overlooked; however, m edial displacem ent of the capital fem oral epiphysis with respect to the m etaphysis results in the lateral cortex of the fem oral neck and the epiphysis being in the same plane (open arrow). The capital fem oral epiphysis is flattened (arrow), and the right hip joint space is widened. B, Medial and posterior displacem ent of the capital fem oral epiphysis (arrow). ((From Harris JH, Harris WH, Novelline RA: The Radiology of Emergency Medicine, 3rd ed. Baltimore, William s & Wilkins, 1993.)William s & Wilkins)

Epidemiology and Pathophysiology

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SCFE occurs in approximately 5 people per 100,000 population per year. Twenty-five percent of cases are bilateral.[83] SCFE occurs twice as frequently in boys as in girls, with the respective peak incidence being 13 and 11 years old. Epidemiologic data have provided clues to the pathophysiology of this injury. SCFE is associated with the onset of puberty and rarely occurs before 10 years of age. It most commonly develops in boys 10 to 17 years of age during their period of rapid growth. It is believed to be the result of a structural weakness in physeal cartilage at the onset of pubescence.[84] The specific cause is not well understood. That SCFE occurs more frequently in male African Americans than in the white population supports the presence of a genetic element in the pathophysiology of this disease.[84] Other risk factors identified are obesity, previous irradiation or chemotherapy, renal osteodystrophy, hypothyroidism, and neglected septic arthritis.[85]

Clinical Features SCFE is usually an insidious process extending over a period of several weeks to months. Initially, there may be only slight discomfort in the groin, thigh, or knee after activity. Eventually, as slippage progresses, the pain occurs at rest as well. Referred pain to the knee is a classic manifestation. Frequently, the ectopic nature of the pain leads to delayed diagnosis, increased displacement, and a worsened prognosis.[86] As the epiphysis continues to slip, the pain increases. Parents often bring the child in for medical evaluation when they notice the child beginning to limp. Physical examination may reveal hip tenderness, decreased hip range of motion, and an abducted, externally rotated thigh.

Diagnostic Strategies Children with unexplained hip or knee pain merit clinical as well as radiographic evaluation. Initially, AP, lateral, and frog-leg lateral radiographs of the hip should be obtained. The frog-leg lateral projection shows the hip in a plane midway between the AP and lateral views. The earliest radiographic findings are subtle, with the abnormality visualized on only one projection. The most reliable initial finding of SCFE is asymmetry of the femoral epiphysis in relation to the neck. Small amounts of slippage can be detected by examining the epiphyseal edge as it becomes flush with the superior border of the femoral neck. This can be thought of as “the scoop slipping off the ice cream cone.” The dome of the epiphysis may be flattened. A line drawn along the medial aspect of the femoral shaft (Klein's line) should intersect some part of the normal femoral head. Failure of this line to intersect the head indicates medial and posterior movement of the head on the epiphysis.[83] Comparative views of the two hips are indicated if initial radiographs are equivocal. If occult fracture is suspected, MRI or CT should be performed.[] Surgery is required to anchor the epiphysis and prevent further slippage.

Perthes' Disease Perthes' disease is the name given to AVN of the pediatric femoral head. It has also been called LeggCalvé-Perthes and Calvé-Perthes disease. It occurs at a younger age than SCFE does—between the ages of 2 and 10. Its peak incidence is at 6 years, and it occurs five times more often in boys than girls. The disease affects both hips in 15% of patients.[88]

Isolated Fracture of the Greater or Lesser Trochanter in Children An isolated fracture of the greater trochanter is a rare injury. In children, a fracture occurs as the entire greater trochanteric epiphysis is avulsed from the femur. This type of fracture occurs in children and adolescents between 7 and 17 years of age. The mechanism of injury is generally a powerful muscular contraction of the lateral rotators of the hip joint during a twisting fall. If the fragment is large and displaced by more than 1 cm, open reduction and internal fixation may be indicated. An isolated fracture of the lesser trochanter occurs as a forceful contraction of the iliopsoas muscle avulses the lesser trochanter from the physis during sudden hip flexion ( Figure 53-36 ). Eighty-five percent of all cases occur in patients younger than 20 years, with a peak incidence between 12 and 16 years.[89] Marked tenderness in the femoral triangle is present, and hip flexion against resistance is painful. Clinically, a seated patient is unable to lift the foot of the affected leg from the floor.

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Figure 53-36 Forceful contraction of the iliopsoas m uscle results in avulsion of the lesser trochanter.

Treatment of an isolated lesser trochanter avulsion fracture usually involves bed rest and early mobilization. Painless active hip motion is achieved within 3 weeks.

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KEY CONCEPTS {,

{, {, {,

{,

Hip dislocation: Hip dislocation is one of the few orthopedic emergencies. The likelihood of its complication, AVN, is related to both the initial degree of trauma and the amount of time that the femoral head remains out of joint. Reduction of the hip within 6 hours after dislocation significantly decreases the incidence of AVN. Hip fracture: When a painful hip prevents ambulation and plain films do not reveal a fracture, magnetic resonance imaging should be performed. Intertrochanteric fractures: Hemodynamic instability may result from dehydration and blood loss of up to 3 U into the fracture site. Up to 70% of these patients are under-resuscitated. Acetabular fractures: It is especially important to identify acetabular fractures before closed reduction is attempted because intra-articular bone fragments may interfere with effective reduction. Oblique radiographs (Judet views) or CT will help visualize the acetabulum and precisely define the injury. Slipped capital femoral epiphysis: This condition is most commonly seen in African American boys 10 to 17 years of age; 25% of cases are bilateral. The most reliable initial finding of SCFE is asymmetry of the femoral epiphysis in relation to the neck wherein small amounts of slippage give the appearance of “the scoop slipping off the ice cream cone.”

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REFERENCES 1. Pare A: The work of that famous chirurgeon, Ambrose Pare, translated out of Latin and compared with the French by Tho Johnson, Book XV, London, T Cotes & R Young, 1634. 2. Von Langenbeck B: Verhandl d, deutch, p 92. Gesellsch F, Chir 1878. As found in Davis GG: The operative treatment of intracapsular fracture of the neck of the femur. Am J Orthop Surg 1908-1909;6:481-483. 3. Gourlay M, Richy F, Reginster JV: Strategies for the prevention of hip fracture. Am J Med2003;115:309. 4. Koval KJ, Zuckerman JD: Functional recovery after fracture of the hip. J Bone Joint Surg Am1994;77:751. 5. AAOS Bulletin: Femoral Neck Fracture (Adult)., Chicago: American Academy of Orthopaedic Surgeons; 1989: 11-12. 6. Sernbo I, Johnell O: Changes in bone mass and fracture type in patients with hip fractures. Clin Orthop 1989;238:139. 7. Wadsworth CT: Manual Examination and Treatment of the Spine and Extremities, Baltimore, Williams & Wilkins, 1988. 8. Gray H: Anatomy, Descriptive and Surgical, revised from English 17th ed, New York, Bounty Books, 1997. 9. Brunner LC, Eshilian-Oates L: Hip fractures in adults. Am Fam Physician2003;67:537. 10. Singh M, Nagrath AR, Maini PS: Changes in trabecular patterns of the upper end of the femur as an index of osteoporosis. J Bone Joint Surg Am1970;52:457. 11. Learmonth ID, Maloon S, Dall G: Core compression of early atraumatic osteonecrosis of the femoral head. J Bone Joint Surg Br1990;72:287. 12. Sahin V: Traumatic dislocation and fracture dislocation of the hip: A long-term follow-up study. J Trauma 2003;54:520. 13. Bachiller FGC, Caballer AP, Portal LF: Avascular necrosis of the femoral head after femoral neck fracture. Clin Orthop2002;399:87. 14. Garland DE: A clinical perspective on common forms of acquired heterotrophic ossification. Clin Orthop 1991;263:13. 15. Booth DW, Westers BM: The management of athletes with myositis ossificans traumatica. Can J Sport Sci1989;14:10. 16. Vestergaard P: Corticosteroid use and risk of hip fracture: A population-based case-controlled study in Denmark. J Intern Med2003;254:486. 17. Koval K: Clinical pathway for hip fractures in the elderly. Clin Orthop2004;425:72. 18. DeLee JC: Fractures and dislocations of the hip. In: Rockwood Jr JC, Green DP, Bucholz RW, ed.Rockwood and Green's Fractures in Adults, vol 2. 4th ed. Philadelphia: JB Lippincott; 1996: 19. Harris JH, Harris WH, Novelline RA: The Radiology of Emergency Medicine, 3rd ed. Baltimore, Williams & Wilkins, 1993. 20. Rizzo PF, Gould ES, Lyden JP, Asnis SE: Diagnosis of occult fractures about the hip: Magnetic resonance imaging compared with bone scanning. J Bone Joint Surg Am1993;73:395. 21. Perron AD, Miller MD, Brady WJ: Orthopedic pitfalls in the emergency department: Radiographically-occult hip fracture. Am J Emerg Med2002;20:234. 22. Guanche CA: The use of MRI in the diagnosis of occult hip fractures in the elderly: A preliminary review. Orthopedics1994;17:327. 23. Needoff M, Radford P, Langstaff R: Preoperative traction for hip fractures in the elderly: A clinical trial. Injury1993;24:317. 24. Brillman J, Quenzer RW: Infectious Disease in Emergency Medicine, 2nd ed. Philadelphia, Lippincott-Raven, 1998. 25. Jones JS, Johnson K, McNinch M: Age as a risk factor for inadequate emergency department analgesia. Am J Emerg Med1996;14:157. 26. Ronchi L: Femoral nerve blockade in children using bupivacaine. Anesthesiology1989;70:622. 27. Fletcher AK, Rigby AS, Heyes FLP: Three-in-one femoral nerve block as analgesia for fractured neck of the femur in the emergency department: A randomized controlled trial. Ann Emerg Med2003;41:227.

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28. Dean E, Orlinsky M: Nerve blocks of the thorax and extremities. In: Roberts J, Hedges J, ed.Clinical Procedures in Emergency Medicine, 3rd ed. Philadelphia: WB Saunders; 1998: 29. Harkness JW: Arthroplasty of the hip. In: Canale ST, ed.Campbell's Operative Orthopaedics, 9th ed. St Louis: CV Mosby; 1998: 30. Cushner F, Friedman RJ: Economic impact of total hip arthroplasty. South Med J1988;81:1379. 31. Thomas BJ, Saa J, Lane JM: Total hip arthroplasty. Curr Opin Rheumatol1996;8:148. 32. Shaw JA, Greer RB: Complications of total hip replacement. In: Epps Jr CH, ed.Complications in Orthopedic Surgery, 3rd ed. Philadelphia: JB Lippincott; 1994: 33. Birge SJ: Osteoporosis and hip fracture. Clin Geriatr Med1993;9:69. 34. Clayer MT, Bauze RJ: Morbidity and mortality following fractures of the femoral neck and trochanteric region: Analysis of risk factors. J Trauma1989;29:1673. 35. Ahmad LA, Eckhof DG, Kramer AM: Outcome studies of hip fractures: A functional viewpoint. Orthop Rev1994;23:19. 36. De Boeck H: Classification of hip fractures. Acta Orthop Belg1994;60(Suppl 1):106. 37. Kovall KJ, Zuckerman JD: Hip fractures II: Evaluation and treatment of intertrochanteric fractures. J Am Acad Orthop Surg1994;2:150. 38. Sernbo I: Unstable trochanteric fractures of the hip: Treatment with Ender pins, compared with a compression hip-screw. J Bone Joint Surg Am1988;70:1297. 39. Davis TRC: Intertrochanteric femoral fractures: Mechanical failure after internal fixation. J Bone Joint Surg Br1990;72:26. 40. Russell TA, Taylor JC: Subtrochanteric fractures of the femur. In: Browner BD, ed.Skeletal Trauma, Philadelphia: WB Saunders; 1992: 41. Bajaj HN, Kumar B, Chacko V: Subtrochanteric fractures of the femur—an analysis of results of operative and non-operative management. Injury1988;19:169. 42. Velasco RU, Comfort TH: Analysis of treatment problems in subtrochanteric fractures. J Trauma 1978;18:513. 43. Arneson TJ: Epidemiology of diaphyseal and distal femoral fractures in Rochester, Minnesota, 1965-1984. Clin Orthop1988;234:188. 44. Kluger Y: Blunt vascular injury associated with closed mid-shaft femur fracture: A plea for concern. J Trauma1994;36:222. 45. Taylor MT, Banerjee B, Alpar EK: Injuries associated with a fractured shaft of the femur. Injury 1994;25:185. 46. Hofeldt F: Proximal femoral fractures. Clin Orthop1987;218:12. 47. Chalmers J, Irvine GB: Fractures of the femoral neck in elderly patients. Clin Orthop1988;229:125. 48. Bucholz RW, Brumback RJ: Fractures of the shaft of the femur. In: Rockwood Jr JC, Green DP, Bucholz RW, ed.Rockwood and Green's Fractures in Adults, vol 2. 4th ed. Philadelphia: JB Lippincott; 1996: 49. Blecher A: Über den Einflup des Parademarsches auf der Entstehung der Fup geschwulst. Med Klin 1905;1:305. 50. Clement DB: Exercise-induced stress injuries to the femur. Int J Sports Med1993;14:347. 51. Leung KS: Treatment of ipsilateral femoral shaft fractures and hip fractures. Injury1993;24:41. 52. Hak DJ, Goulet JA: Severity of injuries associated with traumatic hip dislocation as a result of motor vehicle collisions. J Trauma1999;47:60. 53. Morey BF: Instability after total hip arthroplasty. Orthop Clin North Am1992;23:237. 54. Ferguson KL, Harris V: Inferior hip dislocation in an adult: Does a rare injury now have a common mechanism?. Am J Emerg Med2000;16:117. 55. Sanville P, Nicholson DA, Driscoll PA: The hip: ABC of emergency radiology. BMJ1994;308:524. 56. Bassett LW, Gold RH, Epstein HC: Anterior hip dislocation: Atypical superolateral displacement of the femoral head. AJR Am J Roentgenol1983;141:385. 57. Hougaard K, Thomsen PB: Traumatic posterior fracture-dislocation of the hip with fracture of the femoral head or neck, or both. J Bone Joint Surg Am1988;70:233. 58. Dreinhofer KE: Isolated traumatic dislocation of the hip. J Bone Joint Surg Br1994;76:6. 59. Hillyard RF, Fox J: Sciatic nerve injuries associated with traumatic posterior hip dislocation. Am J Emerg Med2003;21:545. 60. Stefanich RJ: Closed reduction of posterior hip dislocation: The Rochester method. Am J Orthop 1999;28:401. 61. Dahner LE, Hundley JD: Reduction of posterior hip dislocations in the lateral position using traction-countertraction: Safer for the surgeon?. J Orthop Trauma1999;13:373. 62. Potter HG: MR imaging of acetabular fractures: Value of detecting femoral head injury, intraarticular fragments, and sciatic nerve injury. AJR Am J Roentgenol1994;163:881. 63. National Institutes of Health : Total hip replacement. NIH consensus statement online1999;12:1. 64. Yuan L, Shih C: Dislocation after total hip arthroplasty. Arch Orthop Trauma Surg1999;119:263. 65. Young JL, Laskowski ER, Rock MG: Thigh injuries in athletes. Mayo Clin Proc1993;68:1099.

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66. Renstrom AFH: Tendon and muscle injuries in the groin area. Clin Sports Med1992;11:815. 67. Barr H, Santes G, Stephenson I: Occult femoral artery injury in relation to fractures of the femoral shaft. J Cardiovasc Surg1987;28:193. 68. Austin OMB: Vascular trauma—a review. J Am Coll Surg1995;181:91. 69. Frykberg ER: The reliability of physical examination in the evaluation of penetrating extremity trauma for vascular injury: Results at one year. J Trauma1991;31:502. 70. D'Amelio LF, Musser DJ, Rhodes M: Bilateral femoral nerve neuropathy following blunt trauma. J Neurosurg1990;73:630. 71. Sunderland S: Repair of a transected sciatic nerve. J Bone Joint Surg Am1993;75:911. 72. In: Rockwood Jr JC, Green DP, Bucholz RW, ed.Rockwood and Green's Fractures in Children, vol 3. 4th ed. Philadelphia: JB Lippincott; 1996: 73. Dalton HJ: Undiagnosed abuse in children younger than 3 years with femoral fracture. Am J Dis Child 1990;144:875. 74. Azouz EM: Types and complications of femoral neck fractures in children. Pediatr Radiol1993;23:415. 75. Hughes LO, Beaty JH: Fractures of the head and neck of the femur in children. J Bone Joint Surg Am 1994;76:283. 76. Kermond S: A randomized clinical trial: Should the child with transient synovitis of the hip be treated with non-steroidal anti-inflammatory drugs?. Ann Emerg Med2002;40:294. 77. Kocher MS, Zurakowski D, Kasser JR: Differentiating between septic arthritis and transient synovitis of the hip in children: An evidence-based clinical prediction algorithm. J Bone Joint Surg Am1999;81:1662. 78. Kocher MS: Validation of a clinical prediction rule for the differentiation between septic arthritis and transient synovitis of the hip in children. J Bone Joint Surg Am2004;86:1629. 79. Dabney KW, Lipton G: Evaluation of limp in children. Curr Opin Pediatr1995;7:88. 80. Dressler F: Infectious diseases affecting the musculoskeletal system in children and adolescents. Curr Opin Rheumatol1993;5:651. 81. Dagan R: Management of acute hematogenous osteomyelitis and septic arthritis in the pediatric patient. Pediatr Infect Dis J1993;12:88. 82. Betz RR: Late sequelae of septic arthritis of the hip in infancy and childhood. J Pediatr Orthop 1990;10:365. 83. Perron AD, Miller MD, Brady WJ: Orthopedic pitfalls in the emergency department: Slipped capital femoral epiphysis. Am J Emerg Med2002;20:484. 84. Kelsey JL: The incidence of slipped capital femoral epiphysis in Connecticut. J Chronic Dis1997;23:567. 85. Canale ST, King RE: Fractures of the hip. In: Rockwood Jr CA, Wilkins KE, King RE, ed.Rockwood and Green's Fractures in Children, vol 3. 3rd ed. Philadelphia: JB Lippincott; 1991: 86. Ankarath S: Delay in the diagnosis of slipped capital femoral epiphysis. J R Soc Med2002;95:356. 87. Lang P, Genant HK, Jergesen HE: Imaging of the hip joint: Computed tomography versus magnetic resonance imaging. Clin Orthop1992;274:135. 88. McErlean MA: The child with a limp. In: Graff J, ed.Critical Decisions in Emergency Medicine, 18. Irving, Tex: ACEP; 2004: 1-10. 89. Poston HL: Traction fracture of the lesser trochanter of the femur. Br J Surg1921-1922;9:256.

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Chapter 54 – Knee and Lower Leg Everett Lyn Daniel Pallin Robert E. Antosia

KNEE PERSPECTIVE More than 1 million patients are seen annually in North American emergency departments with complaints of acute knee injuries.[1] Injuries range from simple contusions to complete dislocations, which are true limb-threatening emergencies. The knee is the largest and most complicated joint in the body. Motion at the knee is a complex interaction of flexion, extension, rotation, gliding, and rolling. The knee joins the two longest mechanical levers in the body, the thigh and lower leg. The knee is subject to high forces during ambulation, sports, and blunt trauma and is a frequent site of acute or chronic injury. The knee joint also comprises an enormous synovial space and is frequently involved in infectious or autoimmune inflammatory conditions, ranging from septic arthritis to serum sickness.

PRINCIPLES OF DISEASE: ANATOMY AND PATHOPHYSIOLOGY The knee is a modified-hinge diarthrodial synovial joint that consists of the tibiofemoral and patellofemoral joints. The distal femur, proximal tibia, and patella compose the bony articulation. The head of the fibula, although not part of this articulation, is closely approximated laterally and provides a site for the attachment of muscles and ligaments. Joint stability is provided by the capsule, ligaments, and surrounding muscles; however, the stability mainly depends on the integrity of the ligamentous structures ( Figure 54-1 ).

Figure 54-1 Anterior and posterior views of the right knee.

The distal femur terminates in the medial and lateral condyles. The V-shaped femoral trochlea between them articulates with the patella. Small protuberances arise from each of the condyles and are called epicondyles. The medial and lateral epicondyles serve as important sites of origin for the medial collateral ligament (MCL) and lateral collateral ligament (LCL). The femoral condyles articulate with the superior surface of the tibia and the corresponding medial and lateral tibial condyles. Within the joint, medial and lateral menisci are interposed between the femoral and tibial condyles, providing a form of shock absorption. The cruciate ligaments are located in the intercondylar notch. Functionally the knee joint can be divided into three compartments: patellofemoral, medial tibiofemoral, and lateral tibiofemoral. These compartments, defined anatomically by the articulation of the bones, are contained within the same joint capsule. The patellofemoral compartment, located anteriorly, contains the quadriceps tendon, which envelops the patella, continues inferiorly as the patellar tendon, and terminates on the tibial tubercle. The fibers of the medial and lateral retinacula are found on either side of the patella, originating from the vastus medialis and vastus lateralis. The medial and lateral patella retinacula also are called extensor retinacula. Normally the patella glides in a rotational manner that increases the mechanical advantage of the quadriceps tendon. The quadriceps tendon is a continuation of the quadriceps femoris muscle, which consists of the rectus femoris, vastus medialis, vastus lateralis, and vastus intermedius, comprising the important extensor structures of the knee. Improper function or weakness may lead to patellar malalignment, which may manifest clinically by the development of chondromalacia patella and peripatellar pain.

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The medial tibiofemoral compartment is located on the medial aspect of the knee and consists of the medial femoral condyle, concave medial tibial condyle (plateau), medial meniscus, MCL, adductor tubercle, and pes anserinus. The pes anserinus (meaning “goose foot”) is a three-pronged tendinous structure that is the conjoined insertion of the sartorius, semitendinosus, and gracilis muscles. The lateral tibiofemoral compartment encompasses the lateral half of the knee joint and includes the lateral femoral condyle and epicondyle, lateral tibial condyle (plateau), LCL, lateral meniscus, and popliteus tendon. The fibular head can be palpated posterolaterally and inferiorly to the joint line but is not usually considered a structure of the lateral tibiofemoral compartment. There is no complete, independent fibrous capsule uniting the bone. Instead a thick ligamentous sheath constructed largely of tendons or expansions from them surrounds the knee joint. The capsule of the knee joint is reinforced at multiple sites: anteriorly, by the ligamentum patella; medially and laterally, by the medial and lateral patellar retinacula; and posterolaterally, by a combination of structures referred to as the posterolateral corner. The posterolateral corner includes the iliotibial band, biceps femoris, fibular collateral ligament, popliteus complex (tendon, tibial attachment, popliteofibular ligament, lateral meniscal attachments), arcuate complex, fabellofibular ligament, capsular ligament, and joint capsule. The popliteofibular ligament has been identified as an important contributor to posterolateral stability. The synovial capsule of the knee works in unison with the ligamentous structures in strengthening the knee. The capsule communicates with the suprapatellar bursa, which expands in conditions that cause knee effusion. Although the prepatellar bursa does not communicate with the joint space, prepatellar bursitis frequently is confused with a septic knee joint. The popliteal fossa is a rhomboid hollow in the posterior aspect of the knee. It is bounded by the biceps femoris laterally, the semimembranosus and semitendinosus muscles medially, and the two heads of the gastrocnemius muscle inferiorly. Found within the popliteal space are the popliteal artery, the popliteal vein, and the peroneal and tibial nerves. Pathologic conditions localized to this area include popliteal cysts and traumatic injuries to the neurovascular structures within the fossa. The popliteal artery is found deep within the popliteal fossa and represents the direct continuation of the femoral artery beyond the adductor hiatus. The popliteal artery descends across the posterior aspect of the knee joint and terminates at the level of the tibial tubercle, where it divides into the anterior and posterior tibial arteries. The popliteal artery is anchored firmly at the proximal and distal ends of the popliteal fossa, which explains the high incidence of arterial injury with knee dislocations. Blood supply to the knee joint comes from the popliteal artery via the geniculate arteries. Branches of the geniculate arteries interconnect with other vessels, forming a complex anastomosis around the knee. The circumflex fibular artery is a branch from the anterior tibial artery and is the main blood supply to the head of the fibula. Blood supply to the head of the tibia is derived in part from two branches of the anterior tibial artery: the anterior and posterior recurrent tibial arteries. The tibial nerve, along with one of its branches, the common peroneal nerve, is responsible for innervation of the knee. The tibial nerve joins the artery and vein in the popliteal fossa. It is not tethered proximally and seems to be injured less often than the popliteal artery. The common peroneal nerve wraps around the head of the fibula and continues inferiorly as the deep and superficial peroneal nerves. Common peroneal nerve injury may occur in association with injury to the fibula head or due to prolonged compression of the lateral aspect of the knee joint. This causes footdrop, in which dorsiflexion strength at the ankle is reduced. Knee and leg fractures are commonly treated with immobilization. A 19% risk of deep venous thrombosis has been seen with immobilization. Prophylactic treatment with low-molecular-weight heparin reduced this risk to 9%.[3]

CLINICAL FEATURES Presentation When a patient complains of a painful knee, the differential diagnosis must include the hip and lumbar nerve roots. This is especially true in children, in whom problems such as a septic hip or slipped capital femoral epiphysis commonly present as knee pain. A swollen knee may result from infection, hemarthrosis, or inflammatory arthritis, and arthrocentesis is commonly required for diagnosis. In the case of traumatic knee injury, mechanism of injury is more important than any other single piece of information in arriving at a correct diagnosis.[4] By noting the position of the body at the time of injury and the likely forces, predictable patterns of injury are found. High-energy trauma without knee swelling should raise the suspicion of disruption of the joint capsule with expulsion of joint fluid and hemorrhage into the thigh or lower leg. Lower energy injuries are more commonly associated with meniscal tears, patella dislocations,

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and less severe ligament injuries; in particular, activities with twisting and turning are associated with anterior cruciate tears and meniscal pathology. Immediate deformity, hemarthrosis, or instability suggests intra-articular fracture, major ligamentous injury, or vascular injury. In contrast, a torn meniscus may cause an acutely locked knee, but more commonly has delayed onset of swelling over 12 to 24 hours and intermittent locking associated with joint line pain. Locking of the knee is a symptom in which there is inability to extend the joint fully. It typically results from either a meniscal tear or a loose body catching in the joint and preventing full extension. A complaint of “giving way” may indicate instability or involuntary muscle inhibition secondary to pain. This is a nonspecific symptom and may be reported in association with arthritis or patellofemoral disorders when inhibition of quadriceps function occurs in association with episodic pain. Although pain remains a helpful indicator of injury, its absence should not be interpreted as proof that only minor injury is present. Partial ligamentous tears may be painful, whereas complete tears may not be because the completely disrupted ligament has no tension across the injured fibers.

Physical Examination Proper examination of the knee requires the patient to be supine on a stretcher with both legs exposed. The evaluation should begin with an assessment of the neurovascular integrity of the foot. The question of whether knee pain might be the result of hip or spine pathology should be raised early. Examination of the knee begins with visual inspection ( Box 54-1 ). Any obvious deformity, swelling, effusion, or ecchymosis should be noted. Localized swelling must be distinguished from the presence of a joint effusion, which may obliterate the normal contour of the knee. If a large effusion is present, the patella is elevated from the femur by the fluid; ballottement of the patella against the femur is possible by direct pressure on the patella. An effusion also may be shown by tapping the lateral retinaculum with a palpable fluid wave appreciated on the medial side. Loss of the medial peripatellar concavity may be the only sign of a small effusion. A small effusion may be shown by milking the suprapatellar pouch inferiorly to force fluid into the knee joint. BOX 54-1 Examination of the Knee

1.

2.

3.

Outli ne area s of tend erne ss. Note whet her any effus ion is pres ent. Che ck for rang e of moti on, valg us stres s at 0 and 30

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4.

5.

degr ees of flexio n, and varu s stres s at 0 and 30 degr ees of flexio n. Eval uate the patel lar and exte nsor mec hani sm of the knee (qua drice ps and patel la tend ons). Perf orm Lach man' s, anter ior draw er, post erior draw er, and pivot shift tests to chec k for anter

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6.

olate ral rotat ory insta bility and furth er delin eate poss ible injur y to the anter ior cruci ate liga ment . Perf orm meni scal exa mina tion with McM urray 's and Aple y's tests .

Precise localization of pain helps define the pathology. Palpation is most helpful in localizing the site of maximal tenderness ( Figure 54-2 ). In general, it is best to palpate areas of tenderness last because provocation of pain early in the examination may cause anxiety, and the patient may be unable to relax and cooperate fully. In the acute setting, the examination may be limited by the presence of muscle spasm, guarding, and effusion. The patella and the extensor mechanism should be palpated with attention to the superior pole. In the absence of trauma, tenderness localized here is consistent with quadriceps tendinitis. Warmth, erythema, and swelling over the anterior patella may result from prepatellar bursitis. Tenderness along the inferior pole of the patella is seen with peripatellar tendinitis. The insertion of the patellar tendon onto the tibial tubercle should be palpated. Pain at this location in an adolescent is the hallmark of Osgood-Schlatter disease. In an adolescent, pain along the femoral or tibial epiphysis after trauma may represent a nondisplaced fracture through the physis. The joint line should be palpated carefully. Pain along the joint line may indicate meniscal pathology. The posterior aspect of the knee should be examined for fullness, which may indicate a popliteal cyst or popliteal artery pseudoaneursym. Tenderness over the medial or lateral heads of the gastrocnemius may indicate tendinitis or muscle strain.

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Figure 54-2 Palpation of tenderness in the knee. 1, quadriceps tendinitis; 2, prepatella bursitis, patella pain; 3, retinacular pain after patella subluxation; 4, patella tendinitis; 5, fat pad tenderness; 6, Osgood-Schlatter disease (tibial tubercle pain); 7, m eniscus pain; 8, collateral ligam ent pain; 9, pes anserine tendinitis bursitis. ((Adapted from Cailliet R: Knee pain. In Soft Tissue Pain and Disab ility, 3rd ed. Philadelphia, FA Davis, 1976, p 411.)FA Davis)

The range of motion of the knee should be assessed. The knee can be viewed as a hinged joint, with range of motion from slight hyperextension to approximately 135 degrees of flexion. In addition to flexion and extension, complete knee function requires anterior and posterior motion and internal and external rotation. The anatomic arrangement of the knee normally allows the tibia to glide posteriorly and internally rotate about 15 to 30 degrees with knee flexion and move anteriorly and externally rotate with extension. In the extended position, tautness of the ligaments prevents rotary motion. At 90 degrees of flexion, rotation to 40 degrees is possible. Inward rotation is always greater than outward rotation. When range of motion is determined, stability or stress testing should be carried out. Generally the cruciate ligaments provide anteroposterior stability, and medial and lateral stability relies on the joint capsule and collateral ligaments. Range-of-motion evaluation of the knee should include active straight leg raising. Loss of active extension of the knee and inability to maintain the passively extended knee against gravity are the hallmarks of quadriceps and patellar tendon rupture, which otherwise may be clinically occult.

Stability Testing Stability testing seeks to identify disruption of the connective tissues supporting the knee joint. A progressive decrease in laxity occurs with age.[5] Comparison testing with the opposite knee is necessary because sideto-side differences are more important than absolute laxity. Stability to anterior stress means that the tibia cannot be moved anteriorly relative to the femur, and stability to posterior stress means the opposite. Stability to valgus stress means that the tibia cannot be bent laterally relative to the femur, and stability to varus stress means that the tibia cannot be bent medially. As noted earlier, specific diagnosis of ligamentous or meniscal injury is difficult in the acute setting, and the diagnosis ultimately is made later, during orthopedic follow-up. Nonetheless, familiarity with the standard diagnostic maneuvers is essential.

Anterior Drawer Test The anterior drawer test is a test for disruption of the anterior cruciate ligament (ACL). A positive test is defined as the ability of the tibia to move forward relative to the femur compared with the other knee. The test is performed with the patient in a supine position, the hip flexed at 45 degrees, and the knee flexed at 90 degrees. Foot and leg positions are stabilized by sitting on the foot. The examiner determines the amount of step-off between the femoral condyle and the tibial plateau by placing the thumbs over the joint line while exerting a smooth, gentle pull anteriorly on the tibia. The amount of forward displacement is compared with the normal side. The anterior drawer test is not reliable and is of little value in diagnosing acute ACL injuries. It is of more value in a chronic ACL-deficient knee.[6] False-negative findings may occur from an effusion preventing knee flexion to 90 degrees, hamstring muscle spasm caused by pain, or insufficient force applied during performance of the test. A false-positive test can be caused by posterior cruciate ligament (PCL) insufficiency, which allows the tibia to slip back on the femur, showing an abnormal amount of displacement when pulled forward.[7]

Lachman's Test Since the 1970s, Lachman's test has gained popularity in diagnosing ACL injury; before this, the anterior drawer test was used most often.[8] Lachman's test is currently the best clinical test for determining the integrity of the ACL and one of the only reliably performed tests for a patient with an acute hemarthrosis.[9] Accuracy in diagnosing ACL injury increases from 70% to 99% using Lachman's test rather than the anterior drawer test.[10] The test is especially useful for acute injuries, in which muscle spasm and the presence of an effusion often limit knee flexion. It also minimizes the blocking effect of the posterior horns of the menisci. Lachman's test is done with the knee flexed 20 to 30 degrees with one hand grasping the thigh and stabilizing it. The tibia is pulled forward with an anteriorly directed force, and the examiner notes tibial excursion. The examiner records “firmness” or a “soft endpoint.” The endpoint can be graded as 1+ (0 to 5mm more displacement than the normal side), 2+ (5 to 10mm), or 3+ (>10mm). The tibiofemoral joint should be in a neutral position before manipulation, and the PCL must be intact for the test to be valid. In an acute injury, any difference in translation or the feeling of a soft or indistinct endpoint may indicate a ligament tear. A PCL injury results in a false-positive test as the knee is pulled forward. Potential causes of false-negative tests include hamstring spasm, meniscal tears, and third-degree MCL tears with posterior

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medial extension. Specific limitations of Lachman's test include difficulty quantitating the amount of anterior translation and inability to limit motion of the femur. In addition, the detection of partial tears of the ACL is problematic and less reliable.[8] Lachman's test also may be difficult to perform if the examiner's hands are small relative to the patient's thigh.

Posterior Drawer Test The posterior drawer test remains the “gold standard” for evaluating PCL injury. The posterior drawer test can be accomplished with the patient's knee flexed at 90 degrees and the foot stabilized by the examiner's thigh. A smooth backward force is applied to the tibia. Posterior displacement of the tibia more than 5 mm, or a “soft” endpoint, indicates injury to the PCL. A normal knee should exhibit no significant posterior excursion. The posterior drawer test may be positive in only 85% of patients with PCL insufficiency documented operatively. The phenomenon of an absent or inconclusive posterior drawer test is believed to occur when the mechanism of injury does not stress, strain, or tear the posterolateral corner ligaments (arcuate complex).[11]

Posterior Sag Sign The posterior sag sign test is a second method of determining PCL integrity. The test can be done as follows. The patient is placed in a supine position, and a pillow is placed under the distal thigh for support while the heel rests on the stretcher. The knee is flexed to either 45 or 90 degrees, depending on which position provides the greatest muscle relaxation. If the tibia sags backward, the test is positive, indicating PCL insufficiency. If the posterior sag sign is not appreciated before the different drawer tests are performed, a false-positive anterior drawer test is misinterpreted as an ACL injury.[7] Posterior sag also may be shown by passive elevation of the leg in a fully extended position, with the examiner applying the elevating force at the ankle. As the leg is elevated, the tibia may fall back on the femur if the PCL is ruptured.

McMurray's Test McMurray's test is used to identify meniscal tears. The patient is placed in a supine position with the knee hyperflexed. The examiner grasps the lower leg, flexing and extending the knee while simultaneously internally and externally rotating the tibia on the femur with a smooth, firm, controlled movement. A positive test occurs when, with the other hand, a “clicking” sensation is felt along the joint line or the patient experiences pain during internal and external rotation. By twisting the leg into internal rotation, the posterior segment of the lateral meniscus is tested. External rotation tests the posterior segment of the medial meniscus. In the acute setting, limitation of range of motion may not allow sufficient hyperflexion to perform McMurray's test, and the test may be falsely negative.

Apley's Test Apley's test also aids in diagnosing meniscal tears. With the patient prone, the knee is flexed 90 degrees, and the leg is internally and externally rotated with pressure applied to the heel. Downward pressure eliciting pain suggests meniscal pathology. The pain should be relieved with distraction of the knee and rotation of the leg back to a neutral position.

Pivot Shift The pivot shift test, also called subluxation provocation or the “jerk” test, is performed to detect anterolateral rotatory instability associated with an injury to the ACL or lateral capsular structure. This test must be done carefully, if at all, in the acutely injured knee because the test maneuvers can exacerbate the initial injury. The pivot shift test is performed with the patient supine. The knee is examined in full extension. The tibia is internally rotated with one hand grasping the foot and the other hand applying a mild valgus stress at the level of the knee joint. Then, with flexion of the knee to approximately 20 to 30 degrees, a jerk is suddenly experienced at the anterolateral corner of the proximal tibia. In a positive test, the tibia subluxes when the knee is extended and relocates when it is flexed to 20 to 30 degrees. Grading of the relocation event is as follows: absent (0), rolling (1+), moderate (2+), or momentary locking (3+). Because of pain or spasm, the pivot shift test is unreliable without anesthesia.[6]

Collateral Ligament Stress Test The collateral ligament stress test is used to test the integrity of the MCL and LCL. The test is performed as follows. With the patient lying supine, the examiner applies varus and valgus stress with the knee at 0 and 30 degrees of flexion. Joint line opening is the amount of movement produced between the tibia and the femur; this can be palpated and estimated in millimeters. The normal knee should be subjected to the same amount of valgus and varus stress and joint line opening compared with the injured knee. Laxity in full extension implies complete collateral ligament tear, with injury to the secondary restraints, such as the ACL,

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PCL, and posteromedial or posterolateral corners. When the knee is flexed to 30 degrees, the stability provided by the cruciate ligaments to valgus and varus stress is removed. If the knee is stable to valgus stress with the knee in full extension but lax at 30 degrees of flexion, injury is limited to the superficial and deep MCLs. Varus stress at 0 degrees of flexion producing no instability but laxity present at 30 degrees indicates that at least part of the LCL and lateral stability complex has been injured. Laxity may be graded as follows: grade I, some laxity; grade II, marked laxity; and grade III, total laxity.

Instrument Testing More recent developments have seen the advent of instrument testing to evaluate ACL injury. The arthrometer gives numeric quantitative comparison of ACL laxity of the knee. Studies using commercially available arthrometers indicate that a side-to-side difference exceeding 3 mm anterior displacement at 20 lb is predictive of ACL with 94% accuracy.[12] Reports also indicate that quantitative laxity determination with such instruments can yield prognostic information and may aid clinicians in determining how aggressively to treat ACL injuries. However practical and useful such instruments may be, they have not gained widespread usage or acceptance at present.

DIAGNOSTIC STRATEGIES Radiographic Evaluation Plain Radiographs The traditional standard of care was to obtain anteroposterior and lateral radiographs of the knee in all cases of acute knee trauma. More recent work has led to validation of clinical decision rules that help decrease unnecessary radiography.[] The Ottawa Knee Rule states that radiography is necessary only if any one of five conditions is present: (1) age older than 55 years, (2) inability to transfer weight from one foot to the next four times at the time of injury and in the emergency department, (3) inability to flex the knee to 90 degrees, (4) patellar tenderness with no other bony tenderness, or (5) tenderness of the fibular head. Initial tests found that this rule detected 100% of fractures, while allowing significantly fewer radiographs to be done.[] Similarly the Pittsburgh Knee Rule was found to be 100% sensitive.[17] The Pittsburgh Knee Rule states that radiography is necessary only if the patient fell or sustained blunt trauma to the knee, and either of two conditions is present: (1) age younger than 12 or older than 50 or (2) inability to walk four full weight-bearing steps in the emergency department. One study compared these two decision rules and found that both had good sensitivity, but that the Pittsburgh rule was more specific, allowing fewer radiographs to be done without sacrificing sensitivity; in this study, the sensitivity of the Ottawa rule was 97% (95% confidence interval, 90% to 99%), and the sensitivity of the Pittsburgh rule was 99% (95% confidence interval, 94% to 100%).[13] Until further work determines the optimal approach, either rule may be used, but patients should be told that there is about a 1% chance of a missed fracture, and they should seek re-evaluation in the event of persistent or progressive symptoms. One study validated the Ottawa Knee Rule in children older than age 5, finding a sensitivity of 100%. The Ottawa Knee Rule permitted a 31% reduction in the number of radiographic evaluations.[18] In another pediatric study, of 13 fractures, 1 was missed, implying a sensitivity of only 92%, so application of the rule in children still requires clinical judgment.[19] In another approach, Verma and colleagues[20] recognized that fears of malpractice might limit implementation of decision rules and instead asked whether a single lateral x-ray could replace the traditional three-view “knee series” (anteroposterior, lateral, and tunnel views). These investigators found that a single lateral view could detect 100% of fractures identifiable on the full series.[20] Some clinicians may prefer this more conservative approach until the decision rules are validated further. Joint space narrowing, as seen in osteoarthritis, is easily discernible on erect standard views. Lateral views may reveal an abnormally low-riding or high-riding patella. Tangential, “sunrise,” or “skyline” views are especially good for delineating the patellofemoral joint.[21] Tangential views are useful to assess patella tracking or subluxation. Oblique x-ray studies are particularly useful when tibial plateau fractures are suspected but not seen on routine views.[22] “Tunnel” views, which image the intercondylar notch, are used to detect tibial spine fractures and loose bodies within the notch. Although most ligamentous injuries cannot be diagnosed by plain films, avulsion of the attachment site can be seen occasionally and provides indirect evidence of ligament disruption. Stress radiographs may aid in the diagnosis of collateral ligament disruption but generally are not used in the initial evaluation.

Computed Tomography

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Computed tomography (CT) is most useful in detecting and classifying tibial plateau fractures and usually is done when the diagnosis is unclear, or operative intervention is considered.

Ultrasound Ultrasound is useful in diagnosing several pathologic conditions of the knee. It has gained wide acceptance in the diagnosis of clinically suspected popliteal cyst, which appears as a nonechogenic mass with smooth walls lying medially within the popliteal fossa.[23] Small cysts can lead to false-negative ultrasound results. The popliteal artery is the most common site for peripheral aneurysms, yet the clinical diagnosis can be difficult.[21] Typically the aneurysm occurs just distal to the adductor hiatus in the proximal segment and midsegment of the artery and is bilateral in 50% of cases.[23] Realtime ultrasound is an excellent modality for diagnosing popliteal artery aneurysm and can differentiate aneurysm from cyst.[21]

Contrast Arteriography and Color-Flow Doppler Contrast arteriography and color-flow Doppler ultrasonography are used to evaluate the arteries of the knee and leg. Traditionally, arteriography was deemed mandatory in all cases of tibiofemoral knee dislocation and in all cases of penetrating trauma in close proximity to major arteries. More recently, serial examination and Doppler scanning have been studied and found to be acceptable alternatives to arteriography in patients with normal distal neurovascular examinations and low-risk mechanisms.[24]

Radionuclide Bone Scan A radionuclide bone scan can be used to detect osteomyelitis or occult bony injuries, such as stress fractures, osteochondritis dissecans, and avascular necrosis.

Magnetic Resonance Imaging Double-contrast arthrograms are of primarily historical interest because they have been largely replaced by magnetic resonance imaging (MRI).[21] Arthrography may be performed after prosthetic replacement of the knee to detect loosening. It also may be used if there is a contraindication to MRI, or if MRI is not available. MRI can be helpful to identify associated injuries to the menisci and articular cartilage when the clinical examination is limited because of pain and swelling. The diagnostic accuracy of MRI in detecting meniscal and capsuloligamentous injuries of the knee is well documented.[25] Although the sensitivity of MRI in identifying ACL injury may be high (90% to 98%), its specificity, particularly in differentiating partial from complete tears, is low (24 hour s old Esta blish ed infec tion Pen etrati on of joint or tend on shea th Bon e invol vem ent Forei gn body Unre liable patie nt or poor hom e situa

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tion Diab etic or supp ress ed imm une statu s

Patients without Infection Reliable, otherwise healthy patients who present within 24 hours without infection and have no tendon, joint, or bone damage can be treated at home with close follow-up, preferably within 1 to 2 days.[] Discharge instructions should include immobilization, elevation, and sterile dressing changes every 6 hours. High-risk patients, such as those with delayed presentation or deep structure involvement, require prophylactic parenteral antibiotics and close evaluation. Hospitalization is generally recommended. Although many human bites are a consequence of mutual aggression, the physician must keep in mind that the patient may be the victim—or perpetrator—of child, spousal, or elder abuse.[100] All states require reporting of suspected child abuse; laws vary for spousal or elder abuse. In all cases, details of the incident should be documented and the wound carefully described in the record. Counseling or referral should be offered when appropriate.

KEY CONCEPTS {,

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Prop hyla ctic antib iotic s are not indic ated for routi ne dog bite wou nds but are reco mm ende d for dog bites of the hand and in highrisk patie nts. Patie

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{,

{,

nts at risk for C. cani mor sus shou ld recei ve prop hyla ctic antib iotic s for this orga nism after a dog bite. Cat bites have a high rate of infec tion and all warr ant prop hyla ctic antib iotic s. In gene ral, whe na wou nd is at high risk for infec tion, it shou ld not be

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sutur ed. {,

Prop hyla ctic antib iotic s are reco mm ende d for all hum an bites of the hand as well as for highrisk wou nds, inclu ding deep punc tures , seve re crus h injuri es, cont amin ated wou nds, older wou nds, and wou nds in patie nts with unde rlyin g illnes ses. Ordi nary bites

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, such as thos e exch ange d amo ng child ren, are not high risk for infec tions or com plica tions and do not requi re prop hylax is. All bites are cons idere d tetan us-p rone wou nds.

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Marx: Rosen's Emergency Medicine: Concepts and Clinical Practice, 6th ed., Copyright © 2006 Mosby, Inc.

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31. Butler T: Unidentified gram-negative rod infection: A new disease of man. Ann Intern Med1977;86:1. 32. Lion C, Escande F, Burdin JC: Capnocytophaga canimorsus infections in human: Review of the literature and case report. Eur J Epidemiol1996;12:521. 33. Valtonen M: Capnocytophaga canimorsus septicemia: Fifth report of a cat-associated infection and five other cases. Eur J Clin Microbiol Infect Dis1995;14:520. 34. Chadha V, Warady BA: Capnocytophaga canimorsus peritonitis in a pediatric peritoneal dialysis patient. Pediatr Nephrol1999;13:646. 35. Carpenter P, Heppner B, Gnann J: DF-2 bacteremia following cat bites. Am J Med1987;82:621. 36. Job L: Dysgonic fermenter-2: A clinico-epidemiologic review. J Emerg Med1989;7:185. 37. Howell J, Woodward G: Precipitous hypotension in the emergency department caused by Capnocytophaga canimorsus. J Emerg Med1990;8:312. 38. Findling J, Pohlmann G, Rose H: Fulminant gram-negative bacillemia (DF-2) following a dog bite in an asplenic woman. Am J Med1980;68:154. 39. Kullberg BJ: Purpura fulminans and symmetrical peripheral gangrene caused by Capnocytophaga canimorsus (formerly DF-2) septicemia: A complication of dog bite. Medicine (Baltimore)1991;70:287. 40. Depres-Brummer P: Capnocytophaga canimorsus sepsis presenting as an acute abdomen in an asplenic patient. Neth J Med2001;59:213. 41. Dire DJ: Cat bite wounds: Risk factors for infection. Ann Emerg Med1991;20:973. 42. Ejlertsen T: Pasteurella aerogenes isolated from ulcers or wounds in humans with occupational exposure to pigs: A report of 7 Danish cases. Scand J Infect Dis1996;28:567. 43. Kizer KW: Pasteurella multocida infection from a cougar bite: A review of cougar attacks. West J Med 1989;150:87. 44. Tan C, Ti T, Lee E: Pasteurella multocida osteomyelitis of the cervical spine in a patient on chronic hemodialysis. Singapore Med J1990;31:400. 45. Layton CT: Pasteurella multocida meningitis and septic arthritis secondary to a cat bite. J Emerg Med 1999;17:445. 46. Morris JT, McAllister CK: Bacteremia due to Pasteurella multocida. South Med J1992;85:442. 47. Kumar A, Devlin HR, Vellend H: Pasteurella multocida meningitis in an adult: Case report and review. Rev Infect Dis1990;12:440. 48. Al-Allaf AK, Harvey TC, Cunnington AR: Pericardial tamponade caused by Pasteurella multocida infection after a cat bite. Postgrad Med J2001;77:199. 49. Goldstein EJ: In vitro activity of Bay 12-8039, a new 8-methoxyquinolone, compared to the activities of 11 other oral antimicrobial agents against 390 aerobic and anaerobic bacteria isolated from human and animal bite wound skin and soft tissue infections in humans. Antimicrob Agents Chemother1997;41:1552. 50. Goldstein E, Nesbit C, Citron D: Comparative in vitro activities of azithromycin, Bay 3118, levofloxacin, sparfloxacin, and 11 other oral antimicrobial agents against 194 aerobic and anaerobic bite wound isolates. Antimicrob Agents Chemother1995;39:1097. 51. Goldstein E, Citron D, Vagvolgyi A: Susceptibility of bite wound bacteria to seven oral antimicrobial agents, including RU-985, a new erythromycin: Considerations in choosing empiric therapy. Antimicrob Agents Chemother1986;29:556. 52. Fass R: Erythromycin, clarithromycin, and azithromycin: Use of frequency distribution curves, scattergrams, and regression analyses to compare in vitro activities and describe cross-resistance. Antimicrob Agents Chemother1993;37:2080. 53. Elenbaas R, McNabney W, Robinson W: Evaluation of prophylactic oxacillin in cat bite wounds. Ann Emerg Med1984;13:155. 54. Hudsmith L: Clinical picture: Rat bite fever. Lancet Infect Dis2001;1:91. 55. Stehle P: Rat bite fever without fever. Ann Rheum Dis2003;62:894. 56. Janda DH: Nonhuman primate bites. J Orthop Res1990;8:146. 57. Cohen JI: Recommendations for prevention of and therapy for exposure to B virus (cercopithecine herpesvirus 1).. Clin Infect Dis2002;35:1191. 58. Holmes GP: B virus (Herpesvirus simiae) infection in humans: Epidemiologic investigation of a cluster. Ann Intern Med1990;112:833. 59. Ostrowski SR: B-virus from pet macaque monkeys: An emerging threat in the United States?. Emerg Infect Dis1998;4:117. 60. Applegate JA, Walhout MF: Childhood risks from the ferret. J Emerg Med1998;16:425. 61. Paisley J, Lauer B: Severe facial injuries to infants due to unprovoked attacks by pet ferrets. JAMA 1988;259:2005. 62. Rupprecht CE: Current issues in rabies prevention in the United States: Health dilemmas, public coffers, private interests. Public Health Rep1996;111:400. 63. Niezgoda M: Pathogenesis of experimentally induced rabies in domestic ferrets. Am J Vet Res 1997;58:1327. 64. Human rabies prevention—United States, 1999: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep1999;48(RR-1):1.

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65. Compendium of animal rabies control, 1999. National Association of State Public Health Veterinarians, Inc. MMWR Recomm Rep1999;48(RR-3):1. 66. Van Demark RES, Van Demark REJ: Swine bites of the hand. J Hand Surg Am1991;16:136. 67. al Boukai A: Camel bites: Report of severe osteolysis as late bone complications. Postgrad Med J 1989;65:900. 68. Ogunbodede EO, Arotiba JT: Camel bite injuries of the orofacial region: Report of a case. J Oral Maxillofac Surg1997;55:1174. 69. Wiens M, Harrison P: Big cat attack: A case study. J Trauma1996;40:829. 70. Tan JS: Human zoonotic infections transmitted by dogs and cats. Arch Intern Med1997;157:1933. 71. Baker MD, Lanuti M: The management and outcome of lacerations in urban children. Ann Emerg Med 1990;19:1001. 72. Singer AJ, Hollander JE, Quinn JV: Evaluation and management of traumatic lacerations. N Engl J Med 1997;337:1142. 73. Glass K: Factors related to the resolution of treated hand infections. J Hand Surg1982;7:388. 74. Dreyfuss U, Singer M: Human bites of the hand: A study of one hundred six patients. J Hand Surg 1985;10:884. 75. Perron AD, Miller MD, Brady WJ: Orthopedic pitfalls in the ED: Fight bite. Am J Emerg Med2002;20:114. 76. Dire D, Hogan D, Riggs M: A prospective evaluation of risk factors for dog bite wound infections. Ann Emerg Med1990;19:961. 77. Chen E: Primary closure of mammalian bites. Acad Emerg Med2000;7:157. 78. Quinn J: Suturing versus conservative management of lacerations of the hand: Randomised controlled trial. BMJ2002;325:299. 79. Centers for Disease Control : Diphtheria, tetanus and pertussis—recommendations for vaccine use and other preventive measures: Recommendations of the Immunization Practices Advisory Committee (ACIP). MMWR Morb Mortal Wkly Rep1991;40:1. 80. Dire DJ, Hogan DE, Walker JS: Prophylactic oral antibiotics for low-risk dog bite wounds. Pediatr Emerg Care1992;8:194. 81. Goldstein EJ: Activities of HMR 3004 (RU 64004) and HMR 3647 (RU 66647) compared to those of erythromycin, azithromycin, clarithromycin, roxithromycin, and eight other antimicrobial agents against unusual aerobic and anaerobic human and animal bite pathogens isolated from skin and soft tissue infections in humans. Antimicrob Agents Chemother1998;42:11272. 82. Burrows GE, Ewing P: In vitro assessment of the efficacy of erythromycin in combination with oxytetracycline or spectinomycin against Pasteurella haemolytica. J Vet Diagn Invest1989;1:299. 83. Newell P: Value of needle aspiration in bacteriologic diagnosis of cellulitis in adults. J Clin Microbiol 1988;26:401. 84. Perl B: Cost-effectiveness of blood cultures for adult patients with cellulitis. Clin Infect Dis1999;29:1483. 85. Zubowicz VN, Gravier M: Management of early human bites of the hand: A prospective randomized study. Plast Reconstr Surg1991;88:111. 86. Dellinger EP: Hand infections: Bacteriology and treatment—a prospective study. Arch Surg 1988;123:745. 87. Phair IC, Quinton DN: Clenched fist human bite injuries. J Hand Surg (Br)1989;14:86. 88. Baker MD, Moore SE: Human bites in children: A six-year experience. Am J Dis Child1987;141:1285. 89. Schweich P, Fleisher G: Human bites in children. Ped Emerg Care1985;1:51. 90. Steele M: Prophylactic penicillin for intraoral wounds. Ann Emerg Med1989;18:847. 91. Morgan MG, Mardel SN: Clenched fist actinomycosis in a penicillin-allergic female [Letter]. J Infect 1993;26:222. 92. Richman KM, Rickman LS: The potential for transmission of human immunodeficiency virus through human bites. J Acquir Immune Defic Syndr1993;6:402. 93. U.S. Public Health Service Guidelines for the Management of Occupational Exposures to HBV, HCV, and HIV and Recommendations for Postexposure Prophylaxis. MMWR Recomm Rep2001;50(RR-11):1. 94. Groopman J, Salahuddin S, Sarngadharan M: HTLV-III in saliva of people with AIDS-related complex and healthy homosexual men at risk for AIDS. Science1984;226:447. 95. Pretty IA, Anderson GS, Sweet DJ: Human bites and the risk of human immunodeficiency virus transmission. Am J Forensic Med Pathol1999;20:232. 96. Vidmar L: Transmission of HIV-1 by human bite. (Letter). Lancet1996;347:1762. 97. Eyres KS, Allen TR: Skyline view of the metacarpal head in the assessment of human fight-bite injuries. J Hand Surg Br1993;18:43. 98. Agrawal K: Tetanus caused by human bite of the finger. Ann Plast Surg1995;34:201. 99. Donkor P, Bankas DO: A study of primary closure of human bite injuries to the face. J Oral Maxillofac Surg1997;55:479. 100. Fischer H, Hammel PW, Dragovic LJ: Images in clinical medicine: Human bites versus dog bites. N Engl J Med2003;349:e11.

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Marx: Rosen's Emergency Medicine: Concepts and Clinical Practice, 6th ed., Copyright © 2006 Mosby, Inc.

Chapter 59 – Venomous Animal Injuries Edward J. Otten Young primates appear to be born with only three inborn fears—of falling, snakes and the dark[1].

PERSPECTIVE Epidemiology Venomous animals account for considerable morbidity and mortality worldwide. Snakes alone are estimated to inflict 2.5 million venomous bites annually, with approximately 125,000 deaths. The actual numbers may be much larger. Southeast Asia, India, Brazil, and parts of Africa lead the world in snakebite mortality.[2] It is impossible to estimate the worldwide morbidity and mortality resulting from other venomous animals such as bees, wasps, ants, and spiders. Approximately 45,000 snakebites occur annually in the United States; 7000 to 8000 are inflicted by venomous snakes, and 5 to 10 result in death. Table 59-1 categorizes fatalities caused by venomous animals in the United States for the 20-year period from 1950 to 1969.[] Insects were responsible for 52% of the fatalities; snakes, 30%; and spiders, 13%. More specifically, bees were responsible for the most fatalities, followed by rattlesnakes, wasps, and spiders. Historically, most of the recorded spider deaths were caused by the black widow, although the brown recluse spider had been implicated in an increasing number of deaths. Table 59-1 -- Venomous Animal Fatalities in the United States, 1950–1969 Animal

Fatalities

Hymenoptera Bees Wasps Yellow jackets Hornets Ants Ticks Spiders Unidentified insects Coelenterata Stingray Snakes Rattlesnakes Water moccasins Copperheads Coral Cobra Unidentified Animal, not coded Total

175 127 33 12 5 3 92 53 2 1 159 9 2 3 3 67 44 790

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The American Association of Poison Control Centers began collecting data in 1983 on deaths caused by venomous animals. Their 20-year experience shows a significant number of exposures by bite or sting but relatively few deaths ( Table 59-2 ).[7] Although these data include most of the United States, there is no requirement that hospitals, emergency departments, coroners, or public health agencies report deaths or exposure to Regional Drug and Poison Information Centers. This decline may be caused by an actual decrease in mortality or may be due to inadequate reporting. Meaningful morbidity data, such as the number of amputations, hospitalizations, and disabilities, do not exist. The number of exposures and deaths from exotic snakes seems to be increasing, possibly because of interest in collecting so-called hot or venomous varieties such as cobras, mambas, and vipers. The morbidity from marine animal injuries is increasing in proportion to the number of people exposed to the ocean and the number of private collectors, but the number of deaths has not increased dramatically. An increase in outdoor recreational activities such as camping, scuba diving, and wilderness trekking puts more people in proximity to venomous animals and increases the risk of envenomation. Most exposures occur from April to October, when animals are most active and potential victims are outdoors and involved in activities that might increase their risk for envenomation. Of course, many spider bites and exotic animal envenomations that occur indoors can take place at any time. Most deaths seem to occur in very young, elderly, and inappropriately treated patients. Table 59-2 -- Venomous Animal Injuries and Deaths, 1983–2002 Animal Envenomations

Deaths

Coelenterates 11,021 0 Fish 21,145 0 Ants 38,704 0 Bees/wasps/hornets 294,719 19 Caterpillars/centipedes 34,318 0 Other arthropods 193,520 1 Copperheads 7,506 1 Rattlesnakes 12,860 16 Water moccasins 1,303 0 Coral snakes 800 0 Exotic snakes 1,423 2 Nonvenomous snakes 29,983 0 Unknown snakes 29,877 2 Black widow spiders 43,263 0 Brown recluse spiders 30,816 6 Other/unknown spiders 202,549 0 Scorpions 164,973 3 Data compiled from Litovitz TL, et al: American Association of Poison Control Centers data published in the American Journal of Emergency Medicine, vol 2–21, 1984–2003.

Venom Delivery Animals that have developed specific venom glands and venom delivery systems can be found in every class, including most recently birds.[8] The toxin and toxic apparatus vary from class to class. For example, the rattlesnake has modified salivary glands and maxillary teeth and uses this system primarily to obtain food. The bee has a modified ovipositor that is used mainly for defense. Poisonous and venomous animals are not the same and should be differentiated. Animals can be considered poisonous because of various toxins distributed in their tissues. For example, certain shellfish, toads, and barracuda have been known to cause death after ingestion. However, only animals with specific glands for producing venom connected to an apparatus for delivering that venom to another animal can be considered venomous. Most venomous animal injuries seen in the emergency department are minor problems, but some injuries

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must be given priority. Venomous snakebites, black widow spider bites, certain marine animal envenomations, and anaphylactic reactions to insect stings are life-threatening emergencies requiring immediate attention.

VENOMOUS REPTILES Snakes Snakes first appeared in the late Cretaceous period, and venomous snakes evolved about 50 million years later in the Miocene epoch. Of the 3000 species of snakes, about 10% to 15% are venomous. Of the 14 families of snakes, 5 contain venomous species. Snakes are distributed throughout most of the earth's surface, including fresh and salt water. The major exceptions are the Arctic and Antarctic zones, New Zealand, Malagasy, and many small islands. Most snakebites occur in tropical and subtropical climates, especially in agricultural settings where the inhabitants go barefoot. Sea snakes are found only in the Pacific and Indian oceans. Snakes are poikilotherms, which accounts for their distribution and activity. Their inability to raise their body temperature above ambient levels restricts their activity to a fairly narrow temperature range, about 25° C to 35° C. All snakes are carnivorous, and their venom apparatus evolved for the purpose of obtaining food.

Epidemiology The incidence of reported venomous snakebites is greatest in the southern United States, which has the largest number of venomous snakes. States having the highest death rates were North Carolina, Arkansas, Texas, and Georgia. The anatomic distribution of snakebites is not surprising. Of all snakebites, 97% occur on the extremities, with two thirds on the upper extremities and one third on the lower extremities. This is a reversal of the previous trend and may reflect bites being provoked rather than accidental. Bites that occur accidentally are considered “legitimate,” whereas bites that occur when attempting to handle or disturb a snake are considered “illegitimate.” Men are bitten nine times more frequently than women.[9] Imported venomous snakes have recently been an increasing problem throughout the United States. In the past, only zoos, research centers, and herpetologists have kept exotic venomous snakes. Today, however, hundreds of people are raising deadly venomous snakes without the necessary precautions, such as specialized cages, safe handling techniques, and rapid access to specific antivenin. They place not only themselves in danger but also their families and the general public.

Classification and Characteristics The five venomous families of snakes are the Colubridae, Hydrophiidae, Elapidae, Viperidae, and Crotalidae. The Colubridae, though representing 70% of all species of snakes, have very few venomous members dangerous to humans; these include the boomslang and bird snake. The Hydrophiidae are sea snakes. The Elapidae are more common and include the cobras, kraits, mambas, and coral snakes. The Viperidae, or true vipers, are represented by Russell's viper, the puff adder, the Gaboon viper, the saw-scaled viper, and the European viper. The Crotalidae, or pit vipers, are sometimes considered a separate family or a subfamily of the Viperidae. Among the pit vipers are the most common American venomous snakes, such as rattlesnakes, water moccasins, copperheads, the bushmaster, and the fer-de-lance. Several species of Asian pit vipers are responsible for bites in Okinawa and bites by imported snakes in the United States.[] Pit vipers, the most prevalent venomous snakes in the United States, are native to every state except Maine, Alaska, and Hawaii. They are classified into three main groups: true rattlesnakes (genus Crotalus), copperheads and water moccasins (genus Agkistrodon), and pygmy and Massasauga rattlesnakes (genus Sistrurus). Pit vipers account for 98% of all venomous snakebites in the United States.[] The Colubridae and Hydrophiidae families have few venomous members and are responsible for even fewer injuries. Some colubrid species found in the United States that were previously thought to be harmless may indeed be venomous. Examples are the Lyre snake and the wandering garter snake. No deaths have been reported, but the problem has generated much interest among herpetologists and toxicologists.[15] The yellow-bellied sea snake (family Hydrophiidae) has been found off the coast of southern California and western Mexico, but bites by this snake are rare. The yellow-bellied sea snake (Pelamis platurus) has a bright yellow underside. The other major group of venomous snakes in the United States is the coral snakes. The eastern coral snake (Micrurus fulvius) is found in North Carolina, South Carolina, Florida, Louisiana, Mississippi, Georgia, and Texas. The western or Sonoran (Micruroides euryxanthus) coral snake is native to Arizona and New Mexico. Although both species are generally quite shy unless handled, the eastern coral snake is considered deadly. There are no records of fatalities caused by the western species.

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Coral snakes can be readily identified by their color pattern. At first glance, they resemble one of several varieties of king snake found in the southern United States. The coral snake can be differentiated from the king snake by two characteristics: the nose of the coral snake is black, and the red and yellow bands are adjacent on the coral snake but separated by a black band on the king snake. The popular rhyme is as follows: Red next to yellow, kill a fellow. Red next to black, venom lack.

This rhyme can be used only in the United States; Brazilian coral snakes have red next to black bands, and some coral snakes have no red bands.

Identification In the identification of venomous snakes, two principles should be kept in mind: only experts should handle live snakes, and even dead snakes can envenom careless handlers.[16] It is not difficult to differentiate between pit vipers and harmless snakes ( Figure 59-1 ). Pit vipers, as their name implies, have a characteristic pit midway between the eye and the nostril on both sides of the head. This pit is a heat-sensitive organ that enables the snake to locate warm-blooded prey. Pit vipers can be identified through other methods, but this characteristic is 100% consistent. The triangular shape of the head, the presence of an elliptic pupil, the arrangement of subcaudal plates, the tail structure, and the presence of fangs are useful characteristics but may be inconsistent. An individual specimen may not fit the classic description, depending on the age of the snake, the time of the year, and the condition of the tail and mouthparts. A person should never attempt to identify pit vipers by color or skin patterns.[]

Figure 59-1 Identification of venom ous and nonvenom ous snakes.

Size is not an important factor in identifying various snakes and lizards. Venomous snakes range in length from several inches to several feet. Although a 6-ft eastern diamondback rattlesnake is much more dangerous than a 10-inch copperhead, all venomous snakes are able to envenom from birth and should be treated as though they are dangerous. Exotic snakes that are not pit vipers are not as easily identified. If possible, they should be safely transported to an expert for positive identification. Local zoos, herpetology groups, and colleges often have individuals who can identify unknown snakes. Usually, however, a person bitten by an exotic snake knows the type of snake or at least the common name of the snake.

Other Reptiles Only two venomous lizards are found in the world, both in the southwestern United States and Mexico. They are the Gila monster (Heloderma suspectum) and the Mexican beaded lizard (Heloderma horridum). Fortunately, both these lizards are nonaggressive and rarely encountered. Bites usually result from handling the animals in captivity.[17] The Gila monster and the Mexican beaded lizard are easily identifiable. Both have thick bodies, beaded scales, and either white and black or pink and black coloration.

Principles of Disease Toxins The two main factors influencing the pathophysiology of any venomous animal injury are the toxic properties of the venom and the victim's response to these toxins. In the past, snake venoms were classified as either neurotoxic or hematotoxic, depending on the observed response of the victim to the various venoms. Modern toxicologic investigation has shown that this classification is inadequate because most snake venoms studied contain compounds that have other toxic properties. It is true, however, that the venom of a particular species of snake may show a clinical response, predominantly neurotoxic or hematotoxic.[18]

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The toxic components of snake venom can be classified into four broad categories: enzymes, polypeptides, glycoproteins, and low-molecular-weight compounds. They can also be classified as protein and nonprotein compounds ( Table 59-3 ). Proteins, which account for most of the toxic manifestations, make up 90% to 95% of venom. Symptoms can generally be classified as local or systemic. Local effects are usually caused by enzymatic action on the various cellular and noncellular structures in the victim's tissues. These enzymes can cause coagulation, anticoagulation, cell lysis, hemorrhage, hemolysis, and the destruction of nucleic acid, mitochondria, and other organelles. Table 59-3 -- Compounds Identified in Snake Venoms Components

Examples

Nonprotein Compounds (5–10%) Metals

Copper, zinc, sodium, magnesium

Free amino acids

Glycine, valine, isoleucine

Peptides

Pyroglutamylpeptide

Nucleosides

Adenosine, guanosine, inosine

Carbohydrates

Neutral sugars, sialic acid

Lipids

Phospholipids, cholesterol

Biogenic amines

Spermine, histamine, serotonin

Protein Components (90–95%) Enzymes

Proteolytic enzymes, collagenases, phospholipase A, nucleotidase, hyaluronidase, acetylcholinesterase, amino acid oxidase

Polypeptides

Crotoxin, cardiotoxin, crotamine

Polypeptides are structurally smaller and more rapidly absorbed than proteins and account for the venom's systemic effects on the heart, lungs, kidneys, presynaptic and postsynaptic membranes, and other organ systems. Phospholipase A can inhibit electron transfer at the level of cytochrome c and render mitochondrial-bound enzymes soluble. It can hydrolyze phospholipids in nerve axons, break down acetylcholine vesicles at the myoneural junction, cause myonecrosis, and induce lysis of red cell membranes. This single enzyme has been identified in all venoms of Hydrophiidae, Elapidae, Viperidae, and Crotalidae thus far investigated.[] Elapidae and Hydrophiidae venoms have predominantly systemic effects, whereas Colubridae, Viperidae, and Crotalidae venoms have mainly local effects. There are many exceptions to this general division. For example, the venom of the Mojave rattlesnake (Crotalus scutulatus) may show minimal local effects and deadly systemic effects, whereas the venom of the cobra (Naja naja) may cause extensive local tissue destruction.[]

Venom Delivery The mechanism for delivering venom is fairly standard among snakes. It consists of two venom glands, hollow or grooved fangs, and ducts connecting the glands to the fangs. The glands, which evolved from salivary glands, are located on each side of the head above the maxillae and behind the eyes. Each gland has an individual muscle and a separate nerve supply that allow the snake to vary the amount of venom injected. The venom duct leads from the anterior portion of the gland along the maxilla to the fangs. Pit vipers have fangs that are large anterior maxillary teeth. These teeth are hollow and rotate outward from a resting position to a striking position. The coral snake has fixed, hollow maxillary teeth that are much smaller than those of pit vipers. The fangs in most snakes are shed and replaced regularly, and it is not unusual to see a snake with double fangs on one or both sides of its mouth.[] The snake can control the amount of venom injected. In biting a human, a prey much too large to swallow, the snake may become confused or disoriented, especially if injured or surprised. However, the snake may inject more than 90% of the contents of the gland for the same reasons.

Clinical Features

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The signs and symptoms of a venomous snakebite vary considerably and depend on many factors. From 30% to 50% of venomous snakebites result in little or no envenomation. A person with impaired cardiovascular, renal, or pulmonary function is less able to cope with even moderately severe envenomation. Because of these multiple variables, the individual clinical response is the only way to judge the severity of a venomous snakebite.[11] Factors that influence the effects of a snakebite are the age, health, and size of the snake; the relative toxicity of the venom; the condition of the fangs; whether the snake has recently fed or is injured; the size, age, and medical problems of the victim; and the anatomic location of the bite. Local envenomation, if left untreated, can cause serious systemic problems (e.g., disseminated intravascular coagulation, pulmonary edema, shock) as the toxic products are absorbed. The victim's autopharmacologic response to the envenomation must also be taken into account. An IgE-mediated anaphylactic-type reaction may develop in victims of a previous snakebite when re-exposed to the venom. Many venoms contain enzymes that trigger the release of bradykinin, histamine, and serotonin from the patient's cells, which may cause fatal anaphylactic reactions. A wave of effects ranging from minimal pain to multisystem failure and death can occur over a period of several days.

Pit Vipers The most consistent symptom associated with pit viper bites is immediate burning pain in the area of the bite, whereas pain may be minimal with bites of Elapidae and other exotic snakes. With pit vipers, the severity of pain is probably related to the amount of venom injected or the degree of swelling. Edema surrounding the bite that gradually spreads proximally is a common finding. This edema is usually subcutaneous, begins early, and may involve the entire extremity. Compartment syndrome has been described; however, it is unusual even with severe edema. It has been reported more frequently in models involving intracompartmental venom injection.[23] Most fangs do not penetrate into the fascial compartments, although muscle destruction may result from direct toxicity. Mortality is less frequent with distal bites to the toe and finger and is greatly increased with intravenous bites. In fact, an intravenous bite from any venomous snake is likely to be fatal. Petechiae, ecchymosis, and serous or hemorrhagic bullae are other local signs. Necrosis of skin and subcutaneous tissue is noted later and may result from inadequate doses of antivenin. Many systemic symptoms, such as weakness, nausea, fever, vomiting, sweating, numbness and tingling around the mouth, metallic taste in the mouth, muscle fasciculations, and hypotension, often occur after pit viper envenomation. Death from pit viper bites is associated with disruption of the coagulation mechanism and increased capillary membrane permeability. Ultimately, these two processes lead to massive pulmonary edema, shock, and death. Heart and kidney damage occurs secondary to these mechanisms. Specific toxins in certain species may act directly on specific organs, such as the heart or skeletal muscle. An allergic type of reaction may add to this process through release of histamine and bradykinin.[]

Coral Snakes Signs and symptoms can vary considerably with bites of coral snakes, Mojave rattlesnakes, and many exotic snakes, especially cobras and Australian elapids. Little pain and swelling may occur. Many of these species' venoms contain compounds that block neuromuscular transmission at acetylcholine receptor sites and have direct inhibitory effects on cardiac and skeletal muscle. Ptosis is common and often the first outward sign of envenomation. Other signs and symptoms include vertigo, paresthesias, fasciculations, slurred speech, drowsiness, dysphagia, restlessness, increased salivation, nausea, and proximal muscle weakness. The usual cause of death is respiratory failure.[14]

Gila Monster Gila monster bites are generally associated with pain, edema, and weakness. Hypotension is common with severe bites. Envenomation involves secretion of the venom from glands along the lower jaws. The venom is introduced into the victim through grooved teeth and a chewing mechanism. Gila monster bites are seldom fatal.[17]

Infection Although snakebite envenomation has been stressed here, any bite or puncture wound carries a risk for bacterial contamination. Gram-negative organisms predominate when snake venom and mouthparts are cultured. Even though several studies have shown that prophylactic antibiotics are not indicated for snakebite, tetanus, osteomyelitis, cellulitis, or gas gangrene may occur in cases of snakebite with or without envenomation. This is especially true when a large amount of local tissue destruction has occurred, treatment has been delayed, or inappropriate first aid was attempted.[26]

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Management Prehospital Care All snakebites should be considered an emergency, and any victim should be medically evaluated. The initial 6 to 8 hours after a snakebite is critical. During this time, medical therapy can help prevent the morbidity associated with severe envenomation. Effective prehospital care can be important.[27] Prehospital care is relatively simple if guided by four basic concepts. First, the estimated time until arrival at a medical facility, as well as the skill of the on-scene assistants, must be considered when instituting first aid. The victim should be separated from the snake if possible to prevent further bites. A stick, pole, or other object longer than the snake can be used to move the snake away from the victim or, if necessary, to kill the snake by striking it behind the head. Rapid transportation to a medical facility is the best first aid for a snakebite. Second, spread of the venom should be slowed if possible; several methods are known. The patient's excitement and physical activity, movement of the bitten area, alcohol consumption, and greater depth of the bite increase the spread of venom. Except for the last factor, these issues can be addressed by calming the victim, immobilizing the bitten area, and not giving anything by mouth. A new method of first aid for venomous snakebites has been developed in Australia. The immobilization and compression technique, also called the Commonwealth Serum Laboratory technique, slows uptake of Elapidae venom and mock venom in humans. The bitten extremity is either wrapped in an elastic bandage or placed in an air splint. In another technique from Australia called the Monash method, a thick pad and bandage are placed over the bite wound and extremity. Both these methods have similar postulated mechanisms of action: the lymphatic vessels and superficial veins are collapsed, and the proximal spread of venom is slowed. Although this method is successful as first-aid therapy for Elapidae bites, its use for pit vipers has not been demonstrated. [] If less than 30 minutes has elapsed since the bite, a constricting band applied tightly enough to impede superficial venous and lymph flow, but not arterial blood flow, may be used. The band should be loose enough to admit a finger between the band and the skin after application. It should be used with caution to prevent the development of a tourniquet effect under swollen tissue, which may cause more destruction than the snakebite.[28] Incision of bite wounds should be avoided because of lack of proven efficacy and potential danger to underlying structures. The use of ice is not helpful in slowing the spread of venom, but an ice bag wrapped in a towel and applied to the bite area helps relieve pain. Ice water immersion and packing of the extremity in ice are dangerous and only contribute to tissue destruction. The use of suction devices has not been shown to be beneficial.[] Third, when feasible, the snake should be identified or brought to the treating facility with the victim. This should be done safely; usually, only experts should handle live snakes. Dead snakes can be placed in a hard container such as a bucket or ice chest. Care should be taken to not touch the head of the snake because envenomation can occur even after death. Live snakes should not be pursued to capture them. It is more important to get the victim to definitive medical care. Fourth, additional medical interventions should be initiated, if available. Cardiac monitoring, intravenous fluids, analgesics, and blood samples may be helpful, especially with signs of envenomation.

Emergency Department Care Many snakes do not envenom their victims when they bite, which has provided false support for the historical use of whiskey, clam juice, or split chickens. The only proven therapy is antivenin. Emergency department care of a snakebite must focus on supportive care and rapid treatment with antivenin. Rapid decision making is required to determine the optimal type, amount, and route of administration of the antivenin. By the time that the emergency physician examines a snakebite victim, the venom may have already caused much damage both locally and systemically. In this case the emergency physician must be prepared to support the victim's cardiovascular and respiratory systems. The snake should be identified if possible, but this may not be easy. The presence of pits is the most consistent factor in identifying pit vipers, and the color pattern can help identify a coral snake. Most large cities have either zoos or herpetologic societies whose members can help identify exotic or unknown snakes. Fortunately, most victims of exotic snakebite are collectors and can positively identify the snake.

Patient History Specific historical information should include time elapsed since the bite, circumstances surrounding the bite, the number of bites, whether first aid was administered and what type, location of the bite, and any symptoms (e.g., pain, numbness, nausea, tingling around the mouth, metallic taste in the mouth, muscle cramps, dyspnea, dizziness). A brief medical history should include the last tetanus immunization,

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medications, and cardiovascular, hematologic, renal, and respiratory problems. An allergy history with emphasis on symptoms after exposure to horse or sheep products, previous injection of horse or sheep serum, and a history of asthma, hay fever, or urticaria should be obtained if considering antivenin treatment.

Patient Examination The bite area should be examined for signs of fang marks or scratches and local envenomation (e.g., edema, petechiae, ecchymosis, bullae). The area distal to the bite should be checked for pulses. A general physical examination should be performed with emphasis on the cardiorespiratory system. A thorough neurologic examination should be performed and recorded, especially if a Mojave rattlesnake, coral snake, or exotic snake is suspected. If the bite involves an extremity, the circumference of the extremity at the site of the bite and approximately 5 inches proximal to the bite should be measured and recorded. These data aid in objectively estimating both spread of the venom and the effect of antivenin.

Initial Medical Care If the bite occurred less than 30 minutes before arrival in the emergency department, first-aid measures can be instituted, including a constricting band until antivenin can be obtained. Snakebite victims with clinical evidence of envenomation should have a large-bore intravenous line with normal saline placed in an unaffected extremity. An electrocardiogram, complete blood count, urinalysis, coagulation studies, and levels of fibrinogen, fibrin split products, electrolytes, blood urea nitrogen, and creatinine should be obtained. The patient's blood should be typed and crossmatched for 4 U of packed red blood cells. The patient's vital signs must be monitored closely. Snakebite victims are often hypotensive because of third-space losses and hemorrhage. In an edematous extremity, the distal pulse may have to be examined with a Doppler instrument. If a compartment syndrome is suspected, a pressure monitor should be inserted and surgical consultation obtained. Pressure greater than 30 mm Hg may require fasciotomy. At this point the emergency physician should determine the severity of the bite and decide whether to administer antivenin. The more distal the bite on the extremity, the less toxicity associated with the bite.[34] Intravenous bites may be rapidly fatal.[25] Bites occurring on the trunk, neck, and face have increased risk because of rapid transit of the venom.

Antivenin The emergency physician should determine the type of antivenin to administer, how much, and over what period.[14] If the bite is from a pit viper, the problem is not too difficult. Wyeth, the former manufacturer of a polyvalent pit viper antivenin in the United States, supplies complete instructions on the grading of bites, the method of horse serum testing, and the protocol for administration with each vial. These instructions classify envenomation into five levels, starting with grade 0 (no sign of envenomation) to grade IV (very severe envenomation). The amount of antivenin to be given is correlated with the grade of envenomation ( Table 59-4 ). Bites by copperheads usually cause a moderate amount of edema but generally do not require antivenin. Others have advocated slightly different grading systems and higher doses of antivenin. Grades 0 and I correspond to minimal envenomation, grade II represents moderate envenomation, and grades III and IV correspond to severe envenomation.[35] Table 59-4 -- Antivenin Dosage for Pit Viper Envenomation[*] Envenomation

FabAV[†]

Wyeth AV

Moderate

4–6 vials

4–6 vials

Severe

8–12 vials

5–10 vials

Very severe

12–18 vials

10–20+ vials

*

Dosage based on initial findings and clinical response to antivenin.

†

If this dose elicits a clinical response, an additional two vials at 6, 12, and 18 hours is recom m ended.

Grading Envenomation {,

Grade 0 (minimal). There is no

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{,

{,

{,

{,

evidence of envenomation, but snakebite is suspected. A fang wound may be present. Pain is minimal, with less than 1 inch of surrounding edema and erythema. No systemic manifestations are present during the first 12 hours after the bite. No laboratory changes occur. Grade I (minimal). There is minimal envenomation, and snakebite is suspected. A fang wound is usually present. Pain is moderate or throbbing and localized to the fang wound, surrounded by 1 to 5 inches of edema and erythema. No evidence of systemic involvement is present after 12 hours of observation. No laboratory changes occur. Grade II (moderate). There is moderate envenomation, more severe and widely distributed pain, edema spreading toward the trunk, and petechiae and ecchymoses limited to the area of edema. Nausea, vomiting, giddiness, and a mild elevation in temperature are usually present. Grade III (severe). The envenomation is severe. The case may initially resemble a grade I or II envenomation, but the course is rapidly progressive. Within 12 hours, edema spreads up the extremity and may involve part of the trunk. Petechiae and ecchymoses may be generalized. Systemic manifestations may include tachycardia, hypotension, and a subnormal temperature. Laboratory abnormalities may include an elevated white blood cell count, creatine phosphokinase, prothrombin time, and partial thromboplastin time, as well as elevated fibrin degradation products and D-dimer. Decreased platelets and fibrinogen are common. Hematuria, myoglobinuria, increased bleeding time, and renal or hepatic abnormalities may also occur. Grade IV (severe). The envenomation is very severe and is seen most frequently after the bite of a large rattlesnake. It is characterized by sudden pain, rapidly progressive swelling that may reach and involve the trunk within a few hours, ecchymoses, bleb formation, and necrosis.

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Systemic manifestations, often commencing within 15 minutes of the bite, usually include weakness, nausea, vomiting, vertigo, and numbness or tingling of the lips or face. Muscle fasciculations, painful muscular cramping, pallor, sweating, cold and clammy skin, rapid and weak pulse, incontinence, convulsions, and coma may also be observed. Intravenous bites may result in cardiopulmonary arrest soon after the bite. The course of coral snakebites may be delayed and manifested as a variety of neurologic symptoms, including weakness, ptosis, stupor, bulbar paralysis, and other cranial nerve dysfunction, as well as nausea, abdominal pain, and headache.

Administration of Antivenin. Any victim of a venomous snakebite with moderate or severe envenomation is a candidate for antivenin. The choice of antivenin depends on the species of snake, and the antivenin may be horse serum–or sheep-derived Fab fragments. Wyeth laboratories, producer of the polyvalent antivenin for Western Hemisphere pit vipers, no longer manufactures that antivenin. Many zoos and hospitals still maintain vials of this antivenin until it can be replaced with the ovine-derived Fab antivenin (FabAV). This antivenin is derived from four species of U.S. pit vipers and has not been studied with regard to bites from Mexican, Central American, or South American pit vipers. The Wyeth antivenin was derived from two U.S. species, one Mexican and Central American species, and one South American species and was efficacious against most of the world's pit vipers. Most antivenin for exotic snakes is derived from horse serum, and the eastern coral snake antivenin is also horse serum derived. Skin testing was commonly performed before administering horse serum–derived antivenin, but it is not medically indicated because of the inaccuracy of the test. Moreover, testing with normal horse serum may itself precipitate an allergic reaction, and even a positive test may not preclude treatment if a patient has sustained severe envenomation.

Dosage and Precautions 1.

Because anaphylaxis may occur whenever horse serum is administered, appropriate therapeutic agents (e.g., oxygen supply, airway support, epinephrine, other injectable pressors) must be ready for immediate use. Any patient requiring antivenin should have two intravenous lines inserted. If an allergic reaction occurs, the line with the antivenin can be clamped and the other line used for resuscitation. Administering 0.3 mg of 1:1000 epinephrine subcutaneously before administration of antivenin may prevent allergic reactions from horse serum–derived antivenin and, if not contraindicated, should be used.

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2.

3. 4.

5.

6.

The initial dosage of antivenin is prepared (see Table 59-4 ). The smaller the body of the patient, the larger the relative initial dose that may be required. A bitten child usually receives more venom in proportion to body weight and thus requires more antivenin to neutralize it. Because children seem to have less resistance and less body fluid with which to dilute the venom, they may require twice the adult dosage of antivenin. The total fluid requirements of children are less, however, so the antivenin should be given in a more concentrated solution. All antivenin should be administered intravenously. Pregnancy is not a contraindication to antivenin therapy. Administration of antivenin at or around the site of the bite is not recommended. The need for subsequent doses is based on the patient's clinical response. The patient is monitored closely after the initial dose, and local and systemic symptoms, as well as laboratory findings, are determinants of the need for further antivenin. Additional injections of one to five vials of antivenin are administered every 1 to 2 hours if symptoms progress. Even with a history or signs of allergy, patients with severe envenomation should be treated with a diluted form of antivenin and epinephrine.

Current treatment of pit viper envenomation in the United States is to use an FabAV polyvalent antivenin rather than the horse serum product. This is designed to limit the allergic reactions associated with horse serum antivenin by using antigen-binding fragments (Fabs) of sheep (ovine) immunized against four species of venomous snake found in the United States. CroFab has been shown to be as effective as the Wyeth antivenin, with fewer allergic reactions. Because of more rapid clearance of smaller Fab fragments by the kidney, however, a repeat dose regimen must be used to prevent the recurrence of coagulopathy. The duration of action of the venom may be longer than the therapeutic effect of the antivenin. Initial studies have shown promise for a new affinity-purified, mixed monospecific ovine Fab antivenin. This product has been tested with favorable results in humans after minimal to moderate crotalid envenomation.[] Its efficacy in pit vipers from South America or Asia has not been proved, nor has its usefulness for copperhead bites. The use of enzyme-linked immunosorbent assay in the diagnosis of Viperidae and Elapidae bites, especially in Australia, Asia, and Africa, has led to more certain criteria for identifying the responsible snake in a patient with suspected envenomation. Active immunization against specific snakes, similar to that for certain jellyfish and hymenopterans, is being attempted in the Amami Islands. Purification of antivenin by separation of active fractions may lead to safer administration of horse serum–derived antivenin. In the next 10 years, snakebite management will probably change radically throughout the world. Phytotherapy (botanical therapy) and other nonantivenin drug therapies for snakebite have been shown to be efficacious in experimental animals, and some centers have successfully treated snakebite with medical support only.[]

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Coral and Exotic Snakes. All victims of bites by the eastern coral snake (Micrurus fulvius) should be given antivenin (also manufactured by Wyeth) even before any symptoms develop. The toxicity of this venom has a rapid onset, and once symptoms develop, it may be too late to reverse the effects with antivenin. The recommended dose is three to five vials in 300 to 500 mL of normal saline.[42] No antivenin exists for the venom of the Arizona (Sonoran) coral snake, which fortunately is less dangerous. Treatment of this type of snakebite is supportive. The problems with bites of exotic snakes are threefold: positive identification of the specimen is sometimes difficult, even for experts; specific antivenin is not always readily available; and even if the antivenin is available, the instructions for reconstitution and dosage may not be written in English. Many zoos maintain a supply of antivenin for their venomous snakes, and this may be the best source of antivenin for an exotic species. Some collectors keep appropriate antivenin on hand for the species that they collect. The Antivenin Index at the Arizona Poison Center (602-626-6016) can assist in identifying sources of exotic antivenin. As with coral snakes, many patients do not show any early signs after envenomation by exotic snakes. The antivenin should be administered before neurologic changes develop.[35]

Wound Care The wound should be cleansed and immobilized. Elevation at or above heart level may relieve some of the pain. If the snake is a pit viper and the wound is on an extremity, a constricting band that does not occlude arterial blood flow should be applied proximal to any swelling caused by the bite. A constricting band should not be applied, however, if more than 30 minutes has elapsed since the bite occurred. Some authors have previously advised excision of the bitten area, but such management is no longer recommended. Patients should be immunized against tetanus. The use of broad-spectrum antibiotics has not been shown to be useful in uncomplicated snakebites. If there has been a long delay in treatment or if signs of secondary infection develop, ampicillin-clavulanate can be administered. Analgesics should be given as needed to relieve severe pain.[11] The wound should be examined for remains of embedded fangs or teeth and these removed. Patients admitted to the hospital should have the laboratory tests mentioned previously performed, then serial determinations of platelets, prothrombin time, and urinalysis every 4 hours to check for myoglobin and hemoglobin. Blood products should be administered, including packed red blood cells, fresh frozen plasma, and other coagulation factors as needed. Usually, it is best to wait until antivenin therapy has been started or the use of the blood products may be futile. Daily comprehensive laboratory tests should be performed. Awake patients who have no nausea or abdominal pain can be given oral fluids. Strict measurements of intake and output should be recorded. Local wound care should involve daily cleansing with soap and water and the application of a sterile dressing. Surgical consultation should be obtained for debridement or skin grafting. Fasciotomy is not usually indicated unless compartment pressures are elevated above 300 mm Hg. Debridement should probably not be performed earlier than 3 days after the bite, until the coagulopathy has resolved. Surgical exploration of the bite wound is not necessary and may be harmful. Skin grafts are occasionally necessary after bites by pit vipers that produce large necrotic areas. Physical therapy is often needed and should begin soon after the acute phase of the envenomation is over.[]

Serum Sickness In most patients who receive more than 10 vials of horse serum–derived antivenin and in about 15% of those who receive FabAV, serum sickness develops up to a week later. The administration of diphenhydramine plus cimetidine, and in severe cases a tapering dose of steroids, can be used to treat this problem. Serum sickness is the only indication for the use of steroids with snakebite.[]

Other Envenomation Gila monster and Mexican beaded lizard bites are treated similar to pit viper bites in regard to first aid. No definitive medical treatment exists. Antivenin is not commercially available at this time. Local wound care, tetanus prophylaxis, the use of antibiotics and analgesics, and supportive care are the extent of emergency department treatment available for this type of envenomation.[17] Envenomation by the yellow-bellied sea snake causes severe muscle necrosis with the release of large amounts of myoglobin. Although a polyvalent antivenin is available from Australia, maintenance of adequate urine output, alkalinization of urine, and general supportive care are usually sufficient.[]

Disposition

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If no envenomation is evident after clinical examination and the snake was either nonvenomous or a pit viper, the victim can be observed for 6 to 8 hours. With some snakebites, however, toxicity is delayed by up to 8 hours. If no sign of envenomation is seen after 8 hours, the patient may be discharged. These patients should be given tetanus immunization and wound care instructions and referred for follow-up within 24 to 48 hours. They should be told to return to the emergency department immediately if any symptoms of envenomation develop. If only local pain and minimal edema have occurred and the snake is thought to be nonvenomous or a pit viper, the patient should be closely watched for 12 hours in the emergency department. Then, if the pain and swelling have decreased and no systemic symptoms have developed, the patient may be treated with the same precautions as a patient with no signs of envenomation. Any patient with moderate or severe envenomation should be admitted to an intensive care unit for constant monitoring during antivenin therapy. Depending on the severity of the bite, blood products, vasopressors, and invasive monitoring may be necessary. Any patient bitten by a coral snake, a Mojave rattlesnake, or an exotic snake is at risk for severe neurologic sequelae that may not become manifested for many hours. As a result, they should be admitted to the hospital, preferably to an intensive care unit, where blood tests can be performed periodically and the patient can be monitored closely. Arrangements should be made to have a respirator, Swan-Ganz catheter, and dialysis equipment available if necessary. Appropriate antivenin should be obtained and treatment initiated at the earliest onset of symptoms.

VENOMOUS ARTHROPODS Arthropods are animals with segmented bodies and jointed appendages. This phylum (Arthropoda) contains approximately 80% of all known animals. Arthropods first appeared in the Cambrian period of the Paleozoic era 600 million years ago. The living members of this phylum are categorized into 12 classes. Two classes, the Insecta and the Arachnida, are of particular interest in that numerous venomous species have evolved that are harmful to humans. Many species have developed venom glands and an apparatus for delivering the venom to obtain food. Others have developed venom delivery systems used solely for defense, most of which are found in the order Hymenoptera.[18] Arthropods account for a higher percentage of deaths from envenomation than snakes do. They are found inside dwellings, as well as in deserts, forests, and lakes. Although most arthropods are more active in April through October, many are active throughout the colder months. Arthropods are also active 24 hours a day, and many can fly, thus increasing their range. This high level of contact results in millions of cases of envenomation annually. Most fatalities result from an autopharmacologic response by the victim rather than the toxicity of the venom. An individual stung by a bee may have a small amount of pain and local swelling or, in severe cases, an anaphylactic reaction and death. Arthropods use three main methods of delivering venom: stinging, biting, and secreting venom through pores or hairs. Some arthropods combine two systems, one for offense and the other for defense. Generally, venom systems found on the oral pole of an animal are used for offensive purposes or food acquisition, whereas systems found on the caudal pole are used for defense. Humans are not considered prey for any venomous animal, and therefore bites from venomous animals are defensive, accidental, reflexive, or a mistake. Many venomous arthropods are omitted from this discussion because of their infrequent contact with humans or the relative impotence of their venom.[]

Hymenoptera Hymenoptera is a familiar order of arthropods that is composed of the families of bees, wasps, hornets, yellow jackets, and ants. Many of these species are social insects, and their defense response is related to protection of the group rather than the individual organism. Although most members of this order are stinging insects, several species of ant can bite and sting simultaneously. Bees and wasps have similar mechanisms of delivering venom. Female insects of this type have modified ovipositors that protrude from the abdomen and act as hypodermic needles to administer the venom. The barbed stinging apparatus of the bee is quite prominent. The stinging action pulls the stinger from the bee, thereby eviscerating the insect. This action also kills the bee.[50] The wasp, which has an unbarbed stinger, may inflict many stings without damaging itself or its stinging apparatus. The venom is produced in one or two tubular glands that empty into a venom reservoir. The venom reservoir has a duct that connects to the stinger. The venom itself is composed of several classes of substances varying in composition among different species. Proteins, as in snake venom, make up most of

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the venom by dry weight. Peptides, amino acids, carbohydrates, lipids, and other low-molecular-weight substances are also found. The most common enzymes are phospholipase A and hyaluronidase. Peptides are common in some species and compose up to 50% of the dry weight. Most of the toxicity of the venom results from substances of low molecular weight (e.g., bradykinin, acetylcholine, dopamine, histamine, serotonin). Many other antigenic substances have been identified in bee and wasp venom, and they account for the induction of hypersensitivity and anaphylaxis in humans.[]

Clinical Features The signs and symptoms of bee and wasp stings vary, depending on the degree, type, and location of envenomation, as well as the characteristics of the victim. Bee and wasp venom can cause serious injury other than allergic types of reactions, depending on the number of stings, the species of insect, the size and previous health of the victim, and the anatomic area stung. For example, a sting in the tongue or throat may quickly compromise the airway. Honeybee venom causes a much greater release of histamine per gram than other hymenoptera venom does and thus is more dangerous. Certain species of honeybee release a pheromone, isoamylacetate, when the ovipositor is pulled from the abdomen after stinging a victim. This pheromone attracts other bees to the victim and thus incites multiple stings. There is little antigenic overlap between species, which may explain the variability in reaction to stings reported by victims. Victims who are allergic to honeybees and who mistakenly identify a yellow jacket as a honeybee may not have a systemic reaction and thus may think that they are no longer allergic to honeybees.[] The most consistent finding is immediate pain at the site of the sting, followed by local swelling, redness, and itching. A sensitive victim may experience swelling, urticaria, coughing, wheezing, coma, and respiratory arrest. Some large and especially venomous hornets have been known to cause muscle necrosis and renal damage. Most serious reactions to bee stings occur in the first 30 minutes; however, the local effects of a sting may persist for 2 to 3 days. Delayed hypersensitivity may occur 7 to 10 days after the sting.

“Killer Bees” Health officials have been concerned about a particularly aggressive species of bee imported from Africa into Brazil in 1956 that has been known to attack humans and cattle with fatal results. This bee has managed to compete with native species and is gradually replacing some of these species while still retaining its aggressive behavior. Envenomation from these aggressive arthropods is most dangerous to very young or elderly patients and those with concomitant medical conditions.[57] Killer bees have colonized northern Mexico and have now moved into the southern United States, including California, Arizona, and Texas, where the mean high temperature is at least 60° F.[] This type of bee is not more toxic, only more aggressive.

Fire Ants Another unwelcome import to the United States is the fire ant. This insect is a member of the family Formicidae and is another of the Hymenoptera that is harmful to humans. Several species of fire ant are known, some native to North America and some imported. The species responsible for 95% of clinical cases, Solenopsis invicta, was imported from Brazil to Alabama in the 1930s. This ant is now found in nine southern states and is replacing many native species and inhabiting new niches. The only limiting factor keeping the fire ant from progressive migration seems to be cold winters. This ant is small and light reddish brown to dark brown. Its venom is unique to the animal kingdom in that it is 99% alkaloid. The other 1% is quite immunogenic and can sensitize an individual to the venom. Properties of this venom include hemolysis, depolarization of membranes, activation of the alternative complement pathway, and general tissue destruction. The sting is produced when the ant bites the victim with its jaws and, while holding tight, pivots around and stings the victim with its ovipositor. The sting usually produces a sterile pustule within 24 hours. Other symptoms include local burning, redness, and itching. With multiple stings and in sensitive individuals, urticaria, angioedema, dyspnea, nausea, vomiting, wheezing, dizziness, and respiratory arrest may occur. Approximately 10% of victims have some degree of hypersensitivity reaction.[]

Management Home Care First aid for Hymenoptera envenomation depends on the degree of reaction to the sting. With simple stings, an ice bag wrapped in a towel and applied to the sting area usually relieves the pain and swelling. In the event of an anaphylactic reaction, basic life support should be administered until further medical help can be obtained. Many people allergic to Hymenoptera envenomation carry an emergency insect sting kit containing

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a tourniquet, epinephrine in a 1:1000 dilution, and an antihistamine. These kits are readily available, and both the patient and the patient's family should be instructed in the treatment of a severe allergic reaction.

Emergency Department Care No specific antivenin exists for Hymenoptera stings. Treatment consists of local wound care and general supportive measures. A history of any previous allergic reactions to bee stings, hay fever, asthma, or drug reactions should be obtained. The circumstances surrounding the sting and the number and location of stings should be noted. A patient with a single sting and only a local reaction should have the sting area inspected for evidence of a venom apparatus, which is removed by scraping the edge of a scalpel blade parallel to the skin and lifting the apparatus away from the skin without squeezing the venom sac. An ice bag wrapped in a towel may then be applied and the patient given an oral antihistamine (e.g., 50 mg of diphenhydramine). The patient should be monitored and, if no further reaction is observed, may be discharged with instructions to return to the emergency department if wheezing, dyspnea, hives, or burning occurs. Adults in whom a severe urticarial reaction or hypotension develops should be given 0.3 mL of epinephrine in a 1:1000 dilution subcutaneously, 50 mg of diphenhydramine intravenously, and cimetidine, 300 mg intravenously. Patients with severe hypertension, cerebrovascular disease, or heart disease should be given epinephrine cautiously because of the potential for adverse reactions. Children should be given 0.01 mL/kg of body weight of a 1:1000 dilution of epinephrine subcutaneously and 1 mg/kg of diphenhydramine intravenously. These patients must be watched closely for signs of respiratory problems and treated accordingly. After 1 hour these individuals should be totally free of symptoms (except for some itching around the sting site). Symptom-free patients should be discharged and given antihistamines every 6 hours for the next 24 hours. They should be given the same instructions as patients with a minor reaction. Patients with allergic reactions to a single sting should be given an emergency insect sting kit and instructed in its use. They may be referred to an allergist for desensitization. Wheezing should be treated with a p 2-agonist given by hand-held nebulizer and repeated as necessary. A second large-bore intravenous line with normal saline should be established. These patients should be monitored closely and given an intravenous steroid (e.g., 125 mg of methylprednisolone) plus 50 mg of diphenhydramine and 150 mg of cimetidine intravenously. Admission is warranted for any anaphylactic reaction. Patients who have life-threatening reactions may be given 0.1 mg of epinephrine in at least a 1:10,000 dilution, very slowly intravenously. The subcutaneous route should be used for all but the most extreme reactions. Treatment of allergic reactions to fire ant stings is the same. The skin lesions should be kept clean with soap and water. Ice bags may be applied initially to relieve burning and pain. Prophylactic antibiotics are not needed. Of patients who have a systemic reaction to an insect sting, 60% can have a future allergic reaction if they have a positive skin test. These patients should be desensitized to any specific venom to which they are allergic. Purified insect venom is currently available for most Hymenoptera, including fire ants.[63] Patients seen in the emergency department with systemic reactions to stings should be referred for skin testing and desensitization. These patients should be given emergency insect sting kits with instructions for use and should avoid activities that place them in proximity to Hymenoptera species.[]

Spiders and Scorpions The class Arachnida contains the largest number of venomous species known, with approximately 34,000 species of venomous spiders and 1400 species of venomous scorpions. Virtually all known species are venomous, but most are not harmful to humans. Only about 50 species of arachnids in the United States cause human illness because most species do not have fangs or stingers sufficiently long to penetrate human skin. Humans fear spiders and scorpions, which is well founded in certain cases. Ticks, which also belong to this class, are less feared but probably cause more morbidity because of transmission of infectious diseases such as Rocky Mountain spotted fever and Lyme disease. Some spider bites are never diagnosed because of lack of significant symptoms and the fact that they occur while the victim is sleeping. Many non–spider bites are incorrectly diagnosed as spider bites, and unfortunately, there is no “gold standard” for making the diagnosis.

Black Widow Spider The black widow spider, Latrodectus mactans, may be the best known venomous spider in the world. Several other closely related species of Latrodectus or widow spiders are found throughout the United States, including Latrodectus hesperus, which is common in Arizona and other western states. The

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diagnosis and treatment of the bites of all species are the same. The black widow is found throughout the United States (except Alaska) and in southern Canada. The female is about twice as large as the male, and although both are venomous, only the female is able to envenom humans. The black widow is glossy black, occasionally with red stripes, and has a bright red marking on the abdomen. This marking may have an hourglass shape or may appear only as two spots. Abdominal markings may vary, and related Latrodectus species may be similar in appearance and toxicity. The combined length of the black widow's head and abdomen is about 0.5 inch, and the spider is about 1½ inches long, including the legs. It is found in protected places such as under rocks, in woodpiles, and in outhouses and stables. The female is not aggressive except when guarding her eggs. The venom apparatus of the black widow is a modified first appendage of the head known as the chelicera. The spider is able to control the amount of venom injected into its prey. The venom of the black widow is complex and contains both protein and nonprotein compounds. Spiders normally use the venom to paralyze their prey and also to liquefy the tissues of the prey for digestion. The venom probably evolved from digestive glands analogous to the salivary glands in snakes. The ingredient most toxic to humans is thought to be a neurotoxin. This toxin destabilizes neuronal membranes by opening ionic channels, causing depletion of acetylcholine from presynaptic nerve terminals, and increasing the frequency of spontaneous miniature end plate potentials at neuromuscular junctions.[]

Clinical Features The classic symptomatology of the black widow bite is initially a pinprick sensation that may be followed by minimal local swelling and redness. If the area is examined closely, two small fang marks may be noticed. Sometimes the bite is not felt, especially if the victim is working when the bite occurs. From 15 minutes to an hour later, dull crampy pain develops in the area of the bite and gradually spreads to include the entire body. Usually, the pain is concentrated in the chest after upper extremity bites or in the abdomen after lower extremity bites. The abdomen may become boardlike, and the patient may complain of severe crampy pain. The abdominal manifestation may mimic pancreatitis, a peptic ulcer, or acute appendicitis, except that abdominal tenderness is usually minimal. Pregnant women may go into premature labor and precipitous delivery. Associated symptoms include dizziness, restlessness, ptosis, nausea, vomiting, headache, pruritus, dyspnea, conjunctivitis, facial swelling, sweating, weakness, difficulty speaking, anxiety, and cramping pain in all muscle groups. The patient is usually hypertensive, and cerebrospinal fluid pressure is sometimes elevated. There may be electrocardiographic changes similar to those produced by digitalis.[] In adults, the signs and symptoms begin to abate after several hours and usually disappear in 2 to 3 days. A small child bitten by a black widow spider, however, may not survive.[67] As with snake envenomation, the volume of distribution of black widow venom is much smaller in children than in adults. A dose that may cause only a few hours of pain in an adult may lead to complete cardiac decompensation and respiratory arrest in a child. Adult patients with preexisting hypertension, cerebrovascular disease, or cardiovascular disease are also at greater risk for complications. Symptoms usually persist for 8 to 12 hours and then subside, although in severe cases muscle cramps may continue for several days.

Management First aid for a black widow spider bite consists of applying an ice pack to the bite area for relief of pain and transporting the victim to a hospital where supportive, symptomatic, and definitive treatment can be administered. The rescuer should obtain the specimen if at all possible because many dangerous spiders resemble harmless species, and vice versa. The patient should be monitored closely en route to the hospital and basic life support initiated if necessary. Bites in the neck or mouth area may cause airway compromise through muscle spasm. Emergency department care consists of obtaining a history of the circumstances surrounding the bite, a description of the appearance of the spider, any significant past medical history, present medications, and allergies to insect bites, horses, or horse serum. The wound site should be inspected for fang marks and cleansed with soap and water. Tetanus immunization should be instituted. The patient should be observed for about 6 hours. If symptoms do not develop and the spider was not positively identified as a black widow, the patient may be discharged with instructions to return to the emergency department if any symptoms develop. All patients with symptoms of moderate envenomation, pregnant women, children, and those with preexisting cardiovascular disease or hypertension should be admitted to the hospital, have intravenous lines inserted, and have a complete blood count, electrolytes, blood urea nitrogen, creatinine, coagulation studies, urinalysis, and an electrocardiogram performed. Acute hypertensive problems should be treated

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with nitroprusside if diastolic pressure rises above 120 mm Hg. Symptomatic treatment usually involves controlling the muscle cramps responsible for most of the discomfort associated with the bite. Diazepam or other benzodiazepines given intravenously are useful for relieving muscle spasms. Dantrolene sodium has been used both orally and intravenously to provide muscle relaxation for Latrodectus envenomation.[68] Parenteral analgesics may be necessary to control pain. These drugs may affect an already-compromised respiratory condition, and thus their use must be closely monitored. Patients with moderate symptoms should be admitted to the hospital and monitored until symptoms subside; usually 1 day is sufficient. Pregnant women should undergo fetal monitoring, and those with severe symptoms should be admitted to an intensive care unit with cardiovascular monitoring.

Latrodectus Antivenin In general, pediatric patients, pregnant women, and the elderly may need to be given Latrodectus antivenin (Lyovac), which is derived from horse serum. Clinical judgment must be used to adjust the age and category of patients needing antivenin. Antivenin should be administered to patients with severe envenomation manifested as seizures, respiratory failure, or uncontrolled hypertension; to pregnant women; and to patients not able to stand the stress of the envenomation. The dose of the antivenin is one vial diluted in 50 mL of normal saline and administered intravenously over a period of 15 minutes. Precautions for allergic reactions should be taken before administering antivenin. A dose of subcutaneous 1:1000 epinephrine may prevent allergic reactions when given before horse serum antivenin. This antivenin is also useful with other species of the Latrodectus genus.[66]

Brown Recluse Spider Several deaths were attributed to the brown recluse spider, Loxosceles reclusa, in the 1950s, primarily in the south-central United States, thus drawing the attention of toxicologists. Many species of Loxosceles are venomous to humans, and at least five are found in the United States. These spiders are about 1 inch long, including leg span, and range in color from tan to dark brown. The most distinguishing mark is a violin-shaped darker area found on the cephalothorax. Close examination may reveal that the brown recluse has three pairs of eyes rather than the usual four.[] These spiders, as their name implies, are not aggressive and are usually found under rocks, in woodpiles, and occasionally in attics and closets. Their range is concentrated in the south-central United States, especially Missouri, Kansas, Arkansas, Louisiana, eastern Texas, and Oklahoma. However, they have been reported in several large cities outside this range. The venom apparatus is similar to that of most spiders, including the black widow. The composition of brown recluse venom has not been totally determined, but sphingomyelinase D is a primary component. The local tissue destructive effects are thought to be primarily caused by hemolytic enzymes and a levarterenol-like substance that induces severe vasoconstriction. The systemic symptoms seem to be an allergic phenomenon and vary according to the individual's immune response to the venom.[]

Clinical Features The symptoms of a brown recluse spider bite are both local and systemic. Initially, they are similar to those caused by bites of many other spiders and other conditions, including pyoderma gangrenosum, furuncles, viral and fungal infections, and foreign body reactions. The victim may notice some burning pain in the area of the bite. Some victims do not notice the initial bite at all. Pain usually develops within 3 to 4 hours, and a white area of vasoconstriction begins to surround the bite. A bleb then forms in the center of this area, and an erythematous ring arises on the periphery. The lesion at this stage resembles a bull's-eye. The bleb darkens, necroses over the next several hours to days, and continues to spread slowly and gravitationally, with involvement of skin and subcutaneous fat. Systemic symptoms include fever, chills, rash, petechiae, nausea, vomiting, malaise, and weakness. Hemolysis, thrombocytopenia, shock, jaundice, renal failure, hemorrhage, and pulmonary edema are the usual signs of severe envenomation. Fatalities are more common in children, most often the result of severe intravascular hemolysis.[]

Management First aid for a brown recluse spider bite is simple. The specimen is secured if possible and the victim transported to a medical facility. Emergency department treatment is as complicated as the first aid is simple. Because the lesion develops over a period of days, there may not be any local treatment of the lesion that is effective. The physician should try to determine whether any systemic toxicity is present. A

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history of the circumstances surrounding the bite, the time elapsed since the bite, and any past history of allergic reactions, medications, or medical problems should be obtained. If a specimen is available, an attempt should be made to identify it. The assistance of a local entomologist should be obtained if necessary. If signs of systemic toxicity develop, an intravenous line should be placed in an unaffected extremity, and a complete blood count, electrolyte levels, blood urea nitrogen level, and creatinine level should be determined and coagulation studies and urinalysis performed. The wound should be washed with soap and water and tetanus prophylaxis given. Vital signs and urine output should be monitored closely. Excision of the lesion has not been shown to aid healing and may be detrimental.[73] Lesions have been known to cause extensive scarring, infection, and necrosis. Bites that are in fatty areas, such as the thigh or buttocks, may cause more extensive necrosis. All patients should be observed in the emergency department if envenomation is suspected but no signs are present and the elapsed time is less than 6 hours. If no sign of envenomation is present after 6 hours, the patient may be discharged with instructions to return to the emergency department if any signs or symptoms develop. Dapsone, 50 to 200 mg/day, has been shown to be helpful in preventing local effects of the venom.[74] If used within 48 hours, it may limit the size of the lesion that develops. However, dapsone may cause methemoglobinemia and hemolysis in patients with glucose6-phosphate dehydrogenase deficiency. Hyperbaric oxygen has been shown to decrease lesion size in animals.[] Analgesics and antibiotics should be used as indicated during the course of the disease, although infection is not common. All patients with signs of systemic envenomation should be admitted to the hospital and monitored closely with daily blood counts, urinalysis, and urine output. Dialysis may be necessary if acute renal failure develops, and surgical consultation should be obtained for evaluation of the wound. The Instituto Butantan in Sao Paulo, Brazil, produces an antivenin for Loxosceles bites, but it is not available in the United States. Research is currently being conducted to produce a rabbit serum antivenin against Loxosceles, but it is not yet commercially available.[78]

Other Spiders Several other spiders can cause envenomation but are uncommon in the United States. Some of these spiders are large and can be quite aggressive. Most are imported either intentionally or as stowaways on cargo ships. Tarantulas, wandering spiders, funnel-web spiders, pallid spiders, and crab spiders are a few of the imported venomous spiders. Many of these species can cause envenomation similar to that of the brown recluse spider, and some produce neurotoxins. Antivenin is produced for some of these groups (e.g., Brazilian Phoneutria spp., Australian Atrax spp.) but is usually available only in the country where the species is generally found.[79] Emergency care therefore involves symptomatic and supportive treatment. An outbreak of bites by a species of Tegenaria, known as the hobo or aggressive house spider, has been reported. This species was imported from Europe to the Pacific Northwest. This spider is a small brown spider with a herringbone pattern on its abdomen. The lesions are similar to those caused by the brown recluse spider, but systemic symptoms include headache and weakness. Treatment is largely supportive.[69] Tarantulas are popular pets in the United States, and most native species are relatively nontoxic. Tarantulas are unusual in that the abdominal hairs can be thrown by the spider and embedded in human skin and the eye. These hairs can cause allergic reactions and severe conjunctivitis and must be removed under a slit lamp or by an ophthalmologist. A recent import from Thailand, the cobalt blue tarantula, Haplopelma lividum, is a very aggressive spider with toxic venom.

Scorpions Scorpions are arachnids that resemble crustaceans and are among the oldest terrestrial animals. Scorpions are found throughout the world, and several species are located in the southwestern United States. Only one species, Centruroides exilicauda, which is found in Arizona, is particularly dangerous. Scorpions are nocturnal predatory animals that usually spend the day under rocks, logs, or floors and in crevices. C. exilicauda, or the “bark scorpion,” is found on or near trees. The scorpion has a tail-like structure that is actually the last six segments of its abdomen. The last segment, or the telson, contains the two venom glands and stinger. The toxicity of scorpion venom varies greatly from species to species. Generally, the less dangerous species produce more local reactions, and the more dangerous species cause more systemic reactions. Several proteins have been identified in their venom; some cause hemolysis, local tissue destruction, and hemorrhage. The venom of C. exilicauda is predominantly a neurotoxin that causes or enhances repetitive firing of axons by activation of sodium

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channels.[18]

Clinical Features Envenomation causes severe and immediate pain at the sting site. Local edema and erythema may or may not be present, depending on the species. After envenomation by C. exilicauda, the victim may have heightened sensitivity to touch in the area of the sting along with local numbness and weakness. The diagnosis is often made by tapping on the site of the sting and causing an increase in pain at the site. Systemic symptoms may then develop, including anxiety, restlessness, muscle spasms, nausea, vomiting, excessive salivation, sweating, itching of the nose and throat, hyperthermia, blurred vision, myoclonus, hypertension, hemiplegia, syncope, cardiac dysrhythmias, and respiratory arrest. Various systemic complications may occur, depending on the species of scorpion. Tityus trinitatus scorpion stings cause pancreatitis to develop in 80% of its victims. A wave of symptoms sometimes occurs over a 24-hour period, or respiratory failure may develop in the first 30 minutes. As with most envenomation, children are at a greater risk for severe reactions. A grading system has been developed to guide management of bark scorpion stings.

Management First aid for a scorpion sting consists of applying an ice bag to the area of the sting and transporting the victim to the hospital. A history of the circumstances surrounding the bite, any previous medical problems, and a description of the scorpion if no specimen is present should be obtained. It is relatively difficult for a layperson to differentiate the various scorpions. For C. exilicauda envenomations that occur in Arizona, a goat-derived antivenin is available from the Antivenom Production Laboratory of Arizona State University.[80] Expert advice should be obtained before the use of this antivenin. Narcotic analgesics and barbiturates have been reported to increase the toxic effects of the venom and should be avoided. Antivenin should be given in all cases of severe envenomation. All victims should be observed for 24 hours, and children should be admitted to the hospital and monitored closely. Intravenous diazepam or another benzodiazepine may be used for myoclonus and muscle spasms. Phenobarbital, previously used in large doses in children, may be more dangerous than efficacious. Atropine may be administered to control hypersalivation and bradycardia. Nitroprusside and prazosin have been used to control hypertension. Ventilatory assistance may be necessary, especially in children.[81]

Other Arthropods Ticks have been known as vectors of human disease for some time. Certain female ticks also secrete a toxin that causes a progressive ascending paralysis in humans and animals. The precise mechanism and structure of the toxin are unknown. The two species responsible in the United States are Dermacentor andersoni (wood tick) and Dermacentor variabilis (dog tick). The bite of the tick is usually painless, but the victim later has difficulty walking, weakness, flaccid paralysis, slurred speech, and visual disturbances. The victim is usually a child, often with a history of recent outdoor activity. Treatment is removal of the offending tick before the paralysis has progressed too far. Any patient seen with ascending paralysis should be closely examined for the presence of a tick, especially on the head and back. Several species of beetles and caterpillars secrete irritating substances that cause severe burning pain, numbness, pustular contact dermatitis, edema, nausea, vomiting, and headache. Oropharyngeal exposure can cause mucosal edema and irritation.[82] No deaths have been reported. Treatment consists of washing the area thoroughly with soap and water and removing any spines present. Spines can be removed with adhesive tape or by applying white glue or facial peel. Locally applied ice bags and baking soda and water paste may be of benefit. Analgesics should be used as needed, and supportive therapy may be necessary for severe envenomation. Centipedes can inflict bites causing erythema and edema. Treatment is usually local soaks and the use of analgesics. Conenose bugs, or “kissing bugs,” may cause severe local and systemic allergic reactions. Treatment with antihistamines and supportive care, depending on the degree of reaction, are all that is necessary. Many other arthropods can cause local skin reactions and severe allergic reactions, depending on the individual's sensitivity. These patients should be treated symptomatically with local steroid creams, antihistamines, and other symptomatic supportive measures.[83]

VENOMOUS MARINE ANIMALS Epidemiology Almost 2000 species of animals found in the ocean are either venomous or poisonous to humans, and many can produce severe illness or fatalities. An estimated 40,000 to 50,000 marine envenomations occur

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annually. In recent years, the number of injuries caused by these animals has been increasing dramatically because of the greater number of scuba divers, snorkelers, surfers, and others engaging in water sports. These animals are not usually aggressive, and many are completely immobile. Most of the venomous marine animals injure humans with defense or food-procuring devices. Most venomous marine animals in the United States are found along the California, Gulf of Mexico, and southern Atlantic coasts. These animals range in complexity from sponges to bony fishes and contain some of the most complex and toxic venoms known.[20]

Venom Delivery In general, venomous marine animals may be divided into three main classes according to the mechanism of venom delivery: bites, nematocysts, and stings.

Bites Biting animals include several species of cephalopods, most often octopi. Although popular media portray a giant deadly creature that squeezes its victims to death, the most dangerous octopi are seldom larger than 20 cm. Several fatalities have been reported after a bite by the blue-ringed octopus, Hapalochlaena maculosus. Most victims are bitten on the upper extremity as they disturb this normally nonaggressive creature. The octopus has a pair of modified salivary glands that secrete venom into the wound produced by the animal's beak.[21] The venom contains a potent vasodilator and an inhibitor of neuromuscular transmission similar to tetrodotoxin.[] No known antivenin exists, and treatment is largely supportive, with respiratory support the most important lifesaving intervention.[]

Nematocysts The second type of venom mechanism is the nematocyst found in coelenterates (Cnidaria). This group of animals includes the Portuguese man-of-war, true jellyfish, fire corals, stinging hydroids, sea wasps, sea nettle, and anemones. Most of these organisms are sessile, but some are free floating. Because of their large numbers, this group accounts for the greatest number of envenomations by marine animals.[18] Many different types of nematocysts are known, but the basic mechanism is a “spring-loaded” venom gland that can, on mechanical or chemical stimulation, suddenly evert and discharge a structure that penetrates the prey and delivers the venom through a connecting tube. These nematocysts, found on the animal's tentacles, can number in the hundreds of thousands. Tentacles can be up to 100 ft long in some giant species. Nematocysts can still function even if the animal is dead or if the tentacles are separated from the animal's body. These stinging cells can remain active for weeks after an animal becomes beached. Often, not all nematocysts fire on initial contact but may discharge later during attempted rescue and treatment. Certain marine species have evolved methods of using ingested nematocysts for their own defense.

Toxicity Nematocyst venom contains various peptides, phospholipase A, proteolytic enzymes, hemolytic enzymes, quaternary ammonium compounds, serotonin, and other toxic compounds. The venom of the coelenterates is antigenic, and allergic reactions are often seen. The severity of the envenomation is related to several factors. First, the severity of the injury is directly proportional to the number of nematocysts discharged. Second, the toxicity varies from species to species. It is unlikely that the victim or the treating physician is able to identify the species from the appearance of the wound. Symptoms may range from simple isolated stinging to respiratory paralysis, cardiovascular collapse, and death. Therefore, the diagnosis must be made according to the clinical findings. Third, the victim's autopharmacologic response to the venom may turn a relatively minor envenomation into a fatal anaphylactic reaction. Any clinician who regularly treats this type of injury should become acquainted with the common species in the particular area.[89] Although lethal and potentially lethal jellyfish occur worldwide, the extremely toxic specimens are found off the coast of Australia and in other Indo-Pacific waters. Probably the most notable and most toxic coelenterate is the box jellyfish (Chironex fleckeri), also known as the “sea wasp.” More dangerous than the famed great white shark, this small animal causes several deaths along the Australian coast annually.[90] Cardiac arrest may occur within minutes, and early aggressive resuscitation offers the best chance of recovery. Intravenous verapamil and box jellyfish antivenin are advocated for use in treatment.[] Another north Australian jellyfish, Carukia barnesi, also produces a devastating envenomation known as Irukandji syndrome. Although no reported deaths from this small box jellyfish have been reported, its envenomation produces severe toxic heart failure requiring intensive care and treatment.[93] The Portuguese man-of-war (Physalia physalis) is found along the southern U.S. coastline. This organism is

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not a true jellyfish but a hydroid colony and is most often included in the jellyfish literature. Envenomation is usually limited to local pain and paresthesias, but it may progress systemically to nausea, headache, chills, and even cardiopulmonary collapse. This organism has also been responsible for several deaths.[] Most other envenomations are minimal, and the danger is either drowning after being stung or an allergic reaction to the venom. The symptoms resulting from coelenterate envenomation usually consist of a severe burning sensation accompanied by raised erythematous lesions where nematocysts have discharged into the skin. The symptoms may progress, depending on the species and the number of nematocysts, to include nausea, vomiting, chest pain, muscle cramps, dyspnea, diarrhea, cough, convulsions, angioedema, and respiratory arrest. The initial pain and redness may last from a few hours to 2 or 3 days, depending on the therapy. A related type of envenomation is caused by various species of coral, particularly fire coral (Millepora). These injuries combine nematocyst envenomation with wound contamination. Animal protein and calcareous material left behind in these wounds cause infection and chronic inflammation.

Stings Some marine animals cause a “sting” that is produced by a specialized apparatus that punctures the victim's skin and then introduces venom. Common examples of this type of animal are sea urchins, cone shells, bristle worms, sea snakes, crown-of-thorns starfish, stingrays, scorpion fish, weever fish, catfish, stonefish, rabbit fish, and zebra fish. Sea urchins, cone shells (Conus californicus), catfish, scorpion fish, and stingrays account for most of the venomous marine animal injuries in the United States.[96]

Sea Urchins Sea urchins belong to the Echinoderm family along with starfish and sea cucumbers. These animals produce injury and envenomation mostly through toxin-coated spines. These spines often break off and introduce calcareous material and debris into the wound, thereby potentiating severe infection. Symptoms most often include severe local burning, pain, and discoloration, but they may progress systemically in some patients. The degree of symptoms is usually related to the number of spines involved and the species of animal encountered.

Cone Shells Cone shells are much more toxic than sea urchins, and some species have been responsible for fatalities in the Indo-Pacific region. The venom apparatus is a tubular gland that connects to several teeth at the end of a retractable proboscis. All envenomations reported have occurred in persons handling the shells. The venom contains several proteins, protein-carbohydrate complexes, and 3-indolyl derivatives that act mainly on skeletal muscle and cause variably spastic and flaccid paralysis.[97] Symptoms may or may not include pain, depending on the species. Severe envenomation may cause diplopia, slurred speech, numbness, weakness, paralysis, and respiratory arrest. Onset and regression of symptoms may vary from minutes to days. Currently, no antivenin is available for cone shell envenomation.

Stingray The stingray is a member of the shark family. It is a broad, flat fish with a long, whiplike tail that may have one or more stingers with barbed ends. They vary in size from a few inches to several feet, and the stingers are proportional to the size of the fish. The stinger is encased in an integumentary sheath and contains venom glands. Stingrays bury themselves in the sand of shallow water, where they can be easily stepped on inadvertently. The sheath and stinger are often broken or left in the wound. The victim experiences an immediate, intense pain in the area of the wound, which may spread to the entire extremity. Systemic symp-toms include salivation, nausea, vomiting, diarrhea, syncope, muscle cramps, fasciculations, dyspnea, cardiac dysrhythmias, and convulsions. The exact composition of the venom is unknown. Enzymes, proteins, serotonin, and a cholinergic substance have been identified, but the exact toxin responsible for most of the severe symptoms is yet to be isolated. The presence of foreign material may also impair healing and cause infection.

Bony Fishes Bony fishes inflict their wounds through spines located on their fins. The spines and venom glands are encased in a sheath, and grooves along the spines act as channels for the venom. These fish injuries are typically encountered when the fish are stepped on in shallow water or handled by fishermen. The venom is made up of several classes of proteins, most of which are heat labile. The family Scorpaenidae includes three groups of species categorized by venom apparatus: zebra fish, scorpion fish, and stonefish. Zebra fish include the popular aquarium resident the lionfish. Scorpion fish produce intense pain that can spread to the

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entire affected extremity within minutes.[98] Stonefish envenomation may cause serious and even life-threatening systemic illness, but manifestations such as cardiac and respiratory symptoms can be prevented by early administration of the appropriate antivenin.[] Saltwater catfish produce envenomation through contact with dorsal and pectoral spines.[100]

Management Much of the venom can be neutralized at the scene, and most fatalities can be prevented. The most important step is to remove the victim from the water. Drownings after minimal envenomation may account for more fatalities than the end effects of severe envenomation. The patient should be questioned about the circumstances of the bite, allergies, and systemic symptoms. If a severe allergic reaction has occurred, the victim should be treated for this emergency before attending to the wound. The type of wound care largely varies according to the type of venom apparatus involved. As with all wounds encountered in the emergency department, appropriate cleansing, debridement, and tetanus prophylaxis are paramount. Prophylactic antibiotics should be used when indicated and when residual foreign body is suspected. Specific antivenins are available for some species, such as the box jellyfish and stonefish. Bite injuries should be treated with basic life support measures and general wound care consisting of cleansing, debridement, and irrigation. Systemic signs and symptoms are treated accordingly, with aggressive attention paid to the cardiac and respiratory systems.

Nematocysts Nematocyst injuries are treated by first removing the nematocysts without allowing them to discharge. Tentacles should be removed with a gloved hand or forceps. The remaining nematocysts should be fixed by pouring vinegar (dilute acetic acid) over the wound area. Baking soda and alcohol have also been shown to be effective, and deactivation of nematocysts may be species specific. Fresh water should not be used because it may stimulate continued nematocyst discharge.[101] Other methods include scraping off residual material with the use of a shaving cream or baking soda slurry. The affected area should then be debrided and judiciously washed. Most lifeguard stations in areas where coelenterate stings are common have the necessary materials for this regimen. Supportive pharmacologic therapy (e.g., analgesics, antihistamines, steroid creams) is indicated for all but the most trivial envenomation. Delayed cutaneous reactions may persist despite optimal therapy.[]

Bony Fishes Puncture injuries are treated by removing the spine or sting if possible. An x-ray film should be taken of the involved area because many spines and sheaths are radiopaque. Sea urchin spines usually break off in the wound; they are so fragile that removing them is difficult without the proper instruments. The stinger of the stingray should be removed with forceps, although these stingers with their sheaths have been known to penetrate body cavities and require surgery for removal. Though not usually present in the wound itself, the fish spines of bony fish should be removed with forceps. In all cases the wound should be copiously irrigated. Most venoms injected through puncture wounds are heat labile. Significant analgesia can be achieved by submersion of the wound in water as hot as the person can tolerate for 30 to 90 minutes.[98] Patients envenomed by unknown or unfamiliar organisms should be observed for systemic signs and symptoms. Careful discharge instructions should warn the patient to return for increasing pain, numbness, difficulty breathing, and signs of infection.

KEY CONCEPTS {,

Snak e veno m exhi bits neur otoxi city and hem atoto

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{,

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xicity , but one usua lly pred omin ates, depe ndin g on the type of snak e. The amo unt of crota lid antiv enin give n depe nds on the grad e of enve nom ation , from 0 (mini mal or no sign of enve nom ation ) to IV (sev ere enve nom ation ). Pit viper s have a char acter istic

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pit foun d mid way betw een the eye and the nostr il on both side s of the head . Arthr opod s acco unt for mor e deat hs from enve nom ation than snak es do. Nem atoc yst (jellyf ish) sting s shou ld be imm ediat ely neutr alize d with vine gar. Spid er bites may be diffic ult to

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diag nose with out ident ificati on of the offen ding spid er.

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Marx: Rosen's Emergency Medicine: Concepts and Clinical Practice, 6th ed., Copyright © 2006 Mosby, Inc.

REFERENCES 1. Sagan C: The Dragons of Eden, New York, Random House, 1977. 2. White J: Bites and stings from venomous animals: A global overview. Ther Drug Monit2000;22:65. 3. Parrish HM: Analysis of 460 fatalities from venomous animals in the United States. Am J Med Sci 1963;245:129. 4. Parrish HM: Poisonous Snakebites in the United States, New York, Vantage, 1980. 5. Russell FE: Snake venom poisoning in the United States. Annu Rev Med1980;31:247. 6. Ennik F: Deaths from bites and stings of venomous animals. West J Med1980;133:463. 7. Litovitz TL: 1998 annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med1999;17:435. 8. Dumbacher JP: Homobatrachotoxin in the genus Pitohui: Chemical defense in birds?. Science 1992;258:799. 9. Morandi N, Williams J: Snakebite injuries: Contributing factors and intentionality of exposure. Wilderness Environ Med1997;8:152. 10. Kunkel DB: Bites of venomous reptiles. Emerg Med Clin North Am1984;2:563. 11. Kunkel DB: Reptile envenomations. J Toxicol Clin Toxicol1983;21:503. 12. Gold BS, Barish RA: Venomous snakebites: Current concepts in diagnosis, treatment, and management. Emerg Med Clin North Am1992;10:249. 13. Davidson TM, Schafer SF, Jones J: North American pit vipers. J Wilderness Med1992;3:397. 14. Gold BS, Wingert WA: Snake venom poisoning in the United States: A review of therapeutic practice. South Med J1994;87:579. 15. Gomez HF: Human envenomation from a wandering garter snake. Ann Emerg Med1994;23:1119. 16. Suchard JR, LoVecchio F: Envenomations by rattlesnakes thought to be dead [letter]. N Engl J Med 1999;340:1930. 17. Strimple PD: Report on envenomation by a Gila monster (Heloderma suspectum) with a discussion of venom apparatus, clinical findings, and treatment. Wilderness Environ Med1997;8:111. 18. In: Auerbach PS, ed.Wilderness Medicine, 4th ed. St Louis: CV Mosby; 2001: 19. Tu AT: Reptile Venoms and Toxins: The Handbook of Natural Toxins, New York, Marcel Dekker, 1991. 20. Tu AT: Venoms: Chemistry and Molecular Biology, New York, John Wiley & Sons, 1977. 21. Minton SA: Venom Diseases, Springfield, Ill, Charles C Thomas, 1974. 22. Russell FE: Snake venom poisoning. Vet Hum Toxicol1991;33:584. 23. Garfin SR: Rattlesnake bites and surgical decompression: Results using a laboratory model. Toxicon 1984;22:177. 24. Burgess JL, Dart RC: Snake venom coagulopathy: Use and abuse of blood products in the treatment of pit viper envenomation. Ann Emerg Med1991;20:795. 25. Curry SC, Kunkel DB: Toxicology rounds: Death from a rattlesnake bite. Am J Emerg Med1985;3:227. 26. Goldstein EJ: Bacteriology of rattlesnake venom and implications for therapy. J Infect Dis1979;140:818. 27. Norris RL: Snakebite scenario [letter]. Wilderness Environ Med1999;10:55. 28. Burgess JL: Effects of constriction bands on rattlesnake venom absorption: A pharmacokinetic study. Ann Emerg Med1992;21:1086. 29. Anker RL: Retarding the uptake of “mock venom” in humans: Comparison of three first-aid treatments. Med J Aust1982;1:212. 30. Anker RL: Snakebite: Comparison of three methods designed to delay uptake of “mock venom.”. Aust Fam Physician1983;12:365. 31. Blackman JR, Dillon S: Venomous snakebite: Past, present, and future treatment options. J Am Board Fam Pract1992;5:399. 32. Gold BS: Snake venom extractors: A valuable first aid tool [letter]. Vet Hum Toxicol1993;35:255. 33. Forgey WW: More on snake-venom and insect-venom extractors [letter]. N Engl J Med1993;328:516. 34. Moss ST: Association of rattlesnake bite location with severity of clinical manifestations. Ann Emerg Med 1997;30:58. 35. Otten EJ: Antivenin therapy in the emergency department. Am J Emerg Med1983;1:83. 36. Dart RC: Affinity-purified, mixed monospecific crotalid antivenom ovine Fab for the treatment of crotalid

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venom poisoning. Ann Emerg Med1997;30:33. 37. Consroe P: Comparison of a new ovine antigen binding fragment (Fab) antivenin for United States Crotalidae with the commercial antivenin for protection against venom-induced lethality in mice. Am J Trop Med Hyg1995;53:507. 38. Seifert SA: Relationship of venom effects to venom antigen and antivenom serum concentrations in a patient with Crotalus atrox envenomation treated with a Fab antivenom. Ann Emerg Med1997;30:49. 39. Clark RF: Successful treatment of crotalid-induced neurotoxicity with a new polyspecific crotalid Fab antivenom. Ann Emerg Med1997;30:54. 40. Otten EJ, McKimm D: Venomous snakebite in a patient allergic to horse serum. Ann Emerg Med 1983;12:624. 41. Buntain WL: Successful venomous snakebite neutralization with massive antivenin infusion in a child. J Trauma1983;23:1012. 42. Kitchens CS, Van Mierop LH: Envenomation by the Eastern coral snake (Micrurus fulvius fulvius): A study of 39 victims. JAMA1987;258:1615. 43. Lawrence WT, Giannopoulos A, Hansen A: Pit viper bites: Rational management in locales in which copperheads and cottonmouths predominate. Ann Plast Surg1996;36:276. 44. Sutherland SK: Antivenom use in Australia: Premedication, adverse reactions and the use of venom detection kits. Med J Aust1992;157:734. 45. Heard K, O'Malley GF, Dart RC: Antivenom therapy in the Americas. Drugs1999;58:5. 46. Chippaux JP, Goyffon M: Venoms, antivenoms and immunotherapy. Toxicon1998;36:823. 47. Selvanayagam ZE: ELISA for the detection of venoms from four medically important snakes of India. Toxicon1999;37:757. 48. Kunkel DB: Arthropod envenomations. Emerg Med Clin North Am1984;2:579. 49. Binder LS: Acute arthropod envenomation: Incidence, clinical features and management. Med Toxicol Adverse Drug Exp1989;4:163. 50. Normann SA: Venomous insects and reptiles. J Fla Med Assoc1996;83:183. 51. Reisman RE: Insect stings. N Engl J Med1994;331:523. 52. Incorvaia C, Pucci S, Pastorello EA: Clinical aspects of Hymenoptera venom allergy. Allergy 1999;54(Suppl 58):50. 53. Cohen SG, Bianchine PJ: Hymenoptera, hypersensitivity, and history: A prologue to current day concepts and practices in the diagnosis, treatment, and prevention of insect sting allergy. Ann Allergy Asthma Immunol1995;74:198. 54. Valentine MD: Allergy to stinging insects. Ann Allergy1993;70:427.(erratum, 71:96, 1993). 55. Valentine MD: Insect-sting anaphylaxis [editorial]. Ann Intern Med1993;118:225. 56. Valentine MD: Insect venom allergy: Diagnosis and treatment. J Allergy Clin Immunol1984;73:299. 57. Ariue BK: Multiple Africanized bee stings in a child. Pediatrics1994;94:115. 58. Sherman RA: What physicians should know about Africanized honeybees. West J Med1995;163:541. 59. Winston ML: The Africanized “killer” bee: Biology and public health. Q J Med1994;87:263. 60. Freeman TM: Hymenoptera hypersensitivity in an imported fire ant endemic area. Ann Allergy Asthma Immunol1997;78:369. 61. Freeman TM: Insect and fire ant hypersensitivity: What the primary care physician needs to know. Compr Ther1997;23:38. 62. Freeman TM: Imported fire ants: The ants from hell!. Allergy Proc1994;15:11. 63. Stafford CT: Hypersensitivity to fire ant venom. Ann Allergy Asthma Immunol1996;77:87. 64. Hamilton RG: Selection of Hymenoptera venoms for immunotherapy on the basis of patient's IgE antibody cross-reactivity. J Allergy Clin Immunol1993;92:651. 65. Rauber A: Black widow spider bites. J Toxicol Clin Toxicol1983;21:473. 66. Clark RF: Clinical presentation and treatment of black widow spider envenomation: A review of 163 cases. Ann Emerg Med1992;21:782. 67. Woestman R, Perkin R, Van Stralen D: The black widow: Is she deadly to children?. Pediatr Emerg Care 1996;12:360. 68. Ryan PJ: Preliminary report: Experience with the use of dantrolene sodium in the treatment of bites by the black widow spider Latrodectus hesperus. J Toxicol Clin Toxicol1983;21:487. 69. Blackman JR: Spider bites. J Am Board Fam Pract1995;8:288. 70. Anderson PC: Spider bites in the United States. Dermatol Clin1997;15:307. 71. Salm RJ: Brown recluse spider bite: Two case reports and review. J Am Podiatr Med Assoc1998;88:37. 72. Wright SW: Clinical presentation and outcome of brown recluse spider bite. Ann Emerg Med1997;30:28. 73. Futrell JM: Loxoscelism. Am J Med Sci1992;304:261. 74. King Jr JrLE, Rees RS: Dapsone treatment of a brown recluse bite. JAMA1983;250:648. 75. Hobbs GD: Brown recluse spider envenomation: Is hyperbaric oxygen the answer [editorial]?. Acad Emerg Med1997;4:165. 76. Hobbs GD: Comparison of hyperbaric oxygen and dapsone therapy for Loxosceles envenomation. Acad Emerg Med1996;3:758.

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77. Maynor ML: Brown recluse spider envenomation: A prospective trial of hyperbaric oxygen therapy. Acad Emerg Med1997;4:184. 78. Gomez HF: Intradermal anti-Loxosceles Fab fragments attenuate dermonecrotic arachnidism. Acad Emerg Med1999;6:1195. 79. Miller MK: Clinical features and management of Hadronyche envenomation in man. Toxicon2000;38:409. 80. Bond GR: Antivenin administration for Centruroides scorpion sting: Risks and benefits. Ann Emerg Med 1992;21:788. 81. Gateau T, Bloom M, Clark R: Response to specific Centruroides sculpturatus antivenom in 151 cases of scorpion stings. J Toxicol Clin Toxicol1994;32:165. 82. Lee D, Pitetti RD, Casselbrant ML: Oropharyngeal manifestations of lepidopterism. Arch Otolaryngol Head Neck Surg1999;125:50. 83. Lynch PJ, Pinnas JL: “Kissing bug” bites: Triatoma species as an important cause of insect bites in the Southwest. Cutis1978;22:585. 84. Sutherland SK, Lane WR: Toxins and mode of envenomation of the common ringed or blue-banded octopus. Med J Aust1969;1:893. 85. Flachsenberger WA: Respiratory failure and lethal hypotension due to blue-ringed octopus and tetrodotoxin envenomation observed and counteracted in animal models. J Toxicol Clin Toxicol1986;24:485. 86. Edmonds C: A non-fatal case of blue-ringed octopus bite. Med J Aust1969;2:601. 87. Williamson JA: The blue-ringed octopus [letter]. Med J Aust1984;140:308. 88. Williamson JA: The blue-ringed octopus bite and envenomation syndrome. Clin Dermatol1987;5:127. 89. Auerbach PS: Marine envenomations. N Engl J Med1991;325:486. 90. Fenner PJ, Williamson JA: Worldwide deaths and severe envenomation from jellyfish stings. Med J Aust 1996;165:658. 91. Lumley J: Fatal envenomation by Chironex fleckeri, the north Australian box jellyfish: The continuing search for lethal mechanisms. Med J Aust1988;148:527. 92. Burnett JW, Calton GJ: Response of the box-jellyfish (Chironex fleckeri) cardiotoxin to intravenous administration of verapamil. Med J Aust1983;2:192. 93. Fenner P, Carney I: The Irukandji syndrome: A devastating syndrome caused by a north Australian jellyfish. Aust Fam Physician1999;28:1131. 94. Kaufman MB: Portuguese man-of-war envenomation. Pediatr Emerg Care1992;8:27. 95. Stein MR: Fatal Portuguese man-o'-war (Physalia physalis) envenomation. Ann Emerg Med1989;18:312. 96. Cain D: Weever fish sting: An unusual problem. Br Med J (Clin Res Ed)1983;287:406. 97. Gray WR, Olivera BM, Cruz LJ: Peptide toxins from venomous Conus snails. Annu Rev Biochem 1988;57:665. 98. Kizer KW, McKinney HE, Auerbach PS: Scorpaenidae envenomation: A five-year poison center experience. JAMA1985;253:807. 99. Lehmann DF, Hardy JC: Stonefish envenomation [letter]. N Engl J Med1993;329:510. 100. Blomkalns AL, Otten EJ: Catfish spine envenomation: A case report and literature review. Wilderness Environ Med1999;10:242. 101. Burnett JW, Rubinstein H, Calton GJ: First aid for jellyfish envenomation. South Med J1983;76:870. 102. Reed KM, Bronstein BR, Baden HP: Delayed and persistent cutaneous reactions to coelenterates. J Am Acad Dermatol1984;10:462. 103. Auerbach PS, Hays JT: Erythema nodosum following a jellyfish sting. J Emerg Med1987;5:487.

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Marx: Rosen's Emergency Medicine: Concepts and Clinical Practice, 6th ed., Copyright © 2006 Mosby, Inc.

Chapter 60 – Thermal Burns Richard F. Edlich Marcus L. Martin William B. Long, III

PERSPECTIVE Epidemiology Compared with other natural disasters, burns exert a catastrophic influence on people in terms of human life, suffering, disability, and financial loss. Approximately 1.4 million persons in the United States sustain burns each year; an estimated 54,000 to 180,000 are hospitalized.[1] Work-related burns account for 20% to 25% of all serious burns.[2] Burn wounds can be classified into six groups on the basis of the mechanism of injury: scalds, contact burns, fire, chemical (see Chapter 61 ), electrical (see Chapter 140 ), and radiation (see Chapter 144 ). This chapter addresses the first three types of burns. Scald burn injuries can be caused by liquids, grease, or steam. Liquid scalds can be further divided into spill and immersion scalds. Fire burn injuries can be subdivided into flash and flame burns. The mechanism of burn injury can be used as a predictor of outcome. For example, patients with flame burns and electrical burn injuries often require hospitalization ( Figure 60-1 ). In contrast, most patients with burns caused by either contact with hot surfaces or sun exposure are managed as outpatients.

Figure 60-1 Burn incidence and severity according to etiology.

The highest incidence of burn injury occurs during the first few years of life and between 20 and 29 years of age. Serious burn injuries occur most often in males (67%). The highest incidence of serious burn injury occurs in young adults (ages 20 to 29), followed by children younger than 9 years. Individuals older than 50 sustain the fewest serious burn injuries (2.3%). The major causes of severe burn injury are flame burns (37%) and liquid scalds (24%). For children younger than 2 years, liquid scalds and hot surface burns account for nearly all serious burn injuries. After 2 years of age, flame burn is the most common cause of serious burn injury, accounting for nearly one third of all cases. In persons 80 years of age and older, hot surface exposure is a major cause (22%) of serious burns. Five percent of hospitalized burn patients die as a result of their burn injuries; most are caused by flame burns. Liquid scald burns account for the second largest number of deaths. In structural fires, approximately one half of all burn victims, many with only moderate-sized burns of less than 40% of the body surface area, die of asphyxiation or carbon monoxide (CO) poisoning before reaching the hospital. Flame burn injuries are associated with recurring scenarios regarding the most likely burn victims, the circumstances surrounding the burn, the burned victim's response to the situation, and the role of garments in the burn injury. The white population is most often involved (67%), and the highest incidence occurs in the 15- to 29-year-old age group. A flammable liquid is involved in most cases (66%), and gasoline is the most common liquid (63%). The high incidence of gasoline burns during the summer months reflects the increased use in the northern and midwestern United States of gasoline products in farming or for recreational purposes (e.g., bonfires, burning leaves, boating, yard work).[3] The most common contributing factor in flame burn injuries is the consumption of alcohol (26%).

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The patient's or bystander's response to burn incidents has considerable influence on the magnitude of burn injury. When the response is timely and effective, the magnitude of burn injury is reduced (except when flammable liquids are involved). When flammable accelerants are present, the burning process persists even when the victim is rolling on the ground. In this setting, removal of the burning garments or smothering the flames is more likely to be an effective measure. During the past two decades, deaths from burn injuries have decreased. This decline has been attributed to improved firefighting techniques and improved emergency medical services. The use of smoke detectors has significantly reduced the severity of burn injuries, with an estimated 80% reduction in mortality and 74% decline in injuries from residential fires. Educational programs reminding homeowners to lower the thermostat on water heating units as well as teaching children to extinguish flaming cloth by stopping, dropping, and rolling have had a significant impact. Consequently, all medical leaders agree that the best treatment of burn injuries is prevention. Burn injuries are extremely complex and elicit physiologic and metabolic interactions involving all major organ systems. These pathophysiologic changes occur in a time-dependent manner. One of the major goals of this chapter is to describe a system of care of burn injuries and to review current modes of surgical therapy with discussions of wound care and modern burn dressings.

PRINCIPLES OF DISEASE Anatomy Skin is the largest organ of the body. It has three major tissue layers. The outermost layer, the epidermis, is composed of stratified epithelium. The epidermis has two components, an outer layer of anucleate cornified cells (stratum corneum) covering inner layers of viable cells (malpighian layers), from which the cornified surface cells arise by differentiation. The stratum corneum acts as a barrier to impede the entrance of microorganisms and toxic substances while allowing the body to retain water and electrolytes. The malpighian layers provide a continuous production of cornified cells. The malpighian layers can be further subdivided into the germinal basal cell layer, the stratum spinosum, and the stratum granulosum. Beneath the epidermis is the dermis, which is composed of a dense fibroelastic connective tissue stroma, containing collagen and elastic fibers, and an extracellular gel called the ground substance. This amorphous gel is composed of an acid mucopolysaccharide protein combined with salts, water, and glycoproteins; it is believed to contribute to salt and water balance, to serve as a support for other components of the dermis and subcutaneous tissue, and to participate in collagen synthesis. The dermal layer contains an extensive vascular and nerve network and special glands and appendages that communicate with the overlying epidermis. The dermis can be divided into two parts. The most superficial portion, the papillary dermis, is molded against the epidermis and contains superficial elements of the microcirculation of the skin. It consists of a relatively cellular, loose connective tissue with collagen and elastic fibers that are smaller in diameter and fewer in number than the underlying reticular dermis. Within the papillary dermis, dermal elevations indent the inner surface of the epidermis. Between the dermal papillae are peglike downward projections of the epidermis called rete pegs. In the reticular portion of the dermis, the collagen and elastic fibers are thicker and greater in number. Fewer cells and less ground substance are found in the reticular dermis than in the papillary dermis. The thickness of the dermis varies from 1 to 4 mm in different anatomic regions and is thickest in the back, followed by the thigh, abdomen, forehead, wrist, scalp, palm, and eyelid. Its thickness varies with the individual's age. The dermis is thinnest in very old people, in whom it is often atrophic, and in very young children, in whom it is not fully developed. The third layer of skin is the subcutaneous tissue, which is composed primarily of areolar and fatty connective tissue. This layer shows great regional variations in thickness and adipose content. It contains skin appendages, glands, and hair follicles. The hair follicles extend in deep narrow pits or pockets that traverse the dermis to varying depths and usually extend into the subcutaneous tissue. Each hair follicle consists of a shaft that projects above the surface and a root that is embedded within the skin. There are two types of sweat glands in skin: apocrine and eccrine. The apocrine glands are called peridermal because they have a duct that opens into a hair follicle. The eccrine glands are simple, coiled, tubular glands usually extending into the papillary dermis. The eccrine glands are classified as etricheal because their duct opens onto the skin surface independently of a hair follicle. The eccrine glands are found over the entire body surface, except the margins of the lips, eardrum, inner surface of the prepuce, and glans penis. The apocrine glands are largely confined to the axillary and perineal region and do not become functional until just after puberty. The sebaceous glands are connected with the hair follicles. They are simple or branched alveolar glands. Sebaceous glands unconnected with hair follicles occur along the margin of the lips, in the

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nipples, in the glans and prepuce of the penis, and in the labia minora. Depending on the depth of burn injury, epithelial repair can be accomplished from local epithelial elements and skin appendages. When skin is burned, the damaged stratum corneum allows the invasion of microorganisms, and the Langerhans cells, which mediate local immune responses, are also damaged. Burn patients with severe injuries have a diminished systemic immune response, making them susceptible to serious infections.

Pathophysiology Thermodynamics of Burn Injury The severity of burn injury is related to the rate at which heat is transferred from the heating agent to the skin. The rate of heat transfer depends on the (1) heat capacity of the agent, (2) temperature of the agent, (3) duration of contact with the agent, (4) transfer coefficient, and (5) specific heat and conductivity of the local tissues.

Heat Capacity The capacity of a material to hold heat energy is determined by both the specific heat and the heat capacity of the material. The specific heat of a material is defined as the ratio of the amount of heat required to raise an equal mass of a reference substance, usually water, one degree in temperature. Heat capacity refers to the quantity of heat a material contains when it comes in contact with skin. The quantity of heat stored depends on the specific heat of the material and the amount and temperature of the material. The importance of heat capacity as a determinant of the severity of burn injury is best illustrated by comparing the amount of heat stored in 10 g of two different materials (copper and water) heated to the same temperature (100° C). The specific heat of water is 4.2178 W-sec/g-K (watts times seconds of heat per gram of mass times degrees in kelvin), and the specific heat of copper is 0.3831 W-sec/g-K. If these two materials come in contact with skin, they give up their heat by cooling, and the skin accepts the heat by increasing its temperature. If the temperature of each material decreases by 60° C (140° F), the water gives up 2530 W-sec of heat, whereas copper transfers only 230 W-sec of heat. Even if the initial temperatures of the two materials are identical, the heat available from water is much more likely to produce a severe injury. The specific heat of water (the most common cause of scald burns) is the highest of all the gases, metals, and solids so far tested, with the exception of ammonia and ether.

Temperature The initial temperature of a material at the instant of contact is also an important determinant of burn severity. Many materials (e.g., water) cannot be heated beyond a certain temperature without changing state. Water can be heated only to 100° C (212° F) at atmospheric pressure before it ceases to be a liquid and vaporizes. When other liquids reach a specific temperature, they ignite or oxidize, combining with oxygen. The temperature at which the vapors of a volatile liquid mixed with air spontaneously ignite is designated as the flash point of the liquid. A flammable liquid is defined as any liquid having a flash point less than 37.8° C. Liquids with a flash point above this temperature are considered combustible liquids ( Table 60-1 ). In addition to their high temperatures, burning liquids may ignite the victim's clothing, exacerbating the injury. Table 60-1 -- Flash Points of Combustible Liquids Flash Points Liquid

°C

°F

Corn oil

249

480

Lard

215

419

Cottonseed oil

306

581

Olive oil

276

527

Peanut oil

282

540

Oleomargarine

232

450

Duration of Contact Human skin can tolerate temperatures up to 40° C (104° F) for a relatively long time before irreversible injury occurs ( Figure 60-2 ).[4] Higher temperatures cause an almost logarithmic increase in tissue destruction.

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The duration of contact between a liquid and the skin depends on both the viscosity of the liquid and the manner in which it is applied to the victim's skin. When a hot liquid is splashed on a person (spill scalds), it usually flows down the body, having a rate of descent that depends on the fluid's viscosity. Although water streams to the ground unless impeded by clothing, viscous oils and greases usually cling to a victim's skin, prolonging the duration of exposure and the extent of injury.

Figure 60-2 Relationship between tem perature and duration of exposure in the developm ent of full-thickness burn injury.

In immersion scalds the duration of contact between the hot liquid and the skin is considerably longer than with spill scalds, increasing the severity of injury. Certain populations are at high risk for immersion scald burns, including children younger than 5 years, elderly persons (65 and older), and disabled people.[5] These individuals tend to have a slower reaction time and a physical inability to escape from hot water. Immersion burns usually cover a very large percentage of total body surface area (TBSA), almost twice that of other scald burns, which contributes to their high rate of morbidity and mortality.[] Child abuse accounts for a large proportion of immersion scald burns. Immersion burns caused by child abuse can be distinguished from accidental burns by the pattern and site of the burn, the histories given by the caregiver and patient, and a medical history or scars representing previous abuse. Nonaccidental burns often have clear-cut edges, as found in “stocking” scalds, in which a child's foot has been held in scalding water. Spill scald burns, on the other hand, more often have uneven fuzzy edges as a result of the victim's attempts to escape the hot liquid. Burns from abuse tend to occur on the back of hands and feet, the buttocks and perineum, and the legs. Accidental burns, such as those caused by a child spilling a cup of coffee, more often occur on the head, trunk, and palmar surface of hands and feet. Physical evidence of previous injuries (e.g., crater-like cigarette burn scars, bruises) also suggests abuse.

Heat Transfer Even when a substance possesses sufficient heat to cause a burn injury, it does not do so unless its heat can be transferred to the skin. The ability to transfer heat between two different materials is regulated by the heat transfer coefficient, which is defined as the amount of heat that passes through a unit area of contact between two materials when the temperature difference between these materials is one degree. Three different methods of heat transfer exist: conduction, convection, and radiation. The simplest method of heat transfer is conduction, which occurs when a hot solid object comes in direct contact with the skin. Convection is the transfer of heat by a material that involves the physical movement of the material itself and is determined not only by heat conduction but also by energy storage and mixing motion. Convection is most important as the mechanism of energy transfer between skin and a heated liquid or gas. Hot water spilling on skin transfers heat by convection between the water droplets and the skin surface. Steam or very hot air also transfers heat to the skin by convection. In each of these three methods of heat transfer, the amount of energy transferred is determined by the heat transfer coefficient associated with the two materials involved. Because the convective heat transfer coefficient of steam is 30 times greater than that of water, it transfers 30 times more heat to the skin than water ( Table 60-2 ). As a result, steam causes a more severe thermal injury than heated water when the length of exposure is identical. Table 60-2 -- Heat Transfer Coefficients for Various Agents Agent

Convective Heat Transfer Coefficient (watts/m[2] · °C)

Air Water Steam

5–15 150–3000 5500–100,000

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Tissue Conductivity The conductivity of the specific tissue involved significantly affects the extent of burn injury. Heat transfer within skin is influenced by the thermal conductivity of the heated material, the area through which heat is transferred, and the temperature gradient within the material. Water content, natural oils or secretions of the skin, and the presence of insulating material (e.g., cornified keratin layer of skin) influence tissue conductivity. In addition, alterations in local tissue blood flow profoundly affect heat transfer and distribution. The inability to conduct heat away from a contact point efficiently results in varying degrees of tissue injury. Because skin is a relatively poor conductor of heat, it provides an extensive barrier to heat injury. The degree to which it resists injury depends on its anatomic configuration. Its uppermost layer, the epidermis, is relatively uniform in thickness in all body regions (75 to 100 p-m), except for the soles and palms, where it is thicker (0.4 to 0.6 mm). The rarity of full-thickness injury to the palms and soles of the feet can be attributed to their thick epithelial cover. The ultimate outcome of a burn injury is also influenced by the depth of epidermal appendages in the burned tissue, which varies according to the age of the patient. Very young and old individuals have superficial appendages, which makes both groups more susceptible to full-thickness burn injury. By contrast, the epidermal appendages of the human scalp and male beard are very deep, making these sites more refractory to severe burn injury.

Burn Wound Injury The first day after burn injury, three concentric zones of tissue injury characterize a full-thickness burn: the zones of coagulation, stasis, and hyperemia ( Figure 60-3 ).[8]

Figure 60-3 Three concentric zones of burn injury.

The central zone of coagulation has the most intimate contact with the heat source. It consists of dead or dying cells as a result of coagulation necrosis and absent blood flow. It usually appears white or charred. The intermediate zone of stasis is usually red and may blanch on pressure, giving the impression that it has an intact circulation. After 24 hours, however, the circulation through its superficial vessels has often ceased. Petechial hemorrhages may be present. By the third day the intermediate zone of stasis becomes white because its superficial dermis is avascular and necrotic. The outer zone of hyperemia is a red zone that blanches on pressure, indicating that it has intact circulation. By the fourth day, this zone has a deeper red color. Healing is present by the seventh day. Transformation of the zone of stasis to coagulation occurs and has been related to many factors, including progressive dermal ischemia. Experimental studies have implicated prostaglandins, histamine, and bradykinin as the chemical mediators of this progressive vascular occlusion.[9] They can produce edema by altering endothelial cell and basement membrane function to enhance permeability. When this ischemia persists, the zone of stasis eventually becomes a full-thickness burn injury. When Robson and colleagues[9] discovered various prostaglandin derivatives in burn wounds, they suggested that an imbalance in the vasoconstrictive and vasodilatory prostanoids produces a progressive tissue loss in the zone of stasis. In acute burn wounds, an increased level of oxygen free radicals, such as xanthine oxidase, appeared to be involved in the formation of burn edema. This edema formation can be attenuated by pretreatment with xanthine oxidase inhibitors.[10]

Systemic Inflammatory Response In patients whose burns exceed 30% of TBSA, cytokines and other mediators are released into the systemic circulation, causing a systemic inflammatory response. Because vessels in burned tissue exhibit increased

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vascular permeability, an extravasation of fluids into the burned tissues occurs. Hypovolemia is the immediate consequence of this fluid loss, which accounts for decreased perfusion and oxygen delivery. In patients with serious burns, release of catecholamines, vasopressin, and angiotensin causes peripheral and splanchnic bed vasoconstriction that can compromise in-organ perfusion. Myocardial contractility may also be reduced by release of the inflammatory cytokine tumor necrosis factor p . In deep third-degree burns, hemolysis may be encountered, necessitating blood transfusions to restore blood loss. A decrease in pulmonary function can occur in severely burned patients without evidence of inhalation injury from the bronchoconstriction caused by humoral factors, such as histamine, serotonin, and thromboxane A2. A decrease in lung and tissue compliance is a manifestation of this reduction in pulmonary function. Burned skin exhibits increased evaporative water loss associated with obligatory concurrent heat loss, which can cause hypothermia.

Nutritional Support Because burn injury causes a hypermetabolic state that is characterized by a dramatic increase in resting energy expenditure, nutritional support is essential, especially by the enteral route, to reduce intestinal villous atrophy. Deitch and colleagues[11] reported a syndrome of decreased bowel mucosal integrity, capillary leak, and decreased mesenteric blood flow, which allowed bacterial translocation into the portal circulation. These translocated bacteria significantly alter hepatocyte function and spread systemically to cause systemic sepsis. Adequate resuscitation that ensures mesenteric blood flow can prevent the potential development of multisystem organ failure. Enteral nutrition with glutamine has a tropic effect on the enterocytes that preserve mucosal integrity.

Infection In patients with major burn injuries, infection remains the major cause of death. Immune consequences of this injury have been identified and are specific deficits in neutrophil chemotaxis, phagocytosis, and intracellular bacterial killing. Cell-mediated immunity, as measured by skin testing, is also compromised, which has been related to both decreased lymphocyte activation and suppressive mediators present in the serum of burn patients. A reduction in immunoglobulin synthesis has also been encountered in these seriously ill patients.

Burn Shock Severe burn injury causes a coagulation necrosis of tissue that initiates a physiologic response in every organ system that is directly proportional to the size of the burn. Tissue destruction results in increased capillary permeability with profound egress of fluid from the intravascular space to the tissues adjacent to the burn wound. Inordinate amounts of fluid are lost by evaporation from the damaged surface, which is no longer able to retain water. This increase in capillary permeability, coupled with evaporative water loss, causes hypovolemic shock.

Other Physiologic Changes Cardiac. Other physiologic changes seen with thermal injury are, to a large extent, a response to diminished circulating blood volume. The immediate cardiovascular response to thermal injury is a reduction in cardiac output accompanied by an elevation in peripheral vascular resistance. In the absence of heart disease, ventricular ejection fraction and velocity of myocardial fiber shortening are actually increased during thermal injury.[12] With replacement of plasma volume, cardiac output increases to levels that are above normal. This hyperdynamic state is a reflection of the hypermetabolic flow phase of thermal injury.

Pulmonary. Alterations in pulmonary function after burn injury are similar to those seen with other forms of traumatic injury. Minute ventilation usually increases immediately. After resuscitation, respiratory rate and tidal volume progressively increase, resulting in minute ventilation that may be twice normal. Pulmonary vascular resistance also increases after burn injury, which may be a manifestation of the release of vasoactive amines and other mediators.[13] This increase in pulmonary vascular resistance may provide a protective effect during fluid resuscitation by reducing pulmonary capillary hydrostatic pressure and lowering susceptibility to pulmonary edema. In the absence of inhalation injury, no significant change occurs in pulmonary capillary permeability after cutaneous thermal injury.[14]

Renal. In the immediate postburn period, glomerular filtration rate and renal blood flow are reduced in proportion to the reduction in intravascular volume. Gastrointestinal dysfunction also appears to be proportional to the

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magnitude of thermal injury. In patients with burned areas in excess of 25% of TBSA, gastroparesis is commonly noted until the third to fifth postburn day.

Hematologic. Burn shock may be complicated by an acute erythrocyte hemolysis caused by both direct heat damage and a decreased half-life of damaged red blood cells (RBCs). In major burns, the RBC mass may be reduced 3% to 15%. RBCs also exhibit a decreased half-life because of a microangiopathic hemolytic anemia that may persist for up to 2 weeks.

Depth of Burn Injury The depth of burn injury is often classified according to degrees. In first-degree burns, minor epithelial damage of the epidermis exists. Redness, tenderness, and pain are the hallmarks of the injury. Blistering does not occur, and two-point discrimination remains intact. Healing takes place over several days without scarring. The most common causes of first-degree burns are flash burns and sunburns. The two types of second-degree burns are superficial partial-thickness and deep partial-thickness burns. In these burn injuries, some portion of the skin appendages remains viable, allowing epithelial repair of the burn wound without skin grafting. The superficial partial-thickness burn involves the epidermis and superficial (papillary) dermis, often resulting in thin-walled, fluid-filled blisters ( Figure 60-4A ). These burns appear pink, moist, and soft and are exquisitely tender when touched by a gloved hand. They heal in approximately 2 to 3 weeks, usually without scarring, by outgrowth of epithelial buds from the viable pilosebaceous units and sweat glands residing in the papillary and reticular dermis. The deep partial-thickness burn extends into the reticular dermis ( Figure 60-4B ). The skin color is usually a mixture of red and blanched white. Blisters are thick walled and are often ruptured. Two-point discrimination may be diminished, but pressure applied to the burned skin can be felt. This injury may undergo spontaneous epithelialization from the few viable epithelial appendages at this deepest layer of dermis and may heal in 3 to 6 weeks (if no infection arises). Because these burns have less capacity for reepithelializing, a greater potential for hypertrophic scar formation exists. Contraction across joints, with resulting limitation in range of motion, is a common sequela. Splash scalds often cause second-degree burns.

Figure 60-4 First-, second-, and third-degree burns. Stippled areas indicate depth of burn injury. A, Superficial partial-thickness burn. B, Deep partial-thickness burn. C, Full-thickness burn injury.

Third-degree burns are full-thickness burns that destroy both epidermis and dermis ( Figure 60-4C ). The capillary network of the dermis is completely destroyed. The burned skin has a white or leathery appearance with underlying clotted vessels and is anesthetic (numb). Unless a third-degree burn is small enough to heal by contraction (80% of TBSA) do not survive. This decision must be made after thoughtful communica-tion with family members. When resuscitation is not undertaken, patients should be made pain free, kept warm, and allowed to remain in a room with family members.

Pediatric Considerations Most of the burn care in children is similar to that in adults, yet some relevant physiologic differences need to be considered in the care of burned children. The Parkland formula is effective in estimating fluid loss in adults, yet it underestimates the evaporative fluid loss and maintenance needs in children. Compared with adults, children have a larger TBSA relative to weight than adults and generally have somewhat greater fluid needs during resuscitation. The Galveston formula for fluid resuscitation in children should be used as follows: 5% dextrose in LR (5000 mL/m[2] of TBSA burned plus 2000 mL/m2) is administered IV in the first 24 hours. One half is given in the first 8 hours, and the other half is given over the next 16 hours. Dextrose should be added to the resuscitation fluid in children to prevent hypoglycemia because children have smaller glycogen stores than adults. In infants younger than 6 months, temperature is regulated by nonshivering thermogenesis, a metabolic process by which stores of brown fat are catabolized under the influence of norepinephrine, which requires large amounts of oxygen. Consequently, prolonged hypothermia in burned infants may result in excessive lactate production and acidosis. After 6 months, infants and children are able to shiver. Because they have

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greater evaporative water loss relative to weight than adults, infants and children are especially susceptible to hypothermia; therefore, the ambient temperature should be kept high to decrease radiant and evaporative heat loss from burned infants and children to the environment.

Renal Function Differences Differences in renal function between infants and adults may have important therapeutic implications in treating burned children. The glomerular filtration rate in infants does not reach adult levels until 9 to 12 months because of an imbalance in maturation of tubular and glomerular functions. During this interval, infants have approximately half the osmolar concentrating capacity of adults, and a water load is handled inefficiently. The rate of water excretion is time dependent and decreases as water loading continues. During the first several weeks of life, infants are likely to retain a larger portion of a water load administered as part of burn resuscitation. The hyposmolarity of LR solution, when used in accordance with the Parkland formula, already accounts for the free water needs of infants during the first 24 hours after the burn injury. Additional water often results in fluid overloading.

Catheterization of the Patient A Foley catheter is placed into the bladder to monitor the effectiveness of IV fluid replacement. Burns of the perineum are also best cared for with an indwelling Foley catheter to decrease urinary soilage of the wound. In patients with major burn injuries who require IV fluid resuscitation, a nasogastric (NG) tube is passed for initial evacuation of fluid and air from the stomach and feeding access. Removal of the gastric contents prevents vomiting and aspiration, sequelae of the ileus that commonly occur soon after burn injuries involving more than 20% of TBSA. Early feeding through the NG tube within 6 to 8 hours of the burn injury diminishes the hypermetabolic response and maintains intestinal integrity.

Transportation of Patients After stabilization of the burned patient in the emergency department, patients with severe burn injury should be transferred to burn centers. The American Burn Association has established criteria for optimal treatment of burn patients, including both indications for admission to a hospital and criteria for transfer to a burn center. Ground, helicopter, or fixed-wing aircraft may transport burn patients. In addition to the condition of the patient, the mode of transportation (ambulance versus helicopter) depends on such factors as distance, terrain, and prevailing weather. The safety and costs of using helicopters in the transport of burn patients have been questioned. Helicopters transport patients more rapidly than ambulances and, because a nurse or physician usually staffs them, provide a higher level of medical expertise during transport. For burn patients, a helicopter offers little advantage over a ground ambulance if the distance is less than 30 miles. Helicopter transfers may be efficacious if the distance is 30 to 150 miles or if the transfer time is greater than 30 minutes. Over 150 miles, fixed-winged aircraft are best to transport patients. When a burn patient is being transferred from an emergency department to a burn center, early physicianto-physician contact with the burn center is essential. A standard check sheet facilitates assessment of the patient's physiologic status by both the referring and receiving physician. Airway patency, IV access, and other injuries are evaluated prior to transfer. Burn wounds should be covered with dry dressings but use of antimicrobial creams should be postponed until admission to the burn center. The burn wound is considered a dirty wound and tetanus prophylaxis instituted accordingly. Prophylactic antibiotics are not indicated.

Burn Center Treatment Treatment of the patient in the burn center involves three important considerations: supportive care, burn wound management, and nutritional support.

Specific Management Pain The requirement for pain medication is inversely proportional to the depth of burn injury. Full-thickness burns, which appear white, brown, or leathery with clotted vessels, are painless because their intrinsic sensory nerves are damaged. In contrast, partialthickness burns, in which the skin is red with blisters, have intact nerves and are extremely painful. For more than 160 years, morphine has been advocated for the management of pain in burn patients. Its analgesic effect can be easily titrated with incremental IV doses. Morphine has two pharmacologic advantages for use in burn patients: a low amount of protein binding (30%) and a major active metabolite that is conjugated in the liver and removed by glomerular filtration. This rapid elimination may require that doses as high as 50 mg/hr be used in severely burned adults. Any respiratory

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depression caused by morphine can be rapidly reversed by small doses of naloxone.

Gastrointestinal Issues A Foley catheter and nasogastric tube should be placed. Acute upper gastrointestinal erosions and ulcers may occur in patients with severe burn injuries. These lesions are often called stress ulcers or erosions (Curling's ulcer). The most common clinical finding in such patients is painless gastrointestinal hemorrhage. In high-risk patients the occurrence of stress ulcerations can be reduced by the use of antacids to neutralize gastric contents, supplemented by H2 receptor antagonists to inhibit gastric acid secretion. This prophylaxis is best initiated immediately after admission to the burn center.

Carboxyhemoglobin and Cyanide A CO level should be obtained in all patients with a suspected inhalation injury. Such patients should receive 100% oxygen until their COHb level is shown to be less than 10% because the elimination half-life for COHb depends on oxygen tension. Patients who have elevated COHb levels associated with a pH of less than 7.4 should be treated with hyperbaric oxygenation.[31] Because serum COHb levels do not reflect tissue levels, clinical symptoms should be evaluated when considering hyperbaric oxygen therapy. These include a history of unconsciousness, the presence of neuropsychiatric abnormalities, and cardiac instability or cardiac ischemia.[32] Empirical therapy for possible cyanide poisoning may be necessary.

Burn Wound Care All wound management is undertaken using powder-free gloves because of the demonstrated toxicity of glove powders to tissue.

Major Burns Escharotomy A full-thickness circumferential burn of an extremity can result in vascular compromise. Loss of Doppler ultrasound signals in the radial and ulnar arteries and digital vessels is an indication for escharotomies of the upper extremity.[34] Loss of signal in the dorsalis pedis or posterior tibialis artery indicates the need for escharotomy of the lower extremity. Interstitial tissue pressure is usually slightly negative, and the normal arterial capillary perfusion pressure is approximately 5 to 7 mm Hg. After burn injury, rises in interstitial tissue pressure occlude arterial capillary inflow and venous outflow; escharotomies of the full-thickness burn prevent this ischemic injury. A period of 3 to 8 hours is required for edema to develop sufficiently to increase tissue pressure. When tissue compartment pressures are greater than 40 mm Hg, escharotomies of the full-thickness burn prevent ischemic injury. It is important to note that the most common cause of absent pulses in an extremity is hypovolemia with peripheral vasoconstriction, not increased interstitial pressure. Escharotomies are performed on the medial and lateral aspects of the extremity and extend the length of the constricting eschar. Incisions are made using either a scalpel or a high-frequency electrical current, with release of the edematous tissues ensuring adequate depth. After prolonged vascular compromise, escharotomy may cause reperfusion injury to the extremity, with reactive hyperemia and edema of the compartment muscles. In this case, a fasciotomy is required to restore perfusion to the extremity. For full-thickness circumferential burns of the upper extremity, the fingers are first decompressed by a digital escharotomy along each side of the burned finger, cutting down to fat. The palm is decompressed by an incision along the palmar crease ( Figure 60-6 ). At the wrist, the incision continues ulnarward to avoid injury to the palmar cutaneous branch of the median nerve.

Figure 60-6 Skin incisions for digital escharotom y and palm decom pression.

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When intrinsic muscle involvement is suspected, decompression of the interossei muscles is accomplished through short longitudinal skin incisions made in the intermetacarpal spaces and carried down to the dorsal interossei muscles ( Figure 60-7 ). Decompression of the leg is accomplished by midmedial and midlateral incisions. Each toe is decompressed in a manner similar to that used for the fingers.

Figure 60-7 Decom pression of interossei m uscles by skin incisions.

Dressings If transfer to a burn center is imminent, wound care should consist of simply wrapping the patient in a clean dry sheet. If disposition is delayed, however, treatment is begun by (1) gentle cleansing with either sterile saline or commercial products containing poloxamer 188 (e.g., Shur-Clens); (2) debridement of blisters, except those on the palms and soles; and (3) application of a topical antibacterial agent, according to the burn center's preference.[35] Topical antimicrobial agents are used to limit bacterial and fungal colonization of burn wounds until complete reepithelialization occurs. Silver sulfadiazine (Silvadene), mafenide acetate (Sulfamylon), and 0.5% silver nitrate solution are the most frequently used topical antibacterial agents. Agents such as bacitracin and polymyxin B are less bactericidal but also less toxic to reepithelialization of the burn wound. Topical nystatin can be added to the antibacterial agents to prevent fungal growth. The water-soluble carrier poloxamer 188 can be used with these antimicrobial agents.[36] This gel can be easily washed from the wound surface after dressing changes. Sterile gauze followed by sterile sheets can then be used to cover the wounds and body.

Minor Burn Treatment in the Emergency Department Blisters and Tetanus All minor burns should first be cleansed with sterile saline or poloxamer 188. Treatment of burn blisters remains controversial. Exposing an unbroken blister can lead to local wound infection, but studies have demonstrated that burn blister fluid confined by necrotic skin can result in closed-space infection.[] Most authors recommend that blisters on the palms or soles be left intact. Other blisters, particularly when large enough to preclude the application of an adequate dressing, should either be aspirated sterilely or be opened with a No. 15 knife blade and the surface of the blister removed. Tetanus prophylaxis should be provided if indicated. As required under the National Childhood Injury Act, all health care providers in the United States who administer any vaccine shall, prior to administration of the vaccine, provide a copy of the Vaccine Information Statement (VIS) produced by the Centers for Disease Control to the parent or legal representative of any child to whom the provider intends to administer such vaccine or to any adult to whom the provider intends to administer such vaccine. The VIS must be supplemented with visual presentation or oral explanations, as appropriate. Copies of the VIS are available at http://cdc.gov.ezproxy.hsclib.sunysb.edu/nip/publications/VIS . Copies are available in English as well as many other languages. Prophylactic antibiotics are not recommended. Topical antimicrobial agents have little value in the outpatient management of minor burns. Because these agents lose their antibacterial activity within 6 to 24 hours after application, frequent dressing changes are necessary. Unfortunately, removal and reapplication of the cream are painful and time consuming. As a result, many patients resort to reapplication of the cream without initial removal, an invitation to infection.

Ointment and Dressings Burn wounds can be treated by either open or closed technique. Open therapy of minor burn injuries is usually reserved for burns of the face. These burns are covered by bacitracin ointment, which is reapplied every 6 hours after gently washing the skin. An enormous variety of synthetic dressings have been developed. First-generation film dressings (e.g., thin films, hydrocolloidal hydrogel foams, alginate) are based on the concept that epidermal regeneration occurs best in a moist environment.[39] Secondgeneration microenvironmental wound dressings combine the

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fluid-retaining properties of the film dressings with the absorptive properties of the hydrocolloid. In theory, wound fluid is absorbed by the central membrane through the porous inner layer. The external layer allows moisture vapor to escape but is impermeable to exterior fluids and bacteria. Although second-generation dressings have many desirable features, they are relatively expensive. A simple, less costly alternative to these synthetic dressings can be reliably used in minor burns.[40] After cleansing and debridement, strips of sterile fine-mesh gauze (type 1) soaked in 0.9% sodium chloride are placed over the entire wound. This layer of gauze is then covered by multiple layers of fluffed 4 × 4-inch coarse-mesh gauze (type 6), which are secured by an inelastic roller-gauze dressing. The gauze dressing is attached to unburned skin using a microporous tape. When possible, the site of injury should be elevated above the patient's heart. Elevation of the injured site limits accumulation of fluid in the interstitial spaces of the wound. The healing burn extremity with little edema resumes normal function more rapidly than the extremely edematous extremity. Early mobilization of the injured area within 24 hours after injury limits the development of joint stiffness, a particularly challenging problem in both elderly persons and workers who do heavy labor. Oral analgesics should be routinely prescribed for patients with painful burns, and wound care instructions should be given to the patient before departure. A follow-up appointment should be scheduled in 2 to 3 days.

Follow-up and Complications If the patient returns to the emergency department for a follow-up visit, aseptic technique should be used to remove the outer layers of the dressing gently so that the bottom, fine-mesh gauze layer can be visualized. If the gauze is adherent to a relatively dry and pink burn wound, it should be covered again by layers of 4 × 4-inch coarse-mesh gauze and secured. The patient should be instructed to return in 5 to 7 days for reevaluation. Because most superficial partial-thickness burns heal in 10 to 14 days, spontaneous separation of the gauze from the healing burn wound should be evident at the next dressing change. If the burn wound exhibits a purulent discharge, the fine-mesh gauze should be removed and the burn wound cleansed. Silver sulfadiazine cream should be applied twice daily to the burn wound and the area dressed with a sterile roller-gauze dressing. The patient should be instructed to wash the burn wound gently in clean water to remove this cream before applying additional cream. The potential complications of minor burn injury should be reviewed with each patient. The patient must be aware that burn wound infection is a continual threat that can convert a partial-thickness burn to a fullthickness burn. The risk of hypertrophic scar formation, as well as pigmentary skin changes, should also be discussed. The patient should be reminded to use a sun-blocking agent over the healed wounds for at least 6 months after injury to prevent the development of permanent pigmentary changes caused by sun exposure.

Hot Tar Burns Burns from hot tar present a challenging clinical problem. When tar that is heated to a liquid form inadvertently comes into contact with a worker's skin, it transfers sufficient heat to cause a burn injury. As it cools on the skin surface, the tar solidifies, making removal difficult. The term hot tar refers to two distinct groups of materials: coal tar pitches and petroleum-derived asphalts. These two groups are often mistakenly considered synonymous because of similar industrial applications. They are both used for paving and roofing purposes and are used directly in the construction of roofing membranes. However, coal tar and petroleum asphalts are dissimilar in origin and chemical composition. Asphalt cements and roofing asphalts are high-molecular-weight naphthenic and paraffinic hydrocarbons that are produced from crude petroleum by a process that does not involve thermal conversion or cracking. In contrast, coal-derived tars are composed primarily of highly condensed-ring aromatic and heterocyclic hydrocarbons that are obtained by the high-temperature carbonization of bituminous coal. Both products are heated to maintain a liquid form. Substantially lower temperatures (275°F to 300°F) are needed to achieve desirable application viscosities for paving roads than are necessary for roofing purposes (450°F to 500°F). The higher temperatures account for the deeper burn injuries associated with burns from roofing asphalt or pitch. After coming in contact with the skin, the tar rapidly cools, solidifies, and becomes enmeshed in the hair. This cooling process should be expedited by the addition of cold water to the tar at the scene of the accident. Cooling the tar with cold water limits tissue damage and prevents further spread of the tar. Washing the tar with water should be continued until the tar has hardened and is cool. After the tar is cooled, the wet skin

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should be dried with towels to prevent the development of systemic hypothermia. Adherent tar should not be removed at the scene of the accident. Definitive care of the tar burn injury in the emergency department includes early removal of the tar because it may serve as an occlusive barrier over the injured skin that encourages bacterial growth, with subsequent conversion of a partial-thickness burn to a full-thickness injury. The adherence of tar to skin is not a direct bond between the epidermis and the tar but rather a consequence of the tar becoming enmeshed in the hair. Numerous organic solvents have been proposed to remove tar. Aromatic (naphthalene) and aliphatic (hexane) hydrocarbon solvents are useful for asphalts, whereas coal tars are susceptible only to aromatic hydrocarbons. Unfortunately, many of these aromatic and short-chain hydrocarbons are systemically absorbed and have potential side effects. Long-chain aliphatic hydrocarbons and waxes have been used for tar removal without evidence of local or systemic toxicity. These substances are oleaginous colloidal suspensions of solid microcrystalline waxes in petroleum oil (e.g., polymyxin-neomycin-bacitracin [Neosporin] ointment). Antibiotic ointments with a broad spectrum of activity, including bacitracin (400 units/g), polymyxin B (5000 units/g), and neomycin (5 mg/g), complement the action of the solvent by lowering the incidence of infection. These agents need to be removed and reapplied hourly until all the tar is removed. This approach has been used successfully to remove even tar layered over conjunctiva. Unfortunately, the cost of using antibiotic ointments to treat tar burns covering a large percentage of TBSA can be substantial. Besides the cost of the antibiotic preparations, multiple applications are necessary to remove the tar. The use of readily available topical agents may offer a rapid, cost-effective means of tar removal. Sunflower oil has been shown to remove both asphalt and coal-based tar. This inexpensive, nonirritating agent removes adherent tar in 30 minutes.[41] Likewise, butter can emulsify tar in 20 to 30 minutes.[42] Reapplication may be required when large areas are involved, but butter provides another nontoxic alternative for tar removal. Baby oil has been shown to provide similar results in 1 to 1½ hours.[43] Commercial surface-active agents such as polyoxyethylene sorbitan (Tween 80) and polysorbate (De-Solv-It), alone or in combination with a petrolatum ointment, are relatively inexpensive, safe, and effective means of tar removal. Their water solubility is believed to be an additional advantage over petrolatum ointment, which is not as easily removed from skin with water as are these surface-active agents.

DISPOSITION As mentioned, the American Burn Association has established criteria for optimal treatment of burn patients, including the indications for admission to a hospital ( Box 60-1 ) and the criteria for transfer to a burn center ( Box 60-2 ).[44] The safety and costs of using helicopters in the transport of burn patients have been questioned.[] BOX 60-1 Admission Guidelines for Patients with Moderate Burns

Any parti al-thi ckne ss [*] burn injur y invol ving 10% -20 % of BSA in adult s (>10 or

Page 622

10 % of total BSA in patie nts 50 year s old Burn s invol ving >20 % of total BSA in any patie nt Full-t hick ness

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burn s invol ving >5% of total BSA Signi fican t burn s of hand s, face, feet, genit alia, perin eum, or majo r joint s Signi fican t elect rical injur y Signi fican t che mica l injur y Signi fican t inhal ation injur y, conc omit ant mec hani cal trau ma, pree xistin g medi cal

Page 624

disor ders Patie nts with spec ial psyc hoso cial or reha bilitat ive care need s BSA, body surface area. When a burn patient is being transferred from an emergency department to a burn center, early physician-to-physician contact with the burn center is essential. The use of a standard check sheet facilitates assessment of the patient's physiologic status by both the referring physician and the receiving physician. Prophylactic antibiotics are not indicated. The use of antimicrobial creams on the burn wound should be postponed until admission to the burn center. The burn wound should be considered a dirty wound, and tetanus prophylaxis should be instituted accordingly.

KEY CONCEPTS {,

Ther mal burn s: Com pare d with other natur al disa sters , burn s exert a cata strop hic influ ence on peop le in term s of hum an life, suffe ring,

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disa bility, and finan cial loss. More than an esti mate d2 millio n peop le in the Unite d Stat es suffe r burn injuri es, most of whic h are mino r and care d for prim arily in the eme rgen cy depa rtme nt. {,

Ther mal burn s are com monl y clas sifie d as scal d burn s, cont act burn s,

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and fire burn s. {,

The seve rity of burn injur y is relat ed to the rate at whic h heat is trans ferre d from the heati ng agen t to the skin. The rate of heat trans fer depe nds on the (1) heat capa city of the agen t, (2) temp eratu re of the agen t, (3) durat ion of cont act with the

Page 627

agen t, (4) trans fer coeff icien t, and (5) spec ific heat and cond uctivi ty of the local tissu es. {,

The dept h of burn injur y is often clas sifie d acco rding to degr ees: firstdegr ee burn s, seco nd-d egre e burn s (sup erfici al parti al-thi ckne ss and deep parti al-thi ckne ss), thirddegr ee

Page 628

{,

{,

burn s, and fourt h-de gree burn s. The first day after burn injur y, three conc entri c zone s of tissu e injur y char acter ize a full-t hick ness burn: the zone s of coag ulati on, stasi s, and hype remi a. The rule of nine s is a pract ical tech niqu e for esti mati ng the exte nt of total

Page 629

body surfa ce area invol ved in a burn injur y. {,

The seve rity of a burn injur y depe nds on the (1) exte nt, dept h, and locat ion of the burn injur y; (2) age of the patie nt; (3) etiol ogic agen ts invol ved; (4) pres ence of inhal ation injur y; and (5) coex istin g injuri es or pree

Page 630

xistin g illnes ses. {,

Opti mal man age ment of burn victi ms is provi ded by an eche lon syst em of burn care that is deve lope d on a regio nal basi s. Orga nizat ion of burn care shou ld begi n at the site of injur y and conti nue throu gh preh ospit al care and trans porta

Page 631

tion to the clos est burn cent er, or to the clos est eme rgen cy depa rtme nt with adva nced life supp ort capa bility, follo wed by trans fer to a burn cent er whe n appr opria te. {,

Whe n the patie nt arriv es in the eme rgen cy depa rtme nt, the depa rtme nt staff perfo rm a rapid initial

Page 632

asse ssm ent of respi rator y and cardi ovas cular statu s, esta blish the exte nt of burn injur y, and deter mine the need for spec ial proc edur es. Eme rgen cy depa rtme nt treat ment focu ses on airw ay and respi rator y care and fluid resu scita tion, alon g with deter mina tion of

Page 633

the need to trans fer to a burn cent er. {,

After stabi lizati on of the burn ed patie nt in the eme rgen cy depa rtme nt, patie nts with seve re burn injur y are trans ferre d to burn cent ers. The Ame rican Burn Asso ciati on has esta blish ed criter ia for opti mal treat ment of burn patie nts, inclu ding

Page 634

{,

{,

both indic ation s for admi ssio n to a hosp ital and criter ia for trans fer to a burn cent er. Trea tmen t of the patie nt in the burn cent er invol ves three impo rtant cons idera tions : supp ortiv e care, burn wou nd man age ment , and nutrit ional supp ort. Defi nitive care of the tar burn injur y in

Page 635

the eme rgen cy depa rtme nt inclu des early rem oval of the tar beca use it may serv e as an occl usiv e barri er over the injur ed skin that enco urag es bact erial grow th, with subs eque nt conv ersio n of a parti al-thi ckne ss burn to a full-t hick ness injur y. The adhe renc

Page 636

{,

{,

e of tar to skin is not a direc t bond betw een the epid ermi s and the tar but rathe ra cons eque nce of the tar beco ming enm eshe d in the hair. Intub ation rathe r than obse rvati on is reco mm ende d in burn patie nts with sign s of uppe r airw ay injur y. Aggr essi ve fluid resu

Page 637

scita tion is requi red for patie nts with burn s over 20% of TBS A in orde r to resto re effec tive plas ma volu me, avoi d micr ovas cular isch emia , and main tain vital orga n funct ion. {,

The most com mon error is over hydr ation . Adeq uate resu scita tion is evid ence d by a nor

Page 638

{,

{,

mal urine outp ut, nor mal sens oriu m, and stabl e vital sign s. Dext rose is adde d to the resu scita tion fluid in child ren to prev ent hypo glyc emia beca use child ren have smal ler glyc ogen store s than adult s. Bec ause mor phin e is rapid ly elimi nate d, dose s as high as

Page 639

50 mg/h r may be requi red for anal gesi a in seve rely burn ed adult patie nts.

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Marx: Rosen's Emergency Medicine: Concepts and Clinical Practice, 6th ed., Copyright © 2006 Mosby, Inc.

REFERENCES 1. Centers for Disease Control/National Highway Traffic Safety Administration : Position papers from the Third National Injury control conference: Setting the national agenda for injury control in the 1990s, Atlanta: U.S. Department of Health and Human Services, Public Health Service, CDC; 1992: 285. 2. Inansci WI, Guidotti TL: Occupation related burns: 5-year experience of an urban burn center. J Occup Med1987;29:730. 3. Williams JB, Ahrenholtz DH, Solem LD, Warren W: Gasoline burns: The preventable cause of thermal injury. J Burn Care . Rehabil1990;11:446. 4. Moritz AR, Henrique Jr JrFC: Studies of thermal injury: The relative importance of time and surface temperature in the causation of cutaneous burns. Am J Pathol1947;23:695. 5. Weaver AM, Himel HN, Edlich RF: Immersion scald burns: Strategies for prevention. J Emerg Med 1993;11:397. 6. Walker AR: Fatal tap water scald burns in the USA. Burns1990;16:49. 7. Feldman KW, Schaller RT, Feldman JA, McMillon M: Tap water burns in handicapped children. Pediatrics 1978;62:1. 8. Jackson DM: The diagnosis of the depth of burning. Br J Surg1953;40:588. 9. Robson MC, Del Beccaro EJ, Heggers JP: The effect of prostaglandins in the dermal microcirculation after burning and the inhibition of the effect by specific pharmacological agents. Plast Reconstr Surg 1979;63:781. 10. Friedel HP, Till GO, Trentz O: Roles of histamine, complement and xanthine oxidase in thermal injury of skin. Am J Pathol1989;135:203. 11. Deitch EA, Rutan R, Waymack JP: Trauma, shock, and gut translocation. New Horiz1996;4:289. 12. Aulick LH, Wilmore DW, Mason Jr JrAD, Pruitt Jr JrBA: Influence of the burn wound on peripheral circulation in thermally injured patients. Am J Physiol1977;223:520. 13. Demling RH: Early lung dysfunction after major burns: Role of edema and vasoactive mediators. J Trauma1985;26:959. 14. Harms BA, Bodai BI, Kramer GC, Demling RH: Microvascular fluid and protein flux in pulmonary and systemic circulations after thermal injury. Microvasc Res1982;23:77. 15. American Burn Association : Guidelines for service standards and severity classifications in the treatment of burn injury. Am Coll Surg Bull1984;69:24. 16. Boykin Jr JrJV, Eriksson E, Sholley MM, Pittman RN: Histamine-mediated delayed permeability response after scald burn inhibited by cimetidine or cold-water treatment. Science1980;209:815. 17. Heggers JP, Loy GL, Robson MC, Del Beccaro EJ: Cooling and the prostaglandin effect in the thermal injury. J Burn Care . Rehabil1980;3:350. 18. Becker DG, Himel HN, Nicholson WD, Edlich RF: Salvage of a patient with burn inhalation injury and pancreatitis. Burns1993;19:444. 19. Pruitt Jr JrBA, Goodwin CW: Burn injury. In: Moore E, ed.Early Care of the Injured Patient, 4th ed. New York: Decker; 1990: 297-298. 20. Hunt JL, Agee RN, Pruitt Jr JrBA: Fiberoptic bronchoscopy in acute inhalation injury. J Trauma 1975;15:641. 21. Cioffi WG: Decreased pulmonary damage in primates with inhalation injury treated with high-frequency ventilation. Am Surg1993;218:328. 22. Rue 3rd 3rdLW: Improved survival of burned patients with inhalation injury. Arch Surg1993;128:772. 23. Cioffi Jr JrWG: Prophylactic use of high-frequency percussive ventilation in patients with inhalation injury. Am Surg1991;213:575. 24. Kien ND: Small-volume resuscitation using hypertonic saline improves organ perfusion in burned rats. Anesth Analg1996;83:782. 25. Tokyay R: Effects of hypertonic saline dextran resuscitation on oxygen delivery, oxygen consumption, and lipid peroxidation after burn injury. J Trauma1992;32:704. 26. Horton JW, White J, Hunt JL: Delayed hypertonic saline dextran administration after burn injury. J Trauma1995;38:281. 27. Onarheim H, Missavage AE, Kramer GC, Gunther RA: Effectiveness of hypertonic saline-dextran 70 for

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initial fluid resuscitation of major burns. J Trauma1990;30:597. 28. Demling RH: Improved survival after massive burns. J Trauma1983;23:179. 29. Griswold JA, Anglin BL, Love Jr JrRT, Scott-Conner C: Hypertonic saline resuscitation: Efficacy in a community-based burn unit. South Med J1991;84:692. 30. Gunn ML: Prospective, randomized trial of hypertonic sodium lactate versus lactated Ringer's solution for burn shock resuscitation. J Trauma1989;29:1261. 31. Strohl KP, Feldman NT, Saunders NA, O'Conner N: Carbon monoxide poisoning fire victims, a reappraisal of prognosis. J Trauma1980;20:78. 32. Grim PS, Gottlieb LJ, Boddie A, Batson E: Hyperbaric oxygen therapy. JAMA1990;263:2216. 33. Fitzpatrick JC, Cioffi WG: Inhalation injury. Trauma Q1994;11:114. 34. Edlich RF: Technical considerations for fasciotomies in high voltage electrical injuries. J Burn Care Rehabil1980;1:22. 35. Bryant CA: Search for a nontoxic scrub solution for periorbital lacerations. Ann Emerg Med1984;13:317. 36. Rockwell WB, Ehrlich HP: Should burn blister fluid be evacuated?. J Burn Care Rehabil1990;11:93. 37. Garner WL: The effects of burn blister fluid on keratinocyte replication and differentiation. J Burn Care Rehabil1993;14:127. 38. Gear AJ: A new sliver sulfadiazine water soluble gel. Burns1997;23:387. 39. Nangia A, Hung CT: Preclinical evaluation of skin substitutes. Burns1990;16:358. 40. Haynes Jr JrBW: Outpatient burns. Clin Plast Surg1974;1:645. 41. Turegun M, Ozturk S, Selmanpakoglu N: Sunflower oil in the treatment of hot tar burns. Burns 1997;23:442. 42. Tiernan E, Harris A: Butter in the initial treatment of hot tar burns. Burns1993;19:437. 43. Juma A: Bitumen burns and the use of baby oil. Burns1994;20:363. 44. American Burn Association : Hospital and prehospital resources for optimal care of patients with burn injury: Guidelines for development and operation of burn centers. J Burn Care Rehabil1990;11:97. 45. Dimick AR, Dietz PA: An unexpected burden: The safety of air ambulances [letter]. JAMA1988;259:3405. 46. Fromm Jr JrRE, Varon J: Air medical transport. J Fam Pract1993;36:313.

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Use of this content is subject to the Term s and Conditions of the MD Consult web site.

Marx: Rosen's Emergency Medicine: Concepts and Clinical Practice, 6th ed., Copyright © 2006 Mosby, Inc.

Chapter 61 – Chemical Injuries Richard F. Edlich Marcus L. Martin William B. Long III

PERSPECTIVE Chemical injuries are commonly encountered following exposure to acids, alkalis, and highly reactive substances. Injury to the skin, eyes, lung, and other organ systems can be disabling or life threatening. Injury can result from commonly used chemicals, including hydrofluoric acid, formic acid, hydrous ammonia, cement, and phenol. Other specific chemical agents that cause burns include white phosphorus, elemental metals, nitrates, hydrocarbons, and tar. Since World War II, the number of chemicals that have been developed, produced, and used worldwide has increased dramatically. More than 65,000 chemicals are available on the market, and an estimated 60,000 new chemicals are produced each year. Unfortunately, the effects on human health of many of these chemicals are unknown. Toxic chemical releases, whether from manufacturing plants, during transport, or while in use, are prevented through federal and state regulation along with sound industry practices. The federal Superfund Amendments and Reauthorization Act contains extensive provisions for emergency planning and the rights of communities to know about toxic chemical releases. In addition to state health departments, there are five national sources of information in the United States on death and injuries caused by chemical releases: the National Response Center (NRC), Department of Transportation (DOT), Hazardous Materials Information System (HMIS), Acute Hazardous Events (AHE) database, and American Association of Poison Control Centers (AAPCC).[] These resources are valuable for accidental exposures to chemical agents, but they must be greatly expanded to address chemical terrorism. Health departments from five states (Colorado, Iowa, Michigan, New Hampshire, and Wisconsin) evaluated 3125 emergency chemical-release events involving 4034 hazardous substances that occurred from 1990 to 1992. Of these events, 77% involved stationary facilities and 23% were transportation related. In 88% of the events, a single chemical was released. The most commonly released hazardous substances were volatile organic compounds (18%), herbicides (15%), acids (14%), and ammonia (11%). These events resulted in 1446 injuries and 11 deaths. Respiratory irritation (37%) and eye irritation (23%) were the most commonly reported symptoms. Chemical exposures can also occur at home or as the result of an attack. Many common products once believed to be innocuous (e.g., cement, gasoline) are now regarded as potentially hazardous and the cause of serious injury and illness. Exposure to these agents can be reduced significantly through educational programs, cautionary labeling of toxic products, and appropriate use of protective clothing. When poison control centers identify new products that are toxic to skin, information systems must include these products to ensure that injured patients are given the benefit of new data.[3] Concomitantly, this information is shared with the manufacturer and Consumer Products Safety Commission (CPSC) to recognize and address the problem nationally. For example, numerous cases of serious, permanent injury and occasionally death caused by exposure to sulfuric acid drain cleaners have been recorded by the CPSC. As a result, the CPSC currently proposes banning the retail sale of this agent.

PATHOPHYSIOLOGY Most chemical agents damage the skin by producing a chemical reaction rather than a hyperthermic injury.[4] Although some chemicals produce considerable heat as the result of an exothermic reaction when they come into contact with water, their ability to produce direct chemical changes in the skin accounts for the most significant injury. The specific chemical changes depend on the agents, including acids, alkalis, corrosives, oxidizing and reducing agents, desiccants and vesicants, and protoplasmic poisons. The degree

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of skin destruction is determined mainly by the concentration of the toxic agent and the duration of its contact. When the skin is exposed to toxic chemicals, its keratinous covering is destroyed, and its underlying dermal tissues are exposed to continued necrotizing action. Both inorganic and organic acids denature the proteins of the skin, resulting in a coagulum, the color of which depends on the acid involved. Nitric acid burns result in a yellow eschar, whereas sulfuric acid eschar is black or brown. Burns caused by hydrochloric acid or phenol tend to range from white to grayish-brown. After the initial exposure, cellular dehydration and further protein denaturation or coagulation occur. This dehydrative effect results in the characteristic dry surface of acid burns that depends on the nature of the acid. Alkali burns are those caused by lime (cement), ammonia, and caustics (sodium hydroxide, potassium hydroxide). Alkali dissolves protein and collagen, resulting in alkaline complexes of these molecules. Cellular dehydration (as in acid burns) and saponification of fatty tissue also occur. Acid burns are characterized by “dry” edema and extensive fluid loss. Neutralization of alkali exposure is accomplished by first irrigating the burned site with a large amount of water to dilute any unreacted alkali remaining on the wound surface. This protects the wound from further damage caused by heat released during the neutralization reaction. After skin contact, the absorption of some agents may cause systemic toxicity. For example, dichromate poisoning produces liver failure, acute tubular necrosis, and death. Oxalic acid and hydrofluoric acid injuries may result in hypocalcemia. Tannic acid or phosphorus may cause nephrotoxicity. Absorption of phenol may be associated with central nervous system (CNS) depression and hypotension. Inhalation injury may result from exposure to toxic fumes, particularly when the exposure occurs within a closed space.

COMMUNITY PREPAREDNESS AND HAZMAT RESPONSE Hazardous materials (HAZMATs) are substances that can cause physical injury and damage the environ-ment if improperly handled. These substances can be encountered in the home, in urban (industrial) areas, in rural (agricultural) areas, or in any location involved in their release. HAZMAT accidents are particularly dangerous for responding personnel, who are in danger of exposure from the time of arrival on the scene until containment of the accident.[5] The population of the surrounding community is also usually endangered. The Superfund Amendments and Reauthorization Act of 1986 mandated community preparedness for dealing with HAZMAT accidents. Before a community develops its plans for responding to HAZMAT accidents, it needs to determine what types of materials are likely to be involved.[] For those exposed to potentially dangerous chemicals at home, it is best to remove the chemical from the anatomic site by irrigation with copious amounts of water. A friend or a relative then must telephone the regional poison control center certified by the AAPCC. If the chemical is judged to be dangerous, arrangements should be made to transfer the victim to the nearest emergency department for definitive care. The emergency department should be notified as soon as possible after the incident to allow the staff to prepare for receiving the patient.

Identify and Assess Hazardous Environment The paramedics and members of the HAZMAT response team (usually firefighters) must work together to identify toxic chemicals and assess hazardous environments. Placards, shipping papers, United Nations chemical identification numbers, and markings on shipping containers help identify the offending agent. In some cases, chemical analysis may be required to identify the agent. The presence of carbon monoxide, cyanide, hydrogen sulfide, oxygen, and combustible gases can be detected using different instruments. Colorimetric detector tubes can approximate the concentrations of chemicals in the air. Alpha, beta, and gamma radiation detectors can record radioactive contamination. The 24-hour hotline of Chemtrec (Chemical Transportation Emergency Center in Arlington, Virginia; 800-424-9300) can provide helpful information regarding the identification and management of HAZMATs. At the scene of the incident, members of the HAZMAT team should wear self-contained breathing apparatus (SCBA) and protective apparel. For more than 30 years, Chemtrec (Chemical Transportation Emergency Center) has been providing the crucial information needed to assist emergency response personnel in handling HAZMAT incidents in the safest possible manner. It is a mission that Chemtrec personnel perform extremely well. On average, Chemtrec (www.chemtrec.org ) handles 22,000 HAZMAT incidents annually. The organization receives 150 calls a day, all of them handled by a skilled team of emergency specialists with access to a database of 2.8 million material safety data sheets (MSDSs).

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Chemtrec capabilities were significantly enhanced over the past year. The Chemtrec call center in Arlington was completely renovated to accommodate additional on-duty emergency services specialists and technology upgrades to support the call center operations. Seven specialists now work in the call center, with three to four per shift. The 800 number (800-424-9300) has caused some confusion. Chemtrec officials stress that the number is just for emergencies. It is not a customer service phone number. When the Chemtrec phone number is listed on paperwork (such as MSDSs, invoices, and labels), it is important to state clearly that this is an emergency number. Placement of a customer service phone number near the company name can help solve the problem. The HAZMAT emergency clearinghouse also manages the chemical industry's mutual aid emergency response network. Chemtrec was established to provide chemical shippers with timely emergency response and technical assistance at the scene of chemical transportation incidents. The network is composed of emergency response teams from participating chemical companies and teams provided by for-hire contractors. When calls for help come in, Chemtrec's specialists provide immediate assistance and can link emergency responders in the field with shipper or product manufacturers. The specialists provide technical information to responders, along with important medical support information.

Contingency Plan The contingency plan for HAZMAT management can be divided into two parts: initiation of the site plan and the evacuation. Initiation of the site plan begins after identifying the HAZMAT and assessing the surrounding environment. When the substance is identified, the health risks to the environment are determined. A command post away from the exposure site is essential for a widespread HAZMAT incident because it allows coordination of the activities of paramedics, HAZMAT team, firefighters, police, and representatives from the state and local government and the manufacturer and shipper.

Coping with HAZMAT Incidents In dealing with HAZMAT incidents, two distinct goals must be achieved: (1) the material must be contained, fire and explosions must be extinguished, and the site must eventually be cleaned and (2) exposed persons must be treated. Decontamination is initiated by removing and isolating the victim's clothes in plastic bags. Liquid chemicals are washed off the victim's body with water, whereas dry chemicals are first brushed off, followed by copious irrigation with water delivered under low pressures. The priority of decontamination should progress from cleansing of contaminated wounds to eyes, mucous membranes, skin, and hair. While decontamination is being performed, primary and secondary surveys of the patient are conducted to detect life-threatening injuries, and appropriate steps are taken to stabilize the patient's condition (e.g., administration of oxygen to dyspneic patients). Ideally, the patient should be thoroughly decontaminated before arrival in the emergency department. Hospital personnel involved in decontamination should wear chemical-resistant clothing, with built-in hood and boots, at least two layers of gloves, protective eyewear, and some form of respiratory protection. The minimum level of respiratory protection for hospital personnel during decontamination has not been established.

MANAGEMENT Acid and Alkali Skin Injury Chemical burns continue to destroy tissue until the causative agent is inactivated or removed.[6] For example, when hydrotherapy is initiated within 1 minute after skin contact with either an acid or alkali, the skin injury is much less severe than when treatment is delayed for 3 minutes. Early treatment is followed by a return of the pH of skin to normal. When the contact time exceeds 1 hour, the pH of a sodium hydroxide (NaOH) burn cannot be reversed. Similarly, a brief washing of a hydrochloric acid (HCl) burn more than 15 minutes after exposure does not significantly alter the acidity of the damaged skin.

Hydrotherapy Because contact time is a critical determinant of the severity of injury, hydrotherapy of skin exposed to a toxic liquid chemical should be initiated immediately by the victim or witness to the injury. When a worker's clothes are soaked with such agents, valuable time is lost if clothing is removed before copious washing is begun. Gentle irrigation with a large volume of water under low pressure for a long time dilutes the toxic

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agent and washes it out of the skin. During hydrotherapy, the patient's clothes should be removed by the rescuer, wearing powder-free rubber gloves to prevent hand contact with the chemical. After exposure to strong alkalis, prolonged hydrotherapy is especially important to limit the severity of the injury. In experimental animals, the pH of chemically burned skin does not approach a normal concentration unless more than 1 hour of continuous irrigation has been maintained, and pH often does not return to normal for 12 hours despite hydrotherapy. In contrast, with HCl skin burns the pH usually returns to normal within 2 hours after initiation of hydrotherapy. The mechanism by which NaOH maintains an alkaline pH despite treatment is related to the byproducts of its chemical reaction to skin. Alkalis combine with proteins or fats in tissue to form soluble protein complexes or soaps. These complexes permit passage of hydroxyl ions deep into the tissue, limiting their contact with the water diluent on the skin surface. Acids, on the other hand, do not form complexes, and their free hydrogen ions are easily neutralized. Regardless of the causative agent, hydrotherapy should be continued when the patient arrives in the emergency department. If the chemical is localized in the patient's hand, the injured part can be immersed in a sink under flowing tap water. For other anatomic sites the patient should be placed supine in a hydrotherapy tank in which the temperature of the water can be regulated. Hydrotherapy treatment should be continued for 2 to 3 hours in the case of acid burns and for at least 12 hours in the case of strong alkali burns. When it comes in contact with a solid chemical (e.g., lye), clothing must be removed before instituting hydrotherapy. All visible solid particles must be removed from the patient's skin during copious irrigation with water. The water should be delivered to the wound at the lowest possible pressure because high-pressure irrigation (e.g., shower) may disperse the liquid or solid chemical into the patient's or rescuer's eyes. Water is the agent of choice for decontaminating acid and alkali burns of the skin. The deleterious effects of attempting to neutralize acid and alkali burns were first noted in experimental animals in 1927.[9] In every instance, animals with alkali or acid burns that were washed with water survived longer than animals treated with chemical neutralizers. The striking difference between the results of these two treatment methods is attributed to the additional trauma of the heat generated by the neutralization reaction superimposed on the existing burn. Although the same effect may occur when certain chemicals come in contact with water, large volumes of water tend to limit this exothermic reaction. Scientists are beginning to question the belief that neutralization of an alkaline burn of the skin with acid does, indeed, increase tissue damage because of the exothermic nature of acid-based reactions.[10] In experimental studies in animals, surgeons demonstrated that topical treatment of alkaline burns with a weak acid such as 5% acetic acid (i.e., household vinegar) resulted in rapid tissue neutralization and reduction of tissue injury in comparison with water irrigation alone. The observed benefits of treating alkaline burns with 5% acetic acid in the rat model are significant and require clinical testing.

Ocular Injury Acid and alkali injuries involving the eye are among the most disastrous of chemical burns.[4] Alkali substances are the most toxic chemicals, and anhydrous ammonia appears to be the worst offender. Even alkali burns that seem to be mild can result in devastating injury because alkalis tend to react with the lipid in the corneal epithelial cells to form a soluble soap that penetrates the corneal stroma. The alkali moves rapidly through the stroma and the endothelial cells to enter the anterior chamber. Anhydrous ammonia can penetrate into the anterior chamber in less than 1 minute. Alkali usually kills each tissue layer of the anterior segment of the eye that it touches. The result is occlusive vasculitis about the corneoscleral limbus, which makes repair of these tissues difficult. As the tissues of the anterior segment of the eye degenerate, perforation follows, with the development of endophthalmitis and loss of the eye. If perforation can be prevented, recovery of sight may be possible through eventual corneal transplantation. Experimental studies conclude that the destruction of corneal stroma can be minimized by drug therapy (e.g., N-acetylcysteine, steroids).[4] However, drug therapy has limited therapeutic usefulness because of the need for frequent applications, the significant number of clinical failures, and the potential side effects. The eye tolerates acid burns better than alkali burns because, as with other living tissue, this organ has a significant acid-buffering capacity. Acid is rapidly neutralized by the tear film, the proteins present in tears, and the conjunctival epithelial cells. Consequently, acid typically causes epithelial and basement membrane damage but rarely damages deep endothelial cells. Acid burns that injure the periphery of the cornea and conjunctiva often heal uneventfully, leaving a clear corneal epithelium. In contrast, acid burns of the central

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part of the cornea may lead to corneal ulcer formation with neovascularization and scarring, requiring later reconstruction.

Irrigation Regardless of the nature of the chemical involved, immediate institution of copious irrigation is most important. At the scene of injury the victim should submerge the eyes in tap water and continuously open and close them. In the emergency department, hydrotherapy is most easily accomplished by using a low-flow stream of 0.9% sodium chloride from intravenous (IV) tubing. Topical anesthetic agents help improve patients' cooperation. Irrigation should then continue until the pH of the conjunctival sac returns to its physiologic level (pH 7.4). The initial slit-lamp examination of alkali burns often reveals corneal erosion, swelling of the corneal epithelium, and clouding of the anterior chamber. All eyes that demonstrate a corneal abrasion should be treated with an emollient broad-spectrum antibiotic ointment instilled in the conjunctival sac (e.g., chloramphenicol, gentamicin). Ophthalmologic consultation and close follow-up are warranted in all significant exposures, and hospitalization for continuous irrigation may occasionally be required. Measurement of intraocular pressure should be performed serially to detect any pressure increases. The injured eye should be treated with a long-acting cycloplegic, a mydriatic, and occasionally a carbonic anhydrase inhibitor for 2 weeks or until the pain disappears. This treatment decreases the potential for pupillary constriction, increased intraocular pressure, and early glaucoma. The mobility of the globe should be encouraged to avoid the development of conjunctival adhesions (symblepharon). Amniotic membrane patching has been demonstrated to be useful for achieving a desirable outcome for acute ocular chemical burns.[] The human placenta was obtained shortly after elective cesarean delivery from a donor mother. Human immunodeficiency virus, hepatitis virus type B, hepatitis virus type C, and syphilis were serologically excluded. Temporary amniotic membrane patching with modifications in suture placement was performed in patients with acute chemical injury. Clinical results suggest that immediate amniotic membrane patching is quite useful for managing moderately severe acute ocular chemical injury by facilitating rapid epithelialization and pain relief and by securing ocular surface integrity.

Hydrofluoric Acid During 1985 and 1986, the AAPCC Data Collection System received 2367 reports of human exposures to hydrofluoric acid (HF). Four fatalities occurred, three from ingestion and one as a result of dermal exposure. Significant local and systemic toxicity can result from exposure of eye, skin, or lung to HF.

Inhalation Injury Inhalation of HF vapor is rare and usually involves explosions that produce fumes or high concentrations of liquid HF (>50%) that has soaked the clothing of the upper body.[13] Patients' outcomes vary considerably depending on the concentration and duration of exposure to HF. Inhalation and skin exposure to 70% HF have caused pulmonary edema and death within 2 hours.[10] Pulmonary injuries that are not evident until several days after exposure can also occur. Although the patient has no respiratory symptoms and a normal chest radiograph initially, massive purulent tracheobronchitis that is refractory to treatment may develop. Respiratory symptoms may persist for months after inhalation of HF fumes. Sustained irritation of the larynx and pharynx with fibrinous, granulating deposits on thickened vocal cords may cause a persistent cough and hoarseness. After the patient is removed from the source, the clothes and skin should be decontaminated. If respiratory symptoms are present, the patient should be monitored with pulse oximetry, receive humidified oxygen using a nonrebreathing reservoir bag-mask system, and be evaluated for laryngeal edema, pneumonitis, pulmonary edema, pulmonary hemorrhage, and systemic toxicity. The treatment of HF inhalation injury is primarily symptomatic. Administration of 2.5% to 3% calcium gluconate solution by nebulizer as a therapy for inhalation of HF has been suggested but not tested.[14] Asymptomatic patients with possible HF inhalation should be admitted for observation.

Ocular Injury Exposure of the eye to HF vapors produces more extensive damage than that of other acids at a similar concentration. The extent of damage by HF depends on its concentration. Exposure of rabbits to 0.5% HF caused mild initial conjunctival ischemia that resolved in 10 days.[15] Exposure to 8% HF caused severe initial ischemia that was still noted after 65 days. Corneal opacification and necrosis followed exposure to 20% HF.

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Immediate and copious irrigation of the exposed eyes should be initiated at the scene of exposure and continued for at least 30 minutes during transport to the emergency department, where an ophthalmologic examination can be performed promptly.[16] Local ophthalmic anesthetic drops enhance patients' comfort and cooperation during irrigation and evaluation. In experimental animals, single irrigations with 1 L of water, isotonic saline, or magnesium chloride are the only treatments that have been found to be therapeutically beneficial without causing toxicity.[15] Benefits include decreased epithelial loss and reduced corneal inflammation. Repeated irrigations over time have no therapeutic merit and are associated with an increased occurrence of corneal ulceration. Patients with significant ocular exposure to HF should be seen immediately by an ophthalmologist.

Skin Injury A large number of personnel in industry and research handle concentrated solutions of HF. Relatively dilute solutions of HF (0.6% to 12%) are available to the public in the form of rust removal and aluminum cleaning products. During handling of containers containing HF, contamination of inadequately protected fingers and hands often results in a chemical burn injury. HF skin burns have distinct characteristics. The exposure causes progressive tissue destruction; intense pain can be delayed for hours but can persist for days if untreated. The skin at the site of contact develops a tough, coagulated appearance. Untreated sites progress to indurated, whitish, and blistered vesicles that contain caseous, necrotic tissue. In exposure of the digits, HF has a predilection for subungual tissue. Severe untreated burns may progress to full-thickness burns and may even result in the loss of digits.

Initial Care The initial treatment of HF skin exposure is immediate irrigation with copious amounts of water for at least 15 to 30 minutes. Most exposures to dilute solutions of HF respond favorably to immediate irrigation. Severe pain or any pain that persists after irrigation denotes a more severe burn that requires detoxification of the fluoride ion. Detoxification is accomplished by promoting the formation of an insoluble calcium salt. All blisters should be removed because necrotic tissue may harbor fluoride ions. The fluoride ion can then be detoxified through topical treatment, local infiltrative therapy, or intra-arterial infusion of calcium. Calcium gluconate (2.5%) gel is the preferred topical agent.[17] Because skin is impermeable to calcium, topical treatment is effective only for mild, superficial burns. Because this gel is not stocked in most hospital pharmacies, it must be formulated by mixing 3.5 g of calcium gluconate powder in 150 mL of a water-soluble lubricant (e.g., glycerin–hydroxyethyl cellulose [K-Y] jelly). The gel should be secured by an occlusive cover (e.g., powder-free latex glove).

Infiltration Therapy Subcutaneous. Infiltrative therapy is necessary to treat deep and painful HF burns. Calcium gluconate is the agent of choice and can be administered by either direct infiltration or intra-arterial injection. A common technique involves injecting 10% calcium gluconate subcutaneously through a 30-gauge needle at a maximum dose of 0.5 mL/cm[2] of skin.[18] Using 5% calcium gluconate, by diluting the solution with an equal amount of isotonic saline, has been shown to reduce irritation of tissues and decrease subsequent scarring.[17] Patients treated in this manner should be hospitalized for observation and toxicologic consultation. Despite its wide acceptance, notable disadvantages are present with the infiltration technique, especially when treating digits. A regional nerve block is recommended because the injections may be very painful. Removal of the nail to expose the nail bed is required if subungual tissue is involved. Vascular compromise can occur if excessive fluid is injected into the skin exposure sites, and unbound calcium ions have a direct toxic effect on tissue. Because of these disadvantages with subcutaneous infiltration, intra-arterial infusion of calcium is being used more often.

Intra-arterial. An intra-arterial catheter is placed in the appropriate vascular supply close to the site of HF exposure (e.g., radial, ulnar, or brachial artery). Various dilute solutions of calcium salts have been infused over 4 hours, including (1) a 10-mL solution of 10% calcium gluconate or calcium chloride mixed in 40 to 50 mL of 5% dextrose in water (D5W), repeated if pain returns within 4 hours; (2) a 10-mL solution of 20% calcium gluconate in 40 mL of normal saline for radial or ulnar artery infusion; and (3) 20 mL of 20% calcium gluconate in 80 mL of normal saline for brachial artery infusion, repeated at 12-hour intervals if needed.[] If more than 6 hours have elapsed since the time of HF exposure, tissue necrosis cannot be prevented, even

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though pain relief can occur up to 24 hours after exposure. The intra-arterial infusion technique also has potential disadvantages. Arterial spasm or thrombosis may result in significant skin loss. The intra-arterial procedure is more costly because it requires hospitalization for use of the infusion pump and monitoring of serum calcium if repeated infusions are used.

Systemic Toxicity HF binds calcium and magnesium with strong affinity. Systemic fluoride toxicity, including dysrhythmias and hypocalcemia, can result from ingestion, inhalation, or dermal exposure to HF.[21] Consequently, patients with significant HF exposure should be hospitalized and monitored for cardiac dysrhythmias for 24 to 48 hours. Hypocalcemia can occur after significant exposures to HF and should be corrected with 10% calcium gluconate administered IV. If left untreated, a burn caused by 7 mL of 99% HF can theoretically bind all available calcium in a 70-kg person. A prolonged QT interval on the electrocardiogram (ECG) is a reliable indicator of hypocalcemia.

Formic Acid Formic acid is a caustic organic acid used in industry and agriculture.[22] It causes cutaneous injury by coagulation necrosis. Systemic toxicity occurs after absorption and is manifest by acidosis, hemolysis, and hemoglobinuria. Hemolysis is the result of the direct effect of formic acid on the red blood cells. Copious wound lavage should be instituted immediately. Acidosis should be treated by sodium bicarbonate. Mannitol may be used to expand plasma volume and promote osmotic diuresis in patients with hemolysis. Exchange transfusions and hemodialysis may be needed in patients with severe formic acid poisoning.

Anhydrous Ammonia Ammonia is used in the manufacture of explosives, petroleum, cyanide, plastic, and synthetic fibers.[] It is also widely used as a cleaning agent and as a coolant in refrigerator units. As an agricultural fertilizer, ammonia is ideal because of its high nitrogen content (82%). The sudden release of liquid ammonia can cause injury through two different mechanisms. It has an extremely low temperature (−33°C) and freezes any tissue it touches. Ammonia vapors readily dissolve in the moisture in skin, eyes, oropharynx, and lungs to form hydroxyl ions, which cause chemical burns through liquefaction necrosis. The severity of injury is directly related to the concentration of and duration of exposure to ammonia. Treatment consists of prompt irrigation of the eyes and skin with water and management of inhalation injury. If necessary, the airway should be secured by nasal or oral intubation. A large-diameter tube should be used to prevent distal airway obstruction from sloughing of mucosa. After intubation, lower airway injury should be managed with positive end-expiratory pressure ventilation.

Cement Cement burns are alkali burns.[25] When dry cement is combined with water, hydrolysis occurs. The resulting mixture is essentially a solution of slated lime saturated in water and initially has a pH of 10 to 12. As hydrolysis continues, the pH may continue to rise to 12 or 14, which is comparable to that of sodium or potassium hydroxide or lye. In addition, a contact dermatitis from chromate (a trace element) has been reported. The best treatment of cement burns is immediate copious irrigation until the substance is completely gone, a practice performed by the experienced worker who habitually washes off the cement throughout the day. Prominent warning labels on packages containing cement products direct the user to wear protective gloves when using the product in either its wet or dry state. Cement burns of the lower extremities respond well to immediate copious irrigation followed by coverage with a medicated bandage (e.g., Gelcast Unna's boot) that allows the patient to ambulate.

Phenol and Derivatives Phenols are used industrially as starting materials for many organic polymers and plastics. They are used widely in the agricultural, cosmetic, and medical fields. Because of their antiseptic properties (first appreciated by Lister), they are used in many commercial germicidal solutions. A number of phenol derivatives (e.g., hexylresorcinol, resorcinol) are more bactericidal than phenol itself.

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Phenol is an aromatic acidic alcohol. This compound and its derivatives are highly reactive, corrosive contact poisons that damage cells by denaturing and precipitating cellular proteins. Their characteristic odor usually signals their presence. After penetrating the dermis, phenol produces necrosis of the papillary dermis. This necrotic tissue may temporarily delay its absorption. Therefore, when skin comes in contact with phenol, treatment must be instituted immediately. The exposed area should be irrigated with large volumes of water delivered under low pressure. Because dilute solutions of phenol are more rapidly absorbed through skin than concentrated solutions, gentle swabbing of the skin surface with sponges soaked in water should be avoided. Because phenol may become trapped in the victim's hair or beard, any hair that has come into contact with the chemical agent should be removed as soon as possible. In animal studies, exposure to as little as 0.625 mg/kg of phenol causes death.[6] In humans, absorbed phenol causes profound CNS depression, resulting in coma and death from respiratory failure. Marked hypotension may occur as a result of central vasomotor depression in addition to a direct effect on the myocardium and small blood vessels. Phenol is also a powerful antipyretic that decreases body temperature. Metabolic acidosis may result from shock as well as from the direct effect of the acidic phenol. A number of substituted phenols (e.g., resorcinol, picric acid) have systemic actions distinct from those of phenol. CNS stimulation often occurs after absorption of resorcinol. Picric acid hemolyzes red blood cells and causes acute hemorrhagic glomerulonephritis and liver injury. Dilute solutions of phenol are used by plastic surgeons for chemical face peels.[26] Phenol (which is usually mixed with water, soap, and croton oil for this application) can produce a partial-thickness burn of predictable depth in a controlled manner. It has been the standard for many years for new technologies in skin resurfacing to remove both coarse and fine wrinkles, irregular pigmentation, and actinic keratoses. The concentration of phenol is kept sufficiently low to reduce the occurrence of systemic complications. Interestingly, higher concentrations of phenol result in a shallower burn depth. A higher concentration of phenol results in increased coagulation of the keratin in the skin, thus forming a barrier to further penetration. Histologic studies have demonstrated that 100% concentrations of phenol produce 35% to 50% less penetration than a 50% phenol solution. The physician performing phenol chemical peels should be concerned about the possibility of rapid phenol absorption. When phenol was applied to more than 50% of the facial surface in less than 30 minutes, a high incidence of cardiac arrhythmias was reported. When the application time over the same area was increased to 60 minutes, arrhythmias were avoided. Because of the complication of cardiac arrhythmias, all patients undergoing phenol peeling should be monitored electrocardiographically and have an IV line in place. After application of the phenol solution, the skin is covered with an occlusive dressing consisting of either multiple layers of waterproof tape or petroleum jelly to prevent evaporation of the phenol, allowing increased penetration and burn depth. The peeled skin is maintained by daily cleansing and consequent reapplication of ointment, which keeps the surface moist and prevents desiccation. If this protocol is followed, healing is completed within 5 to 7 days.

Polyethylene Glycol Therapy Experimental studies indicate that water alone is effective in reducing the severity of burns and preventing death in animals with skin exposed to phenol and its derivatives. However, the most effective treatment is undiluted polyethylene glycol (PEG) of molecular weight 200 to 400 or isopropanol (isopropyl alcohol). PEG should be stocked in hospitals located near areas of phenol use and can often be found in the chemical section of hospital pharmacies. A quick wipe of the skin with PEG solutions reduces mortality and burn severity in experimental animals. These solutions can be used in phenol burns of the face because they are not irritating to the eyes. Decontamination with water should be performed until a PEG solution is obtained. Large amounts of water must be used because small amounts of water are detrimental, enhancing dermal absorption of phenol. Removal of the phenol should be undertaken in a well-ventilated room so that hospital personnel are not exposed to high concentrations of phenol fumes.

Systemic Toxicity The treatment of systemic symptoms is purely symptomatic. Respiratory depression may require ventilatory support. Hypotension should be treated with isotonic crystalloid fluid and pressor agents as needed. Metabolic acidosis may require treatment with sodium bicarbonate. Alkalinization also prevents precipitation of hemoglobin in the urine that occurs with hemolysis. Hemochromogen excretion in the urine can be enhanced by administering IV mannitol, which causes an osmotic diuresis. Anticonvulsants may be required to treat seizures resulting from CNS stimulation.

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White Phosphorus White phosphorus is a yellow, waxy translucent solid element that burns in the air unless preserved in oil.[6] When it ignites spontaneously in air, it is oxidized to phosphorus pentoside, which forms metaphosphoric and orthophosphoric acids with the addition of water. The capability of phosphorus to ignite spontaneously in air at temperatures greater than 34°C (93.2°F) has encouraged its use as an incendiary agent in military weapons and fireworks. After the explosion of a phosphorous munition, flaming droplets may become embedded beneath the skin, where they oxidize adjacent tissue unless removed. In nonmilitary industry, white phosphorus is used in the manufacture of insecticides, rodent poisons, and fertilizers. Tissue injury from white phosphorus appears to be caused primarily by heat production rather than by liberation of inorganic acids or cellular dehydration from the hygroscopic phosphorus pentoside. The ultimate result of this thermal injury is often a painful partial-thickness or full-thickness burn. Metabolic derangements have been identified after white phosphorus burns. Serum electrolyte changes consist of decreased serum calcium and increased serum phosphorus. ECG abnormalities include prolonged QT interval, bradycardia, and ST segment–T wave changes. These ECG changes may explain the sudden early death occasionally seen in patients with apparently inconsequential white phosphorus burns. Prehospital care includes immediate removal of contaminated clothing followed by submersion of the injured skin in cool water. Warm water should be avoided because white phosphorus becomes a liquid at 44°C (111.2°F). Phosphorus particles should be removed from the victim's skin and submerged in water. The burned skin should be covered with towels soaked in cool water during transport to the emergency department. After the patient's arrival in the emergency department, the burned skin should be washed with a suspension of 5% sodium bicarbonate and 3% copper sulfate in 1% hydroxyethyl cellulose. (This must be made by hospital pharmacies.) Phosphorus particles become coated with black cupric phosphide, allowing their easy identification. Copper sulfate also decreases the rate of oxidation of the phosphorus particles, limiting their damage to the underlying tissue. However, blackened particles can still elicit tissue injury and should be removed. If absorbed systemically, copper sulfate is toxic. Absorption of copper sulfate can be minimized by the surface-active agent in the suspension as well as by sodium lauryl sulfate. Before the advent of these agents, prolonged treatment of phosphorus burns with copper sulfate solutions led to systemic copper poisoning, which is manifested by vomiting, diarrhea, hemolysis, oliguria, hematuria, hepatic necrosis, and cardiopulmonary collapse. After the burned skin is subjected to a suspension of copper sulfate for 30 minutes, the antidote must be thoroughly washed from the skin. This washing limits the development of systemic copper toxicity. An alternative approach is to use a Wood's lamp to identify the phosphorus particles because they fluoresce under ultraviolet light. After hydrotherapy and treatment with the appropriate antidote, definitive management of the skin burns in the hospital intensive care unit setting is accomplished as with any other burn wound.

Nitrates Toxic methemoglobinemia is a well-recognized hazard of ingestion of nitrates and nitrites.[27] Occasionally, severe methemoglobinemia has been reported in patients sustaining burn injury from molten sodium and potassium nitrates. In these cases, methemoglobinemia is caused by absorption of nitrates through burned skin. The diagnosis of methemoglobinemia should be sought in a cyanotic patient who is unresponsive to oxygen therapy and whose blood appears chocolate brown in color. Methemoglobin levels less than 20% to 30% are usually asymptomatic and require no treatment. Patients with levels greater than 30%, with or without symptoms, should be treated by high-flow oxygen and IV methylene blue administered slowly at a dose of 1 to 2 mg/kg body weight. Exchange transfusions may also benefit severe cases by rapidly decreasing circulating methemoglobin concentration.[28]

Hydrocarbons Cutaneous injury from immersion in gasoline and other hydrocarbons may occur in individuals involved in motor vehicle accidents. The solvent properties of hydrocarbons cause cell membrane injury and dissolution of lipids, resulting in skin necrosis. Although full-thickness injuries can occur, most injuries are partial thickness.[29] Once the gasoline damages the protective skin barrier, the hydrocarbons are absorbed. The absorption of hydrocarbons produces systemic toxicity that causes neurologic, pulmonary, cardiovascular, gastrointestinal, and hepatic injuries.[30]

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Treatment of individuals exposed to gasoline includes immediate removal from the site of exposure, removal of all clothing, copious irrigation, and transfer to the emergency department while continuing copious irrigation. Management in the emergency department consists of wound care of burn injuries and a search for evidence of systemic toxicity.

Tar Burns from hot tar are a challenging clinical problem. Hot liquefied tar that comes in contact with skin transfers heat to cause burn injury. Tar then cools and solidifies on the skin surface, making removal difficult. Hot tar includes two distinct groups of materials: coal tar pitches and petroleum-derived asphalts. Both products are heated to maintain liquid form. Paving roads requires tar temperatures from 275°F to 300° F, and roofing demands higher tar temperatures of 450°F to 500° F. Deeper burn injuries are associated with burns from roofing asphalt. Mechanisms of injury include cauldron explosion, falling from buildings, trucks rolling over, pipe explosion, spillage from buckets, and industrial accidents. When hot tar touches skin, it rapidly cools, solidifies, and becomes enmeshed in the hair. It is important to facilitate this cooling process by adding cold water to the tar at the scene of the accident. Cooling tar with cold water limits the amount of tissue damage and prevents the spread of tar. Tar should be continually washed with water until it has cooled and hardened. After cooling, the skin should be dried with towels to prevent systemic hypothermia. Adherent tar should not be removed at the scene of the accident. In the emergency department, definitive care of tar burn injury involves early removal of tar because it occludes injured skin and encourages bacterial growth. This can convert a partial-thickness burn to a full-thickness burn. Tar adheres to skin because it is enmeshed in the hair, not because of a direct bond between epidermis and tar. Solvents used to remove tar ideally should have a close structural affinity to tar. Asphalts are susceptible to both aromatic (e.g., naphthalene) and aliphatic (e.g., hexade) hydrocarbon solvents; coal tars are susceptible only to aromatic hydrocarbons. The cleansing capacity of these solvents is enhanced by prolonged contact with tar. Broad-spectrum antibiotic ointments such as bacitracin (400 U/g), polymyxin B (5000 U/g), and neomycin (5 mg/g) may be added to lower the incidence of infection. Antimicrobial petrolatum ointments should be removed and reapplied every hour until all tar is removed. The process of tar removal usually takes 12 to 48 hours. Antibiotic ointment has been used successfully to remove even tar layered over corneas and conjunctivas. An alternative to petrolatum ointments is surface-active agents, such as polyoxyethylene sorbitan (Tween 80) and polysorbate (De-Solv-It). These are more water soluble and more easily removed from skin with water than petrolatum ointments. These surface-active agents are an effective, safe, and inexpensive means of removing tar from skin. NISA baby oil, sunflower oil, mayonnaise, and butter have also been used to remove adherent tar from skin, taking from 30 to 90 minutes for complete removal. Sunflower oil has proved effective and safe in removing tar without further skin damage.

Elemental Metals The elemental metals sodium and potassium are harmless unless activated by water, which causes an exothermic reaction with the release of heat and the generation of hydrogen gas and hydroxide.[31] The evolved heat is sufficient to ignite the hydrogen gas, which results in greater heat and additional thermal burns. The formation of the hydroxide compound may also result in significant chemical injury to tissue. The reaction occurs more rapidly with elemental potas-sium than with sodium. These deleterious effects of potassium have been attributed to trace amounts of potassium superoxide released on exposure to room air. Water lavage is therefore dangerous in these circumstances. In the prehospital setting, only a class D fire extinguisher (containing sodium chloride, sodium carbonate, or graphite base) or sand should be used to suppress the flames. When the fire is extinguished, the metal is covered by oil (e.g., mineral, cooking), which isolates the metal from water. The patient should be transported to the emergency department for wound debridement and cleansing. Small pieces of metal should be removed from the skin. Sodium fragments should be placed in isopropyl alcohol, containing no more than 2% water, whereas potassium particles should be inserted into terbutyl alcohol for safe deposit.

CHEMICAL TERRORISM The reality of chemical agents as terrorist weapons is a part of news, public policy, and medical preparedness. The sarin gas attack in the Tokyo subway in March 1995 resulted in 12 deaths and more than 5000 casualties.[32] It was subsequently learned that the responsible cult, Aum Shinrikyo, had stored enough of the potent nerve gas, VX, to kill up to 4 million people. In addition, these agents continue to be used in

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modern warfare, despite being banned by the 1925 Geneva Convention. The Iraqi army used sulfur mustard and nerve gases extensively and caused mass casualties in their 6-year war with Iran.[33] As terrorist organizations begin to use nonconventional weapons such as chemical and biologic agents, the civilian medical community needs to better understand their characteristics and pathophysiology.

Response The U.S. federal government recognizes the emerging threat of terrorism and the potential of these organizations to use nonconventional weapons. In 1997 the U.S. Congress enacted the Defense Against Weapons of Mass Destruction Act, with a $52.6 million appropriation.[34] Subtitle A of this document established the Domestic Preparedness Program to enhance the government's capability to respond to terrorist attacks with these weapons. The act also focuses on improving local and state agencies to address these threats and to train communities. The government's direct response was delineated in Presidential Decision Directive 39 (PDD-39), signed by President Clinton in 1995.[35] For all cases of domestic terrorism, the Federal Bureau of Investigation (FBI) is assigned to oversee crisis management and to investigate the case for eventual prosecution. The Federal Emergency Management Agency (FEMA) is to coordinate assistance to state and local governments, provide emergency relief, and protect public health and safety. The sophisticated operations necessary to deal with a large-scale chemical attack could overwhelm local HAZMAT teams, and thus other agencies have been designated to provide operational support, including the U.S. Departments of Defense, Energy, and Transportation and the Environmental Protection Agency. Appropriate casualty triage remains a critical component when dealing with nonconventional weapons. Overall death rates increase when triage systems are poorly coordinated.[36] Triage should be performed by specially trained emergency medical personnel who are familiar with these agents and with the use of personal protective equipment (PPE). The emergency department could be quickly overwhelmed with masses of noncritically injured survivors. Ideally, triage would be conducted both at the scene of the attack and again at a second point before emergency department arrival.

Emergency Department Preparedness Once in the emergency department, noncritical victims should be rapidly removed from the acute setting. Steps should be taken to ensure that other patients and staff are not secondarily exposed. For those directly handling the casualties, PPE such as full-face respiratory masks, SCBAs, and impermeable suits should be available.[37] The use and location of decontamination showers should be well known, and negative flow isolation rooms should be available. A surveillance system should be established to identify groups at high risk and to evaluate medical interventions. Many of these agents can cause long-term adverse heath outcomes, and registries should be established to facilitate appropriate follow-up.

Chemical Agents Chemical agents can be classified as (1) blistering agents, (2) nerve agents, (3) choking gases, or (4) cyanide agents ( Table 61-1 ). Blistering agents, such as sulfur mustard, have been regarded as the chemical weapon of choice in modern warfare. First used in World War I, sulfur mustard is often referred to as the “king of war gases” because of its ability to incapacitate opponents.[38] Nerve agents, such as sarin gas, have been receiving increasing public attention. The first nerve gas synthesized was tabun, and although it was developed in Germany before World War II, it was not documented for military purposes until the Iraqis used the agent in the 1980s.[33] Choking gases, such as phosgene, were first developed during World War I. Phosgene is also used extensively in the industrial setting for the preparation of polyurethanes.[ 39] Cyanide agents, such as hydrogen cyanide, were first discovered in the 18th century by the Swedish chemist Carl Wilhelm Scheele.[40] Although Scheele gave no indication of its lethal characteristics, hydrogen cyanide has become one of the most toxic chemicals known, with potential deadly consequences if used by a terrorist organization. Table 61-1 -- Classification of Chemical Warfare Agents Class

Example

Blistering agents

Sulfur mustard

Treatment Hydr other apy

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Class

Example

Treatment Pun cture and drain blist ers Mois t dres sing s 100 %O 2 if inhal ed Hydr other apy follo wed by antib ioticbase d stero id oint ment for ocul ar injur y

Nerve agents Sari n Tabu n VX

Choking gases Cyanide agents

Phosgene Hydrogen cyanide

Atro pine Prali doxi me (Prot opa m) Supportive care Amyl nitrit e Sodi um nitrit e 100 %O 2

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Blistering Agents Sulfur mustard is a vesicant and alkylating agent known by various names, including mustard gas, Yperite, and HD.[41] It is a bifunctional alkylating agent that can form covalent bonds, resulting in direct damage to DNA. It causes severe vesication of the skin, and at high doses it exerts systemic cytotoxic effects on the hematologic system and intestinal mucosa. Sulfur mustard is stored as an oil-based liquid and is readily aerosolized when attached to a bomb or shell. Because it is slowly vaporized, it poses a particular risk in closed-space or cool environments. Several minutes of exposure result in skin or eye injury, and exposure for longer than 30 minutes can lead to respiratory injury and death. No specific antidote exists for mustard gas. The most effective therapy is rapid decontamination with water and supportive care. All blisters should be opened and covered with moist dressings. Eyes should be irrigated with water for at least 5 minutes. A mydriatic agent should be applied and topical antibiotic therapy instituted. Tetanus prophylaxis is mandatory. Inhalation injury requires the use of 100% oxygen and additional supportive measures.

Nerve Agents The nerve agents, such as sarin and tabun, are members of the class of agents known as organophosphates.[41] These are among the most potent synthetic toxic agents known, and submilligram doses are lethal in mice. These agents tend to be odorless and are irreversible cholinesterase inhibitors. Metabolism of acetylcholine at the nerve endings is blocked, leading to a toxic buildup of this neurotransmitter and eventually paralysis. Complications include seizures, respiratory failure, pulmonary edema, and hypotension. Nerve agents are rapidly absorbed through the skin and pulmonary membranes, with a rapid onset of action. Symptomatic relief can be provided with atropine. Because it is an irreversible inhibitor of acetylcholine, pralidoxime is given and serves to reactivate the enzyme cholinesterase. Atropine must be given repeatedly until the agent has been completely metabolized (several hours to days).

Choking Agents Phosgene is the most common type of choking agent and has been used in warfare.[42] Phosgene has a characteristic odor of freshly mown grass or moldy hay, which may assist in the diagnosis. This class causes pronounced irritation of the upper and lower respiratory tracts. Coughing, tearing, shortness of breath, and chest pain are common symptoms. Pulmonary edema can result, with onset often several hours after exposure. Most patients, however, recover without long-term effects, although secondary bacterial pneumonia has been reported. Treatment for exposure to these agents remains supportive, with oxygen supplementation as required.

Cyanide Cyanide, or hydrocyanic acid, interferes with aerobic metabolism, and death may occur within minutes of exposure.[42] When cyanide is absorbed, it reacts with the trivalent iron of cytochrome oxidase in mitochondria. Because the utilization of oxygen is blocked, venous blood is highly oxygenated and may appear as red as arterial blood. Initially, hyperpnea and headache occur, but ultimately, hypoxic convulsions and respiratory arrest result in death. Thus, rapid diagnosis and treatment are essential. A characteristic odor of bitter almonds is noted. To treat cyanide poisoning, amyl nitrite is given in the inhaled form, and sodium nitrite is administered IV (10 mL of a 3% solution). These substances oxidize hemoglobin to methemoglobin, which competes favorably with cytochrome oxidase for the cyanide ion, allowing reactivation of normal cellular respiration. Hyperbaric oxygen therapy potentiates the effects of nitrites and is clinically useful.[38]

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KEY CONCEPTS {, {,

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Chemical injury: The degree of skin destruction is determined mainly by the concentration of the toxic agent and the duration of its contact. Chemical injuries are commonly encountered after exposure to acids and alkalis, including hydrofluoric acid, formic acid, anhydrous ammonia, cement, and phenol. Other specific chemical agents that cause chemical burns include white phosphorus, elemental metals, nitrates, hydrocarbons, and tar. More than 65,000 chemicals are available on the market, and an estimated 60,000 new chemicals are produced each year. Hazardous materials (HAZMATs) are substances that can cause physical injury and damage the environment if improperly handled. Hazardous materials: In dealing with HAZMAT incidents, two distinct goals must be achieved: (1) the HAZMAT must be contained, fire and explosions must be extinguished, and the site must eventually be cleaned and (2) those exposed to the HAZMAT must be treated. For more than 30 years, Chemtrec (Chemical Transportation Emergency Center) has been providing the crucial information needed to assist emergency response personnel in handling HAZMAT incidents in the safest possible manner. When calls for help come in, Chemtrec's specialists provide immediate assistance and can link emergency responders in the field with shippers or product manufacturers. The management of chemical injuries must be individualized for the specific chemical and continue from the time of injury to rehabilitation. Terrorism: Nonconventional chemical weapons may be placed into four major classifications: blistering agents, nerve agents, choking gases, and cyanide agents.

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REFERENCES 1. Hall HI, Dhara VR, Price-Green PA, Kaye WE: Surveillance for emergency events involving hazardous substances—United States, 1990-1992. MMWR CDC Surveill Summ1994;43(SS-2):1. 2. Litovitz TL, Normann S, Veltri JC: 1985 annual report of the American Association of Poison Control Centers National Data Collection System. Am J Emerg Med1986;5:405. 3. Litovitz TL, Martin TG, Schmitz B: 1986 annual report of the American Association of Poison Control Centers National Data Collection System. Am J Emerg Med1987;5:405. 4. Rodeheaver GT, Hiebert JM, Edlich RF: Initial treatment for chemical skin burns and eye burns. Comp Ther1982;8:37. 5. Binder S: Deaths, injuries, and evacuations from acute hazardous materials release. Am J Public Health 1989;79:1042. 6. Kirk MA, Cisek J, Rose SR: Emergency department response to hazardous vehicle incidents. Emerg Med Clin North Am1994;12:461. 7. DeAtley C: Hazardous materials exposure mandates integrated patient care. Occup Health Saf 1991;60:40. 8. Plante DM, Walker JS: EMS response at a hazardous material incident: Some basic guidelines. J Emerg Med1989;7:55. 9. Davidson EC: The treatment of acid and alkali burns. Ann Surg1927;35:481. 10. Andrews K, Mowlavi A, Milner M: The treatment of alkaline burns of the skin by neutralization. Plast Reconstr Surg2003;6:1918. 11. Sridhar MS, Bansal AK, Sangwan VS, Rao GN: Amniotic membrane transplantation in acute chemical and thermal injury. Am J Ophthalmol2000;130:134. 12. Kobayashi A: Temporary amniotic membrane patching for acute chemical burns. Eye2003;17:149. 13. Mayer L, Guelich J: Hydrogen fluoride inhalation and burns. Arch Environ Health1963;7:445. 14. Trevino MA, Herrmann GH, Sprout WL: Treatment of severe hydrofluoric acid exposures. J Occup Med 1983;25:861. 15. McCulley JP: Hydrofluoric acid burns of the eye. J Occup. Med1983;25:447. 16. Caravati EM: Acute hydrofluoric acid exposure. Am J Emerg Med1988;5:143. 17. Mackinnon MA: Treatment of hydrofluoric acid burns. J Occup Med1986;28:804. 18. Dibbell DG: Hydrofluoric acid burns of the hand. J Bone Joint Surg Am1970;52:931. 19. Vance MV: Digital hydrofluoric acid burn treatment with intra-arterial calcium infusion. Ann Emerg Med 1988;15:890. 20. Kohnlein HE, Merkle P, Springorium HW: Hydrogen fluoride burns: Experiments and treatment. Surg Forum1973;24:50. 21. Reynolds KE, Whitford GM, Pashley DH: Acute fluoride toxicity: The influence of acid-base status. Toxicol Appl Pharmacol1978;45:415. 22. Sigurdsson J, Bjornsson A, Gudmundsson ST: Formic acid burns: Local and systemic effects. Burns 1983;9:358. 23. Birken GA, Fabri PJ, Carey LC: Acute ammonia intoxication complicating multiple trauma. J Trauma 1981;21:820. 24. Arwood R, Hammond J, Ward GG: Ammonia inhalation. J Trauma1983;25:444. 25. Pike J, Patterson Jr JrA, Arons MS: Chemistry of cement burns: Pathogenesis and treatment. J Burn Care. Rehabil1988;9:258. 26. Stuzin JM: Phenol peeling and the history of phenol peeling. Clin Plast Surg1998;25:1. 27. Harris JC, Rumack BH, Peterson RG, McGuire BM: Methemoglobinemia resulting from absorption of nitrates. JAMA1979;242:2869. 28. Kirby NG: Sodium nitrate poisoning treated by exchange transfusions. Lancet1955;1:594. 29. Hansbrough JF: Hydrocarbon contact injuries. J Trauma1985;24:250. 30. Simpson LA, Cruse CW: Gasoline immersion injury. Plast Reconstr Surg1981;67:54. 31. Clare RA, Krenzelok EP: Chemical burns secondary to elemental metal exposure: Two case reports. Am J Emerg Med1988;6:355. 32. Lillibridge SR, Sidell FR: A Report on the Casualties from the Tokyo Subway Incident by the US Medical

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Team, Atlanta, Centers for Disease Control and Prevention, 1995. 33. United Nations Security Council : Report of the Specialists Appointed by the Secretary General to Investigate Allegations by the Islamic Republic of Iran Concerning the Use of Chemical Weapons (UN Report No. S/16433), New York, United Nations, 1986. 34. Department of Defense : Report to Congress: Domestic Preparedness Program in the Defense against Weapons of Mass Destruction, Washington, DC, Department of Defense, 1997. 35. Federal Emergency Management Agency : Federal Response Plan. FEMA1997;229(11): 36. Brismar B, Bergenwald L: The terrorist bomb explosion in Bologna, Italy, 1980: An analysis of the effects and injuries sustained. J Trauma1982;22:216. 37. Brennan RJ, Waeckerle JF, Sharp TW, Lillibridge SR: Chemical warfare agents: Emergency medical and emergency public health issue. Ann Emerg Med1999;34:191. 38. Borak J, Sidell FR: Agents of chemical warfare: Sulfur mustard. Ann Emerg Med1992;21:303. 39. Wyatt JP, Allister CA: Occupational phosgene poisoning: A case report and review. J Accid Emerg Med 1995;12:212. 40. Turrina S, Neri C, De Leo D: Effect of combined exposure to carbon monoxide and cyanides in selected forensic cases. J Clin Forensic Med2004;11:262. 41. Kavidar H, Adams SC: Treatment of chemical and biological warfare injuries: Insights derived from the 1984 Iraqi attack on Majnoon Island. Mil Med1991;4:171. 42. Slater MS, Trunkey DD: Terrorism in America: An evolving threat. Arch Surg1997;132:159.

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Chapter 5 – Blood and Blood Components Gwendolyn L. Hoffman

PERSPECTIVE The era of modern blood transfusion began in the early 1900s with the discovery of A, B, O, and AB blood types. The first blood bank in the United States was established in 1937.[1] Whole blood and plasma were widely used during World War II as resuscitative fluids. In the 1950s the introduction of plastic storage containers and apheresis instruments made component therapy possible. By the 1970s the use of blood components became more popular than whole blood.[2] The number of red blood cell (RBC) units transfused in the United States was 12.4 million in 2000, which was a 4% to 5% increase from 1999.[3] Increased demand for the blood supply is expected in the future because of the predicted increase in population older than 65.[4] Currently, much research is being conducted on the development of blood substitutes. The two major classes are cell-free hemoglobin solutions that approximate the oxygen-carrying capacity and oxygen delivery of cellular hemoglobin and perfluorocarbon emulsions that act as synthetic oxygen carriers. Potential advantages of these products include a prolonged shelf life, ability to be stored at room temperature, universal biocompatibility, and reduced risk of disease transmission. They will help reduce the demand for banked blood.[5]

PATHOPHYSIOLOGIC PRINCIPLES Blood Banking Blood and blood products are provided to most institutions by specific blood bank services such as the American Red Cross. These services offer centralized testing laboratories and record keeping, area-wide inventories of blood components, and simplified medical control. At the time of collection an anticoagulant-preservative of citrate, phosphate, dextrose, and adenine (CPDA-1) is added, ensuring a shelf life (viability of at least 70% of the RBCs 24 hours after infusion) of 35 days and hematocrit of 70% to 80% for packed red blood cells (PRBCs). An alternative additive solution containing higher concentrations of saline and glucose (e.g., Adsol) extends the shelf life to 42 days and decreases the hematocrit to 52% to 60%, which makes it easier to administer.[2] Even though blood must be stored and refrigerated at 1° C to 6° C (usually at 4° C), cell metabolism continues and changes occur (storage lesions). A decrease in pH causes a degree of acidosis that is effectively buffered by the metabolism of the citrate preservative. Levels of 2,3-diphosphoglycerate (2,3-DPG) also decrease, resulting in a shift of the oxyhemoglobin dissociation curve to the left. The level soon rises again and within 24 hours of infusion is usually normal and of little clinical significance. Also, deformability of RBCs causes them to become more spherical and rigid, resulting in increased resistance to flow through capillary beds. This is also corrected with transfusion.[2] The sodium-potassium adenosine triphosphatase–dependent pump also becomes less efficient, resulting in some cell leakage of potassium. In neonates and patients with renal impairment, this could result in hyperkalemia. Normally, the impact is not significant because the increased potassium load is excreted by the kidneys, absorbed by the remaining RBCs, or shifted intracellularly.[1] After 24 hours of storage, granulocytes have no functional capacity and platelets have only 50% capacity, which becomes zero by 72 hours. Levels of factor V and factor VIII also decrease.[6]

Blood Typing More than 400 RBC antigens have been identified. ABO identification and compatibility constitute the most important step of the type-and-crossmatch procedure because any incompatibility produces the most

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serious transfusion reaction, acute hemolysis. Patients who lack A or B red cell antigens have antibodies for the absent A (blood type B) or B (blood type A) antigen. Patients who lack both A and B antigens have antibodies against both A and B antigens (blood type O). Rh typing, antibody screening, and the testing of donor cells with recipient serum are also done. Antibody screening is performed with recipient serum to discover agglutinating or nonagglutinating antibodies. The antiglobulin (Coombs') test is also included.[2] The risk of disease transmission is extremely low because of the development of improved screening and testing techniques ( Table 5-1 ). Table 5-1 -- Risk of Transfusion-Transmitted Viruses Virus Risk per Unit Transferred Hepatitis B 1:58,000 to 1:149,000 Hepatitis C 1:872,000 to 1:1.7 million Human immunodeficiency virus 1:1.4 million to 1:2.4 million Data from Goodnough LT, Shander A, Brecker ME: Transfusion medicine: Looking to the future. Lancet 361:162, 2003.

Universal Donor Blood In crisis situations in which there is no time for type and crossmatch, group O universal donor blood is indicated. RBCs of type O do not have A or B antigens on their surface and therefore are not agglutinated or hemolyzed by anti-A or anti-B antibodies. Because of the relative scarcity of group O–negative blood, its use is restricted to women of childbearing age who are at risk for Rh immunization against subsequent pregnancies. Universal donor group O–positive blood is recommended in all other patients.[6]

Massive Transfusion In a patient's initial resuscitation in the emergency department, abnormalities from massive transfusion are rarely seen, but the physician should be aware of potential problems. Massive transfusion is defined as replacement of the patient's blood volume with stored RBCs in 24 hours or as a transfusion of greater than 10 units of blood over a few hours. A blood volume is estimated at 75 mL/kg or about 5000 mL in a 70-kg man.[7] In addition to storage lesion problems, hypothermia may result when patients receive more than 100 mL/min of cold blood for 30 minutes, placing them at increased risk for ventricular dysrhythmias. This can be prevented by warming the blood to 37° C with a blood warmer.[8] Transiently decreased levels of ionized calcium may result from the citrate preservative. Clinical signs of hypocalcemia include circumoral tingling, skeletal muscle tremors, and a prolongation of the QT segment of the electrocardiogram (ECG). Most normothermic adults can tolerate 1 unit of RBCs every 5 minutes without calcium supplementation. Calcium administration should be used only when the patient's ionized calcium levels drop to abnormal values or when ECG changes occur.[] Dilutional thrombocytopenia may result, but platelet concentrate is not indicated unless there is evidence of microvascular bleeding in a normothermic patient. If disseminated intravascular coagulation (DIC) develops, large doses of platelet concentrate, fresh frozen plasma (FFP), and cryoprecipitate may be required.[1]

CLINICAL FEATURES The need to administer blood component therapy in the emergency department is specific to the situation and the patient. The patient's stability and the time available before intervention is needed determine the specific product that is utilized.

Universal Donor Group O Universal donor group O is immediately available and is used when blood must be given at once to hemorrhaging, unstable patients. Women of childbearing age need group O–negative blood, and all others can receive group O–positive blood, which is more readily available.

Type and Crossmatch If the patient's condition can be initially stabilized with crystalloid infusion, type-specific blood should be available in 5 to 10 minutes. ABO grouping and Rh typing are sufficient.[7]

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Incomplete type and crossmatch take approximately 30 minutes. They involve ABO and Rh compatibility as well as screening of the recipient's serum for unexpected antibodies. An immediate “spin” crossmatch is also performed at room temperature.[6] When blood is not immediately needed, fully crossmatched blood, which takes approximately 45 minutes to process, should be used.[7]

Administration Legal Aspects Before a blood product can be infused, it must be checked at the bedside by two qualified personnel. This check includes recipient and unit identification, compatibility, and expiration.[8] The identification of the patient and the intended product prevents a potentially fatal clerical error. At times a patient may arrive from a transferring facility with type and crossmatched blood. If the blood is administered immediately in the emergency department, the hospital blood bank is not involved and accepts no responsibility for the blood. If the blood is not used immediately and the blood bank is requested to hold the blood for the patient, the blood must be processed and crossmatched as for other issued blood and quarantined for 24 hours. It can be sent back to the blood bank to have this done only if (1) it has been maintained at a temperature below 6° C, (2) all container seals are intact and have not been entered, and (3) segments have remained attached to the blood container.[8]

Infusion Adjuncts Urgent transfusion situations require flow rates faster than gravity can provide. An administration set with an in-line pump that is squeezed by hand is the simplest method to speed infusion. Pressure bags are also available that completely encase the blood bag and apply pressure evenly to the blood bag surface. If external pressure is anticipated, large-bore needles are recommended for venous access to prevent hemolysis by manually forcing RBCs through a small-gauge line.[8] If only a small-gauge needle is available, the transfusion may be diluted with normal saline (NS), but this may cause unwanted volume expansion. In elective transfusions, no significant hemolysis occurs when small-gauge needles are used and when the maximum rate of infusion is less than 100 mL/hr.[8]

MANAGEMENT Decision Making The decision to use blood component therapy must encompass the entire clinical picture. The patient's age, severity of symptoms, cause of the deficit, underlying medical condition, ability to compensate for decreased oxygen-carrying capacity, and tissue oxygen requirements must all be considered. Clinical evaluation, including appearance (pale color, pale conjunctiva, diaphoresis), mentation (alert, confused), heart rate, blood pressure, and the nature of the bleeding (active, controlled, uncontrolled), can be supplemented by laboratory evaluation of hemoglobin, hematocrit, platelets, and clotting functions.[9] Transfusions are needed if a rapid loss is greater than 30% to 40% of blood volume and if tachycardia and hypotension are not corrected by crystalloid replacement alone. Transfusion is rarely needed with a hemoglobin concentration greater than 10 g/dL and almost always needed when the hemoglobin is less than 6 g/dL.[]

Whole Blood Whole blood is not as useful and economical as component therapy. In the United States it is essentially unavailable in the emergency department.[1]

Packed Red Blood Cells PRBCs are administered for acute blood loss in an otherwise healthy patient with signs and symptoms of decreased oxygen delivery and at least two of the following: estimated or expected blood loss of 15% or more of total blood volume (750 mL in 70-kg man), hypotension, tachycardia, oliguria, and mental status changes.[1] PRBCs are also used for patients with symptomatic anemia and evidence of myocardial ischemia, including angina, shortness of breath or dizziness with mild exertion, tachycardia, and mental status changes.[12] RBCs are not indicated with a hemoglobin concentration greater than 10 g/dL (men) or 7 g/dL (women) in an otherwise stable asymptomatic patient.[1]

Fresh Frozen Plasma

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FFP is indicated for emergent reversal of warfarin therapy and correction of known coagulation deficiencies when specific concentrates are unavailable. It is also useful in DIC when prothrombin and partial thromboplastin times are greater than 1.5 times normal. Empirical use during massive transfusion when the patient does not exhibit coagulopathy is questionable. FFP is not recommended for augmentation of plasma volume or albumin concentration.[]

Platelets On occasion, a patient may receive platelets in the emergency department. They are indicated prophylactically when the count is less than 20,000/mL or less than 50,000/mL if there is oozing or a planned invasive procedure. When platelet counts are below 10,000/mm3, spontaneous bleeding is common and may be severe. Patients taking abciximab (ReoPro) who develop bleeding may require platelet transfusion.[ 13] Prophylactic platelet transfusion is ineffective when the thrombocytopenia is caused by increased platelet destruction.[] Also, no evidence indicates that prophylactic transfusion of platelets is beneficial in massive transfusion.[13]

Autotransfusion Autotransfusion may be used in the event of severe chest trauma. There is immediate availability; blood compatibility; normothermic blood; elimination of risk of patient-to-patient disease transmission; higher levels of 2,3-DPG than in stored blood; less risk of circulatory overload; fewer direct complications, such as hyperkalemia, hypocalcemia, and metabolic acidosis; and greater acceptability to some patients whose religious convictions prohibit transfusions.[] Widespread use has not occurred, however, because of the limited number of appropriate trauma patients, the training required to operate the autologous collection and reinfusion equipment, the time required for equipment setup, and the need for improving safety and availability of homologous blood.[]

Therapeutic Modalities Packed Red Blood Cells In acute hemorrhage, PRBCs are used to supplement initial crystalloid replacement. In an average adult, 1 unit of PRBCs increases the hemoglobin by about 1 g/dL or the hematocrit by about 3%. A similar increase in pediatric patients is obtained by administering 3 mL/kg.[] PRBCs must be run through a filter with a large-bore intravenous line with NS. Lactated Ringer's solution could lead to clotting secondary to the added calcium, and hemolysis may result with a hypotonic solution. From 50 to 100 mL of NS may be added for a dilutional effect to permit faster administration. Medications should never be added to the unit or pushed through the transfusion line unless it has been thoroughly flushed. Most transfusions are given over 60 to 90 minutes and no longer than 4 hours. Any excess units should be returned promptly to the blood bank because any units unrefrigerated for more than 30 minutes are discarded.[]

Fresh Frozen Plasma A unit of FFP typically has a volume of 200 to 250 mL, must be ABO compatible, and is given through blood tubing within 2 to 6 hours of thawing. It contains all clotting factors, including factors V and VIII, which are labile. One unit of activity for any coagulation factor is equal to 1 mL of FFP. It should be given in doses calculated to achieve a minimum of 30% of plasma factor concentration, which is usually 10 to 15 mL/kg of FFP. When used for the urgent reversal of warfarin anticoagulation, 5 to 8 mL/kg of FFP is usually sufficient. []

Platelets Crossmatching is unnecessary, but Rh-negative patients should receive Rh-negative platelets because there may be enough cells in the platelet concentrate to cause Rh sensitization. Each bag contains at least 5.5 × 10[10] platelets in 50 to 70 mL of plasma. On average, a single unit raises the platelet count by 5000/mm3. In adults the usual dose is 6 to 10 units, and in children it is 1 U/10 kg body weight. In situations in which human leukocyte antigen (HLA) matching of platelets is required, leukocyte-reduced apheresis platelets can be used to prevent HLA antibodies.[]

OUTCOMES Adverse effects of RBC transfusion can be divided into immune-mediated and non–immune-mediated categories, as well as acute, delayed, and chronic effects.

Immune-Mediated Adverse Effects Acute

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Intravascular Hemolytic Transfusion Reaction Intravascular hemolytic transfusion reaction is the most serious transfusion reaction and is usually the result of ABO incompatibility. It is often the result of a clerical error. An antigen-antibody reaction results in the intravascular destruction of transfused cells. Lysis of the transfused RBCs causes hemoglobin to be released, producing hemoglobinemia and hemoglobinuria. The onset of symptoms is immediate, and the patient may have fever, chills, headache, nausea, vomiting, and a burning sensation at the site of the infusion. A sensation of chest restriction, shock, and severe joint or low back pain may also be present.[] Treatment includes stopping the transfusion immediately, hanging all new tubing, and initiating vigorous crystalloid fluid therapy. Diuretic therapy should be used to maintain urine output at 1 to 2 mL/kg/hr. Dopamine in renal-sparing doses may be needed to sustain the blood pressure and protect the kidneys. The use of steroids is not currently recommended. Renal and coagulation status should be monitored.[] Because acute tubular necrosis and DIC may develop, a urine and a blood specimen should be obtained and sent to the laboratory, as well as the remainder of the transfusion and the blood tubing.

Febrile Transfusion Reaction This most common and least serious transfusion reaction is characterized by fever, chills, and malaise. Reactions are frequently related to antileukocyte and antiplatelet antibodies and seen in multiply transfused patients. Treatment is symptomatic with an analgesic-antipyretic and an antihistamine. If recurrent febrile reactions occur in a patient, leukocyte-poor RBCs (washed, frozen-thawed-deglycerolized, filtered) should be considered. If a febrile reaction occurs in a first-time transfusion, it should be treated in the same way as an extravascular hemolytic reaction until proved otherwise.[]

Allergic Reactions (Urticaria to Anaphylaxis) Urticaria or hives may occur during a transfusion without other signs or symptoms and no serious sequelae. It is generally attributed to an allergic, antibody-mediated response to a donor's plasma proteins. The transfusion does not need to be stopped, and treatment with an antihistamine is usually sufficient. If the patient has a known history of this, the antihistamine should be administered before the transfusion. Occasionally, full anaphylaxis may be caused by an anti–immunoglobulin A (IgA) reaction to IgA in the donor's blood components. The patient is likely to have a genetic IgA deficiency and display hypotension, respiratory and gastrointestinal symptoms, but no fever. Treatment is with epinephrine and corticosteroids. Future transfusions should be with washed RBCs, and plasma products should be from other IgA-deficient individuals.[17]

Transfusion-Related Acute Lung Injury Transfusion-related acute lung injury (TRALI) results from transfusion of white blood cell antibodies (leukoagglutinins) that react with the recipient's leukocytes. Clinically, TRALI is indistinguishable from acute respiratory distress syndrome. The patient has acute respiratory distress, diffuse bilateral alveolar and interstitial infiltrates on the chest radiograph, and varying degrees of hypoxemia. Hypotension and fever are also present. Appearance is usually within 6 hours of transfusion and may occur after the infusion of relatively small quantities of blood or plasma. Treatment consists of stopping the transfusion and providing respiratory support, which may include intubation and mechanical ventilation.[]

Delayed Extravascular Hemolytic Transfusion Reaction The onset of an extravascular hemolytic transfusion reaction is likely to be delayed by several days to weeks. High titers of antibodies to erythrocyte antigens other than anti-A and anti-B are not present in the plasma of most individuals. For a non–ABO-mediated transfusion reaction to occur, an anamnestic immune response must first develop. In other words, a prior exposure to a foreign RBC antigen must occur, followed by rechallenge with the same antigen. The patient may have fever, anemia, and jaundice. Symptoms are not usually severe, and no specific treatment is needed. Because the hemolysis is extravascular, hemoglobinemia and hemoglobinuria are rarely present.[17]

Transfusion-Associated Graft-versus-Host Disease During a transfusion the recipient is exposed to a variety of cells and proteins from the donor, including viable lymphocytes, which in an immunocompromised patient can result in graft-versus-host disease. These multiplying, immunocompetent, histoincompatible lymphocytes attack the recipient, causing further bone marrow suppression. High fever, erythematous maculopapular skin rash (frequently postauricular), anorexia, nausea and vomiting, profuse diarrhea, hepatomegaly, elevated liver enzymes, and pancytopenia may be seen. No effective treatment exists and death ensues, usually the result of overwhelming sepsis. Efforts are therefore directed at prevention by using gamma irradiation of all cellular components, which renders the

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donor lymphocytes incapable of proliferating. The use of leukocyte-poor components is also advocated. This condition is rarely encountered in the emergency department but should be kept in mind when considering transfusion in anemic leukemia or lymphoma patients, especially those who have recently received chemotherapy.[]

Non–Immune-Mediated Adverse Effects Acute Circulatory Overload Chronically anemic, normovolemic elderly patients are at greatest risk for developing congestive heart failure with the rapid infusion of blood. Taking 4 hours to infuse a unit and using diuretics (if needed) should prevent this complication.[]

Bacterial Contamination Bacterial contamination of stored blood is rare but can be a severe risk to the transfusion recipient. Both gram-negative and gram-positive organisms may grow in units of RBCs and more commonly in pooled platelet concentrates.[20] This contamination may result from faulty preparation of collection equipment, contamination of the anticoagulant solution, or poor technique while collecting or administering the blood. Yersinia enterocolitica is the organism most often implicated in RBC contamination, and Staphylococcus aureus is the most common organism in platelet contamination.[19] During or after the transfusion the patient may develop rigors, severe fever, hypotension, and shock. Hemoglobinuria and hemoglobinemia are rarely present. When a septic transfusion reaction is considered, aggressive resuscitative therapy and broad-spectrum antibiotics should be started and the transfusion stopped.[13]

Other Effects Although infrequent, the following complications may occur secondary to multiple unit transfusions: hypocalcemia, hyperkalemia and acidosis, hypothermia, microembolization, and coagulopathies. Treatment is specific to the symptom and problem.[]

Chronic Risk of Transmission-Transmitted Viruses Improved techniques for selecting and testing blood donors have dramatically reduced the risk of viral transmission of disease by transfusion. The blood supply in the United States has never been safer.[] The current rates of transmission of viral infections are too low to measure, so mathematical models have been used to estimate the risks of transmission of human immunodeficiency virus, hepatitis C virus, hepatitis B virus, and human T cell lymphotropic virus types I and II.[] Cytomegalovirus can be transmitted by blood transfusion as well and is largely a problem associated with neonatal or intrauterine transfusions and with immunocompromised patients.[9]

Transfusional Hemosiderosis Transfusional hemosiderosis is a condition of iron overload that may develop in chronically transfused patients. Each milliliter of PRBCs contains 1 mg of iron, and with continued transfusions, iron can accumulate, causing liver and heart damage. Patients may require chelation therapy.[13]

KEY CONCEPTS {,

Type and scre en shou ld be orde red rathe r than

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{,

{,

type and cros smat ch unle ss trans fusio n is inevit able. Cros smat ched bloo d is rese rved for spec ific patie nts for 48 hour s. Nor mal salin e (0.9 % NS) is the only appr oved solut ion for use with bloo d. Lact ated Ring er's solut ion is not used with PRB Cs. O-po sitive bloo

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d can be used if type spec ific or type and cros smat ch bloo d is not yet avail able. O-ne gativ e bloo d shou ld only be used in wom en of child beari ng age. {,

If the trans fusio n is not begu n withi n 30 minu tes of issu e, the bloo d shou ld be retur ned to the bloo d

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{,

{,

{,

bank . Most PRB C trans fusio ns are give n over 60 to 90 minu tes and no long er than 4 hour s. Patie nts may need to be pretr eate d with an antih ista mine , antip yreti c, or stero id 30 minu tes befor e the trans fusio n to redu ce risk of react ion. Intra vasc ular hem olytic trans

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fusio n react ion is life threa tenin g and most often seco ndar y to a cleri cal error .

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Marx: Rosen's Emergency Medicine: Concepts and Clinical Practice, 6th ed., Copyright © 2006 Mosby, Inc.

Section V - Violence and Abuse Chapter 62 – Injury Prevention and Control Stephen W. Hargarten Jeffrey W. Runge

PERSPECTIVE The science of injury control is based on the model of injury, or trauma, as a disease rather than the consequence of fate or random occurrences. The principles of disease control are applied to injury as they have been applied successfully to infectious diseases. Although this model has achieved wide acceptance in the public health community, it depends on acceptance by the medical community for success.[] Control of a disease this widespread can be achieved only through broad interdisciplinary effort, including that of medicine, public health, policy makers, law enforcement, and an educated citizenry ( Box 62-1 ). BOX 62-1 Scientific Approach to Injury Control: Prevention, Acute Care, and Rehabilitation

Prevention {, {, {, {, {, {, {,

Epidemiology—understanding the patterns of disease Biomechanics—understanding how the agent interacts with the host Public and patient education Public policy and law enforcement Engineering enhancements to the vector and the environment Outcome studies of prevention interventions Emergency preparedness

Acute Care {, {, {, {,

Trauma system development, including surge capacity for disasters Emergency medical services medical direction Triage protocols—matching the injuries to the source of care Emergency care

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{, {,

Definitive in-hospital care Outcome studies of trauma care

Rehabilitation {, {, {,

Short-term Long-term Long-term outcome studies

Emergency medicine plays a pivotal role in the care of injured patients and in injury control. One third of all emergency department visits are for the care of injuries.[] Injury is the leading cause of death for many age groups ( Table 62-1 ). Each year, one in four Americans is injured severely enough to seek medical attention.[] An estimated 23 to 28 million people are annually treated in emergency departments for injuries, of which 90% are not admitted to the hospital.[] The emergency physician may be the patient's only interface with the health care system. In addition to providing state-of-the-art acute care, this is also an opportunity for emergency medicine to take a leadership role, with state-of-the-art clinical preventive services for these injured patients,[] working with surgeons, pediatricians, and colleagues in other specialties to decrease injuries through clinical and policy-relevant research and education.[10] Table 62-1 -- Injuries, Including Motor Vehicle Crashes as a Leading Cause of Death in the United States, 2001

From National Center for Statistics and Analysis, Subramanian R: Motor Vehicle Crashes as a Leading Cause of Death in the United States, 2001 (DOT HS 809 695). Washington, DC, National Highway Traffic Safety Administration, 2003. MV, motor vehicle.

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PRINCIPLES OF THE DISEASE OF INJURY Injury is a harmful event caused by the acute transfer of energy to a patient that results in tissue and organ damage.[11] Acute injuries also include the absence of energy and hypothermia and hyperthermia. The major injury events include falls, car crashes, gunshots, drowning, and poisonings. The energy may be in various forms (kinetic, chemical, thermal, radiation, and electrical) and usually involves a vehicle of transmission, such as a car or a gun. Injury is similar to other diseases in which the interaction between the agent and the host in an environment conducive to exposure results in the disease ( Figure 62-1 ). In this model, energy is the agent that is delivered to the host (victim) by a vehicle of transmission in an environment with increased risk. Likewise, injury control is similar to other forms of disease control, with the goal of preventing or attenuating the transfer of energy to the host by several methods: separating the host from the agent through modification of the environment, equipping the host with protection against the agent, or eliminating or modifying the vector that transmits the energy.[]

Figure 62-1 An injury occurs by the interaction of the host and agent with an environm ent conducive to injury. Alteration of any of these interactions prevents the injury.

The first step in the control of injuries is the recognition that injury is a disease. Common public perception is that injuries are accidents or random and unexpected events, similar to the way infectious disease was regarded before the discovery of bacteria. Using the disease model of injury is a prerequisite to a scientific approach to addressing the problem. Kinetic energy accounts for the overwhelming number of injuries, encountered through interactions with motorized vehicles, firearms, piercing or blunt instruments, and falls. Similar to other diseases, characteristics of the host affect prevention strategies, acute care, and rehabilitation outcomes. These include physical characteristics, such as age, gender, size, and motor skills, and mental and behavioral characteristics, such as intelligence, fatigue, alcohol use and abuse, emotional lability, social norms, and lifestyle. Risk for injury and death vary by age (see Table 62-1 ), and interventions for decreasing injury should be age-specific. To decrease the likelihood of an injury, changes in some of these predisposing factors can be made in the host (e.g., through improvement in driving skills). Energy is transmitted to the host through a vehicle, such as motorized and nonmotorized vehicles (i.e., bicycles, skateboards), firearms, piercing instruments, explosives, and cigarettes. Modifying the vehicle by elimination or modification of design and separating the vector from the host are important methods of injury reduction and control. Understanding the biomechanical forces released during an injury event is crucial to understanding vehicle modification.[] For an injury to occur, host-agent interaction and energy transmission take place in an environment. Environmental modifications are effective means of injury control. If the environment does not permit energy transmission, the risk for injury, including intentional injuries to the host (victim), is reduced.[21] In contrast to altering host risk factors, environmental modifications require no cooperation or action on the part of the host and are more effective when implemented. Examples are safer road design and lighting, removal of throw rugs and raised thresholds from the homes of elderly persons, and separating bicycle paths and sidewalks from the roadway.[] William Haddon,[23] the first physician administrator for the National Highway Traffic Safety Commission, described this approach in a landmark article on injury control in 1970. Any type or cluster of injuries can be prevented or reduced in severity using this matrix when the environment, vector, and population most at risk are identified. Examples for reducing car crash injuries are given in Table 62-2 . The key to energy transfer reduction or prevention is understanding that injuries are predictable, following age, gender, and other related patterns, and that relying solely on human factors for prevention has significant limits. A fragile item sent through the mail arrives at its destination intact only if it is properly packaged to reduce the energy we anticipate being delivered to the package. Likewise, injuries to people can be prevented by using the cells of

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Haddon's method to mitigate the energy transfer of predictable events. A simple analysis of the injury event using Haddon's method for any injured patient seen in the emergency department provides an example for generating individual and population-based prevention strategies.[24] Table 62-2 -- Haddon's Strategies for Preventing the Transfer of Energy to the Host Technique 1. Prevent the initial marshalling of energy

2. Reduce the amount of energy marshaled

3. Prevent the release of energy

4. Modify the rate of spatial distribution of the release of energy from its source

Car Crash

Falls Man ual task/ Brea thaly zer igniti on interl ocks Use of alter nativ e trans porta tion

Rem ove floor obst acle s Prev ent unne cess ary clim bing

Climbing height restrictions Spe ed redu ction Vehi cle mas s restri ction s Breakaway light poles, roadway obstacle removal

Auto body cru mple zone

Amb ulati on aids for elder ly Wor ker safet y harn esse s Land with a “roll”

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Technique

Car Crash

Falls s Safe ty belts , air bags Wat er barr el barri ers

5. Separate the energy from the host in space or time

Red uce traffi c dens ity Hom ogen eous traffi c flow Incre ase follo wing dista nce Side walk s for pede stria ns

6. Separate the energy from the host by barrier 7. Modify the surface or structure of impact

Guardrails, concrete median barriers

8. Strengthen the host receiving the energy 9. Rapidly detect and evaluate damage and counter its continuation and extension

Detect and treat premorbid medical conditions

Collapsible steering columns, padded pillars and bolsters, safety glass

911 and EMS avail abilit

Use of safet y nets

Safety zones at edge of raised work areas

Guardrails for scaffolds, raised work areas Pad ded floori ng Hel mets and hard hats Prevent/treat osteoporosis and strengthen hip flexion in elderly patients 911 and EMS avail abilit

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Technique

Car Crash

Falls y Trau ma syst ems plan ning and impl eme ntati ons, and provi sion of state -of-t he-a rt eme rgen cy care

10. Reparative and rehabilitative measures

Provision of state-of-the-art trauma care, rehabilitation, and aftercare

y Trau ma syst ems plan ning and impl eme ntati on, and provi sion of state -of-t he-a rt eme rgen cy care Provision of state-of-the-art trauma care, rehabilitation, and aftercare

Injury and Public Health Since 1900, there have been an estimated 2 million injury deaths and hundreds of millions of injuries in the United States.[25] The avoidance of personal injury is a goal of modern public health, but until the 1940s and 1950s, unintentional injuries were attributed primarily to human error, and prevention was based on educating people to act safely.[13] Unsafe roads were built. Motorized vehicles and other consumer products were manufactured with safety design flaws.[26] Using the disease model, this would be similar to supplying contaminated tap water in homes and relying on the education of people to purify their own drinking water.[14] In the 1920s, attributing vehicle crashes to poor driver performance led to mandatory licensing of drivers. In the 1930s, when it was realized that vehicle crashes were due to human error and mechanical factors, President Roosevelt called for automobiles to be made more crashworthy.[15] In 1942, DeHaven, a former World War I pilot turned physiologist, pondering over his own survival in an airplane crash when another occupant had been killed, suggested structural provisions be made to vehicles that would distribute the forces of energy over the human body to attenuate injury in crashes. He advocated a focus on defining the physical factors that influence survival rather than the human error that caused the crash.[15] Physical factors became a focus of interest as the United States embarked on its space program. Air Force researchers, led by Stapp and Gell,[27] showed that people could withstand splashdown with a sled that decelerates from 30 to 0 mph over a stopping distance of 2 feet. This demonstration was considered to be a significant advance in understanding of the biomechanics of sudden deceleration. The recognition that injuries could be addressed similar to diseases began in the 1940s, when Gordon, an epidemiologist, suggested that injuries have epidemic patterns, seasonal variation, long-term trends, and demographic distribution and can be examined with methodologies applied to infectious diseases. Gordon also believed that, similar to infectious diseases, injury results from the interaction of the agent, the host, and the environment.[15] In the 1960s, Haddon developed a two-dimensional approach to injury analysis by dividing the factors of agent, host, and environment into three phases: preinjury, injury, and postinjury. This phase-factor matrix has become a mainstay of injury control and prevention development. Any injury event can be broken down into the component factors, allowing specific interventions to target specific factors (

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Table 62-3 ).[] Table 62-3 -- Typical Haddon Matrix (Constructed for Motor Vehicle Injury) Host Agent/Vector Environment Pre-event

Alcohol use Fatigue

Brake condition Tire quality

Experience and judgment Center of gravity Vision Jackknife tendency

Event

Amount of travel

Ease of control

Stature Medications

Load weight Speed capacity

Motor skills Cognitive function

Ergonomic controls Mirrors Visual obstructions Speed at impact Direction of impact Vehicle size Automatic restraints Air bag

Safety belt use Age Gender Bone density Stature

Character of contact surfaces

Visibility of hazards Road curvature and gradient Shoulder height Surface coefficient of friction Divided highways, one-way streets Intersections, access control Weather Signalization Speed limits Impaired driving laws Speed limits of traffic Recovery areas Guard rails Characteristics of fixed objects Median barriers Roadside embankments

Load containment Deformation zones Fuel system integrity Postevent

Age Physical condition Medications

911 access EMS response Triage and transfer protocols Preexisting medical EMS training conditions Quality of emergency care Social situation Location of appropriate emergency department Access to definitive care Access to rehabilitation services Adapted from Baker S, et al: The Injury Fact Book, 2nd ed. New York, Oxford University Press, 1992.

In 1985, the publication Injury in America: A Continuing Public Health Problem by the National Research Council and the Institute of Medicine called on the public health and health care community to address the injury epidemic.[17] In the 1990s, the Secretary of Health and Department of Human Services developed a national plan for injury control.[2] The permanent establishment of the National Center for Injury Prevention and Control in the Centers for Disease Control and Prevention was an acknowledgment by the U.S. government that the control of injuries belongs in the disease control community, including health care

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providers such as emergency physicians.

Methods of Prevention The evolution of injury control and prevention began as soon as the first injury occurred. The pain of injury is still a powerful stimulus for avoidance behaviors. Early prevention technology is seen in the instruments and garb of the earliest armies, shielding people from the delivery of harmful kinetic energy by instruments of early warfare. Such technology included helmets, shields, and suits of armor. As the human ability to deliver kinetic energy became more sophisticated, prevention technology did not keep pace.[] The invention of firearms and the automobile represented new plateaus in people's ability to harness kinetic energy for use.[] The cultural belief was that individuals could avoid vehicular injury by safe driving, and if not, an “accident” occurred. It took more than 50 years after the invention of the automobile for policy makers to acknowledge that behavior modification alone is insufficient to mitigate high-energy transmission to persons in a hazardous environment. Cars were not uniformly equipped with seat belts until the 1960s.[29] It took another 2 decades before air bags became standard safety features in cars, despite rapid advancements in understanding energy delivery and dissipation in motor vehicle crashes in the 1950s.[] Implementation of effective injury control and prevention strategies depends on collaborative efforts with health care providers (e.g., emergency physicians, surgeons, and pediatricians), epidemiologists, biomechanical engineers, public policy makers, law enforcement officers, and members of the legal profession.[] A major challenge is the wide diversity of disciplines and interests involved in safety and injury control, many of which are isolated from one another.[13] In the 1990s, important strides were made in community-based injury prevention and control programs that rely on coalitions of existing resources with the support of the National Highway Traffic Safety Administration (NHTSA), the Centers for Disease Control and Prevention, and the State and Territorial Injury Prevention Directors Association. These community coalitions were created to garner existing resources and implement injury countermeasures using the triad of public education, enforcement of laws, and engineering modification of hazardous devices and environmental conditions.[22]

INJURY CONTROL IN MEDICAL PRACTICE Physicians traditionally have focused on treating the patient after the disease has occurred. As the causes of many diseases have become increasingly understood, education about risk assessment and clinically based prevention have been integrated into medical practice, particularly in areas such as infectious (immunizations) and cardiovascular (smoking cessation) disease. Emergency physicians are incorporating risk assessment, counseling, and referral of patients in high-risk groups for injury, such as with domestic violence patients.[8] The Joint Commission for Hospital Accreditation has been instrumental in addressing injury prevention through emergency department requirements for domestic violence patients. Emergency physicians and nurses are pivotal in the recording and accumulation of data about the injury event, which become useful for epidemiologic analysis of the disease in the community, region, and state. Injury control techniques can be incorporated easily into emergency medicine practice as well.[] A rational approach to improve trauma care in a community ( Box 62-2 ) requires that emergency physicians, surgeons, pediatricians, and physiatrists, as the physicians primarily responsible for patients with injuries, assume specific roles and activities in promoting injury control. Documentation of injury information in the medical record, assessing risk factors in individual patients, counseling and referral, provision of systematized acute trauma care, and public heath advocacy all are important in the practice of injury control. []

BOX 62-2 Injury Control in Emergency Medicine Practice EMS, emergency medical services.

Clinical Preventive Services {,

Doc ume nt injur y infor

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{,

{,

{,

{,

mati on in the medi cal reco rd Ens ure that medi cal reco rds of injur y case s cont ain E code s Asse ss beha viora l and com orbid risk facto rs for futur e injur y Provi de risk scre enin g, coun selin g, and refer ral Asse ss biom echa nical risk facto rs in indivi dual patie

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{,

{,

nts Use biom echa nical risk facto rs for direc ted eval uatio n of injur ed patie nts Provi de syst emat ized acut e trau ma care

Population Health, Research, and Policy {,

{,

{,

Parti cipat e in and advo cate for inclu sive trau ma syst ems Dire ct and advo cate rapid , com pete nt EMS resp onse Lead effort

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{,

{,

{,

s in polic y deve lopm ent, impl eme ntati on, and eval uatio n Lead effort s in educ ating highrisk grou ps Lead effort s to addr ess and modi fy the envir onm ent to redu ce risk of injur y Colla borat e in multi disci plina ry rese arch effort s to redu ce injur y risk and to impr

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ove care

Injury Epidemiology and Documentation Gathering accurate data is essential to the science of injury control. To understand the characteristics of a disease—its endemic populations, cyclical variations, geographic characteristics, and effectiveness of interventions—consistent and comprehensive data must be gathered across the population of injured patients. Data may be used for research,[] implying an in-depth examination of a particular question or for surveillance, which is the ongoing monitoring of disease patterns and characteristics.[] The goal of injury data collection is to discover who is being injured, what is injuring them, and the circumstances surrounding the injury.[] Until more recently, good data on the disease of injury have been lacking, and gaps still exist.[44] Before 1980, the only large civilian databases on injury available for study were mortality data collected by coroners and medical examiners. The Fatal Analysis Reporting System, a comprehensive dataset on all car crash deaths in the United States, was established by the National Highway Safety Administration in 1975.[45] It has been a useful tool for examining the epidemiology of car crashes and has been used by injury control researchers for examining important questions.[39] Because death results in only 1 in 1000 people who receive medical care for an injury, many conclusions based solely on mortality data are limited.[] The advent of trauma registries in the 1980s increased the sample from the 0.1% of patients who die to a larger proportion of patients admitted for injury (i.e., patients admitted to trauma centers). Mortality data and patients receiving care in trauma centers are skewed toward the most severe injuries, however, and epidemiologic conclusions based on those data are important but have limitations.[46] Approximately 90% of injured patients seeking medical care for injury are treated and discharged from the emergency department, many of whom experience significant morbidity resulting in long-term disability and significant cost to society.[] In recognition of the importance to the national health care agenda, the Centers for Disease Control and Prevention has developed Data Elements for Emergency Department Systems to define the minimum data essential to the understanding of the disease for physicians and information systems developers.[] The most crucial data element for the understanding of injury is the E code. The E-code is a system for identifying the cause of injury in a patient's medical record, according to a classification published in the International Classification of Diseases (ICD-9-CM).[22] The “E” stands for external cause of injury, such as car crash, fall, or bicycle crash. The causes of injury in a population cannot be extracted from diagnosis codes in medical records. These are “N” codes—the nature of the injury, such as skull fracture, laceration, or contusion. Because injury prevention depends on identifying the etiologic agent/vehicle causing injuries and not the end result, the only way to accomplish this systematically is by E-coding patient visits. Some states now have E-coded all emergency department discharges, and these statewide data are useful for injury control and prevention program development and evaluation.[] The notion that E-coding is expensive has been dispelled, and visits should be able to be coded easily in the emergency department.[] The greatest barrier to the collection of E codes in the emergency department is the lack of adequate physician documentation to assign an accurate E code retrospectively from the medical record.[] The first step in data gathering is to document completely and legibly the cause of injury on patient records. With cause of injury recorded, injuries in a given population can be examined by emergency physicians and others. Because injury problems in a community differ greatly from region to region, community-specific injury control efforts can be generated, implemented, and evaluated.[] E-coded hospital records can provide the who, what, and when of injury. The question of where can be either place of occurrence or place of residence, both of which are important and have implications for planned countermeasures. Hospital records are helpful in determining place of residence of injured patients, which is useful for community education in high-risk neighborhoods. Location-of-injury data are available only from other sources, such as emergency medical services (EMS), police, or traffic engineering. These data are more likely to be useful for environmental modification through engineering enhancements, police enforcement, or hazard removal. Linkage of these records to patient visits, either manually for specific research studies or electronically for surveillance, is the next step in gaining a comprehensive understanding of the epidemiology of injury.[] Statewide injury data linkages exist in some states and are available for surveillance information[53] and research and for unintentional and intentional injuries.[]

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Interest and opportunity to apply injury control principles are growing for medical injuries. Medical injuries account for an estimated 50,000 to 98,000 deaths each year in the United States, with hundreds of thousands of nonfatal events occurring in emer-gency departments, intensive care units, and operating rooms.[44] Emergency physicians have begun to assume leadership roles in addressing this important area of injuries.[] Application of injury control principles for the identification of injury patterns and for the development and evaluation of injury prevention strategies has great potential but has received limited attention.[] Emergency physicians can play an important role in using injury control principles and science for reducing medical injuries.

Risk Factor Assessment Biomechanical Risk Factors Biomechanical factors responsible for the injury event are challenging to understand fully, occurring in car crashes in less than a tenth of a second. Emergency physicians are not trained in engineering principles and have had limited exposure to this “pathophysiology” during medical school or residency training. Ascertaining the forces released to the patient during a blunt (car crash, fall) or penetrating (gunshot, stabbing) injury event leads to a directed approach to injury management. Contrast this scientific evidence-based approach with the practice of obtaining cervical spine radiographs for any patient with a head strike of any severity.[] Extensive research has been done using crash dummies, mathematical models, and computer models to understand the mechanical forces applied in injury events and human impact tolerance.[] Although used extensively by the engineering community for design of products, such knowledge also is valuable to the trauma physician in guiding evaluation and treatment based on energy transfer, tissue tolerance, and risk of occult injury.[11] Injury occurs when energy is delivered to the host in levels that exceed tissue and organ tolerance. This energy can be expressed in G forces. The G force that results from a motor vehicle crash, for instance, can be expressed using the following formula: In this equation, pvV is the change in velocity, stopping distance is the distance over which the change in velocity occurs, and k is a constant. G force is inversely related to stopping distance. To minimize energy transfer to the body during a car crash, one must maximize the stopping distance during the event. The formula shows that doubling the stopping distance reduces the G force by half, but doubling the speed quadruples the force. Less G force is applied as velocity is reduced over increasing distance, which allows the restrained occupant to “ride down” with the vehicle as it slows during preimpact braking or as it deforms during a crash. The same principle underlies engineering features, such as interior padding and collapsible steering columns, water barrel barriers at bridge abutments, and flexible guardrails, all designed to increase stopping distance. This principle is a major underpinning of automobile and highway safety engineering.[] The addition of the air bag in the mid-1980s was a significant improvement in safety engineering by increasing occupant stopping distance during a crash. The NHTSA estimates that 10,271 lives have been saved by air bags 2002.[63] Although these benefits have been largely confined to frontal crashes, increasing stopping distance and reducing head deceleration in side impacts through the use of side curtain air bags are expected to save hundreds of lives per year when fully deployed in the fleet. As with many newly developed safety countermeasures, there were unintended consequences of air bags in the 1990s. First-generation air bags deployed with tremendous force to protect unbelted occupants. These early air bags deployed aggressively at speed of 140 to 200 mph over about 50 msec.[64] Such forces can be lethal to children seated in the front passenger seat, especially when unrestrained by safety belts, or infants seated in rear-facing infant seats exposed to the front seat air bag.[] The NHTSA has documented 149 children killed as a result of air-bag deployment as of 2003.[63] A new generation of advanced, less aggressive air bags has been used in the vehicle fleet since the late 1990s, which is expected to reduce injuries associated with air-bag deployment. For an emergency physician to estimate risk when assessing a patient from a motor vehicle crash, it is essential to understand the differences in risk posed by seating position, restraint type and use, and vehicle type. This information also must be understood to counsel patients properly on safety belt and child restraint use.[] Understanding mechanisms of injury leads to more effective patient counseling to protect patients and their families against injury. Children less than 55 inches tall should ride in only the rear seats of vehicles. Infant seats should never be positioned in the front seat within range of the air bag. Infants 12 months old and

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younger and weighing 20 lb or less should always ride in a rear-facing infant seat, and children older than 12 months and weighing more than 20 lb should ride forward facing in a convertible or toddler seat. A booster seat should be used for children weighing 40 to 80 lb, allowing for better seat belt positioning and discouraging the child from sitting out of position to see out the windows. If circumstances dictate that a smaller child must ride in the front passenger seat, that seat should be positioned as far to the rear as possible and a seat belt should always be worn.[67] Federal rules from the U.S. Department of Transportation allow for air bags to be disabled if there are circumstances necessitating that small children ride in the front seat and for certain medical conditions.[68] Physicians caring for short-stature individuals should counsel these patients about the risk of air-bag injuries and recommend they sit with at least 10 inches between the sternum and the steering wheel equipped with an air bag. This distance should be measured objectively because people tend not to estimate this distance correctly.[69] Other safety features have been associated with specific injuries. Automatic “passive” shoulder belts that require manual fastening of the lap portion may result in “submarining” of the torso toward the floorboard when the lap portion is not fastened, while the shoulder belt squeezes the lower rib cage. Such a mechanism explains the association of these devices with liver, spleen, and lung injuries.[70] Knowing the contact surface in fall injuries may guide diagnostic and therapeutic interventions because soft, forgiving surfaces increase stopping distance compared with concrete or packed earth.[] Understanding the biomechanical risks of other injuries, such as tissue forces from the ballistics of bullet wounds, can guide treatment decisions.[]

Behavioral and Comorbid Risk Factors Recognition of patients at high risk of injury affords opportunity for intervention. Counseling a patient about specific ways to avoid injury in the “teachable moment” after injury is more likely to have an effect than diffuse public education.[72] Family or friends can be recruited to enforce the message to patients or to assist patients in modifying their behavior or environment. Other patient encounters may be used as an opportunity to counsel high-risk patients, such as children at developmental stages that put them at risk for auto-pedestrian injuries, climbing injuries, or poisoning. It is particularly important to explore the circumstances surrounding injuries to children. A brief review of the injury incident would help physicians and parents identify risks for future injury and opportunities for intervention.[73] Children who come to the emergency department for an injury are likely to be injured again, commonly during falls and motor vehicle crashes.[74] When injury admissions in preschool-age children were examined for previous emergency department visits, children admitted to the hospital for trauma were twice as likely as community controls to have been treated previously in the emergency department for injury and more likely to have been in the emergency department more than once.[75] Risk factors for intentional injury are complex and involve behavioral, social, and environmental factors. Risk factors vary by type of trauma, but risks for all types are higher for people in the following categories: male, low income, illicit drug involvement, previous arrest, and young age.[] In studies using psychosocial inventories, recidivists are more likely to have a low sense of autonomy, to have low levels of spirituality, and to have been a victim of crime in the past.[75] As a practical matter in the emergency department, the most obvious risk factor for future violent injury is having had prior violent injury. A history of prior significant trauma is a strong predictor of trauma recidivism, with 10 times the risk of patients with no prior trauma.[] Emergency departments should have protocols in place for the detection and referral of patients likely to be victims of trauma in the future, including victims of domestic violence,[8] and for children younger than 18 years injured intentionally, regardless of the age of the perpetrator. In many states in the United States, there are mandatory reporting laws for gunshot wounds, stabbing, and other violent acts. Physicians should be familiar with local laws regarding reporting to law enforcement.[] In the case of motor vehicle injury, the three behavioral risk factors most likely to result in future crash are speeding, seat belt nonuse, and driving after drinking alcohol. Giving patients the necessary data for them to make an accurate self-assessment about their risks is the essence of patient behavioral intervention.[81] These messages can be delivered during, and should be part of, every injury patient encounter, when it is feasible. Particularly important in this context is the screening and referral for alcohol use disorders (AUDs). Alcohol-related crash injury is a national epidemic in the United States, claiming more than 17,000 lives annually and injuring an estimated 870,000 persons.[82] The reductions in alcohol-related deaths seen in the 1980s and 1990s have been due to more stringent laws to curb impaired driving, more vigilant public education, and a societal shift toward the condemnation of driving while impaired as socially undesirable.

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These changes have not had significant effects on people with AUD, however. Of patients seen in the emergency department after a motor vehicle crash, 17% to 20% meet criteria for AUD.[] Patients with AUD have higher rates of illness and motor vehicle crash injury than the rest of the population, and patients with AUD are more likely to drive after drinking.[79] Emergency physicians have a unique role to play in the identification of high-risk patients. In particular, patients with AUD should be detected and referred for formal evaluation and treatment. A structured approach to these patients is necessary to detect and treat the disease and must be brief and effective if it is to be used in a busy emergency department. Screening techniques validated in the emergency department and methods of brief intervention are described thoroughly.[79] Successfully treating AUD leads to reductions in alcohol consumption and consequently fewer impaired driving episodes, which leads to a reduction in alcohol-related crash injuries. Evidence suggests that being treated for injury in the emergency department may be an important motivational opportunity to reduce drinking and presents a “teachable moment.”[] Motor vehicle crashes are the leading cause of death for children older than 24 months in the United States ( Table 62-4 ; see also Table 62-1 ). The risk of death in a motor vehicle crash can be reduced by half with the use of an age-appropriate child restraint. Emergency physicians should understand the various restraint types and recommendations for their use based on age, weight, and height. Every pediatric visit to the emergency department involves transportation to and from the emergency department. Every pediatric visit is an opportunity to counsel parents on the safe transport of their children. Table 62-4 -- Ten Leading Causes of Injury Deaths by Age Group, 2000

Source: National Center for Health Statistics (NCHS), Vital Statistics System. MV, motor vehicle; NEC, not elsewhere classified. Produced by Office of Statistics and Programming, National Center for Injury Prevention and Control, CDC.

The current recommendation by the NHTSA is that infants should be transported in a rear-facing infant seat in the back seat until they are 12 months old and weigh 20 lb. After reaching this milestone, children may be transported in forward-facing child restraints until they reach the weight limitation for the particular child restraint, usually about 40 lb and 4 years of age. Some child restraints may be designed to remain rear facing for longer periods, as is the practice in much of Europe. At 40 lb, children should be placed in a belt-positioning booster seat until the height of 57 inches or the auto manufacturer's recommendation for appropriate height for belt fit.

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Acute Care The acute care component of injury control involves trauma system planning, direction of out-of-hospital medical care, and provision of systematized resuscitative care after the injury event, whether it occurs close to or far from a trauma center.[87] A crucial part of injury assessment for the trauma physician is identification of local resources for management of the trauma patient. Algorithms and transfer agreements for referral of the patient to definitive care should be established, in the absence of a trauma system with defined triage and transfer protocols, to avoid the secondary injury that may occur from delays in transfer or inappropriate care.[88] Likewise, an environment with ready availability of trauma physician specialists should have clear protocols in place for use of those resources.[89] Cost-effective mobilization of trauma care resources dictates that in-hospital triage criteria be developed for the care of the injured patient to avoid the unneeded overuse of trauma surgery teams.[] In the early 1990s, less than 25% of the United States was served by an organized trauma system.[90] Trauma systems can be created that recognize and complement the exigencies of budgetary, geographic, and political constraints that are specific to states or regions. Such flexibility is often impossible when a trauma system is based only on the locations of hospitals that seek trauma center verification or designation.[91] An inclusive trauma care system is one that comprises all acute care and rehabilitation facilities that treat injured patients and deals with the issues of community access, EMS dispatch and response, triage, transport and transfer protocols, training, communications, availability of definitive care and rehabilitation, and a data collection system. In an inclusive trauma care system, every injured patient, not only patients who live near trauma centers, is cared for by a part of the system. Every hospital has a part in an inclusive trauma system according to the services it is capable of offering, whether it is the expeditious transfer of patients, the treatment of patients without neurotrauma, or the definitive care provided at a trauma center. The system should be designed to monitor patient outcomes and system performance.[92] Out-of-hospital care is an integral part of injury control.[37] EMS response, triage, and treatment are the first critical steps in damage control after an injury event has occurred. Triage protocols must be well established to avoid unnecessary delays in definitive care.[88] EMS providers have a unique vantage point to help the trauma physician assess a patient's risk factors for immediate injuries and the risk of injury recurrence. EMS providers can observe the environment for information about mechanism of injury. Accurately reporting vehicle damage and other environmental circumstances associated with the injury event elucidates important biomechanical risk factors.[93] EMS providers also have become more involved in primary injury prevention, through injury risk identification, documentation of injury data, and safety education programs.[37]

Emergency Medicine Leadership: Advocacy of Public Policy Passing and enforcing laws are more effective than education in effecting individual behavior change for increasing safety actions such as seat belt and helmet usage.[] Emergency physicians and other trauma physicians, such as pediatricians, surgeons, and orthopedists, are well positioned to provide lawmakers with factual information coupled with the perspective of first-hand experience of the effects of injury. Effective prevention interventions and policies with documented cost savings are more likely to occur when sound, scientific studies are made available to policy makers.[94] Most public health regulations and traffic safety laws are under the jurisdiction of state legislatures and city and county governments. These policy makers are generally much more accessible to physicians and are in need of local expertise than policy makers at the federal level. Emergency physician leadership needs to accept its important advocacy role for reducing injuries and incorporate injury control as a professional activity.[] Community education aimed at people not yet injured may be effective when coming from an emergency physician. Emergency physicians are in a leadership role to deliver the message to school systems, the local housing authority, law enforcement, community service organizations, and policy makers.[] Trauma physicians can be effective spokespersons for injury prevention through the news media, especially after a newsworthy injury event, and can reframe the event from one of personal blame and behavior failure to a broader biosocial issue that requires environmental and policy interventions.[97] Public policy also determines where resources are used in a community. Environmental modifications and elimination of hazards are effective, but often expensive. In contrast to education and law enforcement, environmental modifications are passive countermeasures, in that they do not require any action by persons after they are in place. Such modifications might be lengthening a “walk” signal at a busy intersection to

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reduce auto-pedestrian injuries, especially in the elderly,[98] increasing lighting in areas where personal assaults occur,[21] or changing a playground surface from hard-packed earth to wood mulch.[99] The need for such modifications may be known only if the physician is alert to the circumstances by asking “How did this happen?” and documenting the location and circumstances of injuries seen in daily practice. KEY CONCEPTS

{,

{,

Injur y is the seco nd most costl y dise ase to soci ety and the most serio us dise ase of youn g peop le. Thro ugh inter disci plina ry rese arch, a bette r unde rstan ding of the epid emio logy and biom echa nics of injur y will lead to new

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prev entio n strat egie s. Thes e strat egie s woul d com plem ent adva nces in acut e care and trau ma syst ems, whic h impr ove care to the patie nt after the injur y occu rs. {,

Eme rgen cy phys ician s can incor porat e injur y contr ol tech niqu es into daily pract

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{,

ice. Eme rgen cy phys ician s are incre asin gly lead ers in addr essi ng and prev entin g injuri es and com plex bios ocial probl ems.

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Marx: Rosen's Emergency Medicine: Concepts and Clinical Practice, 6th ed., Copyright © 2006 Mosby, Inc.

REFERENCES 1. Teutsch SM: A framework for assessing the effectiveness of disease and injury prevention. MMWR Morb Mortal Wkly Rep1992;41:1. 2. Centers for Disease Control : The National Agenda for Injury Control, 1992, Atlanta, CDC, 1992. 3. Rice DP: Cost of Injury in the United States: A Report to Congress, San Francisco, Institute for Health & Aging, University of California, and Injury Prevention Center, The Johns Hopkins University, 1989. 4. McCaig LF, Burt CW: National Hospital Ambulatory Medical Care Survey: 2001 Emergency Department Summary: Advance data from Vital and Health Statistics (No. 335), Hyattsville, Md, National Center for Health Statistics, 2003. 5. Baker SP: The Injury Fact Book, New York, Oxford University Press, 1992. 6. Consumer Product Safety Commission National Electronic Injury Surveillance System (NEISS) : Available at: http://www.cpsc.gov/cpscpub/pubs/3002.html 7. Muelleman RL: Missouri's emergency department E-code data reporting: A new level of data resource for injury prevention and control. J Public Health Manage Pract1997;3:8. 8. Krasnoff M, Moscati R: Domestic violence screening and referral can be effective. Ann Emerg Med 2002;40:485. 9. Cortes L, Hargarten SW: Preventive care in the emergency department: A systematic literature review on emergency department-based interventions that address smoke detectors in the home. Acad Emerg Med 2001;8:925. 10. Gruen RL: Physician-citizens—public roles and professional obligations. JAMA2004;1:94. 11. Martinez R: Injury control: A primer for physicians. Ann Emerg Med1990;19:72. 12. Rosenberg M, Fenley MA: Violence in America: A Public Health Approach, New York, Oxford University Press, 1991. 13. National Committee for Injury Prevention and Control : Injury Prevention: Meeting the Challenge, Oxford, Oxford University Press, 1989. 14. Mohan D: Injury Control and Safety Promotion: Ethics, Science and Practice, New York, Taylor & Francis, 2000. 15. Robertson L: The problem, history and concepts. Injury Epidemiology, New York: Oxford University Press; 1992: 16. Haddon W: A logical framework for categorizing high-way safety phenomenon and activity. J Trauma 1972;12:193. 17. Committee on Trauma Research, Commission on Life Sciences, National Research Council, Institute of Medicine : Injury in America: A Continuing Public Health Problem, Washington, D.C., National Academy Press, 1985. 18. Yoganandan N: Dynamic analysis of penetrating trauma. J Trauma1997;42:266. 19. Whiting WC, Zernicke RF: Biomechanics of Musculoskeletal Injury, Champaign, Ill, Human Kinetics, 1998. 20. In: Nahum AM, Melvin J, ed.Accidental Injury: Biomechanics and Prevention, 2nd ed. New York: Springer-Velag; 2001: 21. Mair JS, Mair M: Violence prevention and control through environmental modifications. Annu Rev Public Health2003;24:209. 22. Christoffel T, Gallagher S: Injury Prevention and Public Health, Gaithersburg, Md, Aspen, 1999. 23. Haddon W: On the escape of tigers: An ecologic note (strategy options in reducing losses in energy-damaged people and property). MIT Technol Rev1970;72:44. 24. Lambrecht CJ, Hargarten SW: Hunting-related injuries and deaths in Montana: The scope of the problem and a framework for prevention. J Wilderness Med1993;4:175. 25. Committee on Trauma Research, Commission on Life Science, National Research Council, Institute of Medicine : Injury in America: A Continuing Public Health Problem, Washington, D.C., National Academy Press, 1985. 26. Freed LH, Vernick JS, Hargarten SW: Prevention of firearms-related injuries and deaths among youth—a product orientated approach. Pediatr Clin North Am1998;45:427. 27. Stapp JP, Gell CF: Human exposure to linear declarative force in the backward and forward facing

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seated positions. Milit Surg1951;109:106. 28. Karlson T, Hargarten SW: Reducing Injury and Death: A Public Health Sourcebook on Guns, New Brunswick, NJ: Rutgers University Press; 1997: 29. Nader R: Unsafe at Any Speed: The Designed-In Dangers of the American Automobile, New York, Grossman, 1965. 30. Chistoffel T, Teret SP: Protecting the Public: Legal Issues in Injury Prevention, New York, Oxford University Press, 1993. 31. Rivara F: Injury Control: A Guide to Research and Program Evaluation, Cambridge, Cambridge University Press, 2001. 32. Anglin D, Hutson HR, Kyriacou DN: Emergency medicine residents' perspectives on injury prevention. Ann Emerg Med1996;28:31. 33. Hargarten SW, Karlson T: Injury control: A crucial aspect of emergency medicine. Emerg Med Clin North Am1993;11:255. 34. Bernstein E: The emergency physician's role in injury prevention. Pediatr Emerg Care1988;4:207. 35. Ribbeck BM: Injury surveillance: A method for recording E codes for injured emergency department patients. Ann Emerg Med1992;21:37. 36. Rivara F, Thompson DC, Patterson MQ: Prevention of bicycle-related injuries: Helmets, education, and legislation. Annu Rev Public Health1998;19:293. 37. Garrison HG: The role of emergency medical services in primary injury prevention. Consensus workshop, Arlington, Virginia, August 25-26, 1995. Ann Emerg Med1997;30:84. 38. Mann N: Research recommendations and proposed action items to facilitate trauma system implementation and evaluation. J Trauma1999;47(Suppl):S75-S78. 39. Cummings P, Rivara F: Car occupant death according to the restraint use of other occupants: A matched cohort study. JAMA2004;291:343. 40. Runge J: Linking data for injury control research. Ann Emerg Med2000;35:613. 41. Wadman MC: The pyramid of injury—Using E-codes to accurately describe the burden of injury. Ann Emerg Med2003;42:468. 42. Sniezek JE, Finklea JF, Graitcer PL: Injury coding and hospital discharge data. JAMA1989;262:2270. 43. Muelleman RL, Hansen K, Sears W: Decoding the E-code. Nebr Med J1993;78:184. 44. Institute of Medicine : To Err is Human: Building a Safer Health System, Washington DC, National Academy Press, 1999. 45. National Highway Traffic Safety Administration, Office of Statistics and Analysis : Fatal Accident Reporting System, 1975 Annual Report, Washington, D.C., U.S. Department of Transportation, 1976. 46. Waller J: Injury Control: A Guide to the Causes and Prevention of Trauma, Lanham, Md, Lexington Books, DC Heath, 1995. 47. Centers for Disease Control and Prevention : Data Elements for Emergency Department Systems (DEEDS), Washington, D.C., U.S. Department of Health & Human Services, 1996. 48. Hirshon JM:for the SAEM Public Health Task Force Preventive Care Project: The rationale for developing public health surveillance system based on emergency department data. Acad Emerg Med2000;7:1428. 49. Schwartz RJ, Nightingale BS, Jacobs LM: Accuracy of E-codes assigned to emergency department records. Acad Emerg Med1995;2:615. 50. Sheane K, Wright A, Bierlein LA: A Comprehensive Statewide Injury Surveillance System: What Are the Issues?, Tempe, Ariz, Morrison Institute for Public Policy, 1995. 51. Johnson SW, Walker J: The Crash Outcome Evaluation System (CODES) (DOT HS 808 338), Washington, D.C., Department of Transportation, National Highway Traffic Safety Administration, 1996. 52. Hargarten SW: Characteristics of firearms involved in fatalities. JAMA1996;275:42. 53. National Violent Injury Statistics System Work Group : Violent Death Reporting System Training Manual, Milwaukee, Wis, FIC & NVISS, 2002. 54. Adams JG, Bohan JS: System contributions to error. Acad Emerg Med2000;7:1189. 55. Kyriacou DN, Cohen JH: Errors in emergency medicine: Research strategies. Acad Emerg Med 2000;7:1201. 56. Brasel KJ: Evaluation of error in medicine: Applica-tion of a public health model. Acad Emerg Med 2000;7:1298. 57. Layde PM: Patient safety efforts should focus on medical injuries. JAMA2002;287:1993. 58. Norcross ED: Application of American College of Surgeons' field triage guidelines by pre-hospital personnel. J Am Coll Surg1995;181:539. 59. Ryan GA: Neck strain in car occupants: Injury status after 6 months and crash-related factors. Injury 1994;25:533. 60. Velmahos GC: Radiographic cervical spine evaluation in the alert asymptomatic blunt trauma victim: Much ado about nothing?. J Trauma1996;40:768. 61. Ono K, Kanno M: Influences of the physical parameters on the risk to neck injuries in low impact speed rear-end collisions. Accid Anal Prev1996;28:493. 62. Peterson TD: Motor vehicle safety: Current concepts and challenges for emergency physicians. Ann

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Emerg Med1999;34:384. 63. National Center for Statistics and Analysis : Special Crash Investigations: Counts of Airbag Related Fatalities and Seriously Injured Persons, Washington, D.C., National Highway Traffic Safety Administration, 2004. 64. National Highway Traffic Safety Administration : Update: Air bag-related fatalities to children—United States, 1993-1996. MMWR Morb Mortal Wkly Rep1996;49:1073. 65. Arbogast KB, Durbin DR, Kallan MJ, Winston FK: Effect of vehicle type on the performance of second generation air bags for child occupants. Ann Proc Assoc Adv Auto Med2003;47:85. 66. Moran SG: Relationship between age and lower extremity fractures in frontal motor vehicle collisions. J Trauma2003;65:261. 67. Durbin DR: Belt-positioning booster seats and reduction in risk of injury among children in vehicle crashes. JAMA2003;289:2835. 68. Jolly BT: Air bags—the changing landscape. Ann Emerg Med1998;31:783. 69. Segui-Gomez M, Levy J, Graham JD: Airbag safety and the distance of the driver from the steering wheel. N Engl J Med1998;339:132. 70. Augenstein JS: Chest and abdominal injuries suffered by restraint occupants (950657), Detroit, Society of Automotive Engineers, 1995. 71. Pryor JP: Nonoperative management of abdominal gunshot wounds. Ann Emerg Med2004;43:344. 72. Hazinski MF: Pediatric injury prevention. Ann Emerg Med1993;22:456. 73. Mace SE: Injury prevention and control in children. Ann Emerg Med2001;38:405. 74. McCaig LF, Burt CW: Poisoning-related visits to emergency departments in the United States, 1993-1996. J Toxicol Clin Toxicol1999;37:817. 75. Redeker N: Risk factors of adolescent and young adult trauma victims. Am J Crit Care1995;4:370. 76. Cooper C: Repeat victims of violence: Report of a large concurrent case-control study. Arch Surg 2000;135:837. 77. Kaufmann CR, Branas CC, Brawley M: A population-based study of trauma recidivism. J Trauma 1998;45:325. 78. Sayfan J, Berlin Y: Previous trauma as a risk factor for recurrent trauma in rural northern Israel. J Trauma1997;43:123. 79. National Highway Traffic Safety Administration : Identification and referral of impaired drivers through emergency department protocols (DOT HS 809 412), Washington, D.C., U.S. Department of Transportation, 2002. 80. Hargarten SW: Docs and cops: A collaborating or colliding partnership?. Ann Emerg Med2001;38:438. 81. Miller WR, Rollnick S: Motivational Interviewing: Preparing People to Change Addictive Behavior, New York, Guilford Press, 1991. 82. Maio RF: Alcohol abuse/dependence in motor vehicle crash victims presenting to the emergency department. Acad Emerg Med1997;4:256. 83. Cherpitel CJ: Alcohol consumption among emergency room patients: Comparison of county/community hospitals and an HMO. J Stud Alcohol1993;54:432. 84. Becker BM: Alcohol use among sub-critically injured emergency department patients and injury as a motivator to reduce drinking. Acad Emerg Med1995;2:784. 85. CDC : Alcohol problems among emergency department patients, proceedings of a research conference on identification and intervention. CDC, National Center for Injury Prevention and Control. Available at: www.cdc.gov/ncipc 86. Hungerford DW, Pollock DA: Emergency department services for patients with alcohol problems: research directions. Acad Emerg Med2003;10:79. 87. Mullins RJ: Population-based research assessing the effectiveness of trauma systems. J Trauma 1999;47(Suppl):S59. 88. Mullins RJ: Survival of seriously injured patients first treated in rural hospitals. J Trauma2002;52:1019. 89. Shatney CH, Sensaki K: Trauma team activation for ‘mechanism of injury’ blunt trauma victims: Time for a change?. J Trauma1994;37:275. 90. Eastman AB: Blood in our streets: The status and evolution of trauma care systems. Arch Surg 1992;127:677. 91. MacKenzie EJ: National inventory of hospital trauma centers. JAMA2003;289:1515. 92. Trunkey DD: Trauma centers and trauma systems. JAMA2003;289:1566. 93. Augenstein JS: Occult abdominal injuries to airbag-protected crash victims: A challenge to trauma systems. J Trauma1995;38:502. 94. Thacker SB: Assessing prevention effectiveness using data to drive program decisions. Public Health Rep1994;109:187. 95. Physician's charter and the new professionalism. Lancet2002;359:520. 96. Medical professionalism in the new millennium: A physician charter. Ann Intern Med2002;136:243. 97. Woodruff K: Physicians as advocates: Promoting healthy public policy via the media. California

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Physician1994;11:48. 98. Retting RA, Ferguson SA, McCartt AT: A review of evidence-based traffic engineering measures designed to reduce pedestrian-motor vehicle crashes. Am J Public Health2003;93:1456. 99. Lewis LM: Quantitation of impact attenuation of different playground surfaces under various environmental conditions using a tri-axial accelerometer. J Trauma1993;35:932.

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Marx: Rosen's Emergency Medicine: Concepts and Clinical Practice, 6th ed., Copyright © 2006 Mosby, Inc.

Chapter 63 – Forensic Emergency Medicine William S. Smock

PERSPECTIVE Clinical forensic medicine is the application of postmortem forensic medical knowledge and techniques to live patients in a clinical setting. European and British physicians, known as police surgeons, forensic physicians, forensic medical examiners, or forensic medical officers,[1] have performed clinical forensic examinations for more than 200 years.[2] The Metropolitan Police Force in London employs 20 full-time medical officers who perform forensic evaluations on prisoners and victims of physical and sexual assault.[3] Clinical forensic medicine programs are also well established in Asia, Latin America, and Australia.[4] All patients who are victims of assault, abuse, trauma, or a terrorist event have forensic needs. When emergency physicians treat injuries without considering the forensic issues, they may misinterpret wounds, miss victims of abuse or domestic violence, and inadequately document the nature of injuries. During the provision of patient care, evidence that can be of critical significance to criminal or civil proceedings can be lost, discarded, or inadvertently washed away.[] Wound evaluation and evidence collection take on additional significance when the patients are victims of a terrorist incident. Their wounds may contain radioactive materials, trace evidence, or bomb fragments that will be an important component of the criminal investigation.[15] In 1991 the University of Louisville School of Medicine and the Kentucky Medical Examiner's Office established a clinical forensic medicine training and consultative program in the United States.[] A forensically trained emergency physician or a forensic pathologist and a forensic nurse respond to the emergency department or other inpatient facility on a 24-hour basis. Consultations are initiated by a treating physician or a local, state, or federal law enforcement agency. Forensic examinations are conducted with the consent of the patient, legal guardian, or court or by implied consent. The evaluation includes a history and physical examination, photographs, and anatomic diagrams.[] Evidentiary material, including clothing, hair, blood, saliva, bullets, and bomb fragments, is collected when indicated or when ordered by the court. If a patient has been admitted from the emergency department to surgery, an evaluation is done in the operating suite in concert with the trauma surgeons. Evaluations of gunshot and stab wounds, physical or sexual abuse, domestic violence, explosion-related injuries, and motor vehicle–related trauma should be adequately documented and include photographs as well as a narrative and diagram for possible use in future legal actions.[] However, in one trauma center, 70% of cases had improper or inadequate documentation, and 38% had potential evidence improperly secured, incorrectly documented, or inadvertently discarded.[6] Surgeon General Dr. Richard Carmona and Prince reported that trauma physicians “usually have little or no training in the forensic aspects of trauma care and therefore necessary evidence may often be overlooked, lost, inadvertently discarded or its admissibility denied because of improper handling or documentation.”[6] It is easy to overlook or destroy both gross and trace evidence. Misinterpretation of physical injuries and evidence may be recorded in the medical record and complicate future legal proceedings.[]

FORENSIC ASPECTS OF GUNSHOT WOUNDS Firearm-related deaths, 29,737 in 2002, are the second leading cause of injury-related deaths in the United States after motor vehicle trauma.[21] Emergency physicians treat more than 115,000 victims of gunshot wounds each year, principally from handguns.[22] The direct and indirect costs associated with gunshot wounds have been estimated at $14 billion annually.[]

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Errors of Interpretation and Terminology The emergency physician is in the ideal position to evaluate and document the state of a gunshot wound before it is disturbed, distorted, or destroyed by surgical intervention. Such evaluation requires a basic understanding of ammunition, ballistics, and relevant forensic terminology.[] Documentation of gunshot wounds should include the anatomic location, size, shape, and characteristics of the wound. Wounds should be described according to the standard anatomic position with the arms to the side and palms up. Clinicians should not describe wounds as “entrance” or “exit,” but should document a detailed description of the appearance and location of a wound with the use of appropriate forensic terminology without speculating on an interpretation or the caliber of the bullet.[] Despite common belief, exit wounds are not always larger than the entrance wound, and wound size does not correspond to bullet caliber.[] The size of any wound (entrance or exit) is determined by five factors: the size, shape, configuration, and velocity of the projectile at the instant of its impact with tissue and the physical characteristics of the impacted tissue itself. If the projectile is slow and its shape unchanged on exiting the skin, the exit wound may be equal to or smaller than its corresponding entrance wound.[] If the projectile increases its surface area by fragmenting or changing its configuration while maintaining substantial velocity, the exit wound may be significantly larger than the entrance wound.[] If the bullet strikes bone, fragments may extrude from the exit wound and contribute to the size and shape of the wound. Tissue elasticity also affects the wound size, so entrance or exit wound size may be smaller, equal to, or larger than the projectile that caused it.[] Palm or sole wounds may appear only as slits and are easily mistaken for stab wounds.[] Inappropriate terminology should not be used to describe wounds.[] Soot rather than the obsolete term powder burns should describe the carbonaceous material associated with close-range wounds.[] Powder burns are literally the burns associated with the coincidental ignition of clothing by the flaming black powder used in muzzle loaders, antique weapons, and blank cartridges. Such burns do not occur with the smokeless powder used in modern commercial ammunition. Powder burns, therefore, is an obsolete and potentially misleading expression. It is unnecessary to write in the medical record the manner of a gunshot victim's death. Whether a death is accidental, suicidal, or homicidal is the responsibility of the coroner or medical examiner and should be determined only after a detailed investigation of the scene and circumstances of the incident. The patient's position at the time of injury can be established only after an examination of the scene and collection of all forensic evidence. An emergency physician, nurse, or paramedic may be required to render “factual” or “expert” testimony in a criminal case. Such testimony, without an appropriate forensic examination or adequate forensic training, may deny the criminal justice system, a suspect, or the patient access to short-lived evidence. This evidence could assist in the identification of entrance versus exit or the range of fire and affect the determination of a suspected assailant's innocence or guilt.[] The speculation over the number and type of wounds in the assassination of President Kennedy is one example of the legal implications of the forensic evaluation.[]

Forensic Aspects of Handguns The Weapon Four categories of handguns exist: single-shot weapon (usually a target pistol); derringer (a small, concealable weapon, usually with two barrels); revolver (a weapon with a rotating cylinder that advances with the pull of the trigger); and autoloading or semiautomatic pistol (which fires with each pull of the trigger), most popular because the magazine, or clip, can hold up to 17 cartridges versus the 5 or 6 cartridges of revolvers. An automatic submachine gun fires pistol ammunition as long as the trigger is held until its ammunition is exhausted. A submachine gun's magazine may hold up to 60 cartridges. Weapons such as the Israeli UZI and the Heckler & Koch MP-5 use 9-mm or .40-caliber ammunition and are commonly used by police special weapons and tactics (SWAT) teams. Semiautomatic versions of the submachine gun are available to the general public, and kits to make these weapons fully automatic, though illegal, are sold through gun magazines.

Handgun Ammunition This discussion is limited to handgun and submachine gun ammunition. The cartridge, or round, is

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composed of a primer, cartridge case, powder, and bullet ( Figure 63-1 ). The bullet is the missile or projectile that is propelled out of the end of the muzzle.

Figure 63-1 A cartridge consists of several distinct com ponents: bullet, cartridge case, gunpowder, flash hole, and primer.

The primer is a small explosive charge located in the base of the cartridge that ignites the gunpowder. The primer is a chemical compound that may contain lead, barium, or antimony. These compounds may be deposited on the hands of the shooter, on the victim of a close-range assault, and on objects within a room in which the weapon is discharged. The cartridge case is typically made of brass, although other materials may be used. The function of the cartridge case is to expand slightly and seal the chamber against the escaping gases.[32] On detonation, a cartridge case is imprinted with unique microscopic marks that are valuable evidence and should be preserved for law enforcement. The gunpowder found in all commercial cartridges, except blanks, is smokeless powder made with a single base (nitrocellulose) or a double base (nitrocellulose and nitroglycerin). Gunpowder comes in different shapes and sizes, including ball powder, flattened ball powder, flake powder, cylindrical powder, and in some cartridges, a combination of powders.[32] When a weapon is discharged, not all the gun-powder is consumed in the combustion process. A percentage of the unburned gunpowder will travel out of the end of the muzzle for a distance, depending on the physical characteristics of the powder. Blank cartridges, muzzleloaders, and other antiques or replicas may use black powder. Black powder (a combination of potassium nitrate, charcoal, and sulfur) does not burn as efficiently as smokeless powder and results in a large flame and white smoke. The bullet is forced from the muzzle of a handgun at velocities ranging from 700 ft/sec to 1600 ft/sec (in magnum loads). The term magnum indicates that additional gunpowder has been added to the cartridge case to increase the velocity of the projectile. The most common bullet types include the round nose, full metal jacket, hollow point, wadcutter, and semiwadcutter. Bullets generally have a solid core of lead or steel and have a jacket if the bullet core is covered with a metal, usually copper or aluminum. If the jacket covers the entire projectile, it is called a full metal jacket, and if the jacket leaves some portion of the core exposed, it is semijacketed. The term hollow point denotes a hole in the tip of the bullet that causes expansion on contact with tissue. Recent additions to the armamentarium include bullets such as the Winchester Black Talon and the Federal Hydra-Shok, which supposedly increase tissue damage. Bullet caliber is described in 100ths of an inch or in millimeters. Handgun bullets range from .22 caliber, or 5.56 mm, to .45 caliber, or 11.3 mm. A bullet's weight is measured in grains, with 7000 grains/lb.

Handgun Wound Ballistics Wound ballistics is the study of the effects of penetrating projectiles on the body.[] Many misconceptions surround the science of wound ballistics.[] Injury results from the transference of a bullet's kinetic energy to the relatively stationary tissue. Wound severity is directly related to the amount of kinetic energy transferred to the tissue and direct tissue damage, not to the total amount of kinetic energy possessed by the bullet itself.[] Bullets fired from rifles generally have a higher velocity than those fired from handguns, 1500 to 4000 ft/sec versus 700 to 1600 ft/sec in handguns. Therefore, rifled bullets have more kinetic energy and a theoretically higher wounding potential, but wound severity is the result of many variables such as bullet velocity, weight, deformation, and fragmentation on

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impact with tissue and the characteristics and location of the impacted tissue itself.[] The principal mechanism of tissue damage is crushing. A bullet traveling through tissue generates two cavities, one permanent and the other temporary. The temporary cavity, a result of tissue stretching, lasts 5 to 10 msec from its generation until its collapse and leaves behind the permanently crushed tissue, the permanent cavity.[] The size of the permanent cavity varies with the size, shape, and configuration of the bullet. A hollow-point bullet that mushrooms can increase its diameter 2.5 times on impact and will increase the area of tissue crushing 6.25 times over that of a nondeformed bullet.[32]

Forensic Evaluation of Handgun Wounds Entrance Wounds Range of fire is the distance from the muzzle to the victim and can be divided into four general categories: contact, near contact or close range, intermediate or medium range, and indeterminate or distant range. The size of the entrance wound does not correlate with the caliber of the bullet[] because entrance wounds over elastic tissue will contract around the tissue defect and have a diameter much less than the caliber of the bullet.[]

Contact Wounds In contact wounds, the barrel or muzzle is in actual contact with the skin or clothing. Contact wounds can be subdivided into tight contact, in which the muzzle is pushed hard against the skin, and loose contact, in which the muzzle is incompletely or loosely held against the skin or clothing. In a tight-contact wound, all material—the bullet, gases, soot, incompletely burned pieces of gunpowder, and metal fragments—is driven into the wound. These wounds can vary from a small hole with seared blackened edges from the discharge of hot gases and an actual flame to a gaping stellate wound ( Figure 63-2 ). Large wounds occur when the wound is inflicted over thin or bony tissue and the injected hot gases cause the skin to expand to such an extent that the skin stretches and tears. These tears will have a triangular shape, with the base of the triangle overlying the entrance wound. Tears are generally associated with .32 caliber or greater, or magnum loads. Large stellate contact wounds are easily misinterpreted as exit wounds if based solely on their size.[] Stellate tears are not pathognomonic for contact wounds, however. Tangential wounds, ricochet or tumbling bullets, and some exit wounds may also be stellate in appearance but lack soot and powder within the wound and seared wound margins.[]

Figure 63-2 A, Tight-contact entrance wound from a .38-caliber revolver. The wound margins are seared from the discharge of hot gases and an actual flam e from the end of the barrel. The triangular-shaped tear is the result of tissue expansion from the discharge of gases into the tissue. B, Tight-contact entrance wound with large stellate tears from a .380 sem iautom atic pistol. The large triangular-shaped tears are the result of rapid expansion of gases under the skin. C, Tangential-contact wound from a 9-m m pistol on the m edial aspect of the left calf. The presence of soot at the superior aspect indicates a close range of fire. The patient initially reported that he was shot from a distance of 3 to 4 ft and later admitted that he accidentally shot him self while withdrawing his pistol from his boot. Large wounds as seen in B and C m ay be m isinterpreted as exit wounds because of their size.

In some tight-contact wounds, expanding skin is forced back against the muzzle of the gun, and a characteristic pattern called a muzzle contusion is formed ( Figure 63-3 ).[] Patterns like these should be documented before wound debridement or surgery because they are helpful in determining the type of weapon (revolver or semiautomatic).[]

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Figure 63-3 A “m uzzle contusion” is a contusion caused by skin expansion against the barrel of the weapon. Muzzle contusions are associated with contact wounds.

When a gun's muzzle or barrel is not in complete (or with loose) contact or is angled relative to the skin, the soot and gunpowder residue are present both within and surrounding the wound. The angle between the muzzle and the skin determines the soot pattern. A perpendicular loose- or near-contact wound results in searing of skin and deposition of soot around the wound. A tangential-, loose-, or near-contact wound produces elongated searing and a soot deposit around the wound.

Close-Range Wounds Close range is the maximum range at which soot is deposited on the wound or clothing, usually with a muzzle-to-target distance of less than 6 inches. Beyond 6 inches the soot usually falls away and does not reach the target. On rare occasion, soot has been noted on victims as far away as 12 inches.[] The concentration of the soot varies inversely with the muzzle-to-target distance and is influenced by the type of gunpowder, ammunition, barrel length, caliber, and type of weapon ( Figure 63-4 ).

Figure 63-4 Close-range wound with soot deposition. Soot is associated with a range of fire of 6 inches or less.

At close range, the partially and unburned pieces of gunpowder have dispersed inadequately to cause powder tattooing. A precise range of fire, for example, 1 cm versus 10 cm, cannot be determined from an examination of the wound. A forensic crime laboratory can attempt to reproduce the patient's soot pattern on a target by test-firing the offending weapon at different ranges with ammunition similar to that causing the wound. The accuracy of this test depends principally on an exact and detailed description of the patient's soot pattern. Because soot can be removed with debridement or wound cleansing, its presence and configuration surrounding the wound should be noted and photographed unless the patient's clinical condition precludes such attention to detail.[]

Intermediate-Range Wounds “Tattooing,” or “stippling,” is pathognomonic for an intermediate-range gunshot wound. It appears as punctate abrasions and is caused by contact with partially burned and wholly unburned pieces of gunpowder ( Figure 63-5 ). Tattooing, or stippling, cannot be wiped away. Tattooing rarely occurs on the palms of the hands or the soles of the feet because of the thickness of the epithelium.[32]

Figure 63-5 “Tattooing” results from contact with pieces of unburned gunpowder. These punctate abrasions are associated with an interm ediate range of fire, generally less than 36 inches. The density of these abrasions depends on the length of the gun's barrel, the distance from the m uzzle to the skin, the type of gunpowder used, and the presence of any intervening objects.

Tattooing occurs as close as 1 cm and as far away as 1 m but is generally found at distances of 60 cm or less.[] The density of the tattooing and the associated pattern depend on the length of the barrel, the caliber, the type of ammunition/gunpowder, the muzzle-to-skin distance, and the presence of intermediate objects. Clothing, hair, or other intermediate barriers may prevent tattooing from occurring. Ball powder, because of its shape, travels farther and has greater penetration than flattened ball powder does.[32] Flattened ball powder travels farther than flake powder.[32] The presence of partially or entirely unburned pieces of gunpowder and gunpowder residue on clothing or skin is a clue that can aid in determination of the range of

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fire. If gunpowder penetrates even thin clothing, it will generally lack the energy to penetrate skin.

Long-Range Wounds A long-range wound is inflicted from a distance far enough away that only the bullet makes contact with the skin. There is no tattooing or deposition of soot with distant entrance wounds. As the bullet penetrates the skin, the skin is indented, which results in the creation of an “abrasion collar,” or interchangeably, an abrasion margin, abrasion rim, or abrasion ring ( Figure 63-6 ). This collar is an abraded area of tissue that surrounds an entry wound, the result of friction between the bullet and the epithelium. The width of the abrasion collar varies with the angle of impact. Most entrance wounds will have an abrasion collar. Entrance wounds on the palms and soles are exceptions in that they usually appear slitlike.[32]

Figure 63-6 An “abrasion collar” is the abraded area surrounding the entrance wound created by the bullet when it indents and passes through the epithelium . The collar or rim is the result of friction between the bullet and the epithelium. The width of the abrasion collar will vary with the angle of impact.

The abrasion collar is not the result of thermal changes associated with a hot projectile. The edges of a contact or close-range wound may be seared by the release of hot gases and flame. This clinical finding may overlap or obscure the abrasion collar. When an abrasion collar is the only superficial clinical finding present, the physician may also use the term indeterminate range to describe the range of fire. A wound inflicted from a distance of 10 ft will appear the same as a wound inflicted from 50 or 100 ft. An exact range of fire cannot be determined with a distant wound. Determining the range of fire may be complicated by clothing that prevents the deposition of soot and powder on the skin. When such a wound is examined without the overlying clothing or without information regarding the crime scene, the wound may appear to be from a distant range of fire. In reality, the range may have been close or intermediate. Conversely, a projectile discharged from a distant range of fire may mimic an intermediate range if it strikes an object such as glass, which fragments. As with unburned gunpowder, when the glass fragments strike the skin, they may also cause punctate abrasions resulting in pseudotattooing ( Figure 63-7 ).[]

Figure 63-7 A and B, “Pseudotattooing,” or punctate abrasions from glass fragm ents, not unburned gunpowder, on the m edial aspect of the thigh associated with a gunshot wound. The leg was showered with glass fragm ents after the round penetrated the windowpane.

Atypical Entrance Wounds Some atypical entrance wounds are indicative of a bullet having encountered an intermediate object, such as a window, wall, or door, before striking the victim. The intermediate object may change the bullet's size, shape, or path. Such changes can result in entrance wounds with large stellate configurations that mimic close-range or contact wounds.[] Ricochet bullets may also produce atypical entrance wounds. Graze wounds occur as a result of tangential contact with a passing bullet. The directionality of the bullet can be determined from close examination of the wound.[] The bullet produces a trough with the formation of skin tags on the lateral wound margins. The bases of these skin tags point toward the weapon and away from the direction of bullet travel.[46]

Exit Wounds

Page 698

Exit wounds are the result of a bullet pushing and stretching the skin from inside out. The skin edges are generally everted with sharp, but irregular margins. Abrasion collars, soot, and tattooing are never seen at an exit wound. Exit wounds have a variety of shapes and configurations and are not consistently larger than their corresponding entrance wounds ( Figure 63-8 ). The exit wound's size is determined primarily by the amount of energy possessed by the bullet as it exits the skin and by the bullet's size and configuration. On entering the skin, a bullet's configuration will change from its usual nose-first attitude to tumbling and yawing. A bullet with sufficient energy to exit the skin sideways, or one that has increased its surface area by mushrooming, will produce an exit wound larger than its entrance wound.[]

Figure 63-8 A, Slitlike exit wound from a .22-caliber bullet. B, Perforating gunshot wound to the left deltoid area with soot deposition around the larger entrance wound. No soot is present around the sm aller exit wound. Exit wounds are not consistently larger than their corresponding entrance wounds.

Atypical Exit Wounds A “shored-exit” wound is a wound that has an associated false abrasion collar. If the skin is pressed against or supported by a firm object or surface at the moment that the bullet exits, the skin can be compressed between the exiting bullet and the supporting surface ( Figure 63-9 ).[] Examples of supporting structures include belts, floors, walls, doors, chairs, and mattresses.

Figure 63-9 “Shored” exit wound with a false abrasion collar. This type of wound occurs when the skin in the region of the exiting bullet is in contact with a supporting structure (e.g., a wall, floor, or m attress). The skin is slapped against the supporting structure, which results in a false abrasion collar.

On rare occasion, soot may also be present at an atypical exit wound site.[49] If a contact entrance wound is located close to its associated exit wound, soot can be propelled through the short wound track and appear faintly on the exit wound surface.

Forensic Evaluation of Centerfire Rifle Wounds Projectiles discharged from centerfire rifles have the potential to inflict massive tissue damage ( Figure 63-10 ). A bullet's wounding potential is based on the kinetic energy that it possesses. The calibers of centerfire bullets, .223 to .308, are similar in diameter to handgun ammunition, but their wounding potential is greatly enhanced by the velocity of the round.[32] The higher the velocity of a projectile, the greater the potential to inflict tissue damage based on the formula kinetic energy = mass × velocity[2]/g. Injuries result from the transference of energy from the projectile to organs and bony structures. With high-velocity rounds greater than 2000 ft/sec, a temporary cavity is formed along the wound tract. The temporary cavity may approach 11 to 12 times the diameter of the bullet and can result in tissue damage away from the physical tract taken by the projectile itself.[36] Temporary cavitation, in combination with direct tissue disruption and energy transfer from a fragmenting or yawing (turning sideways) projectile, is what determines the size of the internal injury and that of the exit wound. Because of the amount of energy possessed and transferred to underlying tissue, exit wounds associated with centerfire rifles, in contrast to those associated with handguns, are generally larger than their corresponding entrance wounds ( Figure 63-11 ).[32]

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Figure 63-10 This patient sustained a high-velocity gunshot wound to the forehead. High-velocity rifle rounds, because of their kinetic energy, can cause m assive dam age when the energy is transferred to underlying tissue.

Figure 63-11 Exit wound from a high-velocity rifle round. Exit wounds from high-velocity rounds are generally larger than their corresponding entrance wounds. The large size is due to energy transfer from the projectile to underlying tissue with the expulsion of tissue, principally bone.

Entrance wounds associated with high-velocity, centerfire projectiles do not significantly differ from those of handguns. Entrance wounds will generally exhibit abrasion collars or microtears on the skin surface ( Figure 63-12 ). Wounds will also have associated soot deposition and tattooing, but because of a number of variables, such as muzzle length, amount of power in a given cartridge, muzzle configuration, and type of gunpowder (ball versus cylindrical), the range of fire in rifle wounds is not as clearly defined as in handgun wounds. Determination of an exact range of fire for rifles and shotguns is best established through controlled testing performed by a firearms examiner at a crime laboratory.

Figure 63-12 Entrance wound from a high-velocity rifle round. Entrance wounds of high-velocity projectiles will also display an abrasion collar.

High-velocity lead core and jacketed bullets generally break up into hundreds of fragments, called a “lead snowstorm,” on entering tissues and create significant tissue damage ( Figure 63-13 ).[32] If the tissue is deep, the bullet fragments may fail to exit and remain embedded. Thus, it is possible to sustain an injury with a high-velocity round and not exhibit an exit wound. High-velocity rounds with steel cores will almost uniformly exit intact and continue down range. Both of these facts can confound a forensic investigator's efforts to find an adequate projectile sample to submit to the firearms examiner as evidence for ballistic analysis.

Figure 63-13 “Lead snowstorm ” from a high-velocity rifle round. High-velocity projectiles have a tendency to fragment into hundreds of tiny particles on contact with bone. This fragm entation contributes to the massive tissue dam age associated with these projectiles.

Microscopic Examination of Wounds The debrided epithelial margins of wounds should be submitted to the pathology department for histologic

Page 700

examination to help determine the projectile's entrance, exit, and range of fire.[]

Evidence A victim's clothing may yield information about a bullet's range of fire and help distinguish entrance from exit wounds.[] Clothing fibers deform in the direction of the passing projectile.[] Gunpowder residue and soot will be deposited on clothing as they are on skin. Residue may be invisible to the naked eye but can be visualized with standard forensic staining techniques for nitrates and vaporized lead. Some bullets, as they make initial contact with clothing, leave a lead or lubricant residue that is termed bullet wipe. Articles of clothing removed from a wounded patient need to be placed in separate paper bags to avoid cross-contamination of evidence. A gunshot residue (GSR) test may determine whether a victim or suspect has fired a weapon.[] The GSR test checks for the presence of invisible residue from the primer: barium nitrate, antimony sulfide, and lead peroxide. There are two methods of checking for residue: the palms and the dorsum of the hands can be swabbed with a 5% nitric acid solution and analyzed by atomic absorption spectrophotometry, or tape or an adhesive disk can be placed on the hands and removed for examination under a scanning electron microscope. The specificity and sensitivity of the GSR test are unclear.[] Residue will be deposited on the hands of the individual who fired a weapon in only 50% of cases.[33] Residue may spread about a crime scene, and secondary contact with the weapon or furniture on which residue was deposited will result in a false-positive test. The possibility of transferring residue from police officers to suspects has also been reported.[63] The sensitivity of the test decreases with time, and law enforcement agents may not have access to a patient during the “golden hour.”[33] Factors that decrease the test's sensitivity include washing the skin with alcohol or povidone-iodine (Betadine), placing tape on the skin, rubbing the hands against clothing, and placing plastic bags over the patient's hands, which precipitates moisture on the skin. If a GSR test is to be performed or if soot is noted on the patient's hand, paper bags should be placed over the hands early during treatment of the patient. The bullet, the bullet jacket, and the cartridge case are invaluable when identifying or excluding a weapon.[] When a weapon is discharged, it imprints multiple unique microscopic marks on the side of the bullet and on the bottom or side of the cartridge case.[] The bullet's markings result from its contact with the tool marks, or “rifling,” in the gun's barrel. The marks on the cartridge case result from contact with the firing pin, the breechblock, the magazine of semiautomatic weapons, and the extractor and ejector mechanisms. The emergency physician must work diligently to preserve these microscopic fingerprints and not obliterate the markings by removing a bullet with hemostats or pickups.[] Bullets should be handled with gloves and surgical instruments covered with gauze to ensure the preservation of these microscopic “fingerprint” marks. It is not necessary to place initials or other markings on the bullet if adequate notes are made in the patient's medical record regarding the chain of custody. Radiographs also help locate retained projectiles and may be of evidentiary value when determining the number of projectiles and the direction of fire.[]

FORENSIC ASPECTS OF PHYSICAL ASSAULT Identifying Assault Victims Studies estimate that 22% to 33% of the patients in an urban emergency department are victims of domestic violence, yet only a small percentage of these patients are recognized as such.[] In one study of emergency department visits, 43% of abused patients were treated for acute trauma 6 or more times before they were identified as victims of abuse; nearly half of these patients were seen at least 12 times.[78] Every weapon leaves a mark, design, or pattern stamped or imprinted on or just below the epithelium. The epithelial imprints of these weapons, called pattern injuries, are consistently reproducible.[] These injuries fall into three major categories according to their source: blunt force, sharp force, and thermal. Knowledge of pattern injuries and accurate documentation regarding the anatomic location of the injuries make determining what implement, tool, or weapon was responsible for producing each wound much easier.

Blunt Force Pattern Injuries The most common blunt force injury is a contusion, along with abrasions and lacerations. A weapon with a

Page 701

unique shape or configuration may stamp a mirror image of itself on the skin ( Box 63-1 ).[79] BOX 63-1 Commonly Inflicted Pattern Injuries

{,

{,

{,

{,

{,

Slap mark s with digit s delin eate d Loop ed or flat cont usio ns from belts or cord s Circ ular cont usio ns from finge rtip pres sure Para llel cont usio ns with centr al clear ing from linea r obje cts Cont usio ns from shoe heel s and sole s

Page 702

{,

Sem icirc ular cont usio ns and abra sion s from bite mark s

Pattern Contusions A pattern contusion is a common injury that helps identify the causative weapon. A blow from a linear object leaves a contusion that is characterized by a set of parallel lines separated by an area of central clearing ( Figure 63-14 ).[] The blood underlying the striking object is forcibly displaced to the sides, which accounts for the pattern's appearance ( Figure 63-15 ).

Figure 63-14 A direct blow from a linear object results in a pattern contusion with central clearing surrounded by parallel linear contusions. The blood directly beneath the impacting object is displaced laterally and accounts for the distinctive contusion.

Figure 63-15 Pattern contusion with parallel lines and central clearing from contact with a baseball bat.

Circular or linear contusions should suggest abuse or battery. Circular contusions 1.0 to 1.5 cm in diameter are consistent with fingertip pressure and grab marks ( Figure 63-16 ). One commonly overlooked anatomic location where fingertip pressure contusions are often present is the medial aspect of the upper part of the arm.[79] Contact with the sole of a shoe from a kick or stomp may also leave a pattern contusion that can assist in identifying the patient's assailant.

Figure 63-16 Three som ewhat circular contusions and a linear contusion on the anterior aspect of the neck. These injuries resulted from hand and fingertip pressure applied during an attem pted strangulation.

The emergency physician may be requested to evaluate injuries that allegedly occurred as a result of police

Page 703

brutality. Specific pattern contusions can include parallel contusions from contact with a flashlight or nightstick. Handcuff or shackle marks are seen as narrow parallel contusions or abrasions on the wrists or ankles. Handcuff and shackle marks are generally more prominent on the lateral aspects of the extremity.[33] The emergency physician should record a history and document the injuries with diagrams and photographs when possible. The investigation of all the circumstances surrounding the incident is best reviewed by an internal affairs or professional standards unit of the investigating law enforcement agency and not by the emergency physician. A bite mark may appear as a pattern contusion, an abrasion, or a combination of both ( Figure 63-17 ). Bite marks vary greatly in the quality of their identifiable features, depending on the anatomic location of the bite and the motion of the teeth relative to the skin. Some bite marks may not be readily identifiable as a bite and appear as a nonspecific contusion, abrasion, or contused abrasion.

Figure 63-17 Bite m ark with two sem icircular arched contusions over the anterior lateral aspect of the patient's neck. A bite m ark can be used to identify the assailant if the injury is correctly docum ented by a forensic photographer or forensic odontologist. A circular contusion on the right lateral aspect of the neck was the result of fingertip pressure.

When an acute bite mark is identified, the emergency physician should not wash away potential evidence. The skin surface should be swabbed with a sterile cotton-tipped applicator moistened with sterile saline. Such swabbing may detect the presence of the assailant's saliva. This evidence is short lived because of rapid degradation of blood group antigens and should be collected and sent to the crime laboratory as quickly as possible. Eighty percent of the population secretes an ABO blood group protein antigen in saliva. DNA from buccal cells may also be deposited over an acute bite mark.[13] When available, a forensic odontologist can evaluate a bite wound with accuracy. The use of alternative light sources, such as ultraviolet or infrared, may reveal a pattern contusion within or under the epithelium that is not visible to the naked eye.[33] These light sources are routinely used by forensic odontologists on faint, old, or difficult bite marks. Assailants have been identified from bite marks up to 6 months after injury. The emergency physician may be asked to render an opinion regarding the age of a contusion. The development of a contusion is based on a number of variables: the amount of blunt force applied to the skin, the vascularity of the tissue, the fragility of the blood vessels, the density of the tissue, and the amount of blood that escapes into the surrounding tissue.[] As a result, no reproducible standard for dating a contusion based on its color is possible.[81]

Pattern Abrasions A pattern abrasion is a rubbing or scraping away of the superficial layers of the epidermis ( Figure 63-18 ). The presence of such pattern injuries, though not important from the standpoint of treatment, may be invaluable from a forensic and injury reconstruction perspective.[79]

Figure 63-18 Four fingernail scratch m arks on the m edial aspect of a forearm .

Pattern Lacerations A pattern laceration is defined as a tear produced by blunt trauma and should not be confused with an

Page 704

incised wound produced when a sharp-edged implement (knife or scalpel) is drawn across the skin.[13] A pattern laceration has characteristically abraded or crushed skin edges and unique “tissue bridges” ( Figure 63-19 ).

Figure 63-19 A laceration is the result of blunt traum a and characteristically displays tissue bridges and crushed wound m argins.

Sharp Force Pattern Injuries Two types of sharp force injuries may be encountered. An incised wound is longer than it is deep, and a stab wound is defined as a puncture wound that is deeper than it is wide. The wound margins of sharp force injuries are clean and lack the abraded edges of injuries resulting from blunt force. Forensic information can be gathered during the examination of a stab wound. Some of the characteristics of a knife blade, single edged or double edged, can be determined from visual inspection ( Figure 63-20A and B ).[] Additional characteristics, such as serrated versus sharp, can be determined if the blade was drawn across the skin during insertion or withdrawal ( Figure 63-20C ). Serrated blades do not always leave these characteristic marks.[]

Figure 63-20 A, A stab wound with a single-edged knife blade will cause a wound to be form ed with a sharp edge and a dull edge. If the blade penetrates to its hilt, a “hilt mark” m ay be seen overlying the sharp edge. B, Single-edged stab wound. C, Single-edged stab wound m ade by a serrated blade. Abrasions from the blade's serrated edges are seen on the left margin of the wound.

Thermal Pattern Injuries A thermal pattern injury is a common form of abuse or battery. The detailed history of the incident should include the position of the patient relative to the thermal source. When this information is available and reliable, it will help determine whether the injury was intentional or accidental.[79] Immersion or dipping burns are characterized by a sharp or clear line of demarcation between burned and unburned tissue. In contrast, splash burns are characterized by an irregular or undulating line or by isolated areas of thermal injury, usually round or oval, caused by droplets of hot liquid. The severity of a thermal or scald injury depends on the length of time of contact and the temperature. Water causes full-thickness burns in 1 second at 158° F (70° C) and 600 seconds at 120° F (48.9° C) ( Figure 63-21 ).[82] Law enforcement agents routinely measure the household's or institution's water temperature in any investigation involving a scald injury.

Figure 63-21 Relationship between water tem perature and the duration of contact required to produce a full-thickness therm al injury ((From Katcher ML: Scald b urns from hot tap water. JAMA 246:1219, 1981.))

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FORENSIC ASPECTS OF MOTOR VEHICLE TRAUMA Law enforcement officials investigating an incident involving serious injuries from a motor vehicle crash or pedestrian collision benefit from information regarding injury patterns and collection of trace evidence from the victim. This information can help determine whether an occupant was the driver or a passenger. It may also help identify a suspect vehicle involved in a hit-and-run pedestrian collision. A pedestrian's position (standing or lying) when struck in the roadway may be determined. The treating physicians may be involved in subsequent legal proceedings that arise in both civil and criminal court. Determination of a vehicle occupant's role may be simple, if the driver is pinned behind the steering wheel, or complex, if the vehicle's occupants are ejected. Many impaired drivers claim to be passengers. Short-lived evidence or pattern injuries that might be destroyed or altered in the delivery of patient care should optimally be preserved.[] The emergency physician should avoid rendering an opinion on an occupant's position because it is difficult to determine based solely on statements and physical findings in the emergency department.[] Such an opinion is better based on an examination of the scene, the vehicle, other occupants, and information regarding trace evidence. Expert opinions are best rendered only after forensic examinations, including postmortem examinations, are performed on all the vehicle's occupants and all forensic evidence has been evaluated ( Box 63-2 ).[] BOX 63-2 Evidence Collection—Driver versus Passenger

Victim

Examine for Pattern Injuries Stee ring whe el cont usio n Radi o knob cont usio n Win dow cran k cont usio n Stria ted incis ed facia l wou nds “Dici ng” wou nds

Page 706

Examine Clothing for Transferred Materia

[*][†]

Glas s (fron t and side wind ows) Fiber s Ped al impri nt on shoe Das hboa rd com pone nts

Collect Biologic Standards

[†]

Hair Bloo d

Collect Clothing Standards

[†]

Dam age

Vehicle

Examine for Pattern Damage Stee ring whe el Radi o/kn obs/ dash boar d Win dow cran

Page 707

k/sid e door Win dshi eld (lami nate d glas s) Side/ rear wind ow (tem pere d glas s)

Collect Standards Glas s Carp ets and seat s Gas and brak e peda ls Brok en dash boar d com pone nts

Examine for Transferred Material of Pedestrian Hair on wind shiel d/co mpo nent s Bloo

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d on wind shiel d/co mpo nent s

Examine for Transferred Material on Car Occupants Fabri c fiber s Impri nted fabri c patte rn * Each article of clothing should be collected in a separate paper bag. This avoids cross-contamination, and wet m aterial will dry. Do not collect evidence in plastic bags because moisture will condense within the bag and m ay degrade biologic m aterial. † Each article should be m arked with the patient's nam e, item collected, date and tim e collected, location of collection, nam e of the collector, and nam e of law enforcem ent official to whom the evidence was given. This information will preserve the “chain of custody.”

Pattern Injuries Matching pattern injuries with components within a vehicle often reveals an occupant's position during a portion of the vehicle's collision sequence.[] Common pattern contusions, abrasions, and lacerations occur as a result of contact with steering wheels, air bags, air bag module covers, window cranks, radio knobs, door latches, dashboard components, and front and side window glass.[] An occupant's movement and subsequent contact with a vehicle's components are dictated by the force applied to the vehicle through its interaction with the environment. Vehicle occupants, restrained or unrestrained, will initially move toward the primary area of impact.[] This movement within the vehicle, called occupant kinematics, is described as a motion parallel to and opposite the direction of the force developed by the impacting object.[] Applying the principles of occupant kinematics will predict in what direction a particular occupant will move and therefore what component will be struck. A deploying air bag may induce a pattern abrasion on the face, cornea, forearms, or other exposed tissue. Pattern lacerations, specific fracture patterns, and amputations are seen when the deploying air bag module cover impacts the hand or forearm ( Figure 63-22 ).[] Correlation of these injuries to the driver or passenger air bag system is helpful in assessing an occupant's role.[]

Figure 63-22 Com m inuted, bending-type fracture of the radius and ulna from im pact with a deploying air bag m odule cover.

Both laminated glass (windshield) and tempered glass (side and rear windows) produce pattern injuries. The windshield is composed of two layers of glass laminated together with a thin layer of clear plastic sandwiched between. Laminated glass breaks into shards on impact. Tempered, or “safety,” glass is a single layer of glass that breaks into small cubes when fractured. Shattered tempered glass from side and rear windows imparts a “dicing” pattern to the skin, whereas shattered laminated windshield glass causes linear incised wounds.

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Trace Evidence Clothing, shoes, and biologic standards (hair and blood) may determine an occupant's role.[] Examination of the soles of leather shoes may reveal an imprint of the gas or brake pedal ( Figure 63-23 ). Preservation of clothing permits a comparison of clothing fibers with fibers transferred to vehicle components during the crash.[] Imprints of fabric may also be transferred to components within the vehicle, including the steering wheel. Contact with the windshield often transfers hair and tissue to the glass. Glass collected from within a patient's wound can be matched with a particular window within the vehicle. Airbags are also a tremendous source of trace evidence, including skin, blood, makeup, and hair.[87]

Figure 63-23 Im print of a brake pedal on a leather-soled shoe. This inform ation will assist in determ ining the occupant's role and in determ ining whether the patient's foot was on the brake or accelerator pedal at the m om ent of im pact.

Evaluation of Pedestrian Collisions Pattern Injuries Approximately 75,000 persons are killed or seriously injured annually in pedestrian collisions[89]; 82% are struck by a vehicle's front bumper/grill area. A standing adult struck by the front of a vehicle will sustain “bumper injuries,” which include open and closed fractures of the tibia and fibula, soft tissue damage, and pattern injuries from vehicle components and hardware.[33] The height of bumper injuries, measured from the heel and including the height of the patient's shoe, can be correlated with the height of the vehicle's bumper to determine whether the vehicle was braking at the moment of impact. Application of the brake results in dipping of a vehicle's front end. The presence or absence of braking may help determine the driver's intent. The presence of bumper injuries at one height on one leg and at another height on the other may indicate that the pedestrian was walking or running at the moment of impact, with one leg elevated. Examination of the soles may show lateral striations when a patient has been dragged. A victim who is struck from behind may have pattern contusions on the calf or thigh ( Figure 63-24 ), whereas pattern contusions from a grill on the anterior aspect of the thigh indicate that the pedestrian was standing and facing the vehicle. Victims who are run over may display a tire tread pattern. Tire marks and the absence of bumper injuries may indicate that the patient was supine or prone in the roadway ( Box 63-3 ).

Figure 63-24 A, A circular pattern contusion on the posterior aspect of a pedestrian's left calf was the result of contact with the head of a bolt. The location of the contusion provides inform ation about the configuration of the patient at the m om ent that the car struck him . The patient was struck from the rear. B, A puncture wound on the posterior aspect of the left thigh resulted from contact with the headlight filam ent.

BOX 63-3 Evidence Collection—Pedestrian Collisions

Victim

Examine for Pattern Injuries

Page 710

Height of bumper injuries Cont usio n Frac ture Head/neck injuries Crush injuries

Examine Clothing for Transferred Materia

[*][†]

Paint Glas s (win dshi eld, head light) Oil or grea se

Collect Biologic Standards

[*]

Hair Bloo d or tissu e

Collect Clothing Standards

[†]

Dam age or tears

Vehicle

Examine for Pattern Damage Bum per heig ht and dam

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age Spe cific com pone nts Win dshi eld dam age Whe els and unde rcarr iage

Collect Standards Paint Glas s Oil or grea se

Examine for Transferred Material Hair Bloo d or tissu e

Examine for Transferred Material Fabri c fiber s Impri nted fabri c patte rn * Each article of clothing should be collected in a separate paper bag. This avoids cross-contamination, and wet m aterial will dry. Do not collect evidence in plastic bags because moisture will condense within the bag and m ay degrade biologic m aterial. † Each article should be m arket with the patient's nam e, item collected, date and tim e collected, location of collection, nam e of the collector, and nam e of law enforcem ent official to whom the evidence was given. This information will preserve the “chain of custody.”

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KEY CONCEPTS

{,

{,

{,

Kno wled ge of wou nd mec hani cs and prod uctio n, as well as wou nd appe aran ce, can provi de pract icing eme rgen cy phys ician s with impo rtant clue s to the foren sic inter preta tion of injuri es. Diag ram and phot ogra ph wou nds and injuri es. The medi

Page 713

cal reco rd shou ld accu ratel y docu ment obje ctive findi ngs but shou ld not spec ulate on the caus e or mec hani sm.

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Marx: Rosen's Emergency Medicine: Concepts and Clinical Practice, 6th ed., Copyright © 2006 Mosby, Inc.

REFERENCES 1. McLay WDS: Clinical Forensic Medicine, London, Pinter, 1990. 2. Eckert W: The development of forensic medicine in the United Kingdom from the 18th century. Am J Forensic Med Pathol1992;13:124. 3. Payne-James JJ, Dean PJ: Assault and injury in clinical forensic medical practice. Med Sci Law 1994;34:202. 4. Goldsmith MF: US forensic pathologists on a new case: Examination of living patients. JAMA 1986;256:1685. 5. Smialek JE: Forensic medicine in the emergency department. Emerg Med Clin North Am1983;1:1685. 6. Carmona R, Prince K: Trauma and forensic medicine. J Trauma1989;29:1222. 7. Smock WS, Nichols GR, Fuller PM: Development and implementation of the first clinical forensic medicine training program. J Forensic Sci1993;38:835. 8. Smock WS: Development of a clinical forensic medicine curriculum for emergency physicians in the USA. J Clin Forensic Med1994;1:27. 9. Smock WS, Ross CS, Hamilton FN: Clinical forensic medicine: How ED physicians can help with the sleuthing. Emerg Legal Briefings1994;5:1. 10. Eckert WG: Clinical forensic medicine. Am J Forensic Med Pathol1986;7:182. 11. Mittleman RE, Goldberg HS, Waksman DM: Preserving evidence in the emergency department. Am J Nurs1983;83:1652. 12. Godley DR, Smith TK: Some medicolegal aspects of gunshot wounds. J Trauma1977;17:866. 13. Smock WS: Forensic emergency medicine. In: Olhaker JS, Jackson MC, Smock WS, ed.Forensic Emergency Medicine, Philadelphia: Lippincott, Williams & Wilkins; 2001: 14. Busuttil A, Smock WS: Training in clinical forensic medicine in Kentucky. Police Surgeon1990;14:26. 15. In: Wade C, ed.FBI Forensic Sciences Handbook. An FBI Laboratory Publication, Quantico, Va: Federal Bureau of Investigation; 2003: 16. Smock WS: Forensic photography. In: Stack LB, Storrow AB, Morris A, Patton DR, ed.Handbook of Medical Photography, Philadelphia: Hanley & Belfus; 2001: 397-408. 17. Collins KA, Lantz PE: Interpretation of fatal, multiple, and exiting gunshot wounds by trauma specialists. J Forensic Sci1994;39:94. 18. McLeer SV: Education is not enough: A systems failure in protecting battered women. Ann Emerg Med 1989;18:651. 19. Breo DL: JFK's death: The plain truth from the MDs who did the autopsy. JAMA1992;267:2794. 20. Randall T: Clinicians' forensic interpretations of fatal gunshot wounds often miss the mark. JAMA 1993;269:2058. 21. Centers for Disease Control and Prevention : Death, preliminary data for 2002. Natl Vital Stat Rep 2004;52:13. 22. Surveillance for fatal and nonfatal firearm-related injuries—United States, 1993-1998. Mor Mortal Wkly Rep CDC Surveill Summ2001;13:1. 23. Voelker R: Taking aim at handgun violence. JAMA1995;273:1739. 24. Annest JL: National estimates of nonfatal firearm-related injuries. JAMA1995;273:1749. 25. Dana SE, DiMaio VJM: Gunshot trauma. In: Payne-James J, Busuttil A, Smock W, ed.Forensic Medicine: Clinical and Pathological Aspects, London: Greenwich Medical Media; 2003: 149-168. 26. Fackler ML, Riddick L: Clinicians' inadequate descriptions of gunshot wounds obstruct justice: Clinical journals refuse to expose the problem. Proceedings of the American Academy of Forensic Sciences, vol 2. Colorado Springs, Colo: McCormick-Armstrong; 1996: 150. 27. Smock WS: Forensic medicine, pattern injuries of domestic violence, assault and abuse. In: Knoop KH, Stack LB, Storrow AB, ed.Atlas of Emergency Medicine, 2nd ed. New York: McGraw-Hill; 2002: 565-576. 28. Marlowe AL, Smock WS: The forensic evaluation of gunshot wounds by prehospital personnel. Proceedings of the American Academy of Forensic Sciences, vol 2. Colorado Springs, Colo: McCormick-Armstrong; 1996: 149. 29. DiMaio VJM, Spitz WU: Variations in wounding due to unusual firearms and recently available

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ammunition. J Forensic Sci1972;17:377. 30. Fackler ML: Wound ballistics: A review of common misconceptions. JAMA1988;259:2730. 31. Fatteh A: Medicolegal Investigation of Gunshot Wounds, Philadelphia, JB Lippincott, 1976. 32. DiMaio VJM: Gunshot Wounds, 2nd ed. Boca Raton, Fla, CRC Press, 1999. 33. Spitz WU: Medicolegal Investigation of Death, 3rd ed. Springfield, Ill, Charles C Thomas, 1993. 34. Rich NM: Missile injuries. Am J Surg1980;139:414. 35. Breo DL: JFK's death, part II—Dallas MDs recall their memories. JAMA1992;267:2791. 36. Sellier KG, Kneubuehl BP: Wound Ballistics and the Scientific Background, Amsterdam, Elsevier, 1994. 37. Le Garde LA: Gunshot injuries, 2nd ed, revised, Mt. Ida, Ark, Lancer Militaria, 1991. 38. Lindsey D: The idolatry of velocity, or lies, damn lies, and ballistics. J Trauma1980;20:1068. 39. Lindsey D: Review of management of gunshot wounds by Ordog. Am J Emerg Med1989;7:117. 40. Fackler ML: Review of management of gunshot wounds by Ordog. Ann Emerg Med1988;17:1004. 41. Barach EM, Tomlanovich MC: Letter to editor. J Trauma1988;28:1610. 42. Mason JK: The Pathology of Trauma, 2nd ed. London, Hodder & Stoughton, 1993. 43. Dixon DS: Tempered plate glass as an intermediate target and its effects on gunshot wound characteristics. J Forensic Sci1982;27:205. 44. Stahl CJ: The effect of glass as an intermediate target on bullets: Experimental studies and report of a case. J Forensic Sci1979;24:6. 45. Donoghue ER: Atypical gunshot wounds of entrance: An empirical study. J Forensic Sci1984;29:379. 46. Dixon DS: Determination of direction of fire from graze gunshot wounds. J Forensic Sci1980;25:272. 47. Dixon DS: Determination of direction of fire from graze gunshot wounds of internal organs. J Forensic Sci1984;29:331. 48. Dixon DS: Characteristics of shored exit wounds. J Forensic Sci1981;26:691. 49. Adelson L: A microscopic study of dermal gunshot wounds. Am J Clin Pathol1961;35:393. 50. Murphy GK: The study of gunshot wounds in surgical pathology. Am J Forensic Med Pathol1980;1:123. 51. Finck PA: Ballistic and forensic pathologic aspects of missile wounds: Conversion between Anglo-American and metric-system units. Mil Med1965;130:545. 52. Torre C, Varetto L, Ricchiardi P: New observations on cutaneous firearm wounds. Am J Forensic Med Pathol1986;7:186. 53. Dixon DS: Gunshot wounds: Forensic implications in a surgical practice. In: Ordog GJ, ed.Management of Gunshot Wounds, New York: Elsevier; 1988: 54. Lee HC, Palmbach T, Miller MT: Henry Lee's Crime Scene Handbook, San Diego, Calif, Academic Press, 2001. 55. Wolten GM: Particle analysis for the detection of gunshot residue—I: Scanning electron microscopy/energy dispersive x-ray characterization of hand deposits from firing. J Forensic Sci 1979;24:409. 56. Andrasko K, Maehly AC: Detection of gunshot residues on hands by scanning electron microscopy. J Forensic Sci1977;22:279. 57. Matricardi VR, Kilty JW: Detection of gunshot particles from the hands of a shooter by SEM. J Forensic Sci1977;22:725. 58. Wolten GM: Particle analysis for the detection of gunshot residue—II: Occupational and environmental particles. J Forensic Sci1979;24:423. 59. Wolten GM: Particle analysis for the detection of gunshot residue—III: The case record. J Forensic Sci 1979;24:864. 60. Tillman J: Automated gunshot residue particle search and characterization. J Forensic Sci1987;32:62. 61. Kee TG, Beck C: Casework assessment of an automated scanning electron microscope/microanalysis system for the detection of firearms discharge particles. J Forensic Sci Soc1987;27:321. 62. Zeichner A, Levin N: Casework experience of GSR detection in Israel, on samples from hands, hair, and clothing using an autosearch SEM/EDX system. J Forensic Sci1995;40:1082. 63. Gialamas DM: Officers, their weapons and their hands: An empirical study of GSR on the hands of non-shooting police officers. J Forensic Sci1995;40:1086. 64. Goldberg WG, Tomlanovich MC: Domestic violence victims in the emergency department. JAMA 1984;251:3259. 65. Tilden VP: Response of the health care delivery system to battered women. Issues Ment Health Nurs 1989;10:309. 66. Randall T: Domestic violence intervention calls for more than treating injuries. JAMA1990;254:939. 67. McLeer SV, Anwar RA: The role of the emergency physician in the prevention of domestic violence. Ann Emerg Med1987;16:1155. 68. Morrison LJ: The battering syndrome: A poor record of detection in the emergency department. J Emerg Med1988;6:521. 69. Tilden VP, Shepherd P: Increasing the rate of identification of battered women in an emergency department: Use of a nursing protocol. Res Nurs Health1987;10:209. 70. Goldberg W, Carey AL: Domestic violence victims in the emergency setting. Top Emerg Med1982;3:65.

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71. Delahunta EA: Hidden trauma: The most missed diagnosis of domestic violence. Am J Emerg Med 1995;13:74. 72. Grunfeld AF: Detecting domestic violence against women in the emergency department: A nursing triage model. J Emerg Nurs1994;20:271. 73. Isaac NE, Sanches RL: Emergency department response to battered women in Massachusetts. Ann Emerg Med1994;23:85. 74. Abbott J: Domestic violence against women: Incidence and prevalence in an emergency department population. JAMA1995;273:1763. 75. Gremillion DH, Evins G: Why don't doctors identify and refer victims of domestic violence?. N C Med J 1994;55:428. 76. Education about adult domestic violence in U.S. and Canadian medical schools, 1987-88. MMWR Morb Mortal Wkly Rep1989;38(2):17. 77. Chambliss LR, Bay RC, Jones RF: Domestic violence: An educational imperative?. Am J Obstet Gynecol1995;172:1035. 78. Stark E, Flitcraft A, Frazier W: Medicine and patriarchal violence: The social construction of a “private” event. Int J Health Serv1979;9:461. 79. Smock WS: Recognition of pattern injuries in domestic violence victims. In: Siegel JA, Saukko PJ, Knupfer GC, ed.Encyclopedia of Forensic Sciences, San Diego, Calif: Academic Press; 2000: 384-390. 80. Adelson L: The Pathology of Homicide, Springfield, Ill, Charles C Thomas, 1974. 81. Wilson EF: Estimation of the age of cutaneous contusions in child abuse. Pediatrics1977;60:750. 82. Katcher ML: Scald burns from hot tap water. JAMA1981;246:1219. 83. Smock WS: The forensic pathologist and the determination of driver versus passenger in motor vehicle collisions. Am J Forensic Med Pathol1989;10:105. 84. Smock WS: Driver versus passenger in motor vehicle collisions. In: Siegel JA, Saukko PJ, Knupfer GC, ed.Encyclopedia of Forensic Sciences, San Diego, Calif: Academic Press; 2000: 24-32. 85. Blackbourne BD: Injury-vehicle correlations in the investigation of motor vehicle accidents. In: Wecht CH, ed.Legal Medicine Annual 1980, New York: Appleton-Century-Crofts; 1980: 86. Smock WS, Nichols GR: Air bag module cover injuries. J Trauma Injury Infect Crit Care1995;38:489. 87. Smock WS: Airbag related injuries and deaths. In: Siegel JA, Saukko PJ, Knupfer GC, ed.Encyclopedia of Forensic Sciences, San Diego, Calif: Academic Press; 2000: 1-8. 88. Laing DK: A fiber data collection for forensic scientists: Collection and examination methods. J Forensic Sci1987;32:364. 89. National Highway Traffic Safety Administration : Traffic Safety Facts 2002, Washington, DC, Department of Transportation, 2003.

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Marx: Rosen's Emergency Medicine: Concepts and Clinical Practice, 6th ed., Copyright © 2006 Mosby, Inc.

Chapter 64 – Child Maltreatment Carol D. Berkowitz

PERSPECTIVE Background Child maltreatment is an all-encompassing term that includes all forms of child abuse: physical abuse, sexual abuse, emotional abuse, child neglect (physical, emotional, educational), and factitious disease by proxy (also known as Munchausen syndrome by proxy).[1] Although the recognition of these conditions by the medical community has occurred at different times, the pivotal report describing child physical abuse occurred in 1962 with the publication of the article “The Battered Child Syndrome” by Kempe and colleagues.[2] The article noted the presence of a complex of physical findings, including fractures, cutaneous bruises, and internal injuries. Since that time, multiple articles and books have described the spectrum of the disorders. During the 1980s, much of the literature focused on child sexual abuse, including the refinement of understanding of normal anogenital anatomy of prepubescent children.[3] Child sexual abuse is defined as the involvement of children and adolescents in sexual activity to which they cannot give consent, based on their devel-opmental level, involving an age disparity between the victim and the perpetrator and for the sexual gratification of the older individual. Child sexual abuse may involve physical contact between the child and the adult or the involvement of the child in other activities, such as photography or the production of pornographic material. The role of the physician in caring for an abused child is multifold. Most importantly, the physician must recognize which presenting complaints are attributable to child abuse and initiate medical management of diagnosed medical conditions, some of which may be life-threatening. Differentiating between inflicted injuries, noninflicted injuries, and other medical conditions is paramount to the correct diagnosis and the proper management of the case. In addition, the clinician has the primary responsibility for reporting the suspicion of child abuse to the appropriate authorities which usually include child protective services and law enforcement.

Epidemiology There are nearly 1 million cases of suspected child abuse and an equal number of child neglect cases noted annually in the United States. Table 64-1 summarizes the data by category of abuse or neglect as noted by the 1996 National Incidence Surveillance report.[4] This process asks individuals who have contact with children (e.g., teachers) to record cases in which they suspect a child has been abused or neglected. Although child abuse occurs across the spectrum of race, ethnicity, and socioeconomic class, certain factors are associated with an increased prevalence of abuse,[5] including poverty, social isolation, parental alcohol and substance abuse, parental mental illness, and domestic violence. Table 64-1 -- Overview of Incidence of Child Abuse Type Physical abuse Sexual abuse Emotional abuse Total abuse Physical neglect Emotional neglect Educational neglect Total neglect

No. of cases 381,700 217,700 204,500 803,900 338,901 212,800 397,300 949,001

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Data from National Incidence Surveillance Data, 1996.

PRINCIPLES OF DISEASE Child Physical Abuse Child physical abuse refers to the infliction of injury on any part of a child's body. Injuries may be manifest in the form of cutaneous bruises, burns, skeletal fractures, internal hemorrhage, organ perforation, and brain injury. Bruises may appear as petechiae or ecchymoses. They occur at the point of impact between the striking object, such as the hand, and the child's body. Often they mirror the form of the inflicting object and may appear as a hand print, belt outline, or other object ( Figure 64-1 ). These bruises are referred to as pat-terned injuries. When the blow occurs at high velocity, the bruising may resemble the outline of the object as the soft tissue in the center of the impacted field moves laterally (negative image). When the thrust of the strike is slower, the central portion of the skin also may be discolored (positive image). The extent of an injury is influenced by many factors, including the force of blow and the area struck. Frequently the struck area initially may be only erythematous, swollen, or tender, and 24 hours may lapse before bleeding into the skin and subsequent discoloration is noted. The degree of discoloration and the rapidity of resolution of the discoloration are influenced by the location of the injury; large muscle masses, such as the buttocks, can hold larger volumes of blood, and resolution takes longer. In general, extravasated blood goes through a predictable color change pattern as it resolves, progressing from purple to green to yellow and eventually to brown. In general, a minimum of 18 hours needs to elapse before a bruise achieves a yellow color.[] Accidentally incurred bruises tend to occur over bony prominences, such as the shin and forehead. In addition, nonambulatory children (3 cm) Gro wing Invol ving >1 crani al bone Non parie tal

Head injuries, including those associated with shaken baby syndrome, account for most child abuse–related fatalities. The syndrome includes evidence of head trauma in association with retinal hemorrhages and skeletal injuries and occurs generally in infants younger than 1 year of age, but may be seen in children 3 years old. Most often, there is no evidence of an impact injury to the head, such as a scalp hematoma or skull fracture. The impact may be against a soft or compressible surface, such as the mattress of the crib. Such an impact results in a rapid deceleration of the head, and the brain experiences a coup-contrecoup injury by moving back and forth within the confines of the skull.[15] Shaking of an infant or young child

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subjects the brain to rotational acceleration, which is capable of generating greater force and speed than linear acceleration, the type of acceleration that occurs with a fall. Rotational acceleration occurs when a discus thrower spins around before releasing the discus. It has been postulated that severe repeated shaking of an infant or young child can lead to disruption of the neuronal cells, with or without the presence of either subarachnoid or subdural hemorrhage. Hemorrhage is a marker for the event, but may be of limited clinical significance, and death, when it occurs, may not be related to bleeding, brain compression, or brain displacement. Injury to the brain cells is referred to as traumatic axonal injury.[16] This injury results in disruption of the cell membrane and subsequent cerebral edema. Cerebral edema impedes the cerebral circulation with resultant brain death. At autopsy, special staining techniques allow for the recognition of axonal injury, which may be diffuse (diffuse axonal injury).[17] Retinal hemorrhages are another common associated finding and are reported to be present in about 75% of cases of shaken baby syndrome.[18] The pathophysiology of retinal hemorrhages is uncertain. It is unclear whether bleeding is a result of increased intracranial pressure that is transmitted to the eye or occurs directly within the eye itself, perhaps through increased pressure along the retinal vein with subsequent disruption of the vessel. Retinal hemorrhages may involve the area in front of the retina (preretinal hemorrhages), the vitreous, and the subretina in addition to the retina. Hemorrhages may be described as “dot and blot” hemorrhages or flame or splinter hemorrhages. Clinically, the hemorrhages may be localized or extend to the ora serrata (the retinal edge). Abdominal trauma accounts for about 10% of injuries in abused children and represents the second most common type of fatal injury, implicated in 40% to 50% of abuse-related deaths.[19] Trauma is often blunt and includes blows and kicks to the abdomen. Frequently, there is no external evidence of the injury because the force has been transmitted to the intra-abdominal structures. Injuries can include lacerations to the liver (more commonly) or the spleen. In addition, children may develop duodenal hematomas, an injury that leads to symptoms of upper intestinal obstruction. Perforations of the intestine or other hollow viscera can follow a blow to the abdomen with subsequent progression to secondary peritonitis. Pancreatitis is also a sequela of inflicted abdominal trauma, and the latter is said to be the most common mechanism of non– medication-associated pancreatitis in children.

Child Sexual Abuse Physical findings present when a child or adolescent has been sexually abused depend on the nature of the abuse, the time since the abuse, and whether the abuse was repetitive or isolated. Acute injuries include disruptions (tears) of the hymen, petechiae, hematomas, or rarely vaginal tears. The prepubescent hymen is significantly more fragile and more easily traumatized than the postpubertal hymen, which thickens and becomes redundant under the influence of estrogen. Evidence of recent trauma also may be visible in the anal area. Acutely, there may be lacerations that appear as perianal fissures, which are characteristically wider distal to the anus. There may be posttraumatic dila-tion, or alternatively anal spasm may occur in response to submucosal injury. In abused boys, the penis rarely has a noticeable injury. More recent studies have evaluated genital healing that occurs after traumatic injury.[20] Physical changes in the anogenital area also may be noted when there has been prior or recurrent sexual abuse. Changes include loss of hymenal tissue and the appearance of u-shaped disruptions in the hymenal contour. Anal findings include the presence of scars and changes in anal tone and the anal contour.[21]

CLINICAL FEATURES Signs and Symptoms Child Physical Abuse Children who have been physically abused may have complaints related to the abuse, or injuries may be noted during the course of an evaluation for an unrelated medical condition. Infants with head injuries may present with nonspecific symptoms that go unrecognized as being related to inflicted head trauma. Jenny and coworkers[22] reported that 31% of infants ultimately diagnosed with inflicted head injury had been evaluated previously in an emergency department and diagnosed with another condition. Infants with head injury may present with apnea, an apparent life-threatening event, vomiting, or a seizure. Clinicians must remain alert that these symptoms may be related to intra-cranial bleeding or elevated intracranial pressure. A careful physical examination should include an attempt to visualize the eye grounds to determine if there is any evidence of retinal hemorrhages. Bruises on a young infant's face are suspicious of head injury. Refusal to use an extremity or to weight bear may be an indication of fracture. Similarly, swelling of an extremity may be a sign of a skeletal injury.

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Children with abdominal injuries may present with abdominal pain, vomiting, abdominal distention, or shock. In cases of inflicted trauma, the history may be unrevealing or be inconsistent with the medical findings. It is common for a parent to state that he or she is uncertain how a child sustained the injury, or that the child was well at bedtime and awoke in the morning refusing to walk or with severe abdominal pain. Caregivers always should be queried about how they think the injury was sustained. In cases of inflicted head trauma, the scenario often includes a young infant left in the care of a male friend or partner of the mother who has gone to work or to run errands. The male companion asserts that the infant was fine, sleeping in the crib when the companion went to take a shower or make some coffee, and when he returned to check on the infant, the infant was not breathing or was seizing. Often the mother is called before calling 911, or the infant is scooped up by the individual and carried to a hospital. The part of the history that is omitted is that the infant was crying, and the companion shook the infant and thrust the infant back into the crib. The infant sustained acute traumatic axonal injury and stopped crying. The infant is then left unattended, seemingly asleep. As bleeding and cerebral edema develop, other symptoms intervene. Sometimes a family member fallaciously relates a history of a fall, usually from a bed (about 18 to 24 inches above the ground) to a floor that is often carpeted. Or the family member may relate that a young sibling, for instance an 18-month-old, hit or jumped on the infant. Such events are not consistent with severe intracranial injuries. Histories of falls also are related in children presenting with severe inflicted abdominal trauma. Although falls may lead to bruises of the abdominal wall and rarely splenic injuries, they are unlikely to cause duodenal hematomas, intestinal perforation, or liver lacerations.[23] In addition to obtaining a history of the current event, past medical, developmental, and social histories are important. In children presenting with acute injuries consistent with physical abuse, there is always the possibility that the findings or their severity may be related to an underlying medical condition. A careful medical history may help exclude such conditions or bring these disorders into consideration. A history of epistaxis and bleeding gums in a child who presents with bruises suggests an underlying coagulopathy. A family history of fractures raises the possibility of a bone disorder, such as osteogenesis imperfecta. Documenting a developmental history is important when attempting to assess the likelihood that children's injuries were related to their own activity. It is crucial to be suspicious of injuries in young infants who have limited motor skills. A caregiver may allege that a 3-week-old infant sustained a head injury when he or she fell after having been placed in the center of the bed, but a 3-week-old infant is developmentally unable to scoot or roll from the center to the edge of the bed. The developmental history should document major milestones, such as age of rolling over, sitting unsupported, crawling, and walking. A social history also is important. It may be helpful for a social worker to assist with a comprehensive social interview, but the clinician can obtain basic information, such as family financial resources (e.g., are the parents working?), where the family lives, what the family's support system is (is there extended family around?), whether there has been domestic violence within the family unit, whether there is substance abuse, and whether the family has ever been reported to protective children's services. A comprehensive physical examination should be conducted. Growth parameters should be obtained and plotted to determine if there is evidence of growth impairment or failure to thrive. The child should always be completely undressed to allow for visualization of the entire cutaneous surface and an assessment of the child's overall nutritional status and hygiene. It is helpful to have a diagram or outline of the body to allow for precise documentation of the size and location of bruises. Often such diagrams are incorporated into state-generated forms used for the formal reporting of suspected abuse. In addition to the routine examination, there should be a thorough inspection of the infant to detect areas of swelling or tenderness as might occur with fractures. The abdomen should be palpated carefully for tenderness or masses. A careful ophthalmologic examination should be carried out. It is frequently difficult to visualize the fundi of young infants without the benefit of pupil dilation and an indirect ophthalmoscope. Specialized retinal cameras allow for documentation of the findings.

Child Sexual Abuse Children who have been sexually abused may present with complaints related to an abusive event (e.g., “My Uncle Joey touched me”), anogenital injuries, or other related anogenital physical findings, such as a vaginal discharge. Some children present with stress-related symptoms, such as recurrent headaches or abdominal pain. Concerns about sexual abuse may be raised by divorcing parents when child custody is in dispute. Other patients, particularly older children and adolescents, may be brought to the emergency department by investigative agencies for a physical examination because of a disclosure about recent or prior abuse, even in the absence of any physical or medical complaints. The medical evaluation should include a history of the events surrounding the alleged molestation. If the child is verbal and willing to disclose to the clinician, this information should be obtained and recorded in the

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medical record using the patient's own words as much as possible. The report with the disclosure is admissible as evidence. In other cases, the history may be related by other individuals, such as parents, social workers, or law enforcement officers, who are accompanying the patient. The history should include who did what, when, where, and how often. To facilitate communication and understand what the child is discussing, inquiring about the terms the child uses for different parts of the body and the use of anatomically detailed dolls are helpful. Past medical history also should be noted, including previous anogenital injuries, surgeries, or symptoms such as the presence of vaginal discharges or recurrent urinary tract infections. Stool patterns should be noted and, if constipation is reported, whether any anal medications (suppositories or enemas) are used. In postpubertal girls, a menstrual history, including age of menarche and type of sanitary protection, should be recorded. The physical examination should include a full head-to-toe assessment to determine if there are acute nongenital injuries (e.g., grip marks or oral injuries) or dermatologic conditions, such as lichen planus, which may explain changes in the anogenital area. The anogenital examination should note the level of pubertal development, recording if the child is prepubertal or at a more advanced stage of sexual maturity.[24] Prepubertal children should be examined using a multimethod approach.[25] Initially, children should be evaluated in the supine position. The labia majora and surrounding tissues should be assessed for evidence of injuries or other abnormalities. Separation or traction should be applied the labia to visualize the structures covered by the labia majora.[26] In prepubertal children, the labia majora are large and full and cover the underlying area. The labia minora are small and delicate and do not fully encircle the vaginal orifice. The clitoris and urethra should be examined. The hymen should be inspected visually for evidence of disruptions and irregularities. The hymen should be precisely described—the phrase “hymen intact” is not sufficiently descriptive for the purposes of a forensic medical assessment. An appropriate description would be: “hymen pink, annular, with smooth thin edge and no disruptions.” Some examiners include the size of the hymenal orifice (e.g., “hymenal orifice 3 mm in supine position using traction”). Although the hymenal diameter is said to measure about 1 mm per year of age, an enlarged hymenal orifice without other changes in the hymen is not thought to have forensic significance. Prepubertal girls also should be examined in the prone knee-chest position. The hymen often relaxes more fully in this position, allowing for a more thorough assessment. Speculum examinations are neither indicated nor appropriate for a prepubertal child. If intravaginal trauma is suspected on the basis of vaginal hemorrhage, examination of the child in the operating room under anesthesia is mandatory. Postpubertal adolescents should be examined using a traditional pelvic examination table with stirrups. Findings of forensic significance in an adolescent with a history of prior sexual abuse relate to the appearance of the hymen and the surrounding tissues. In cases of acute sexual assault, a full evidentiary assessment, including speculum examination for the purpose of evaluation and collection of forensic material, is indicated.

DIAGNOSTIC STRATEGIES Child Physical Abuse Diagnostic studies should be done to determine the extent of the injuries, detect occult injuries, and exclude medical conditions that may account for the findings. If there is evidence of hemorrhage, such as cutaneous bruises or intramuscular hematomas, coagulation studies are indicated. As a baseline, these studies would include a platelet count, prothrombin time, and partial thromboplastin time. It would be appropriate also to obtain a complete blood count to rule out a blood dyscrasia, such as leukemia in a child who presents with multiple ecchymoses. Occasionally, rarer coagulation deficiencies may present with bruising; the detection of such disorders requires more specific diagnostic studies. In a child with suspected burn injuries, skin cultures are appropriate to rule out infections with Staphylococcus aureus, such as occur with bullous impetigo. In general, children younger than age 2 to 3 years with suspected inflicted injuries should be evaluated with a skeletal series, sometimes referred to as a trauma X or trauma series. A trauma series includes x-rays of the skull, long bones, ribs, and vertebrae. The presence of multiple fractures, particularly ones in different stages of healing, is the hallmark of the battered child syndrome. Acutely, some fractures, such as rib injuries, may not be readily visible. Repeat studies in 1 to 2 weeks show evidence of callus formation and make the fracture more readily appreciated. Alternatively a radionucleotide bone scan can detect subtle injuries and should be obtained if there is a skeletal injury but a negative skeletal survey. Urinalysis, liver function studies, and serum amylase and lipase should be considered in children with symptoms of abdominal injury, such as vomiting, abdominal pain, or guarding. Elevated aspartate aminotransferase greater than 450 IU/dL and alanine aminotransferase greater than 250 IU/dL are sensitive

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signs of liver injury.[27] Plain x-rays are rarely helpful, but should be considered if clinical findings suggest perforation or obstruction. Computed tomography (CT) scan of the abdomen is a more precise way of delineating any abdominal injury. CT scan of the head is indicated when symptoms are consistent with head trauma or in an infant with facial bruising. CT scans may reveal extra-axial hemorrhage or findings consistent with cerebral edema. If the child is sufficiently stable, magnetic resonance imaging is helpful in determining the age of the hemorrhages and in assessing whether there has been prior intracranial hemorrhage. In recent years, certain metabolic disorders have been described that also may be associated with intracranial hemorrhage. In particular, glutaric aciduria type I may be mistaken for inflicted head trauma.[28] Urinalysis for organic and amino acids would detect this condition. A careful ophthalmologic examination is crucial. The examination is best done by a pediatric ophthalmologist. Photographic recording of the retinal findings is an important part of the diagnostic workup. Photographing cutaneous injuries is also important and frequently can be carried out by a police criminalist, whose equipment includes color bars for accurate documentation of the coloration of the bruising.

Child Sexual Abuse Child sexual abuse assessments are sometimes best done with equipment that allows for magnification of the genital tissue. An otoscope or hand-held magnifier is usually available in an emergency department. Centers that evaluate sexually abused children often use colposcopes with photographic or video capability or both to allow for recording of the physical findings. Magnification allows for the detection of microtrauma or small changes in the hymen that may not be readily apparent to the naked eye. Toluidine blue is a stain that is used to increase the ease with which minor injuries are detected. The dye is selectively taken up by exposed endothelial cells. The collection of forensic specimens for the detection of sperm or for the retrieval of DNA of the alleged perpetrator is indicated in cases of acute sexual assault. Evaluating a child or adolescent for the presence of a sexually transmitted disease depends on many factors, including disease prevalence in the community, patient symptoms, and the nature of the abuse. In cases of acute assault, the recommendation is often to treat the patient prophylactically against sexually transmitted diseases such as gonorrhea and chlamydia. The decision to offer prophylaxis against human immunodeficiency virus is often based on disease prevalence and other risk factors ( Table 64-4 ). Table 64-4 -- Sexually Transmitted Disease Prophylaxis or Treatment After Sexual Abuse/Assault Disease Treatment Child, or Weight 45 kg Ceftriaxone 250 mg IM Azithromycin 1 g PO, or doxycycline, 100 mg PO BID · 7 days Metronidazole 2 g PO (or 500 mg PO BID · 7 days) Metronidazole 2 g PO (or 500 mg PO BID · 7 days) Ceftriaxone 250 mg IM (incubating) Acyclovir 400 mg PO TID (· episode) 7–10 days, or valacyclovir, 1 g PO BID · 7–10 days

HIV Gonorrhea Chlamydia Gardnerella Trichomonas Syphilis HSV (first clinical episode) Hepatitis B[*] HIV

HBIG 0.06 mg/kg IM + vaccine series Contact local infectious disease specialist before starting Combivir (ziduvidine/lamivudine), 1 tablet PO BID · 28 days, and indinavir, 800 mg PO q 8 hr · 28 days Adapted from APLS: The Pediatric Emergency Medicine Resource, 4th ed. Gausche-Hill M, Fuchs S,

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Yamamoto L (eds): Sudbury, Mass, Jones & Bartlett Publishers, 2004. HBIG, hepatitis B immunoglobulin; HIV, human immunodeficiency virus; HSV, herpes simplex virus. *

Unim m unized child and perpetrator with acute hepatitis B infection.

Part of the assessment of a sexually abused child may include a detailed interview. Forensic interviews are carried out by an individual with expertise in interviewing children, such as a social worker or clinical psychologist. Although the preliminary interview may be carried out in an emergency department, a more in-depth interview often takes place in a diagnostic center where it may be videotaped or observed (through a one-way mirror) by other individuals, such as law enforcement officers or criminal prosecutors, to minimize the number of times a child or adolescent needs to be questioned about the alleged abusive events.

DIFFERENTIAL CONSIDERATIONS Child Physical Abuse The major differential diagnosis when considering child abuse is unintentional injury. Differentiating between inflicted and noninflicted injuries requires the consideration of multiple factors, including the developmental stage of the child, the extent of the injuries, whether the injuries appear to have occurred over a period of time, whether there were witnesses to the alleged event, whether medical care was sought in a timely manner, and whether the injuries could have been sustained in the stated manner. It is important for the evaluating clinician to have an understanding of normal child development, particularly the acquisition of motor skills. Children who are ambulatory, particularly toddlers and young school-age children, are prone to bruises over bony prominences, such as the shins and forehead. Noninflicted bruises are usually unilateral, occurring on the side where a fall or collision with a solid object has occurred. Mongolian spots are bluish discolorations that are seen normally over the buttocks and lower spine in children with darker complexions ( Figure 64-4 ). Mongolian spots can appear on other parts of the body, such as the face and upper arm. They are usually present from birth but may not appear until the infant is several weeks old. When seen in a typical location, they are readily recognized as Mongolian spots. When located elsewhere on the body, they may be mistaken for bruises. Bruises resolve over time, Mongolian spots remain unchanged (do not go through purple-green-yellow-brown transformation) because they are undistributed melanocytes.

Figure 64-4 Mongolian spots in an infant. ((Courtesy of the EMSC Slide Set, National EMSC Resource Alliance.))

Phytophotodermatitis also may be mistaken for bruises. This is a condition that develops on sun-exposed areas of the body that have been in contact with certain fruits or juices, such as lime or lemon juice. The lesion appears as a brown discoloration, which may take the shape of the dripped juice or the object with which the juice came in contact. For instance, if a mother is making lemonade, has the lemon juice on her hand, and holds her child, a brown discoloration in the form of a handprint may appear if the child is in the sun. These lesions fade over time, and with a careful history and physician familiarity with the condition, the correct diagnosis can be made. Burns also may occur unintentionally. Unintentional burns are usually secondary to spills and may take the form of drip marks down a child's chest. Bullous impetigo can be mistaken for second-degree burns because of its blister-like appearance. Culturing the lesion reveals the presence of S. aureus in the case of bullous impetigo. Certain dermatologic conditions, such as epidermolysis bullosa, also may cause bullous lesions that may resemble second-degree burns. The history and generalized appearance of these lesions help establish the correct diagnosis. Fractures may occur unintentionally. In young infants, fractures may be a result of birth-related injuries. The most common fractures sustained during birth are clavicular and humeral fractures. These fractures may

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not be appreciated immediately after birth, but become apparent when callus formation is noted. Ambulatory children may sustain fractures related to falls. A toddler's fracture, also referred to as a CAST fracture (c hildhood accidental spiral tibial fracture), occurs when there is a twisting injury to the tibia as the child falls on it.[29] In general, the fracture is a nondisplaced distal fracture of the tibia that is detected when a child presents with a limp. Sometimes the fracture may not be apparent on the initial x-ray, and a bone scan shows the presence of increased bony uptake. Fractures occur with increased frequency and with lower amounts of force in certain conditions. Premature infants may experience osteopenia of prematurity (sometimes referred to as rickets of prematurity), which can be mistaken for metaphyseal fracture.[30] In addition, osteopenic bones may fracture more easily. Osteopenia can be noted on a plain film of the bones. Osteogenesis imperfecta is a condition in which the bone is more brittle and easily disrupted.[31] There are four types of osteogenesis imperfecta, each with a different gene frequency. The overall incidence of osteogenesis imperfecta is 1 in 20,000. Generally, osteogenesis imperfecta is associated with other clinical findings, such as blue sclerae and brown discoloration of the teeth (dentogenesis imperfecta). Rarely, bone fragility may be present in isolation. Scurvy, congenital syphilis, and congenital rubella are associated with bony changes that may be misinterpreted as evidence of prior bony injury. Cerebral edema may occur with infection, such as encephalitis and meningitis, or after a hypoxic event. The history and the presence of associated medical findings help with the differentiation of these conditions.

Child Sexual Abuse Numerous medical conditions may be misdiagnosed as child sexual abuse. Accidental trauma, most commonly straddle injuries, may occur after a fall onto the perineum. Such falls occur with climbing on monkey bars, riding on boys' bicycles, or exiting from a swimming pool. Straddle injuries usually involve the labia minora, labia majora, or periurethral area. The hymen remains uninjured. Lichen sclerosis et atrophicus is a dermatologic condition of unclear etiology affecting prepubertal girls and boys and postmenopausal women. The hymen is unaffected, but the adjacent skin becomes atrophic and may sustain blood blisters or petechiae. Characteristically the skin in the perianal and perihymenal areas becomes hypopigmented and surrounds these orifices with a pale figure-of-eight configuration. Urethral prolapse characteristically affects African-American girls between the ages of 5 and 8 years. The mucosal lining of the urethra slides forward and protrudes from the urethral orifice, appearing as an erythematous, edematous mass. Symptoms include pain and bleeding. Management may involve sitz baths, antibiotic ointment, or referral to an urologist for ligation. Vaginal discharge may occur secondary to conditions other than sexually transmitted diseases. Shigella, group A beta-hemolytic streptococcus, Candida, and pinworm infestation can cause a vaginal discharge. Penile swelling may occur with priapism (often secondary to sickle cell disease), paraphimosis, or an infestation with chiggers. Fissures and tags in the perianal area may result from trauma, but also may be associated with constipation and inflammatory bowel disease. Group A beta-hemolytic streptococcus can cause painful inflammation with erythema in the perianal area. Affected children may be febrile and experience pain with defecation. Hemorrhoids are rare in children and are associated with conditions that lead to an elevation of intra-abdominal venous pressure as occurs with cirrhosis of the liver.

MANAGEMENT The focus of management is to attend to serious or life-threatening injuries, such as significant head or abdominal trauma, and stabilize the patient. Physical problems requiring medical intervention, such as fractures, lacerations, burns, or sexually transmitted diseases, should be managed appropriately. Key to the ultimate management of the abused child is the precise recording of the pertinent history, particularly any disclosure made by the child, and the physical findings. Most states require the completion of a specific child abuse reporting form as a means of notifying the authorities about the suspected case of child abuse. In addition, many jurisdictions require immediate telephonic notification to initiate an investigation of the circumstances surrounding the abuse.

Disposition Admission to the hospital may be warranted because of the patient's injuries, to complete the medical evaluation, and to protect the child while the evaluation is occurring. Many hospitals have SCAN (Suspected Child Abuse and Neglect) teams. These teams can offer expert consultation either in the emergency department or after the child has been admitted. SCAN teams usually have unique expertise in assessing the genital findings in prepubertal girls.

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The outcome for an abused child varies with the nature, extent, and duration of the abuse. Some children die as a result of their inflicted injuries. Others have irreversible brain damage and may spend the remainder of their lives confined to wheelchairs or be blind or otherwise disabled. For other children, intervention and therapy for themselves and their offending parents may help reverse the adverse psychological effects of the abuse. The emergency physician has a key role in the early detection of the problem. The entire medical team along with social services, law enforcement, and the judicial system is responsible for implementing a treatment plan that prevents against recidivism. KEY CONCEPTS

{,

The eme rgen cy phys ician is man date d to repo rt susp icion of child phys ical or sexu al abus e.

{,

In infan ts and youn g child ren pres entin g with any injur y, the eme rgen cy phys ician must cons ider child phys ical abus

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e as a diag nosi s and espe cially with certa in injuri es, such as facia l bruis ing; skull, rib, or mids haft hum erus fract ures; and patte rned burn s. {,

Child ren who have been sexu ally abus ed may pres ent with vagu e com plain ts, such as poor slee p patte rn or abdo mina l pain,

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{,

or may pres ent with vagi nal blee ding or disc harg e. Num erou s cond ition s mimi c child abus e and must be cons idere d in the differ entia l diag nosi s, such as Mon golia n spot s, liche n scler osis, impe tigo, or ureth ral prola pse.

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REFERENCES 1. Department of Health and Human Services Releases : 2000 Child Abuse Report Data. AHA Legislative Activities, American Humane Association. Available at: http://www.americanhumane.org/actnoww/2000_abuse_data.htm 2. Kempe CH: The battered child syndrome. JAMA1962;181:17. 3. Woodling BA, Kossoris PD: Sexual misuse: Rape, molestation and incest. Pediatr Clin North Am 1981;28:481. 4. U.S. Department of Health and Human Services National Center on Child Abuse and Neglect : The Third National Incidence Study of Child Abuse and Neglect (NIS-3), Washington, DC, U.S. Government Printing Office, 1996. 5. Sinal S, Petree AN, Herman-Giddens M: Is race or ethnicity a predictive factor in shaken baby syndrome?. Child Abuse Negl2000;24:1241. 6. Jenny C: Cutaneous manifestations of child abuse. In: Reece RM, Ludwig S, ed.Child Abuse Medical Diagnosis and Management, 2nd ed. Philadelphia: Lippincott Williams & Wilkins; 2001: 23-45. 7. Labbe J, Caouette G: Recent skin injuries in normal children. Pediatrics2001;108:271. 8. Schwartz AJ, Ricci LR: How accurately can bruises be aged in abused children? Literature review and synthesis. Pediatrics1996;97:254. 9. Sugar NF, Taylor JA, Feldman KW: Bruises in infants and toddlers: Those who don't cruise don't bruise. Arch Pediatr Adolesc Med1999;153:399. 10. Peck MD, Priolo-Kapel D: Child abuse by burning: A review of the literature and an algorithm for medical investigation. J Trauma2003;53:1013. 11. Johnson CF, Oral R, Gullberg L: Diaper burn: Accident, abuse or neglect. Pediatr Emerg Care 2000;16:173. 12. Thompson S: Fractures, sprains, and dislocations. In: Osborn LM, DeWitt TG, First LR, Zenel JA, ed. Pediatrics, Philadelphia: Elsevier Mosby; 2005: 13. Bullock B: Cause and clinical characteristics of rib fractures in infants. Pediatrics2000;105:e48. 14. Feldman KW, Brewer DK: Child abuse, cardiopulmonary resuscitation, and rib fractures. Pediatrics 1984;73:339. 15. Saternus K-S, Kernbach-Wighton G, Oehmichen M: The shaking trauma in infants—kinetic chains. Forensic Sci Int2000;109:203. 16. Geddes JF, Whitwell HL, Graham DI: Traumatic axonal injury: Practical issues for diagnosis in medicolegal cases. Neuropathol Appl Neurobiol2000;26:105. 17. Paterakis K: Outcome of patients with diffuse axonal injury: The significance and prognostic value of MRI in the acute phase. J Trauma2000;49:1071. 18. Levin A: Retinal hemorrhages and child abuse. Rec Adv Paediatr2000;18:151. 19. Holmes JF, Sokolove PE, Land C, Kuppermann N: Identification of intra-abdominal injuries in children hospitalized following blunt torso trauma. Acad Emerg Med1999;6:799. 20. Heppenstall-Heger A: Healing patterns in anogenital injuries: A longitudinal study of injuries associated with sexual abuse, accidental injuries, or genital surgery in the preadolescent child. Pediatrics2003;112:829. 21. McCann J, Voris J: Perianal injuries resulting from sexual abuse: A longitudinal study. Pediatrics 1993;91:390. 22. Jenny C: Analysis of missed cases of abusive head trauma. JAMA1999;281:621. 23. Joffe M, Ludwig S: Stairway injuries in children. Pediatrics1988;82:457. 24. Herman-Giddens ME, Bourdony CJ: Assessment of Sexual Maturity in Girls, Elk Grove Village, Ill, American Academy of Pediatrics, 1995. 25. McCann J, Voris J, Simon M, Wells R: Comparison of genital examination techniques in prepubertal girls. Pediatrics1990;85:182. 26. Heger AH: Appearance of the genitalia in girls selected for nonabuse: Review of hymenal morphology and nonspecific findings. J Pediatr Adolesc Gynecol2002;15:27. 27. Hennes HN: Elevated liver transaminase levels in children with blunt abdominal trauma: A predictor of injury. Pediatrics1990;86:87. 28. Hartley LM, Khwaja OS, Verity CM: Glutaric aciduria type 1 and nonaccidental head injury. Pediatrics

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2001;107:174. 29. Mellinek LB, Milker L, Egsieker E: Childhood accidental spiral tibial (CAST) fractures. Pediatr Emerg Care1999;15:10. 30. Miller ME: The bone disease of preterm birth: A biomechanical perspective. Pediatr Res2003;53:10. 31. Lachman RS, Krakow D, Kleinman PK: Differential diagnosis. II. Osteogenesis imperfecta. In: Kleinman PK, ed.Diagnostic Imaging of Child Abuse, 2nd ed. St Louis: Mosby; 1998: 197-213.

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Chapter 65 – Sexual Assault Laura Slaughter

PERSPECTIVE Background Several major advances in the evaluation and management of sexual assault victims (SAVs) have occurred. The formation of community-based multidisciplinary teams, which first took hold in California, is probably the most important. The development of the sexual assault response team (SART), comprising members of the district attorney's office, law enforcement, medical personnel including physicians and nurses, social service agencies, and victim advocates, brought together all of the major players to solve the logistical, medical, psychological, legal, and social problems incurred by SAVs. The commitment and mutual cooperation of the SART led to the development of standardized protocols for the care and treatment of SAVs. Many of these protocols have been adopted by jurisdictions throughout the United States; this has facilitated greatly the documentation for medical and legal purposes. The necessity of having trained forensic examiners is now well recognized, and SART programs and their forensic organizations have generated training on local, regional, and national levels. Clinical forensic examiners have taken the examination to a different level by employing new technologies, including colposcopy, special staining techniques, and alternative light sources. Much information about the characteristics, physical examination findings, and correlates of injury in SAVs is now available. This information makes the job of the forensic examiner more interesting, facilitates the management of the SAV, and ultimately assists in the identification of the perpetrator.

Epidemiology An emergency department study has shown that the lifetime prevalence rate of female sexual assault is 39% significantly higher than in other studies. Although it is true that most SAVs do not seek medical care, of those who did, most (78%) were treated, and 61% had an evidentiary examination performed.[1] Sexual assault does not seem to be declining at the rate of other violent crimes; nearly every category of crime was significantly lower in 2001-2002 than in the preceding 2 years except for sexual assault.[2] Women remain the predominant victims (94%) of sexual assault. Historically, sexual assault has been a largely unreported crime, with only about one third of SAVs coming forward. The major reasons given for not reporting include that the matter was personal, fear of reprisal, or fear of police bias. The closer the relationship between the victim and offender, the less likely the SAV has been to report the crime. The underreporting trend may be changing, however. Of SAVs who report the crime, most do so within 24 hours. A substantial proportion of SAVs report at or after 72 hours, and they are typically adolescents. There is a high positive correlation between reporting to the police and receiving medical treatment.[3] Sexual assault is an extremely common crime, with estimates of one in three females and one in seven males being assaulted during a lifetime.[4] The mean age of the SAV is approximately 20 years old. She is most often single. Adolescents account for less than half of all victims seen, yet the incidence of sexual assault peaks in the 16- to 19-year age group.[5] For nearly 40% of SAVs, sexual assault is the first sexual experience.[6] A person known to the victim commonly perpetrates the assault. The younger the victim, the more likely the perpetrator is to be a relative. The location of the sexual assault varies with the victim and the type of perpetrator. In general, adults are assaulted in their own home, whereas adolescents are more likely to be assaulted in the assailant's residence.[7] Stranger assaults are less common; they are more likely to involve adults, occur outdoors, and include the use of a weapon.[8] Alcohol and drug use are common accompaniments to sexual assault.[] Most assaults involve penile-vaginal penetration,[] and penile penetration is significantly associated with genital injury.[11] Typically, digital-vaginal penetration is the second most common sexual act reported. Oral

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genital contact occurs in less than 30%, and anal assault is slightly less common.[] The use of a foreign object is unusual (≤10%).[] Anal assault is associated with increased violence,[] offender preference for anal sex,[14] and offender problems with sexual dysfunction.[15] Atypical types of assault seem to be increasing over time.[16] The detection of genital injury is multifactorial and may depend in part on the forensic training of the examiner [] and the technology[] used to perform the examination. Regardless of the methods employed, injury is not an inevitable consequence of sexual assault.[] Adolescent SAVs have been shown to sustain more anogenital injuries than their adult counterparts.[] Nongenital trauma occurs in 40% to 81% of SAVs,[] and its presence is associated with genital injury.[] The extremities are most commonly injured, followed by the head and neck. Serious injury involving hospitalization occurs in about 5%,[3] and death associated with sexual assault is estimated at 1% or less, although this latter figure is probably a gross underestimate. Psychological distress and interpersonal difficulties are the major sequelae after a sexual assault. These problems are exacerbated in SAVs with known attackers who delay reporting.[24]

MANAGEMENT Emergency Department Preparation: Multidisciplinary Teams A standardized approach to the management of the SAV is important. This approach should include the development of a multidisciplinary team that works together under a protocol. The protocol must address every detail, from the handling of the SAV's first call to dispatch to the referral for psychological support. The SAV must be taken out of the medical triage system that typifies the emergency department not only to provide privacy and security for the SAV, but also to prevent the deterioration of evidence. This approach ensures a consistent process of evaluation, treatment, and collection of evidence. The medical team must receive forensic training on interviewing and examination techniques; collecting, preserving, and storing evidence; and chain of custody issues. The team must be trained to use the examination form (in some states this form is 8 pages long) and be thoroughly familiar with the sexual assault kit (rape kit) provided by the state or local crime laboratory. Advocates, whether provided through law enforcement or by a separate entity, need to receive training from the SART about examination procedures and staff roles so that they can best advise and counsel the SAV. A SART program cannot be successful unless advocates believe that the SAV will be treated with respect and receive the best treatment available. Because the SART examiner is the first person on the medical team to greet the victim, a kind, calm, knowledgeable, and professional demeanor is of the utmost importance. The emergency department also must be prepared for the unusual SAV with significant or life-threatening injuries. In this instance, the emergency physician needs to delegate the forensic responsibility to another forensically trained staff member whose sole purpose is to collect the evidence and, if required, follow the SAV to surgery. In cases in which there is substantial injury, following the patient from intake allows the examiner to understand better and document the nature and extent of the trauma and continue the forensic process with little further distress to the patient.

Obtaining the History and Consent Numerous consents must be obtained from the SAV, depending on state and local laws ( Box 65-1 ). The forensic examiner must be knowledgeable about all statutes governing consent, including whether minors need parental consent. In some states, even if parental consent is not required, the forensic examiner still may be required to contact the parents and document the success or failure of this attempt. Although not part of the official consent process, most SAVs are concerned about access to the SART record and photographs, particularly, when the SART examination facility is within the hospital setting. Keeping these records separate from the primary hospital chart system has a precedent in the similar handling of psychiatric records. Surveys of SAVs have identified that they desire information about sexually transmitted diseases (STDs), pregnancy, emergency contraception, follow-up care, and physical and psychological health effects of sexual assault.[25] Providing written information on these topics with signature confirmation is warranted. BOX 65-1 Consent Issues in Sexual Assault Cases

Consents should specify that the sexual assault victim signature acknowledges:

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{, {, {, {, {, {, {,

That hospitals and health care professionals are mandated reporters Receipt of information about victim compensation funds Specific understanding of the examination and evidence collection procedures Specific understanding of the use of photography in documenting physical and genital injuries That information collected will be sent to law enforcement and is obtainable by defense counsel That data without patient identity can be collected for valid educational and scientific interest That consent may be withdrawn at any time

With the exception of the medical history, group history taking makes the most sense because everyone gathers the same information, and this saves time and avoids contradictions. Before getting started with the history, the SAV's immediate privacy and personal needs need to be addressed. Box 65-2 outlines some of the issues that may make the interview more comfortable for the patient and ensure reliable historical information from the patient. The group taking the history should include a law enforcement officer, patient advocate, medical assistant, and forensic examiner. BOX 65-2 Preliminary Issues and Strategies in Preparing for Taking the History from a Sexual Assault Victim

{, {, {, {, {, {, {, {, {,

Provide quiet, confidential, safe environment Briefly review the interview and examination process in private with the sexual assault victim Explain sensitive/personal/embarrassing nature of questions and right to be interviewed without family or friends Show concern for immediate comfort (e.g., if thirsty take oral swabs first so the victim may drink) Provide advocacy Always conduct interview the same way Leave difficult questions until the end Explain why you are asking the question and the possible responses Explain that all questions must be asked

A detailed history is important. California was the first state to mandate a uniform examination protocol and specific training for examiners. The protocol subsequently has undergone revision ( Figure 65-1 ).[26] A

B

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C

Figure 65-1 Data collection form from State of California Forensic Medical Report for adults and adolescents, OCJP 923. ((From Forensic Medical Report: Acute [1 cm) and deeper lacerations may require repair by an ophthalmologist.

Corneal and Scleral Lacerations Clinical Features and Management Corneal Lacerations. Signs of corneal perforation (full-thickness corneal lacerations) include loss of anterior chamber depth, teardrop-shaped pupil caused by iris prolapse through the corneal laceration, and blood in the anterior chamber ( Figure 70-14 ). Small corneal lacerations can be difficult to diagnose. If aqueous humor is leaking from the corneal wound, it appears as streaming fluorescent dye surrounded by an orange pool of solution on slit-lamp examination (Seidel's test).[32] Full-thickness corneal lacerations are managed as described for blunt traumatic globe rupture.

Figure 70-14 Teardrop-shaped pupil dem onstrating anterior cham ber perforation through corneal laceration.

Superficial partial-thickness corneal lacerations without a widened wound can be treated with a cycloplegic, topical antibiotic, and a pressure patch. Repairs of partial-thickness corneal lacerations requiring suture closure are performed in the operating room.

Scleral Lacerations. Penetrating scleral lacerations occur with the signs and symptoms of blunt globe rupture. Globe perforation may be unrecognized in the absence of significant physical examination findings.

Orbital and Intraocular Foreign Bodies Clinical Features and Management Any orbital and intraocular penetration should be approached with the possibility of intracranial injury. Small intraocular and intraorbital foreign bodies can occur with any perforating injury and be difficult to diagnose. Physical examination of the eye may be completely normal at initial presentation. Occult foreign bodies should be suspected with any penetrating injury associated with mechanical grinding, sanding, drilling, and hammering. Plain orbital films, orbital CT scan, magnetic resonance imaging (MRI) scans, and ultrasonography aid in diagnosis. Although the decision to use one modality over another is dictated by individual clinical circumstances, an orbital CT scan is probably the most useful diagnostic tool. The MRI scan should not be used when an iron-containing foreign body is suspected. Treatment of intraocular foreign bodies is dictated by clinical circumstances and is left to the ophthalmologist. Patients with acute intraocular foreign bodies should be hospitalized, have nothing by mouth, have a protective shield placed, and given antibiotics. Generally speaking, acute intraocular foreign bodies are surgically removed.[27] Plastic, glass, and many metals are relatively inert, and their nonacute removal is sometimes likely to cause more damage than their permanent presence. Organic foreign bodies are more important to remove because of their propensity for infection. Siderous oxidation of ocular tissues is a late complication of iron-containing intraocular foreign bodies that can lead to visual loss. Chalcosis, a sterile inflammatory reaction to copper-containing compounds, may occur, requiring removal of the offending object.

Complications of Ocular Trauma Clinical Features and Management Posttraumatic Corneal Ulcers. Any defect in the corneal epithelium may become infected with bacteria or fungi. Ulcerations are surrounded by a cloudy white or gray appearing cornea ( Figure 70-15 ). A reactive sterile hypopyon may be present in the anterior chamber. Emergent ophthalmologic consultation is needed. Treatment includes cycloplegia, topical antibiotics, and often admission to the hospital. Corneal perforation is a complication.

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Figure 70-15 Peripherally located corneal ulcer.

Endophthalmitis. Endophthalmitis is an infection involving the deep structures of the eye, namely the anterior, posterior, and vitreous chambers. Patients complain of pain and visual loss. Examination reveals decreased visual acuity, chemosis, and hyperemia of the conjunctiva, and the infected chambers are hazy or opaque ( Figure 70-16 ). Endophthalmitis is a complication of blunt globe rupture, penetrating eye injury, foreign bodies, and ocular surgery. Prompt diagnosis and early treatment with intraocular and systemic antibiotics are important in the successful management of post-traumatic endophthalmitis.[33] Common pathogens are Staphylococcus, Streptococcus, and Bacillus.[34] Topical, intravitreal, and systemic antibiotics are all used.

Figure 70-16 Endophthalm itis resulting from globe rupture.

Sympathetic Ophthalmia. This is an inflammation that occurs in the uninjured eye weeks to months after the initial insult to the injured eye. It is thought to be an autoimmune response to the normally sequestered uveal tissues of the injured eye becoming exposed with injury. Patients have pain, photophobia, and decreased visual acuity. Treatment includes steroids and other immunosuppressive agents.[34] Enucleation of the blind injured eye can reduce symptoms even after the sympathetic ophthalmia has developed.

DISEASE OF THE CONJUNCTIVA Clinical Features and Management Conjunctivitis Conjunctivitis is an inflammation of the bulbar and palpebral conjunctiva caused by various viral, bacterial, mechanical, allergic, and toxic agents. When the cornea is also involved, it is known as keratoconjunctivitis. Multiple viral and bacterial pathogens are responsible for acute conjunctivitis. Adenovirus, coxsackievirus, and enteroviruses have been isolated as causes of conjunctivitis. Common bacterial agents include Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus organisms, Moraxella catarrhalis, and Neisseria gonorrhoeae. Less common bacterial causes are Klebsiella and Pseudomonas.

Acute Bacterial Conjunctivitis Patients complain of pink eye, redness, a foreign body sensation, lid swelling, drainage, and eye crusting in the morning. Photophobia and visual loss are notably absent. Treatment of acute bacterial conjunctivitis includes warm compresses and topical ophthalmic antibiotics. In uncomplicated acute bacterial conjunctivitis, topical trimethoprim and polymyxin are a good initial selection.[ 35] Neomycin ophthalmic solutions should be avoided because of the high incidence of hypersensitivity reactions.[35] Medications should be continued for 7 days. Corticosteroids and eye patching should be avoided. Cultures are indicated when symptoms are severe or when prior treatment has been inadequate or unsuccessful.[35] Complications of acute bacterial conjunctivitis include corneal ulcer formation, keratitis, and corneal perforation. Patients with complicated bacterial conjunctivitis should be referred to an ophthalmologist.

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Acute bacterial infection caused by N. gonorrhoeae is uncommon but important because of its significant complications. Infection results from direct contact with individuals infected with urethritis or pelvic inflammatory disease. Signs and symptoms are markedly increased, including a copious purulent discharge. Gram's stain may reveal the diagnosis, although cultures are more sensitive. Treatment is more aggressive than with other causes of bacterial conjunctivitis. Hospital admission for IV antibiotics, saline irrigation, and topical ophthalmic antibiotics is warranted in moderate and severe cases and any patient with corneal involvement. Outpatient management may be used in selected mild cases with ceftriaxone 1 g intramuscularly as a single dose, topical erythromycin ointment, and saline solution irrigation of the conjunctiva.[35] A substantial proportion of patients have concomitant Chlamydia trachomatis infection and should be treated with oral doxycycline, tetracycline, or erythromycin (20 mg/kg PO) or a single dose of 1 g of azithromycin.[35]

Viral Conjunctivitis Viral infection is the most common cause of conjunctivitis. Viral conjunctivitis generally produces more redness, itching, eye irritation, and preauricular lymphadenopathy ( Figure 70-17 ). It commonly occurs in the setting of other viral symptoms (e.g., fever, myalgias, malaise).

Figure 70-17 Conjunctival injection resulting from viral conjunctivitis.

Viral conjunctivitis is very contagious for 10 to 12 days after onset and appropriate preventive measures should be taken. Treatment consists of artificial tears and cool compresses. A vasoconstrictor and antihistamine combination can be used if itching is severe.

Ophthalmia Neonatorum Conjunctivitis that occurs within the first month of life is termed ophthalmia neonatorum and has several causes. A bacterial cause should be investigated with Gram's stain and cultures within the first 2 weeks of life. N. gonorrhoeae and Chlamydia are both transmitted from mother to infant through the birth canal.[35] Infection with N. gonorrhoeae is manifest within 2 to 4 days after birth. The infant should be carefully examined for evidence of systemic gonococcal infection. Hospitalization and blood and cerebrospinal fluid examination may be indicated. Nonsystemically infected neonates can be effectively treated with a single dose of ceftriaxone, 125 mg intramuscularly, topical polymyxin B–bacitracin ointment, and saline washes.[35] These patients should also be treated for ocular chlamydial infection. Close follow-up is needed. Infants with chlamydial infection develop symp-toms between 5 and 13 days after birth. Topical erythromycin ointment and oral erythromycin are the antibiotics used.[36] Treatment is for 14 days. Chemical conjunctivitis from antibiotic ointment administration immediately after delivery occurs within 1 to 2 days of birth but should not be the diagnosis if the infant has significant symptoms, the time course is inappropriate, or other historic and physical examination parameters are not classical. In such cases, a bacterial cause should be assumed. In neonates with no information from stains or cultures and in whom an organism is not known or suspected, topical erythromycin ointment and oral erythromycin are utilized.

Miscellaneous Conjunctivitis Allergic conjunctivitis is common. Allergens include drugs, cosmetics, and environmental agents. Eye itching is generally more pronounced in patients with allergic conjunctivitis and tends to be bilateral. Artificial tears, cool compresses, combination topical ocular decongestants, topical vasoconstrictor-antihistamine combinations, and topical nonsteroidal agents may be used for treatment. Other types of conjunctivitis include toxic conjunctivitis from topical ocular medications (aminoglycosides, antivirals, and preservatives), molluscum contagiosum, and chronic conjunctivitis.

DISEASE OF THE CORNEA

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Differential Considerations Clinical Features and Management Pterygium and Pinguecula A pterygium is a wedge-shaped area of conjunctival fibrovascular tissue that extends onto the cornea. A pinguecula is white or yellow, flat to slightly raised tissue on the conjunctiva, immediately next to but not on the cornea. Patients can be asymptomatic or present with irritation and redness. Treatment includes protection from wind, dust, and sunlight and artificial tears. An inflamed pinguecula can be treated with a short course of a topical nonsteroidal agent. Nonemergent referral to an ophthalmologist is recommended. Surgical removal is possible for selected individuals.

Superficial Punctate Keratitis Superficial punctate keratitis consists of superficial, multiple, pinpoint corneal epithelial defects. Patients present with pain, photophobia, redness, and a foreign body sensation. Superficial punctate keratitis is a nonspecific finding that is seen in many conditions. The most common precipitating conditions are ultraviolet burns (welders or sunlamps), conjunctivitis, topical eye drug toxicity (neomycin, gentamicin, drugs with preservatives including artificial tears), contact lens disorders, dry eye and exposure keratopathy, blepharitis, mild chemical injury, and minor trauma. Specific treatment is aimed at the underlying offending cause. Nonspecific treatment for a significant non–contact lens–associated superficial punctate keratitis includes nonpreserved artificial tears, topical antibiotics such as trimethoprim-polymyxin drops, and cycloplegia. Patients with a significant contact lens–associated superficial punctate keratitis should stop wearing their contact lenses and be treated with a topical fluoroquinolone or tobramycin drops during the day and ointment at night. Patients should have ophthalmologic follow-up the next day.

Corneal Ulcers and Infiltrate from Infection Corneal infiltrates arise as a focal white opacity without an epithelial defect. Corneal ulcers have an overlying corneal epithelial defect that stains with fluorescein in addition to the corneal infiltrate. Patients present with pain, redness, photophobia, and decreased vision. The most common cause is bacterial, but fungal and herpes simplex infections are also possible. Patients should be immediately referred to an ophthalmologist for corneal culturing before treatment is initiated.

Herpes Simplex Infections Infection with herpes simplex may be either primary or reactivation of preexisting disease. Symptoms include foreign body sensation, tearing, photophobia, clear discharge, and decreased visual acuity. Physical examination reveals a red eye and may or may not include the classical herpetic vesicles located on the lids or conjunctiva. Corneal involvement is seen on slit-lamp examination and may appear as a superficial punctate keratitis, ulcer, or the classical dendritic lesions ( Figure 70-18 ). Treatment for epithelial keratitis consists of topical antiviral agents such as trifluridine 1% every 2 hours for 14 to 21 days.[37] Topical prophylactic antibiotics and cycloplegia are also employed. Topical steroids are contraindicated in corneal epithelial disease but have proved to be beneficial in stromal disease.[37] Emergent ophthalmologic consultation is advised.

Figure 70-18 Herpes sim plex infection. Note typical dendritic pattern on cornea.

Herpes Zoster Infection Herpes zoster keratoconjunctivitis occurs as a result of activation of the virus along the ophthalmic division of the trigeminal nerve. The rash follows dermatomal patterns, involves the forehead and upper eyelid, and produces significant pain. Involvement of the nasociliary nerve, manifested by zoster lesions on the tip of the nose (Hutchinson's sign), is associated with a 76% risk of ocular involvement versus 34% risk if the nerve is not involved.[38] Ophthalmic zoster mandates emergent ophthalmologic consultation. Treatment is complex and depends upon the type, location, and degree of ocular involvement. Oral and topical antiviral and steroid agents as well as antibiotics are used.[]

Contact Lens Complications

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The common complications of contact lens use involving the cornea include mechanical damage such as abrasions, corneal neovascularization, infections producing corneal ulcers, hypersensitivity or toxicity reactions to preservatives in solutions, and contact lens deposits. If no significant signs or symptoms exist that indicate corneal infection, the patient should discontinue contact lens use and follow up with his or her ophthalmologist. When corneal infection is present or suspected, immediate ophthalmologic consultation is indicated.

DISORDERS OF THE LIDS AND OCULAR SOFT TISSUES Differential Considerations Clinical Features and Management Hordeolum and Chalazion Hordeolums and chalazions are localized, nodular, inflammatory processes of the eyelids. Symptoms and signs include pain, swelling, and redness ( Figure 70-19 ). Spontaneous rupture may occur, and most resolve with warm compresses applied for 15 minutes four to six times each day. Topical antibiotics (erythromycin) may be used. Incision and drainage are indicated for chalazia unresponsive to conservative therapy.[41]

Figure 70-19 Chalazion of the upper eyelid.

Dacryocystitis Dacryocystitis is an acute infection of the lacrimal sac from nasolacrimal duct obstruction. The most common organism is S. aureus. Symptoms and signs include pain, tenderness, swelling, and erythema over the lacrimal sac ( Figure 70-20 ). Pressure over the sac may express purulent material from the puncta. Treatment includes topical ocular and oral anti-Staphylococcal antibiotics and warm compresses. Gentle massage of the area during warm compress application may help decompress purulent material and relieve symptoms. Systemically ill patients should be hospitalized.

Figure 70-20 Dacryocystitis.

Blepharitis Patients present with thickened, mattered, red eyelid margins with pronounced blood vessels. Patients complain of burning, itching, tearing, foreign body sensation, and morning crusting of the eyelids. Treatment includes rubbing the eyelid margins with a mild shampoo using a cotton-tipped applicator or cloth twice per day, warm compresses, and artificial tears. Severe blepharitis can also be treated with topical antibiotic ointment applied at night.

Preseptal Cellulitis Patients present with lid erythema and warmth, tenderness, and swelling and may have a low-grade fever. It is important to note the absence of findings associated with orbital (postseptal) cellulitis (i.e., proptosis, restriction of extraocular movements, pain with eye movement, and patient's toxicity). If any of these findings are present, orbital cellulitis or abscess should be suspected and the patient managed more aggressively with imaging studies (CT scan of brain and orbits) and hospitalization. Preseptal cellulitis is characterized by a continuum of disease, and treatment is tailored for the degree of patient's toxicity. Mild disease can be treated on an outpatient basis with oral antibiotics, but hospitalization with IV antibiotics may be needed for

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moderate to severe disease.

GLAUCOMA Clinical Features and Management Aqueous humor is produced by the ciliary processes. In addition to providing structural support to the eye, aqueous humor delivers oxygen and nutrients to the avascular lens and cornea and removes their waste products. This fluid passes from the posterior chamber to the anterior chamber through the pupillary aperture. The aqueous humor is transported into the trabecular meshwork located at the anterior chamber angle formed by the junction of the root of the iris and the peripheral cornea. The trabecular meshwork serves as a one-way valve and filter for the aqueous humor into the canal of Schlemm, which in turn drains into episcleral veins. Intraocular pressure is determined by the rate of aqueous humor production relative to its outflow and removal. Normal intraocular pressure is between 10 and 20 mm Hg.[42] Glaucoma is an optic neuropathy caused by increased intraocular pressure. Irreparable optic nerve damage can result. The simplest classification is to divide the glaucomas into primary or secondary and open angle or closed angle. Secondary glaucoma is associated with another ocular or nonocular event, whereas primary glaucoma is not. Closed-angle glaucoma is caused when the anterior chamber angle is narrowed, reducing the outflow and removal of aqueous humor, whereas open-angle glaucoma occurs with a normal anterior chamber angle. Patients vary in their susceptibility to a given level of intraocular pressure. Some may develop significant optic nerve findings despite a relatively low intraocular pressure (low-tension glaucoma), whereas others may have scant optic nerve changes despite relatively high intraocular pressure (ocular hypertension).[43]

Primary Open-Angle Glaucoma Primary open-angle glaucoma is the most common form of glaucoma and is a leading cause of blindness in the United States. There is increased resistance to aqueous humor outflow through the trabecular meshwork. Primary open-angle glaucoma is generally insidious, slowly progressive, chronic, bilateral, and painless. Advanced disease occurs before symptoms. Symptoms begin as visual field loss at the periphery that progresses centrally. Signs include an optic cup to optic nerve ratio of greater than 0.6.[44] Other findings include vertically oval, deep, and pale optic cups, with nasal displacement of blood vessels. The three treatment options are medications, argon laser trabeculoplasty, and guarded filtration surgery. Initial treatment is generally with one or more topical agents. p -Blockers, selective p 2-receptor agonists, carbonic anhydrase inhibitors, prostaglandin agonists, miotics, and sympathomimetics are all used. Topical ocular medications are absorbed and may produce significant systemic side effects.[45] Topical p -blockers have produced asthma, heart block, congestive heart failure, hypoglycemia, and depression. Adrenergics have produced hypertension and cardiac dysrhythmias, whereas carbonic anhydrase inhibitors have produced renal calculi and hypokalemia. Complications may arise as a result of drug interaction. Prolonged apnea, for example, has resulted when succinylcholine has been given to a patient receiving topical ophthalmologic acetylcholinesterase inhibitors.[46]

Secondary Open-Angle Glaucoma Secondary open-angle glaucoma can have a number of causes, including lens induced, inflammatory, exfoliative, pigmentary, steroid induced, traumatic, angle recession, and ocular tumor. Treatment is directed to the offending mechanism and includes the methods used for primary open-angle glaucoma.

Primary Angle Closure Glaucoma Primary angle closure glaucoma occurs in patients who have anatomically small and shallow anterior chambers. This anatomic variation results in the iris being nearly in contact with the lens, resulting in resistance to aqueous humor flow from the posterior to anterior chamber. This is called pupillary block.[47] Attacks of primary angle closure glaucoma are precipitated by pupillary dilatation. Dimly lit rooms, emotional upset, and various anticholinergic and sympathomimetic medications are common precipitating events. The dilatation of the pupil increases the degree of pupillary block, leading to an accumulation of aqueous humor in the posterior chamber. The iris bulges forward, obliterating the angle between the cornea and iris,

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obstructing the trabecular meshwork, decreasing outflow, and leading to a rapid rise in intraocular pressure.[ 48]

A second, less common mechanism of acute angle closure glaucoma, produced without pupillary block, is caused by a flat or plateau iris. This leads to a narrow angle recess. Dilatation of the pupil causes the iris to fold and bunch over the angle, blocking aqueous humor outflow into the trabecular meshwork. Symptoms are abrupt in onset and include severe eye pain, blurred vision, headache, nausea, vomiting, and occasionally abdominal pain. Patients see a halo around lights. Signs include conjunctival injection and a cloudy (steamy) cornea with a midpositioned to dilated pupil that is sluggish or fixed ( Figure 70-21 ). Visual acuity may be significantly decreased, and intraocular pressures are markedly elevated.

Figure 70-21 Acute narrow-angle glaucom a. Note steam y appearance of cornea with a m idpositioned and sluggish pupil.

Treatment should begin promptly. If visual acuity is markedly reduced (hand movements or less), a combination of all topical glaucoma medications with IV osmotics and acetazolamide should be utilized.[39] Intraocular pressures less than 50 mm Hg without significant visual acuity change can be managed without the IV medications.[39] Topically administered timolol 0.5% decreases intraocular pressure within 30 to 60 minutes.[49] Pilocarpine 1% to 2% is topically administered, one drop every 15 minutes for two doses, and one drop may be placed prophylactically in the unaffected eye. A topical p 2-agonist (apraclonidine 1.0%) for one dose and topical steroid (prednisolone acetate 1% every 15 minutes for four doses) should be given.[39] In the setting of a severe attack, acetazolamide, a carbonic anhydrase inhibitor, is given in an IV dose of 250 to 500 mg, and mannitol 1 to 2 mg/kg over 45 minutes.[50] Sedatives and antiemetics may be administered as needed. Ophthalmologic consultation is warranted. The definitive therapy for primary angle closure glaucoma is surgical.

Secondary Angle Closure Glaucoma Pupillary block may develop from a swollen or dislocated lens or posterior synechia (adhesions between the iris and lens). Secondary angle closure glaucoma, without pupillary block, can be caused by intraocular tumors, central retinal vein occlusion, or postoperatively. Treatment is directed at the offending cause.

ACUTE VISUAL LOSS Differential Considerations Acute visual loss, usually in only one eye, occurs over a period ranging from a few seconds to a day or two. The vision is generally reduced to 20/200 or worse. Patients need to be quickly evaluated to determine whether a treatable lesion exists. The differential diagnosis of acute visual loss not related to trauma includes vascular occlusion, retinal detachment, vitreous hemorrhage, macular disorders, neuroophthalmologic disease, and hysteria. Most of these patients need ophthalmic or neurologic referral for a complete workup. Patients may complain of acute visual loss when they may have neither an acute process nor a visual loss caused by the eye itself. For example, a patient with a visual field cut secondary to a neuroophthalmologic lesion may have an acute visual loss when the patient discovers the field cut. A patient with a hemianopia usually has normal visual acuity even though both eyes are affected. An accurate history of how the patient discovered the visual loss, as well as the timing of that loss, is vital.

Clinical Features and Management Central Retinal Artery Occlusion Acute visual loss as a result of vascular occlusion of the central retinal artery is typically painless. Central retinal artery occlusion causes an ischemic stroke of the retina. It occurs most commonly in those between 50 and 70 years of age, and 45% have carotid artery disease.[51] Risk factors include hypertension,

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cardiac disease, diabetes, collagen vascular disease, vasculitis, cardiac valvular abnormality, and sickle cell disease. Patients with increased orbital pressure are also at risk, including patients with acute glaucoma, retrobulbar hemorrhage, and endocrine exophthalmos. Patients complain of a severe loss of vision that develops over seconds. Examination reveals a markedly reduced visual acuity with a prominent afferent pupillary defect. On funduscopic examination, the retina is edematous with a pale gray-white appearance, and the fovea appears as a cherry-red spot ( Figure 70-22 ).

Figure 70-22 Central retinal artery occlusion. Note cherry-red spot (fovea).

Therapy should be instituted immediately and should be directed at dislodging the embolus, dilating the artery to promote forward blood flow, and reducing intraocular pressure to allow an increase in perfusion gradient. Digital global massage should be begun immediately in the emergency department. Global massage is performed by applying direct digital pressure through closed eyelids. The pressure can be applied for 10 to 15 seconds and followed by a sudden release.[52] Increases in carbon dioxide pressure (P CO2) lead to retinal artery vasodilation and increased retinal blood flow. Increases in PCO2 are obtained by either rebreathing into a paper bag for 10 minutes each hour or inhaling a 95% oxygen, 5% carbon dioxide mixture (carbogen). Intraocular pressure may be reduced by instilling timolol maleate 0.5% topically. Acetazolamide, 500 mg IV or by mouth, lowers intraocular pressure as well as increases retinal blood flow.[ 53] Emergent ophthalmologic consultation should be obtained as anterior chamber paracentesis may be attempted. One study, however, failed to find any therapeutic benefit for patients who received anterior chamber paracentesis and inhaled carbogen.[54] Thrombolytic agents have been studied, but no clear guidelines for their use exist.[52] A complete medical evaluation is necessary because central retinal artery occlusion is usually an embolic event.

Central Retinal Vein Occlusion A painless loss of vision, central retinal vein occlusion leads to edema, hemorrhage, and vascular leakage. The wide spectrum of clinical appearances depends on the degree of venous obstruction present. Loss of vision can range from minimal to recognition of hand motion only. There are two types of central retinal vein occlusion, ischemic and nonischemic. The nonischemic type involves mild fundus changes and does not have an afferent pupillary defect. These patients tend to have less severe visual loss, with two thirds of the patients having 20/40 or better visual acuity without therapy.[55] Patients with ischemic central retinal vein occlusion have a marked decrease in visual acuity and often an afferent pupillary defect. Appearance can vary but classically includes dilated and tortuous veins, retinal hemorrhages, and disk edema ( Figure 70-23 ). Branch retinal vein occlusions occur just distal to an arteriovenous crossing, and hemorrhages occur distal to the site of occlusion. The differential diagnosis of central retinal vein occlusion includes hypertension, diabetes mellitus, hyperviscosity syndromes, and papilledema. All of these are bilateral processes, whereas central retinal vein occlusion is generally unilateral. Neovascular glaucoma is the major complication of ischemic central retinal vein occlusion. Treatment is complex and includes lowering of intraocular pressure, topical steroids, cyclocryotherapy, and photocoagulation.[] Underlying medical disease should be managed as well. The prognosis depends on the degree of obstruction and resultant complications.

Figure 70-23 Central vein occlusion.

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Retinal Breaks and Detachment The retina has two layers, the inner neuronal retina layer and the outer retinal pigment epithelial layer, which can be separated by fluid accumulation. A retinal break is a tear in the retinal membranes and may or may not lead to retinal detachment. Retinal detachments occur by three mechanisms: rhegmatogenous, exudative, and tractional. Rhegmatogenous retinal detachment occurs as a result of a tear or hole in the neuronal layer, causing fluid from the vitreous cavity to leak between and separate the two retinal layers. Rhegmatogenous retinal detachment generally occurs in patients older than 45 years, is more common in men than women, and is associated with degenerative myopia.[57] Trauma may be associated with rhegmatogenous detachment by causing tears in the retina or by causing a disinsertion of the retina from its attachment at the ora serrata anteriorly. Traumatic retinal detachment can occur at any age. There is greater risk with severe myopia. Exudative retinal detachment occurs as a result of fluid or blood leakage from vessels within the retina. Conditions leading to exudative retinal detachment include hypertension, toxemia of pregnancy, central retinal venous occlusion, glomerulonephritis, papilledema, vasculitis, and choroidal tumor. Traction retinal detachment is a consequence of fibrous band formation in the vitreous and contraction of these bands. These fibrous bands result from the organization of inflammatory exudates or blood from prior vitreous hemorrhage. Typically, patients complain of flashes of light related to the traction on the retina, floaters related to vitreal blood or pigmented debris, and visual loss. The visual loss is commonly described as a filmy, cloudy, or curtain-like appearance. Pain is absent. Visual acuity can be minimally changed to severely decreased. Visual field cuts relate to the location of the retinal detachment, and an afferent pupillary defect occurs if the detachment is large enough. When the detachment is visualized by ophthalmoscopy, the retina appears out of focus at the site of the detachment. In large retinal detachments with large fluid accumulation, the bullous detachment, with retinal folds, can easily be seen (see Figure 70-12 ). Retinal detachment cannot be ruled out by direct funduscopy. Indirect ophthalmoscopy is needed to visualize the more anterior portions of the retina. Acute rhegmatogenous and tractional detachment that threaten the fovea should be urgently surgically repaired.[39] Acute retinal breaks are surgically repaired within 24 hours. All other acute rhegmatogenous and tractional retinal detachments can be repaired within a few days.[39] Treatment of exudative detachment is aimed at the underlying cause or use of laser photocoagulation. Any patient suspected of having retinal break or detachment requires immediate ophthalmologic consultation.

Posterior Vitreous Detachment Posterior vitreous detachment is a common occurrence in patients older than 60 years. With aging, the vitreous gel pulls away from the retina, which can lead to symptoms similar to those of retinal break, vitreous hemorrhage, and retinal detachment. No specific treatment is indicated for posterior vitreous detachment unless it is accompanied by a retinal break, vitreous hemorrhage, or retinal detachment.[39] Patients with a new posterior vitreous detachment should have prompt evaluation by an ophthalmologist to rule out these surgically amenable complications.

Vitreous Hemorrhage Vitreous hemorrhage results from bleeding into the preretinal space or into the vitreous cavity. The most common causes are diabetic retinopathy and retinal tears. Additional causes include neovascularization associated with branch vein occlusion, sickle cell disease, retinal detachment, posterior vitreous detachment, trauma, age-related macular degeneration, retinal artery microaneurysms, trauma, and intraocular tumor. Symptoms begin with floaters or “cobwebs” in the vision and may progress over a few hours to severe visual loss without pain. Direct ophthalmoscopy reveals a reddish haze in mild cases to a black reflex in severe cases. Details of the fundus are usually difficult to visualize. Vitreous hemorrhage by itself does not cause an afferent pupillary defect, which, if present, indicates a retinal detachment behind the vitreous hemorrhage. The hemorrhage may be evenly distributed throughout the vitreous or focal. Long-standing preretinal hemorrhage can become a white mass that may be misdiagnosed as a tumor, exudate, or infection. Initial therapy consists of bed rest with elevation of the head of the bed and avoidance of anticoagulative medications. Definitive therapy is targeted at the underlying cause. Vascular retinopathy is treated with laser photocoagulation or cryotherapy, and retinal tears and detachments are repaired. If the cause of the hemorrhage is unknown, prompt diagnostic workup is indicated to look for surgically correctable lesions. Ultrasonography can be used to determine whether a retinal detachment is present and

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may also determine the cause.[58] Vitrectomy is indicated in certain patients.

Macular Disorders Many disease processes cause acute changes in the macula leading to acute visual loss. The role of the emergency physician is to recognize the maculopathy and refer the patient to an ophthalmologist. Keys to the diagnosis of macular dysfunction include loss of central vision with preservation of peripheral vision, complaints of central visual distortion, and anatomic changes in the retina. Degenerative maculopathies occur as the result of trauma, radiation exposure, inflammatory or infectious disease, vascular disease, toxins, or hereditary disease or may be idiopathic in nature. The most common form is age-related macular degeneration after the age of 65 years.[59] It is a leading reason for legal blindness in the United States. Patients present with either a gradual or rapid onset of visual loss. Funduscopy reveals scattered drusen. Drusen are small, sharply defined yellow-white masses ( Figure 70-24 ). Some patients with age-related macular degeneration and drusen develop a choroidal (subretinal) neovascular membrane, which appears as a grayish-green membrane beneath the retina. If this membrane is left untreated, hemorrhage, transudation, scar formation, or exudative detachment of the retina can result. If a large hemorrhage occurs from the neovascular membrane, it can cause severe central visual loss and may break through the retina into the vitreous, causing peripheral visual loss. Laser photocoagulation is the treatment for choroidal neovascular membrane formation and should be performed as soon as possible.[59]

Figure 70-24 Drusen occurring in m acular degeneration.

Inflammatory processes involving the retina may also cause visual loss, especially if the macula is involved. Bacterial, viral, and protozoal agents have been shown to cause maculopathy. The presenting symptoms and signs vary according to the disease process and severity. Inflammatory debris from exudative processes may fill the vitreous, leading to a cloudy appearance. Infections within the eye are often associated with severe pain, redness, and periocular edema. If the retina and choroid are obliterated, the lesions appear white. Patients suspected of having an inflammatory maculopathy need emergent consultation and thorough medical evaluation.

Neuroophthalmologic Visual Loss Visual loss not readily explained by an obvious abnormality on physical examination is called neuroophthalmologic visual loss. Patients can be divided into those who complain of decreased vision and have reduced visual acuity and those who complain of visual loss but have normal visual acuity. It is important to conduct careful visual field testing in the latter group. Neuroophthalmologic visual loss can be further divided into prechiasmal, chiasmal, and postchiasmal anatomic areas.

Prechiasmal Visual Loss. Patients with prechiasmal disease have decreased visual acuity or visual field loss in the eye on the affected side. Prechiasmal disease may be a unilateral or bilateral process. The swinging flashlight test reveals an afferent pupillary defect on the side involved unless the process is bilateral. In such cases, the relative degree of afferent defect determines the results. Visual field testing demonstrates a field defect that does not respect the vertical meridian and is often localized to the center of the visual field. Causes of prechiasmal visual loss include optic neuritis, ischemic optic neuritis, compressive optic neuritis, and toxic and metabolic optic neuritis.

Optic Neuritis. Optic neuritis is an acute monocular loss of vision caused by focal demyelination of the optic nerve. The patients' ages range from 15 to 45 years. Symptoms include a progressive loss of vision over several hours or days and ocular pain with eye movement. Visual acuity can range from minimal loss to no light

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perception. An afferent pupillary defect is always present, and direct ophthalmoscopic examination reveals a normal or swollen disk.[60] The natural history of optic neuritis is for visual acuity to reach its poorest within 1 week and then slowly improve over the next several weeks. Approximately 30% of patients presenting with acute optic neuritis develop multiple sclerosis within 5 years.[61] In an initial study of patients with acute optic neuritis, treatment with a 3-day course of IV methylprednisolone reduced the rate of development of multiple sclerosis over a 2-year period.[62] However, 5-year follow-up of the same cohort of patients revealed no significant differences among treatment groups in the development of multiple sclerosis.[61] Use of oral steroids for hastening optic neuritis is controversial. The Optic Neuritis Study Group showed an increased risk of optic neuritis recurrences in patients treated with oral prednisone.[] However, a randomized and controlled study of high-dose oral methylprednisolone in acute optic neuritis showed improved recovery from optic neuritis at 1 and 3 weeks but no effect at 8 weeks or on subsequent attack frequency.[63] Long-term visual outcome is no different from that with observation alone.

Ischemic Optic Neuropathy. Ischemic optic neuropathy is the most common optic neuropathy and one of the most common causes of visual loss past middle age. Ischemic optic neuropathy can be giant cell arteritis or idiopathic. Temporal arteritis (giant cell arteritis) is characterized by weight loss, malaise, jaw pain, headache, scalp tenderness, polymyalgia rheumatica, low-grade fever, and severe painless visual loss. It is extremely rare in people younger than 50 years, but the incidence rises with each subsequent decade. A significant proportion of patients sustain visual loss, which can be sudden, severe, and bilateral.[64] Occasionally, visual loss is preceded by episodes of amaurosis fugax. In one series of patients, visual loss was unilateral in 46%, sequential in 37%, and simultaneously bilateral in 17%.[65] There is a large afferent pupillary defect, visual loss, and a visual field defect that may respect the horizontal meridian. The optic disk shows pallor and swelling. The diagnosis can be aided with an elevated erythrocyte sedimentation rate (ESR), but can be seen with normal sedimentation rates.[66] A guide to the upper limit of normal ESR is age/2 for men and (age + 10)/2 for women.[39] The diagnosis is confirmed by temporal artery biopsy, although biopsy has been normal early in the disease. Treatment for temporal arteritis should be instituted when typical signs and symptoms, particularly visual loss, exist. The standard treatment is high-dosage corticosteroids, which should be started as soon as the diagnosis is suspected. Treatment should not wait for biopsy results. Biopsy should be performed within 1 week of diagnosis. Patients treated with oral prednisone were less likely to have visual improvement and more likely to develop fellow eye involvement than those receiving high-dose IV methylprednisolone.[65] Patients with visual loss had a 34% chance of improvement with IV methylprednisolone.[65]

Nonarteritic Ischemic Optic Neuropathy. Nonarteritic ischemic optic neuropathy is much more common than temporal arteritis. These patients lack the classical symptoms of temporal arteritis and do not have an elevated ESR. Most of these patients have systemic vascular disease, diabetes, or hypertension, and they tend to be younger. They have painless visual loss, afferent pupillary defects, disk swelling, and visual field defects that respect the horizontal meridian. The visual loss is less severe than with temporal arteritis, and improvement occurs in one third of patients. Steroids have been advocated, but the results are unclear. If there is doubt about whether a particular patient has temporal arteritis or an idiopathic form of ischemic optic neuropathy, treatment with steroids should be started until a temporal artery biopsy is performed.

Compressive Optic Neuropathy. Compressive optic neuropathy occurs at any age and can be caused by tumor, aneurysm, sphenoid sinusitis or mucocele, blunt trauma, and thyroid disorders. Although defined as a prechiasmal disorder, compression can occasionally occur far enough posteriorly to affect the optic chiasm. Patients with compressive optic neuropathy have visual loss that continues to progress beyond 7 days. Compressive optic neuropathies require neuroradiographic evaluation and rapid medical and surgical intervention. Optic neuritis can be difficult to distinguish from a compressive optic neuropathy, but compressive syndromes tend to involve other cranial nerves. If the signs and symptoms do not closely fit optic neuritis or ischemic optic neuropathy, a compressive lesion exists until proved otherwise.

Toxic and Metabolic Optic Neuropathy. A large number of toxic and metabolic neuropathies exists. Common toxic causes include barbiturates, chloramphenicol, emetine, ethambutol, ethylene glycol, isoniazid, heavy metals, and methanol. Causes of metabolic optic neuropathies include thiamine deficiency and pernicious anemia. These processes are bilateral, progressive, and symmetrical. Visual loss can be severe, and visual field testing reveals central

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defects. Treatment is aimed at the underlying toxin or metabolite involved.

Chiasmal Visual Loss. Chiasmal disease is the second category of neuroophthalmologic visual loss, most commonly caused by chiasmal compression from pituitary tumors, craniopharyngioma, or meningioma. Visual loss is gradual and progressive. Although formal visual field testing is necessary to stage the condition, the diagnosis can usually be made by confrontation visual field testing. The classical defect is a bitemporal hemianopsia; however, tumors often compress the optic chiasm and optic nerves asymmetrically, resulting in combined central and temporal defects. When a visual field defect respects the vertical meridian from a neuroophthalmologic visual loss, the lesion is out of the globe and must be either chiasmal or postchiasmal.

Postchiasmal Visual Loss. Postchiasmal disease represents the third category of neuroophthalmologic visual loss. The most common causes are infarction, tumor, arteriovenous malformation, and migraine disorders. Patients complain of difficulty in performing a certain task, such as reading. Lesions can be located from the immediate postchiasmal optic tract to the occipital cortex. The classical visual field defect is homonymous hemianopsia. Patients with such lesions have a focal neurologic deficit and need neurologic consultation. Cortical blindness is a special cause of neuroophthalmologic visual loss that is most commonly caused by bilateral occipital infarction. Cortical blindness is often mistaken for functional blindness because patients have both normal funduscopic examinations and intact pupillary reflexes. Anton's syndrome is characterized by bilateral blindness, normal pupillary reflexes, bilateral occipital lesions, and, interestingly, denial of blindness. It is this denial of blindness that may be incorrectly assumed to be evidence for a functional process.

Functional Visual Loss. Patients with functional visual loss fall into two categories: hysterical conversion reactions and malingering. Patients with hysterical conversion reactions have a nondeliberate, imagined visual loss. The patient has a flatter affect than one would expect under the circumstances of acute visual loss. The patient might appear completely unaffected emotionally by the acute visual loss. The malingerer, on the other hand, is a patient who is well aware that no visual loss exists, yet deliberately feigns visual loss for secondary gain. This patient is typically overemotional concerning the visual loss. Examination of a patient with a suspected functional visual loss should be conducted in the same manner as every other ophthalmologic examination, with particular attention to possible neuroophthalmologic deficits. Normal pupillary reflexes and the absence of an afferent pupillary defect, together with a normal funduscopic examination, point toward functional visual loss. Multiple tests can ascertain whether a visual loss is organic or functional. Patients with feigned visual loss are hesitant to try to appose the index fingers of each hand and often write their names in a disorderly fashion, whereas genuinely blind patients can sign their names without difficulty. One effective test involves placing a large mirror directly in front of the patient's face and asking the patient to look straight ahead. The mirror is then tilted slightly back and forth. Most patients follow the reflection of their eyes in the mirror as it changes position, proving feigned visual loss. Some difficult cases require more sophisticated tests. If the diagnosis of feigned visual loss cannot be definitively made, consultation is required to rule out neuroophthalmologic visual loss.

ANISOCORIA Clinical Features Anisocoria in a patient with head trauma or decreased level of consciousness requires immediate and aggressive evaluation and intervention because it may result from increased intracranial pressure. If a patient is awake and alert, has no signs of trauma, and has anisocoria of unknown cause, less urgency exists. The first step is to determine which pupil is abnormal. If one pupil constricts poorly to a light stimulus, it is likely to be the abnormal one. Anisocoria greater in dark suggests that the abnormal pupil is the smaller pupil, whereas anisocoria greater in light suggests that the abnormal pupil is the larger pupil. If aniso-coria exists in a patient with a normal afferent visual system, either an innervational or structural defect in the iris sphincter exists. Most structural defects in the iris can be diagnosed by slit-lamp examination. If both pupils react well to light and no iris abnormalities are seen with slit-lamp examination, the next step is to determine whether the anisocoria increases in light or darkness. Adie's tonic pupil, pharmacologic blockade, and third-nerve palsy are associated with anisocoria that increases in light, whereas benign anisocoria and Horner's syndrome are associated with anisocoria that increases in darkness.[39] Comparing pupillary size in a brightly and dimly lit room is the easiest method to evaluate the effect of lighting on anisocoria.

Adie's Tonic Pupil

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With Adie's tonic pupil, patients complain of blurred near vision but have normal distant vision. Adie's syndrome is seen in young women 70% of the time and has associated symmetrically reduced deep tendon reflexes. Examination reveals poor accommodation with a very slow constriction to near testing. The pupil redilates slowly when the vision is again made distant. Slit-lamp examination reveals sector palsies of the iris. The diagnosis is confirmed when a weak cholinergic agent (pilocarpine 0.1%) causes an intense pupillary constriction as a result of cholinergic supersensitivity in the affected pupil compared with the normal pupil. These patients need to be referred to an ophthalmologist on a nonemergent basis for cholinergic agent therapy.

Pharmacologic Mydriasis Pharmacologic mydriasis can be caused by deliberate or inadvertent local administration of both sympathomimetic and parasympatholytic agents. Phenylephrine and cocaine are two sympathomimetic substances commonly used as a nasal premedicant for nasotracheal intubation; careless administration may lead to anisocoria. Parasympatholytic agents, such as atropine and scopolamine, have been implicated in the development of anisocoria. The transdermal scopolamine patches placed for the prevention of motion sickness can cause anisocoria. Pilocarpine 1.0% can be used in special circumstances to help differentiate a third-nerve palsy from pharmacologically mediated mydriasis. The administration of pilocarpine 1.0% rapidly constricts the pupil that is dilated secondary to a third-nerve palsy but does not produce miosis in a pupil dilated from anticholinergic agents.

Third-Nerve Palsy Patients with anisocoria that increases in light, without evidence of Adie's tonic pupil or pharmacologic medication, should be suspected of having a third-nerve palsy. They almost always have other signs of third-nerve involvement, including ptosis and extraocular muscle dysfunction. Patients complain of diplopia, and the involved eye is turned down and out. Patients may have ptosis and extraocular dysfunction with or without pupil dilatation. Any patient who has a new-onset third-nerve lesion involving the pupil should be admitted to the hospital to rule out aneurysm.

Horner's Syndrome Horner's syndrome consists of ptosis, miosis, and facial anhidrosis resulting from an interruption of sympathetic innervation. The dilatation lag, a classical finding, results from the Horner's pupil requiring up to 15 seconds to dilate fully. The anisocoria is greater at 3 to 5 seconds of darkness than at 15 seconds of darkness, although the anisocoria is still more pronounced than in light. Topical ophthalmologic cocaine 10% can be used to aid the diagnosis. A Horner's pupil dilates less than the normal pupil in reaction to topical cocaine. Central nervous system strokes and tumors, lung carcinomas, thyroid adenomas, Pancoast's tumors, headache syndrome, carotid dissection, herpes zoster, otitis media, and congenital Horner's syndrome (trauma during delivery) are all causes of Horner's syndrome. Hydroxyamphetamine 1% administered 24 hours after the cocaine test can be used to determine the level of sympathetic interruption and dictate the type of workup indicated. In general, patients with new-onset Horner's syndrome should receive a thorough and immediate workup to determine the etiology.

Physiologic Anisocoria Twenty percent of the population may have anisocoria of greater than 0.4 mm at any given examination.[67] This anisocoria may be transient or prolonged and may alternate pupils. Although the anisocoria increases in darkness, there is no dilatation lag as seen with Horner's syndrome.

ABNORMAL OPTIC DISK Clinical Features and Differential Considerations An important acquired cause of an abnormal optic disk is papilledema. Papilledema refers to the changes in the optic disk from increased intracranial pressure. Causes include intracranial tumor, pseudotumor cerebri, intracranial hematomas from trauma, subarachnoid hemorrhage, brain abscess, and meningitis or encephalitis. There is swelling of the optic disk and blurring of the disk margins, hyperemia, and loss of physiologic cupping. Flame-shaped hemorrhages and yellow exudates appear near the disk margins as the edema progresses. Patients may have significant headaches or be completely asymptomatic. Visual acuity is not affected until the papilledema is long standing. Brief obscurations of vision, enlargement of the physiologic blind spot, and inferior nasal visual field loss are common. Papilledema is a bilateral process but may be asymmetric. A patient with newly diagnosed papilledema should be admitted to the hospital for immediate neuroradiographic evaluation. Many conditions may mimic papilledema, including central retinal vein occlusion, papillitis, hypertensive retinopathy, ischemic optic neuropathy, optic disk vasculitis, and diabetic papillitis with retinopathy.

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NYSTAGMUS Clinical Features and Differential Considerations Clinically significant nystagmus is an oscillation of the eyes that occurs within 30 degrees of the midline. Pendular nystagmus is of equal velocity in both directions. With jerk nystagmus, the velocity is faster in one direction. The pathologic component is the slow movement, but the nystagmus is named according to the direction of the fast component. Nystagmus can also be divided into monocular or binocular, conjugate (both eyes moving in the same direction) or disconjugate (eyes moving in opposite directions), and primary gaze position or gaze position nystagmus. Important questions include the presence of tinnitus, nausea, vomiting, oscillopsia, and vertigo. Congenital nystagmus is noted at birth or within the perinatal period and is usually horizontal, conjugate, bilateral, symmetrical, and pendular. On lateral gaze, this nystagmus may become jerky in nature but remains horizontal despite upward or downward gaze. Congenital nystagmus is damped by convergence, increased with fixation, accentuated by covering one eye, and abolished with sleep. These patients do not have oscillopsia, nor do they have other neurologic complaints. Almost all of these patients have recognized their nystagmus previously, and the diagnosis is generally straightforward. There are many causes of acquired nystagmus. General categories of disease that result in nystagmus include toxic exposure, defective retinal impulses, diseases of the labyrinths or of the vestibular nuclei, and lesions of the brainstem or cerebellum controlling ocular posture. The workup includes drug and toxic screening and neuroradiologic testing with a CT or MRI scan.

DISORDERS OF EXTRAOCULAR MOVEMENT Clinical Features and Differential Considerations Patients complain of diplopia produced or exacerbated by certain eye movements. The first step is to deter-mine whether the diplopia is monocular or binocular. Binocular diplopia disappears with either eye covered. Monocular diplopia is less concerning, caused most commonly by refractive errors, dislocated lens, iridodialysis, and feigned disease. Binocular diplopia from misalignment of the eyes has a multitude of causes. Local mechanical defects such as hematoma, orbital floor fractures, or abscess and palsy of cranial nerve III, IV, or VI can lead to motility problems. Thyroid disease, progressive ophthalmoplegia, extraocular muscle fibrosis syndrome, multiple sclerosis, and myasthenia gravis can all lead to newly acquired extraocular movement dysfunction. The most common cause is cranial nerve palsy. Patients with brainstem disease often have involvement of other cranial nerves, disturbances in level of consciousness, and sensorimotor loss. Isolated third-nerve lesions produce a palsy in which the patient develops ptosis, an inability to turn the eye inward or upward, and pupillary mydriasis. The causes of third-nerve palsy are varied and require aggressive and immediate neurologic and radiologic examination. Isolated fourth-nerve palsy is an easily missed disorder. Patients complain of double vision, which is made worse in downgaze, or gaze away from the paretic side. These patients typically have a head tilt to the opposite shoulder to compensate for the vertical extorsion and have weakness in downward gaze. Trauma and vascular disease account for most cases of isolated fourth-nerve palsy, but aneurysm, intracranial tumor, and myasthenia gravis have been implicated. Sixth cranial nerve palsies are the most commonly reported ocular motor palsies. Patients with sixth cranial nerve palsies have an esotropia that is worsened by lateral gaze and often turn their heads laterally toward the paretic side to compensate. Sixth-nerve palsy is caused by a variety of diseases. Wernicke-Korsakoff Syndrome, aneurysm, vascular disease (diabetes, hypertension, atherosclerosis), trauma, neoplasm, multiple sclerosis, meningitis, thyroid eye disease, and increased intracranial pressure may all cause dysfunction. Workup consists of careful neurologic and radiologic examination.

MANAGEMENT Ophthalmic Drugs General Considerations Most ocular medications are administered as drops, which have the advantage of concentrating drug delivery to the anterior segment of the eye and reducing unwanted systemic side effects. Eye drops have the additional advantages of rapid absorption, brief effect, and minimal interference with the visual media. Unfortunately, the eye retains only a small amount of the drug; the remainder is cleared by the rapid turnover

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of tears. To improve absorption, patients who are taking more than one eye drop should ideally wait 10 minutes between drops to prevent the second drop from wash-ing out the first. Patients should apply digital pressure at the medial canthus of the eye to prevent drainage of drug through the nasolacrimal duct and keep their eyes closed for several minutes after instilling their drops to halt the lacrimal pumping mechanisms. Ointments increase the contact time of the medication with the anterior segment of the eye. Ointments blur vision but provide a pleasant lubrication to the eye that has been traumatized and patched and do not seem to interfere with corneal wound healing.

Drug Classification Box 70-1 provides a listing of the most commonly used agents in each of these categories. BOX 70-1 Commonly Used Ophthalmologic Medications

Anesthetics Prop arac aine Tetr acai ne

Antibiotics Bacit racin Cipr oflox acin Eryt hro myci n Gent amic in Neo myci n/ba citra cin/p olym yxin B Norfl oxac in Oflo xaci n Poly myxi n B/ba citra

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cin Poly myxi n B/tri meth opri m Sulfa ceta mide Tobr amy cin

Antivirals Fomi virse n Triflu ridin e Vidar abin e

Corticosteroids Dex amet haso ne Fluor omet holo ne Lote pred nol Pred nisol one Rim exol one

Decongestants/Antiallergy Cro moly n Sodi

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um Levo caba stine Lodo xami de trom etha mine Nap hazo line Nap hazo line/ phen irami ne Olop atadi ne

Glaucoma: p -Blockers Beta xolol Cart eolol Levo buno lol Timo lol

Glaucoma: Carbonic Anhydrase Inhibitors Acet azol amid e Brin zola mide Dorz olam ide

Glaucoma: Other Apra cloni dine

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Brim onidi ne Cos opt Dipiv efrin Ech othio phat e Lata nopr ost Piloc arpin e

Mydriatics/Cycloplegics Atro pine Cycl open tolat e Hom atrop ine Phe nyle phrin e Tropi cami de

Nonsteroidal Diclo fena c Keto rolac

Other Medications Artifi cial tears Local anesthetics block neurotransmission along sensory nerve fibers. Ocular procedures facilitated by topical anesthetics include direct inspection, foreign body removal, irrigation, tonometry, and contact lens

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removal. Topical anesthetics inhibit wound healing, and severe keratopathy can result from indiscriminate use of topical anesthetics. Local anesthetic drops should not be prescribed as pain medicine for self-administration by patients. Antibiotics and antiviral agents are commonly prescribed. The choice of antibiotic agent should be guided by culture, Gram's stain, or suspected bacteria or virus. Antiviral agents are generally prescribed after consultation with an ophthalmologist. Corticosteroids are used by ophthalmologists for many ocular conditions, but their use by emergency physicians should be limited. Corticosteroids can accelerate the activity of herpes simplex virus and should not be given to a patient when the diagnosis is uncertain. Posttraumatic iridocyclitis is one of the few conditions in which an emergency physician might consider prescribing a topical steroid agent, but close follow-up with an ophthalmologist is highly recommended. Cycloplegics block the muscarinic receptors, producing paralysis of the ciliary muscle, which always causes mydriasis. Cycloplegics are useful in relieving pain and photophobia secondary to ciliary spasm related to corneal abrasion, ocular trauma, and iridocyclitis.[7] Mydriatics dilate the pupil, but not all mydriatics are cycloplegics. Mydriatics are contraindicated in any patient with a history of glaucoma, evidence of increased intraocular pressure, presence of a shallow anterior chamber, suspicion of a ruptured globe, or if a lens implant is present. Atropine has a long duration of action (1 to 2 weeks) and should be prescribed only by an ophthalmologist. Decongestants and antiallergy ocular medications are commonly prescribed and lessen allergic ocular symptoms. A number of agents are used to treat glaucoma. It is important to know that these are absorbed and can have systemic effects. For example, topical p -blocker agents can result in symptomatic bradycardia or increased bronchospasm. Nonsteroidal anti-inflammatory agents are useful in alleviating the symptoms of inflammation in a wide variety of ocular conditions. Artificial tears relieve symptoms related to dry eyes and protect the corneas of unconscious patients as well as patients suffering from Bell's palsy.

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KEY CONCEPTS {, {,

{, {,

{,

{,

{,

Orbital floor fractures: Surgical repair is only for persistent diplopia or cosmetic concerns and is generally not performed until swelling subsides in 7 to 10 days. Retrobulbar hematoma: When a retrobulbar hematoma compromises retinal circulation, immediate treatment of increased intraocular pressure includes carbonic anhydrase inhibitor, topical p -blocker, and IV mannitol. A lateral canthotomy can be done in the emergency department as a temporizing measure before definitive decompression. Corneal abrasions: Data suggest that eye patching confers no benefit in healing small, uncomplicated corneal abrasions. Globe rupture: Treatment includes avoidance of further examination or manipulation and placement of a protective metal eye shield to prevent accidental pressure on the globe. Antiemetics should be given if nausea is present. Broad-spectrum IV antibiotics should be instituted. Retinal detachments: Retinal tears or detachments do not cause pain. Examination may reveal the hazy gray membrane of the retina billowing forward, but many tears are peripherally located and not seen with direct ophthalmoscopy. Visual acuity may be normal unless the macula is involved. Indirect ophthalmoscopy is warranted if historical clues to the presence of retinal tears are present. Bacterial conjunctivitis: In uncomplicated acute bacterial conjunctivitis, neomycin ophthalmic solutions should be avoided because of the high incidence of hypersensitivity reactions. Corticosteroids and eye patching should be avoided. Glaucoma: Attacks of primary angle closure glaucoma produce symptoms that are abrupt in onset and include severe eye pain, blurred vision, headache, nausea, vomiting, and occasionally abdominal pain. Signs include conjunctival injection and a cloudy (steamy) cornea with a midpositioned to dilated pupil that is sluggish or fixed. Intraocular pressures are markedly elevated.

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REFERENCES 1. Department of Emergency Medicine, Hennepin County Medical Center, Emstat, 1999. 2. Baker SM, Hurwitz JJ: Sports and industrial ophthalmology: Management of orbital and ocular adnexal trauma. Ophthalmol Clin North Am1999;12:435. 3. O'Hare TH: Blowout fractures: A review. J Emerg Med1991;9:253. 4. Mathong RH: Management of orbital blowout fractures. Otolaryngol Clin North Am1991;24:79. 5. Spoor TC, Nesi FA: Management of Ocular, Orbital, and Adnexal Trauma, New York, Raven Press, 1988. 6. Birrer RB, Robinson T, Papachristos P: Orbital emphysema: How common, how significant?. Ann Emerg Med1994;24:1115. 7. Dobler AA: A case of orbital emphysema as an ocular emergency. Retina1993;13:166. 8. Zimmer-Galler IE, Bartley GB: Orbital emphysema: Case reports and review of the literature. Mayo Clin Proc1994;69:115. 9. Joondeph BC: Blunt ocular trauma. Emerg Med Clin North Am1988;6:147. 10. Murphy JC: Ocular irritancy responses to various pHs of acids and bases with and without irrigation. Toxicology1982;23:281. 11. Janda AM: Ocular trauma. Postgrad Med1991;90:51. 12. Dean BS: Cyanoacrylate and corneal abrasion. Clin Toxicol1989;27:169. 13. Leahey AB, Gottsch JD, Stark WJ: Clinical experience with N-butyl cyanoacrylate (Nexacryl) tissue adhesive. Ophthalmology1993;100:173. 14. Lubeck D, Greene JS: Corneal injuries. Emerg Med Clin North Am1988;6:73. 15. Rosenwasser GO: Topical anesthetic abuse. Ophthalmology1990;97:967. 16. Sklar DP, Lauth JE, Johnson DR: Topical anesthesia of the eye as a diagnostic test. Ann Emerg Med 1989;18:1209. 17. Hulbert MF: Efficacy of eye pad in corneal healing after corneal foreign body removal. Lancet 1991;337:643. 18. Roberts JR: Myths and misconceptions: An eye patch for simple corneal abrasions. Emerg Med News 1995;February:4. 19. Hamill MB: Sports and industrial ophthalmology. Current concepts in the treatment of traumatic injury to the anterior segment. Ophthalmol Clin North Am1999;12:457. 20. Safran MJ: Management of traumatic hyphema. Hosp Physician1987;June:20. 21. Farber MD, Fiscella R, Goldberg MF: Aminocaproic acid versus prednisone for the treatment of traumatic hyphema: A randomized clinical trial. Ophthalmology1991;98:279. 22. Jackson J: Hyphema. Optom Clin1993;3:27. 23. Pavan-Langston D: Manual of Ocular Diagnosis and Therapy, 3rd ed. Boston, Little, Brown, 1991. 24. Fong LP: Secondary hemorrhage in traumatic hyphema: Predictive factors for selective prophylaxis. Ophthalmology1994;101:1583. 25. Charache S: Sickle cell disease: Eye disease in sickling disorders. Hematol Oncol Clin North Am 1996;10:1357. 26. Weisman RA, Savino PJ: Management of patients with facial trauma and associated ocular/orbital injuries. Otolaryngol Clin North Am1991;24:37. 27. Lubeck D: Penetrating ocular injuries. Emerg Med Clin North Am1988;6:127. 28. Shingleton BJ: Eye injuries. N Engl J Med1991;325:408. 29. Ferrari LR: Trauma. The injured eye. Anesthesiol Clin North Am1996;14:125. 30. Libonati MM, Leahy JJ, Ellison N: The use of succinylcholine in open eye surgery. Anesthesiology 1985;62:637. 31. Reppucci VS, Movshovich A: Sports and industrial ophthalmology. Current concepts in the treatment of traumatic injury to the posterior segment. Ophthalmol Clin North Am1999;12:465. 32. Solley WA, Broocker G: Ocular trauma. In: Palay DA, Krachmer JH, ed.Ophthalmology for the Primary Care Physician, St. Louis: Mosby; 1997: 268-269. 33. Alfaro DV, Roth D, Liggett PE: Posttraumatic endophthalmitis. Causative organisms, treatment, and prevention. Retina1994;14:206.

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34. Linden JA, Renner GS: Trauma to the globe. Emerg Med Clin North Am1995;13:581. 35. Diamant JI, Hwang DG: Ocular infections: Update on therapy. Therapy for bacterial conjunctivitis. Ophthalmol Clin North Am1999;12:15. 36. Treatment of sexually transmitted disease. Med Lett1990;32:5. 37. Barequet IS, O'Brien TP: Ocular infections: Update on therapy. Therapy of herpes simplex viral keratitis. Ophthalmol Clin North Am1999;12:63. 38. Harding SSP: Management of ophthalmic zoster. J Med Virol1993;1(Suppl):97. 39. Rhee DJ, Pyfer MF: Conjunctival/scleral/external disease. In: Friedberg MA, Rapuano CJ, ed.The Wills Eye Manual, 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 1999: 86-89. 40. Miedziak AI, O'Brien TP: Ocular infections: Update of therapy. Therapy of varicella-zoster virus ocular infections. Ophthalmol Clin North Am1999;12:51. 41. Lederman C, Miller M: Hordeola and chalazia. Pediatr Rev1999;20:283. 42. Pederson JE: Glaucoma: A primer for primary care physicians. Glaucoma1991;90:41. 43. Shiose Y: Intraocular pressure: New perspectives. Surv Ophthalmol1990;34:413. 44. Beck AD: Glaucoma. In: Palay DA, Krachmer JH, ed.Ophthalmology for the Primary Care Physician, St. Louis: Mosby; 1997: 139. 45. Urtti A, Salminen L: Minimizing systemic absorption of topically administered ophthalmic drugs. Surv Ophthalmol1993;37:435. 46. Fraunfelder FT: Drug Induced Ocular Side Effects and Drug Interactions, 3rd ed. Philadelphia, Lea & Febiger, 1989. 47. Kooner KS, Zimmermann TJ: Management of acute elevated intraocular pressure, I. Diagnosis. Ann Ophthalmol1988;20:46. 48. Yanofsky NN: The acute painful eye. Emerg Med Clin North Am1988;6:21. 49. Morgan A, Hemphill RR: The difficult diagnosis: Acute visual change. Emerg Med Clin North Am 1998;16:825. 50. Bertolini J, Pelucio M: The red eye. Emerg Med Clin North Am1995;13:561. 51. Delaney Jr JrWV: Ocular vascular disease: In-office primary care diagnosis. Geriatrics1993;48:60. 52. Sharma S, Brown M, Brown GC: Retinal vascular disorders: Retinal artery occlusions. Ophthalmol Clin North Am1998;11:591. 53. Rassam SM, Patel V, Kohner EM: The effect of acetazolamide on the retinal circulation. Eye1993;7:697. 54. Atebara N, Brown GC, Cater J: Efficacy of anterior chamber paracentesis and carbogen in treating nonarteritic central retinal artery occlusion. Ophthalmology1995;102:2029. 55. Hayreh SS: Retinal vascular disorders: Central retinal vein occlusion. Ophthalmol Clin North Am 1998;11:559. 56. Bolling JP, Hernan DC, Pach JM: Disorders of retina, vitreous, and choroid. In: Bartley GB, Liesegang TJ, ed.Essentials of Ophthalmology, Philadelphia: JB Lippincott; 1992: 136-139. 57. Hardy RA, Crawford JB: Retina. In: Vaughan D, Asbury T, Riordan-Eva P, ed.General Ophthalmology, 15th ed. New York: Appleton & Lange; 1999: 188. 58. O'Malley C: Vitreous. In: Vaughan D, Asbury T, Riordan-Eva P, ed.General Ophthalmology, 15th ed. New Jessey: Appleton & Lange; 1999: 167-168. 59. Alexander LJ: Age related macular degeneration: The current understanding of the status of clinicopathology, diagnosis and management. J Am Optom Assoc1993;64:822. 60. Miller NR: Walsh and Hoyt's Clinical Neuro-Ophthalmology, 4th ed. Baltimore, Williams & Wilkins, 1991. 61. Optic Neuritis Study Group : The 5 year risk of MS after optic neuritis: Experience of the optic neuritis treatment trial. Neurology1997;49:1404. 62. Beck RW: The effect of corticosteroids for acute optic neuritis on the subsequent development of multiple sclerosis. N Engl J Med1993;329:1764. 63. Sellebjerg F: A randomized, controlled trial of oral high-dose methylprednisolone in acute optic neuritis. Neurology1999;52:1479. 64. Weinberg DA: Giant cell arteritis: Corticosteroids, temporal artery biopsy, and blindness. Arch Fam Med 1994;3:623. 65. Liu GT: Visual morbidity in giant cell arteritis: Clinical characteristics and prognosis for vision. Ophthalmology1994;101:1779. 66. Wong RL: Temporal arteritis without an elevated erythrocyte sedimentation rate: Case report and review of the literature. Am J Med1986;80:959. 67. Lam BL, Thompson HS, Corbett JJ: The prevalence of simple anisocoria. Am J Ophthalmol1987;104:69.

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Chapter 71 – Otolaryngology James A. Pfaff Gregory P. Moore

OTITIS MEDIA Perspective Background Otitis media (OM) is the most common diagnosis made by U.S. physicians for children younger than 15 years old.[1] In the greater Boston area, 60% of 877 children were diagnosed at least once with acute otitis media (AOM) by 1 year of age; by 3 years of age, more than 80% had AOM, with 40% having more than three episodes.[2] The financial impact is enormous; one estimate is that $5 billion per year is spent on the evaluation, treatment, and socioeconomic effects of OM.[3]

Epidemiology Male gender, day care attendance, parental smoking, and a family history of middle ear disease have been implicated to increase risk.[4] Children with anatomic abnormalities, such as cleft palate and Down syndrome, have a higher rate of OM, probably because of eustachian tube abnormalities. Some immunocompromised patients, including patients with human immunodeficiency virus, may have recurrent OM as an initial symptom of their underlying disease. OM and upper respiratory infections occur primarily in the winter. Breast-feeding seems to be protective.[5]

Definitions Otitits media is broadly defined as inflammation of the inner ear and is a continuum of disease. Acute otitis media is defined as the signs and symptoms of an acute infection, with evidence of effusion; this has also been called acute suppurative or purulent OM. Otitis media with effusion (OME) has effusion without signs or symptoms of an acute infection; additional descriptive terms include serous, mucoid, nonsuppurative, or secretory OM. OME is classified further into acute (3 months). Chronic OM, or chronic suppurative otitis media, refers to chronic discharge from the ear through perforation of an intact membrane. Recurrent OM is defined by three or more episodes over 6 months or four episodes in 1 year.

Principles of Disease Pathophysiology Eustachian tube dysfunction is the central theme to most theories of AOM pathogenesis. The eustachian tube, between the middle ear cavity and the nasopharynx, ventilates the middle ear to equilibrate pressure, allow for middle ear drainage, and provide protection from nasopharyngeal secretions. In children, it measures approximately 18 mm and is almost horizontal. As individuals age, the eustachian tube widens, doubles in length, becomes more vertically oriented, and stiffens (which may explain the decreased incidence of AOM in adults). Normally, the tube is collapsed, but it opens during yawning, chewing, and swallowing. The eustachian tube may become either mechanically or functionally obstructed, decreasing middle ear ventilation. Examples of mechanical obstruction include inflammations from an upper respiratory infection, hypertrophied adenoids, and a cleft palate.[6] Functional obstruction from persistent tubal collapse occurs primarily in young children, who have less fibrocartilage support of the medial eustachian tube than older children or adults.[6] It has been postulated that this dysfunction results in negative middle ear cavity pressure, causing a transudate of fluid that combines with the reflux of nasopharyngeal secretions and bacteria.

Etiology

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The most common bacterial causes are Streptococcus pneumoniae, Haemophilus influenzae (primarily nontypeable), and Moraxella (Branhamella) catarrhalis. Streptococcus pyogenes, Staphylococcus aureus, and gram-negative bacteria are much less common.[7] Adult infection involves similar organisms. In OME, there is a greater proportion of H. influenzae and a higher percentage of sterile effusions.[8] Viruses also have been found in the middle ear aspirates of children with OM. In one study, viruses were identified in 90% of children with AOM and as the sole source in 5% to 6% of cases.[9] Some authors believe that viral infection is the cause of the inflammatory reaction in most cases and antibiotics are not necessary. Respiratory syncytial virus is the most common virus, followed by rhi-novirus, influenzavirus, and adenovirus.[8] These viruses may be responsible for some of the treatment failures seen in AOM, possibly by interfering with eradication of bacterial pathogens. In young children, it was believed that gram-negative organisms and S. aureus were the causative factors. Although these organisms may be the causes in intubated patients or patients in the neonatal intensive care unit, healthy newborns tend to be infected by the same pathogens as healthy older children.[10] A special note should be made about bullous myringitis. Middle ear aspirates in this condition generally grow the usual organisms that cause AOM.[11] Mycoplasma pneumoniae is uncommon. Other, less likely, organisms that can cause AOM include Mycobacterium tuberculosis (primarily in children) and Chlamydia trachomatis (most commonly seen in children younger than 6 months old with pneumonia).[12]

Clinical Features OM may be manifested by a multitude of symptoms, such as cough, poor appetite, diarrhea, vomiting, fever, and pulling at ears, all of which are nonspecific. Older children may be able to verbalize pain, but otalgia is not universally present. In OM, pain usually precedes otorrhea, in contrast to OME, in which pain accompanies the drainage. Children often have associated upper respiratory tract infections. Fever may be present, but in one large series, a temperature of 38.3°C or greater was present in only 26% of the episodes, with only 4% having a fever of 40°C or greater.[13] Some authorities have modified the definition to include otoscopic findings of acute inflammation regardless of symptoms; with this definition, one third of cases are not accompanied initially by acute symptoms.[14] The auricle and external canal should be inspected for signs of erythema, discharge, or tenderness. If the canal is occluded with cerumen, an ear curet with direct visualization may be successful in clearing the canal. If not, the placement of 3% hydrogen peroxide or emulsifying drops, followed by gentle irrigation, may cleanse the canal. The tympanic membrane (TM) may be bulging (as in AOM), neutral, or retracted as seen in chronic OME.[15] The color may be red, pink, yellow, or a normal pearly gray or translucent. The presence of erythema in itself does not indicate infection because crying or fever may cause hyperemia; however, a TM that is distinctly red (defined as hemorrhagic, strongly or moderately red) suggests AOM.[15] Landmarks that should be visible include the pars flaccida, the malleolus, and the light reflex below the umbo.[15] The TM may have air-fluid levels, may have bubbles behind the TM, or may be completely opacified, all of which indicate middle ear effusion. The lack of mobility is one of the most sensitive indicators of middle ear effusion. A TM that is cloudy, bulging, or distinctly immobile indicates AOM.[15] In OME, the TM often is retracted, with the malleolus being particularly prominent. The landmarks all may be obscured in the presence of significant fluid. A comparison examination of the other ear may help in confirming suspected infection. In neonates, the TM appears thickened and opaque normally in the first few weeks of life, and the TM is in a highly oblique position. With tympanostomy tubes, in the absence of infection, the TM may have decreased mobility, altered landmarks, opacity, or dullness. If the tube is patent, erythema and discharge may indicate infection. If not, erythema, bulging of the TM, and immobility indicate AOM.

Complications Before the use of antibiotics, there was a 20% in-cidence of complications from AOM, with mastoiditis and otic meningitis relatively common.[16] Complications generally are considered either intratemporal or intracranial. The development of either complication of OM is thought to occur by one of three mechanisms: (1) direct extension of infection through bone weakened by osteomyelitis or cholesteatoma; (2) retrograde spread of infection by thrombophlebitis; or (3) extension of infection along preformed path-ways, such as the round or oval windows or through dehiscences that are the result of congenital malformations.[17]

Intratemporal

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Hearing impairment is the most common complication in OM. Almost all children with OM have a temporary conductive hearing loss; sensorineural deficit occurs less commonly, probably as a spread of infection through the round window. This deficit may contribute to the association of OM with decreased or delayed speech, language, or cognitive development. TM perforation occurs most commonly at the pars tensa and usually resolves spontaneously. It may persist for a longer period, resulting in a chronic perforation, chronic OM, or both.[12] Chronic OM refers to chronic discharge from the ear through perforation of an intact membrane. It can occur spontaneously or through tympanostomy tubes for 2 to 3 months or longer.[17] The organisms involved are usually Pseudomonas aeruginosa or S. aureus. Treatment begins with oral/topical antibiotics; patients should be referred to an otolaryngologist. Cholesteatoma is an accumulation of keratin-producing squamous epithelium in the middle ear and may result in erosion of bone within the middle ear cavity. It is seen most often in OME, in which retraction of the TM is a common problem. Treatment is usually surgical. Labyrinthitis occurs when infection spreads to the cochlear and vestibular apparatus, usually through the round or oval windows. Serous labyrinthitis results when bacteria from the middle ear spread into the labyrinth space, resulting in a mixed conductive/sensorineural hearing loss and vestibular symptoms. Suppurative labyrinthitis is the development of purulence directly into the labyrinth as a result of bacterial invasion through the round window or around the annular ligament of the round window. It generally begins suddenly with mixed hearing loss and vestibular symptoms and is generally more severe than the serous form.[17] Facial nerve paralysis is a rec-ognized complication in children with OM. The facial nerve courses through the middle ear and may be affected by infection.[12] Treatment consists of intravenous antibiotics, myringotomy, and tube placement. Infectious eczematoid dermatitis may result from the otorrhea of OM, with perforation or tympanostomy tubes infecting the external auditory canal. Treatment involves otic suspension (not solution). Although caution is urged with these products, the incidence of adverse effects is small.[18]

Intracranial Before antibiotics, intracranial complications occurred in 2.5% of patients. The incidence has decreased significantly, and complications usually result from chronic middle ear disease.[12] Meningitis is the most common intracranial complication, resulting from hematogenous spread and direct invasion. An extradural abscess may result from destruction of bone adjacent to the dura by cholesteatoma, infection, or both. Subdural empyema is a collection of fluid between the dura and arachnoid membrane as a result of infection or venous thrombophlebitis. Focal otic encephalitis is an edematous or inflamed area in the brain from a complication of OM, extradural abscess, or sinus dural thrombophlebitis.[19] It may be distinguished from brain abscess by computed tomography (CT). A brain abscess results from direct extension of the infection or follows the development of an adjacent infection, such as lateral sinus thrombosis. Organisms include S. pyogenes, S. aureus, and S. pneumoniae.[19] The treatment for these conditions includes intravenous antibiotics and surgical drainage. Lateral venous sinus thrombosis occurs when the mastoid infection comes in contact with the sinus wall, which inflames the adventitia and penetrates the venous wall. Thrombosis and embolization occur. Patients may have fever and chills, earache, headache, and mastoid and neck tenderness. Treatment involves intravenous antibiotics and surgical drainage.

Diagnostic Strategies Tympanocentesis is aspiration of the middle ear effusion to identify causative organisms. Indications include patients with AOM who are seriously ill or toxic, are unresponsive to therapy, are younger than 4 weeks old, are immunocompromised, are receiving antimicrobials, or have suppurative complications.

Differential Considerations OM usually does not cause a significantly high fever; in approaching a febrile, ill-appearing infant, the physician should seek other sources. If a child or adult complains of otalgia, additional considerations or possibilities include OME, trauma, foreign bodies, and complications of OM such as mastoiditis. Ear pain also may be referred from the teeth, sinuses, throat, or temporomandibular joint.

Management The most frequent outpatient use of antimicrobials in the United States is for OM, with the number of

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prescriptions increasing from 12 million in 1980 to more than 23.6 million in 1992.[20] Although there are more than 16 antibiotics that have been approved by the Food and Drug Administration for OM, few have shown efficacy against all of the main causative pathogens.[3] Given this and the increasing resistance against S. pneumoniae, the predominant organism, a Centers for Disease Control and Prevention working group published recommendations for the treatment of AOM in 1999. Although p -lactamase production can occur in S. pneumoniae, H. influenzae, and M. catarrhalis, OM associated with the latter two organisms is far more likely to resolve spontaneously.[21] Concern about the rising rates of antibacterial resistance and the growing costs of antibacterial prescriptions has focused the attention of the medical community and the general public on the need for judicious use of bacterial agents.[22] Based on this and other factors, the American Academy of Pediatrics, the American Academy of Family Physicians, the Agency for Healthcare Research and Quality, and the Southern California Evidence Based Practice Center met to develop guidelines for the diagnosis and management of AOM to assist physicians in providing a framework for clinical decision making. As with all guidelines, these are tools for the management of the disease and should be used in the context of patient care and in the context of local practice patterns. These guidelines apply specifically to an otherwise healthy child between the ages of 2 months and 12 years without underlying conditions that may alter the natural course of acute AOM ( Table 71-1 ).[22] Table 71-1 -- Clinical Practice Guidelines: Diagnosis and Management of Acute Otitis Media

Page 944

1.

To diag nose acut e otitis medi a, the clinic ian shou ld confi rm a histo ry of acut e onse t and ident ify sign s of midd le ear effus ion (bulg ing of the TM, limit ed or abse nt mobi lity of the TM, air-fl uid level behi nd the TM, otorr hea) and sign s or sym ptom s of midd le ear infla mm ation as indic

Page 945

1.

To diag nose acut e otitis medi a, the clinic ian shou ld confi rm a histo ry of acut e onse t and ident ify sign s of midd le ear effus ion (bulg ing of the TM, limit ed or abse nt mobi lity of the TM, air-fl uid level behi nd the TM, otorr hea) and sign s or sym ptom s of midd le ear infla mm ation as indic

Page 946

1.

To diag nose acut e otitis medi a, the clinic ian shou ld confi rm a histo ry of acut e onse t and ident ify sign s of midd le ear effus ion (bulg ing of the TM, limit ed or abse nt mobi lity of the TM, air-fl uid level behi nd the TM, otorr hea) and sign s or sym ptom s of midd le ear infla mm ation as indic

Page 947

1.

To diag nose acut e otitis medi a, the clinic ian shou ld confi rm a histo ry of acut e onse t and ident ify sign s of midd le ear effus ion (bulg ing of the TM, limit ed or abse nt mobi lity of the TM, air-fl uid level behi nd the TM, otorr hea) and sign s or sym ptom s of midd le ear infla mm ation as indic

Page 948

1.

To diag nose acut e otitis medi a, the clinic ian shou ld confi rm a histo ry of acut e onse t and ident ify sign s of midd le ear effus ion (bulg ing of the TM, limit ed or abse nt mobi lity of the TM, air-fl uid level behi nd the TM, otorr hea) and sign s or sym ptom s of midd le ear infla mm ation as indic

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1.

To diag nose acut e otitis medi a, the clinic ian shou ld confi rm a histo ry of acut e onse t and ident ify sign s of midd le ear effus ion (bulg ing of the TM, limit ed or abse nt mobi lity of the TM, air-fl uid level behi nd the TM, otorr hea) and sign s or sym ptom s of midd le ear infla mm ation as indic

Page 950

1.

To diag nose acut e otitis medi a, the clinic ian shou ld confi rm a histo ry of acut e onse t and ident ify sign s of midd le ear effus ion (bulg ing of the TM, limit ed or abse nt mobi lity of the TM, air-fl uid level behi nd the TM, otorr hea) and sign s or sym ptom s of midd le ear infla mm ation as indic

Page 951

1.

To diag nose acut e otitis medi a, the clinic ian shou ld confi rm a histo ry of acut e onse t and ident ify sign s of midd le ear effus ion (bulg ing of the TM, limit ed or abse nt mobi lity of the TM, air-fl uid level behi nd the TM, otorr hea) and sign s or sym ptom s of midd le ear infla mm ation as indic

Page 952

From American Academy of Pediatrics Subcommittee on Management of Acute Otitis Media: Diagnosis and management of acute otitis media. Pediatrics 113:1451, 2004. AOM, acute otitis media; TM, tympanic membrane. Note: Nonsevere illness is mild otalgia and fever < 39°C in the past 24 hours. Severe illness is moderate to severe otalgia or fever ≥ 39° C. A certain diagnosis meets all three criteria: (1) rapid onset (2) signs of middle ear effusion, and (3) signs and symptoms of middle ear inflammation.

The decision to treat is based on the age of the patient and certainty of the diagnosis.[22] The guidelines recommend an age-stratified approach that incorporates the age with a combination of diagnostic certainty and illness severity. Observation is an option in children older than 2 years old, unless the child has severe otalgia or temperature of 39°C or greater ( Table 71-2 ). In children 6 months to 2 years old, treatment recommendations are based on the certainty of the diagnosis and severity of illness, with recommended observation if the diagnosis is uncertain. The guidelines recommend treatment in children younger than 6 months old. Observation recommendations are based on the reliabilty of the caregivers and the ability for close follow-up, an option often not available to many children presenting for care in the emergency department. Table 71-2 -- Treatment Guidelines for Otitis Media At Diagnosis for Clinically Defined Treatment Patients Being Failure at 48–72 Hours after Treated Initially Initial Management with with Observation Option Antibacterial Agents Temperature ≤ Recom Alternat Recommended Alternative for mende ive for Penicillin 39° C or Penicilli Allergy Severe Otalgia d n or Both Allergy No Amoxicil Non– Amoxicillin (80– Non–type I: lin (80– type I: 90 mg/kg/day) cefdinir, 90 cefdinir, cefuroxime, mg/kg/d cefuroxi cefpodoxime ay) me, cefpodo xime

Clinically Defined Treatment Failure at 48–72 Hours after Initial Management with Antibacterial Agents

Recommended Alternative for Penicillin Allergy

Amoxicillin-clavul Non–type I: anate (90 ceftriaxone—3 mg/kg/day of days amoxicillin with 6.4 mg/kg/day of clavulanate)

Type I[*]: azithro mycin, Type I[*]: clarithro azithromycin, Type I[*]: mycin clarithromycin clindamycin Yes Amoxicil Ceftriax Amoxicillin-clavul Ceftriaxone—1 Ceftriaxone—3 Tympanocentesi lin-clavul one—1 anate (90 or 3 days days s—clindamycin anate or 3 mg/kg/day of (90 days amoxicillin with mg/kg/d 6.4 mg/kg/day of ay of clavulanate) amoxicill in with 6.4 mg/kg/d ay of clavulan ate) From American Academy of Pediatrics Subcommittee on Management of Acute Otitis Media: Diagnosis

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and management of acute otitis media. Pediatrics 113:1451, 2004. *

Type I sensitivity—urticaria or anaphylaxis.

Amoxicillin's cost, efficacy, safety profile, and palatability continue to make it a good first-line agent. While previous working groups had developed high/low risk criteria for different amoxicillin doses (40 vs. 80-90 mg/kg/day), many authorities now recommend an initial dose of 80-90 mg/kg/day. This higher concentration is effective against susceptible and intermediate resistant strains of Streptococcus pneumoniae. Patients should be re-evaluated in 3 days if treatment failure occurs. Treatment failure is defined by lack of clinical improvement in signs and symptoms, such as ear pain; fever; and TM findings of redness, bulging, or otorrhea. Treatment should include agents effective against p -lactamase-producing H. influenzae and M. catarrhalis. Recommended agents include amoxicillin-clavulanate (using 80 to 90 mg/kg/day of the amoxicillin component), oral cefuroxime axetil, and intramuscular ceftriaxone. Although ceftriaxone has been as effective as amoxillicin in patients with a history of vomiting, poor compliance, and a lack of follow-up,[23] a 3-day regimen may improve its effectiveness.[21] If patients have an identified treatment failure within the first 28 days, recommended antibiotics are the same as at 3 days. Patients who have been on antibiotics in the prior month should receive high-dose amoxicillin, high-dose amoxicillin-clavulanate, or cefuroxime axetil as the initial treatment. Cefdinir may be preferred over cefuroxime because of its more pleasing taste, which can equate to improved compliance.[3] Treatment failures at 3 days should be treated with intramuscular ceftriaxone or clindamycin, with tympanocentesis strongly encouraged. Clindamycin should be used only for treatment of S. pneumoniae because it is not effective against either H. influenzae or M. catarrhalis.[] Treatment failures within 1 month should be treated with high-dose amoxicillin-clavulanate, cefuroxime axetil, or intramuscular ceftriaxone.[21] Trimethoprim-sulfamethoxazole and macrolides traditionally have been second-line agents, but there is increasing resistance—40% for trimethoprim-sulfamethoxazole and 30% for macrolides.[3] In addition, there is substantial cross-resistance between these drugs and the p -lactams, resulting in further treatment failures in children finishing a course of amoxicillin.[] Fluoroquinolines may be effective, but their use in children is not approved.[21] Response to antibiotics is only one of a number of factors that affect clinical outcome. Other factors include impairment of Etb function, co-infection with nonbacterial pathogens and host immune response.[42] Local practice patterns and antimicrobial sensitivities may also play a role in the types of treatment given. Other antibiotics available for treatment include erythromycin-sulfisoxazole, azithromycin, clarithromycin, cephalexin, cefaclor, cefprozil, loracarbef, cefdinir, cefixime, cefpodoxime, and ceftibuten. These were not included in the CDC guidelines primarily because there was a lack of data on their efficacy. Treatment historically involved a 10-day course. Numerous studies have compared traditional treatment courses with shorter therapy, which is most appropriate for uncomplicated AOM.[] Patients with TM perforations and patients at high risk for treatment failures or with chronic or recurrent OM probably are more appropriately treated with a longer course.[24] Shorter courses also are not appropriate for children younger than 2 years old.[] The antibiotic treatment of AOM in adults is the same as in older children. There is no indication for the use of antihistamines, decongestants, steroids, or tympanostomy tubes for an acute episode of AOM.[6] Benzocaine-antipyrine, a local anesthetic, may be helpful in some patients with an intact TM. Recurrent AOM occurs primarily in the winter months, often in conjunction with upper respiratory infections. Individuals at risk include children younger than 2 years old, children in day care, and Native American children.[25] These children may benefit from prophylaxis with either amoxicillin, 20 mg/kg, or sulfisoxazole, 50 mg/kg given at night. After a 10-day treatment with antibiotics, 50% of children may exhibit OME, but 90% of cases resolve within 3 months.[28] The treatment of OME is controversial, but OME may interfere with hearing and subsequent development of speech and language. OME is by definition asymptomatic, and the effusion may be sterile or contain infectious agents. Clinical guidelines developed by the Agency for Health Care Policy recommend observation or the use of antibiotics in patients with acute or subacute OME, although some experts recommend observation alone given increasing antibiotic resistance.[] Antihistamines, decongestants, steroids, or surgical procedures are not beneficial in patients with acute or subacute OME.[25] Myringotomy and tympanostomy tubes may be beneficial in children who have failed medical treatment, have had OME

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for 4 to 6 months, and have a greater than 20-dB hearing loss.[1] Tonsillectomy is not beneficial, but adenoidectomy may be helpful in older children. Tympanostomy tubes also have been used in recurrent AOM unresponsive to prophylactic antibiotics; complications of AOM, including mastoiditis, meningitis, brain abscess, and facial nerve paralysis; and complications of eustachian tube dysfunction, including TM retraction with hearing loss, ossicular erosions, or retraction pocket formation.[28] Conjugate pneumococcal vaccine has been effective in markedly reducing invasive disease in young children and decreasing the incidence of OM.[29] It is estimated that its use would decrease the number of visits for OM by 1 million, and the number of children receiving tympanostomy tubes might decrease by 500,000.[30]

Disposition Children normally are seen in 10 to 14 days for follow-up. This follow-up appointment may not be necessary in children older than age 2 years with resolution of symptoms and no recurrent risk factors.[31] Infants younger than 2 months old with OM should be evaluated with blood, cerebrospinal fluid, and urine cultures.[6] Patients with complications need ear, nose, and throat (ENT) referral. Adults who have persistent OME need ENT referral to rule out nasopharyngeal carcinoma.

OTITIS EXTERNA Principles of Disease External otitis is an inflammation of the external auditory canal. The canal is lined with squamous epithelial cells and cerumen glands that provide a protective lipid layer.[32] This protective layer may be disrupted by high humidity, increased temperature, maceration of the skin after prolonged exposure to moisture, and local trauma (e.g., cotton swabs or the use of hearing aids), resulting in the introduction of bacteria.[33] The most common bacterial causes are P. aeruginosa, S. aureus, and S. epidermidis. Otitis externa occurs most often in the summer and is common in the tropics.

Clinical Features The canal is initially pruritic and becomes erythematous and increasingly swollen. The diagnosis is made clinically with ear pain, erythema or edema of the canal, and reproduction of the discomfort with pulling on the auricle or tragus. Severe otitis externa is manifested by intense pain, canal occlusion, and conductive hearing loss.[32] Cultures are unnecessary. The disease may progress to a chronic form with itching, eczema, and flaking of the epithelium, which may be from bacterial, fungal, or dermatologic conditions. In children, it is usually secondary to OME.

Differential Considerations It may be difficult to distinguish otitis externa from OM, particularly in children. The TM may be erythematous in both conditions, and the edema may preclude diagnosis. The discharge may be from otitis externa or a perforated TM, and in equivocal cases it is prudent to treat for both conditions. Otomycosis or fungal infection can occur as a primary or secondary infection and accounts for 10% of cases of otitis externa.[34] Itching is the prominent symptom, often with minimal pain or otorrhea. Aspergillosis is the cause in most cases. Otomycosis appears most often in individuals in tropical climates, in patients with diabetes, in immunocompromised patients, and in patients on immunosuppressive therapy. Treatment involves cleansing and acidifying and antifungal eardrops, such as thimerosal or gentian violet. Specific antifungal agents, such as clotrimazole and itraconazole, also are effective.[34] Furunculosis is a small, erythematous, and well-circumscribed infection of the cartilaginous portions of the external canal, usually caused by S. aureus.[32] There is usually no drainage, and treatment involves incision, drainage, and an oral antistaphylococcal antibiotic. Cellulitis of the auricle and canal may cause erythema, induration, and other systemic signs. Treatment is with antibiotics directed at the offending organisms. Parenteral antistaphylococcal antibiotics (e.g., nafcillin) may be required in severe infections. Herpes zoster oticus, also known as the Ramsay Hunt syndrome, is a viral manifestation of disease affecting the auricle, with resulting facial paralysis that may involve multiple cranial nerves. It initially causes pain, with erythema, swelling, and vesicles developing approximately 3 to 7 days later.[34] These patients need ENT referral. Treatment consists of analgesia, warm compresses, and acyclovir.

Management

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Historically, combination drugs containing neomycin, polymyxin B, and hydrocortisone four times a day have been effective for treatment, although there has been a problem with hypersensitivity. The new fluoroquinolones are less reactive, need to be given only twice a day, and are rapidly becoming the preferred therapy.[35] Initial management may involve cleansing the external canal with a combination of gentle suctioning and irrigation, depending on the amount of obstructing exudate. Cleansing solutions include tap water, sterile saline, 2% acetic acid, and Burow's solution. In severe infections, a wick of cotton, gauze, or compressed hydroxycellulose facilitates medication delivery. The wick is placed 10 to 12 mm into the canal, moistened with antibiotic drops, and left in place for 2 to 3 days. Cephalosporins and ciprofloxacin, among others, may be necessary in infections involving the skin and periauricular areas.[34] Opioid analgesia may be necessary. Patients with severe inflammation (fever, cervical lymphadenopathy, or periauricular nodes) need close follow-up and ENT referral.

NECROTIZING (MALIGNANT) EXTERNAL OTITIS Previously known as malignant otitis externa because of its high mortality, necrotizing external otitis is an extremely aggressive form of otitis externa. It occurs primarily in adults with diabetes mellitus but also has been seen rarely in immunocompromised children. Pseudomonas is the predominant pathogen, but S. aureus, S. epidermidis, Proteus mirabilis, Klebsiella, Aspergillus, and Salmonella all have been described.[36] The infection begins in the external canal and progresses through the periauricular tissue and cartilaginous bony junction of the external auditory meatus. It then spreads into the adjacent tissues along clefts in the floor of the meatus known as the fissures of Santorini.[37] It may spread to the base of the skull at the temporal bone, with a resultant skull-base osteomyelitis, another term often used to describe this entity. The facial nerve is the first cranial nerve affected, but additional nerves may be involved. The pathogenesis is uncertain but may be related to vascular insufficiency or immune dysfunction.[38] Clinical symptoms include pain, tenderness, and swelling around the periauricular area, headache, and otorrhea. It may be difficult to distinguish this entity from a severe external otitis, a further reason for close follow-up. Any persistent external otitis in an elderly person with diabetes with associated pain should be considered to be temporal bone osteomyelitis. The clinical finding characteristic for the disease is granulation tissue in the floor of the ear canal at the bony cartilaginous junction. Facial paralysis occurs when there is involvement of the stylomastoid foramen, and further extension can result in cranial nerve IX, X, and XI palsies.[39] Further complications include thrombosis of the sigmoid sinus and meningitis. Bone scanning (technetium 99m) and gallium are sensitive radiographic tests, but they are not specific for the disease. CT is useful for detecting infratemporal spread of the disease and abscess formation,[37] which further define the extent of the disease. Treatment includes an aminoglycoside and a semisynthetic penicillin. There has been excellent success with ciprofloxacin, and its oral availability makes it ideal. Although extensive surgical debridement was used previously, its role is now limited. Hyperbaric oxygen has been used as an adjunct therapy.[32] Because of the incidence of external otitis in adults with diabetes, a blood glucose level should be obtained in all patients with severe external otitis.

MASTOIDITIS The incidence of acute and chronic mastoiditis has decreased significantly since the advent of antibiotics in the United States, but in Denmark, where antibiotic use is restricted, the rate of mastoiditis is twice that of the United States, although still low. Although it is still associated primarily with OM, many patients have not had an episode of OM.[] Mastoiditis also has been described as a complication of leukemia, mononucleosis, sarcoma of the temporal bone, and Kawasaki disease.[42]

Pathophysiology Acute mastoiditis is a natural extension of middle ear infections because the mastoid air cells are generally inflamed during an episode of AOM. The aditus ad antrum is a narrow connection between the middle ear and mastoid air cells. If this connection becomes blocked, a closed space is formed, with the potential for abscess development and bone destruction. The infection may spread from the mastoid air cells by venous channels, resulting in inflammation of the overlying periosteum. Progression results in the destruction of the mastoid bone trabeculae and coalescence of the cells, resulting in acute mastoid osteitis or coalescent mastoiditis. The resulting pus may track through many routes: (1) through the aditus ad antrum with resultant spontaneous resolution; (2) lateral to the surface of the mastoid process, resulting in a subperiosteal abscess; (3) anteriorly, forming an abscess below the pinna or behind the sternocleidomastoid muscle of the neck, resulting in an abscess (often called a Bezold abscess); (4) medial

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to the petrous air cells of the temporal bone, resulting in a rare condition known as petrositis; and (5) posterior to the occipital bone, resulting in osteomyelitis of the calvaria or a Citelli abscess.[] Chronic mastoiditis is generally a complication of chronic OM. There may be extensive invasion of granulation tissue from the middle ear into the mastoid air cells. Another entity, latent or “masked” mastoiditis, also has been described. It is indolent in nature, with minimal signs and symptoms, little or no fever, and a history of otalgia. The TM may be intact or perforated. Suspicion should be raised in the presence of intracranial complications without an apparent source.[43] Patients at risk for this condition include newborns and immunosuppressed patients (recent chemotherapy, steroids, or diabetic or geriatric patients).

Etiology S. pneumoniae is the most common organism found in mastoiditis, but other organisms involved do not always mirror those of acute otitis.[40] Mixed cultures of aerobes and anaerobes are common. Common aerobes include group A streptococci, S. aureus, and S. epidermidis. Chronic mastoiditis also often has mixed cultures, with P. aeruginosa as the predominant organism.

Diagnostic Findings Clinical findings in acute mastoiditis include fever, headache, and erythema. Pain is universally present.[40] Physical findings include postauricular or supraauricular tenderness, with late edema. The TM is similar to AOM (erythema, bulging, and decreased mobility) but may be normal in 10% of cases.[40] Suspicions should be heightened if symptoms of AOM have lasted longer than 2 weeks.[44] In chronic mastoiditis, symptoms include persistent drainage through the perforated TM, redness, edema, and retroauricular sensitivity.[45]

Ancillary Testing Radiographs of the mastoid area may be negative.[] CT is of greater value, especially when there is abscess formation.[45] Magnetic resonance imaging (MRI) may be more useful, particularly if there is evidence of intracranial complications.

Management The diagnosis of mastoiditis requires admitting the patient for antibiotic therapy. Traditional antibiotic choices include a semisynthetic penicillin combined with chloramphenicol or, more commonly, a third-generation cephalosporin such as cefuroxime (50 to 150 mg/kg/day) or ceftriaxone (50 to 75 mg/kg/day), usually for 1 week. Surgical procedures may range from myringotomy drainage and tympanostomy tube placement to mastoidectomy and drainage for more extensive disease progression. Mastoidectomy is required in approximately half of mastoiditis cases.[42] Antibiotic choices for chronic mastoiditis are based on culture of the persistent drainage but often include medication to cover Pseudomonas, such as ticarcillin-clavulanate or ticarcillin alone. Local cleansing also is efficacious. Antibiotics may obviate the need for surgery, although mastoidectomy may be required in some cases.[44]

SUDDEN HEARING LOSS Sudden hearing loss, although uncommon, may be of great concern to the patient. It may be noticed gradually or have a sudden onset. Although there is no accepted definition of sudden hearing loss, it is most often sensorineural in nature and occurs over a brief period, usually about 3 days.[46] Severity ranges from difficulty with conversation to complete hearing loss. The speed of onset may give clues to the etiology ( Box 71-1 ).[] A sudden onset may be from trauma or a vascular complication; gradual hearing loss suggests a tumor.[47] A history of trauma, medications, illnesses, physical activity at the time of the event, and unilateral or bilateral involvement all are helpful clues. The presence of tinnitus, vertigo, and neurologic symptoms ranging from cranial nerve abnormalities to brainstem or cerebellar dysfunction is helpful. In conductive hearing losses, such as otosclerosis, individuals hear better in noisy environments.[47] BOX 71-1 Causes of Sudden Hearing Loss

Infectious

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Mum ps Mea sles Influ enza Herp es simp lex Herp es zost er Cyto meg alovi rus Mon onuc leosi s Syph ilis

Vascular Macr oglo bulin emia Sickl e cell dise ase Berg er's dise ase Leuk emia Poly cyth emia Fat emb oli Hype rcoa gula ble state s

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Metabolic Diab etes Preg nanc y Hype rlipo prote inem ia

Conductive Ceru men impa ction Forei gn bodi es Otiti s medi a Otiti s exter na Baro trau ma Trau ma

Medications Amin ogly cosi des (gent amic in, neo myci n, vanc omy cin, kana

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myci n, strep tomy cin) Loop diure tics (furo semi de, etha cryni c acid) Antin eopl astic s Salic ylate s

Neoplasm Acou stic neur oma From Shikowitz MJ: Med Clin North Am 75:1239, 1991; Lawrence LJ, Brown CG: Emerg Med Clin North Am 5:193, 1987; and Nadol JB: N Engl J Med 329:1092, 1993.

Physical examination should include a thorough inspection of the external canal and TM integrity. Weber's test for hearing and Rinne's test may help in distinguishing conductive versus sensorineural deficits. A comprehensive neurologic examination including cranial nerves and cerebellar testing may localize brainstem involvement. CT may reveal trauma or tumors, and neurologic and chemical screening should be based on the history and physical findings.[48] Sudden sensorineural hearing loss is an otologic emergency.[ 46] Treatment is directed at the underlying causes.

EPISTAXIS Perspective Epidemiology Epistaxis is a common otolaryngologic problem, with 15 per 10,000 people requiring physician care annually and 1.6 per 10,000 requiring admission to the hospital.[49] Most cases occur in children younger than age 10 years, and the incidence decreases with age. It is more common in colder seasons and in northern climates because of decreased humidity and subsequent drying of the nasal mucosa. Epistaxis is a frightening condition for patients but is seldom life-threatening. A solid understanding of physiology and treatment allows for prompt and efficient management of the disorder.

Definition Anterior epistaxis accounts for 90% of all nosebleeds and usually involves Kiesselbach's plexus on the anteroinferior nasal septum.[50] Epistaxis is unilateral and can be controlled with anterior packing. Posterior epistaxis accounts for 10% of nosebleeds and usually arises from a posterior branch of the sphenopalatine artery.[50] It cannot be controlled with a well-placed anterior pack. Posterior bleeding is rare in children.[50]

Principles of Disease

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Anatomy Three arteries with anastomoses between them supply the nasal area. The sphenopalatine artery supplies the turbinates and meatus laterally and the posterior and inferior septum medially. The anterior and posterior ethmoidal arteries from the ophthalmic branch of the internal carotid artery supply the superior mucosa medially and laterally. The superior labial branch of the facial artery provides circulation to the anterior mucosal septum and anterior lateral mucosa ( Figure 71-1 ).

Figure 71-1 Arterial supply to m edial wall of nose.

Etiology There are many reasons for epistaxis, but the most common are upper respiratory infection with concomitant mucosal congestion and vasodilation and trauma, either accidental or iatrogenic (i.e., nose picking) ( Box 71-2 ). BOX 71-2 Etiology of Epistaxis

Local Nas al or facia l trau ma Upp er respi rator y tract infec tions Nos e picki ng Aller gies Low hom e humi dity Nas al poly ps Forei gn body in the

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nose Envir onm ental irrita nts Nas opha ryng eal muc ormy cosi s Trau mati c inter nal carot id arter y aneu rysm Chla mydi al rhinit is neon atoru m Post oper ative

Idiopathic Habit ual Fami lial

Systemic Athe roscl erosi s of nasa l bloo d vess els

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Hype rtens ion (cont rover sial) Antic oagu lant thera py Preg nanc y Abru pt chan ges in baro metri c pres sure Here ditar y hem orrh agic telan giect asia (Ren du-O slerWeb er dise ase) Bloo d dysc rasia s (e.g., hem ophili a, leuk emia , lymp hom a, poly cyth emia vera, ane mias

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, idiop athic thro mbo cyto peni c purp ura, gran uloc ytosi s, inher ited plate let disor ders, acqu ired plate let disor ders [i.e., aspir in]) Hep atic dise ase Rupt ure of inter nal carot id arter y aneu rysm Diab etes melli tus Alco holis m Vita min K defic ienc y Folic acid defic ienc

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y Chro nic neph ritis Che moth erap y Bloo d trans fusio n react ions Migr aine head ache Drug -indu ced thro mbo cyto peni a From Myers A, Kulig K: Epistaxis emergindex; and Wurman LH, et al: Am J Otolaryngology 13:193, 1992.

Diagnostic Strategies Patients initially should have their hemodynamic status evaluated, with resuscitation and laboratory studies performed as needed based on suspicion of possible etiologies mentioned in Box 71-2 .[50] Patients often are anxious and hypertensive. Elevated blood pressure is usually from stress and anxiety and resolves with treatment. Hypertension has never been shown to cause epistaxis, although it can worsen the bleeding when present.[50] Sedation with benzodiazepines or narcotics may help these patients. The key to successful management is identifying the site of nasal bleeding and whether it is anterior or posterior. If the nose is actively bleeding, the patient should clear clots by blowing the nose, then apply bilateral pressure on the nasal septum by compressing the cartilaginous part of the nose for 10 to 15 minutes. This simple maneuver also educates the patient on how to self-manage further episodes. During this time, materials for illumination, suction, visualization, and treatment should be assembled. Discharge without identification and treatment of the bleeding site often results in recurrences. Anterior clots and obstructions may give the appearance of a posterior epistaxis if the blood runs posteriorly. Persistent bleeding should be controlled with pledgets soaked in cocaine, lidocaine-epinephrine, or phenylephrine (Neo-Synephrine) to promote vasoconstriction and anesthesia.

Management With an identified site of bleeding in anterior epistaxis, several treatments are available. Application of silver nitrate chemically cauterizes the area but is unsuccessful during active bleeding. With 4 to 5 seconds of application, nitric acid is formed and coagulates tissue. Coagulation should never be maintained longer than 15 seconds because septal damage may occur.[50] The area should be cauterized peripherally to centrally and superiorly to inferiorly to avoid blood, which renders the sticks ineffectual. Bilateral application of silver nitrate to the septum is not advised because it may deprive the septum of blood supply and theoretically could lead to necrosis. Cautery should not be done in the face of a coagulopathy.[50] An alternative treatment is the application of topical agents, such as absorbable gelatin sponge (Gelfoam) and absorbable knitted fabric (Surgicel), with light packing, which induces coagulation at the site. Patients are instructed on

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compression techniques and to keep mucosa moist with antibiotic ointment. They should avoid closed-mouth sneezing, nose picking, coughing, nose blowing, and aspirin. If bleeding persists, anterior tamponade with a commercially available nasal tampon or balloon or a formal anterior nasal pack may be necessary. These work by three mechanisms. Direct pressure is applied, resultant mucosal irritation from the foreign body decreases bleeding, and surrounding clot formation adds further pressure. When placed, anterior packs should be left in place for about 48 hours. Discomfort caused by anterior packs may require sedatives and narcotic pain medication. Bilateral packs usually are required to obtain adequate compression. It is customary to place patients on antibiotics to prevent sinusitis from obstruction. Posterior epistaxis is identified when posterior bleeding occurs with a properly placed anterior nasal pack. A posterior pack is necessary in this case. A standard Foley catheter may be inserted into the nasopharynx, partially inflated, then pulled anteriorly, creating pressure posteriorly. A small amount of fluid can be added to the balloon, but caution should be exercised to avoid pressure necrosis. Vaseline gauze should be packed around the catheter anteriorly. Commercially available balloons, such as the Nasostat and Epistat, are more comfortable than the posterior pack. The packs are left in for 2 to 5 days, and antibiotics, such as cephalexin and amoxicillin-clavulanate, traditionally are administered. If these techniques do not provide successful control, ENT consultation is necessary. Definitive care may require internal maxillary artery ligation or embolization with Gelfoam or posterior endoscopic cautery. Patients with posterior nasal packs should be admitted to the hospital and may require sedation and supplemental oxygen. The partial pressure of oxygen (Po2) may decrease 10 mm Hg, and partial pressure of carbon dioxide (Pco2) may increase 10 mm Hg after posterior packing. This is thought to be secondary to a postulated nasopulmonary reflex. Dysrhythmias, bradycardia, myocardial infarction, stroke, and aspiration also have been reported after posterior nasal packing.

SIALOLITHIASIS Stones of the salivary glands occur in 1% of the population.[51] They are found most commonly in people between ages 30 and 50 years, although they are reported rarely in children. The most common gland affected is the submandibular (submaxillary) gland, accounting for 80% to 95% of cases. The patient has pain and swelling of the gland. Differential diagnosis includes infections, inflammation, and granulomatous and neoplastic processes. The most common viral pathogen is mumps. Staphylococcus, Streptococcus viridans, S. pneumoniae, and H. influenzae predominate in bacterial infections. Stones may be confirmed by palpation or purulent discharge from the glandular duct with massage. Ultrasonography can be helpful, potentially revealing diagnoses other than stones. Treatment consists of antibiotics (covering penicillinase-resistant organisms), moist heat, massage, sialagogues (tart hard candies to promote glandular secretions), and sialolithotomy, if necessary, using probes or endoscopy.[52] Follow-up within 24 hours should be arranged for stones not removed in the emergency department and 4 to 5 days otherwise.

NECK MASSES Perspective Neck masses are a relatively common clinical finding and are usually the result of inflammation but may be an indicator of head and neck malignancy as well. An extensive discussion of head and neck cancer is beyond the scope of this chapter, but some basics are discussed. Children and young adults are more likely to have benign disorders, such as inflammatory or developmental abnormalities, including thyroglossal or brachial cleft cysts. Adult neck masses are more likely to be neoplastic. In general, 80% of nonthyroid neck masses in adults are neoplastic, of which 80% are malignant.[53] In children, however, more than 80% of neck masses are benign. This is often referred to as the rule of 80 or 80% rule. Risk factors that may predispose patients to ENT malignancies include alcohol and tobacco use, viruses such as herpesvirus, sunlight exposure, genetics, diet, exposure to dust, and inhalation exposures.[54]

Principles of Disease It is crucial for the clinician to be familiar with some basic anatomy of the neck. Identifying the location of the parotid and submandibular glands and thyroid cartilage and gland can help avoid confusion when evaluating the neck mass. In addition, knowing where the lymph nodes are can help distinguish lymph nodes from other types of masses ( Figure 71-2 ).

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Figure 71-2 Major lym ph node groups in the head and neck: I, parotid nodes; II, subm ental nodes; III, subm andibular nodes; IV, jugulodigastric nodes (superior jugular nodes); V, m idjugular nodes; VI, lower jugular nodes; VII, spinal accessory nodes; VIII, subclavian nodes. Groups VI and VII are often term ed “scalene nodes.” ((Redrawn and m odified from Moloy PJ: How to (and how not to) m anage the patient with lum p in the neck. In Am erican Academ y of Otolaryngology–Head and Neck Surgery Foundation: Com m on Prob lem s of the Head and Neck Region. Philadelphia, WB Saunders, 1995.)Elsevier Inc.)

Clinical Features Numerous symptoms should be inquired about in head and neck disease, including dysphagia, odynophagia, otalgia, stridor, speech disorders, and globus phenomena. Dysphagia is difficulty swallowing and may be caused by physical obstruction or neurologic disorders. Odynophagia is pain on swallowing and can be caused by many entities, such as tonsillitis or carcinoma of the pharynx. Otalgia is pain felt in the ear that may be referred from the larynx, pharynx, and cranial nerves V, IX, and X. Referred ear pain is considered an ominous sign in adults and should be presumed to be cancer until proved otherwise.[55] Unilateral OME in older adults should be considered nasopharyngeal carcinoma until proved otherwise. Stridor, specifically inspiratory stridor, is diagnostic of upper airway obstruction. It localizes a lesion to above or at the level of the larynx and, when present in adults with a neck mass, should increase the suspicion for carcinoma. Speech disorders, particularly that of hot potato speech, are suspicious for space-occupying lesions above the oropharynx, a classic example being peritonsillar abscess. The globus symptom is a lump in the throat. It has occurred in almost everyone at one time or another, is localized to the pharynx, and is often a functional complaint.[55] Hoarseness, the final symptom, is a fairly common complaint, with a myriad of etiologies ranging from viral pharyngitis to laryngeal cancer. Also, similar to the term dizziness, hoarseness has many descriptions, including breathiness, muffling, harshness, scratchiness, or unnatural deepening of the voice.[56] Hoarseness lasting longer than 2 weeks needs investigation.

Physical Examination A thorough head and neck examination should be performed looking for masses, lesions, mucosal ulcerations or discolorations, and cranial nerve abnormalities. The mass itself should be palpated for location, size, and consistency. Lymph nodes are generally smaller than 1 to 1.5 cm, so any nodes larger than 1.5 cm should be considered abnormal.[57] Lymph nodes are also mobile, soft, and fleshy. Decreased mobility and firmness are warning signs of malignancy.[57]

Diagnostic Strategies The diagnostic strategy should be tailored to results of the history and physical examination. Hoarseness for longer than 2 weeks should be investigated, generally with fiberoptic examination. Serologic and skin tests may be helpful in certain instances, but are best performed by the referring specialist. Chest radiography may identify lung carcinoma as the source of metastasis. Ultrasonography, CT, MRI, and needle biopsy can aid in the diagnosis, but usually are not required in the emergency department.

Differential Considerations Box 71-3 lists common causes in the differential diagnosis of neck masses.[] BOX 71-3 Differential Diagnosis of Neck Masses

Inflammatory Adenitis Bact erial (

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Stre ptoc occu s, Stap hylo cocc us) Viral (HIV, EBV, HSV ) Fung al (coc cidioi dom ycos is) Para sitic (toxo plas mosi s) Cat-scratch disease Tularemia Local cutaneous infections Sialoadenitis (parotid and submaxillary glands) Thyroiditis Mycobacterium avium Mycobacterium tuberculosis

Congenital/Developmental Brac hial cleft cyst Thyr oglo ssal duct cyst Der moid cyst Cysti c

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hydr oma s Torti collis Thy mic mas ses Tera toma s Ran ula Lym phan giom a Lary ngoc ele

Neoplastic

Benign Mes ench ymal tumo rs (lipo ma, fibro ma, neur al tumo r) Saliv ary glan d mas ses Vasc ular abno rmali ties (he man giom as, AVM, lymp hang ioma s,

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aneu rysm )

Malignant Primary tumors Sarc oma Saliv ary glan d tumo r Thyr oid or parat hyroi d tumo rs Lym pho ma

Metastasis Fro m prim ary head and neck tumo rs Fro m infra clavi cular prim ary tumo rs (e.g., lung or esop hage al canc er)

Management and Disposition

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Most masses in children are inflammatory; it is a reasonable strategy to start the patient on antibiotics with 2-week follow-up. If inflammation is considered in adults, a similar strategy can be used.[58] Adults generally need ENT referral if the mass does not resolve in 2 weeks, the mass is enlarging, the mass is fixed, cervical lymph nodes are matted, or masses are noted in the parotid or thyroid gland.[59]

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KEY CONCEPTS {,

{, {, {,

Most cases of acute OM are likely viral. Children older than age 2 years may be observed for 3 days to determine whether antibiotics are required. When indicated, amoxicillin is the initial choice for treatment of AOM at a dose of 80 to 90 mg/kg/day. Necrotizing otitis externa should be considered in immunocompromised patients who have a persistent otitis externa. Patients with epistaxis with posterior nasal packing should be admitted to the hospital. Antibiotic therapy typically is prescribed. All neck masses that do not respond to antibiotics or persist for more than 2 weeks or hoarseness lasting for more than 2 weeks need ENT referral.

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REFERENCES 1. Stool SE: Managing Otitis Media with Effusion in Young Children: Quick Reference Guide for Clinicians (AHCPR Publication No. 94-0623), Rockville, Md, Agency for Health Care Policy and Research, Public Health Service, U.S. Department of Health and Human Services, 1994. 2. Teele DW, Klein JO, Rosner B: Epidemiology of otitis media during the first seven years of life in children in greater Boston: A prospective cohort study. J Infect Dis1989;160:83. 3. McCracken Jr JrGH: Diagnosis and management of acute otitis media in the urgent care setting. Ann Emerg Med2002;39:413. 4. Daly K: Risk factors for otitis media sequelae and chronicity. Ann Otol Rhinol Laryngol Suppl1994;103:39. 5. Paradise JL: Otitis media in 2253 Pittsburgh-area infants: Prevalence and risk factors during the first two years of life. Pediatrics1997;99:318. 6. Bonadio WA: The evaluation and management of acute otitis media in children. Am J Emerg Med 1994;12:193. 7. Hoberman A, Paradise JL: Acute otitis media: Diagnosis and management in the year 2000. Pediatr Ann 2000;29:609. 8. Ruuskanen O, Heikkinen T: Otitis media: Etiology and diagnosis. Pediatr Infect Dis J1994;13:S23. 9. Heikkinen T: Role of viruses in the pathogenesis of acute otitis media. Pediatr Infect Dis J2000;9:S17. 10. Burton DM: Neonatal otitis media: An update. Arch Otolaryngol Head Neck Surg1993;119:672. 11. McCormick DP: Bullous myringitis: A case controlled study. Pediatrics2003;112:982. 12. Haddad J: Treatment of acute otitis media and its complications. Otolaryngol Clin North Am1994;27:431. 13. Howie VM, Schwartz RH: Acute otitis media: A year in general practice. Am J Dis Child1983;137:155. 14. Berman S: Otitis media in children. N Engl J Med1995;332:1560. 15. Rothman R, Owens T, Simel D: Does this child have acute otitis media?. JAMA2003;290:1633. 16. Giebink GS: Antimicrobial treatment of acute otitis media. J Pediatr1991;119:495. 17. Wetmore RF: Complications of otitis media. Pediatr Ann2000;29:637. 18. Roland PS: Clinical ototoxicity of topical antibiotic drops. Otolaryngol Head Neck Surg1994;110:598. 19. Bluestone CD, Klein JO: Intracranial suppurative complications of otitis media and mastoiditis. In: Bluestone CD, Stool SE, ed.Pediatric Otolaryngology, Philadelphia: WB Saunders; 1990: 20. Culpepper L, Froom J: Routine antimicrobial treatment of acute otitis media: Is it necessary?. JAMA 1997;278:1643. 21. Dowell SF: Acute otitis media: Management and surveillance in an era of pneumococcal resistance—A report from the Drug Resistant S. pneumoniae Therapeutic Working Group. Pediatr Infect Dis J1999;18:1. 22. American Academy of Pediatrics Subcommittee on Management of Acute Otitis Media : Diagnosis and management of acute otitis media. Pediatrics2004;113:1451. 23. Green SM, Rothrock SG: Single dose intramuscular ceftriaxone for acute otitis media in children. Pediatrics1993;91:23. 24. Barnett ED: Antibiotic resistance and choice of antimicrobial agents for acute otitis media. Pediatr Ann 2002;31:794. 25. Dowell SF: Otitis media: Principle of judicious use of antimicrobial agents. Pediatrics1998;101:165. 26. Kozyyrskyj AL: Treatment of acute otitis media with a shortened course of antibiotics: A meta-analysis. JAMA1998;279:1736. 27. Paradise JL: Short course antimicrobial treatment for acute otitis media: Not best for infants and young children. JAMA1997;278:1640. 28. Rosenfeld RM: Comprehensive management of otitis media with effusion. Otolaryngol Clin North Am 1994;27:443. 29. Black S: Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children. Pediatr Infect Dis J2000;19:187. 30. Black S, Shinefield H: Vaccines and otitis media. Pediatr Ann2000;29:648. 31. Hathaway TJ: Acute otitis media: Who needs posttreatment follow up?. Pediatrics1994;94:143. 32. Hirsch BE: Infections of the external ear. Am J Otolaryngol1992;13:145. 33. Roland PS, Stroman DW: The microbiology of acute otitis externa. Laryngoscope2002;112:1166. 34. Bojrab DI: Otitis externa. Otolaryngol Clin North Am1996;29:761.

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35. Dohar JE: Evolution of management approaches for otitis externa. Pediatr Infect Dis J2003;22:299. 36. Evans P, Hofman L: Malignant external otitis: A case report and review. Am Fam Physician1994;49:427. 37. Guy RL: Computed tomography in malignant external otitis. Clin Radiol1991;43:166. 38. Rubin J: Malignant external otitis in children. J Pediatr1988;113:965. 39. Slattery WH, Brackman DE: Skull base osteomyelitis: Malignant external otitis. Otolaryngol Clin North Am1996;21:795. 40. Gliklich RE: A contemporary analysis of acute mastoiditis. Arch Otolaryngol Head Neck Surg 1996;122:135. 41. Hoppe JE: Acute mastoiditis: Relevant once again. Infection1994;22:178. 42. Nadol JB, Eavery RD: Acute and chronic mastoiditis: Clinical presentation, diagnosis, and management. Curr Clin Topics Infect Dis1995;15:204. 43. Martin-Hirsch DP: Latent mastoiditis: No room for complacency. J Laryngol Otol1991;102:115. 44. Ogle JW, Lauer B: Acute mastoiditis: Diagnosis and complications. Am J Dis Child1986;140:1178. 45. Betar CN, Kluka EA, Steele RW: Mastoiditis in children. Clin Pediatr1996;35:391. 46. Shikowitz MJ: Sudden sensorineural hearing loss. Med Clin North Am1991;75:1239. 47. Lawrence LJ, Brown CG: Approach to decreased hearing. Emerg Med Clin North Am1987;5:193. 48. Nadol JB: Hearing loss. N Engl J Med1993;329:1092. 49. Josephson GD: Practical management of epistaxis. Med Clin North Am1991;75:1311. 50. Wurman LH: The management of epistaxis. Am J Otolaryngol1992;13:193. 51. Pollack CV, Severance HW: Sialolithiasis: Case studies and review. J Emerg Med1990;8:561. 52. Nahlieli O, Neder A, Baruchin AM: Salivary gland endoscopy: A new technique for diagnosis and treatment of sialolithiasis. J Oral Maxillofac Surg1994;52:1240. 53. Alvi A, Johnson JT: The neck mass: A challenging differential diagnosis. Postgrad Med1995;97:87. 54. Walton F, Masuredis C: The epidemiology of maxillofacial malignancy. Oral Maxillofac Surg Clin North Am1993;5:189. 55. Moloy PJ: How to (and how not to) manage the patient with lump in the neck. American Academy of Otolaryngology–Head and Neck Surgery Foundation: Common Problems of the Head and Neck Region, Philadelphia, WB Saunders, 1995. 56. Kenna MA: Hoarseness. Pediatr Rev1995;16:69. 57. Armstrong WB, Giglio MF: Is this lump in the neck anything to worry about?. Postgrad Med1998;104:63. 58. McGuirt WF: The neck mass. Med Clin North Am1999;83:219. 59. Brown RL, Azizkhan RG: Pediatric head and neck lesions. Pediatr Clin North Am1998;45:889.

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Section II - Pulmonary System Chapter 72 – Asthma Richard M. Nowak Glenn Tokarski

PERSPECTIVE The word asthma is derived from the Greek p Nbp;p-p , signifying panting, and was used initially as a synonym for “breathlessness.” In 1698 Floyer published “A Treatise of the Asthma,” in which he attempted to differentiate asthma more clearly from other pulmonary disorders. Subsequent definitions of asthma highlight concepts of airway hyperresponsiveness, bronchospasm, and reversible airway obstruction but fail to encompass the many facets of this disease. The National Heart, Lung, and Blood Institute summarized our current understanding of asthma as “a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role…this inflammation causes recurrent episodes of wheezing, breathlessness, chest tightness, and coughing…episodes are usually associated with widespread but variable airflow obstruction that is often reversible either spontaneously or with treatment.”[1] Asthma is thus a chronic inflammatory disease, and control of symptoms is ultimately dependent on ameliorating the inflammatory reaction that produces alterations in airway function and structure.

EPIDEMIOLOGY The United States National Health Interview Survey for 1980 to 1999 reported that 96.6 of 1000 (26.7 million) people have been diagnosed with asthma during their lifetime.[2] In 2001 ( Figure 72-1 )[3] this number increased to 114 of 1000 (31.3 million); the current prevalence (individuals having asthma at the time of the interview) is 69 of 1000 (14 million) in adults and 87 of 1000 (6.3 million) in children. Asthma attack prevalence (the number of persons who had at least one asthma attack in the previous year) is 43 of 1000 (12 million) people. Asthma was responsible for more than 1.7 million emergency department visits and nearly 500,000 hospitalizations in 2001.

Figure 72-1 Prevalence of lifetim e asthm a diagnosis, 2001. ((National Center for Health Statistics, 2004.))

The estimated financial burden of this disease totaled $12.7 billion in 1998, with almost 60% attributable to direct costs (hospital inpatient, outpatient, emergency department and physician services); it is estimated that less than 20% of asthma patients account for 80% of the direct costs.[4] Emergency department visits related to asthma in the United States increased from 1992 to 1999 ( Figure 72-2 ).[2] Emergency department visit rates were more than three times greater for non-Hispanic blacks than non-Hispanic whites[5] and highest among children 0 to 4 years old. In 2000 the rate of hospitalization was 220% greater in non-Hispanic blacks than non-Hispanic whites and 25% higher in females than males.

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Figure 72-2 Estim ated annual rate of em ergency departm ent visits for asthm a. ((From Mannino DM, et al: Surveillance for asthm a—United States 1980-1999. MMWR Surveill Summ 51[SS01]:1, 2002.))

Disturbing increases in mortality related to asthma were reported in the 1980s, with a disproportionate number of deaths occurring in the age range 5 to 34. In the United States, moderation of this trend was noted in the early 1990s and continued throughout the decade. A total of 4487 deaths from asthma were reported in 2000 and decreased to 4269 in 2001. Deaths caused by asthma were infrequent in children (0.3 per 100,000) compared with adults (2.1 per 100,000). Non-Hispanic blacks had an asthma death rate more than 200% greater than that of non-Hispanic whites and 160% higher than that of Hispanic Americans. Females had an asthma death rate 40% higher than that of males. New Zealand, Australia, Great Britain, and Canada all reported increases in asthma prevalence, hospitalizations, and deaths during the 1980s, with reversal of these trends during the 1990s. Developed nations have higher rates of asthma, which suggests that urbanization and westernization are correlated with increased asthma prevalence. Interestingly, migrants who move from an area of low asthma prevalence to an area of high asthma prevalence assume an increased asthma prevalence, suggesting that environmental factors play a role. Urban areas in the United States (New York City, Los Angeles, and Chicago) have high mortality rates associated with asthma, indicating that poverty and lack of access to medical care may also be major determinants of asthma complications. Factors believed to contribute to asthma morbidity and mortality include inadequate patient and physician assessment of an acute episode resulting in undertreatment, overuse of prescribed or over-the-counter medications leading to delays in seeking treatment, failure of physicians to consider previous hospitalizations or life-threatening episodes of asthma, and failure to initiate corticosteroid therapy early in the course of an exacerbation. Socioeconomic factors, environmental influences, and overreliance on emergency facilities for all asthma care are also contributing factors. Initiatives to educate physicians and patients about asthma pathophysiology, monitoring, and therapy may be in part responsible for the moderation of asthma mortality.

PRINCIPLES OF DISEASE Pathophysiology Bronchial reactivity refers to the responsiveness of the airways to a bronchoconstricting stimulus (e.g., methacholine). Compared with healthy individuals, patients with asthma show bronchial hyperreactivity (also called hyperresponsiveness) in response to bronchoconstricting stimuli. This hyperresponsiveness of the airways is characteristic of asthma and correlates with the severity of the disease and the need for treatment. Although bronchial hyperreactivity and airflow obstruction remain basic to our understanding of asthma, allergic airway inflammation is established as the primary pathologic process of this disease. Immunoglobulin E (IgE)–mediated immune responses, airway inflammation, and airway remodeling supersede previous theories of intrinsic and extrinsic triggers, smooth muscle dysfunction, and imbalances in the adrenergic and cholinergic nervous systems. Immune response and inflammatory cells, their messengers and metabolic products, and effector cells are responsible for the clinical manifestations of acute and chronic asthma. Understanding of the various aspects of the allergic and inflammatory processes occurring in the airways is fundamental in directing therapy. The concept of the role of allergic inflammation in asthma has its basis in the pathologic findings in the airways of asthmatic patients. Intense inflammation is evidenced by infiltration of mast cells, macrophages, eosinophils, neutrophils, and lymphocytes; loss of airway epithelium; basement membrane thickening; and bronchial smooth muscle hyperplasia. Significant inflammatory changes can occur even in mild cases. These changes are found in both the central and peripheral airways and vary with asthma severity.[] Inflammatory and chemotactic cytokines are produced by both resident airway and recruited inflammatory cells. They are identified in bronchoalveolar lavage fluid in patients with various degrees of asthma severity,

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and they participate in initiation, propagation, and amplification of the local inflammatory response. Epidemiologic and clinical observations link IgE to asthma and establish the allergic nature of airway inflammation.[10] IgE synthesis is triggered[] when inhaled allergens such as environmental antigens (pollen, dander, mites), occupational antigens, and viruses encounter dendritic cells lining the airways.[13] Airway dendritic cells process the antigenic stimulus and migrate to local lymph nodes, where antigen presentation to T and B lymphocytes occurs. The cytokines interleukin 4 (IL-4) and IL-13 induce differentiation of activated B lymphocytes that synthesize and release IgE in response to the antigenic stimulus ( Figure 72-3 ). IgE circulates briefly in the blood before binding to surface receptors on airway mast cells and peripheral blood basophils, lymphocytes, eosinophils, and macrophages. Further interaction of antigen with membrane-bound IgE activates and then releases preformed and generated mediators from these cells.

Figure 72-3 Cellular interactions involved in im m unoglobulin E (IgE) and inflam m atory reactions in asthm a.

Mast cells reside in the mucosa and submucosa of the airways. Cross linking of antigen and surface-bound IgE on the mast cells induces release of preformed mediators such as histamine and initiates the production of prostaglandins (PGs) and leukotrienes (LTs). Antigen-induced IgE cross linking on mast cells also stimulates synthesis and subsequent release of cytokines such as IL-1 to IL-5, tumor necrosis factor p , interferon p~, and granulocyte-macrophage colony-stimulating factor (GM-CSF). These cytokines induce further differentiation and proliferation of inflammatory cells, have chemoattractant properties, and increase adhesion of inflammatory cells to pulmonary vascular endothelial cells.[14] Thus, mast cells may contribute to both the acute and chronic inflammatory reactions occurring in the airways. Release of preformed histamine from mast cell granules constricts bronchial smooth muscle and causes airway edema, resulting in wheezing and airflow obstruction. This reaction usually resolves within an hour and is referred to as the early asthmatic response. Similar clinical manifestations occur 4 to 6 hours later as a result of cytokines generated and released by mast cells and other local and recruited inflammatory cells. The airflow obstruction and bronchospasm may be prolonged and are referred to as the late asthmatic response. Eosinophils are major effector cells in asthma, and their presence is evidence of the allergic nature of this disease. They contain granules that release inflammatory mediators including major basic protein, cationic protein, and LTs. Major basic protein causes constriction of airway smooth muscle and desquamation of the airway epithelium. This effect exposes nerve endings, provides submucosal access for inflammatory cells and mediators, and negates epithelial cell regulation of the inflammatory process. Eosinophil cationic protein increases airway mucus production and can cause histamine release from mast cells. LTs are potent bronchoconstrictors produced by eosinophils that are more potent than methacholine.[15] LTs also promote the secretion of thick viscid mucus, leading to airway plugging, and enhance airway vascular permeability, leading to airway edema. Eosinophil-produced ILs and GM-CSF stimulate eosinophil proliferation and enhance pulmonary vascular endothelial cell adhesion, which locally amplifies the inflammatory process. Platelet-activating factor, superoxides, and free radicals produced by eosinophils also cause bronchospasm and bronchial tissue destruction.[16] The role of the eosinophil as the central effector cell in asthma is challenged by studies that demonstrate that reductions in sputum and blood eosinophilia do not reduce airway hyperresponsiveness.[] Preformed mediator and cytokine release from other airway inflammatory cells (neutrophils, basophils, macrophages) following the triggering stimulus also contributes to bronchial smooth muscle spasm, edema, and mucus production. Extensive intercellular communication and widespread activation of the immune system occur with the lung and tracheobronchial tree as the target organ.[11] Ongoing synthesis and release of cytokines (e.g., IL-1 to IL-18, GM-CSF), PGs, and LTs ( Figure 72-4 ) are responsible for propagation and intensification of airway inflammation[19] and disruption of the airway epithelial border. Further migration of inflammatory cells from the circulating blood into the airway mucosa and submucosa is influenced by activation of cellular adhesion molecules on pulmonary endothelial cells. The end result of persistent and self-reinforcing inflammation is airway smooth muscle stimulation and structural alterations evidenced by

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wheezing and airflow obstruction. The inflammatory response may continue because of persistent exposure to triggers, lack of appropriate therapy, and impairment or destruction of cellular reparative processes. This continuing response leads to prolonged symptoms, worsening obstruction, fatigue, and, ultimately, respiratory failure.

Figure 72-4 Metabolism of arachidonic acid into prostaglandins (PG) and leukotrienes (LT). COX, cyclooxygenase; 5-HPETE, 5-hydroperoxyeicosatetraenoic acid; 5-LO, 5-lipoxygenase.

Airway remodeling is distinctive in chronic asthma, and advanced airway remodeling is probably due to the presence of repetitive or chronic airway inflammation. It consists of airway wall thickening, subepithelial fibrosis, mucous gland metaplasia, increases in airway smooth muscle, myofibroblast hyperplasia, and epithelial hypertrophy.[20] Basement membrane thickening may be protective by preventing inflammatory cells and proteins from entering the airway submucosa through a damaged epithelium; simultaneously, this process may be counterproductive by reducing the elasticity of the small airways, leading to severe obstruction from mucosal swelling and smooth muscle contraction. Airway remodeling may explain the resistance to therapy observed in patients with prolonged asthma histories and the decline in pulmonary function noted with age in adults with asthma.[] Finally, if asthma is improperly treated, airway remodeling induced by chronic inflammation may lead to the development of chronic irreversible airflow limitation and a shortened life expectancy.[23] The clinical implications of the immune and inflammatory nature of the early and late asthmatic responses are crucial because therapy may be directed differently toward each phase. Mast cell stabilizers (e.g., p 2 -agonists) are more effective in the early asthmatic response but are of less use later in the course of an exacerbation. Anti-inflammatory therapy (e.g., corticosteroids, LT antagonists) are more effective in the late asthmatic response. Interference or inhibition of cytokine activities, suppression of chronic inflammation, and modulation of airway remodeling are potential therapeutic targets.

Miscellaneous Situations Aspirin-exacerbated respiratory disease (AERD) was first described more than 100 years ago. The triad of aspirin sensitivity, asthma, and nasal polyps was described in 1922 and popularized in 1968. The prevalence of AERD is 21% in adult and 5% in childhood asthmatics.[24] It occurs more often in women than men. Nonsteroidal anti-inflammatory drugs (NSAIDs) can also precipitate AERD. AERD is a common precipitant of life-threatening asthma—one survey noted that 25% of asthmatics requiring mechanical ventilation have AERD.[25] Clinically, most patients with AERD develop symptoms in the third decade, frequently after a viral respiratory illness. Over several months, chronic nasal congestion, rhinorrhea, and nasal polyps develop. Bronchial asthma and sensitivity to aspirin (acetylsalicylic acid, ASA) then result. After ingestion of aspirin or a nonsteroidal drug, acute asthma symptoms occur within 3 hours, usually accompanied by profuse rhinorrhea, conjunctival injection, periorbital edema, and occasionally a scarlet flushing of the head and neck. The pathogenesis of AERD is being elucidated. Metabolically, ASA inhibits cyclooxygenase (COX), of which two isoforms are identified. COX-1 produces PGs that are involved in normal physiologic maintenance of renal function, gastric mucosal integrity and hemostasis, and inflammatory states. COX-2 is not expressed in normal physiologic circumstances but produces PGs only in response to inflammatory stimuli. AERD occurs as a result of ASA inhibition of COX leading to increases in the production of LTs, some of which are potent bronchoconstrictors (see Figure 72-4 ). An alternative view is that LT production remains at basal levels while there is a decrease in the COX-1–dependent production of PGE2. This modulates LT production by regulating the activity of 5-lipoxygenase and preventing release of mast cell mediators—a decrease in the amount of PGE2 removes the modulation of LT synthesis and decreases mast cell stability, resulting in asthma symptoms.

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Anti-LT drugs treat AERD. These agents block synthesis of LTs (e.g., zileuton) or block specific LT receptors (e.g., zafirlukast). Most patients with AERD benefit from treatment with these agents. COX-2 inhibitors have the advantage of inhibiting inflammation without inducing renal, gastrointestinal, or hematologic side effects. AERD is not reported after administration of COX-2 inhibitors. These agents provide a potentially safe alternative for treatment of inflammatory conditions in patients with AERD.[26] Exercise-induced asthma (EIA) has been recognized since the first Olympic games. It occurs in 40% to 90% of asthmatic patients and 6% to 13% of the general population. Atopy is strongly associated with EIA, and up to 40% of patients with allergic rhinitis have EIA.[27] Clinically, EIA is usually preceded by 3 to 8 minutes of exercise. Peak symptoms usually occur 8 to 15 minutes after exercise is complete and then begin to remit spontaneously; recovery occurs within 60 minutes. Treatment is required only to abort the acute symptoms of bronchial narrowing. The etiology of EIA remains unclear. In the “osmotic” hypothesis, airway cooling leads to mucosal drying and increased surface osmolality that causes mast cell degranulation and release of inflammatory mediators. The “thermal” hypothesis suggests that airway cooling during exercise followed by rapid rewarming after exercise causes airway vascular congestion and increased permeability resulting in airway edema and obstruction. It is likely that a combination of these events occurs. Prophylaxis with an inhaled p 2-agonist is the therapy of choice. Inhaled cromolyn and LT antagonists are also effective. Menstruation-associated asthma affects 30% to 40% of asthmatic women; health care for asthma increases in the premenstrual phase. Premenstrual reductions in peak expiratory flow rates of 35% to 80% are reported. Fluctuations in estrogen and progesterone levels are postulated as causal factors.[28] Estradiol inhibits eosinophil degranulation and suppresses LT activity—estrogen withdrawal in the luteal phase may enhance these actions. In animals, estrogen withdrawal downregulates p -receptors and increases cholinergic induced bronchoconstriction. Adult women present more often than men to the emergency department and have higher hospitalization rates with longer stays, possibly because of hormonal, biochemical, or weight differences. Psychological factors may precipitate bronchospasm. Associations between emotional states and asthma are described. Panic disorder and generalized anxiety disorders are more common in asthmatics than the general population. An association between asthma and depression is noted in children. The mechanisms of bronchospasm associated with psychological factors may be related to autonomic nervous system activation or hyperventilation; the influence of immunologic mediators is unknown. Compliance may be adversely affected by psychological factors. Relaxation as a therapy for asthma has inconsistent effects[29]; hypnosis may be beneficial.[30] The actual influence of psychological factors in the induction or continuation of an episode of asthma is unknown but probably varies from patient to patient and episode to episode.

Genetics and Asthma Identifying the predisposing genes is complex. The lack of absolute qualitative or quantitative criteria for the diagnosis of asthma is problematic; thus, identification of “true” asthmatics to study for genetic inheritance patterns is subjective. Environmental factors undoubtedly influence the phenotypic manifestations of asthma. The extent of exposure to environmental factors is also contributory. In the western world, many environmental factors are ubiquitous, leaving genetic factors to determine individual risk. The significance of genetic studies in asthma lies not only in knowing the basic molecular defects in asthma but also in developing a diagnostic test for asthma. As a result, if infants at high risk for asthma could be identified, subsequent allergen avoidance might modulate the development or the severity of asthma. The application of pharmacology to genetics has tremendous importance. Some pharmacologic targets of asthma therapy show genetic variability, and knowledge of any treatment response may assist in therapeutic decision making.

Pathology Airway secretions evaluated by bronchoalveolar lavage in patients with mild to moderate asthma reveal increased numbers of mast cells, eosinophils, lymphocytes, and airway epithelial cells. Their presence supports the concept of chronic inflammation in the airways. Antemortem endobronchial biopsies demonstrate submucosal infiltration with eosinophils and other inflammatory cells along with epithelial cell denudation, increased numbers of goblet cells, mucous gland hyperplasia, and thickening of airway basement membranes. These findings, which are noted in both small and large airways, suggest airway remodeling.[31] In contrast to patients with mild to moderate asthma, patients with acute severe asthma have

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inflammatory cells in the airways that consist of more neutrophils than eosinophils and elevated levels of IL-8 responsible for neutrophil activation.[32] This difference suggests an alternative pathologic mechanism. Necropsies of patients with status asthmaticus reveal grossly inflated lungs that may fail to collapse on opening of the pleural cavities. Histologic examination reveals luminal plugs consisting of inflammatory cells, desquamated epithelial cells, and mucus. Marked thickening of the airway basement membrane, submucosal inflammatory cells, increased deposition of connective tissue, mucous gland hyperplasia, and hypertrophy of airway smooth muscle are also observed. Reports of patients experiencing sudden-onset fatal asthma demonstrated less mucus in the airway lumens, suggesting that terminal events in this group may be dominated by bronchoconstriction without excessive luminal plugging.[33] Another investigation disputed this concept[34]; the contribution of mucus production and composition to airway plugging may play a greater role in fatal asthma than previously appreciated.[35]

CLINICAL FEATURES National and International Guidelines for the Diagnosis and Management of Asthma In response to the increasing prevalence, morbidity, and mortality of asthma in the industrialized world, many guidelines have improved the detection and treatment of this disease. Some of these, including the U.S. National Institutes of Health (NIH) Expert Panel Report 2 (EPR-2), have specific portions devoted to the management of acute exacerbations of asthma.[36] The NIH EPR-2 has been further condensed as a practical summary for emergency physicians[37] and has been critically analyzed regarding limitations and identifying areas for further study.[38] Although these guidelines initially reflected multidisciplinary expert recommendations, they are now graded evidence based[] and serve as a basis for education. They also provide a common set of recommendations for asthma management through which patients' care can be audited, studied, and subsequently improved.[40] Emergency practice programs based on the EPR-2 and the 2002 update[1] have improved acute asthma care[41] with effective resource utilization.[42] Many studies have shown suboptimal guideline implementation in chronic asthma management, especially in the use of anti-inflammatory medications, resulting in more frequent emergency department and hospital use.[] The chronic asthma management strategies in EPR-2 and the implementation of anti-inflammatory therapy when appropriate on emergency department discharge can improve care.[45]

Symptoms Most patients with acute asthma have a constellation of symptoms consisting of cough, dyspnea, and wheezing. Cough often begins early in the attack, may be the sole manifestation of the disease in cough-variant asthma and elderly patients, can be associated with sputum production, and is probably the result of subepithelial vagal stimulation. Nocturnal worsening is common, with most patients reporting cough or wheeze at least once per week. Nighttime mortality is higher than in the general population. Although increased airway resistance, diminished flow rates, and increased bronchial hyperactivity are contributing factors, asthmatic patients who present nocturnally to the emergency department have disease severity similar to that of other asthmatics and are treated in the same way. Up to 40% of asthmatic women suffer from premenstrual worsening of symptoms, which peak 2 to 3 days before menses and are associated with more severe disease.[46] Emergency department visits increase during the preovulatory and perimenstrual intervals. There are interindividual differences in the dyspnea perceived by asthmatic subjects for the same level of airway narrowing. This difference results in poor correlation of symptoms with airway obstruction as determined by pulmonary function testing (PFT), both chronically and on presentation to the emergency department. Patients with a blunted perception of dyspnea (the “poor perceivers”) have more emergency department visits, hospitalizations, and near-fatal and fatal asthma attacks.[47] The wheezing that develops depends on the air movement velocity and turbulence, and its intensity varies according to the radius of the bronchi. With severe airway obstruction, it decreases or vanishes because there is insufficient air movement velocity to produce sound. Many asthmatics report symptoms of gastroesophageal reflux that are thought to cause airway narrowing through a vagally mediated pathway or microaspiration. Proton pump inhibitor therapy decreases asthma symptoms in these patients. Approximately 80% of patients with asthma have symptoms of rhinitis.

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Approximately 5% to 15% of patients with perennial rhinitis have asthma, and control of sinonasal inflammation can lead to asthma improvement. Lastly, as asthma can appear at any age, including the ninth decade, it is important to realize that the classical picture of wheezing and dyspnea may be ascribed by both patients and physicians to heart failure, bronchitis, chronic obstructive pulmonary disease, occupational lung disease, or poor exercise capacity.

Historic Components In the past, most asthma deaths appeared to follow a period of poor overall control, with increasing use of noneffective bronchodilator therapy, underestimation of symptom severity, and late arrival for care. It is now clear that a minority of patients suffer a predominantly hyperacute, bronchospastic “sudden asphyxic asthma” that kills within hours. Studies of nonfatal, sudden, severe acute asthma show that these patients have less identifiable triggers but also have rapid recovery.[48] It is important to obtain a brief asthma history as acute episodes tend to have similar courses, which helps in decision making concerning therapy and disposition. Risk factors for death from asthma are important to determine and are listed in Box 72-1 .[] BOX 72-1 Risk Factors for Death From Asthma

1.

2.

3.

4.

Past histo ry of sudd en seve re exac erbat ions Prior intub ation for asth ma Prior asth ma admi ssio n to an inten sive care unit Two or mor e hosp italiz ation s for asth ma in the

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5.

6.

7.

8.

past year Thre e or mor e eme rgen cy depa rtme nt care visits for asth ma in the past year Hos pitali zatio n or an eme rgen cy depa rtme nt care visit for asth ma withi n the past mont h Use of >2 MDI short -acti ng p 2 -ago nist cani sters per mont h Curr ent use of or rece

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9.

10.

11.

12.

nt with draw al from syst emic corti cost eroid s Diffic ulty perc eivin g seve rity of airflo w obstr uctio n Com orbid ities such as cardi ovas cular dise ases or other syst emic probl ems Seri ous psyc hiatri c dise ase or psyc hoso cial probl ems Illicit drug use, espe cially inhal ed coca

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ine and heroi n

MDI, metered-dose inhaler. The brief history pertinent to the current exacerbation should include onset and possible triggers, severity of symptoms, and other comorbidities (especially those that may be worsened by systemic corticosteroids such as diabetes, peptic ulcer, hypertension, and psychosis). In addition, one should note all current asthma medications, including times and amounts recently used, and any potential asthma exacerbators such as aspirin or NSAIDs, p -blockers (including topical agents used for glaucoma), and angiotensin-converting enzyme inhibitors.

Physical Assessment Although alterations in mentation or consciousness indicate severe asthma, restlessness and agitation do not reliably indicate hypoxia or hypercapnia. Patients who are sitting upright have severe airway obstruction; cyanosis is uncommon because of the left shift of the oxyhemoglobin dissociation curve produced by respiratory alkalosis. Diaphoresis can occur secondary to the work of breathing, but profound diaphoresis, usually accompanied by a decreasing level of agitation and interaction with caregivers, may be a preterminal event. Tachypnea and tachycardia with a heart rate greater than 120 beats/min are associated with severe obstruction, but a lower or normal rate does not rule out severe asthma.[51] The respiratory rate correlates poorly with PFT and indicates severe obstruction only if it is greater than 40 breaths/min.[51] A pulsus paradoxus or inspiratory fall in systolic blood pressure greater than 10 mm Hg usually signifies severe disease, but its absence does not exclude it. Rarely does measurement of a pulsus paradoxus provide new information when taken in the context of the patient's overall evaluation. When pulsus paradoxus is present, it may disappear with minimal improvement in airflow through larger airways.[51] Similarly, the presence or absence of the use of accessory muscles of respiration (sternocleidomastoid and scalenus muscles) is not prognostic. Wheezing does not designate the presence, severity, or duration of asthma. It correlates poorly with the degree of functional derangement and may be absent when maximal effort produces minimal airflow. Physical examination may help to identify the complications of asthma such as pneumonia, pneumothorax, or pneumomediastinum that may arise atypically as subcutaneus emphysema or simulate upper airway obstruction.

DIAGNOSTIC STRATEGIES Pulmonary Function Studies Because physicians tend to underestimate the degree of airway obstruction in acute asthma, particularly on initial assessment, routine PFT should be part of the emergency department assessment and monitoring of these patients.[52] The forced expiratory volume in 1 second from maximal inspiration (FEV1) or the peak expiratory flow rate (PEFR) in liters per second starting with fully inflated lungs and sustained for at least 10 milliseconds may be used in the emergency department. Both measurements require the patient's cooperation for maximal effort and are effort dependent. Whenever possible, the best of three consecutive values should be recorded. Most asthmatic assessments in the emergency department use single-patient-use portable peak flow meters. Although they record valid values, there is wide limit of agreement between different devices, and different portable meters should not be used interchangeably.[53] Lastly, although generally similar, the FEV1 and PEFR measurements do not appear to be interchangeable in assessing acute airway obstruction, which is not addressed in all management guidelines.[54] Although absolute PFT measurements can be used,[55] percentage of predicted performance (% predicted) values are preferable because they account for the individual's age (now to age 85 years), sex, and height. More ideal recordings are the percentage of the patient's personal best effort as this individualizes the assessment and treatment.

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Arterial Blood Gas Analysis Assessment of oxygenation can be done quickly, continuously, and noninvasively in most patients using pulse oximetry, with changes in equilibration of oxygen saturation with supplemental oxygen occurring in 3 to 4 minutes. With initial onset of an asthma attack, stimulated hyperventilation leads to a modest fall in the partial pressure of carbon dioxide in arterial blood (Paco2). As airway obstruction increases, the Paco2 becomes normal (PFT 15% to 25% predicted) and then increases (PFT < 15% predicted) with worsening hypoxemia. Because neither pretreatment nor posttreatment arterial blood gases (ABGs) correlate with PFTs or predict clinical outcome, ABG determination is rarely clinically useful in acute asthma exacerbations unless oxygen saturation cannot be obtained reliably using pulse oximetry. ABG determination is of no value in determining the need for tracheal intubation. Clinical evaluation over time, particularly of the patient's stamina, guides the decision. ABG sampling should be limited to a subset of patients with PFTs less than 30% predicted whose clinical course is perplexing. Occasionally, despite improving PFTs with bronchodilator therapy, some patients have a transient fall in the partial pressure of oxygen in arterial gas (Pao2) secondary to pulmonary vasodilation and worsening ventilation-perfusion mismatch.[56]

Other Blood Testing Leukocytosis is common in patients with acute asthma exacerbation and has little meaning. A white blood cell count is of marginal discriminatory value in attempting to determine whether patients with fever or purulent sputum have acute superimposed pulmonary infection, and it should not be interpreted in this way. A white cell count over 20,000 should be associated with concern about infection. In addition to the effects of the asthma exacerbation, corticosteroid and epinephrine therapy demarginates polymorphonuclear leukocytes after 1 to 2 hours. Serum electrolytes are likewise of little value unless the patient is taking corticosteroids or diuretics or has cardiovascular disease and is receiving aggressive p 2-agonist therapy. In theory, frequent albuterol treatments can cause transient hypokalemia, hypomagnesemia, and hypophosphatemia, but this is generally of no clinical significance. The serum theophylline concentration should be measured in patients receiving chronic theophylline therapy because there are no reliable clinical predictors of these levels. In the older asthmatic with cardiovascular comorbidities who presents with wheezing, it may be prudent to measure the B-type natriuretic peptide level to determine the contribution of unrecognized congestive heart failure to the clinical picture.

Radiology Studies A chest radiograph is of little or no value in acute asthma exacerbation, and its use should be restricted to patients suspected of having a complicating cardiopulmonary process such as pneumonia, pneumothorax, pneumomediastinum, or congestive heart failure. Also, patients who do not respond to optimal therapy and who require hospital admission are at risk for radiographically identifiable, unsuspected, clinically significant pulmonary complications (e.g., pneumothorax, pneumomediastinum) of asthma in 15% of cases.[57]

Electrocardiogram and Cardiac Monitoring The electrocardiogram in patients with severe asthma may show a right ventricular strain pattern that reverses with improvement in airflow. Older patients, especially those with coexistent heart disease or with severe exacerbation, may require continuous cardiac monitoring to detect dysrhythmias. All patients with severe hypoxemia, and those for whom intubation is contemplated, should have continuous cardiac monitoring.

Future Monitoring Strategies Nasal capnography is a noninvasive and independent method of continuous, real-time monitoring of severity of bronchospasm. This technique requires further study before being routinely used in the emergency department.[58] Noninvasive monitoring of bronchial inflammation may find a place in the emergency department assessment of acute asthma as a method of customizing care for individual patients. It may include measurement of cytokine profiles in the blood, evaluation of LTE4 in the urine, and monitoring of exhaled pentane, hydrogen peroxide, nitric oxide, or carbon monoxide levels.

Assessment Summary The severity of airflow obstruction cannot be accurately judged when relying on patients' symptoms, physical

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examination, and laboratory tests. Measurements of airflow obstruction (FEV1 or PEFR) are key components of disease assessment and response to therapy. A more detailed comparison between commonly measured variables and PFTs is shown in Table 72-1 . Table 72-1 -- Objective Findings in Asthma Assessment Factor Severe Asthma (FEV1 20, therefore nondiscriminating ≥10, but may be absent with equally severe asthma in 50% of cases If all three abnormal, 90% with severe asthma, but only 40% with FEV1 50%

Unable or 90%

Maintain SaO2 >90%

Nebulized albuterol solution

Levalbuterol (optimal)

Racemic albuterol

1.25 mg q20–30 min × 3 doses

2.5 mg q20–30 min × 3 doses

1.25 mg q20– 30 min ×3 dose s Cont inuo us for 1 hr if seve re 5.0 mg q20– 30 min ×3 dose s Cont inuo us for 1 hr if seve re

MDI with spacer Racemic albuterol (90 6–12 puffs q20 min for Same but may be unable to do mg/puff) up to 4 hr (with (with supervision) supervision) Inhaled anticholinergics

Systemic corticosteroids

Nebulized ipratropium If known with previous 0.5 mg q20–30 min × 3 doses (mix solution response (same dose with albuterol solution) as for severe) Oral (preferred) IV (unable to take PO or absorb)

IV magnesium sulfate (FEV1 95% in pregnant women and those with coexistent heart disease) rather than using predetermined concentrations or flow rates. Continual oxygen saturation monitoring is essential during the acute phase. Humidification of the inspired air-oxygen mixture is not recommended, although studies suggest that active airway rehydration should be revisited.[61]

Adrenergic Medications Controversies in Use Epidemiologic studies report an association between death and near death from asthma and the use of inhaled p 2-agonists, with use of more than one canister per month increasing this risk and the risk doubling for each additional monthly canister used.[62] This relationship does not imply causality but may be a marker for more severe disease, particularly if anti-inflammatory treatment is underused. Recommendations for chronic use of inhaled p 2-agonists, however, allow limited daily use in a rescue-only mode.[1] The commonly used form of albuterol is a racemic mixture of equal amounts of R and S isomers. Data from animal and human studies suggest that the S isomer, which contributes no bronchodilator activity, is proinflammatory, spasmogenic, and induces bronchial hyperreactivity, thus possibly explaining the adverse effects of increased morbidity and mortality associated with regular or excessive use of this drug.[63] Some investigations of the p -adrenergic receptor polymorphisms show differential responsiveness to inhaled albuterol, a possible explanation for the varying responses seen clinically when treating patients with acute disease.

Inhaled p

2

-Agonist Choice and Dosing Schedule

Racemic albuterol has been the main p 2-agonist used in the emergency department for treatment of acute asthma for over 30 years. It is more p 2 selective, longer acting, and with fewer side effects than other previously available drugs such as metaproterenol or isoetharine. Other agents such as bitolterol and pirbuterol have not been studied in acute asthma. Levalbuterol (Sepracor), the R isomer of racemic albuterol, is commercially available as a preservative-free nebulizer solution (unit doses of 0.31, 0.63, or 1.25 mg) for prevention and treatment of bronchospasm. In chronic asthma, levalbuterol seems to provide a better therapeutic index than the standard dose of racemic albuterol, further fueling the debate on the potential adverse effects of the S isomer of p -agonists. [64] Clinical studies in acute disease report that levalbuterol on a milligram for milligram basis is a better bronchodilator than similar amounts of R-albuterol delivered with the S isomer in the racemic mixture.[] This implies that the noninertness of the S isomer of albuterol has problematic clinical implications in acute therapy for asthma. The amount and frequency of delivery of levalbuterol and racemic albuterol are dependent on the initial severity and response to therapy, as shown in Table 72-2 and Table 72-3 . Patients with more severe obstruction on arrival at the emergency department with a poor response to initial therapy should receive higher dosing schedules. When patients are stable but require non–intensive care unit (ICU) admission, it may be possible to dose nebulized levalbuterol at 1.25 mg every 8 hours as opposed to racemic albuterol at 2.5 mg every 4 to 6 hours.[67]

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Table 72-3 -- Response to Initial Management Strategies Moderate Exacerbation Severe Exacerbation FEV1 or PEFR%

50%-80%

90%

Nebulized albuterol solution

Levalbuterol (optimal) Racemic albuterol

Reassess as may need Reassess as may need less than racemic therapy less than racemic therapy Hourly for 1–3 hr Hourly or continuous

Inhaled anticholinergics Nebulized ipratropium solution Corticosteroids

Unnecessary

Every 4–6 hr

Every 6–8 hr

Every 6–8 hr

FEV1, forced expiratory volume in 1 second; PEFR, peak expiratory flow rate; SaO2, oxygen saturation in arterial blood.

Nebulizer versus Metered-Dose Inhaler and Spacer/Holding Chamber A metered-dose inhaler (MDI) plus spacer/holding chamber, used often and frequently (see Table 72-2 ), provides similar bronchodilation and side effects, even in severe asthma, when compared with wet nebulization.[68] This therapy requires more supervision because some patients have difficulty firing the canister before inhalation, inhaling slowly, and breath holding for 5 to 10 seconds. Wet nebulization by mouthpiece or mask requires no coordination and minimal cooperation and is less expensive.[69]

Intravenous Use of Adrenergic Agonists Most international asthma guidelines, with the exception of those in the United States, recommend the use of intravenous p -agonists for very severe and nonresponsive acute asthma. Intravenous (IV) albuterol (not available in the United States) is given as a load of 4 p-g/kg for 2 to 5 minutes followed by an infusion of 0.1 to 0.2 p-g/kg/min, with close cardiopulmonary monitoring.[36] Likewise, intravenous epinephrine with similar close cardiopulmonary monitoring can be given as a loading dose of 200 p-g to 1 mg of a 1 : 10,000 solution over 5 minutes and followed by an infusion of 1 to 20 p-g/min if there is improvement with therapy. Some reviews conclude that evidence is lacking to support the use of IV p -agonists in emergency department patients with severe acute asthma because the potential risks are obvious and that they should be considered only when inhaled therapy is not feasible.[70]

Subcutaneous Adrenergic Agents Epinephrine has been used in the treatment of asthma for almost 100 years. It has both p and p effects and can produce tachycardia, hypertension, dysrhythmias, and vasoconstriction, especially in older asthmatics with heart disease. Given the potential for increased side effects, it should be given subcutaneously (1 : 1000 solution 0.2 to 0.5 mL every 20 to 30 minutes as needed for three doses) only to asthmatics who are severely bronchospastic and not able to inhale adequate albuterol. Terbutaline is a longer acting p 2-agonist with bronchodilating properties equivalent to those of epinephrine in acute asthma. It can cause skeletal muscle tremor and tachycardia. A 0.25-mg dose can be given subcutaneously every 20 minutes for three doses and, as with epinephrine, it should be used only in those unable to inhale bronchodilating drugs adequately.

Long-Acting p

2

-Agonists and Acute Disease

Salmeterol (Serevent) is a long-acting (12 hours) p

2-agonist

that is an effective additional medication for

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management of daytime and nocturnal symptoms that are not adequately controlled by regular and adequate doses of effective controller medications such as inhaled steroids. It has an onset of action of 20 minutes and thus is not indicated for the treatment of acute attacks. Manufacturer-sponsored studies indicate that regular use of this drug without concomitant use of inhaled steroids results in greater asthma-related deaths; thus, the controversies regarding regular use of short acting p -agonists now extend to the long-acting classes. Formoterol (Foradil) is another long-acting p 2-agonist that has an onset of action within minutes (similar to albuterol) and maximal effect within 2 hours. This agent could evolve as a rescue medication with extended length of action (12 hours). Patients receiving long-acting p -agonists but with acute asthma attacks are treated in the same way as all other asthmatics.

Corticosteroids Corticosteroids have been used to treat asthma for approximately 50 years and there is general agreement about their effectiveness. Their main action in the airways is inhibition of recruitment of inflammatory cells and inhibition of release of proinflammatory mediators and cytokines from activated inflammatory and epithelial cells. Corticosteroids activate cytoplasmic glucocorticoid receptors to regulate directly or indirectly the transcription of certain target genes. Despite the long history of corticosteroid use, the resolution of fundamental acute care issues remains uncertain. These include the types and quantities required to induce a rapid remission, the time needed for drug action, the route of administration, the existence of dose-response effects, and the determination of which populations of patients respond to this therapy.[71]

Systemic Corticosteroids in the Emergency Department These medications should be given promptly to patients with moderate to severe attacks or those experiencing an incomplete response to initial p -agonist therapy. In addition, early systemic corticosteroids should be considered for patients who are taking oral or inhaled corticosteroids, have relapsed after a recent exacerbation, or have had prolonged symptoms. Steroid effects begin within hours (not minutes) in acute asthma and increase to peak over about 24 hours. Early use of systemic steroids decreases admissions in severe asthma but not in mild to moderate attacks.[71] Some data, however, suggest that the PEFR may improve within 2 hours of steroid therapy in those not responding to initial albuterol inhalation.[72] Injectable preparations include methylprednisolone and hydrocortisone. The former has five times more anti-inflammatory effects, whereas the latter has marked mineralocorticoid effects resulting in sodium retention (making it unsuitable for some patients). Emergency department initial dosing of intravenous methylprednisolone is 60 to 125 mg for adults and of hydrocortisone is 200 to 500 mg, each given every 6 to 8 hours until improvement, at which time the frequency can be decreased. Oral steroids used are prednisone or its active form, prednisolone (Medrol). Prednisone is commonly the agent of choice for oral therapy and is given in an adult dose of 40 to 60 mg in the same regimen as the intravenous agents. No study demonstrates the superiority of intravenous corticosteroids over oral preparations. Oral steroid therapy is preferred unless the patient is very ill, is unable to swallow or vomiting, or is suspected of having impaired gastrointestinal transit or absorption. Side effects of short-term (hours or days) steroid use include reversible increases in glucose (important in diabetics) and decreases in potassium, fluid retention with weight gain, mood alterations including rare psychosis, hypertension, peptic ulcers, aseptic necrosis of the femur, and rare allergic reactions to these agents.

Inhaled Corticosteroids in the Emergency Department Use of these agents in acute asthma has the potential benefits of reduced systemic side effects, direct delivery to the airway, and greater efficacy in reducing airway reactivity and edema alone or in addition to systemic steroids. Patients treated with inhaled steroids are less likely to be admitted whether they received systemic steroids or not, and no increased cough or bronchospasm is seen with their use.[73] The optimal agent, delivery system, and dosing regimens need to be determined, as well as whether these agents can replace systemic steroids in all or some patients.

Corticosteroids and Discharged Patients Discharged patients who have received systemic corticosteroids in the emergency department should continue oral therapy for 3 to 10 days to control disease and prevent relapse, and the need for additional

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steroids should be determined at the patient's follow-up visit. An acceptable regimen is 40 to 60 mg of prednisone (or equivalent) per day in a single or divided dose. Dose tapering to prevent asthma rebound is unnecessary[74] unless the patient was already receiving systemic steroids or a prolonged course of therapy (more than 2 weeks) is deemed necessary. An alternative approach, if compliance is an issue, is to give an equally efficacious single intramuscular 40-mg dose of triamcinolone diacetate before emergency department discharge.[75] Patients who present to the emergency department for acute exacerbations of asthma may be taking insufficient amounts of chronic controller medications based on their symptoms and excessive use of p 2 -agonists.[1] If the patient is not taking oral or inhaled steroids, the addition of inhaled high-dose budesonide (Pulmicort, 400 p-g, two puffs twice per day) to the patient's regular asthma medications on emergency department discharge improves symptoms and decreases relapse by approximately 50% in the ensuing 3 weeks.[76] Patients already inhaling steroids at low to medium doses may double the inhalation regimen until seen by their physician. These patients should use a spacer device and be reminded to rinse their mouths after steroid inhalation to decrease the side effects of dysphonia and oral or esophageal candidiasis.

Corticosteroid-Resistant Asthma Chronic asthma is considered a steroid-responsive disease. A small proportion of asthmatics do not respond to even high doses of oral and inhaled glucocorticoids, which presents considerable management problems. The mechanism of this steroid resistance may be related to abnormalities in the glucocorticoid receptor number or binding properties. These patients present in the emergency department with alternative therapies such as cyclosporine, methotrexate, troleandomycin, hydroxychloroquine, azathioprine, gold, intravenous immune globulin, or (if with severe allergic asthma) maintenance anti-IgE recombinant humanized monoclonal antibody (omalizumab).

Anticholinergic Agents The atropine-containing botanicals Datura stramonium (stinkweed or thorn apple) and Atropa belladonna (deadly nightshade) were smoked centuries ago in India for treatment of asthma. In the 19th century smoking leaves of the Datura species was common in England, and by the middle of the last century Salter's treatise on asthma listed D. stramonium as one of asthma's truly effective remedies. Atropine-containing cigarettes or powders smoked in pipes were available into the 20th century, but their use faded after the introduction of the adrenergic agents. The anticholinergic drugs available for inhalation therapy include atropine sulfate, atropine methylnitrate, glycopyrrolate, and ipratropium bromide. They are all bronchodilators that override the smooth muscle constrictor and secretory consequences of the parasympathetic nervous system, blocking reflex bronchoconstriction and reversing acute airway obstruction. As atropine use is associated with side effects and glycopyrrolate is not well studied, the discussion is limited to ipratropium bromide (Atrovent), a quaternary derivative of atropine that is poorly absorbed from the mucosal surfaces of the lung, resulting in decreased side effects. The maximum effect with inhaled ipratropium is in 30 to 120 minutes, with the effect lasting for up to 6 hours. Its bronchodilating potency is lower and onset of action slower than those of the p 2-agonists; hence, it should not be used alone in patients with acute asthma. Reviews of trials assessing the role of this drug in combination therapy with p 2-agonists for acute disease found that ipratropium provides a modest improvement in PFTs and a reduction in hospitalizations.[] This benefit is higher in patients with more severe disease.[79] There is wide interpatient variability in response to anticholinergic therapy, implying that cholinergic mechanisms play a varied role in acute attacks. Accurate prediction of who will respond is not yet established. Treatment recommendations (see Table 72-2 ) include adding the inhalation of ipratropium (0.5 mg) with the first three racemic albuterol treatments with severe acute asthma (50% but 0.14 sec

QRS often > 1.14 sec

If it is conducted to the ventricles, a PAC results in a QRS complex occurring earlier than the expected sinus QRS complex. The QRS complex from a PAC is narrow and identical to the sinus rhythm complex unless aberrant conduction occurs ( Figure 78-20 ). Aberrancy is likely to occur if a PAC arrives early within the cardiac cycle, with a right bundle branch block pattern commonly seen on the ECG. In a similar fashion, a PAC that follows a long cardiac cycle (reflected as a preceding long RR interval) may also be aberrantly conducted because the bundles require more time to repolarize. In the latter setting, aberrant conduction occurs because of the relatively early arrival of the PAC for the given cycle length. This aberrant conduction is called the Ashman phenomenon and can occur with any irregular atrial rhythm, including PACs and atrial fibrillation.

Figure 78-20 Prem ature atrial contractions (PACs) with noncompensatory pauses and one aberrantly conducted impulse (upper strip). Note that both conducted and nonconducted PACs reset the sinus node, with the latter creating a pause.

A PAC is the most common cause of a pause on the ECG. Although the source of this type of pause is obvious when a PAC is conducted, nonconducted PACs are frequently responsible for pauses. In this situation, the sinus node is depolarized by the PAC, causing an interruption and resetting of the regular rate. If the same extrasystolic impulse reaches the AV node or infranodal conducting system during the refractory period, no ventricular depolarization is possible. This combined sinus node reset with a nonconducted atrial extrasystole creates the pause seen on the ECG. Often the PAC responsible for a pause falls within the previous T wave and is not visible on the ECG. On rare occasions an extremely late PAC can cause atrial depolarization in combination with the sinus node impulse. The P′ waves in these cases represent a fusion complex and have qualities of both impulses. The management of PACs is based on recognition, with no need for specific therapy. Underlying causes, such as catecholamine excess, hypoxia, myocardial ischemia, congestive heart failure, or acid-base and electrolyte imbalance, should be treated if symptomatic or frequent PACs occur. If caused by a reentrant mechanism, frequent PACs can be terminated with a calcium channel blocker, a p -adrenergic blocker, or magnesium; however, this treatment is rarely needed.

Premature Junctional Contractions Premature junctional contractions (PJCs) are the result of either altered automaticity or nodal microreentry. On the ECG, a P′ wave from retrograde atrial depolarization is buried within the QRS complex, and the extrasystole appears as a lone additional QRS complex (from a high nodal focus) that may be seen as a

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result of retrograde conduction to the atria. If seen, the P′ waves from PJCs are usually inverted because of the opposite direction of the depolarization wave compared with the normal sinus impulses and can be difficult to distinguish from PACs emanating from a low atrial source. If a high nodal focus is involved, the QRS complex is narrow; wide QRS complexes imply a lower His source or abnormal infranodal conduction (bundle branch block). Fully compensatory pauses and aberrant conduction occur more often with PJCs than with PACs. The causes and treatment of PJCs are the same as those of PACs.

Premature Ventricular Contractions PVCs can occur in a variety of pathologic and nonpathologic states. Their major importance is related to the clinical scenario accompanying their presence and the risk of more serious ventricular dysrhythmias (i.e., ventricular tachycardia and fibrillation).[52] Extrasystoles that occur during ventricular repolarization (the “R-on-T phenomenon”) are believed to carry a higher risk of precipitating ventricular tachycardia, although the magnitude of this effect is debated. Other data suggest that PVCs occurring during the next atrial depolarization (the “R-on-P phenomenon”) carry as high or a higher risk of precipitating serious ventricular dysrhythmias as R-on-T PVCs.[53] PVCs can be caused by varying mechanisms ( Box 78-7 ), including reentry, abnormal automaticity, and triggered afterdepolarizations. Classically, PVCs appear on the ECG as wide QRS complex extrasystoles (greater than 0.12 second) unassociated with a preceding P wave ( Figure 78-21 ). In a single lead a PVC may appear as a narrow QRS complex. This narrow complex occurs if the wave of depolarization is traveling directly perpendicular to the ECG lead and underscores the need to examine multiple leads to identify PVCs accurately. Although P waves from nonconducted sinus impulses may be seen on the ECG, these should have no consistent relationship with the QRS complexes from the PVCs. Rarely, retrograde conduction of PVCs can produce an inverted P′ wave after each QRS complex. PVCs usually cause a fully compensatory pause, with the resulting RR interval encompassing the PVC equal to twice the intrinsic RR interval length (see Figure 78-21 ). Rarely, noncompensatory or subcompensatory pauses can be seen with PVCs and are associated with retrograde conduction and sinus node depolarization. Interpolated PVCs refer to another rare instance when the underlying sinus rhythm is unaffected by a PVC ( Figure 78-22 ). BOX 78-7 Causes of Premature Ventricular Contractions and Ventricular Tachycardia

Acut e myo cardi al infar ction Hypo kale mia Hypo xemi a Isch emic heart dise ase Valv ular dise ase Cate chol amin e

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exce ss [*] Othe r drug intoxi catio ns Idiop athic caus es[*] Digit alis toxici ty Hypo mag nese mia Hype rcap nia Type I agen ts Alco hol Myo cardi al cont usio n (esp eciall y cycli c antid epre ssan ts) Card iomy opat hy Acid osis Alkal osis Meth ylxan thine toxici ty * Relative increase in sym pathetic tone from drugs (direct or indirect) or conditions that augm ent catecholam ine release or decrease parasym pathetic tone.

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† Isolated PVCs can occur in up to 50% of young subjects without obvious cardiac or noncardiac disease; however, m ultiform and repetitive PVCs and ventricular tachycardia are rarely seen in this population.

Figure 78-21 Prem ature ventricular contractions with compensatory pause. Note that a sinus P wave can be seen in the T wave of the extrasystolic beat. Also note the secondary T wave changes in beats 1 and 4 (T wave is opposite the main deflection of the QRS com plex).

Figure 78-22 Interpolated prem ature ventricular contraction.

The structure of the QRS complexes depends on the origin of the impulse. PVCs with a left bundle branch appearance result from a wave of depolarization beginning in a right ventricular source and vice versa. Multiform (or “multifocal”) PVCs refer to ventricular extrasystoles from more than one source and appear as varying QRS complex structures. When a PVC depolarizes the ventricles at a similar time as a conducted atrial beat, a fusion QRS complex is seen ( Figure 78-23 ). Identification of fusion QRS beats indicates the presence of PVCs.

Figure 78-23 Sinus rhythm with run of accelerated idioventricular rhythm. Note fusion beats (F) displaying hybrid appearance of both m orphologies.

PVCs produce abnormal repolarization as a direct result of the abnormal depolarization of the ventricles. Secondary T wave abnormalities refer to the repolarization changes seen as a result of pathologic depolarization and are seen with PVCs along with bundle branch blocks and left ventricular hypertrophy. These secondary T wave changes consist of widening and deflection opposite the main QRS deflection (see Figure 78-21 ). Primary T wave abnormalities refer to changes in ventricular repolarization caused by underlying cardiac disease (such as ischemia) and are not solely the result of depolarization abnormalities. Primary T wave changes often consist of T wave deflection in the same direction as the main QRS vector. The pattern of PVCs is commonly classified by the Lown criteria ( Table 78-6 ). In general, these criteria are intended to distinguish benign PVCs from those likely to degenerate into ventricular tachycardia and ventricular fibrillation. After myocardial infarction, PVCs in Lown classes 3 to 5 carry a high risk for these malignant ventricular dysrhythmias and sudden death, with class 4 having the highest risk. The use of this classification system in other patients with PVCs does not predict the risk of morbidity and mortality. PVCs are found in healthy young patients and their frequency generally increases with age. Table 78-6 -- Lown Classification of Premature Ventricular Contractions Class

Description

0 1 2 3 4A 4B 5

None 200 beats/m in.

Atrial fibrillation may also result from the degeneration of atrial flutter, irrespective of the cause. In this case, an intermediary condition called atrial fibrillation-flutter shows characteristics of both rhythms on ECG. It may be manifested as fine fibrillatory waves with irregular QRS complexes intermixed with flutter waves and a stretch of regular QRS complexes. Rapid atrial fibrillation followed by sinus bradycardia in an elderly patient suggests the aforementioned bradycardia-tachycardia syndrome. Finally, irregular atrial fibrillatory waves coupled with regular narrow or wide QRS complexes may represent atrial fibrillation coupled with complete heart block and an accelerated junctional or ventricular rhythm; this syndrome strongly suggests digitalis toxicity. The treatment of atrial fibrillation is based on distinguishing it from other chaotic rhythms ( Box 78-11 ) and the recognition of any underlying causes and symptoms. Asymptomatic atrial fibrillation at a rate of 120 beats/min or less requires no specific emergency therapy. Patients who are unstable from acute rapid atrial fibrillation should receive sedation and synchronized cardioversion starting at 50 to 100 J. Electrical cardioversion is not associated with an increased risk of malignant ventricular dysrhythmias in patients receiving digitalis unless clinical or laboratory evidence of toxicity coexists. BOX 78-11 Pharmacologic Approach to Atrial Fibrillation Conversion

Intra veno us proc aina mide , 50 mg/ min, up to a total dose of 18 to 20 mg/k g (12 mg/k g in patie nts with cong estiv e heart failur e) or until conv ersio n or side effec ts occu

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r or Ibutili de, 0.01 5-0.0 2 mg/k g IV, over 10-1 5 minu tes (con versi on usua lly occu rs withi n 20 minu tes if succ essf ul) or Amio daro ne, 5 mg/k g IV, over 15-2 0 minu tes or Oral quini dine sulfa te, 200300 mg initial ly, then 200300 mg ever y hour until conv ersio n,

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side effec ts, or a total dose of 1000 mg has been admi niste red If need ed: A calci um chan nel bloc ker (vera pami l, 40 to 80 mg PO or 5-10 mg IV, or diltia zem, 60 to 120 PO or 20-2 5 mg IV) can be give n befor e the type IA agen t (if no contr aindi catio ns are pres ent)

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to lowe r the ventr icula r resp onse rate to 50 mm Hg) systolic gradients, severe symptoms, and poor quality of life who do not respond to drug therapy. The most common procedure is septal myomectomy, in which a portion of the basal septum is resected. Success rates are 95%, with improvement in symptoms and quality of life despite the lack of effect on diastolic dysfunction or the other components of HCM. Dual-chamber pacing decreases outflow gradient and improves symptoms but does not improve outcome.[73]

Disposition The natural history of HCM is variable and probably reflects the many different genetic etiologies. The annual mortality rate is 1%.[70] The annual incidence of sudden cardiac death is higher in young patients with HCM (6%) than in the elderly (1%).[72] The risk of cardiac death is 0.7% per year.[78] The onset of atrial fibrillation in some patients with HCM may precipitate marked hemodynamic compromise and severe CHF. Cardioversion is indicated. Rate control and anticoagulation to prevent thromboembolism are the hallmarks of therapy for chronic atrial fibrillation. Embolic phenomena also can occur in HCM secondary to bacterial endocarditis, which most commonly affects the mitral valve.[73]

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The best predictor of outcome may be the genetic defect. At present, clinical risk factors for sudden death are young age, syncope, malignant family history, cardiac functional status, outflow obstruction, sustained ventricular tachycardia, and ventricular tachycardia on ambulatory monitoring.[70] Syncope is the only independent predictor of sudden death.[79] Sudden death usually occurs with exercise. Patients with HCM who do not have the aforementioned risk factors may engage in low-intensity sports. Patients with HCM initially diagnosed in the emergency department should have strenuous physical activity specifically proscribed until cleared by their cardiologist. In the emergency department, patients with HCM who have angina, syncope, near-syncope, dysrhythmias, and abrupt changes in cardiopulmonary status should be hospitalized.

RESTRICTIVE CARDIOMYOPATHY Perspective The hallmark of RCM is a gradual and progressive limitation of ventricular filling secondary to myocardial lesions. RCM is the least common type of cardiomyopathy in countries where the most common etiology is amyloidosis. Other etiologies include sarcoidosis, hemochromatosis, scleroderma, neoplastic cardiac infiltration, radiation heart disease, glycogen storage disorders, Fabry's disease, and Gaucher's disease. The most common cause of RCM worldwide is tropical endomyocardial fibrosis. Endomyocardial fibrosis is endemic to India, Africa, and Latin America. Symptoms include an initial viral-like illness followed by persistent fever, malaise, and the development of severe right-sided heart failure. Infectious and immunologic causes are proposed. Only 2% of all childhood cardiomyopathies are RCM. Children also have a more rapid deterioration than adults, with only 29% survival at 4 years.[80] Some patients with RCM show an abnormal accumulation of desmin (the major intermediate filament of muscle) in a disorganized pattern. There is also an autosomal dominant inheritance of RCM in some families.[81] These two findings led to the hypothesis that RCM may have a pathophysiologic etiology in common with the other cardiomyopathies. This hypothesis is supported further by the finding of a mutation within the cardiac troponin I gene that leads to RCM. Similar to DCM and HCM, this finding supports the theory that the cardiomyopathies may be a spectrum of hereditary diseases of sarcomeric contractile proteins.[82]

Principles of Disease Restriction of ventricular filling results in low enddiastolic ventricular volumes, high end-diastolic ventricular pressures, and decreased cardiac output. Systolic function is maintained. Grossly, there is atrial enlargement with nondilated ventricles. As the disease progresses, the ventricular cavities may become obliterated by fibrous tissue, scarring, or thrombus.

Clinical Features and Diagnostic Strategies Symptoms are those of worsening diastolic dysfunction and include exercise intolerance (cardiac output cannot be increased because ventricular filling is compromised), elevated central venous pressure, peripheral edema, pulmonary edema, and S3 and S4 gallops on auscultation. Children can present with failure to thrive.[80] Differentiation from constrictive pericarditis requires CT, MRI, or Doppler echocardiography. Occasionally, pericardial calcification can be seen on chest radiograph. This calcification favors a diagnosis of constrictive pericarditis over the diagnosis of RCM. Echocardiography shows a thickened left ventricle and no change in the left ventricular isovolumic relaxation time with respirations, as occurs with constrictive pericarditis. Atrial dimensions are often increased, which is rarely true in constrictive pericarditis. Biopsy is the gold standard for making the diagnosis and can rule out treatable causes.

Management and Disposition With few exceptions (e.g., hemochromatosis), there is no specific treatment for RCM. Treatment is symptomatic until transplantation. Close management is important because RCM has a relentless progression, with 90% of patients dying within 10 years of diagnosis.

PERIPARTUM CARDIOMYOPATHY Perspective Peripartum cardiomyopathy (PPCM) is uncommon. It represents less than 1% of the cardiovascular problems associated with pregnancy. PPCM is a form of DCM with symptoms and signs of heart failure that

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presents for the first time during the last 3 months of pregnancy or the first 6 months postpartum.

Etiology and Epidemiology The etiology of PPCM is unknown. PPCM may be the result of a cardiovascular stressor during pregnancy, such as preeclampsia or cesarean section, superimposed on an underlying (and probably undiagnosed) cardiovascular disorder. Other proposed etiologies include myocarditis and nutrition factors. The incidence is estimated to be 1 case of PPCM per 3000 to 15,000 pregnancies[83] and is greater in women who are multiparous, have twin pregnancies, have gestational hypertension, have preeclampsia, are older than age 30, or are African American.[84]

Clinical Features and Diagnostic Strategies Patients usually have symptoms of CHF, chest pain, palpitations, and occasionally thromboembolism. Physical examination often reveals tachycardia, tachypnea, pulmonary rales, an enlarged heart, and an S3 heart sound. The ECG may show left ventricular hypertrophy or nonspecific ST–T wave changes. On echocardiography, all four chambers are enlarged, with marked reduction in left ventricular systolic function. A small to moderate pericardial effusion may be found. PPCM is clinically identical to DCM.

Management and Disposition Treatment of PPCM includes limitation of physical activity, p -blockers, alteration of preload with nitrates and diuretics, increase in ventricular contractility using agents such as digitalis, and afterload reduction. Hydralazine is an effective and safe afterload-reducing agent during pregnancy. Angiotensin-converting enzyme inhibitors may be started in the postpartum period.[84] One third of patients with PPCM may die. Of survivors, half show complete or near-complete recovery of cardiac function within the first 6 months. Patients who do not recover completely show either continuous clinical deterioration or persistent left ventricular dysfunction. Subsequent pregnancies may be associated with relapses and a high risk of maternal mortality, although women with stable DCM before pregnancy often do well.[83] In the emergency department, patients with signs of hemodynamic instability or failure to maintain oxygenation should be admitted, and fetal monitoring should be initiated.

SPECIFIC HEART MUSCLE DISEASES Amyloidosis Disorders of amyloid deposition are divided into two categories: primary amyloidosis (associated with a high incidence of cardiac involvement) and amyloidosis secondary to multiple myeloma, RA, tuberculosis, or lymphoma, in which the heart is involved in approximately 50% of cases. Cardiac amyloidosis is a disease of the immune system in which cells of the reticuloendothelial system are stimulated to deposit amorphous material in the ventricle, coronary arteries, or valves. Massive amyloid deposition results in an increased cardiac weight and the diastolic dysfunction of RCM. CHF occurs in 85% of cases of cardiac amyloidosis. Standard CHF and antidysrhythmic therapy are indicated, although the dysrhythmias in amyloid heart disease are often refractory to treatment. The presence of high-grade atrioventricular block may require pacemaker insertion. The prognosis is poor, with death often resulting from progressive heart failure within 1 year of symptom onset.

Sarcoidosis Cardiac granulomas are reported in approximately 25% of cases of systemic sarcoidosis. Granulomas are preferentially located in the septum (where they cause severe conduction defects, especially complete heart block), in the papillary muscles (causing mitral regurgitation), and in the ventricular walls (producing scarring and wall motion abnormalities). Cardiac involvement is clinically unrecognized in one third of these cases. The remaining two thirds present with dysrhythmias, conduction defects, or CHF. Complete heart block is the most common conduction block and is associated with a high risk of sudden death. Ventricular dysrhythmias also predispose to sudden death and are often refractory to therapy. Myocardial involvement in sarcoidosis is an indication for systemic corticosteroid therapy. Refractory cardiac failure and dysrhythmias are indications for heart transplantation.

Connective Tissue Disorders and Disease of the Myocardium Myocarditis associated with various connective tissue diseases occurs more often than is recognized clinically. Cardiac abnormalities occur in RA, juvenile RA (Still's disease), mixed connective tissue disease, and primary Sjögren's syndrome. SLE is the connective tissue disease most commonly associated with

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cardiac abnormalities. Cardiac involvement in SLE includes pericarditis, endocarditis, and myocarditis. Primary myocardial involvement is a major complication of diffuse scleroderma and develops as scleroderma worsens. Estimates of the frequency of myocardial involvement in scleroderma vary widely. Presentation includes CHF, angina, and dysrhythmias. Pericardial disease also can occur. Azathioprine may be a beneficial adjunct to steroid therapy.

Sudden Death Sudden death in patients younger than 21 years of age can be attributed to disease of the myocardium approximately 25% of the time. Cardiac etiologies include myocarditis, HCM, and anomalous coronary artery circulation. In patients with sudden death attributed to cardiac etiologies, prodromal symptoms are reported in more than half of the patients, most commonly chest pain (25%) in patients older than age 20 and dizziness (16%) in patients younger than 20.[85] The distribution of sudden death etiologies by age is as follows: {, {, {,

Age less than 20 years— myocarditis 22% and HCM 22% Age 20 to 29 years—myocarditis 22% and HCM 13% Age 30 to 39 years—myocarditis 11% and HCM 2%

Coronary artery disease becomes the leading cardiac etiology (58%) in sudden death in people age 30 to 39 years. HCM is the cardiac disease most commonly found on postmortem diagnosis of athletes with sudden death. HCM and anomalous coronary arteries are seen more often in sports-related deaths than in deaths not related to sports.

Other Specific Heart Muscle Diseases Box 81-2 lists the numerous other conditions associated with myocardial dysfunction. BOX 81-2 Specific Heart Muscle Diseases

Nutritional Beri beri (vita min B1 defic ienc y), pella gra (vita min B6 defic ienc y), scur vy (vita min C defic ienc y), hype

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rvita mino sis D, kwa shior kor

Metabolic Amyl oido sis, glyc ogen stora ge dise ase type II (Po mpe' s dise ase), McAr dle's synd rom e, carni tine defic ienc y, hem ochr omat osis, acqu ired hem osid erosi s, Fabr y's dise ase, TaySac hs dise ase, San dhoff 's dise ase,

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GM1 gang liosid osis, Nie man n-Pi ck dise ase, Gau cher' s dise ase, cardi ac lipido sis, porp hyria , Hurl er's synd rom e, other muc opol ysac chari dose s, type II hype rlipo prote inem ia (fami lial xant hom atosi s), Han d-Sc hülle r-Ch ristia n dise ase, gout, oxal osis, alka pton uria, ure

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mia

Hematologic Leuk emia , myel oma, sickl e cell dise ase, sickl e cell trait, thro mbot ic thro mbo cyto peni c purp ura, here ditar y hem orrh agic telan giect asia, Hen ochSch önlei n purp ura

Neuromuscular Duc henn e's mus cular dystr ophy , Erb' s (limb

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-girdl e) mus cular dystr ophy , facio scap uloh ume ral mus cular dystr ophy , Fried reich 's ataxi a, myot onic dystr ophy , mya sthe nia gravi s, tuber ous scler osis

Toxic/Hypersensitivity Etha nol, coba lt (bee r-dri nker s' cardi omy opat hy), emet ine, chlor oqui ne, phen othia zine s,

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lithiu m, tricy clic antid epre ssan ts, meth yser gide, cycl opho spha mide , daun orubi cin, doxo rubic in (Adri amy cin), heav y meta ls (ars enic, anti mon y, fluori de, mer cury, lead) , phos phor us, carb on mon oxid e, cate chol amin es, dextr oam phet amin e, phen ylpro pano lami ne,

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veno ms (sco rpion , blac k wido w, snak e, was p), tick paral ysis

Physical Radi ation , hypo ther mia, elect ric shoc k, trau ma, heat strok e

Miscellaneous Sarc oido sis, rheu mato id arthri tis, Reit er synd rom e, Beh çet's synd rom e, trans plant rejec

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tion, Noo nan' s synd rom e, Weg ener' s gran ulom atosi s, Rey e's synd rom e, infla mm atory bow el dise ase, acqu ired imm unod efici ency synd rom e Modified from Wenger NK, Ablemann WH, Robert WC: Cardiomyopathy and specific heart muscle disease. In Hurst JW, Schlant RC (eds): The Heart, 7th ed. New York, McGraw-Hill, 1990.

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Marx: Rosen's Emergency Medicine: Concepts and Clinical Practice, 6th ed., Copyright © 2006 Mosby, Inc.

KEY CONCEPTS {, {,

{, {, {, {,

Pericarditis must be differentiated from acute MI. Thrombolytic therapy is contraindicated in pericarditis because of the potential for hemorrhagic pericarditis or tamponade. Cardiac tamponade must be suspected (distended neck veins, hypotension, and muffled heart sounds), diagnosed (echocardiography), and treated (pericardiocentesis) quickly. If echocardiography is not readily available and the patient is unstable, pericardiocentesis may be diagnostic and therapeutic. Myocarditis should be considered in any patient with the combination of viral illness symptoms and signs of cardiac disease. The symptoms and signs of constrictive pericarditis are virtually indistinguishable from RCM. Lyme disease–related carditis should be suspected in otherwise healthy patients with unexplained heart block and potential exposure to ticks in an endemic area. p -Blockers are the mainstay of therapy for HCM; avoid nitrates.

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Page 1372

Use of this content is subject to the Term s and Conditions of the MD Consult web site.

Marx: Rosen's Emergency Medicine: Concepts and Clinical Practice, 6th ed., Copyright © 2006 Mosby, Inc.

REFERENCES 1. Spodick DH: Medical history of the pericardium. Am J Cardiol1970;26:447. 2. Beck CS: Two cardiac compression triads. JAMA1935;104:714. 3. Zayas R: Incidence of specific etiology and role of methods for specific etiologic diagnosis of primary acute pericarditis. Am J Cardiol1995;75:378. 4. Maisch B, Risitc A: The classification of pericardial disease in the age of modern medicine. Curr Sci 2002;4:13. 5. Chan T, Brady WJ, Pollack M: Electrocardiographic manifestations: Acute myopericarditis. J Emerg Med 1999;17:864. 6. Spodick DH: Macrophysiology, microphysiology, and anatomy of the pericardium: A synopsis. Am Heart J 1992;124:1046. 7. Shifferdecker B, Spodick D: Nonsteroidal anti-inflammatory drugs in the treatment of pericarditis. Cardiol Rev2003;11:211. 8. Mast HL: Pericardial effusion and its relationship to cardiac disease in children with acquired immunodeficiency syndrome. Pediatr Radiol1992;22:548. 9. Gunukula S, Spodick D: Pericardial disease in renal patients. Semin Nephrol2001;21:52. 10. Correale E: Pericardial involvement in acute myocardial infarction in the post-thrombolytic era: Clinical meaning and value. Clin Cardiol1997;20:327. 11. Dressler W: A post-myocardial infarction syndrome. JAMA1956;160:1379. 12. Kahn AH: The postcardiac injury syndromes. Clin Cardiol1992;15:67. 13. Wolfenden H, Newman DC: Constrictive pericarditis associated with trauma and pectus excavatum. Aust N Z J Surg1992;62:750. 14. Retter A: Pericardial disease in the oncology patient. Heart Dis2002;4:387. 15. Wilkes JD: Malignancy-related pericardial effusion: 127 cases from the Roswell Park Cancer Institute. Cancer1995;76:1377. 16. Schultz-Hector S: Radiation-induced heart disease: Review of experimental data on dose response and pathogenesis. Int J Radiat Biol1992;61:149. 17. Moder KG, Miller TD, Tazelaar HD: Cardiac involvement in systemic lupus erythematosus. Mayo Clin Proc1999;74:275. 18. Spodick DH: Pathophysiology of cardiac tamponade. Chest1998;113:1372. 19. Vasquez A, Butman S: Pathophysiologic mechanisms in pericardial disease. Curr Cardiol Rep 2002;4:26. 20. Park S, Bayer AS: Purulent pericarditis. Curr Clin Top Infect Dis1992;12:56. 21. Thavendrarajah V: Catheter lavage and drainage of pneumococcal pericarditis. Cathet Cardiovasc Diagn 1993;29:322. 22. Brook I: Pericarditis due to anaerobic bacteria. Cardiology2002;97:55. 23. Defouilloy C: Intrapericardial fibrinolysis: A useful treatment in the management of purulent pericarditis. Intensive Care Med1997;23:117. 24. Fowler NO: Tuberculous pericarditis. JAMA1991;266:99. 25. Silva-Cardoso J: Pericardial involvement in human immunodeficiency virus infection. Chest 1999;115:418. 26. Ivey MJ, Gross BH: Back pain and fever in an elderly patient. Chest1993;103:1851. 27. Osterberg L, Vagelos R, Atwood JE: Case presentation and review: Constrictive pericarditis. West J Med1998;169:232. 28. Nishimura R: Constrictive pericarditis in the modern era. Heart2001;86:619. 29. Lieberman EB, Hutchins GM, Herskowitz A: Clinicopathologic description of myocarditis. J Am Coll Cardiol1991;18:1617. 30. Richardson P: Report of the 1995 World Health Organization/International Society and Federation of Cardiology Task Force on the definition and classification of cardiomyopathies. Circulation1996;93:841. 31. Wheeler D, Kooy N: A formidable challenge: The diagnosis and treatment of myocarditis in children. Crit Care Clin2003;19:365. 32. Liu P: Viral myocarditis: Balance between viral infection and immune response. Can J Cardiol

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1996;12:935. 33. Olinde KD, O'Connell JB: Inflammatory heart disease: Pathogenesis, clinical manifestations, and treatment of myocarditis. Annu Rev Med1994;45:481. 34. Bowles N: Detection of viruses in myocardial tissues by polymerase chain reaction: Evidence of adenovirus as a common cause of myocarditis in children and adults. J Am Coll Cardiol2003;42:466. 35. Caforio A: Circulating cardiac-specific autoantibodies as markers of autoimmunity in clinical and biopsy-proven myocarditis. Eur Heart J1997;18:270. 36. Sole MJ, Liu P: Viral myocarditis: A paradigm for understanding the pathogenesis and treatment of dilated cardiomyopathy. J Am Coll Cardiol1993;22:99A. 37. Narula J: Brief report: Recognition of acute myocarditis masquerading as acute myocardial infarction. N Engl J Med1993;328:100. 38. Matsuura H: Intraventricular conduction abnormalities in patients with clinically suspected myocarditis are associated with myocardial necrosis. Am Heart J1994;127:1290. 39. Sarda L: Myocarditis in patients with clinical presentation of myocardial infarction and normal coronary angiograms. J Am Coll Cardiol2001;37:786. 40. Batra A, Lewis A: Acute myocarditis. Curr Opin Pediatr2001;13:234. 41. Why HJ: Clinical and prognostic significance of detection of enteroviral RNA in the myocardium of patients with myocarditis of dilated cardiomyopathy. Circulation1994;89:2582. 42. Dec GW: Viral myocarditis mimicking acute myocardial infarction. J Am Coll Cardiol1992;20:85. 43. Mason JW: A clinical trial of immunosuppressive therapy for myocarditis. N Engl J Med1995;333:269. 44. Drucker NA: Gammaglobulin treatment of acute myocarditis in the pediatric population. Circulation 1994;89:252. 45. Kumpati G, McCarthy P, Hoercher K: Left ventricular assist device bridge to recovery: A review of the current status. Ann Thorac Surg2001;71:S103. 46. Brown CA, O'Connell JB: Myocarditis and idiopathic dilated cardiomyopathy. Am J Med1999;99:309. 47. Mengel JO, Rossi MA: Chronic chagasic myocarditis pathogenesis: Dependence on autoimmune and microvascular factors. Am Heart J1992;124:1052. 48. Case records of the Massachusetts General Hospital: Weekly clinicopathological exercises. Case 32-1993: A native of El Salvador with tachycardia and syncope. N Engl J Med1993;329:488. 49. Kociecka W: Trichinellosis: Human disease, diagnosis and treatment. Vet Parasitol2000;93:365. 50. Munford L: Cardiac diphtheria in a previously immunized individual. J Natl Med Assoc2003;95:875. 51. Nagi K, Joshi R, Thakur R: Cardiac manifestations of Lyme disease: A review. Can J Cardiol 1996;12:503. 52. Currie PF, Boon NA: Cardiac involvement in human immunodeficiency virus infection. QJM1993;86:751. 53. Chan AC, Dickens P: Tuberculous myocarditis presenting as sudden cardiac death. Forensic Sci Int 1992;57:45. 54. Wesslen L: Myocarditis caused by Chlamydia pneumoniae (TWAR) and sudden unexpected death in a Swedish elite orienteer [letter]. Lancet1992;340:427. 55. Cregler LL: Cocaine: The newest risk factor for cardiovascular disease. Clin Cardiol1991;14:449. 56. Barron KS: Report of the National Institute of Health Workshop on Kawasaki Disease. J Rheumatol 1999;26:170. 57. Burns JC, Kushner HL, Bastian JF: Kawasaki disease: A brief history. Pediatrics2000;106:1. 58. Farrow G: Pathogenesis and treatment of cardiomyopathy. Adv Intern Med2001;47:1. 59. Seidman J, Seidman C: The genetic basis for cardiomyopathy: From mutation identification to mechanistic paradigms. Cell2001;104:557. 60. Morgensen J, Kubo T, Duque M: Idiopathic restrictive cardiomyopathy is part of the clinical expression of cardiac troponin I mutations. J Clin Invest2003;111:209. 61. Dec GW, Fuster V: Idiopathic dilated cardiomyopathy. N Engl J Med1994;331:1564. 62. Katz A: Pathophysiology of heart failure: Identifying targets for pharmacotherapy. Med Clin North Am 2003;87:303. 63. Garg R: The Digitalis Investigation Group: The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med1997;336:525. 64. Packer M, Bristow M, Cohn J: The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. N Engl J Med1996;334:1349. 65. Lowes B, Gilbert E, Abraham W: Myocardial gene expression in dilated cardiomyopathy treated with beta blockers. N Engl J Med2002;346:1357. 66. Borrowman T, Love R, Mason JW: Dilated cardiomyopathy: Problems in diagnosis and management. Chest1999;115:569. 67. Peacock WF, Albert NM: Observation unit management of heart failure. Emerg Clin North Am 2001;19:209. 68. Ciszewski A: Dilated cardiomyopathy in children: Clinical course and prognosis. Pediatr Cardiol 1994;15:121. 69. Fananapazir L: Advances in molecular genetics and management of hypertrophic cardiomyopathy.

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JAMA1999;281:1746. 70. Wigle E: Hypertrophic cardiomyopathy: Clinical spectrum and treatment. Circulation1995;92:1680. 71. Sangwatanaroj S: Mutations in the gene for cardiac myosin-binding protein C and late-onset familial hypertrophic cardiomyopathy. N Engl J Med1998;338:1245. 72. Roberts M, Roberts R: Recent advances in the molecular genetics of hypertrophic cardiomyopathy. Circulation1995;92:136. 73. Spirito P: The management of hypertrophic cardiomyopathy. N Engl J Med1997;336:775. 74. Lerakis S, Sheahan R, Stouffer G: Hypertrophic cardiomyopathy: Presentation and pathophysiology. Am J Med Sci1997;314:324. 75. Behr E, Elliott P, McKenna W: Role of invasive EP testing in the evaluation and management of hypertrophic cardiomyopathy. Card Electrophysiol Rev2002;6:482. 76. Maron B: Risk stratification and prevention of sudden death in hypertrophic cardiomyopathy. Cardiol Rev 2002;10:173. 77. McKenna W, Firoozi S, Sharma S: Arrhythmias and sudden death in hypertrophic cardiomyopathy. Card Electrophysiol Rev2002;6:26. 78. Cannan C: Natural history of hypertrophic cardiomyopathy: A population-based study, 1976 through 1990. Circulation1995;92:2488. 79. Kofflard M, Ten Cate F, van der Lee C: Hypertrophic cardiomyopathy in a large community population: Clinical outcome and identification of risk factors for sudden cardiac death and clinical deterioration. J Am Coll Cardiol2003;41:987. 80. Weller R: Outcome of idiopathic restrictive cardiomyopathy in children. Am J Cardiol2002;90:501. 81. Zhang J: Clinical and molecular studies of a large family with desmin-associated restrictive cardiomyopathy. Clin Genet2001;59:248. 82. Morgensen J, Kubo T, Duque M: Idiopathic restrictive cardiomyopathy is part of the clinical expression of cardiac troponin I mutations. J Clin Invest2003;111:209. 83. Bernstein P, Magriples U: Cardiomyopathy in pregnancy: A retrospective study. Am J Perinatol 2001;18:163. 84. Mehta N, Mehta R, Khan I: Peripartum cardiomyopathy: Clinical and therapeutic aspects. Angiology 2001;52:759. 85. Drory Y: Sudden unexpected death in persons less than 40 years of age. Am J Cardiol1991;68:1388.

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Marx: Rosen's Emergency Medicine: Concepts and Clinical Practice, 6th ed., Copyright © 2006 Mosby, Inc.

Chapter 82 – Infective Endocarditis and Valvular Heart Disease Susan M. Dunmire

INFECTIVE ENDOCARDITIS Perspective The term infective endocarditis (IE) has replaced the older classifications of acute, subacute, and chronic as they have become less meaningful in the antibiotic era. Although bacteria remain the most common etiology, virtually all organisms (including viruses, fungi, and rickettsiae) can cause endocarditis. Early diagnosis of endocarditis and identification of the causative organism play a significant role in the clinical outcome of this life-threatening disease.

Principles of Disease In the United States, more recent studies indicate the incidence of IE is 1.7 to 6.2 cases per 100,000 person-years with a slight predominance in males.[] In the preantibiotic era, the average age of a patient with IE was younger than 39 years. Currently, mean age has increased to 49 to 67 years, probably because of the increased prevalence of prosthetic heart valves and the increase in degenerative valve disease in an aging population.[3] Most patients with bacterial endocarditis have one of the following predisposing factors: rheumatic or congenital heart disease, calcific degenerative valve disease, prosthetic heart valve, mitral valve prolapse (MVP), a history of intravenous (IV) drug use, or a history of endocarditis. Although the incidence of rheumatic heart disease has decreased, it remains an important predisposing factor for endocarditis with the mitral valve as the most common site of infection. Congenital cardiac lesions involving high-pressure gradients (e.g., ventricular septal defects, pulmonary stenosis, tetralogy of Fallot) place a patient at increased risk for IE. Calcific or degenerative disease of the aortic and the mitral valve is now recognized (owing to increased use of echocardiography) as being an extremely common entity in elderly patients. Prosthetic valve endocarditis is a devastating complication of valve replacement. The incidence of endocarditis in prosthetic valve recipients ranges from 0.5% to 4% per year.[4] MVP is a particularly important and common predisposing factor for IE. The risk is greatest when regurgitant flow is identified by echocardiography or the presence of a murmur. The incidence of IE associated with injection drug use is estimated at 150 to 2000 per 100,000 person-years.[5] Although any valve can be affected, it is the most common cause of right-sided endocarditis. The recurrence rate of endocarditis in injection drug users is approximately 41%, in contrast to a recurrence rate of less than 20% in other patients.[] Endocarditis is a major risk factor for recurrence because infected valves heal with irregularities that become sites for future vegetations.

Pathophysiology The classic lesion of endocarditis is the vegetation. It originates as a sterile thrombus on which microorganisms adhere and colonize. The initial thrombus may form at a site of trauma, inflammation, or abnormal turbulence induced by mechanical damage. In injection drug users, contaminants such as talc can injure the previously normal valve leaflets and produce a site for bacterial implantation. A subclinical bacteremia usually precedes the onset of symptoms of bacterial endocarditis by approximately 1 week. A variety of surgical procedures result in transient bacteremia, including dental procedures, cystoscopy, urethral dilation, endoscopic retrograde cholangiopancreatography, and esophageal dilation.[] The infective organism depends on the predisposing factor for endocarditis. Streptococcus remains the

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most common pathogen for left-sided endocarditis in patients with congenital valvular disease or MVP. There is an association between Streptococcus bovis endocarditis and coexisting gastrointestinal malignancy. Staphylococcus accounts for approximately 30% of native valve endocarditis and more than 80% of cases of bacterial endocarditis in patients with a history of injection drug use.[10] Coagulase-negative staphylococci are the most common infecting organisms in prosthetic valve endocarditis. Staphylococcus lugdenesis is a virulent coagulase-negative staphylococcus that infects native valves, resulting in rapid valve destruction and paravalvular abscess formation.[11] The HACEK group (Haemophilus aphrophilus, Actinobacillus, Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae) are fastidious gram-negative bacilli that can cause culture-negative (owing to fastidious nature and slow multiplication) endocarditis.[12] These organisms are known to result in large vessel septic thrombi. The fastidious Bartonella species of bacteria may cause endocarditis, particularly in disadvantaged, nutritionally compromised patients.[13] Candida and Aspergillus species account for most cases of fungal endocarditis. Predisposing factors for fungal endocarditis include patients with long-term indwelling IV catheters, pacemakers, or implantable defibrillators; patients who are immunosuppressed because of malignancy, acquired immunodeficiency syndrome, or organ transplantation; and IV drug users. The large fungal vegetations often embolize, lodging in arteries. Because these patients usually have negative blood cultures, histologic and serologic study of these emboli may be the first clue to the presence of fungal endocarditis.

Clinical Features Symptoms associated with IE are nonspecific and diverse. Many patients who present early during the bacteremic phase of the illness do not have a cardiac murmur and are indistinguishable from the large population of patients who present to the emergency department with a febrile viral illness, particularly during epidemic influenza season. In the absence of specific risks or a disproportionately ill appearance, the diagnosis of IE may be suspected only when the symptoms persist or the illness does not follow a typical course for viremia. The classic triad of fever, anemia, and heart murmur should suggest the presence of IE, but is rare. All presenting symptoms of IE are nonspecific. The most common symptoms are intermittent fever (85%) and malaise (80%). Fever is more common in an IV drug user with endocarditis (98%). Other symptoms (e.g., weakness, myalgias, dyspnea, chest pain, cough, headaches, and anorexia) vary widely in their incidence and are nonspecific. Thirty percent to 40% of patients have neurologic symptoms or signs, such as confusion, personality changes, decreased level of consciousness, or focal motor deficits. These symptoms are most commonly caused by embolization. Almost all patients with IE have a cardiac murmur at some time during the course of their illness. The murmur may be absent in 15% of patients at the time of presentation. The most common murmurs are aortic, mitral, or tricuspid regurgitation. Fewer than 35% of IV drug users with endocarditis have a murmur on initial presentation.[14] This is most likely due to the fact that most endocarditis associated with IV drug use is right-sided, and consequently the murmur is much more difficult to elicit on physical examination. Approximately 35% of patients have some form of vasculitic lesion, including petechiae, splinter hemorrhages, Osler's nodes, and Janeway lesions. Petechiae may be present on either a mucosal surface or the skin. Often the petechiae on mucous membranes or the conjunctivae have a pale center. These petechiae are nontender and do not blanch with pressure. Approximately 30% of patients have splenomegaly. Several ocular findings are associated with IE, including conjunctival or retinal hemorrhages. Retinal hemorrhages may be flame shaped or may have a pale center surrounded by a red halo (Roth's spots).

Diagnostic Strategies Laboratory findings in bacterial endocarditis are nonspecific. Similar to virtually all infectious conditions, leukocytosis is insensitive (occurring in only approximately 50% of patients diagnosed with IE) and nonspecific. An elevated erythrocyte sedimentation rate or C-reactive protein may be present, but also is nonspecific. Most patients have a mild anemia, and more than 50% have microscopic hematuria as a result of embolic lesions of the kidney. Three blood cultures should be obtained on all patients with suspected endocarditis, with the first and last culture being drawn at least 1 hour apart. Approximately 90% to 95% of blood cultures are positive unless antibiotics already have been administered.[15] An electrocardiogram (ECG) may show conduction abnormalities if an abscess has formed in the myocardium. Transthoracic echocardiography (TTE) is a rapid, noninvasive tool for the diagnosis of vegetations. Although TTE is highly specific, it may be nondiagnostic in 20% of patients because of obesity, chronic obstructive

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pulmonary disease, and chest wall deformities. The sensitivity of TTE for the diagnosis of endocarditis is 60% to 70%.[] Transesophageal echocardiography (TEE) is more invasive and time-consuming, but is far superior to TTE in diagnostic sensitivity for IE.[] The negative predictive value of TEE for IE is greater than 92%.[20] The Duke criteria stratify patients with suspected bacterial endocarditis into three distinct categories: definite, possible, and rejected ( Box 82-1 ).[21] Proposed modifications to the Duke criteria expand the minor criteria to include an elevated C-reactive protein or erythrocyte sedimentation rate, new splenomegaly, splinter hemorrhages, or hematuria.[22] The specificity and sensitivity of the Duke criteria are estimated to be approximately 99% and 95%, respectively.[] BOX 82-1 Duke Criteria for Diagnosis of Infective Endocarditis

Clinical diagnosis requires the following: {, Two major criteria or {, One major and three minor criteria or {, Five minor criteria

Major Criteria {, {,

Positive blood cultures (of typical pathogens) from at least two separate cultures Evidence of endocardial involvement by echocardiography, such as the following: {, Endocardial vegetation {, {, {,

Paravalvular abscess New partial dehiscence of prosthetic valve New valvular regurgitation

Minor Criteria {, {, {, {, {, {,

Predisposition: Predisposing heart condition or IV drug use Fever: ≥38° C Vascular phenomena: Arterial emboli, septic pulmonary infarcts, mycotic aneurysm, conjunctival hemorrhages, or Janeway lesions Immunologic phenomena: Osler's nodes, Roth's spots, and rheumatoid factor Microbiologic evidence: Single positive blood culture (except for coagulase-negative staphylococcus or an organism that does not cause endocarditis) Echocardiogram findings: Consistent with endocarditis, but do not meet major criteria

Management

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Appropriate antibiotics must be selected before the causative organism is known or before the diagnosis is proven. Box 82-2 provides guidelines for empiric therapy. It is helpful to obtain all necessary blood cultures before starting antibiotics. Patients who are IV drug users or have a prosthetic heart valve and are febrile should be admitted for evaluation of bacteremia and the possibility of endocarditis.[27] An exception would be a transient fever in an IV drug user that resolves spontaneously in the emergency department and is thought to be a result of an injected contaminant (“cotton fever”). BOX 82-2 Initial Therapy for Bacterial Endocarditis

Vancomycin Initial dose for adult s: 15 mg/k g Initial dose for child ren: 10 mg/k g Sub sequ ent dose for adult s: 500 mg q 6 hr Sub sequ ent dose for child ren: 10 mg/k gq6 hr Plus Gentamicin Initial dose 1–3 mg/k g (sub sequ ent dose 1

Page 1379

mg/k gq8 hr) Or Ceftriaxone Adult s: 1– 2gq 12 hr Child ren: 50– 75 mg/k gq day Plus Gentamicin Initial dose 1–3 mg/k g (sub sequ ent dose 1 mg/k gq8 hr) Acute valve replacement is rarely necessary during the active episode of IE. Indications for surgery include severe congestive heart failure (CHF) resulting from valvular incompetence, paravalvular leak around a prosthetic valve, fungal endocarditis, and persistent bacteremia despite antibiotics. With proper antibiotic therapy, patients defervesce within 1 week. The 5-year mortality rate for native valve endocarditis is 20%, but in the presence of a prosthetic valve, it is 20% to 60%.[] The mortality for right-sided endocarditis in a patient with a history of injection drug use is approximately 10%.[30]

Prophylaxis Antibiotic prophylaxis in patients undergoing procedures in the emergency department is important for patients with prosthetic heart valves, a history of endocarditis, or congenital cardiac malformations ( Box 82-3 ). Antibiotics are thought to prevent IE by decreasing the degree of bacteremia and reducing the ability of bacteria to adhere to the valve surface. Common procedures for which prophylaxis is recommended are listed in Box 82-4 .[31] Relatively clean procedures, such as suturing of clean lacerations, endotracheal intubation, or the placement of a central venous catheter, do not require prophylaxis. Table 82-1 summarizes recommendations for prophylaxis against bacterial endocarditis. BOX 82-3 Moderate to High Risk Conditions for Bacterial Endocarditis

{,

Pros theti c heart valve

{,

Histo

Page 1380

{,

{,

{,

{,

ry of endo cardi tis Con genit al cardi ac malf orm ation s, parti cular ly cyan otic lesio ns (e.g., tetral ogy of Fallo t, trans posit ion of great vess els) Rhe umat ic heart dise ase Mitra l valve prola pse with regu rgitat ion Hype rtrop hic cardi omy opat hy

BOX 82-4 Indications for Endocarditis Prophylaxis

Prophylaxis Recommended

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Prop hyla ctic clea ning of teeth Bron chos copy (with rigid bron chos cope only) End osco pic retro grad e chol angi opan creat ogra phy Cyst osco py Uret hral dilati on

Prophylaxis Not Recommended Loca l anes theti c injec tions (noni ntrali gam entar y) End otrac heal intub ation Tym pano stom y

Page 1382

tube inser tion Tran seso phag eal echo cardi ogra phy End osco py Vagi nal deliv ery Uret hral cath eteri zatio n Uteri ne dilati on and curet tage Inser tion or rem oval of an intra uteri ne devi ce From Dajani AS, et al: Prevention of bacterial endocarditis. JAMA 227:1794, 1997.

Table 82-1 -- Prophylactic Regimens for Bacterial Endocarditis Dental Procedures Agent Regimen Standard oral prophylaxis

Amoxicillin Aduit s: 2 g1 hr befor e proc edur e Child ren:

Page 1383

Dental Procedures

Agent

Regimen 50 mg/k g1 hr befor e proc edur e

Unable to take oral medication Ampicillin Adult s: 2 g IM or IV 30 min befor e proc edur e Child ren: 50 mg/k g 30 min befor e proc edur e Allergic to penicillin

Clindamycin Adult s: 600 mg orall y1 hr befor e proc edur e or 600 mg IV 30 min befor e Child ren: 20 mg/k g orall y1 hr

Page 1384

Dental Procedures

Agent

Regimen befor e proc edur e or IV 30 min befor e

Azithromycin or clarithromycin Adult s: 500 mg orall y1 hr befor e proc edur e Child ren: 15 mg/k g orall y 1hr befor e proc edur e From Dajani AS, et al: Prevention of bacterial endocarditis. JAMA 227:1794, 1997.

RHEUMATIC FEVER Perspective From 1920 to 1950, acute rheumatic fever was the leading cause of death in American children and the most common cause of heart disease in individuals younger than age 40. During the 1960s and 1970s, the incidence of rheumatic fever in developed countries declined dramatically because of widespread antibiotic use to treat streptococcal infections, declining prevalence of the more virulent strains of group A streptococci, and improved living conditions. In the mid-1980s, a resurgence of rheumatic fever occurred in several areas of the United States. This resurgence was thought to be caused by the emergence of a more virulent strain of group A streptococcus.[34] The incidence of rheumatic fever during epidemics of streptococcal pharyngitis is 3%, although sporadic cases of streptococcal sore throat rarely result in this disease. Children between the ages of 4 and 18 years are at greatest risk of developing rheumatic fever. In many developing nations, rheumatic fever continues to be a leading cause of death in infants and adolescents.

Principles of Disease Although the exact pathogenesis of rheumatic fever is unclear, all affected individuals show an antibody response indicating a recent infection with group A beta-hemolytic streptococcus. The most popular theory is that rheumatic fever results from an abnormal immunologic response to group A streptococcus resulting in antibodies that cross-react with certain tissues within the heart, joints, skin, and central nervous system.

Clinical Features

Page 1385

One third of patients with rheumatic fever do not remember having pharyngitis in the preceding month. The average latent period between pharyngitis and rheumatic fever is 18 days (range 1 to 5 weeks). In 1944, Jones[35] formulated major and minor criteria for the diagnosis of rheumatic fever. Revised in 1965 and further modified in 1984 and 1992, the Jones criteria remain the diagnostic basis for this disease ( Box 82-5 ).[36] The diagnosis of rheumatic fever requires evidence of an antecedent streptococcal infection plus at least one major and two minor or two major manifestations from the Jones criteria. A presumptive diagnosis of recurrent rheumatic fever may be made if one major or more than three minor criteria are present in addition to recent evidence of a group A streptococcal infection. Use of the traditional Jones criteria may lead to underdiagnosis of recurrent rheumatic fever.[37] BOX 82-5 Jones Criteria (Revised) for the Diagnosis of Rheumatic Fever

Major Manifestations Card itis Poly arteri tis Chor ea Eryt hem a mar ginat um Sub cuta neou s nodu les

Minor Manifestations Arthr algia s Feve r Incre ased eryth rocyt e sedi ment ation rate or C-re activ e prote in

Page 1386

Prol onge d P-R inter val A migratory polyarthritis is the most common symptom of rheumatic fever. This polyarthritis often affects larger joints, such as the knees, ankles, elbows, and wrists, and the pain is usually much more severe than physical findings suggest. Arthritis occurs early in the course of rheumatic fever and often coincides with a rising titer of streptococcal antibodies. Forty percent of patients with rheumatic fever have a pancarditis manifested by a heart murmur, cardiomegaly, pericardial effusion, and occasionally CHF. The mitral valve is the most common valve affected by rheumatic fever, often resulting in mitral regurgitation and its classically high-pitched blowing systolic murmur. Chorea (Sydenham's chorea, St. Vitus' dance) consists of random, rapid, purposeless movements usually of the upper extremities and face. It is a rare manifestation of rheumatic fever. Chorea may coexist with carditis, but it never occurs simultaneously with arthritis. If chorea is the only finding, diagnosis may become difficult because all other clinical and laboratory signs may be absent. Erythema marginatum and subcutaneous nodules are found in fewer than 10% of cases of acute rheumatic fever; however, their presence should immediately suggest the diagnosis. Erythema marginatum is a nonpruritic, painless, evanescent “smoke ring” of erythema that commonly appears on the trunk and proximal extremities. Subcutaneous nodules are pea sized; nontender; and usually appear over the extensor surfaces of the wrists, elbows, knees, and occasionally the spine. Fever is present during the acute phase of rheumatic fever. It rarely lasts more than 2 weeks and has no characteristic pattern.

Diagnostic Strategies In diagnosing rheumatic fever, it is helpful to document a recent streptococcal infection. Although throat cultures are usually negative at the time of clinical onset of rheumatic fever, antistreptococcal antibody titers remain positive for 4 to 6 weeks after the streptococcal infection. The erythrocyte sedimentation rate and C-reactive protein level typically are elevated. Approximately 50% of patients have mild proteinuria or casts in their urine. There are no ECG findings pathognomonic of rheumatic fever, although a prolonged P-R interval is common and suggestive.

Management Acute rheumatic fever can be prevented by appropriate treatment of streptococcal pharyngitis. Pharyngitis should be treated early with either a single injection of benzathine penicillin (600,000 U in children weighing 2 yr: 0.04 mg/k g TDD IV. ½ TDD initial ly, then 1/4 TDD q4–8 hr IV ×2

Hypotension, hyperglycemia

maintenance medication; may give higher dose rectally (0.5 mg/kg) Monitor (very prompt onset)

Dysrhythmia, heart block, vomiting

Monitor electrocardiogram; may also load PO in stable, nonurgent situation; if mild CHF, may give PO without loading

Dobutami 2–20 mg/kg/min IV ne (Dobutrex) (vial: 250 mg) Dopamine (200 mg/5 Low: mL) 2–5 mg/k g/mi n IV Mod:

Tachycardia, dysrhythmia, hypotension, hypertension

p -Adrenergic; positive inotropic; may be synergistic with dopamine or isoproterenol p -Adrenergic; avoid in hypovolemic shock; may use in combination with epinephrine or levarterenol (norepinephrine)

(Valium) (maximum: 10 (5 mg/mL) mg/dose) IV

Cardiogenic shock

Card ioge nic shoc k (mo

Tachycardia, bradycardia, vasoconstriction (increase with higher doses)

Page 1421

Drug Dose/Route Availabilit y 5–20 mg/k g/mi n IV High: >20 mg/k g/mi n IV

Epinephrin e (1 : 10,000) (0.1 mg/mL)

Epinephrin e (1:1,000) (1 mg/mL)

Initial : 0.01 mg (0.1 mL; 1:10, 000)/ kg/d ose (max imu m: 10 mL/d ose) IV ET: 0.1 mg (0.1 mL; 1:1,0 00)/k g/do se q3–5 min prn 0.01 mL/kg/dose SC (maximum: 0.35 mL/dose) q10–20 min SC ×3 prn

Indications

Adverse Reactions

Comments

Tachycardia, dysrhythmia, hypertension, decreased renal and splanchnic blood flow

p -and p -adrenergic; inotropic

Tachycardia, headache, nausea

Rarely used because of side effects; may use for ET or second IV dose (above and text)

derat e dose ) Main tain renal perfu sion Septi c shoc k Asys tole Vent ricul ar fibrill ation (fine) Anap hylax is Hem odyn amic ally signi fican t brad ycar dia

High -dos e epin ephri ne or ET epin ephri ne for cardi ac

Page 1422

Drug Dose/Route Availabilit y

Indications

Adverse Reactions

Comments

Tachycardia, palpitations, dysrhythmia, nausea, vomiting

Monitor; observe over time

Respiratory depression, apnea, muscle rigidity, bradycardia, nausea, vomiting, cardiac arrest May precipitate benzodiazepine withdrawal, seizures

Monitor; be prepared to manage the airway

Hypotension, bradycardia (less common than with phenytoin)

1 PE ≈ 1 mg phenytoin; less side effects; can administer more rapidly than phenytoin

arre st (abo ve) Rea ctive airw ay dise ase Epinephrin 0.25–0.75 mL/dose by Croup, airway edema e racemic inhalation (Vaponefri n) (2.25% solution) Fentanyl 1–5 mg/kg/dose IV, IM Analgesia (Sublimaz e) (50 mg/mL) Flumazeni 0.01–0.03 mg/kg IV l (maximum: 1 mg) (Romazic on) (0.1 mg/mL) (5, 10 mL) Fosphenyt oin 15– (Cerebyx) 20 (50 phen mg/mL) ytoin (2, 10 mL) equi vale nts (PE) /kg IV/IM Give slowl y IV (2 PE/k g/mi n)

Benzodiazepine overdose

Seizures

Furosemi 1 mg/kg/dose q6-12 hr Fluid overload, de (Lasix) IV up to 6 mg/kg; may pulmonary edema, (10 repeat q2hr prn cerebral edema mg/mL)

Glucagon 0.1 mg/kg/dose q20 (1 mg [1 min prn IV, SC, IM unit]/mL)

p Bloc ker over dose

Onset: 1–3 min; duration of action: 1 hr

Hypokalemia, Reduce interval in hyponatremia, prerenal newborn to q12 hr; if azotemia no response in urine output in 30 min, repeat; do not use if hypovolemic Hypotension, nausea, Not adequate as only vomiting glucose support in neonate; inotropic

Page 1423

Drug Dose/Route Availabilit y

Indications

Adverse Reactions

Comments

Hypo glyc emia Hydrocorti 1–5 mg/kg/24 hr (max: Adrenal failure sone 100 mg IV (Solu-Cort ef) (100, 250, 500 mg) Labetalol Hypertension 0.2 mg/k g IV Dou ble dose q15 min prn (Max 2–3 mg/k g/do se)

Check electrolytes/glucose, replace fluid loss, treat hyperkalemia

Bronchospasm p -a nd p -b lock er Doe s not incre ase ICP

Lidocaine (1%-10 mg/mL) (2%-20 mg/mL)

1 mg/kg/dose q5–10 min IV, ET up to 5 mg/kg, then 20-50 mg/kg/min

Lorazepa m (Ativan) (2, 4 mg/mL) Methylpre dnisolone (Solu-Med rol) (40, 125, 500, 1000 mg)

0.05–0.10 mg/kg/dose Status epilepticus IV (maximum: 4 mg/dose); may repeat

Respiratory depression Longer acting than diazepam

Asthma: 1–2 mg/kg/dose q6 hr IV; usual maximum: 125 mg 0.05–0.1 mg/kg/dose (maximum: 6 mg) IV

Hyperglycemia

Midazola

Vent ricul ar dysr hyth mias Card iac arre st caus ed by ventr icula r fibrill ation

Hypotension, Decreased bradycardia with block, automaticity; for ET, seizures give 1:1 dilution, with 2 –3 times IV dose

Adre nal failur e Asth ma Sedation

Respiratory

Page 1424

Drug Dose/Route Availabilit y

Indications

m (Versed) (1, 5 mg/mL)

depression, hypotension, bradycardia

Milrinone

Inotrope

Hypotension during load

Load : 50– 75 mg/k g Infus e: 0.5– 1.0 mg/k g/mi n Morphine 0.1–0.2 mg/kg/dose (8, 10, 15 (maximum: 15 mg/mL) mg/dose) q2–4 hr IV

Naloxone (Narcan) (0.4 mg/mL) (1

Adverse Reactions

Anal gesi a Pul mon ary ede ma Tetr alog y spell Red uce prelo ad and afterl oad Narcotic overdose

For a drug

Comments

Antid ote: flum azen il (Ro mazi con) Moni tor: be prep ared to man age the airw ay Inodilator (inotrope/vasodilator)

Hypotension, Antidote: naloxone respiratory depression (Narcan)

Give empirically in suspected opiate overdose; may be given ET

Page 1425

Drug Dose/Route Availabilit y mg/mL)

Nicardipin e

Indications

Adverse Reactions

Comments

Hypertension

Increases ICP, HR

Ca channel blocker

over dose 0.1 mg/k g/do se (max imu m: 0.8 mg) IV, ET; if no resp onse in 10 min give 2 mg IV To rever se adve rse effec ts of thera peuti c narc otics , 0.050.01 mg/k g/do se 0.03 mg/k g Then 1–5 p-g/k g/mi n

Nitropruss 0.5–10 mg (average: 3 ide (50 mg)/kg/min IV mg/vial)

Hype rtens ive eme rgen cy Afterl oad

Hypotension, nausea, vomiting, thiocyanate toxicity, cyanide poisoning

Moni tor clos ely; light sens itive Thio

Page 1426

Drug Dose/Route Availabilit y

Indications

Adverse Reactions

redu ction

Oxygen

100% mask, ET Hypo xia Majo r injur y

Comments

cyan ate toxici ty com mon in patie nt with impa ired renal funct ion Toxicity not a problem with acute short-term use

Use high flow (3–6 L/min); monitor ABGs

Pancuroni um (Pavulon) (1, 2 mg/mL) Phenobar bital (65 mg/mL)

0.04–0.1 mg/kg/dose Muscle relaxation IV; may repeat 0.01– 0.02 mg/kg/dose q20– 40 min IV prn

Tachycardia

Rapid onset; support respirations; lower dose in newborn

15–20 mg/kg load IV/IM Seizures (adult: 100 mg/dose q20 min prn ×3), then 5 mg/kg/24 hr PO, IV, IM

Sedation

Phenytoin (Dilantin 50 mg/mL) Procaina mide

15–20 mg/kg load IV Seizures slowly, then 5–10 mg/kg/24 hr PO, IV q12 –24 hr 15 mg/kg IV over 30– Recurrent or refractory 60 min VT/SVT

Hypotension, bradycardia when given too rapidly; cerebral disturbance

If not controlled after load, repeat 10 mg/kg/dose IV; administer 100 beats/min Cardia c

Unknown

Unknown Unknown

+

++ + +++

++++

Minimal ++

Minimal

Minimal

+

+++ Minimal

+++

Page 1521

Factor

Mecha Strength of Association with PE in nisms Emergency Department Populations

Pulse oximetry reading 2500 ng/mL) more strongly suggest the presence of PE, as opposed to a nonspecific cause, no cutoff of D-dimer concentration can be used to confirm the diagnosis. The posttest probability where the clinician can exclude the diagnosis of PE safely using a D-dimer as the only test must be approximately 1%, which is reasonably equivalent to imaging.[22] This combination can be achieved by several routes that include the combination of pretest probability assessment and either qualitative or quantitative D-dimer testing. By this rationale, it is safe to assume that an ELISA D-dimer concentration less than 500 ng/mL excludes the presence of PE, if the pretest probability is less than 40%. When the pretest probability is relatively high, or the screening D-dimer is positive, pulmonary vascular imaging, by either V/Q scanning or CT angiography, is advised. Although neither V/Q scanning nor CT angi-ography is perfect, both can be combined with pretest probability to diagnose and exclude the presence of PE. The relative accuracy and precision of the V/Q scan were shown in the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) study, which compared the results of V/Q scanning with the most accurate criterion standard test possible—formal pulmonary angiography ( Table 87-3 ).[26] This multicenter study showed that a high-probability V/Q scan can be used to diagnose PE, and a normal V/Q scan excludes the diagnosis of PE with a degree of certainty that is acceptable to the medical community. A

Page 1526

moderate probability or indeterminate scan requires additional testing, either formal pulmonary angiography or a CT angiography. Except in patients with a low pretest probability, a low-probability V/Q scan requires additional testing. Suggestions include either CT angiography or venous duplex ultrasonography of the legs. The latter should be repeated at least once, 5 to 7 days later, if negative at the initial presentation. In patients with a chest radiograph that shows airspace disease, the specificity of V/Q scanning can be expected to decrease, and the relative diagnostic utility of CT angiography can be expected to increase. Table 87-3 -- Prevalence of Pulmonary Embolism Stratified by Ventilation-Perfusion Scan Result and Pretest Probability Estimate Clinician Estimate of Pretest Probability for PE V/Q Scan Result

80–100%

20–79%

0–19%

All

High probability

28/29 (96%) 27/41 (66%) 6/15 (40%)

70/80 (88%) 66/236 (28%) 30/191 (16%) 4/62 (6%) 170/569 (30%)

5/9 (56%)

103/118 (87%) 104/345 (30%) 40/296 (14%) 5/128 (4%) 252/887 (28%)

Intermediate probability Low probability Near-normal/normal Total

0/5 (0%) 61/90 (68%)

11/68 (16%) 4/90 (4%) 1/61 (2%) 21/228 (9%)

V/Q, ventilation-perfusion; PE, pulmonary embolism. Adapted from The PIOPED Investigators: Value of the ventilation/perfusion scan in acute pulmonary embolism. JAMA 263:2753, 1990.

Most academic centers now employ CT angiography as the primary method of evaluating for PE.[27] Images can be obtained in a few seconds, so that the time required for the test primarily depends on scanner availability, transport time, transferring the patient to and from the CT table, and radiologist interpretation time. One of the greatest advantages of CT angiography over V/Q scanning is that for the most part the radiologist indicates the test is positive or negative, similar to the results of conventional catheter-based pulmonary angiography. This binary output makes CT angiography simpler for the clinician to interpret and to integrate into medical decisions compared with the “probability” output of the V/Q scan. The PIOPED II study currently is being conducted to evaluate the performance characteristics of CT angiography for the evaluation of PE and is expected to complete recruitment in 2004. To date, large multicenter management studies have found a lower than 1% rate of subsequent anticoagulation in patients with negative CT angiography, but questions remain as to how many patients in these studies had untreated PE and were never diagnosed.[28] The authors believe that a growing concern exists about the false-positive rate of CT angiography. At present, the best evidence available suggests that CT angiography has about a 90% sensitivity and a 90% specificity.[] When the results of CT angiography seem questionable in view of clinical suspicion, it is often worth the time to investigate issues of image acquisition quality that can affect the certainty of the radiologist's call on the presence or absence of PE. Good contrast enhancement of the pulmonary vasculature probably is the most important factor determining the diagnostic quality of CT angiography. Poor heart function complicates the timing of vascular opacification, but using bolus-timing software that is readily available on almost all CT scanners today essentially should eliminate this factor. Obesity also can compromise image quality and must be considered when determining the appropriate scanning parameters for each patient (i.e., mAs, kVp). Motion artifact can severely degrade the quality of the images, as can severe intrinsic lung disease, such as stage 4 sarcoidosis or bulky carcinoma that can distort the vasculature and give false-positive appearances.[31] Technical aspects that seem associated with better accuracy of the interpretation include specialty training of the reader, review of images in cine mode on a picture archival and communication system (PACS), a greater number of detectors on the scanner, and thinner collimation of the x-ray beam.

Page 1527

There is no quantitative method to fold these findings into the computation of posttest probability except to say that if the scan quality was good, this should inspire more confidence in the radiologist's interpretation. As with any imaging study, if CT angiography quality was poor, and the results do not match the clinical picture, PE cannot be excluded or diagnosed with certainty, and more testing should be performed. Clinicians often raise the question of the importance of isolated subsegmental pulmonary embolus either missed or detected by CT angiography. This concern can arise because of a radiologist's statement that subsegmental clot cannot be excluded by CT angiography, or more recently, as a consequence of increased detection of isolated subsegmental filling defects on more thinly collimated images acquired with a higher number multidetector scanner. No firm evidence exists to guide the treating clinician in these circumstances. When two radiologists independently evaluate CT angiography, their agreement on the presence of isolated subsegmental filling defects is poor.[] The same lack of agreement in subsegmental clots holds for formal pulmonary angiography.[34] It is important that this lack of agreement refers to scans without other larger defects seen by either radiologist. Our opinion is that if the patient has no evidence of DVT, no signs of cardiopulmonary stress, and no ongoing major risk for thrombosis, isolated subsegmental findings or no findings together comprise a nonissue, and for either case, withholding anticoagulation would afford more benefit than harm. If a patient with negative CT angiography has signs of pulmonary hypertension or hypoxemia or has a known thrombophilia, further testing is advised. These patients are at a high risk for PE, and as such, we recommend a V/Q scan be performed. Unless the V/Q scan yields a normal or high-probability result, a formal pulmonary angiogram is advised. In reality, radiologists often are reluctant to perform these tests after good-quality, negative CT angiography study. Another option is to perform duplex ultrasound of the extremities, which can clinch the diagnosis if positive. A negative sonogram does not exclude the diagnosis, however, and should be repeated in 5 to 7 days. CT angiography can provide additional information to enhance its utility in the emergency department. First, without requiring any additional contrast injection, the legs can be scanned a few seconds later to provide a CT venogram, which can evaluate for DVT.[35] Indirect CT venography has been shown to be equally accurate as venous ultrasound, and when two radiologists interpret CT venography independently, the rate of agreement is good.[36] CT pulmonary angiography often provides information about alternative processes that might explain the patient's symptoms ( Box 87-3 ). Pneumonia is the most common alternative diagnosis found in emergency department patients.[37] It can be hypothesized that in about 10% of emergency department patients evaluated for PE, the CT scan as a single test could (1) show absence of PE; (2) provide evidence of alternative disease, which can be used with other evidence to reduce the probability of PE to a reasonably low level to stop the workup; and (3) facilitate treatment for the alternative disease. BOX 87-3 Frequency of Potentially Important Non–Pulmonary Embolism Diagnoses Disclosed on Computed Tomography

Pne umo nia (6%) [*]

Uns uspe cted peric ardia l effus ion (1%) Mas s sugg estin g

Page 1528

new carci nom a (1%) Aorti c diss ectio n (0.5 %) Pne umot hora x (0.5 %) * Percentage of all 1025 emergency departm ent patients who underwent com puted tom ography to evaluate for pulm onary em bolism .

Management Anticoagulation A high-probability V/Q scan, positive CT angiography, or ultrasound evidence of DVT in a patient with a symptom or sign suggesting PE confirms the diagnosis and mandates initiation of therapy. Either unfractionated heparin (80 U/kg intravenous bolus, followed by 18 U/kg/hr intravenous infusion) or fractionated heparin (e.g., enoxaparin, 1 mg/kg subcutaneously or intravenously every 12 hours) represents current standard treatment for most patients with PE. At present, no published evidence has proved the superiority of either form of heparin over the other. Both forms of heparin work equally well, and both are safe in the absence of contraindications to anticoagulation. Heparin provides several known benefits, including the reduction in formation of new clot (which can occur rapidly as clot volume increases exponentially with existing clot mass), and reduces the theoretical transient hypercoagulable effect of warfarin treatment, thought to be mediated by relative decrease in circulating protein C activity. Heparin also possesses antichemokine and antimitogenic properties that may help prevent inflammatory-mediated damage in the lung vasculature. As with DVT, administration of the first 10-mg dose of warfarin in the emergency department can help shorten the hospital stay. Physicians often question when to administer heparin based on pretest probability, before the results of imaging are known. Published evidence has not addressed this question directly. This choice would seem to confer more benefit than harm when the implicit or explicit pretest probability of PE exceeds 40%, the patient has no major contraindication to anticoagulation, and imaging would delay heparin initiation for greater than 2 hours. The intransitive logic used to support the 2-hour statement derives from the fact that about one third of all normotensive patients who die from PE during hospitalization die within 24 hours of diagnosis. For a patient diagnosed with PE in presence of a major contraindication to anticoagulation, such as a recent cerebral hemorrhage or a 7-day old large cerebral infarction, the appropriate consultant should be contacted for urgent placement of an inferior vena caval filter. If vena caval interruption cannot be performed within 12 hours, one option is to perform a baseline head CT scan, then start an unfractionated heparin infusion at 18 U/kg/hr (without a bolus), admit the patient to the intensive care unit for neurologic checks every 15 minutes, and monitor the partial thromboplastin time every 4 hours. The rationale for unfractionated heparin is that it can be reversed more reliably (by discontinuing the heparin drip and administering protamine, 1 mg/kg intravenously) than fractionated heparin. Most patients with PE look and feel better the day after starting heparin anticoagulation, and more than half go on to a nearly full recovery of pre-PE health status. The in-hospital mortality of patients diagnosed with PE who remain hemodynamically stable while in the emergency department is about 10%. Another 10% to 20% complain of persistent dyspnea and exercise intolerance that permanently degrades their quality of life. Systolic hypotension (0.4 ng/mL or T >0.04 ng/mL

60

85

Pulse oximetry

90 pg/mL

85

75

Echocardiography

RV dilation or hypokinesis 86

39

*

Sensitivity and specificity for the predication of circulatory shock requiring vasopressor treatm ent, need for intubation, or death during hospitalization. RV, right ventricular.

Thrombolytic Therapy Thrombolytic therapy in suspected or proven PE is controversial. Administration of alteplase to patients with PE results in more rapid symptomatic improvement than standard antithrombotic therapy alone[43] and causes more rapid normalization of right ventricular function.[44] Alteplase administration also increases the risk of hemorrhage, however. It is not known how many patient lives would be saved—or definitively improved—by the addition of thrombolytic treatment to heparin therapy versus the number of patients who would experience a fatal or life-threatening bleeding event as a result of thrombolytic treatment.[45] On balance, the benefit/risk analysis argues that fibrinolysis is of greatest value in the subset of patients with PE who are likely to die, develop circulatory shock, or progress to respiratory failure in the first week. The criteria in Table 87-4 facilitate the identification of these high-risk patients. In the absence of a contraindication to thrombolytic therapy (see Chapter 94 ), a patient with even one documented episode of systolic hypotension, persistent hypoxemia, an elevated troponin, or an elevated plasma concentration of brain natriuretic peptide likely would benefit from thrombolytic therapy. If possible, consultation with cardiology or cardiac surgery should be obtained before administering fibrinolytic therapy for patients with PE who are not in extremis. The Food and Drug Administration–approved regimens for thrombolysis are shown in Table 87-5 . Table 87-5 -- Food and Drug Administration–Approved Fibrinolytic Regimens for Acute Treatment of Pulmonary Embolism Streptokinase

1 million U infused over 24 hr

Urokinase

1 million U bolus followed by 24-hr infusion at 300,000 U/hr

Alteplase

15-mg bolus followed by 2-hr infusion of 85 mg. Discontinue heparin during infusion

The clinical course of patients with obstructive PE can be unpredictable. Many patients with massive PE remain stable in the emergency department. Other patients “look fine” on arrival, but progressively deteriorate over hours as right ventricular function declines. Three percent of emergency department patients have no hypotension while in the emergency department, but experience cardiac arrest and die within 24 hours.[11] A patient can be stable and then hypotensive within minutes because of the effect of variable right ventricular outflow obstruction from a large clot perched in the main pulmonary artery. The massive filling defect illustrated in Figure 87-4 represents a huge PE in a 19-year-old woman from our emergency department who would develop severe hypotension with cyanosis when supine, but was normotensive without severe distress when sitting upright. Additional mechanisms of rapid instability include

Page 1530

new embolization of clot material, release of mediators of pulmonary vasospasm, sudden brady-asystolic arrhythmias, or respiratory failure. Clues to oncoming cardiopulmonary decompensation include worsening respiratory distress and worsening hypoxemia, a rising shock index (the heart rate divided by the systolic blood pressure), systolic arterial blood pressure less than 90 mm Hg, and syncope or a seizure-like convulsive episode while in the emergency department. A particularly ominous finding is the evolution on ECG from a narrow-complex tachycardia to an incomplete right bundle branch block to a complete right bundle branch block ( Figure 87-5 ). This progression (or regression) is evidence of life-threatening pulmonary hypertension and incipient cardiac arrest.[21]

Figure 87-4 Massive pulm onary em bolism observed on a contrast-enhanced computed tom ography (CT) scan of the chest. This CT scan was obtained at the level of the bifurcation of the m ain pulm onary artery. The left m ain branch of the pulm onary artery shows a m assive filling defect (arrows). The patient was a young wom an who recently began taking oral contraceptive pills who presented to the em ergency departm ent after passing out at work after a 1-week duration of dyspnea. The clinicians had a high suspicion for pulm onary em bolism and ordered a CT scan imm ediately. The patient showed orthodeoxia and reverse orthostasis of blood pressure (hypoxemia and worsened hem odynam ic findings when supine). She was treated with anticoagulation and em ergent surgical em bolectom y and survived with excellent outcome. Her DNA was exam ined by polym erase chain reaction testing, and both alleles were found to have the factor V Leiden mutation.

A

B

Figure 87-5 A and B, Serial electrocardiogram s obtained 2 m inutes apart show the progression from a narrow com plex rhythm (A) to a right bundle branch block pattern (B) in a patient with massive bilateral pulm onary em boli. Shortly after the second tracing was obtained, the patient developed cardiovascular collapse refractory to vigorous resuscitation efforts.

Increasing arterial partial pressure of carbon dioxide with a decreasing pulse oximetry defines respiratory failure and predicts a clinical course heading toward respiratory arrest. Respiratory failure mandates endotracheal tube intubation using standard rapid sequence intubation with either ketamine or etomidate used for induction of anesthesia before neuromuscular blockade (see Chapter 1 ). Other induction agents that depress cardiac function or reduce preload may precipitate severe hypotension and should be avoided. In the case of impending respiratory or cardiac arrest, fibrinolytic therapy should be strongly considered. For patients with known floating thrombi in the right heart or for patients with severe refractory hypotension, surgery is the most likely intervention to save the patient's life. Surgical embolectomy requires extracorporeal cardiopulmonary bypass and an experienced cardiothoracic surgeon. Surgery may be the best option for patients who have severe PE with a contraindication to fibrinolysis; however, extracorporeal perfusion requires intensive heparin anticoagulation, and the patient's mental status cannot be monitored during surgery—a key concern in patients with high risk of intracranial hemorrhage. Catheter thrombectomy also may be lifesaving and can be performed in an awake patient, but requires that the patient be sent to the relatively uncontrolled environment of the interventional radiology suite. In the worst case, PE can cause cardiac arrest. In the prehospital setting, the arrest often initially appears to occur suddenly and unexpectedly. Most patients with incipiently fatal PE have overt respiratory distress, syncope or seizure, or a high heart rate relative to the systolic blood pressure before arrest. Compared with pure cardiac causes of arrest, a higher percentage of patients with arrest from PE have the initial arrest event witnessed, in particular by health care providers. First responders most commonly observe PEA as the initial cardiac arrest rhythm (>20 depolarizations per minute without palpable pulses). The mechanism for PEA seems to be pure right ventricular outflow obstruction complicated by impaired right ventricular contractility. Ultrasound performed during PEA arrest from PE usually shows weak cardiac contractions.

Page 1531

The second most common rhythm observed after arrest from PE is asystole, or an agonal escape type rhythm with less than 20 complexes per minute. Mechanisms for brady-asystolic arrest include septal wall tension leading to ischemia or ischemic-equivalent effect on the atrioventricular node and infranodal conducting pathways. Regardless of the initial rhythm, the development of pulselessness from PE imparts a horrendous mortality, exceeding 70% in published studies. Numerous case reports have suggested heroic results from bolus administration of thrombolytic therapy to patients with cardiac arrest from PE. Notwithstanding these reports, the goal is to administer fibrinolytic therapy before cardiac arrest supervenes. The administration of fibrinolytic therapy does not absolutely preclude surgical intervention. Patients who have been treated with a fibrinolytic agent can undergo sternotomy or thoracotomy for embolectomy and survive without fatal hemorrhage. The decision to perform embolectomy ultimately resides with the cardiac surgeon.

Unique Questions That Commonly Arise in the Emergency Department I cannot get imaging at night. Is it reasonable to treat the patient with heparin until morning? The short answer to this question is yes, if the patient has no contraindications. Many smaller hospitals routinely employ this method, using a single dose of enoxaparin. How do I deal with the patient who is being treated for pulmonary embolism who keeps returning to the emergency department for chest pain? If the patient has a therapeutic international normalized ratio (1.5 to 2.5) and returns with symptoms only (e.g., chest pain, dyspnea) and without syncope, appears relatively comfortable, has normal vital signs, and has no new changes suggesting pulmonary hypertension on ECG (in particular, no S1Q3T3 pattern and no T wave inversion in leads V1 through V4), follow-up imaging is probably not needed. Other causes of chest pain (especially acute coronary syndrome) must be considered (see Chapters 19 and 77 ). In the absence of an identified alternative diagnosis, symptomatic care with an anti-inflammatory agent is safe and reasonable therapy for the return complaint of chest pain. Persistent dyspnea at rest raises more concerns of unresolved or recurrent thrombosis with secondary effects, including bronchospasm or, worse, pulmonary vascular hyperplasia with pulmonary hypertension. Repeat pulmonary vascular imaging may provide evidence of unresolved or new clot. More importantly, a transthoracic echocardiogram can disclose evidence of persistent right ventricular dysfunction and pulmonary hypertension. Symptomatic patients with unresolved filling defects and pulmonary hypertension can progress to chronic thromboembolic pulmonary hypertension. To prevent this decline, patients who return to the emergency department with persistent rest dyspnea and have unresolved filling defects and pulmonary hypertension should be admitted or referred to a pulmonologist or pulmonology clinic that has a program that offers the option of pulmonary thrombectomy. How can I rule out pulmonary embolism in a pregnant patient without use of ionizing radiation? PE is the most common nontraumatic cause of death in pregnant women, so clinicians are justified to adopt a liberal “rule-out PE” approach to all pregnant women with dyspnea. Pulmonary V/Q scanning is safe in pregnancy and provides almost no risk to the fetus. A chest CT scan delivers about 250 mrad of energy, whereas the common threshold at which fetomaternal experts believe fetal teratogenicity becomes a concern is about 5 rad. The mother's abdomen can be shielded, but the fetus will still receive a small fraction of the 250 mrad. There is a rapidly growing body of literature that suggests that exposure of the young brain to even small amounts of radiation can produce subtle cognitive deficits later in life, and at present the long-term consequences of CT scanning of pregnant patients are unknown. It seems logical to try to rule out PE with the D-dimer in pregnant patients; if D-dimer is negative in a patient believed to be at low pretest probability, this excludes the diagnosis. Coagulation systems are hyperactive in pregnancy, elevating the circulating D-dimer concentration. The D-dimer concentration increases linearly with duration of normal pregnancy, and about 75% of all pregnant patients evaluated for PE have a D-dimer concentration greater than the abnormal cutoff of 500 ng/mL.[46] About 60% of healthy pregnant patients have a D-dimer less than 1000 ng/mL, however, and virtually all pregnant patients with a PE have a D-dimer greater than 1000 ng/mL. A reasonable interpretation of these data suggests the following approach. If the D-dimer concentration is less than 1000 ng/mL, and the patient meets the criteria in Box 87-2 , the diagnosis of PE may be considered reasonably excluded, and pulmonary vascular imaging is not necessary. As an additional margin of safety, a negative venous ultrasound of the lower extremities excludes DVT and helps reduce the probability of PE by about half. V/Q scanning, if normal, excludes the diagnosis. A high-probability V/Q scan establishes the diagnosis, and heparin (which does not cross the placental barrier) can be initiated. If neither normal nor high probability, the V/Q scan is nondiagnostic, and further imaging (perhaps beginning with venous duplex ultrasound of the legs) is indicated. How do I evaluate the patient with possible pulmonary embolism who is too obese to fit in a CT or V/Q scanner? When a patient weighs more than 400 lb, the imaging options become limited because many

Page 1532

CT and gamma scanner tables cannot accommodate body mass greater than 400 lb. We recommend an attempt to perform compression venous ultrasound of the lower extremities to rule out DVT. Although often technically suboptimal in a massively obese patient, venous ultrasound occasionally provides positive evidence of DVT, ostensibly clinching the diagnosis. Another option is to decide to anticoagulate empirically based on a moderate-to-high pretest probability and a D-dimer concentration that exceeds 1000 ng/mL. The adequate regimen for anticoagulation is uncertain, but many experts recommend subcutaneous enoxaparin, 1 mg/kg of actual body weight up to a maximum of 200 p-/kg.

KEY CONCEPTS {,

{,

{,

Dee p vein thro mbo sis often pres ents as a cra mpy sens ation in the calf. “Sud den onse t” is usel ess as a discr imin ator for pres ence or abse nce of PE. A D-di mer conc entra tion 1000 mg/dL)

Obstructive Biliary tract disease Ampullary tumors Pancreas divisum with obstruction of the accessory duct Periampullary duodenal diverticula ERCP and postpancreatography Pancreatic neuroendocrine tumors Pancreatic carcinoma Sphincter of Oddi fibrosis, stricture, tumor, or hypertension

Infectious

Viral Adenovirus Coxsackievirus CMV EBV Echovirus Hepatitis A, B, C virus HIV Varicella Rubella

Other Infections Aspergillus

Page 1617

Campylobacter Clonorchiasis Cryptococcus Cryptosporidium Dysentery MAI Mumps Mycobacterium TB Mycoplasma sp. Legionella sp. Leptospirosis Salmonella typhimurium Scarlet fever Streptococcal food poisoning Toxoplasma Tuberculosis Ascariasis

Other Etiologies Diabetic mellitus, DKA Crohn's disease Cystic fibrosis Emboli (atherosclerotic) Hemochromatosis Hereditary pancreatitis Hypothermia Vasculitis Lupus Polyarteritis nodosa, malignant hypertension Ischemia from hypoperfusion Perforated ulcer Postoperative Pregnancy Reye's syndrome Trauma Uremia Idiopathic Alcohol is the cause of about 35% of pancreatitis cases. The mechanism by which alcohol is toxic to the pancreas is not well understood. Possible mechanisms include toxic effects of the ethanol metabolite acetaldehyde, ethanol-related lipid metabolism, or spasm of the sphincter of Oddi. Patients with alcoholic pancreatitis have usually had 5 to 10 years of chronic alcohol use before the onset of pancreatitis.[] Underlying chronic pancreatitis may precede and follow exacerbations of acute pancreatitis. In addition to alcohol, a number of other medications and toxins cause pancreatitis, including didanosine, pentamidine, organophosphates, and selected scorpion bites. The list of definite and potential drugs causing pancreatitis is quite extensive ( Box 90-2 ). Another cause of pancreatitis is hypertriglyceridemia, with levels less than 500 mg/dL being implicated, although often the level is above 1000 mg/dL. In pregnancy, both gallstones and increased triglycerides levels can cause pancreatitis.[5] When this occurs, both maternal and fetal mortality is high (20%). BOX 90-2

Page 1618

Drug-Induced Pancreatitis

Definite Acet amin ophe n Azat hiopr ine Cim etidi ne Cispl atin Corti cost eroid s Dida nosi ne Eryt hro myci n Estr ogen s Ethyl alco hol Furo semi de l-Asp aragi nase Merc apto purin e Metr onid azol e Meth yldo pa Nitro furan toin Octr eotid e Orga noph

Page 1619

osph ates Pent amid ine Rani tidin e Tetr acyc line Salic ylate s Sulfo nami des, trime thopr im-s ulfa meth oxaz ole, sulfa sala zine Sulin dac Valpr oic acid

Possible Bum etani de Carb ama zepi ne Chlo rthali done Cloni dine Colc hicin e Cycl ospo rin Cyta rabin e Diaz

Page 1620

oxid e Enal april Ergo tami ne Etha cryni c acid Indo meth acin Isoni azid Isotr etino in Mefe nami c acid Opia tes Phe nfor min Pirox icam Proc aina mide Rifa mpin Thia zide s Both blunt and penetrating abdominal trauma can disrupt the ductal system and the pancreatic cells, setting off the enzyme cascade that results in acute pancreatitis. Pancreatitis may also develop in 1% to 10% of ERCP procedures, resulting from iatrogenic ductal injury.[22] Likewise, postoperative pancreatitis is well recognized and is associated with a higher mortality than other etiologies. Although both viral and bacterial etiologies for pancreatitis are known, the two most common viral causes of pancreatitis are mumps and Coxsackie B. Pancreatitis is more common in patients with human immunodeficiency virus (HIV) than in the general population.[22] In addition to the common etiologies, this population is at risk for pancreatitis from opportunistic infections, HIV-specific medications, and acquired immunodeficiency syndrome (AIDS)–related cancers.[] Ultimately, the cause of acute pancreatitis is idiopathic in about 10% of cases.[15] The etiology of pancreatitis in adults and children is similar, although incidences are different. Trauma (including child abuse), infection, and idiopathic causes make up 70% of the etiologies in children.[3] Hereditary pancreatitis is an autosomal dominant trait with the onset frequently noted during childhood. Other causes include infections and congenital anomalies.[25] In elders, gallstones are the most common cause of acute pancreatitis, causing up to 55% of the cases.[26]

Clinical Features Pancreatitis should be suspected in all patients with epigastric abdominal pain, regardless of age. When the

Page 1621

diagnosis has been made, the etiology and complications related to the disease should be sought. By history, almost all patients have abdominal pain, most commonly in the midepigastric area; however, the pain can also be in the right or left upper quadrant. If significant inflammation is present, the pain may be diffuse and the patient may have difficulty localizing the discomfort. Typically, the onset of symptoms is relatively rapid, and the symptoms increase in severity over 30 to 60 minutes. The pain is generally described as constant and severe and may radiate to the midback. The degree of pain does not correlate with the severity of disease. Even though gallstones are frequently the cause of pancreatitis, the onset of pain is not usually related to eating. Nausea and vomiting often accompany the pain. Although the discomfort may be improved by lying on the side or sitting up, more typically there is little relief with position change, moving, eating, vomiting, or bowel movement. Colicky pain or pain that waxes and wanes suggests another diagnosis. Approximately 50% of patients have a history of similar abdominal pain that may represent biliary colic or mild pancreatitis.[27] On physical examination, vital signs may be stable but are frequently abnormal. Hypotension, tachycardia, and shock indicate severe disease with complications or an alternative diagnosis. Vital signs may also be influenced by pain (tachycardia, tachypnea, hypertension) or alcohol withdrawal (tachycardia, hypertension, fever). A low-grade fever is present in about half of patients with pancreatitis after 1 to 3 days even in the absence of infection.[] High fever is uncommon during the acute presentation of pancreatitis because infection is generally a late complication. Pulse oximetry should be measured as acute hypoxia is an indicator of systemic complication and severe disease. Patients with pancreatitis generally appear restless and in moderate distress. They may be jaundiced if an obstructing stone is present. The cardiopulmonary examination may be significant for rales or diminished breath sounds if the patient is hypoventilating because of pain or if a pleural effusion is present. Observation of the abdomen may be normal or notable for distention. Only rarely is there evidence of blood within the peritoneum or retroperitoneum resulting from severe hemorrhagic pancreatitis. Blood within these areas is classically described by Cullen's sign (discoloration around the umbilicus) and Grey Turner's sign (discoloration of the flank). Auscultation of the abdomen may reveal normal, decreased, or absent bowel sounds depending on whether the patient has a concomitant ileus. Because the pancreas is a retroperitoneal organ, palpation of the abdomen generally reveals epigastric guarding, with rebound tenderness being a less common finding. Murphy's sign may be present if the pancreatitis developed secondary to a biliary source. Very rarely, the physician may see evidence of subcutaneous fat necrosis, which appears as red nodules most prominent on the extremities. Other physical findings such as the stigmata of alcoholism or xanthomas of hyperlipidemia may help point to the etiology of the pancreatitis.

Complications Complications are common and may be related to local damage as well as systemic injury. The multiorgan involvement arises from the direct release of pancreatic enzymes into the bloodstream and, perhaps more important, from the initiation of the systemic inflammatory response through mediators. Most of the major organ systems can be affected.[] Shock may result from multiple sources of volume loss. Fluid sequestration occurs in both the pancreas and the bowel lumen and wall. There may also be hemorrhage into necrotic pancreatic tissue. In addition, release of vasodilator and cardiodepressive substances may occur. About 18% to 30% of patients may have pulmonary complications, including (1) degradation of surfactant by pancreatic phospholipases; (2) pleural effusions (more commonly on the left and frequently with elevated amylase); (3) hypoxia from atelectasis, hypoventilation, and intrapulmonary shunting; and (4) ARDS. Although ARDS from the loss of surfactant as well as from the inflammatory mediators causing capillary leak is rare, it carries a 60% mortality.[6] Metabolic complications of pancreatitis include both hyperglycemia and hypocalcemia. Hyperglycemia is caused by decreased insulin and increased glucagon. Hypocalcemia is caused by (1) sequestration or saponification of calcium in areas of fat necrosis; (2) hypoalbuminemia, hypomagnesemia, and hyperglucagonemia; and (3) inactivation of parathyroid hormone. Coagulopathy develops from circulating proteases affecting the coagulation cascade. Acute tubular necrosis can cause acute renal failure and results from circulating inflammatory mediators or from hypotension and hypoperfusion. Late complications occur after the second week of illness and include local structure involvement, abscess

Page 1622

formation (1% to 4%), gastrointestinal bleeding from stress ulcers, splenic vein thrombosis, rupture of pancreatic pseudoaneurysms, fistula formation, splenic rupture, venous thrombosis, and right hydronephrosis.[5] Pancreatic pseudocysts develop in 1% to 8% of patients after 4 to 6 weeks and are more common in alcoholic pancreatitis ( Figure 90-2 ).[28] Long-term complications of pancreatitis include recurrent or chronic pancreatitis, diabetes mellitus, and digestive and malabsorption problems.

Figure 90-2 Pancreatic pseudocyst form ation. In this patient, the pseudocyst was so large as to compress the com m on bile duct, causing obstructive jaundice. GB, gallbladder; PP, pancreatic pseudocyst.

Diagnostic Strategies Laboratory Tests The diagnosis of acute pancreatitis and its differentiation from other abdominal disorders depend on careful clinical assessment in conjunction with abnormality of certain laboratory values and supportive radiographic findings. The elevation of amylase has been the cornerstone of the diagnosis of pancreatitis, although it is an imperfect assay. Amylase is an enzyme that cleaves carbohydrates. It is produced primarily in the salivary glands and pancreas, although it can also be found in small amounts in the fallopian tubes, ovary, testis, muscle, intestines, and other organs. Elevations of amylase may be seen in normal individuals as well as in ectopic pregnancy, macroamylasemia, parotitis, renal failure (decreased clearance), mesenteric ischemia, bowel obstruction or infarction, perforated duodenal ulcer, acute peritonitis from other causes, and other diseases.[ 29] Pancreatic amylase can be differentiated from these other sources by electrophoresis, a test that is not readily available in the emergency department. Because of the other nonspecific sources of amylase, elevations of amylase lack specificity for the diagnosis of pancreatitis [] In acute pancreatitis amylase rises within 6 to 24 hours and peaks in 48 hours, becoming normal in 5 to 7 days. Thus, sensitivity of amylase decreases after the first 24 to 48 hours. In addition to the unclear origin of amylase, there are several other limitations to using amylase to diagnose acute pancreatitis. The use of different assays and the lack of an international standard lead to varying measured levels of “normal” or “elevated” across institutions. Complicating matters, there is no universal “gold standard” to diagnose pancreatitis; amylase, autopsy, computed tomography (CT), and laparoscopy have all been used. Thus, amylase is commonly used as an imperfect standard with which to make the diagnosis of pancreatitis because of its low cost and rapid availability. However, it is difficult to determine the precise value of this test to the clinician trying to make the initial diagnosis, particularly in the presence of an unclear clinical presentation. According to one author, the sensitivity of amylase for the diagnosis of pancreatitis ranges from 79% to 95% depending on the comparative choice of gold standard test.[29] As expected, the sensitivity and specificity of amylase vary depending upon the cutoff value selected to make the diagnosis of pancreatitis. With a cutoff value of total amylase that is at the upper limit of normal, the sensitivity is 91% to 100%, but the specificity is 71% to 98%. Increasing the cutoff value to approximately three times the normal value increases the specificity to about 100% but decreases the sensitivity to as low as 61%.[31] The higher cutoff of amylase results in a related drop in sensitivity that is unacceptable for a serious disease such as acute pancreatitis. In up to 25% of patients with pancreatitis, especially in alcoholics and patients with hypertriglyceridemia or chronic pancreatitis, the amylase can be normal.[29] The emergency physician should be aware that mild amylase elevations in patients presenting with acute abdominal pain of unclear etiology, particularly in elders, should raise the suspicion of an acute surgical abdomen. Essentially, amylase levels alone, whether normal, mildly elevated, or extremely elevated, do not diagnose pancreatitis unless accompanied by the appropriate clinical picture. Lipase is a pancreatic enzyme that hydrolyzes triglycerides and has been used as both an adjunctive and an alternative test for the diagnosis of pancreatitis. Unfortunately, its use has many of the same pitfalls as amylase. In the presence of pancreatic inflammation, lipase increases within 4 to 8 hours and peaks at 24 hours. The levels stay elevated longer than those of amylase, falling over 8 to 14 days.[29] Lipase, like

Page 1623

amylase, exists in other tissues and tends to be elevated in similar clinical situations. Improved assays have rendered lipase more specific than amylase. Yet, there are still cases of nonpancreatic elevations of lipase, such as elevations with duodenal ulcers or bowel obstruction and idiopathic elevations.[] Comparisons between amylase and lipase are limited by the lack of a true gold standard for the diagnosis of pancreatitis as well as the choice of cutoff values used for the diagnosis. Despite these limitations, lipase is at least equally sensitive and probably more specific than amylase (specificity 80% to 99%). At five times the upper limits of normal, lipase is 60% sensitive and 100% specific. The use of two times the upper limit of normal for lipase has been recommended to decrease the possibility of missing the diagnosis of pancreatitis.[29] Using elevation of either amylase or lipase as evidence of disease increases the sensitivity but decreases the specificity. Requiring both levels to be elevated does the reverse. Several expert authors recommend using lipase over amylase when seeking the diagnosis, but this remains a point of debate, particularly when considering the entire differential diagnosis of pancreatitis.[] The degree of elevation of amylase or lipase is not a marker of disease severity.[] In a study of patients with pancreatitis, those with amylase elevation less than three times normal had the same severity of disease as those with higher elevations of amylase. In fact, alcoholics frequently have lower amylase levels but may develop more severe disease than nonalcoholic patients.[34] In a patient with prolonged abdominal pain or the history of pancreatitis, an elevated amylase for longer than a week may suggest pseudocyst or pancreatic abscess. Use of the amylase-to-lipase ratio has not proved helpful in the determination of a specific etiology of pancreatitis.[30] There are several new tests still under development to aid in diagnosis. However, at this time, none of these has yet proved useful in diagnosing acute pancreatitis.[] In evaluating a patient with abdominal pain, amylase or lipase levels, or both, along with other blood tests are necessary to narrow the differential, detect complications, and determine prognosis. With this in mind, additional testing should consist of a complete blood count (CBC), lactate dehydrogenase (LDH), and a comprehensive metabolic panel (including liver enzymes, calcium, renal function, and glucose). Patients with liver disease should have coagulation studies performed to determine the degree of liver dysfunction. Arterial blood gas tests should be used selectively in patients who are acidotic or hypoxic. Magnesium levels should be determined in alcoholics and in patients with electrolyte abnormalities. Both hypocalcemia and hyperglycemia are common in pancreatitis, with the hyperglycemia resulting from glucagon and insulin abnormalities. Calcium is best determined using the ionized calcium level. Serum calcium is falsely lowered because of low albumin levels that may be present in patients with pancreatitis. The creatinine and blood urea nitrogen may indicate both the presence of hypovolemia and renal involvement. Elevation in liver enzymes may result from a biliary etiology of pancreatitis or from other diseases of the liver or biliary tract. In addition, liver enzymes may increase from the pressure on the common bile duct that results from the surrounding pancreatic inflammation. Mild elevations of bilirubin are common in all types of pancreatitis as well as many other liver disorders. For the patient diagnosed with pancreatitis, higher elevations of aspartate transaminase (AST) and LDH are related to a worse prognosis according to Ranson's criteria. When liver enzymes are elevated, the pattern of elevation may help determine the etiology of the pancreatitis ( Table 90-1 ). Alanine aminotransferase (ALT) is the best single marker for biliary etiology; levels greater than three times baseline support the diagnosis of biliary pancreatitis.[] The higher the elevation of ALT, the greater the specificity and predictive value for gallstones. ALT levels more than 150 IU/L have 96% specificity, positive predictive value of 95%, and 48% sensitivity for gallstone pancreatitis. Significant rises in AST, alkaline phosphatase, and bilirubin are also more likely to be related to biliary pancreatitis but are not as sensitive as ALT.[35] Table 90-1 -- Sensitivity and Specificity for the Etiology of Pancreatitis of Liver Enzymes[35] Sensitivity (%) Specificity (%) PPV (%) ALT >150 mmol/L AST Alkaline phosphatase >300 units/L Bilirubin 2.8 mg/dL

48 44 24

96 95 95

95 87 87

38

93

89

Page 1624

Sensitivity (%)

Specificity (%)

PPV (%)

ALT, alanine aminotransferase; AST, aspartate transaminase; PPV, positive predictive value.

The CBC may be notable for an elevated white blood cell count and the hematocrit may be either high or low. Early in the course, the hematocrit may be elevated because of third space volume loss. A decrease in hematocrit is a poor prognostic factor because it indicates intra-abdominal hemorrhage and severe pancreatitis. An electrocardiogram should also be obtained early to determine whether the patient's abdominal pain may be cardiac in origin. There are several scoring systems for judging the prognosis for the patient with acute pancreatitis. The most commonly used are Ranson's criteria, which were developed in 1974 ( Box 90-3 ) and are a two-step list of primarily laboratory parameters, determined at admission and after 48 hours, to predict mortality from pancreatitis.[] Five criteria on admission note the degree of local inflammation, whereas the six criteria at 48 hours note the development of systemic complications. Ranson noted that the model did not work well for patients with gallstone pancreatitis and revised the criteria to reflect the improved mortality. Although Ranson's criteria have a 90% negative predictive value, the obvious drawback to the use of this system in the emergency department is that the scoring cannot be completed until 48 hours after diagnosis.[] Although it is a simple and well-known scoring system, relying on it may result in delayed recognition of illness severity.[21] The Acute Physiology and Chronic Health Evaluation (APACHE-II) system may also be used to judge severity.[] This score includes 12 physiologic variables, age, and chronic health status to generate a total point score. The score can be determined on admission and throughout the hospital stay. Different studies use different cutoff numbers to determine sensitivity and specificity. In one study, APACHE-II scores greater than 7 at admission indicated severe disease with a sensitivity of 68% and specificity of 67%.[39] A score greater than 13 is associated with a high likelihood of death.[5] An APACHE-III scoring system has also been developed and includes additional physiologic variables. However, a study did not find that it was better able to predict outcome in patients with acute pancreatitis.[41] The difficulty with the APACHE scores is that they are time consuming to calculate because they include multiple variables. Both the Ranson and APACHE scores are better in predicting for patients with disease of low to moderate severity. In severe disease the scoring system becomes less accurate.[12] In patients with AIDS, Ranson's criteria may not be as accurate because of HIV-induced changes in laboratory values such as calcium and LDH.[] BOX 90-3 Ranson's Criteria AST, aspartate transaminase; BUN, blood urea nitrogen; LDH, lactate dehydrogenase; WBC, white blood cells.

At Admission Age >55 year s WB C >16, 000/ mm [ 3]

Gluc ose >200

Page 1625

mg/d l LDH >350 IU/L AST >250 SF units

Substitute if Gallstone Induced Admission Age >70 year s WB C >18, 000/ mm [ 3]

Gluc ose >220 mg/d L LDH >400 IU/L AST >250 SF units

Add the Total Number of Signs at 48 Hours 0-3 3-4 5-6 >7

Within 48 Hours of Admission Hem atocr it fall >10 % BUN rise >5 mg/d

Page 1626

L Calci um 6 L

Within 48 Hours of Admission Hem atocr it fall >10 % BUN rise >2 mg/d L Calci um 5 mEq /L Fluid sequ estra tion >4 L

Mortality 1% 15%

Page 1627

40% 100 % Because numerous factors contribute to disease severity and prognosis in patients with acute pancreatitis, an expert consensus of gastroenterologists has developed a uniform definition for severe pancreatitis.[15] This definition includes extensive local injury or systemic complications ( Box 90-4 ), a level greater than 2 on Ranson's criteria at 48 hours, or an APACHE score greater than 7.[] Again, because some markers of severity do not develop until later in the disease course, the search continues for early methods to detect patients who have a high risk for clinical deterioration. Several laboratory tests such as serum C-reactive protein, urinary trypsinogen activation peptides, and interleukins are still being evaluated and show some promise.[] BOX 90-4 Severe Pancreatitis ARDS, adult respiratory distress syndrome; DIC, disseminated intravascular coagulation; FSP, fibrin split products.

Local Complications of the Pancreas Pse udoc yst Rela ted ascit es Fistu la Pan creat ic necr osis

Systemic Complications Infec tion (by cultu re) Refr actor y hypo tensi on Ren al failur e (cre atini ne >2.0 mg/d

Page 1628

L if no renal insuf ficie ncy or rise >1 mg/d L) New onse t pulm onar y insuf ficie ncy (O2 satur ation 100 (100–180)

40–80

60–70 (45–55)

100 (100–180)

2. The approach to newborn resuscitation focuses almost entirely on respiratory, not cardiac, management. 3. Equipment needs are specific owing to the infant's size.

PATHOPHYSIOLOGY Transition from Fetal to Extrauterine Life The successful transition from the fetal to the extrauterine environment requires two major cardiorespiratory changes: (1) removal of fluid from unexpanded alveoli to allow ventilation and (2) redistribution of cardiac output to provide lung perfusion. Failure of the development of either adequate ventilation or adequate perfusion leads to shunting, hypoxia, and ultimately reversion to fetal physiology.[1] In utero, the pulmonary alveoli are filled with pulmonary fluid. Removal of this fluid is partially accomplished by vaginal delivery, which compresses the fluid into the bronchi, trachea, and pulmonary capillary bed. Most pulmonary fluid is removed by the first few breaths; the amount of fluid removed depends on the forcefulness of these breaths. Expansion of alveoli requires the generation of high intrathoracic pressures and the presence of surfactant to maintain alveolar patency. The quality of the first few breaths is crucial to the establishment of adequate ventilation. The fetal lung is poorly perfused. Because the pulmonary arterial bed is intensely vasoconstricted, the fetal lung receives only 40% of the right ventricular cardiac output; most of the right ventricular output is shunted from the pulmonary artery through the ductus arteriosus to the descending aorta. After the first few breaths, with exposure to diffused alveolar oxygen, pulmonary vascular resistance decreases. The fetal shunt through the ductus arteriosus reverses as systemic vascular resistance increases, then the shunt ceases by 15 hours of age as the ductus also constricts. This reversal of flow allows all right ventricular output to perfuse the lungs. If hypoxia or severe acidosis occurs, however, the muscular pulmonary vascular bed

Page 1733

constricts again, and the ductus may reopen. The reinstitution of fetal circulation, with its attendant shunting, leads to ongoing hypoxia and is termed persistent fetal circulation. The role of the resuscitator is to facilitate the first few breaths, prevent and reverse ongoing hypoxia and acidosis, and assist the newborn in the transition to extrauterine life.

Neonatal Responses Hypoxia The newborn's clinical response to severe hypoxia is unique.[3] In utero or intrapartum asphyxia (pathologic lack of oxygen to the fetus before or during delivery) precipitates a sequence of events termed primary apnea and secondary apnea. After initial hypoxia, the infant has rapid gasping, followed by cessation of respirations (primary apnea) and a decreasing heart rate. At this point, only simple stimulation and oxygen are needed to reverse bradycardia and assist the development of ventilation. With ongoing asphyxia, however, the infant takes several final deep, gasping respirations, followed by secondary apnea, worsening bradycardia, and decreasing blood pressure. More vigorous and prolonged resuscitation is needed to restore ventilation and an adequate circulation. Apnea in the newborn should be assumed to be secondary apnea and treated rapidly with ventilatory assistance. The presence of respirations may not ensure adequate ventilation. In addition, signs of hypoxia (e.g., cyanosis, lethargy, unresponsiveness) may have other causes. Bradycardia in the newborn (heart rate 500 mg in 24 hours). When differentiating between proteinuria produced by renal parenchymal disease and that simply produced by admixture of urine with extravasated blood, a useful rule of thumb is that 1 mL of whole blood contains approximately 5 billion RBCs and approximately 50 mg of albumin. BOX 96-2 Causes of Hematuria

Hematologic Coa gulo path y Sickl e hem oglo bino pathi es Renal (glomerular) Prim ary glom erula r dise ase Multi syst em dise ase (e.g., syst emic lupu s eryth emat osus , Hen ochSch önlei n purp ura,

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hem olytic ure mic synd rom e, poly arteri tis nodo sa, Weg ener' s gran ulom atosi s, Goo dpas ture' s synd rom e) Renal (nonglomerular) Ren al infar ction Tube rculo sis Pyel onep hritis Poly cysti c kidn ey dise ase Med ullar y spon ge kidn ey Acut e inter stitial neph ritis Tum or

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Vasc ular malf orm ation Trau ma Papil lary necr osis Postrenal Ston es Tum or of urete r, blad der, ureth ra Cysti tis Tube rculo sis Pros tatiti s, ureth ritis Fole y cath eter plac eme nt Exer cise Beni gn prost atic hype rtrop hy Table 96-2 -- Most Common Causes of Hematuria by Age 60

VG UTI Stone Carcinoma (bladder, kidney)

Page 1815

Adapted from Restropo NC, Carey PO: Evaluating hematuria in adults. Am Fam Physician 40:149, 1989. BPH, benign prostatic hyperplasia; UTI, urinary tract infection.

The evaluation of the emergency department patient who has gross or microscopic hematuria should begin with a complete history so that the pattern and character of the hematuria can be defined. Blood noted only on initiation of voiding suggests a urethral source, whereas blood noted only in the last few drops of urine suggests a prostatic or bladder neck source. Total hematuria (i.e., hematuria present throughout urination) suggests a source in the bladder, ureter, or kidney. Brown or smoky-colored urine usually has a renal source. Blood clots indicate a nonglomerular renal or lower urinary tract source of bleeding. Hematuria may rarely be cyclic or associated with menses, suggesting endometriosis of the ureter or bladder. Flank pain suggests calculus, neoplasm, renal infarction, obstruction, or infection as cause. Symptoms of frequency, dysuria, or suprapubic pain suggest cystitis or urethritis; in adult men, perineal pain, dysuria, and terminal hematuria suggest prostatitis. Other clues to the cause should be sought by careful questioning. Because glomerulonephritis or interstitial nephritis may be caused by a variety of bacterial, viral, and parasitic infections, a history of recent infection is important. In particular, a recent sore throat suggests the possibility of poststreptococcal glomerulonephritis; a history of foreign travel or residence abroad may suggest schistosomiasis or tuberculosis. Symptoms suggestive of a multisystem disorder (e.g., systemic lupus erythematosus) should also be sought, as should a history of human immunodeficiency virus infection.[7] Because drugs may cause acute interstitial nephritis (AIN),[8] papillary necrosis, or hemorrhagic cystitis, a complete medication history should be elicited. When hematuria is associated with anticoagulant use, significant underlying disease can be identified in at least 70% of patients.[9] The family history should be elicited because it may provide a clue to the presence of polycystic or other familial kidney disease, sickle cell disease, or renal calculi. A history of strenuous exercise is important; 15% to 20% of normal individuals exhibit hematuria after strenuous exercise. The mechanism is unclear, but the hematuria resolves spontaneously within a few days.

Clinical Features On physical examination, findings of arthritis, skin lesions, hypertension, or edema suggest underlying glomerulonephritis. Because endocarditis or atrial fibrillation may cause renal embolism, the physician should check for a new heart murmur or an irregular rhythm. Costovertebral angle tenderness suggests pyelonephritis or stone disease, and a palpably enlarged kidney suggests polycystic kidney disease or renal malignancy. The prostatic examination may offer clues to the presence of prostatitis, benign prostatic hypertrophy, or cancer. Examination of the external genitalia may reveal a urethral meatal lesion that may be the source of bleeding; in adult women, a pelvic examination should be performed to exclude vulvovaginal sources of blood.

Laboratory Evaluation of hematuria in the emergency department should include assessment of the blood pressure and measurement of the BUN and serum creatinine levels to gauge the patient's underlying renal function, but urinalysis can be expected to provide more specific information. Red urine that is dipstick negative and free of red cells on microscopy may be caused by ingestion of beets, red berries, or food coloring; by urate crystals; or by drugs such as phenazopyridine (Pyridium) and rifampin. A finding of red cell casts, other casts, or lipiduria or significant proteinuria in combination with hematuria suggests intrinsic renal disease, and appropriate referral should be made. (The urine should be examined as soon as possible after voiding because structures such as red cell casts may disintegrate over time.) Microscopic hematuria usually does not produce a positive dipstick test result for protein, but gross hematuria may contribute enough protein to cause a positive result; thus, a finding of proteinuria should be confirmed and the amount quantitated in a 24-hour urine collection. Hematuria in combination with pyuria or bacteriuria suggests UTI; infection should be treated and hematuria reassessed after therapy has been completed. Even if white cells or organisms are not seen on urinalysis, the urine should be cultured to rule out hemorrhagic cystitis, especially when lower tract symptoms are present. Eosinophiluria (appreciable on Wright's stain or Hansel's stain of the urine sediment) suggests AIN. Blood studies should be ordered only as necessary to gauge renal function and to confirm causes suggested by the clinical presentation. In the emergency department, routine ordering of the full gamut of chemical and serologic studies necessary to rule out all possible causes of hematuria is rarely appropriate.

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In particular, a platelet count and coagulation studies are extremely unlikely to be helpful in the absence of a suggestive history or other specific clinical clues.

Radiography and Ultrasonography The role of urinary tract imaging studies in the immediate evaluation of hematuria is also limited. Visualization of the urinary tract is generally helpful only when the history suggests renal colic or other disorders of the upper urinary tract (e.g., polycystic kidney disease, tumor, or obstruction). Helical CT scanning without contrast has emerged as the imaging modality of choice.[] Ultrasonography can be used to determine kidney size and shape and to detect renal masses or obstruction. Further imaging studies, if indicated, should be planned after urologic consultation. If no upper tract lesions are identified on initial imaging studies, cystoscopy is usually the next step in evaluation because it is the most effective means of visualizing the bladder and the male urethra. It is the initial study of choice for patients with active gross hematuria; in fact, some urologists prefer to perform endoscopic procedures promptly during an acute bleeding episode to maximize the chance of localizing the source. In older patients whose urinalysis shows only hematuria and whose history and physical examination are otherwise unhelpful, urinary cytologic examination may also be undertaken. Patients with hematuria who have no other abnormality revealed by urinalysis; who are otherwise asymptomatic; who are not azotemic, hypertensive, or severely anemic; and who have no evidence of intrinsic renal disease may be monitored as outpatients. (A possible exception may be the patient with a known bleeding disorder.) Others should generally be admitted to the hospital for prompt evaluation. Extensive outpatient evaluation of an isolated episode of hematuria is usually not undertaken in patients younger than 40 years unless hematuria is persistent, but most patients older than 40 should undergo a thorough evaluation after even a single episode of hematuria. The cause of hematuria can be determined on initial medical and urologic evaluation in 70% to 80% of cases. In others, a diagnosis of small calculi, occult bladder tumor, arteriovenous malformation, or early glomerulonephritis is made only after repeated examination or the development of further signs or symptoms. In 5% to 10% of cases no cause can be determined.

Approach to Proteinuria Principles of Disease During a 24-hour period, the kidneys normally filter 180 L of plasma containing approximately 12 kg of protein. The 1 to 2 L of urine produced from this filtrate contains only 40 to 80 mg of protein in normal individuals. Abnormal proteinuria is defined as excretion of more than 150 mg per 24 hours in adults or more than 140 mg/m[2] per 24 hours in children. Patients with mild to moderate degrees of proteinuria are commonly identified incidentally on routine urinalysis; patients with more severe degrees of proteinuria often seek medical attention because of edema or other effects of hypoproteinemia. Proteinuria may be classified broadly as glomerular or tubular. Glomerular proteinuria, the more common type, results from increased permeability of the glomerular capillaries to plasma proteins. With alteration in the glomerular capillary barrier (e.g., with the nephrotic syndrome and the many varieties of primary and secondary glomerulonephritis), albumin and globulins, which under normal circumstances are restricted from the glomerular ultrafiltrate because of their ionic charge and size, are lost into the urine. Protein losses of 10 g or more per day are not uncommon. Tubular proteinuria occurs in patients with normal glomeruli when the smaller proteins that are normally filtered at the glomerulus and then reabsorbed in the tubule appear in the urine because of tubular or interstitial abnormality. This occurs in disorders such as urinary tract obstruction, sickle cell disease, and other causes of acute or chronic interstitial nephritis. In these disorders, daily urinary protein losses rarely exceed 2 g. The term overflow proteinuria refers to the urinary loss of small proteins that are present in the blood in excessive concentrations and appear in the glomerular filtrate in amounts exceeding the normal tubular reabsorptive capacity (e.g., the light chains produced in multiple myeloma). Miscellaneous causes of transient proteinuria include exertion, stress, and fever. Low-grade proteinuria can occur during an otherwise normal pregnancy. Orthostatic proteinuria is characterized by the occurrence of proteinuria during periods when the patient is upright but not during recumbency; the condition is usually transient and benign. However, persistent proteinuria is a marker for renal disease even in the absence of azotemia or an abnormal urine sediment. Excretion of more than 2 g of protein in 24 hours is likely to be caused by a glomerular process, whereas excretion of less than 2 g is typical of tubular overflow or orthostatic proteinuria. In the nephrotic syndrome,

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protein losses exceed the liver's capacity to synthesize albumin and result in hypoalbuminemia. This leads to decreased plasma oncotic pressure and accumulation of edema fluid in the extravascular interstitial space. Increased aldosterone secretion and further retention of salt and water ensue. Thus, edema is the clinical hallmark of the nephrotic syndrome and is often the initial complaint of patients who have significant proteinuria. Edema ranges in severity from mild dependent peripheral edema or periorbital swelling to frank anasarca with pleural effusions and ascites. Nephrotic-range proteinuria is defined arbitrarily as being greater than 3.5 g per 24 hours. Patients with the nephrotic syndrome are at increased risk for thromboembolic events, including deep venous thrombosis of the lower extremity, renal vein thrombosis, and pulmonary embolism. The reason for this propensity appears to be a hypercoagulable state that may be related in part to urinary loss and decreased plasma levels of antithrombin III, proteins, and fibrinolytic factors.[1] Hyperlipidemia is another typical feature of the nephrotic syndrome; the mechanism is thought to be related indirectly to hypoalbuminemia and decreased oncotic pressure or viscosity. However, the major clinical significance of the nephrotic syndrome is that it indicates the presence of an underlying renal process or systemic disease affecting the glomerulus ( Box 96-3 ). BOX 96-3 Causes of the Nephrotic Syndrome

Primary Renal Disease  

Multisystem Disease Diab etes melli tus Colla gen vasc ular dise ase Syst emic lupu s eryth emat osus Rhe umat oid arthri tis Hen ochSch önlei n purp ura Poly arteri tis nodo sa Weg

Page 1818

ener' s gran ulom atosi s Amyl oido sis Cryo glob uline mia

Drugs and Toxins Hero in Capt opril Heav y meta ls Non stero idal anti-i nfla mm atory drug s Peni cilla mine Othe rs

Allergens  

Infection Bact erial Infec tive endo cardi tis Post strep toco ccal

Page 1819

Syph ilis Viral Hep atitis B Hum an imm unod efici ency virus Cyto meg alovi rus Prot ozoa l Mala ria Toxo plas mosi s

Malignancy Solid tumo rs Multi ple myel oma Lym pho ma Leuk emia

Miscellaneous Here ditar y neph ritis Pree clam psia Malig nant hype

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rtens ion Refl ux neph ropat hy Tran spla nt rejec tion

Clinical Features Evaluation of the patient with proteinuria focuses not only on gauging the severity of proteinuria and the likelihood of complications but also on identifying any associated signs of underlying renal disease or systemic illness. One should seek to elicit a history of recent illnesses (including pharyngitis), use of medications or drugs, or a past history of proteinuria, hypertension, edema, or renal disease. In young female patients, the possibility of pregnancy should be kept in mind because pregnancy can exacerbate previously inapparent renal disease; in late pregnancy, proteinuria may be the first sign of preeclampsia. Clues to the presence of systemic diseases that commonly affect the kidneys (e.g., diabetes or collagen vascular disease) should be sought as well. On physical examination the emergency physician should evaluate the blood pressure, note the presence or absence of edema, and assess for signs of systemic disease or renal insufficiency.

Laboratory The laboratory evaluation of the patient with proteinuria should include urinalysis and measurement of the BUN and serum creatinine. Special attention should be given to detecting lipiduria in the form of oval fat bodies (desquamated fat-laden renal epithelial cells), fatty casts, or free fat droplets. The identification of lipiduria is made easier by the characteristic appearance of lipid droplets when viewed under the polarizing microscope (“Maltese crosses”) (see Figure 96-1E ). Although the finding of isolated proteinuria may or may not be clinically important, proteinuria is almost always significant when it occurs in combination with hematuria. RBCs and red cell casts suggest glomerulonephritis; proteinuria with pyuria may be seen with AIN. The combination of proteinuria and glycosuria suggests diabetic nephropathy. A 24-hour urine collection should be ordered to provide an accurate measure of GFR and to quantitate protein excretion. Abnormal findings on the history, physical examination, or laboratory evaluation greatly increase the probability of the presence of significant renal disease, and early referral to an internist or nephrologist is indicated. However, in the absence of edema, azotemia, hypertension, active urine sediment, or known systemic illness affecting the kidney, patients with proteinuria may be referred to their primary care provider for follow-up observation. Because transient, mild proteinuria is not uncommon in healthy individuals, patients with mild proteinuria indicated by dipstick (particularly if the urine is concentrated) should have dipstick testing repeated at follow-up observation before further evaluation is undertaken. Persistent proteinuria may require referral to a nephrologist; in some cases renal biopsy is necessary to establish a diagnosis and guide management.

ACUTE RENAL FAILURE Perspective ARF is a generic term used to describe a precipitous decline in kidney function. Its hallmark is progressive azotemia caused by the accumulation of nitrogenous end products of metabolism, but this is commonly accompanied by a wide range of other disturbances depending on the severity and duration of renal dysfunction. These include metabolic derangements (e.g., metabolic acidosis and hyperkalemia), disturbances of body fluid balance (particularly volume overload), and a variety of effects on almost every organ system ( Box 96-4 ). BOX 96-4 Clinical Features of Acute Renal Failure

Cardiovascular

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Pul mon ary ede ma Arrh ythm ia Hype rtens ion Peri cardi tis Peri cardi al effus ion Myo cardi al infar ction Pul mon ary emb olis m

Metabolic Hypo natre mia Hype rkale mia Acid osis Hypo calc emia Hype rpho spha temi a Hype rma gnes emia Hype ruric

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emia

Neurologic Aste rixis Neur omu scul ar irrita bility Ment al statu s chan ges Som nole nce Com a Seiz ures

Gastrointestinal Nau sea Vomi ting Gast ritis Gast rodu oden al ulcer s Gast roint estin al blee ding Pan creat itis Maln utriti on

Hematologic

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Ane mia Hem orrh agic diath esis

Infectious Pne umo nia Septi cemi a Urin ary tract infec tion Wou nd infec tion From Brady HR, Brenner BM, Clarkson MR, Lieberthal W: Acute renal failure. In Brenner BM: The Kidney, 6th ed. Philadelphia, WB Saunders, 2000, pp 1201-1246.

The causes of ARF may be divided into those that decrease renal blood flow (prerenal), produce a renal parenchymal insult (intrarenal), or obstruct urine flow (obstructive or postrenal ARF). Identification of either a prerenal or a postrenal cause of ARF generally makes the prompt initiation of specific corrective therapy possible; if these two broad categories of ARF can be excluded, an intrarenal cause is implicated. The renal parenchymal causes of ARF can be usefully subdivided into those primarily affecting the glomeruli, the intrarenal vasculature, or the renal interstitium.[5] The term acute tubular necrosis denotes another broad category of intrinsic renal failure that cannot be attributed to specific glomerular, vascular, or interstitial causes ( Figure 96-3 ).[5]

Figure 96-3 Evaluation of azotem ia.

Principles of Disease Prerenal Azotemia Decreased renal perfusion that is sufficient to cause a decrease in the GFR results in azotemia. The possible causes can be grouped into entities causing intravascular volume depletion, volume redistribution, or decreased cardiac output ( Box 96-5 ). Individuals who have preexisting renal disease are particularly sensitive to the effects of diminished renal perfusion.

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BOX 96-5 Causes of Prerenal Azotemia

Volume Loss Gast roint estin al: vomi ting, diarr hea, naso gastr ic drain age Ren al: diure sis Bloo d loss Inse nsibl e loss es Third spac e sequ estra tion Pan creat itis Perit oniti s Trau ma Burn s

Cardiac Myo cardi al infar ction Valv ular dise

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ase Card iomy opat hy Decr ease d effec tive arteri al volu me Antih ypert ensi ve medi catio n Nitra tes

Neurogenic Sep sis Anap hylax is Hypo albu mine mia Nep hroti c synd rom e Liver dise ase Prerenal azotemia is characterized by increased urine specific gravity, BUN/creatinine ratio greater than 10:1, UNa concentration less than 20 mEq/dL, and FENa less than 1%. The condition can generally be corrected readily by expanding extracellular fluid volume, augmenting cardiac output, or discontinuing vasodilating antihypertensive drugs. However, severe prolonged prerenal azotemia can eventuate in ATN. Patients who have congestive heart failure (CHF) or cirrhosis form an important subset of those with prerenal azotemia. These individuals are often salt overloaded and water overloaded, yet their effective intra-arterial volume is decreased. Administration of diuretics has the potential to decrease intravascular volume further, resulting in decreased glomerular filtration and prerenal azotemia. For some patients with advanced CHF or hepatic disease, a state of chronic stable prerenal azotemia may be the best achievable compromise between symptomatic volume overload and severe renal hypoperfusion.[13] Glomerular perfusion may also be decreased in patients with normal intravascular volume and normal renal

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blood flow who take angiotensin-converting enzyme (ACE) inhibitors or, more commonly, prostaglandin inhibitors. All nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, inhibit prostaglandin synthesis. Renal vasodilator prostaglandins are critical in maintaining glomerular perfusion in patients with conditions such as CHF, chronic renal insufficiency, and cirrhosis, in which elevated circulating levels of renin and angiotensin II act to diminish renal blood flow and GFR. In this setting, decreased production of vasodilator prostaglandins may result in acute intrarenal hemodynamic changes and a reversible decrease in renal function. This phenomenon is also seen with the newer, selective cyclooxygenase 2 inhibitor class of NSAIDs.[] Other risk factors include advanced age, diuretic use, renovascular disease, and diabetes. This entity is distinct from other renal complications of NSAIDs, including interstitial nephritis and papillary necrosis. Renal insufficiency secondary to NSAIDs is generally reversible after cessation of the causative agent. For patients who are at increased risk but require treatment with NSAIDs, a short-acting preparation (e.g., ibuprofen) should be prescribed and follow-up monitoring of renal function and serum potassium level should be undertaken in days rather than weeks. If renal function is unchanged after a short course of treatment, adverse effects from continuing therapy are unlikely, although other potential mechanisms for the production of renal dysfunction (e.g., interstitial nephritis) should be kept in mind.

Postrenal (Obstructive) Acute Renal Failure Obstruction is an eminently reversible cause of ARF and should be considered in every patient with newly discovered azotemia or worsening renal function. Obstruction may occur at any level of the urinary tract but is most commonly produced by prostatic hypertrophy or by functional bladder neck obstruction (e.g., secondary to medication side effects or neurogenic bladder) ( Box 96-6 ). Intrarenal obstruction may result from intratubular precipitation of uric acid crystals (e.g., with tumor lysis), oxalic acid (as in ethylene glycol ingestion), myeloma proteins, methotrexate, sulfadiazine, acyclovir, or indinavir.[16] Bilateral ureteral obstruction (or obstruction of the ureter of a solitary kidney) may be caused by retroperitoneal fibrosis, tumor, surgical misadventure, stones, or blood clots. A sudden deterioration of renal function in the setting of diabetes mellitus, analgesic nephropathy, or sickle cell disease should suggest papillary necrosis. BOX 96-6 Causes of Postrenal Acute Renal Failure

Intrarenal and Ureteral Kidn ey ston e Slou ghed papill a Malig nanc y Retr operi tone al fibro sis Uric acid or oxali c acid cryst al preci

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pitati on Sulfo nami de, meth otrex ate, acyc lovir, or indin avir preci pitati on

Bladder Kidn ey ston e Bloo d clot Pros tatic hype rtrop hy Blad der carci nom a Neur ogen ic blad der

Urethra Phi mosi s Stric ture Treatment of postrenal ARF consists of relief of the obstruction. In the absence of infection, full renal recovery is said to be possible even after 1 to 2 weeks of total obstruction, although the serum creatinine level may not return to baseline for several weeks. Because the onset of irreversible loss of renal function with obstruction appears to be gradual, a few days' delay in diagnosis is generally considered acceptable. Still, common sense dictates that obstructions should be detected and relieved as expeditiously as possible.

Intrinsic Acute Renal Failure

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Of the specific intrarenal disorders that cause ARF, glomerulonephritis, interstitial nephritis, and abnormalities of the intrarenal vasculature are amenable to specific therapy and thus should be carefully considered as possible causes. However, these entities are responsible for only 5% to 10% of cases of ARF in adult inpatients; most are due to ATN. The incidence of glomerular, interstitial, and small vessel disease is much greater in adults who develop ARF outside the hospital. In children, these entities account for approximately half the cases of ARF ( Box 96-7 ).[5] BOX 96-7 Intrinsic Renal Diseases That Cause ARF ARF, acute renal failure; HIV, human immunodeficiency virus; NSAID, nonsteroidal anti-inflammatory drug.

Vascular Large vessel Ren al arter y thro mbo sis or sten osis Ren al vein thro mbo sis Athe roe mbol ic dise ase Small and medium vessel Scle rode rma Malig nant hype rtens ion Hem olytic ure mic synd rom e Thro mbot ic thro

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mbo cyto peni c purp ura HIVasso ciate d micr oang iopat hy

Glomerular Systemic diseases Syst emic lupu s eryth emat osus Infec tive endo cardi tis Syst emic vasc ulitis (e.g., peria rteriti s nodo sum, Weg ener' s gran ulom atosi s) Hen ochSch önlei n purp ura HIVasso ciate

Page 1830

d neph ropat hy Ess entia l mixe d cryo glob uline mia Goo dpas ture' s synd rom e Primary renal disease Post strep toco ccal glom erulo neph ritis Othe r posti nfect ious glom erulo neph ritis Rapi dly prog ressi ve glom erulo neph ritis

Tubulointerstitial Drug s (ma ny) Toxi ns (e.g.,

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heav y meta ls, ethyl ene glyc ol) Infec tions Multi ple myel oma

Acute Tubular Necrosis Ischemia Sho ck Sep sis Seve re prer enal azot emia Nephrotoxins Antib iotic s Radi ogra phic contr ast agen ts Myo globi nuria Hem oglo binur ia

Other Seve re liver dise ase[ 22]

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Aller gic react ions NSAI Ds [ 23]

Glomerular Disease Acute glomerulonephritis may represent a primary renal process or may be the manifestation of any of a wide range of other disease entities (see Box 96-7 ). Patients may have dark urine, hypertension, edema, or CHF (secondary to volume overload) or may be completely asymptomatic, in which case the diagnosis results from an incidental finding on urinalysis. The hematuria associated with glomerular disease may be microscopic or gross and may be persistent or intermittent. Proteinuria, although often in the range of 500 mg/day to 3 g/day, is not uncommonly in the nephrotic range. Hematuria, proteinuria, or red cell casts are very suggestive of glomerulonephritis. In fact, red cell casts are essentially diagnostic of active glomerular disease, although occasionally they are seen with other types of renal disease. Conversely, the absence of red cell casts, proteinuria, and hematuria essentially excludes glomerulonephritis as the cause of ARF. The specific diagnosis of acute glomerulonephritis caused by primary renal disease is often ultimately made by renal biopsy. However, when glomerulonephritis is secondary to a systemic disease such as systemic lupus erythematosus, the patient's clinical signs and symptoms, in combination with the results of laboratory assessment, aid considerably in narrowing the differential diagnosis. As a rule, extensive laboratory testing to identify the cause of acute glomerulonephritis is not indicated in the emergency department and is more appropriately performed as part of an inpatient evaluation.

Interstitial Disease AIN is most commonly precipitated by drug exposure or by infection. Drug-induced AIN is poorly understood, but the absence of a clear relationship to the dose and the recurrence of the syndrome on rechallenge with the offending agent suggest that an immunologic mechanism is responsible. The most commonly incriminated drugs are the penicillins, diuretics, anticoagulants, and NSAIDs. AIN has been reported in association with bacterial, fungal, protozoan, and rickettsial infections. Patients with AIN classically have rash, fever, eosinophilia, and eosinophiluria, but it is common for one or more of these cardinal signs to be absent. Pyuria, gross or microscopic hematuria, and mild proteinuria are observed in some cases. A definite diagnosis sometimes can be made only on renal biopsy. Treatment of AIN is directed at removing the presumed cause; infections should be treated and offending drugs discontinued. Renal function generally returns to baseline over several weeks, although chronic renal failure has been reported to occur.

Intrarenal Vascular Disease Vascular disease of the kidney can be classified according to the size of the vessel that is affected. Disorders such as renal arterial thrombosis or embolism, which affect large blood vessels, must be bilateral (or must affect a single functioning kidney) to produce ARF. Whether to attribute such cases of ARF to prerenal or intrarenal vascular causes is a matter of semantics. The most common cause of thrombosis is probably trauma; thrombosis may also occur after angiography or may be secondary to aortic or renal arterial dissection. Renal atheroembolism is thought to occur commonly—at least on a microscopic level— after arteriography but is an uncommon cause of ARF. Similarly, patients with chronic atrial fibrillation or infective endocarditis may throw emboli to the kidney but rarely suffer ARF as a result. Renal arterial embolism can cause acute renal infarction, generally manifested by sudden flank, back, chest, or upper abdominal pain. Urinary findings, including hematuria, are variable. Fever, nausea, and vomiting are not uncommon; in some cases, evidence of embolization to other vessels provides a useful clue. The diagnosis is usually made by renal flow scanning or arteriography. Surgical embolectomy has been reported to restore function when undertaken within several hours of occlusion, but significant return of function has been documented in patients operated on as long as 6 weeks after total occlusion. This is presumably because they develop collateral circulation in association with a preexisting partial occlusion. An interesting but relatively uncommon type of ARF occurs when an ACE inhibitor is given to a patient with underlying bilateral renal artery stenosis (or unilateral stenosis in a solitary functioning kidney). With inhibition of angiotensin synthesis, efferent arteriolar tone is not maintained and GFR decreases. The condition is reversible with cessation of therapy.

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Several diseases that affect the smaller intrarenal vessels can cause ARF (see Box 96-7 ). Patients whose disease is severe enough to cause ARF are also generally found to have hypertension, microangiopathic hemolytic anemia, and other systemic and organ-specific manifestations. Infection with Escherichia coli O157:H7 has emerged as a major cause of hemolytic-uremic syndrome, an important cause of ARF in children.[17] Malignant hypertension, although much less common since the advent of more effective antihypertensive therapy, has by no means disappeared. Patients with scleroderma (systemic sclerosis) may have “scleroderma renal crisis,”[18] characterized by malignant hypertension and rapidly progressive renal failure. Whereas vasculitis associated with glomerular capillary inflammation typically causes gross or microscopic hematuria and formation of red cell casts, vascular involvement of the medium-size vessels, such as that produced by scleroderma, often spares the preglomerular vessels and tends not to produce an active urine sediment. Extrarenal manifestations (rash, fever, arthritis, pulmonary symptoms) are usually evident. For both malignant hypertension and scleroderma renal crisis, appropriate treatment can produce a gratifying remission of ARF. Patients with malignant hypertension have been reported to recover renal function after aggressive antihypertensive therapy, with temporary maintenance with dialysis if necessary.[19] For individuals who have scleroderma renal crisis, specific therapy with ACE inhibitors has been shown to result in improvement in renal function in a significant proportion of patients.[20]

Acute Tubular Necrosis The term ATN refers to a generally reversible deterioration of kidney function associated with a variety of renal insults. Oliguria may or may not be a feature. The diagnosis is made after prerenal and postrenal causes of ARF and disorders of glomeruli, interstitium, and intrarenal vasculature have been excluded. These discrete categories do overlap in a few disorders. For example, ARF associated with multiple myeloma or ethylene glycol toxicity is associated with both intrarenal obstruction and interstitial disease as well as a probable direct toxic effect on the renal tubule itself. The most common precipitants of ATN are renal ischemia during surgery or after trauma and sepsis. The remainder of cases occur in the setting of medical illness, most commonly as a result of the administration of nephrotoxic aminoglycoside antibiotics or radiocontrast agents or in association with rhabdomyolysis. Multiple causes can be identified in some cases; in others a definitive cause is never established. Several competing theories have been put forward to explain the pathophysiology of ATN.[21] One proposes that casts and cellular debris physically obstruct the tubular lumen, which leads to an increase in intratubular pressure and a consequent decrease in net glomerular filtration pressure. Another theory holds that damage to the renal tubular epithelium allows back-leak of glomerular filtrate into the peritubular capillaries. Other investigators suggest a primarily vascular mechanism for renal failure in which afferent arteriolar vasoconstriction or efferent arteriolar vasodilation is sufficient to decrease glomerular filtration. Yet another view emphasizes the importance of changes in glomerular capillary permeability. Decreased renal perfusion results in a continuum of renal dysfunction that ranges from transient prerenal azotemia at one extreme to ATN at the other. Early during the period of renal ischemia, renal function can be restored completely by restoring renal blood flow, but at some point, continued hypoperfusion results in renal dysfunction unresponsive to volume repletion, and ATN supervenes. ATN may occur in the absence of frank hypotension; even modest renal ischemia may result in ATN in susceptible individuals. Individual susceptibility to ATN may be related to the balance of prostaglandin-mediated vasopressor and vasodilatory influences on the renal vasculature. Postischemic ATN can occur in the setting of volume loss from the GI tract (upper or lower), skin, or kidneys or can result from severe hemorrhage or major burns. Heatstroke is commonly associated with the development of ATN, which is thought to result from a combination of volume loss, hyperpyrexia, and rhabdomyolysis. Another cause of ATN is hyperglycemic hyperosmolar nonketotic coma, which can be associated with loss of as much as 25% of total body water. ATN is also seen in the setting of cardiogenic shock, sepsis, and the “third spacing” of fluids in pancreatitis and peritonitis. ATN is common in postoperative patients, although not all cases can be attributed to intraoperative hypotension or hemorrhage. Concomitant sepsis, increased age, preexisting renal disease, and other comorbidities are associated with a worse outcome.[] Nephrotoxins are the other major cause of ATN. Among the most prominent of these are the endogenous

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pigments myoglobin and hemoglobin. Rhabdomyolysis and ARF resulting from crush injuries first received widespread attention after their description in survivors of the London blitz during World War II, but many other causes of pigment nephropathy have been reported ( Box 96-8 ). Hypotension secondary to fluid loss into damaged muscle is thought to worsen the effects of myoglobinuria on the renal tubule, as is acidosis. Hemolysis, resulting in the release of hemoglobin into the circulation and hemoglobinuria, can cause ATN but usually only in the presence of coexisting dehydration, acidosis, or other causes of decreased renal perfusion. ATN may be produced by the hemolysis of as little as 100 mL of blood. BOX 96-8 Causes of Pigment-Induced Acute Renal Failure

Rha bdo myol ysis and myo globi nuria Vigor ous exer cise Arter ial emb oliza tion Stat us epile pticu s Stat us asth mati cus Com a-ind uced and pres sure -indu ced myo necr osis Heat stres s Diab etic keto acid osis Myo path

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y Alco holis m Hypo kale mia Hypo phos phat emia Hem oglo binur ia Tran sfusi on react ions Snak e enve nom ation Mala ria Mec hani cal destr uctio n of RBC s by prost hetic valve s G6P D defic ienc y

RBC, red blood cells. ATN associated with rhabdomyolysis is often oliguric; it is characterized by rapid increases in the serum creatinine, potassium, phosphorus, and uric acid levels.[] Creatine released from muscle is metabolized to creatinine, which may result in serum creatinine increases of more than 2 mg/dL/day, in contrast to the increase of 0.5 to 1.0 mg/dL/day typically seen in other forms of ARF. The BUN/creatinine ratio is often less than 10:1. Intracellular potassium released from damaged muscle may raise the serum potassium by 1 to 2 mEq/L in several hours. Likewise, phosphate released from muscle may cause dramatic increases in the serum phosphate level. Uric acid, produced by metabolism of purines released from damaged muscle, may accumulate to levels high enough to suggest acute uric acid nephropathy. The urine dipstick yields a positive result for heme in only 50% of patients with rhabdomyolysis because myoglobin is rapidly cleared from the serum and therefore may be undetectable in the urine at the time of presentation. Thus, a negative urine dipstick result does not rule out the diagnosis. Serum creatine

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phosphokinase (CPK) is cleared much more slowly and is therefore a much more sensitive test. No biochemical parameter can be used to predict which patients who have rhabdomyolysis will develop ARF. In one classical study of patients in whom alcoholism, muscle compression, and seizures were the most common causes of rhabdomyolysis, ARF developed in only one third. Neither the height of the serum CPK elevation, the presence or absence of myoglobinuria, nor the degree of hyperkalemia correlated well with the development of ARF.[24] Antibiotics and radiographic contrast agents are other nephrotoxins that are commonly implicated in the development of ATN. Aminoglycosides are the most commonly implicated antibiotics. Higher doses and longer duration of therapy are associated with higher serum drug levels, leading to greater accumulation of drug in the renal parenchyma and a greater likelihood of nephrotoxicity. Increased age, impaired renal function, dehydration, and exposure to other nephrotoxins are additional risk factors. Once-daily administration of a somewhat higher dose is associated with less nephrotoxicity but equal effectiveness.[] Aminoglycoside-induced ATN typically has a gradual onset. Clinically significant renal dysfunction usually occurs only after several days and often after more than a week of therapy. However, renal failure can develop as long as 10 days after a drug has been discontinued, an observation that appears to be explained by the prolonged tissue half-life characteristic of these agents. Renal function returns to normal after an average of 6 weeks, but the condition occasionally progresses to permanent renal injury. Radiographic contrast agents are a common cause of hospital-acquired renal insufficiency. Renal failure produced by these agents may be defined as an increase in serum creatinine level of 25% over baseline with a temporal relation to contrast medium administration and in the absence of other identifiable causes. Contrast-induced ATN encompasses a spectrum ranging from asymptomatic nonoliguric renal insufficiency to severe renal failure requiring dialysis, but most cases are mild. It can occur after any procedure involving intravascular contrast. Typically, an increase in the serum creatinine level is noted within 3 days of exposure, with a return to normal within 10 to 14 days. The most important risk factors for contrast-induced ATN are preexisting renal insufficiency, diabetes mellitus, multiple myeloma, age older than 60 years, volume depletion, and higher doses of contrast material. Of these, preexisting renal insufficiency is the most important.[28] Diabetic patients with a serum creatinine level less than 1.5 mg/dL are at low risk for the development of contrast-induced ATN, whereas those whose serum creatinine is greater than 1.5 mg/dL are at significant risk.[29] Multiple myeloma, particularly when dehydration is present, is another reasonably well-documented risk factor. Advanced age also appears to make ATN more likely, possibly because of decreased renal mass and cortical blood flow. Volume depletion appears to be an independent risk factor, and aggressive volume expansion before contrast exposure has been shown to have a protective effect.[] Finally, large doses and repeated doses of contrast material are associated with increased risk of ATN, particularly if two studies are performed within 72 hours of one another. Use of low-osmolality contrast media appears to be associated with a lower risk of nephrotoxicity than use of standard high-osmolality agents.[] Oral N-acetylcysteine has been shown to have some protective effect when given prophylactically for 2 days before coronary angiography.[] A rapid intravenous (IV) regimen, administered with IV saline, also appeared to prevent nephrotoxicity, but the overall clinical effect was modest.[37] The mechanism of this protective effect remains unclear,[38] and the regimen has not yet been tested in patients with moderate to severe degrees of renal dysfunction.

Clinical Features When the presence of azotemia or renal failure has been discovered, the emergency physician should first consider potentially life-threatening complications (e.g., hyperkalemia and pulmonary edema). Assuming these have been satisfactorily ruled out, the next step is to determine whether the condition represents ARF or is the result of preexisting renal disease. The clinical distinction between ARF and chronic renal failure is often difficult; old records and laboratory results are invaluable. The finding of small kidneys on abdominal radiography or bone changes of secondary hyperparathyroidism on hand films suggests that renal failure is chronic. Anemia, hypocalcemia, and hyperphosphatemia, on the other hand, should not be relied on to identify patients who have chronic renal failure because these abnormalities can develop rapidly in ARF. In evaluating the patient with azotemia, the history, physical examination, and laboratory studies should seek clues to the cause and identify signs and symptoms of uremia, volume overload, or other complications of renal failure. In attempting to identify the cause of azotemia, the general strategy is to rule out both prerenal

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and postrenal causes before considering the many intrinsic renal causes. First, potential sources of volume loss and causes of decreased cardiac output should be sought in the history, and the patient should be questioned about lightheadedness, bleeding, GI fluid loss, abnormal polyuria, or symptoms of CHF. In men, a history of nocturia, frequency, hesitancy, or decrement of urinary stream suggests prostatic obstruction. A history of lower tract symptoms or of abdominal or pelvic tumor in either sex should likewise be elicited, as should a history of kidney stones or chronic UTI. A documented history of acute anuria (defined as the production of urine at less than 100 mL/day) is most often the result of high-grade urinary tract obstruction, although it may also accompany severe volume depletion, severe acute glomerulonephritis, cortical necrosis, or bilateral renal vascular occlusion. Intermittent anuria, on the other hand, is characteristic of obstructive disease. The patient should be questioned about medication use and possible exposure to radiographic contrast agents or other exogenous toxins. A history of pharyngitis, hypertension, dark-colored urine, rash, fever, or arthritis suggests intrinsic renal disease or a multisystem disorder. In older patients, symptoms that suggest multiple myeloma should be elicited. The physical examination should focus on signs of volume depletion such as orthostatic hypotension, tachycardia, and decreased skin turgor; documented short-term changes in body weight offer a valuable clue in assessing volume status, particularly in chronically ill patients. In addition, suspected bleeding should be specifically excluded. Similarly, volume overload should be sought by assessment of jugular venous distention and attention to the presence of rales, an S3 gallop, or edema. An attempt to percuss the bladder should be made. A distended bladder is percussible when it contains 150 mL of urine, and the dome is palpable abdominally when it contains 500 mL. Ultrasonography can be used to detect bladder distention if there is a question of urinary retention.[39] Prostate examination in adult men or pelvic examination in adult women should not be neglected. Rash, purpura, pallor, or petechiae should be noted, as should arthritis, musculoskeletal tenderness, or findings suggestive of infection or malignancy.

Diagnostic Strategy Laboratory The laboratory evaluation should begin with a careful dipstick and microscopic urinalysis and measurement of urine output. BUN, serum creatinine, UNa, and FENa levels should be determined to help evaluate renal function and to provide clues to the cause of ARF. A complete blood count, serum electrolyte calcium, phosphorus, and magnesium levels, electrocardiogram (ECG), and chest radiograph should be ordered to establish the patient's baseline status and to provide information about possible complications. Other studies may be of value in the emergency department when the history or physical findings suggest a specific role in immediate diagnosis or management. Prerenal azotemia should be suspected in the setting of volume loss, volume redistribution, or decreased effective renal perfusion. It is typically associated with a normal urinalysis, high BUN/creatinine ratio, increased urine osmolality, UNa concentration less than 20 mEq/L, and FENa less than 1%. A rapid response to volume repletion is also characteristic. Urethral or bladder neck obstruction is documented by the finding of significant amounts of residual urine in the bladder on catheterization after the patient has voided or attempted to void spontaneously. It should be emphasized that the ability to void does not rule out obstruction. In fact, the urine volume in the presence of obstruction may vary from zero to several liters per day. Flank pain is likewise an insensitive marker for obstruction. Urine indices and the BUN/creatinine ratio tend not to be helpful, although an increase in the latter is common in obstruction. The presence of a renal parenchymal disorder can often be diagnosed by its manifestations on microscopic urinalysis or by associated extrarenal manifestations (e.g., with multisystem disease) or the clinical setting (e.g., recent exposure to a new medication). In the absence of these clues, the failure to find evidence for prerenal or postrenal causes in a patient with ARF may also be taken as presumptive evidence of an intrarenal parenchymal process. Among these, the emergency physician should keep in mind the possibility of an acute or ongoing vascular insult because timely intervention may be important in preserving ultimate renal function.

Radiography and Ultrasonography Significant hydronephrosis is usually readily demonstrable by ultrasonography and may indicate either upper or lower tract obstruction. In questionable cases, or if bilateral ureteral obstruction is strongly suspected clinically, the next step is retrograde urography performed by a urologist.[40] CT imaging is less useful in this

Page 1838

setting; in fact, IV contrast material may compound the injury to the kidney.

Management Emergency department management of ARF is directed to reversing decreases in GFR and urine output (if possible) while minimizing further hemodynamic and toxic insults, maintaining normal fluid and electrolyte balance, and managing other complications of ARF as required. Because renal failure alters the metabolism and action of many drugs, often in ways that are not predictable, the physician must exercise care when prescribing all medications. A compendium of guidelines for drug dosing in renal failure, such as the one by Aronoff and colleagues,[41] is of great help for this purpose. After ensuring that the vital signs are adequate and that the patient is in no immediate danger from volume or metabolic derangements, the next step is to correct prerenal and postrenal factors, if any are identified. Intravascular volume should be repleted in hypovolemic patients and maintained in euvolemic patients by matching input to measured and insensible output. Inadequate cardiac output should be augmented when possible. Postrenal or obstructive ARF is treated by restoration of normal urine outflow. Bladder outlet obstruction may be relieved by passage of a Foley catheter, whereas upper tract obstruction may require percutaneous nephrostomy. When prerenal and postrenal factors have been ruled out, the challenge to the emergency physician is to identify the cause of intrinsic renal ARF, keeping in mind the multitude of known possible causes (see Box 96-7 ). The clinical setting and physical and laboratory findings often allow the differential diagnosis to be considerably narrowed. The clinical picture is often most consistent with the broad category of ATN. It has been noted repeatedly that patients who have oliguric ARF have a significantly higher mortality rate and a much greater risk of complications than those who are not oliguric. The difference in prognosis may simply reflect a more severe renal insult in patients who are oliguric, however, and it is not clear that interventions aimed at converting oliguric to nonoliguric ARF have an effect on renal function or mortality.[42] Nevertheless, because nonoliguric patients are easier to manage, an attempt to increase urine flow is warranted. Loop diuretics or mannitol is often effective in increasing urine flow when intravascular volume deficits are corrected. Although furosemide has been shown to decrease dialysis requirements and complications caused by volume overload, it has not been shown to shorten the clinical course or affect mortality.[] Mannitol appears to be most useful when given at the time of or shortly after the renal insult; the recommended dose is 12.5 to 25 g intravenously. If urine output does not increase, further doses may cause hyperosmolality and clinically significant intravascular volume overload in patients with impaired renal function.[46] Dopamine (1 to 3 p-g/kg/min) and atrial natriuretic peptide have also been used, with and without furosemide, in an effort to increase urine output, but their efficacy has not been validated in prospective studies.[] Certain specific considerations apply to toxin-induced ATN. Pigment-induced ATN may be prevented by avoidance of hemolysis and muscle injury and by correction of the factors (e.g., dehydration, acidosis) that are known to predispose patients with pigmenturia to the development of renal failure. When hemolysis or rhabdomyolysis has occurred, treatment is directed at eliminating the cause and preventing the development of renal failure. Mannitol has been shown to prevent ARF in experimental models of myoglobinuria, presumably by inducing osmotic diuresis and decreasing intratubular deposition of pigment. Furosemide, on the other hand, has not consistently shown a beneficial effect. Other studies have suggested that myoglobin precipitates in an acid urine but not in an alkaline urine. Thus, aggressive volume repletion, alkalinization, and mannitol infusion have been recommended after crush injuries to reduce the likelihood or severity of ARF.[50] This regimen also helps control hyperkalemia. When ARF has occurred, management is similar to that of other forms of ARF, but early dialysis may be required to control rapidly developing hyperkalemia, hyperphosphatemia, and hyperuricemia. Patients who have contrast-induced ATN require only supportive therapy but should be hospitalized and seen by a nephrologist. A more significant role for the emergency physician is in preventing the occurrence of contrast-induced ATN, particularly by recognizing risk factors in patients for whom contrast studies are being considered. BUN and serum creatinine levels should be checked before contrast exposure in patients with risk factors. Moreover, before contrast medium is administered to a high-risk patient, it should be established that there is a compelling reason to perform the contrast study and that there is no adequate alternative to using a contrast agent. The patient should be volume repleted before the study, the

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administered dose of contrast agent should be kept as low as possible, and multiple studies should be avoided, as should concomitant use of other nephrotoxins. IV saline, given before and after contrast agent administration, may be protective.[]

Volume and Metabolic Complications In addition to these general measures aimed at minimizing decreases in GFR and increasing urine output, an important component of the management of ARF is the prevention or control of systemic complications. Particularly important are metabolic derangements (e.g., hyperkalemia, hypocalcemia, hyperphosphatemia, and metabolic acidosis) and complications of volume overload (e.g., hypertension and CHF). Hyperkalemia, the most common metabolic cause of death in patients with ARF, results from an inability to excrete endogenous and exogenous potassium loads. In oliguric patients the serum potassium level typically increases by 0.3 to 0.5 mEq/L/day, but greater increases occur in catabolic, septic, or traumatized patients and in the presence of acidosis or exogenous potassium loads from diet or medication. Hyperkalemia results in serious disturbances in cardiac electrophysiology that may culminate in cardiac arrest. Although some hyperkalemic patients note muscular weakness, most are generally asymptomatic until major manifestations of cardiotoxicity supervene. Thus, hyperkalemia is particularly dangerous and should be considered and sought out. ECG changes correlate only roughly with the serum potassium level. Mild hyperkalemia (K+ 90% versus 60-80%, respectively), with specificities greater than 99%. These new NAATs are more sensitive than other nonculture tests (DNA probe testing, latex agglutination testing) by 17% to 35%.[] NAATs can be performed on swabs (endocervical or urethral) and urine. Sensitivities of NAATs are lower when performed on urine than on endocervical swabs,[] making endocervical swabs the test of choice in females. Urine screening using NAATs is adequate for symptomatic males, and urethral swabs are generally not necessary.[] In sexual abuse cases, culture should still be performed in addition to the NAAT for medicolegal purposes.[1] Treatment of chlamydia consists of azithromycin 1 g PO as a single dose or doxycycline 100 mg PO bid for 7 days.[1] Coinfection with gonorrhea is common, so treating patients for both diseases is recommended unless gonorrhea is definitively ruled out (see Table 97-3 for alternative regimens). Patients should be instructed to abstain from sexual intercourse for 7 days after completion of treatment (either single-dose therapy or the 7-day regimen of doxycycline). Sexual partners need to be tested and treated, and the index patient should be instructed to abstain from sexual intercourse until all sexual partners are treated. Follow-up for test of cure is not required unless symptoms persist or reinfection is suspected.

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Nongonococcal Urethritis Nongonococcal urethritis is characterized by urethral discharge, dysuria, or urethral pruritus. Although C. trachomatis is implicated in many cases,[12] the cause in some cases is unknown. All patients with suggestive presenting symptoms should be evaluated for both gonorrhea and chlamydia. The diagnosis is made by Gram stain (>5 white blood cells [WBCs] per high-power field and no gram-negative diplococci),[1] positive leukocyte esterase test on urinalysis, or more than 10 WBCs per high-power field on urinalysis. Treatment consists of azithromycin 1 g (single oral dose) or doxycycline 100 mg PO bid for 7 days.[1] In women, other causes of vaginal discharge must be ruled out, including chlamydia, trichomoniasis, and candidiasis.

Gonorrhea Gonorrhea is the second most frequently reported STD after chlamydia, with an estimated 600,000 new N. gonorrhoeae infections in the United States each year.[1] As infection affects columnar or transitional epithelium, this organism affects the urethra, rectum, cervical canal, pharynx, upper female genital tract, and conjunctival sac. The most common clinical presentation in men is acute urethritis, characterized by dysuria and a penile discharge ( Figure 97-10 ), starting within 1 to 14 days of exposure. On examination, the patient may have urethral meatal erythema and a purulent urethral discharge. Patients may present with epididymitis, although this is uncommon.

Figure 97-10 Purulent urethral discharge in a patient with gonorrhea.

In women, primary infections are often asymptomatic or produce only vague symptoms such as vaginal discharge, abnormal vaginal bleeding, abdominal or pelvic pain, dyspareunia or dysuria, and frequency. Patients may not present until complications such as pelvic inflammatury disease (PID) have occurred, and up to 20% of women with untreated gonorrhea develop PID. Like chlamydia, symptomatic and asymptomatic gonorrhea infection can cause PID with subsequent tubal scarring that may lead to infertility or ectopic pregnancy. Gonorrhea can also infect the oropharynx and anorectal area. Gonococcal infection of the pharynx is often asymptomatic, but in symptomatic cases patients present with sore throat and exudative tonsillitis. Most cases are self-limited. Anorectal involvement is more common in individuals who engage in receptive anal intercourse. Like pharyngeal infection, it is often asymptomatic. When symptomatic, patients complain of rectal discomfort or pain, tenesmus, constipation, dyspareunia, pruritus ani, and purulent or mucoid anal discharge or bleeding. Anoscopy reveals friable mucosa and mucopurulent exudate. Gonococcal conjunctivitis can be a sight-threatening infection, so recognition of this infection is crucial. This infection can occur in newborns (acquired during passage through an infected birth canal) and in adults, who often acquire the infection by direct inoculation from organisms on the fingers and then rubbed onto the eye. Symptomatic conjunctivitis is characterized by beefy red conjunctiva, chemosis, and purulent eye discharge that is often copious. If untreated, it can progress to corneal ulceration or, in severe cases, gonococcal endophthalmitis. Disseminated gonococcal infection (DGI) results from gonococcal bacteremia and occurs more frequently in women than men. Typically, it presents with the arthritis-dermatitis syndrome, characterized by a combination of any or all of the following: fevers, chills, oligoarticular arthritis or arthralgias, rash, and tenosynovitis. The rash of DGI is pustular acral skin lesions, usually found peripherally on the extremities. The lesions are described as necrotic pustules on an erythematous base and are tender to palpation. These lesions represent septic emboli to small blood vessels during bacteremia. Joint involvement, the second most common manifestation of DGI, manifests with an acute monoarticular or oligoarticular septic arthritis. The knees are most commonly involved, followed by elbows, ankles, wrists, and small joints of the hands and feet. The involved joint is erythematous, is warm, often has an effusion, and is painful to range of motion.

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Other manifestations of DGI, although very rare, include hepatitis, myocarditis, endocarditis, and meningitis. Definitive diagnosis of DGI is confirmed by isolating gonococci from the blood, synovial fluid, or infected skin; unfortunately, such isolation has relatively poor sensitivity. Presumptive diagnosis of DGI is based on the appropriate clinical presentation, plus isolation of gonococci from a source site.

Diagnosis Diagnostic tests for gonorrhea include Gram stain, culture, and NAATs. Gram stain is most useful in symptomatic men with urethritis or in patients with gonococcal conjunctivitis. In these cases, it is an excellent diagnostic test, with a sensitivity and specificity approaching 100%,[] and results are available rapidly. However, this test is less useful in asymptomatic men and all women, owing to its decreased sensitivity in these groups. Culture for gonorrhea is considered the gold standard for diagnosis.[13] Because this test can be used to isolate the organism for antimicrobial testing and determination of antibiotic sensitivities, it is useful in areas of rapidly emerging resistance. However, the utility of this test may be limited by improper specimen collection and handling. To maximize the yield of gonococcal culture, inoculating the specimen directly onto the appropriate medium optimizes viability of the organisms. If the specimen is from a sterile site, such as cerebrospinal fluid or synovial fluid, a nonselective medium such as chocolate agar is best. Specimens from nonsterile sites such as the cervix, urethra, rectum, or oropharynx, where normal bacterial flora are present, should be inoculated on selective media such as Martin-Lewis agar. If not transported immediately to the laboratory, specimens should be incubated at 35° to 36.5° C in a carbon dioxide–enriched atmosphere after collection and transported to the laboratory in a carbon dioxide–enriched atmosphere.[] The NAATs have good sensitivity and excellent specificity for detection of gonorrhea from endocervical, urethral, and urine samples. These tests are approved by the Food and Drug Administration for the detection of C. trachomatis and N. gonorrhoeae in endocervical swabs from women, urethral swabs from men, and urine from both men and women.[13] Although sensitivities of NAATs are comparable with culture (95-99%), selected NAATs may be less sensitive when performed on urine than when performed on endocervical specimens or male urethral swabs. Therefore, in symptomatic patients, NAATs of endocervical swabs from women or urethral swabs from males are good alternatives to gonococcal culture, particularly when appropriate techniques for maximizing organism viability and culture cannot be achieved.[] Although NAATs are useful for diagnosing cervical and urethral gonorrhea, culture is required for diagnosing organisms from sites such as the oropharynx, synovial fluid, anorectal area, and cerebrospinal fluid. In addition, culture is the test of choice when the results will be used as evidence in legal investigations.

Treatment There are several recommendations for single-dose therapy for gonorrhea (see Table 97-3 ); the most universally recommended are single doses of ceftriaxone 125 mg IM or cefixime 400 mg PO.[1] Although quinolones are listed as possible choices, the increasing frequency of quinolone-resistant strains in Asia, Hawaii, and California has led to the recommendation that these agents not be used to treat gonorrhea acquired in these areas.[1] Because co-infection with chlamydia is so common, treatment for presumptive chlamydia should also be provided unless co-infection can be ruled out. Sexual partners need referral for evaluation, testing, and treatment. Patients should be instructed to avoid sexual intercourse until therapy is completed and until they and their sexual partners are no longer symptomatic. Referral for HIV testing should be offered. Because emergency departments are often used as a source of primary health care, the role of emergency departments in screening and treating STDs has been debated. A major area of difficulty in using emergency departments for this purpose is that many test results are not available during the emergency department visit, and treatment decisions are therefore made presumptively. Errors are made in both overtreating and undertreating STDs in this setting. Although it has been shown that health care providers are significantly overtreating women who test negative for gonorrhea and chlamydia,[16] one third of patients who test positive for STDs in the emergency department are not treated during the initial visit, and the majority of untreated patients do not return for subsequent treatment.[] As a result, providers must weigh the cost of overtreatment against the risk of untreated disease. Because these diseases pose a significant public health risk, it is recommended that patients be treated presumptively in the emergency department unless good follow-up for test results can be ensured.

Trichomonas

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Trichomoniasis is caused by Trichomonas vaginalis, a flagellated protozoan. It is the most common nonviral sexually transmitted disease in the world, with an estimated 173 million new infections worldwide in 1999. As with other vaginal infections, up to 50% of infected women are asymptomatic. The most common presenting symptoms include dysuria, vulvar irritation or itching, and vaginal discharge, often described as thin, malodorous, and yellow-green. Affected patients may also report lower abdominal pain, discomfort, or dyspareunia. Males are frequently asymptomatic, and most often present as partners of infected women. Trichomonas has been implicated as a cause of nongonococcal urethritis in men, possibly responsible for up to 20% of cases.[19] Rarely, men report purulent urethral discharge or symptoms consistent with prostatitis or epididymitis. On physical examination, vaginal discharge is noted in up to 70% of patients, ranging in description from thin and scanty to the classic description of thick, frothy yellow discharge. Vaginal pH is above 4.5. Punctate mucosal hemorrhages of the cervix (“strawberry” cervix) has been described in 2% to 10% of patients. The history and examination findings are not sensitive or specific enough to make the diagnosis on clinical grounds alone, however. The diagnosis is most often made by microscopic examination of a wet-mount slide, but this method has a sensitivity of only 60% to 70%, and sensitivity varies with the skill and thoroughness of the examiner. Culture is more sensitive than wet mount but is not widely performed. Results are not available in a timely manner for emergency department diagnosis and treatment, and few clinical laboratories have the culture material. In men, urine sediment can be examined for trichomonads and can also be sent for culture. PCR is being studied as an alternate method for diagnosis of trichomoniasis. Several PCR primers have been studied and each has demonstrated higher sensitivity than wet mount or culture.[] PCR has also been found to be highly specific, exceeding 95%. In addition, PCR analysis of specimens obtained from the distal vagina had a higher sensitivity and specificity for diagnosis of trichomoniasis than wet mount or culture of specimens obtained during a speculum examination, suggesting a role for less invasive diagnostic techniques such as vaginal introitus swabs.[] Despite these promising studies, results of PCR testing are not available for point-of-care testing. At this point, the most promising role for PCR testing for trichomonas is as part of a combination screening test with chlamydia and gonorrhea.[21] The only drug approved by the Food and Drug Administration for treatment of trichomoniasis in the United States is metronidazole, with a recommended single dose of 2 g PO. Alternate therapy is metronidazole 500 mg PO bid for 7 days (see Table 97-4 ). These recommendations are the same in HIV-positive women with trichomoniasis. Topical metronidazole is available but is less efficacious for treatment of trichomoniasis than oral preparations and is not recommended for use. Table 97-4 -- Characteristics of Vulvovaginitis by Cause pH

Discharge Appearance

Wet Mount

Treatment

Bacterial vaginosis

>4.5

Gray, white, Clue cells present milky/creamy; amine odor present

Metronidazole 500 mg PO bid × 7 days or clindamycin cream 2% intravaginally qhs × 7 days or metronidazole gel 0.75% intravaginally bid × 5 days

Trichomonas

>4.5

Gray, yellow, greenish or white; often frothy; homogeneous

Trichomonads present

Metronidazole 2 g PO × 1 or metronidazole 500 mg PO bid × 7 days

Candida

400,000) may be a risk factor for permanent visual loss.[67] The diagnosis is confirmed by temporal artery biopsy. Because this is a patchy disease, multiple biopsies of a long segment of the artery may need to be examined.

Treatment Because of the risk of visual loss, giant cell arteritis is a medical emergency and treatment should be initiated promptly when the diagnosis is suspected. Steroids are the mainstay of therapy; the recommended initial dose of prednisone ranges from 60 to 120 mg/day. Symptomatic response usually occurs rapidly over days, although therapy must be continued for months, with close ESR monitoring.

Carotid and Vertebral Dissection Principles of Disease Carotid and vertebral dissections are more common than previously realized. They are the most frequent cause of stroke in persons younger than 45 years, accounting for approximately 20% of all cases in this age group.[68] Although dissections may occur spontaneously, careful history taking frequently identifies an association with sudden neck movement or trauma preceding the event [] Reported mechanisms include neck torsion, chiropractic manipulation, coughing, minor falls, and motor vehicle accidents. Early symptoms and signs are often subtle, and in the absence of neurologic findings delays in diagnosis are common. The pathologic lesion is intramural hemorrhage within the media of the arterial wall. The hematoma can be localized or extend circumferentially along the length of the vessel, resulting in partial or complete occlusion.

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Platelet aggregation and thrombus formation also occur, further compromising vessel patency or causing distal embolization. The timing of these events is variable, and a patient may experience symptoms of cerebral ischemia days to years after dissection.[]

Clinical Presentation The typical presentation of the patient with carotid or vertebral dissection is the abrupt onset of pain in the neck or face. Neurologic findings usually occur within the first few hours, but autopsy studies have shown that strokes may occur months later.[68]

Carotid Dissection The classical triad of symptoms for carotid dissection includes unilateral headache, ipsilateral partial Horner's syndrome, and contralateral hemispheric findings that may include aphasia, neglect, visual disturbances, or hemiparesis. The headache is often severe and throbbing but may be subacute and similar to previous headaches. Acute severe retro-orbital pain in a previously healthy person with no history of cluster headaches is particularly suggestive of carotid dissection.[9] Most patients eventually develop signs of cerebral ischemia. Warning symptoms include transient ischemic attacks, amaurosis fugax, episodic lightheadedness, and syncope. Spontaneous dissection of the carotid artery has a favorable prognosis and recurrence is uncommon.[71] Factors associated with a worse prognosis include older age, occlusive disease on angiography, or stroke as the initial presenting symptom.[72]

Vertebral Dissection Vertebral artery dissections are less common than carotid dissections. The classical presentation is that of a relatively young person with severe unilateral posterior headache and neurologic findings.[73] The majority of patients develop a rapidly progressive neurologic deficit with symptoms of brainstem and cerebellar ischemia. Common findings include vertigo, severe vomiting, ataxia, diplopia, hemiparesis, unilateral facial weakness, and tinnitus.[74] Spontaneous vertebral artery dissection appears to be relatively rare. Approximately 10% of patients who develop a vertebral dissection die during the acute phase, secondary to massive stroke. For patients who survive, the prognosis is usually good.[69]

Diagnosis and Treatment The diagnosis of dissection may prove to be difficult. A CT scan should be obtained first but is often normal in uncomplicated dissection. Further imaging studies including MRI, magnetic resonance angiography, or catheter angiography are required to confirm the diagnosis.[68] Figure 101-2 shows an example of carotid artery dissection on MRI. Duplex imaging is of limited value.[68] Treatment is aimed at stroke prevention and usually includes early anticoagulation followed by antiplatelet therapy.

Figure 101-2 Axial T1-weighted m agnetic resonance im age dem onstrating a crescent sign (arrow) in a patient with a left internal carotid artery dissection. ((From Kidwell C: Dissection syndrom es. Online article at eMedicine.com . http://www.em edicine.com .ezproxy.hsclib .sunysb .edu/neuro/topic99.htm , picture 2.))

Identifying patients with dissection is challenging. More than 50% of patients see their physician for symptoms before admission. The emergency physician must consider this diagnosis in any young patient who presents with head or neck pain with focal neurologic findings.

Idiopathic Intracranial Hypertension Principles of Disease Idiopathic intracranial hypertension (IIH) is also known as pseudotumor cerebri or benign intracranial hypertension. The term idiopathic intracranial hypertension, however, is preferred because this disorder is not always benign and may have significant neurologic sequelae in affected individuals.

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IIH is a relatively common neurologic disease seen primarily in young obese women of childbearing age. Several predisposing factors have been identified, including the use of oral contraceptives, anabolic steroids, tetracyclines, and vitamin A.[75]

Pathophysiology and Clinical Features The pathophysiology of this disease remains controversial, with increased brain water content and decreased CSF outflow considered the two major causative factors.[76] The most prominent symptom is generalized headache, which is often gradual in onset and of moderate intensity. There is no specific localizing pattern, although in some patients it is worsened by eye movement. It may awaken patients from sleep and is exacerbated by bending forward and the Valsalva maneuver, which impede cerebral venous return. Visual complaints are common, and patients may experience transient visual obscuration several times a day secondary to ischemia of the visual pathways. These episodes can be followed by prolonged periods of visual loss, which can become permanent in up to 10% of patients.[77] Patients may also complain of nausea, vomiting, and dizziness. On physical examination, patients have papilledema and visual field defects, including an enlarged blind spot initially followed by loss of peripheral vision. Occasionally, a sixth nerve palsy is noted.

Diagnosis The diagnosis of IIH should not be made without neuroimaging and measurement of ICP. The diagnostic criteria are listed in box 101-4 . BOX 101-4 Diagnostic Criteria for Idiopathic Intracranial Hypertension (IIH)

{,

{,

Incre ased intra crani al pres sure (ICP ) (>20 0 mm H2O) mea sure d by open ing pres sure from a lumb ar punc ture Sign s and sym ptom s of incre ased

Page 2032

{,

{,

{,

ICP, with abse nce of locali zing sign s No mas s lesio ns or ventr icula r enlar gem ent on neur oima ging Nor mal or low cere bros pinal fluid prote in and nor mal cell coun t No clinic al or neur oima ging susp icion of veno us sinu s thro mbo sis[ 76]

Treatment Predisposing factors (e.g., discontinuation of implicated medications) should be corrected. Symptomatic treatment often includes lowering ICP and managing the headache. Acetazolamide (a carbonic anhydrase

Page 2033

inhibitor) can be used to decrease CSF production alone or with a loop diuretic such as furosemide. Steroids have also been used, although their mechanism of action is unclear. Prolonged therapy is problematic, and rebound IIH often occurs when doses are tapered. Repeated LPs can be attempted, but most patients find this approach objectionable. In patients with impending visual loss or incapacitating symptoms, a ventricular shunt or optic nerve sheath fenestration may be indicated.

Posttraumatic Headache Headache is the most common symptom following minor head injury. It is often part of a complex syndrome that can include dizziness, fatigue, insomnia, irritability, memory loss, and difficulty with concentration. The prevalence of headache with posttraumatic syndrome is not known because most patients are not admitted for this condition. There are approximately 2 million closed head injuries per year, and it is estimated that 30% to 50% of these patients develop posttraumatic headache (PTHA).[78] Acute PTHA develops hours to days after the injury and resolves within 8 weeks. Chronic PTHA may last from several months to years and may mimic other forms of headache, including tension and migraine headaches. The presence of headache, dizziness, or nausea on initial presentation is strongly associated with the development of chronic PTHA.[79] Patients who develop PTHA after minor head injuries have normal neurologic examinations and normal neuroimaging studies. The pathophysiology of their symptoms is unclear and may include both anatomic and functional components. Most patients are more concerned about the cause of the headache rather than the headache itself. Treatment is symptomatic. For acute PTHA, analgesics such as acetaminophen or NSAIDs are adequate for pain control. For chronic PTHA, treatment must be individualized depending on the type of headache and associated symptoms the patient is experiencing. Novel therapies, such as antidepressants and p -blockers, may be effective in selected patients.

Acute Glaucoma Patients with acute angle closure glaucoma present with sudden onset of severe pain localized to the affected eye that may radiate to the ear, sinuses, teeth, or forehead.[62] Visual symptoms, including blurriness, halos around lights, and scotomas, are typically present, and many patients also experience nausea and vomiting. The underlying pathophysiology is congenital narrowing of the anterior chamber angle that, under certain conditions, closes, resulting in a significant rise in intraocular pressure (IOP). Episodes can be precipitated by entering a low-light environment such as a movie theater, with resultant pupillary dilatation, or by the use of medications such as mydriatics (e.g., dilated ocular examination), sympathomimetics (e.g., pseudoephedrine), or agents with anticholinergic properties (e.g., antiemetics, antihistamines, antipsychotics, and antidepressants).[] Physical examination reveals a red eye with a fixed, middilated pupil, corneal clouding, and shallow anterior chamber. The diagnosis is confirmed by demonstrating markedly elevated IOP in the range of 60 to 90 mm Hg (normal proximal Normal to fatigue

Decreased Decreased

Yes

Normal

Normal

N

Decreased Proximal > distal

Normal

Normal

Yes

Yes

ALS, amyotrophic lateral sclerosis; DTR, deep tendon reflex.

Page 2185

Neuropathies involve the axon itself or the myelin sheath (or the Schwann cells that make the myelin sheath) of the nerve. Nerve conduction studies can differentiate the locations of involvement. As the conduction along the axon is disrupted, the subsequent delay in transmission first causes symptoms in the muscles controlled by longer nerve axons, resulting in a history of weakness beginning in the distal extremities. As the myelin destruction or axonal degeneration progresses, patients usually note a slowly progressive course of symptoms. The motor nerve branches into multiple terminals as it approaches the muscle. The neuromuscular junction is composed of the presynaptic membrane, the postsynaptic membrane, and the synaptic cleft. The neurotransmitter is acetylcholine (ACh). The motor synapse is a nicotinic receptor, whereas muscarinic synapses link the central nervous system with the autonomic nervous system. Disorders of the postsynaptic nicotinic receptors produce weakness. Postsynaptic ACh receptors are continually turned over at a rate that is related to the amount of stimulation. A disorder of transmission often leads to increased production of ACh receptors. Myasthenia gravis (MG) is the prototype of neuromuscular junction diseases.

CLINICAL FINDINGS History The history of patients with complaints of weakness initially focuses on establishing the acuity and progression of onset and the potential for airway compromise. Any complaint of difficulty breathing or swallowing raises suspicion of bulbar involvement and concern for life-threatening deterioration. The history must elicit whether the weakness is muscular or nonspecific generalized fatigue. Weakness implies the inability to exert normal force, whereas fatigue implies a decrease in force with repetitive use. When muscular weakness exists, the clinician should determine whether it is focal or generalized, proximal or distal. The history of present illness must include the duration of symptoms, exacerbating and mitigating factors, and presence of associated symptoms such as fever, weight loss, and bowel or bladder changes. The patient should be asked about the presence of a preexisting neuromuscular disorder; an acute exacerbation or end-stage degeneration of some genetic muscular dystrophies and MG may be the cause of the current difficulty. Prior episodes or a family history of weakness suggests the familial forms of the periodic paralyses. A history of a recent illness (often respiratory or diarrheal) supports a diagnosis of postinfectious autoimmune causes of weakness such as transverse myelitis or Guillain-Barré syndrome (GBS). Past history or risk factors for cancer may indicate a metastatic tumor as the cause of a compressive myelopathy. Questions about recent travel can help exclude tick bites or snakebites, and a dietary history may elicit shellfish toxin ingestion or the ingestion of canned goods suggesting botulism.

Physical Examination The physical examination should first assess the patient's airway and ventilation and then proceed to localize the level of the lesion. The presence of swallowing and a strong cough suggest that the patient has sufficient protective and ventilatory reserve. The muscles used to lift the head off the bed may weaken before those of respiration and should be assessed. A patient who is not yet intubated but is complaining of shortness of breath or difficulty breathing should have frequent vital capacity measurements. Normally, these values range from 60 to 70 mL/kg. When the forced vital capacity reaches 15 mL/kg, intubation is necessary. If vital capacity cannot be measured, a maximal negative inspiratory force is easily determined. A negative inspiratory force less than 15 mm Hg suggests the need for endotracheal intubation. An easy bedside assessment used to follow ventilatory status is to have the patient count numbers with one breath.[1] With sequential performance of this test, a decline in respiratory function is detected as the patient fails to count as high as before. Arterial blood gas is not necessarily helpful because functional reserve can be severely diminished by the time a patient develops either hypercarbia or hypoxia. The assessment of vital signs is important because some causes of weakness may result in dysregulation of the autonomic system. A systematic neurologic examination should assess the patient's mental status, cranial nerves, motor function, sensory function, deep tendon reflexes (DTRs), and coordination, including cerebellar function. The motor examination begins by determining whether the weakness is unilateral or bilateral and which muscle groups are involved. Key components of the examination include motor strength, muscle bulk, and presence of fasciculations. Box 106-1 provides the grading system used in motor strength assessment. Table 106-2 provides the findings used to distinguish upper motor neuron from lower motor neuron processes. BOX 106-1

Page 2186

Grading Score for Motor Strength

5 = Normal strength 4 = Weak but able to resist examiner 3 = Moves against gravity but unable to resist examiner 2 = Moves but unable to resist gravity 1 = Flicker but no movement 0 = No movement Table 106-2 -- Distinguishing Upper Motor Neuron (UMN) from Lower Motor Neuron (LMN) Involvement Motor Neuron DTR Muscle Tone Atrophy Fasciculations Babinski UMN LMN

Increased Decreased

Increased Decreased

No[*] Yes

No Yes

Present Absent

DTR, deep tendon reflex. *

Not significant, but can occur.

Differential Considerations Myelopathies A myelopathy shows signs of upper motor neuron dysfunction. Without upper motor neuron function, muscle weakness is present with increased spinal reflexes, including an extensor plantar reflex (Babinski response). The same reflex arcs eventually creates spasticity in the affected muscles. The weakness is ascending in nature, and there is often bladder and bowel involvement. When sensory findings are present, they often define the distinct level of the lesion.

Motor Neuron Disease Amyotrophic lateral sclerosis is the prototypical disease process resulting from a degeneration of the motor neuron without sensory involvement. These patients may complain of dysarthria or dysphagia; however, the characteristic findings are those of combined upper and lower motor neuron dysfunction. Consequently, findings include hyperreflexia, muscle wasting, and fasciculation. Pain is not a component of the clinical picture. Poliomyelitis affects the anterior horn cells and results in lower motor neuron disease without sensory involvement. The weakness can be symmetrical or more often asymmetric. Patients initially have a clinical picture similar to that of viral meningitis, with fever and neck stiffness. Currently, most cases follow exposure of an immunocompromised host to the oral polio vaccine, and this should be sought in the history. The cerebrospinal fluid analysis resembles that of viral meningitis.

Neuropathies Weakness from a neuropathy is often noted in distal muscles first and ascends. Grip strength or footdrop may be noted first. As all outflow from the spinal cord is affected, DTRs are diminished or absent. Patients exhibit varying degrees of altered sensation, muscle wasting, and fasciculation depending on the duration of the symptoms.

Diseases of the Neuromuscular Junction Disorders of the neuromuscular junction cause progressive motor fatigability. The initial depolarization of the muscle causes stimulation of a maximum number of receptors, producing a normal, or nearly normal, strength response. Repeated stimulation leads to diminishing motor strength, which is caused by blockage of the receptors (as in MG) or by a decrease in the amount of ACh released (as in botulism). A decrease in the release of ACh may produce a combination of nicotinic and muscarinic effects leading to anticholinergic

Page 2187

findings such as decreased visual acuity, confusion, urinary retention, tachycardia, low-grade fever, and dry, flushed skin. In the case of Lambert-Eaton myasthenic syndrome, weakness is more pronounced at the beginning of muscle use and improves with repeated use as more ACh builds up in the synaptic cleft with each stimulation.

Myopathies These disorders usually produce generalized, symmetrical weakness. Reflexes are present but markedly decreased, whereas sensation is preserved. Myopathies caused by inflammatory processes (i.e., viral myositis) may cause muscle tenderness and, over time, some wasting may occur as a result of disuse.

DIAGNOSTIC STRATEGIES Laboratory Studies Serum potassium, calcium, and phosphorus should be assessed in patients with acute weakness. Thyroid function tests are recommended in cases of suspected myopathies. A creatine kinase (CK) level assesses for muscular inflammation; a urinalysis should be performed for the presence of myoglobinuria and possible rhabdomyolysis.

Special Studies Magnetic resonance imaging (MRI) is the preferred test for suspected cases of acute myelopathy. Computed tomography of the spinal cord with myelography can help to differentiate compressive (herniation, abscess, tumor) from noncompressive causes when MRI is not available. Cerebrospinal fluid analysis has limited use in the evaluation of weakness. It is indicated when GBS or transverse myelitis is suspected.

SPECIFIC DISORDERS Disorders of the Neuromuscular Junction Myasthenia Gravis Perspective It is rare for the emergency physician to diagnose a new case of MG; more commonly, patients with established disease come to the emergency department with an exacerbation. In addition, the emergency physician must be cognizant of medication interactions in patients with MG.

Principles of Disease MG has a prevalence of 50 to 125 per million.[2] Age of onset is bimodal, with the first peak among women in the 20s and 30s and a second peak among men in the sixth and seventh decades. MG results from autoantibodies directed against the nicotinic acetylcholine receptor (AChR) at the neuromuscular junction. This leads to complement-mediated destruction of AChRs with a decrease in the total number of available receptors. The autoantibodies further compete with ACh for binding at remaining receptors. Thus, with repeated stimulation of the same muscle, fewer and fewer sites are available and fatigue develops. Fatigability and muscular weakness are the hallmarks of MG. Considering the slow clinical progression of MG and the low likelihood of complications from its progression, the importance of suspecting the diagnosis is to facilitate proper referral for further evaluation.

Clinical Features Ocular symptoms are often the first manifestation of MG. The typical symptoms are ptosis, diplopia, or blurred vision. Ocular muscle weakness may be the first sign in up to 40% of patients, although 85% of patients with MG eventually have ocular involvement. When present, ptosis is often worse toward the end of the day. Respiratory failure is rarely the initial symptom of MG. Even so, up to 17% of patients may have weakness of the muscles of respiration.[3] Bulbar muscles may be involved, producing dysarthria or dysphagia. The Lambert-Eaton myasthenic syndrome is a rare disorder often associated with small cell carcinoma of the lung. Autoantibodies cause inadequate release of ACh from nerve terminals, affecting both nicotinic and muscarinic receptors. With repeated stimulation the amount of ACh in the synaptic cleft increases, leading to an increase in strength, the opposite of that seen with MG. The classical syndrome includes weakness that increases with use of muscles, particularly proximal hip and shoulder muscles; hyporeflexia; and autonomic dysfunction, most commonly seen as dry mouth.[4] Management primarily focuses on treating the underlying neoplastic disorder, although plasmapheresis and immunoglobulin G have been reported to be

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useful.[5]

Diagnostic Strategies New-Onset Myasthenia Gravis. The diagnosis of MG is based on clinical findings and a combination of serologic testing, electromyographic testing, and the edrophonium test. The first two tests are not usually done in the emergency department, although serum can be sent for AChR antibody testing. Results are positive in 80% to 90% of patients with MG. Many patients who are seronegative still respond to traditional therapy aimed at lowering levels of circulating antibodies, suggesting that antibodies are present but not detected.[2] The edrophonium (Tensilon) test is a simple pharmacologic test that can be performed safely at the patient's bedside. The sensitivity and specificity of the test have not been well documented, and there are reports of false positives in cases of botulism and in cases of MG occurring concurrently with other disorders. It is performed by measuring the distance from the upper to the lower eyelid in the most severely affected eye before and after the intravenous administration of the short-acting acetylcholinesterase (AChE) blocking agent edrophonium. Because some patients have a severe reaction to edrophonium, an intravenous test dose of 1 to 2 mg is given first. If no adverse reaction is found and the patient does not dramatically improve in 30 to 90 seconds, a second dose of 3 mg is given. If there is still no response, a final dose of 5 mg is given for a total maximum dosage of 10 mg.[6] Because of potential bradycardia from edrophonium, atropine should be available at the bedside. Also, because of the potential cholinergic effect of increased airway secretions, this test should be used with caution in asthmatics and patients with chronic obstructive pulmonary disease. Another bedside test is the ice test. Cooling decreases symptoms in MG,[7] and heat exacerbates symptoms.[8] In a patient with ptosis who is suspected of having MG, the distance between the upper and lower lids is measured (as in the edrophonium test). An ice pack is then applied to the affected eye for approximately 2 minutes, and the distance between the lids is measured again. A prospective evaluation of this approach that compared patients with MG and patients without MG found the test to be positive (an improvement in distance of at least 2 mm) in 80% of patients with MG and in no patients without MG.[9]

Acute Myasthenic Crisis. Myasthenic crisis is defined as respiratory failure leading to mechanical ventilation.[1] It occurs in 15% to 20% of patients with MG,[] usually within the first 2 years of disease onset. Although it is potentially life-threatening, the mortality from this complication of MG has declined from 40% to 5% since the 1960s with the use of better and more aggressive intensive care unit techniques. Underlying infection, aspiration, and changes in medications—stopping anticholinergic medications or taking a new medication that precipitates weakness—most often set off crisis, but the precipitant may not be found in up to 30% of cases.[12] Some patients experience a severe increase in weakness on starting steroids for chronic therapy. Other precipitants can be surgery and pregnancy ( Box 106-2 ).[1] BOX 106-2 Drugs that May Exacerbate Myasthenia Gravis

Cardiovascular ß-Bl ocke rs Calci um chan nel bloc kers Quin idine Lido

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cain e Proc aina mide

Antibiotics Amin ogly cosi des Tetr acyc lines Clind amy cin Linc omy cin Poly myxi nB Colis tin

Other Phe nytoi n Neur omu scul ar bloc kers Corti cost eroid s Thyr oid repla cem ent The initial step in managing the patient in crisis is stabilization of the airway. In less severe cases in which intubation is not imminent, it is imperative to monitor ventilatory status in the emergency department pending intensive care unit admission. Airway compromise can be detected by various mechanisms already discussed. It is important to look for signs of myasthenic crisis in any patient with MG who presents to the emergency department, even with no complaint of weakness. Many commonly used drugs can adversely affect the treatment of a patient with MG (see Box 106-2 ). A patient with stable MG who has an acute medical or

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surgical condition requires a full neurologic examination. The decision to admit or discharge a patient from the emergency department should take into account the potential for neurologic deterioration in patients with MG.

Management Cholinesterase Inhibitors. Pyridostigmine (60 to 120 mg every 4 to 6 hours) and neostigmine (15 to 30 mg every 4 to 6 hours) are the backbone of chronic outpatient therapy and provide symptomatic improvement, although they are not directed at the underlying immunologic basis of the disease. This class of drugs inhibits the hydrolysis of ACh, leading to increased circulating ACh to stimulate the decreased number of receptors and to compete with the antibodies for binding sites. The most common side effects are those of excessive cholinergic stimulation, such as increased airway secretions and increased bowel motility. At extremes there may be bradycardia or even worsening of weakness, simulating a myasthenic crisis. These drugs are often used as adjunctive therapy to control symptoms while other therapy is being instituted, after which they are often discontinued.[13] The use of intravenous pyridostigmine in the setting of acute exacerbation is controversial. In a review of various therapies for myasthenic crisis, pyridostigmine alone or in combination with prednisolone or plasma exchange appeared comparable to plasma exchange alone. The study reported that 11 of the 63 patients treated for MG crisis suffered cardiac arrest and that 7 of the 10 patients who developed asystole had received pyridostigmine, although there is no evidence that the pyridostigmine was the cause.[12] In addition, some authors reported that most patients with crisis have not responded to AChE inhibition and may benefit from a rest period from AChE inhibitors.[14] Thus, cholinergic drug therapy should be discontinued during crisis when the patient is intubated. In addition, pyridostigmine may complicate mechanical ventilation by increasing the production of pulmonary secretions. It has been proposed that acute decompensation and excessive muscarinic stimulation can be caused by overmedication with AChE inhibitors. The prevalence and importance of this cholinergic crisis are debated in the literature. Nevertheless, the physical examination should distinguish a cholinergic crisis from an exacerbation of the disease. The weakness comes from the excessive stimulation of AChRs by the additional ACh, preventing repolarization, and thus no further muscle contractions can be stimulated. Muscarinic effects of AChE inhibition may include excessive sweating, salivation, lacrimation, miosis, tachycardia, and gastrointestinal hyperactivity.

Immunosuppressant Drugs. Immunosuppressant drugs are often used for the chronic control of MG. Although they have no role in the acute management of a myasthenic crisis, they may be started before extubation of a patient recovering from crisis. Corticosteroids, azathioprine, and cyclosporine have all been used. Of note, the initiation of corticosteroids in patients with moderate to severe weakness may actually precipitate a worsening of weakness or even myasthenic crisis.

Thymectomy. Although the association between thymoma and MG is still not fully elaborated, it is well known that thymectomy for patients with thymoma can lead to remission of MG or enable a reduction in other medications. Thymectomy for patients with MG but without thymoma has been shown to have similar benefits and is recommended for patients younger than 60. Thymectomy in patients between adolescence and 60 years of age leads to remission or improvement in up to 50% of cases.[14] The onset of improvement after thymectomy is often delayed for 2 to 5 years.

Immunomodulatory Therapy. Plasma exchange (plasmapheresis) and intravenous immune globulin (IVIG) can be used for patients with severe exacerbations or preoperatively in patients with stable MG. Plasma exchange removes the AChR antibodies and other immune complexes from the blood. The fall in AChR levels is associated with improvement in symptoms of MG. There is a risk of complications from hypotension or anticoagulation. Because of safety concerns, clinical trials have not been done in children. Although there are no randomized controlled studies of the efficacy of plasma exchange, it is an accepted therapy and is recommended by the American Academy of Neurology for acute exacerbations and for preoperative prophylaxis.[15] Research is exploring plasmapheresis with a staphylococcal protein A immunoa-immunoadsorption system that is more selective for the antibodies.

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Small, uncontrolled studies and case reports of IVIG for patients not responsive to other therapies began to appear in the 1970s. It is difficult to compare these studies because different protocols and preparations have been used. From 50% to 90% of patients treated with IVIG have some improvement after infusion. Current consensus suggests a dose of 0.4 g/kg/day for 5 days in cases of uncontrolled acute exacerbations. There are no blind, controlled comparisons of plasma exchange versus IVIG. One study concluded that IVIG is as effective as plasma exchange.[16] Another retrospective study comparing the two techniques found that plasma exchange leads to improved ventilatory status at 2 weeks compared with IVIG, but it has a higher complication rate.[17] The decision to institute either therapy is based on the input of the consulting neurologist and the resources available at the admitting hospital.

Botulism Principles of Disease Botulism is a toxin-mediated illness that can cause acute weakness leading to respiratory insufficiency. In 1998 the Centers for Disease Control and Prevention (CDC) reported 116 cases of botulism in the United States, 65 of which were categorized as infantile botulism.[18] Clostridium botulinum is an anaerobic, spore-forming bacterium. Three of eight known toxins produced by C. botulinum cause human disease. These are toxin types A, B, and E. Although most cases are isolated events associated with improperly preserved canned foods,[19] there has been an increase in the incidence of botulism from wound infections. In 1995 and 1996, 42 cases of wound botulism were reported in heroin users who injected subcutaneously,[ 20] and in 2003, 4 more cases in Washington were reported from black tar heroin. Botulism is also thought to be a potential agent in bioterrorism. Toxin type E is associated with preserved or fermented fish and marine mammals. These are the most important sources of botulism in Alaska, Japan, Russia, and Scandinavia.[21] The botulinum toxin works by binding irreversibly to the presynaptic membrane of peripheral and cranial nerves, inhibiting the release of ACh at the peripheral nerve synapse. As new receptors are generated, the patient improves.

Clinical Features The toxin blocks both voluntary motor and autonomic functions. Because the disorder is at the neuromuscular junction, there is no sensory deficit and no sense of pain. The onset of symptoms is 6 to 48 hours after the ingestion of tainted food. There may or may not be accompanying signs and symptoms of gastroenteritis, with nausea, vomiting, abdominal cramps, diarrhea, or constipation. The classical feature of botulism is a descending, symmetrical flaccid paralysis. The muscles often affected first are the cranial nerves and bulbar muscles, and the patient presents with diplopia, dysarthria, and dysphagia, followed later by generalized weakness. There may be associated blurring of vision. Because the toxin decreases cholinergic output, anticholinergic signs may be seen in the form of constipation, urinary retention, dry skin and eyes, and increased temperature. Pupils are often dilated and not reactive to light. This can be a point of differentiation from MG. DTRs are normal or diminished. Infantile botulism results from the ingestion of C. botulinum spores that are able to germinate and produce toxin in the high pH of the gastrointestinal tract of infants. The same spores are not active in the gut of adults because of the lower pH. It occurs in infants between the age of 1 week and 11 months and has been implicated as a cause of sudden infant death syndrome. Because spores can survive in honey, it is recommended that it not be fed to infants. The clinical presentation includes constipation, poor feeding, lethargy, and weak cry; consequently, this diagnosis must be in the differential of the floppy infant.[22]

Diagnostic Strategies The diagnosis is made by both clinical findings and exclusion of other processes. The toxin can be identified in serum and stool, but the assay is not commonly available in most hospitals and requires a prolonged turnaround time. If the suspected food source is available, it should also be tested for the toxin.

Management The treatment is initially focused on stabilizing the airway and supportive measures. There is trivalent antitoxin that can shorten the disease course, although it is not clear that the antitoxin decreases ventilator dependence. Nevertheless, the antitoxin should be administered as soon as possible. It is made from horse serum, and allergy testing should be performed before administration. The toxin is available through the CDC (404-639-2888).

Tick Paralysis Principles of Disease

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The pathogenesis of tick paralysis, also known as tick toxicosis, is not fully understood. It is known that a toxin is injected while the tick feeds, and it is referred to as an ixovotoxin. The toxin appears to diminish the release of ACh at the neuromuscular junction and also reduces nerve conduction velocity. It may also have effects at autonomic ganglia, leading to pupillary signs.

Clinical Features Tick paralysis is an acute, ascending, flaccid motor paralysis that can be confused with GBS, botulism, and MG. It typically begins with the development of an unsteady gait, followed by ascending, symmetrical, flaccid paralysis. Although symptoms usually begin 1 to 2 days after the female tick has attached and begun to feed, delays of up to 6 days have been reported.[23] There may be associated ocular signs, such as fixed and dilated pupils, that can help distinguish it from GBS.

Management A tick can be removed using forceps to grasp it as closely as possible to the point of attachment. Care must be taken not to leave mouth parts in the patient's tissue. Although symptoms may resolve rapidly after removal of the tick, supportive measures such as intubation should not be withheld pending resolution of symptoms. It has been noted that the Ixodes holocyclus tick in Australia elaborates a toxin that is very similar to botulinum toxin and that after removal of this tick symptoms may worsen during the succeeding 24 to 48 hours.[24] Recovery in these patients may also be prolonged.

Disorders of the Muscles Perspective Newly acquired weakness originating at the muscular level can be divided into two types: inflammatory and toxic-metabolic. Inflammatory disorders usually produce pain and tenderness, but metabolic disorders do not.

Inflammatory Disorders Principles of Disease The most common inflammatory myopathies are polymyositis (PM) and dermatomyositis (DM). PM may be idiopathic in nature, occur secondary to infections (viral or bacterial), or be seen in conjunction with other disorders such as sarcoidosis or hypereosinophilic syndromes. Inflammatory myopathies cause weakness, pain, and tenderness of the muscles involved. They must be distinguished from simple myalgias related to a fever or cramping that may suggest a myotonia (inability to relax the muscle).

Clinical Features DM and PM can occur at any adult age, although DM may also affect children. There is a slightly increased incidence in women. An associated increased risk of malignancy, especially breast, ovary, lung, gastrointestinal, and lymphoproliferative disorders, has been noted after the diagnosis of DM or PM, although the reported rate of malignancy varies widely. Proximal muscle weakness predominates and leads to complaints of difficulty rising from a seated position or climbing stairs and weakness in lifting the arms over the head. There is often pain and tenderness in these proximal muscles as well. There is a decrease in reflexes as the weakened muscles fail to contract. Thus, the decrease in reflexes is in proportion to the decrease in strength. Fasciculations are not seen, and atrophy is a very late finding. DM is similar to PM, but it is also associated with classical skin findings. These are more prominent in childhood but are also found in adults. They include a periorbital heliotrope and erythema and swelling of the extensor surfaces of joints. The facial rash is usually photosensitive and may also involve the exposed areas of the chest and neck.

Diagnostic Strategies Electrolyte abnormalities must be ruled out and the serum CK checked. If possible, the skeletal muscle isoform (MM) should be distinguished from the cardiac muscle isoform (MB). The CK must be interpreted in light of the entire clinical picture. The presence of an elevated CK does not establish the cause of weakness as a myopathy because some neuropathies can also produce an elevated CK. Similarly, a normal CK does not rule out a myopathy as the cause of weakness. Electromyography and muscle biopsy are used to confirm the diagnosis.[25]

Management PM and DM are usually managed with oral prednisone in a dose of 1 to 2 mg/kg day. When steroids prove ineffective and during acute exacerbations, cytotoxic drugs such as azathioprine or methotrexate are added.

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Fortunately, the degree of rhabdomyolysis seen with the inflammatory myopathies is not sufficient to cause renal impairment.

Metabolic Disorders Perspective Acute, generalized muscle weakness can be seen with severe electrolyte abnormalities of any cause: hypokalemia, hyperkalemia, hypocalcemia, hypercalcemia, hypomagnesemia, and hypophosphatemia. Acute painless myopathies can also be seen with endocrine disorders involving the thyroid, parathyroid, or adrenal glands. Of particular interest are several disorders referred to collectively as the periodic paralyses. This group of entities includes familial periodic paralysis (FPP) of the hyperkalemic and hypokalemic forms and thyrotoxic periodic paralysis (TPP), which is similar to hypokalemic FPP except that it is associated with hyperthyroidism.

Familial Periodic Paralysis Principles of Disease. Patients with FPP experience intermittent attacks of extremity weakness associated with either hyperkalemia or hypokalemia, although the latter is more common. It is most often associated with an inherited genetic mutation.[26] Patients usually report a personal and family history of similar episodes.

Clinical Features and Diagnostic Strategies. Patients may suffer either isolated or recurrent episodes of flaccid paralysis. The lower limbs are involved more often than the upper, although both can be affected. Bulbar, ocular, and respiratory muscles are usually not involved.[27] Onset is rapid; a prodrome of myalgias and muscle cramps may occur but is uncommon; mental status and sensory function are typically preserved, but reports of sensory nerve involvement have been documented.[28] Males are more often affected than females, and there is a higher incidence in Asians, particularly Japanese, although it does occur in other ethnic groups. Attacks may be induced by the injection of insulin, epinephrine, or glucose. The onset of symptoms often follows a high carbohydrate intake (with subsequent insulin rise) and a period of rest.[29] A typical complaint is the acute onset of weakness noted on waking in the morning after a large meal the preceding evening. An electrocardiogram, which should be done immediately in all patients suffering from acute paralysis, demonstrates signs of hyperkalemia or hypokalemia. An immediate potassium level should be ordered; in the hypokalemic form, the potassium level during an attack falls to values below 3.0 mEq/L.

Management. Many cases resolve spontaneously with supportive care alone. The mainstay of management is the treatment of the underlying electrolyte imbalance. In the hypokalemic state the total body potassium is not depleted but has shifted intracellularly.[] Thus, in the repletion of potassium, caution is necessary to prevent overtreatment. For this reason, intravenous potassium should be used sparingly; one or two 10 mEq doses of potassium chloride (KCl), each administered over 1 hour, should be the maximum given intravenously. This can be done in parallel with 40 mEq oral potassium repletion and retesting of serum potassium levels. Intravenous hydration helps to redistribute the body's potassium stores.

Thyrotoxic Periodic Paralysis The clinical picture of TPP is almost identical to that of hypokalemic FPP, and indeed a small number of patients with hypokalemic FPP have hyperthyroidism. In TPP, symptoms related to hyperthyroidism are often present at the same time the patient develops weakness. The relation of the hyperthyroidism to hypokalemia is probably due to increased sodium-potassium adenosine triphosphatase activity[32] but research is limited. Treatment of the hyperthyroid symptoms, such as tachycardia, may help the treatment of the paralysis as well. There is one case report of TPP in which the patient's weakness did not respond to potassium replacement until propranolol was given to treat tachycardia.[33] There is probably a genetic feature underlying this disorder because there is a higher incidence of repeated attacks of hypokalemic periodic paralysis among Japanese and Chinese patients with hyperthyroidism. It is important that all patients have thyroid function testing done after a first episode of hypokalemic paralysis.

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KEY CONCEPTS {, {,

{,

In patients with bilateral upper motor neuron signs and a normal mental status, neuroimaging of the spinal cord should be strongly considered. In patients presenting with acute neuromuscular weakness, complaints of difficulty in breathing or swallowing should heighten suspicion of bulbar involvement with possible airway compromise. In such patients, a forced vital capacity less than 15 mL/kg or a maximal negative inspiratory force less than 15 mm Hg are potential indications for mechanical ventilation. Botulism usually arises as a painless descending paralysis, often first affecting the cranial nerves and bulbar muscles, without sensory deficits or significant alteration of consciousness. The treatment is airway management and administration of antitoxin.

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REFERENCES 1. Thomas CE: Myasthenic crisis: Clinical features, mortality, complications and risk factors for prolonged intubation. Neurology1997;48:1253. 2. Drachman DB: Myasthenia gravis. N Engl J Med1994;330:1797. 3. Massey JM: Acquired myasthenia gravis. Neurol Clin1997;15:577. 4. O'Neill JH, Murray NM, Newsom-Davis J: The Lambert-Eaton myasthenic syndrome. A review of 50 cases. Brain1988;111:577. 5. Penn AS: Lambert-Eaton myasthenic syndrome. In: Rowland LP, ed.Merritt's Textbook of Neurology, 9th ed. Philadelphia: Williams & Wilkins; 1995: 6. Seybold ME: Office Tensilon test for ocular myasthenia gravis. Arch Neurol1986;43:842. 7. Borenstein S, Desmedt JE: Local cooling in myasthenia: Improvement of neuromuscular failure. Arch Neurol1975;32:152. 8. Gutmann L: Heat-induced myasthenic crisis. Arch Neurol1980;37:271. 9. Golnik KC: An ice test for the diagnosis of myasthenia gravis. Ophthalmology1999;106:1282. 10. Fink ME: Treatment of the critically ill patient with myasthenia gravis. In: Ropper AH, ed.Neurological and Neurosurgical Intensive Care, 3rd ed. New York: Raven Press; 1993: 11. Cohen MS, Younger D: Aspects of the natural history of myasthenia gravis: Crisis and death. Ann NY Acad Sci1981;377:670. 12. Mayer SA: Intensive care of the myasthenic patient. Neurology1997;48(Suppl 5):S70. 13. Berrouschot J: Therapy of myasthenic crisis. Crit Care Med1997;25:1228. 14. Mayer SA: Therapy of myasthenic crisis [letter]. Crit Care Med1998;26:1136. 15. Gajdos PH: Clinical trial of plasma exchange and high-dose intravenous immunoglobulin in myasthenia gravis. Ann Neurol1997;41:789. 16. Quershi AI: Plasma exchange versus intravenous immunoglobulin treatment in myasthenic crisis. Neurology1999;52:629. 17. Summary of Notifiable Diseases, United States, 1998. MMWR Morb Mortal Wkly Rep1999;47:1. 18. Shapiro RL: Botulism in the United States: A clinical and epidemiologic review. Ann Intern Med 1998;129:221. 19. Passaro D: Wound botulism associated with black tar heroin among injecting drug users. JAMA 1998;279:859. 20. Mines D: Poisonings: food, fish, shellfish. Emerg Med Clin North Am1997;15:58. 21. Jagoda A, Renner G: Infant botulism: Case report and clinical update. Am J Emerg Med1990;8:318. 22. Tick paralysis—Washington, 1995. MMWR Morb Mortal Wkly Rep1996;45:325. 23. Felz MW: A six-year-old girl with tick paralysis. N Engl J Med2000;342:90. 24. Bartt R: Autoimmune and inflammatory disorders. In: Goetz CG, ed.Goetz Textbook of Clinical Neurology, Philadelphia: WB Saunders; 1999: 25. Rowland LP: Familial periodic paralyses. In: Rowland LP, ed.Merritt's Textbook of Neurology, 9th ed. Philadelphia: Williams & Wilkins; 1995: 26. Ober KP: Thyrotoxic periodic paralysis in the United States: Report of 7 cases and review of the literature. Medicine (Baltimore)1992;71:109. 27. Inshasi J: Dysfunction of sensory nerves during attacks of hypokalemic periodic paralysis. Neuromuscul Disord1999;9:227. 28. Miller D: Severe hypokalemia in thyrotoxic periodic paralysis. Am J Emerg Med1989;7:584. 29. Cannon L: Hypokalemic periodic paralysis. J Emerg Med1986;4:287. 30. Miller JD: Nonfamilial hypokalemic periodic paralysis and thyrotoxicosis in a 16-year-old male. Pediatrics 1997;100:413. 31. Shayne P, Hart A: Thyrotoxic periodic paralysis terminated with intravenous propranolol. Ann Emerg Med 1994;24:734. 32. Chan A: In vivo and in vitro sodium pump activity in subjects with thyrotoxic periodic paralysis. BMJ 1991;303:1096. 33. Rowland LP: Familial periodic paralysis. In: Rowland LP, ed.Merritt's Textbook of Neurology, 9th ed. Philadelphia: Williams & Wilkins; 1995:

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Chapter 107 – Central Nervous System Infections Frank W. Lavoie John R. Saucier

PERSPECTIVE Background Central nervous system (CNS) infections have always been among the most perplexing and devastating illnesses. “Epidemic cerebrospinal fever,” classically described by Viesseux in 1805, was associated with almost universal mortality.[1] The first American epidemic of meningococcal meningitis was recorded in 1806.[2] Since that time, epidemiologic changes have occurred in concert with advances in understanding of disease processes and evolution of effective treatment strategies. The etiologic spectrum of CNS infection has changed considerably as a result of the development and aggressive use of antibiotics and the epidemic emergence of immunocompromising disorders such as infection with the human immunodeficiency virus (HIV). Some of the research on CNS infections has markedly increased in sophistication, which provides insights into pathogenesis, including the role of host mechanisms such as cytokines and other immune components. The pathophysiologic alterations are increasingly understood at the cellular and molecular levels. Likewise, diagnostic tools have been developed that allow precise pathogen identification, most recently using molecular technologies such as polymerase chain reaction (PCR) tests for viral nucleic acids in cerebrospinal fluid (CSF). The initial treatment methodologies began by demonstrating the efficacy of antiserum treatment by Flexner in 1913 and of antibiotics by Colebrook and Kenny in 1936.[] The mortality rates were decreased further with the use of high-dose penicillin by Dowling and colleagues in the 1940s.[5] Unfortunately, despite historical advances, the morbidity and mortality of these disorders remain considerable.

Definitions CNS infections comprise a broad spectrum of disease entities. Meningitis is defined as inflammation of the membranes of the brain or spinal cord and is also called arachnoiditis or leptomeningitis. Encephalitis denotes inflammation of the brain itself, whereas myelitis refers to inflammation of the spinal cord. The terms meningoencephalitis and encephalomyelitis describe more diffusely localized inflammatory processes. Collections of infective and purulent materials may form within the CNS as abscesses. Abscesses may be intraparenchymal, in epidural or subdural intracranial locations, or may be found in intramedullary or epidural spinal locations. This chapter focuses on the more common acute and subacute CNS infections. Infections of the nervous system with HIV or human T lymphotrophic virus, rabies virus, polio or hepatitis viruses, Borrelia burgdorferi (Lyme disease), Treponema organisms (syphilis), parasites, rickettsia, and the chronic and slow infections of the CNS (subacute sclerosing panencephalitis, progressive multifocal leukoencephalopathy, and the prion-mediated spongiform encephalopathies, such as Creutzfeldt-Jakob disease, bovine spongiform encephalopathy, and kuru) are not addressed.

Epidemiology Bacterial meningitis is a common disease worldwide. Meningococcal meningitis is endemic in parts of Africa, and epidemics commonly occur in other countries, including the United States. A variety of other pathogens are also causative.[] The overall incidence of bacterial meningitis in the United States is 5 to 10 cases per 100,000 people per year.[11] Men are affected more often than women.[11] The incidence of bacterial meningitis increases in late winter and early spring, but the disease may occur at any time of the year.

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Because most cases are unreported, the actual incidence of viral meningitis is unknown. It is estimated to affect between 11 and 27 individuals per 100,000 people.[12] A prominent increase of cases is seen in summer months, which is concurrent with seasonal predominance of the enterovirus group of the picornaviruses. The same organisms responsible for viral meningitis may also be associated with encephalitis. Encephalitis is, however, far less common, and the ratio of cases of meningitis to encephalitis varies according to the specific pathogen. Arbovirus infection is transmitted by an insect vector, although clinical disease develops in only a small percentage of the people bitten. Before 1999, approximately 19,000 cases of encephalitis were hospitalized in the United States annually. Since then, there has been a rapid increase because of the West Nile virus (WNV). In 2003, more than 8000 additional cases were hospitalized because of WNV alone.[] Approximately 2000 cases of brain abscess occur in the United States annually.[15] Although CNS abscesses may occur at any age and any time of year, they are more commonly seen in men than women.[] CNS abscesses are associated with local contiguous and remote systemic infections, intravenous (IV) drug use, neurologic surgery, and cranial trauma. Brain abscess secondary to otitis media most often occurs in pediatric or older adult populations. When associated with sinusitis, it most often arises among young adults. Increasingly, CNS abscesses are seen in the immunocompromised population, particularly those with HIV infection, and among bone marrow and solid organ transplant recipients. However, antimicrobial prophylaxis of immunosuppressed patients and more aggressive treatment of otitis and sinusitis have decreased the overall incidence to 0.9 per 100,000 person-years.[15]

PRINCIPLES OF DISEASE Etiology Meningitis Meningeal inflammation may be caused by a variety of disease processes, but the infectious etiologies predominate. Some of the more common and important infectious etiologic agents in CNS infection, with emphasis on the United States, are listed in Boxes 107-1 and 107-2 .[] Among the bacterial etiologies, Streptococcus pneumoniae remains the predominant pathogen in adult patients, followed by Neisseria meningitidis and Listeria monocytogenes.[] N. meningitidis is the predominant organism in adults younger than 45 years. Five major serogroups cause most meningococcal disease worldwide (A, B, C, Y, and W-135). Serogroup A accounts for the majority of cases of meningococcal meningitis in developing nations.[ 21] Serogroup distribution for invasive disease has changed markedly in the United States, with B, C, and Y now most commonly responsible.[] These pathogens account for the bulk of cases in nontraumatic meningitis, although virtually any organism can be encountered, particularly among patients who are elderly, alcoholic, or immunosuppressed and those who have cancer. Regional variations should also be considered. For example, Lyme meningitis has become more prevalent in the northeastern United States. BOX 107-1 Bacterial, Fungal, and Parasitic Pathogens in Central Nervous System Infection

Bacterial Bacillus sp. Bacteroides Borrelia burgdorferi (Lyme disease) Other Enterobacteriaceae Escherichia coli Haemophilus influenzae Listeria monocytogenes Mycobacterium tuberculosis Mycoplasma Neisseria meningitidis Proteus Pseudomonas aeruginosa Staphylococcus aureus

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Streptococci Streptococcus pneumoniae Treponema (syphilis) Others

Fungi Blastomyces Candida Cladosporium Coccidioides Cryptococcus Histoplasma Paracoccidioides Others

Parasites Amoebae Taenia solium (cysticercosis) Toxoplasma gondii Others

Rickettsia Rickettsia rickettsii (Rocky Mountain spotted fever) Others BOX 107-2 Viral Etiologies in CNS Infection

Arboviruses Bunyaviruses Calif ornia ence phali tis virus Alphaviruses East ern equi ne ence phali tis virus

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Wes tern equi ne ence phali tis virus Vene zuel an equi ne ence phali tis virus Flaviviruses Japa nese B ence phali tis virus Colo rado tick fever virus St. Loui s ence phali tis virus Wes t Nile virus Others Herpes viruses Herp es simp lex virus es (HS V) Epst einBarr virus Cyto meg alovi rus

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Varic ellazost er virus Enteroviruses Cox sack ievir uses Ech oviru ses Polio virus Lymphocytic choriomeningitis virus (LCMV) Retroviruses Hum an imm unod efici ency virus (HIV) Hum an T lymp hotro phic virus (HTL V) Paramyxoviruses Mea sles virus Mum ps virus Rabies virus Others Meningeal infection may also occur in associa-tion with a dural leak secondary to neurosurgery or neurotrauma. S. pneumoniae, Staphylococcus aureus, Pseudomonas aeruginosa, and coliform bacteria are seen most commonly in this population. Viral meningitis may likewise be caused by a variety of etiologic agents.[18] Enteroviruses are statistically encountered most commonly.[26] Unfortunately, precise definition of the etiologic agent is often impossible. Fungal and parasitic meningitides are additional concerns, particularly among immunocompromised patients.[] Noninfectious meningitides include drug-induced meningitis, carcinomatous meningitis, CNS involvement in serum sickness, vasculitis, systemic lupus erythematosus, Behçet's disease, sarcoidosis, and others ( Box 107-3 ). The differentiation of noninfectious from infectious etiologies can occasionally be perplexing. BOX 107-3 Noninfectious Meningitides

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Drug-induced meningitis Non stero idal anti-i nfla mm atory drug s (NS AIDs ) Trim etho prim Isoni azid Othe rs Carcinomatous meningitis Serum sickness Vasculitis Systemic lupus erythematosus Behçet's disease Sarcoidosis Others

Encephalitis Arboviruses and herpes simplex virus (HSV), a human herpes virus (HHV), are the most common causes of endemic and sporadic cases of encephalitis, respectively. Children are the most vulnerable to infection with these viruses, although adults are also commonly affected. Epidemics of viral encephalitis have been attributed to a wide variety of viral agents. WNV, a flavivirus, first infected humans in the New York City area and rapidly spread to 47 states by 2003.[27] Varicella, herpes zoster, HHV 6 and 7, and Epstein-Barr virus have been increasingly reported to be the cause of encephalitis in immunocompetent hosts.[] Vaccinia encephalitis has been recognized in those receiving vaccination for smallpox.[30] Postinfectious encephalomyelitis is also induced by a variety of viral pathogens, most commonly by the measles virus.[31] However, Mycoplasma pneumoniae and idiopathic causes are becoming more common in developed countries.

Central Nervous System Abscess The etiologies of CNS abscess are multiple and reflect the primary infective process and the immune state of the human host. A variety of mixed pathogens may be responsible for intracranial abscesses. Streptococci, particularly the Streptococcus milleri group, have been identified in nearly 50% of brain abscesses.[32] Anaerobic bacteria, predominantly Bacteroides species, are commonly seen when the primary infectious process is chronic otitis media or pulmonary disease. S. aureus is also often identified, particularly after cranial penetration from surgery or trauma.[33] The Enterobacteriaceae are an additional common isolate. Opportunistic fungal and parasitic etiologies are often seen in the immunosuppressed.[32] Culture of epidural and subdural abscesses more often yields a single organism, with streptococci most commonly seen when associated with contiguous spread and S. aureus and gram-negative rods most commonly encountered after neurologic trauma.[9] Etiologic agents in spinal abscess are similarly varied. S. aureus is most commonly encountered.

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Pathophysiology Bacterial Meningitis The pathogenetic sequence in bacterial meningitis has been well characterized.[] The first step is nasopharyngeal colonization and mucosal invasion. Although colonization rates vary, virulent microbes use secretion of immunoglobulin A proteases and induce cilio-stasis of mucosal cells. After penetration occurs by a variety of mechanisms, bacterial intravascular survival occurs because of evasion of the complement pathway. The varying capsular properties of each organism protect the bacteria. The third step occurs when the bacteria cross the blood-brain barrier to enter the CSF. The dural venous sinuses, cribriform plate area, and choroid plexus have all been implicated as potential sites of invasion. Although the mechanism of invasion is not completely understood, host defense mechanisms within the CSF are often ineffective; there are low levels of complement, immunoglobulin, and opsonic activity. Bacterial proliferation then occurs, which stimulates a convergence of leukocytes into the CSF. Meningeal and subarachnoid space inflammations are also associated with the release of cytokines into the CSF, most notably tumor necrosis factor and interleukins 1 and 6.[] This results in increased permeability of the blood-brain barrier, cerebral vasculitis, edema, and increased intracranial pressure. A subsequent decrease in cerebral blood flow leads to cerebral hypoxia. Glucose transport into the CSF is decreased coincidentally with an increased use by brain, bacteria, and leukocytes, which depresses CSF glucose concentrations. The increased permeability leads to increased CSF proteins.

Viral Meningitis and Encephalitis Viruses enter the human host through the skin, as in arbovirus injection from a mosquito vector; through the respiratory, gastrointestinal, or urogenital tract; or by receipt of infected blood products or donor organs.[] Viral replication subsequently occurs outside the CNS, most often followed by hematogenous spread to the CNS. Additional routes into the CNS include retrograde transmission along neuronal axons and direct invasion of the subarachnoid space after infection of the olfactory submucosa.[] Fortunately, most systemic viral infections do not result in meningitis or encephalitis. The development and subsequent magnitude of viral infection depend on the virulence of the specific virus, the viral inoculum level, and the state of immunity of the human host. The tropism of the virus for specific CNS cell types also influences the focality of disease and its manifestations.[39] Particular viruses may preferentially attack cortical, limbic, or spinal neurons, oligodendria, or ependymal cells. An example is the tropism of HSV for the temporal lobes and the development of temporal lobe seizures and behavioral changes in afflicted patients.

Fungal Meningitis Fungal meningitis probably develops in much the same way as bacterial meningitis, although this has been incompletely studied. Pulmonary exposure followed by hematogenous spread is the primary pathogenetic mechanism in most cases. Immune system defects or immunosuppression compromises host defense mechanisms, with ensuing development of CNS infection.

Central Nervous System Abscess Intraparenchymal brain abscesses, subdural empyema, or intracranial or spinal epidural abscesses form by inoculation of the CNS from contiguous spread of organisms from a sinus, middle ear, or dental infection or metastatic seeding from a distant site, usually from pulmonary infection, endocarditis, or osteomyelitis[] ( Figure 107-1 ). The primary infection can be identified in 75% to 85% of cases. These conditions may also follow surgery or penetrating cranial trauma, particularly when bone fragments are retained in brain tissue. Otogenic abscesses occur most commonly in the temporal lobe in adults and cerebellum in children, whereas sinogenic abscesses typically occur in frontal areas.[32] Multiple brain abscesses suggest hematogenous spread of organisms, although solitary lesions may also occur. The pulmonary system is the most common source of hematogenous spread.[9]

Figure 107-1 Central nervous system abscess: com puted tom ography of an intraparenchym al abscess (arrows).

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CLINICAL FEATURES Symptoms and Signs Numerous host factors have been implicated in the acquisition of meningitis ( Box 107-4 ).[41] Although these factors alone and in combination increase the risk of meningitis, the disease often occurs in patients with none of these factors. BOX 107-4 Host Factors Predisposing to Meningitis

Age 60 yr Male gend er Low soci oeco nomi c statu s Cro wdin g (e.g., milit ary recr uits) Sple nect omy Sickl e cell dise ase Afric an-A meri can race Alco holis m and cirrh osis Diab etes Imm unol ogic defe

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cts Rec ent colo nizat ion Dura l defe ct (e.g., trau mati c, surgi cal, cong enita l) Cont inuo us infec tion (e.g., sinu sitis) Hou seho ld cont act with meni ngiti s patie nt Thal asse mia majo r Intra veno us drug abus e Bact erial endo cardi tis Vent ricul operi tone al shun

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t Malig nanc y Many patients with meningitis present with advanced disease; in these patients, the diagnosis of acute meningitis is strongly suspected. The constellation of symptoms that may classically occur in an acute CNS infection consists of fever, headache, photophobia, nuchal rigidity, lethargy, malaise, altered sensorium, seizures, vomiting, and chills.[] Unfortunately, more subtle presentations are also common. Immunosuppressed and geriatric patients present a diagnostic challenge because the classical signs and symptoms of meningitis may not be present. Although some degree of fever is present in most patients, as are a headache and neck stiffness, meningitis should be carefully considered in any immunosuppressed patient with symptoms or signs of infectious disease. Often, the only presenting sign of meningitis in the elderly patient is an alteration of mental status. However, a meta-analysis suggested that the absence of fever, stiff neck, and mental status change excludes meningitis in immunocompetent adults.[42] The presentation of fungal meningitis can be obscure even in the healthy adult population. Headache, low-grade fever, lassitude, and weight loss may be present but often to such a mild degree that the correct diagnosis is not initially considered.[7] This is also true of tuberculous meningitis, which often has a protracted course and a vague nonspecific presentation consisting of fever, weight loss, night sweats, and malaise, with or without headache and meningismus.[6] The physical findings in meningitis vary, depending on the host, causative organism, and severity of the illness. Nuchal rigidity or discomfort on flexion of the neck is common. Kernig's and Brudzinski's signs are present in approximately 50% of adults.[9] Described in 1882 by Vladimir Kernig, Kernig's sign is present in the patient if the examiner is unable, because of resistance and hamstring pain, to straighten the patient's leg passively to a position of full knee extension when the patient is lying supine with the hip flexed to a right angle. Jozef Brudzinski initially described five signs, two of which are currently utilized.[2] The contralateral sign is present if an attempt to flex the hip passively on one side is accompanied by a similar movement of the other leg. The neck sign is present if attempts to flex the neck passively are accompanied by flexion of the hips. The absence of jolt accentuation of headache with this maneuver may be useful in obviating the need for lumbar puncture (LP) in a patient with low suspi-cion for meningitis.[43] Deep tendon reflexes may be increased, and ophthalmoplegia may be present—especially of the lateral rectus muscles. The systemic findings may include an obvious source of infection such as sinusitis, otitis media, mastoiditis, pneumonia, or urinary tract infection. Various manifestations of endocarditis may be present. Arthritis may be seen with N. meningitidis and occasionally with other bacteria.[41] Petechiae and cutaneous hemorrhages are widely reported with meningococcemia but also occur with Haemophilus influenzae, pneumococcal organisms, L. monocytogenes, and echovirus infections, in addition to staphylococcal endocarditis.[41] Endotoxic shock with vascular collapse often develops in severe meningococcal disease, but shock may be present in the advanced stages of any bacterial meningitis. Any determination of a serious systemic infection should encourage rather than dissuade the clinician from considering the possibility of a concomitant CNS infection. Patients with encephalitis may also have symptoms of meningeal irritation. An alteration of consciousness occurs in virtually all patients. Fever, headache, and a change of personality are also usually present.[44] Hallucinations and bizarre behavior may precede motor, reflex, and other neurologic manifestations by several days, occasionally prompting an initial diagnosis of a psychiatric disorder. Because focal neurologic deficits and seizures occur much more commonly with encephalitis than meningitis, there may also be diagnostic confusion with a brain abscess. Distinguishing the etiologic agent in encephalitis is clinically difficult, although HSV encephalitis results in a higher incidence of dysphasia and seizures.[45] In some patients, WNV produces a myelitis that affects the anterior horn cells of the spinal column, resulting in a flaccid paralysis with a clear sensorium, similar to findings in polio or Guillain-Barré syndrome.[27] Patients with intracranial abscess may be indistinguishable from those with meningitis or encephalitis. Most patients with intraparenchymal abscess have a subacute course of illness, with symptoms progressing during the course of 2 or more weeks. However, nuchal rigidity and fever are present in fewer than 50% of cases. Focal neurologic deficits are present in most of these patients. A large number of patients exhibit papilledema, which is a rare finding in meningitis. An abrupt neurologic deterioration that results from uncal

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herniation or rupture into the ventricular system may occur. Patients with a subdural or epidural abscess most often have headache, fever, and focal signs, although more subtle presentations are common. Most of the patients with spinal abscess typically present with spinal pain and other symptoms and signs of cord compression but not necessarily with fever.[46]

Complications Bacterial Meningitis The immediate complications of bacterial meningitis include coma (with loss of protective airway reflexes), seizures, cerebral edema, vasomotor collapse, disseminated intravascular coagulation, respiratory arrest, dehydration, syndrome of inappropriate secretion of antidiuretic hormone, pericardial effusion, and death ( Box 107-5 ).[10] Various delayed complications include multiple seizures, focal paralysis, subdural effusions, hydrocephalus, intellectual deficits, sensorineural hearing loss, ataxia, blindness, bilateral adrenal hemorrhage (Waterhouse-Friderichsen syndrome), peripheral gangrene, and death.[41] BOX 107-5 Complications of Bacterial Meningitis

Immediate Com a Loss of airw ay refle xes Seiz ures Cere bral ede ma Vaso moto r colla pse Diss emin ated intra vasc ular coag ulati on (DIC ) Res pirat ory arre st Deh ydrat ion Peri

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cardi al effus ion Deat h Othe rs

Delayed Seiz ure disor der Foca l paral ysis Sub dural effus ion Hydr ocep halu s Intell ectu al defic its Sen sorin eural heari ng loss Ataxi a Blind ness Bilat eral adre nal hem orrh age Deat h Othe rs The case fatality rate for pneumococcal meningitis averages 20% to 25%, with higher fatality rates occurring in patients with serious underlying or concomitant disease or advanced age.[] The prognosis is related to the degree of neurologic impairment on presentation. Overall, 20% to 30% of the survivors of pneumococcal

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meningitis have some residual neurologic deficit.[41] The case fatality rate for Listeria meningitis may be as high as 40%.[20] With the advent of antibiotic therapy, the mortal-ity from meningococcal meningitis has markedly decreased to less than 20%, but it remains substantially higher in elderly patients or in those who also have meningococcemia.[48] Although most of the complications and sequelae are less common than with pneumococcal disease, the incidence of Waterhouse-Friderichsen syndrome is dramatically higher when meningococcemia is present.[41] The overall mortality rate in community-acquired gram-negative meningitis has been less than 20% since the introduction of the third-generation cephalosporins.[8]

Viral Meningitis With rare exceptions, the overall prognosis for complete recovery from viral meningitis is excellent. Various complications related to the systemic effects of the particular virus include orchitis, parotitis, pancreatitis, and various dermatoses. Usually all of these complications resolve without sequelae.[18]

Viral Encephalitis The outcomes in viral encephalitis are dependent on the infecting agent. Encephalitis caused by Japanese encephalitis virus, Eastern equine virus, and St. Louis encephalitis virus is severe, with high mortality rates and virtually universal neurologic sequelae among survivors.[49] WNV produces encephalitis in only 0.5% of those infected, yet it resulted in 120 deaths in 2003.[14] Western equine virus and California encephalitis virus cause milder infections, and death is rare. The incidence of neurologic sequelae is highly variable and appears to depend on both the host and the infecting agent.[49] The mortality from HSV encephalitis before the use of acyclovir was 60% to 70%. Acyclovir treatment has reduced the mortality to approximately 30%.[31] Common sequelae observed among survivors include seizure disorders, motor deficits, and changes in mentation.

Tuberculous Meningitis Death from tuberculous meningitis in the adult age group ranges from 10% to 50% of cases, with the incidence directly proportional to the patient's age and the duration of symptoms before presentation. Focal ischemic stroke may result from the associated cerebral vasculitis. In advanced disease, up to 25% of patients may require some neurosurgical procedure for obstruction (ventriculoperitoneal shunt or drainage).[ 50] In most patients some neurologic deficit develops, but severe long-term sequelae among survivors are unusual.[]

Fungal Meningitis Common CNS complications with fungal meningitis include abscesses, papilledema, neurologic deficits, seizures, bone invasion, and fluid collections. Direct invasion of the optic nerve results in ocular abnormalities in up to 40% of patients with cryptococcal meningitis.[7] The mortality rate is high but variable and is related to the timeliness of diagnosis, underlying illness, and therapeutic regimens.

Central Nervous System Abscess With the early diagnosis afforded by the use of the cranial computed tomography (CT) scan; appropriate antimicrobial therapy; and combined management approaches with surgery, aspiration, and medical therapy, the mortality from brain abscess has declined dramatically from approximately 50% to less than 20%.[] A seizure disorder is the most common sequela of intracranial abscess, occurring in 80% of patients.[ 8] Other neurologic sequelae of intracranial abscesses, including focal motor or sensory deficits or changes in mentation, are common. Complications of spinal abscess primarily result from cord compression, including paralysis, motor and sensory deficits, and bowel and bladder dysfunction. Generalized spread of CNS infection and death may also occur.[46]

DIAGNOSTIC STRATEGIES Lumbar Puncture General Considerations Because the consequences of missing a CNS infection are devastating, CNS infection must be presumed to be present until excluded. The possibility of the diagnosis of meningitis mandates LP unless the procedure is contraindicated by the presence of infection in the skin or soft tissues at the puncture site or the likelihood of brain herniation.[31] Adherence to this principle prevents a delay in diagnosis, which substantially

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increases the morbidity and mortality of the disease. Some patients have clinically obvious bacterial meningitis, and CSF examination serves primarily to help identify the organism, thereby facilitating the appropriate treatment. Most patients, however, present more of a diagnostic problem, and analysis of the CSF fluid constitutes the critical step in the elucidation of the presence of CNS infection.

Increased Intracranial Pressure In most patients with bacterial meningitis, LP may be safely performed without antecedent neuroimaging studies. As this may not be the case in other brain pathologies, in many circumstances it is advisable to obtain a CT scan of the head before performing an LP ( Box 107-6 ).[52] These indications must be carefully weighed against the patient's condition, the probability of meningitis, and the availability of the CT or magnetic resonance imaging (MRI) scan.[8] BOX 107-6 Indications for Computed Tomography Scan before Lumbar Puncture in Suspected Bacterial Meningitis

Immunocompro mised state History of Stro ke Mas s lesio n Foca l infec tion Hea d trau ma Seizure within last 7 days Abnormal level of consciousness Inability to answer questions or follow commands appropriately Abnormal visual fields or paresis of gaze Focal weakness Abnormal speech It has been conventionally asserted that an LP in the presence of increased intracranial pressure may be harmful or fatal to the patient. Although data to address this concern are limited, the presence of focal neurologic signs does appear to be associated with a dramatic increase in complications from LP. These patients may deteriorate precipitously during or after the procedure.[53] Patients with a markedly depressed sensorium that precludes careful neurologic examination or those with a focal neurologic deficit, papilledema, seizures, or evidence of head trauma must be considered to be at risk

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for a herniation syndrome that may be exacerbated by an LP. If the presentation is an acute, fulminating, febrile illness and bacterial meningitis is the concerning diagnosis, early initiation of antimicrobial therapy is mandatory because of the association of prognosis and time to treatment.[54] The algorithmic alternatives are therefore (1) immediate LP followed by initiation of antibiotic treatment before obtaining the results or (2) initiation of antibiotic treatment followed by a cranial CT scan and then an LP. The latter choice of empirical treatment with antibiotics is now the routine in many institutions. This reflects the efficacy of current methodologies of identification of causative organisms by means other than bacteriologic cultures.

Cerebrospinal Fluid Analysis Opening Pressure The normal CSF pressure in an adult varies from 50 to 200 mm H2O. This value applies only to patients in the lateral recumbent position and may increase severalfold when the patient is in the sitting position. The pressure is often elevated in bacterial, tuberculous, and fungal meningitides and a variety of noninfectious processes.[44] Pressure may be falsely elevated when the patient is tense or obese or has marked muscle contraction.

Collection of Fluid At least three sterile tubes each containing at least 1 to 1.5 mL of CSF should be obtained and numbered in sequence. A fourth tube may be desirable should later studies such as viral cultures or a Venereal Disease Research Laboratories (VDRL) test for syphilis become necessary. The fluid should be sent to the laboratory for immediate analysis of turbidity, xanthochromia, glucose, protein, cell count and differential, Gram's stain, bacterial culture, and antigen testing ( Table 107-1 ). In certain cases an India ink stain, a bacteriologic stain for acid-fast bacilli, or a VDRL test should be obtained. When only a small amount of fluid can be obtained, the most important studies are the cell count with differential, Gram's stain, and bacterial cultures. Ideally, the cell count should be performed on both the first and third or fourth tubes to help differentiate true CSF pleocytosis from contamination of the specimen by a traumatic LP. Table 107-1 -- Analysis of Cerebrospinal Fluid Test Normal Value

Significance of Abnormality

1000 mg/dL) in the presence of a relatively benign clinical presentation should suggest fungal disease.[7]

India Ink Preparation India ink staining of the CSF should be performed when a diagnosis of cryptococcal meningitis is being considered. The demonstration of budding organisms ( Figure 107-2 ) is virtually diagnostic for cryptococcal disease but occurs in only one third of the cases.[7] A more definitive diagnostic test is the cryptococcal antigen.

Figure 107-2 India ink staining of the cerebrospinal fluid.

Lactic Acid Although nonspecific, elevations in CSF lactic acid concentrations (>35 mg/dL) are potentially indicative of bacterial meningitis. Normal lactate levels (>35 mg/dL) are seen in patients with viral meningitides.

Antigen Detection Counterimmunoelectrophoresis (CIE), latex agglutination, and coagglutination are methods of detecting specific antigens. These tests are particularly useful in patients receiving antibiotic treatment before CSF sampling because the tests depend on the presence of only an antigen and not viable organisms. The CIE techniques that are performed for the most common bacterial pathogens demonstrate high sensitivity and specificity for bacterial antigens, particularly when performed on CSF, blood, and urine simultaneously. Latex agglutination techniques are, however, more rapid and sensitive and are replacing the use of CIE in many facilities. Although reported results vary, the sensitivities of antigen tests are 50% to 90% for Neisseria organisms, 50% to 100% for S. pneumoniae, and approximately 80% for H. influenzae. A specific agglutination test for cryptococcal antigen is also highly sensitive (90%) and specific. Cultures are always indicated because a negative antigen test does not exclude the possibility of any particular bacterial or fungal etiology. Antigen and antibody testing is also being used to identify viral and atypical pathogens. These have particular utility in HSV encephalitis. Enzyme-linked immunosorbent assays can detect HSV antibody production.[64] Unfortunately, the appearance of antibody in CSF occurs too late to aid in any therapeutic decision analysis. PCR amplification and the identification of HSV DNA have demonstrated a sensitivity of 95% to 100% and a specificity of 100% early in the disease and have markedly decreased the need for diagnostic brain biopsy in this disorder.[] PCR has improved the diagnosis of tuberculous meningitis, with a sensitivity of 80% to 85% and a specificity of 97% to 100%, and is superior to standard techniques.[] PCR has additionally been shown to be superior in identifying bacteria, enteroviruses, and other viral etiologies in both immunocompromised and immunocompetent patients.[] Reported sensitivities of detection in CSF by PCR for N. meningitidis, H. influenzae, and S. pneumoniae are 88%, 100%, and 92%, with nearly 100% specificity.[] The sensitivities of bacteriologic culture are much lower, especially for N. meningitidis at 37% to 55% and H. influenzae at 50%.

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[]

In addition, PCR assays have nearly tripled the yield of viral culture in identifying the etiologic agent.[77] In studies of enteroviral meningitis, sensitivities and specificities for PCR ranged from 86% to 100% and 92% to 100%, respectively.[78] PCR has been shown to be at least as sensitive as culture technique in detecting cryptococcal meningitis. Quantitative PCR may be of benefit in monitoring response to therapy in some forms of severe disease.[28] The growing availability of these molecular techniques does not, however, suggest that they should be routinely employed. Most cases of acute bacterial meningitis are readily diagnosed and treated on the basis of the standard Gram stain and culture. PCR should be reserved for less clear presentations, patients pretreated with antibiotics, and cases in which concern exists for tuberculous, cryptococcal, and treatable viral CNS infections.[79]

Bacteriologic Cultures Although results are not available for emergency management, bacteriologic cultures of CSF should be performed. Bacterial culture yields are significantly decreased in patients pretreated with antibiotics. Viral cultures may also be indicated.

Other Tests A variety of additional, nonspecific tests of CSF have been advocated. These include measuring CSF lactate dehydrogenase, C-reactive protein, and the limulus lysate test; however, none of these have demonstrated a high degree of clinical usefulness. Likewise, the evaluation of CSF chloride as a diagnostic aid for tuberculous meningitis is no longer clinically relevant.

Neuroimaging Techniques A cranial CT scan or MRI scan is indicated in the evaluation of any patient with presumed CNS infection in whom there is the possibility of an intracranial abscess, intracranial hemorrhage, or mass lesion. In the diagnostic evaluation of acute meningitis, however, a CT scan should not unnecessarily delay LP or antimicrobial therapy. The CT scan may also show hypodense lesions in the temporal lobes in patients with HSV encephalitis, although an MRI scan reveals this abnormality much earlier in the disease process. A contrast-enhanced cranial CT scan or MRI scan is invaluable in the diagnosis of a CNS abscess.[16] MRI scanning is also helpful in the evaluation of other infectious and noninfectious encephalitides.

Additional Investigations As with other infectious diseases, the complete blood count with differential is a nonspecific adjunct in the diagnostic evaluation of a patient suspected to have a CNS infection. The peripheral cell counts are often normal in the presence of significant disease and may even be depressed, particularly in elderly or immunosuppressed persons. A “normal” leukocyte count and differential should not dissuade the emergency physician from performing a diagnostic LP, obtaining a CT scan, or otherwise pursuing the diagnosis of a CNS infection. Even when antimicrobial therapy has already been administered, two or three blood cultures should be obtained for all patients who are being evaluated for a CNS infection. The blood cultures can identify the causative organisms more often when the meningitis is caused by pneumococcus than meningococcus. Although blood cultures are not immediately useful in the acute diagnosis of meningitis in the emergency department, they may be of considerable clinical importance later in the management of the disease. The cultures are helpful in identifying a causative organism in only a small minority of cases of brain abscess. As many as 50% of patients with pneumococcal meningitis also have evidence of pneumonia on an initial chest x-ray study. This association occurs in fewer than 10% of the cases of meningitis caused by H. influenzae type B and N. meningitidis and in approximately 20% of cases of meningitis caused by other organisms. The identification of a pulmonary infection on chest radiography may assist in identification of causative organisms and appropriate antimicrobial therapy in approximately 10% of cases of brain abscess.[ 16]

Other ancillary investigations such as echocardiography, cultures of other body fluids, and bone scans may be undertaken as necessary to evaluate coexistent or complicated disease. Serum electrolytes, glucose, urea nitrogen, and creatinine levels should be measured to facilitate the interpretation of the CSF glucose level and to establish the level of renal function and the state of electrolyte balance. Although organism-specific abnormalities are uncommon, hyponatremia has been associated with tuberculous

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meningitis. A number of characteristic but not pathognomonic electroencephalographic (EEG) abnormalities have been associated with HSV type 1 encephalitis. The presence of focal or lateralized EEG abnormalities in the presence of an encephalitis syndrome should be considered strong evidence supporting a diagnosis of HSV encephalitis.[80]

DIFFERENTIAL CONSIDERATIONS Patients with meningitis may have symptoms and signs ranging from mild headache with fever to frank coma and shock. To facilitate the discussion of diagnosis and treatment, meningitis may be divided into three clinical syndromes: acute meningitis, subacute meningitis, and chronic meningitis. Acute meningitis encompasses patients with ob-vious signs and symptoms of meningitis who are evaluated in less than 24 hours after the onset of their symptoms and who rapidly deteriorate. In many of these patients the diagnosis of meningitis is not in doubt, and the crucial step is to initiate antimicrobial therapy immediately. The most likely pathogens in this syndrome are S. pneumoniae and N. meningitidis. Although H. influenzae has been reported in this context, it is not commonly implicated in the adult population.[] In the syndrome of subacute meningitis, the symptoms and signs causing the patient to seek care have developed during a period of 1 to 7 days. This syndrome includes virtually all cases of viral meningitis, along with most of the bacterial and some of the fungal etiologies.[] The differential diagnosis depends on the symptoms and signs at presentation. Among elderly and immunosuppressed individuals, a change in the patient's mental status may be the only presenting sign in meningitis. Even when a fever is present, the patient's change in mental status may be misattributed to another disease outside the CNS, such as pneumonia or urinary tract infection; neck stiffness may be misattributed to degenerative joint disease. The elderly patient is at high risk for meningitis and, rather than constituting a diagnostic endpoint, the identification of an infection outside the CNS in such a patient is a clear indication for LP because of the risk of bacteremic seeding by the involved organisms. The differential diagnosis of encephalitis and brain abscess occurs in the context of the subacute meningitis syndrome. Brain abscess should be considered, especially if fever is minimal or absent or if there are focal neurologic findings. The presence of fever, altered sensorium, headache, seizures, and personality change is consistent with encephalitis. In addition, diagnoses such as subdural empyema, brain tumor, subarachnoid hemorrhage, subdural hematoma, and traumatic intracranial hemorrhage should be considered. In these circumstances a cranial CT scan should be obtained before performing an LP. The spectrum of chronic meningitis includes some of the viral meningitides as well as meningitis caused by tubercle bacilli, syphilis, and fungi. Many of the patients in this group have had symptoms for at least 1 week before presentation and generally have a prolonged indolent course marked by difficult and changing diagnoses and multiple therapies.[] In addition to tuberculous, fungal, and syphilitic meningitides, the differential diagnosis of the chronic meningitis syndrome is extensive ( Box 107-7 ).[9] BOX 107-7 Differential Considerations in Chronic Meningitis

Tube rculo us meni ngiti s Fung al centr al nerv ous syst em (CN

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S) infec tions Terti ary syph ilis CNS neop lasm Lupu s cere britis Sarc oido sis Rhe umat oid arthri tis Gran ulom atou s angii tis Vario us ence phali tides Toxi c ence phal opat hies Meta bolic ence phal opat hies Multi ple scler osis Chro nic subd ural hem atom a Othe rs

MANAGEMENT

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Prehospital Care The field stabilization and transport of the patient with a suspected CNS infection are dictated by the patient's condition. In cases in which the patient is stable and alert with normal vital signs, application of oxygen and rapid transport suffice, with or without establishing an IV line. If an altered mental status is present, protection or establishment of an adequate airway may be necessary. Shock, if present, may require IV crystalloid infusion. Seizures may usually be managed supportively through protection of the patient's airway and prevention of injury, although prolonged or recurrent seizures may require IV anticonvulsants.

Assessment and Stabilization Septic shock, hypoxemia, seizures, cerebral edema, and hypotension resulting from dehydration require aggressive management. When possible, a thorough history should be obtained from the patient, family members, or ambulance personnel with particular emphasis on preexisting conditions that may complicate the patient's disease. Examples include recent neurosurgery, trauma, a history of leukopenia, immunocompromise, or diabetes mellitus. Hypotension or shock should be treated as indicated with isotonic crystalloid infusion, high-flow oxygen, and pressors. IV dextrose may be required for hypoglycemia secondary to depletion of glycogen stores. Alcoholic or nutritionally compromised patients should also receive 50 to 100 mg of thiamine IV. In cases of moderate to severe hypotension, central venous pressure monitoring should be initiated and used as a guide for additional IV fluids or vasopressors. Active airway management with endotracheal intubation may be required, particularly in cases of coma, recurrent seizures, or severe accompanying pulmonary infection. Cardiac monitoring may also be necessary, particularly in elderly patients, those with known coronary disease, and those with an altered mental status. Seizures are a particularly prominent component of the clinical presentation in patients with a brain abscess but may also occur with any CNS infection, especially when an underlying seizure disorder is present. If acute cerebral edema or an elevated intracranial pressure is present, it should be managed by immediate intubation and adequate ventilation. Osmotic agents such as mannitol or diuretics such as furosemide may be used, but caution should be exercised if shock or uncontrolled hypotension is present. If diuretics or osmotic agents are administered, the emergency physician must ensure that the patient does not become volume depleted and hypotensive.

Definitive Therapy Bacterial Meningitis Therapy for bacterial meningitis requires antibiotics that penetrate the blood-brain barrier and achieve adequate CSF concentrations, are bactericidal against the offending organism in vivo, and maintain adequate tissue levels to treat the infection effectively. Until the pathogenetic organism is identified, broad-spectrum coverage of the most common pathogens is necessary ( Table 107-3 ). Many authorities recommend cefotaxime or ceftriaxone, plus vancomycin to cover potentially resistant organisms.[81] High-dose ampicillin is also added if concern exists about Listeria.[ 81] In patients allergic to penicillin and cephalosporins, meropenem or chloramphenicol plus vancomycin may be effective while awaiting the outcome of desensitization techniques.[81] Table 107-3 -- Antimicrobial Therapy for Bacterial Meningitis Organism

Treatment of Choice

Alternative Treatment

Neisseria meningitidis

Penicillin G, 4 million units IV q4h

Streptococcus pneumoniae

Penicillin G, 4 million units IV q4h

Haemophilus influenzae

Ceftriaxone 2 g IV q12h

Listeria monocytogenes

Ampicillin 2 g IV q4h, plus gentamicin 2 mg/kg IV loading, then 1.7 mg/kg q8h

Chloramphenicol 50 mg/kg IV q6h (maximum dose 1g) Chloramphenicol 50 mg/kg IV q6h (maximum dose 1 g), OR vancomycin 15 mg/kg IV q6–12h, plus rifampin 600 mg IV or PO qd Chloramphenicol 50 mg/kg IV q6h (maximum dose 1 g) Trimethoprim-sulfamethoxazole 240 mg/1200 mg IV q6h

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Organism

Treatment of Choice

Alternative Treatment

After the pathogen is identified, more targeted therapy can be instituted. It is prudent to refer to a current antimicrobial reference to guide therapy in all instances, given rapid changes in etiologic spectrum, drug resistance, and available agents. Corticosteroid treatment is additionally recommended in acute bacterial meningitis. Animal studies demonstrate the salutary effects of the administration of corticosteroids in experimental pneumococcal meningitis, including reduced brain edema, CSF pressure, and CSF lactate levels.[82] Earlier resolution of the clinical and CSF stigmata of meningitis and a decrease in long-term hearing loss are observed in infants and children given dexamethasone with cefuroxime or ceftriaxone compared with those receiving the antibiotic alone, particularly when H. influenzae is the offending agent.[] In adult bacterial meningitis, an absolute risk reduction of 10% for unfavorable outcome is seen when dexamethasone is given either 15 minutes before or concomitantly with antibiotics and continued for 4 days at 6-hour intervals.[85] This benefit is greatest in those with S. pneumoniae. No benefit has been seen in N. meningitidis infection.

Viral Meningitis No specific agents are available for treating most types of viral meningitis. Investigational agents in development may reduce symptoms in enterovirus meningitis[86]; however, with the exception of HSV meningitis, the viral meningitides contracted in the United States are generally characterized by a short, benign, self-limited course followed by a complete recovery. The primary therapeutic consideration in cases of viral meningitis is therefore the validity of the diagnosis. Early cases of viral meningitis may be indistinguishable from bacterial meningitis, and this confusion may not be resolved by CSF analysis; therefore, when any doubt exists about the veracity of the diagnosis, appropriate cultures should be obtained and the patient admitted to the hospital. Antimicrobial therapy for presumed bacterial meningitis may be initiated on the basis of the clinical presentation or may be withheld pending the outcome of close clinical observation and repeated LP in 8 to 12 hours.

Viral Encephalitis Specific therapy for meningoencephalitis from HHV is available. Acyclovir remains the current choice and is capable of substantially improving the patient's outcome. When the diagnosis of herpes meningoencephalitis is suspected or established, IV acyclovir should be administered in a dose of 10 mg/kg every 8 hours.[81] Ganciclovir, foscarnet, and cidofovir are also effective in HHV infections, and pleconaril has been effective in enteroviral disease. Additional antiviral treatments are in development.[]

Tuberculous Meningitis Early chemotherapeutic intervention in acute tuberculous meningitis improves the patient's prognosis. A strong clinical suggestion of this disease is an adequate indication to begin antituberculous therapy. A standard treatment regimen consists of isoniazid, rifampin, pyrazinamide, and ethambutol or streptomycin.[ 81] Corticosteroids have also been shown to decrease secondary complications.[]

Fungal Meningitis The treatment of fungal meningitis is complex.[7] Four agents are commonly used: amphotericin B, flucytosine, miconazole, and fluconazole. Of these, amphotericin B, either alone or in combination with flucytosine, is the most commonly recommended initial therapeutic regimen.[81] These diseases are rarely acutely life threatening but rather are slowly progressive. Prolonged therapy, often with multiple agents, is necessary. The initiation of antifungal therapy is rarely indicated in the emergency department.

Central Nervous System Abscess The treatment of cerebral abscess is complex, and neurosurgical consultation is indicated. The location, size, and number of abscesses influence the choice of medical management, surgical excision, aspiration, or a combination of these modalities.[32] In general, small multiple abscesses are more appropriately treated medically, whereas large, surgically accessible lesions should be excised. Empirical antimicrobial therapy before identification of specific organisms by aspiration or surgical excision should be guided by the principles of CSF penetration and the coverage of likely pathogens. Otogenic and sinogenic abscesses are often treated with cefotaxime or ceftriaxone plus metronidazole.[81]

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Abscesses with traumatic or neurosurgical causes should have antimicrobial coverage for S. aureus or methicillin-resistant S. aureus. Patients at high risk for tuberculous, fungal, or parasitic abscess should also receive coverage for the suspected etiologic agent. Corticosteroids should be reserved specifically for managing any attendant cerebral edema; in other circumstances, steroid use is associated with increased mortality.

Chemoprophylaxis Among household contacts the incidence of transmission of meningococcus is approximately 5%; therefore, it is recommended that household contacts of bacteriologically confirmed cases receive rifampin (adults, 600 mg; children older than 1 month, 10 mg/kg; children younger than 1 month, 5 mg/kg) orally every 12 hours for a total of four doses.[81] In addition, these contacts should be advised to watch for fever, sore throat, rash, or any symptoms of meningitis. They should be hospitalized with appropriate IV antimicrobial therapy if there are signs that active meningococcal disease is developing because rifampin is ineffective against invasive meningococcal disease. Intimate, nonhousehold contacts who have had mucosal exposure to the patient's oral secretions should also receive rifampin prophylaxis. Health care workers are not at increased risk for the disease and do not require prophylaxis unless they have had direct mucosal contact with the patient's secretions, as might occur during mouth-to-mouth resuscitation, endotracheal intubation, or nasotracheal suctioning. Ciprofloxacin 500 mg by mouth (adults only) and ceftriaxone 250 mg intramuscularly (125 mg intramuscularly for children younger than 15 years) provide single-dose alternatives.[81] There is no indication for chemoprophylaxis in pneumococcal meningitis. Rifampin prophylaxis for the contacts of patients with H. influenzae type B meningitis is recommended for nonpregnant household contacts when there are children younger than 4 years of age in the household[81] (adults, 600 mg by mouth; children, 20 mg/kg by mouth daily for 4 days).

Immunoprophylaxis A quadrivalent vaccine based on the polysaccharide capsule and conferring protection against group A, C, Y, and W-135 meningococci has been in routine use by the U.S. military since the 1980s.[88] However, the capsular polysaccharide vaccines used to immunize adults are neither immunogenic nor protective in children younger than 2 years because of poor antibody response. In addition, no licensed vaccine is currently available against the serogroup B meningococcus.[25] The serogroup B capsular polysaccharide has proved to be poorly immunogenic in both adults and children.[89] The sequence variation of the surface proteins and cross-reactivity of the group B polysaccharide with human tissues have further impeded efforts to develop a successful vaccine. Efforts to enhance the immunogenicity and protective efficacy of meningococcal vaccines have focused on using conjugate methods that link polysaccharides and carrier proteins. Serogroup C and serogroup C + Y conjugate vaccines have been developed and utilized effectively.[90] Current recommendations for the quadrivalent vaccine are evolving. The vaccine is recommended in established meningococcal epidemics and for travelers to countries where meningococcal disease is currently epidemic. Elective vaccination of college freshmen has been recommended by the Advisory Committee on Immunization Practices (ACIP) in the United States and public health authorities in the United Kingdom.[] The United Kingdom has also implemented universal childhood immunization with a group C conjugate vaccine.[90] The development of effective pneumococcal vaccines has been hampered by the large number of serotypes of the organism. A small number of serotypes, however, is responsible for most clinical pneumococcal disease, and a 23-valent vaccine effective against many of these principal serotypes has been developed.[92] The recommendations for this polyvalent pneumococcal vaccine are targeted primarily at prevention of pneumonia, despite a potential beneficial effect for meningitis. A single dose of the vaccine should be considered for elderly or debilitated patients, especially those with pulmonary disease, and for patients with impaired splenic function, splenectomy, or sickle cell anemia.[93] A heptavalent conjugated pneumococcal vaccine has also been developed and is recommended for universal childhood immunization by the ACIP.[94] A conjugate vaccine effective against H. influenzae type B has been developed for use in the pediatric, but not adult, population. It appears to be approximately 90% protective and has a very low incidence of adverse reactions.[] Modern childhood immunization against H. influenzae type b has raised the average age of patients afflicted with Haemophilus meningitis to 25 years and decreased the incidence of meningitis of any etiology by 55%.[98] Vaccination is also available to confer immune protection against Japanese encephalitis virus, and it is recommended for people performing extensive outdoor activities or spending more than 30 days in endemic

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areas during transmission seasons.[] The reported protective efficacy of the vaccine is approximately 90%. Although there is no current human vaccine for the WNV, vaccines for nonhuman mammals have been developed.[27]

DISPOSITION With the exception of viral meningitis, all but the most chronic CNS infections require initial inpatient evaluation and treatment. Bed rest, analgesics, and the institution of appropriate IV antimicrobials are indicated. Some patients with suspected viral meningitides merit hospitalization. These include patients with more severe disease, immunocompromise, suspicion of HSV meningitis, or potential nonviral causes. Some authorities manage patients with classical presentations of viral meningitis as outpatients and ensure close follow-up within 24 hours. Others admit all patients until the more serious causes, such as early bacterial meningitis or encephalitis, can be excluded with certainty.

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KEY CONCEPTS {, {,

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CNS infection should be considered in all patients with headache, neck stiffness, fever, altered sensorium, or diffuse or focal neurologic findings. Lumbar puncture with sampling of cerebrospinal fluid is the only reliable method of assessing the presence or absence of meningitis. In the absence of contraindications, any suspicion of meningitis mandates performance of LP. Early initiation of antimicrobial therapy is mandatory in any case of suspected acute CNS infection. Antibiotic administration must not be delayed for CSF analysis or performance of neuroimaging studies. Antibiotic chemoprophylaxis should be assured for close contacts of patients with meningitis resulting from Neisseria meningitidis or Haemophilus influenzae. Single-dose and multiple-dose regimens are available. Vaccination against N. meningitidis is recommended for certain at-risk populations but does not afford protection against serogroup B infection. Concomitant CNS infection should be strongly considered in any patient with another severe systemic infection, such as urinary tract infection or pneumonia.

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REFERENCES 1. Elstein AS, Schwarz A: Clinical problem solving and diagnostic decision making: Selective review of the cognitive literature. BMJ2002;324:729. 2. Wears RL: Comments on clinical decision making: An emergency medicine perspective. Acad Emerg Med2000;7:411. 3. Kovacs G, Croskerry P: Clinical decision making: An emergency medicine perspective. Acad Emerg Med 1999;6:947. 4. Wears RL, Leape LL: Human error in emergency medicine. Ann Emerg Med1999;34:370. 5. Leape LL: Error in medicine. JAMA1994;272:1851. 6. Graber M, Gordon R, Franklin N: Reducing diagnostic errors in medicine: What's the goal?. Acad Med 2002;77:981. 7. Chapman DM, Calhoun JG, Davis WK, VanMondfrans AP: Acquiring clinical reasoning competency: Group versus individual practice using patient management computer simulations. Acad Emerg Med 1997;4:511. 8. Cosby KS, Croskerry P: Patient safety: A curriculum for teaching patient safety in emergency medicine. Acad Emerg Med2003;10:69. 9. Croskerry P: Achieving quality in clinical decision making: Cognitive strategies and detection of bias. Acad Emerg Med2002;9:1184. 10. Hamilton G: Emergency Medicine: An Approach to Clinical Problem Solving, 2nd ed. Philadelphia, WB Saunders, 2003. 11. Moche JA, Gauer KA, Chapman DM: Emergency medicine faculty time utilization: Implications for faculty funding and medical student and resident education. Acad Emerg Med1999;6:413. 12. Chisholm CD, Collison EK, Nelson DR, Cordell WH: Emergency department workplace interruptions: Are emergency physicians “interrupt-driven” and “multitasking”?. Acad Emerg Med2000;7:1239. 13. In: Kohn LT, Corrigan JM, Donaldson MS, ed.To Err Is Human: Building a Safer Health System. Institute of Medicine report, Washington, DC: National Academy Press, November 21; 1999: 14. Kyriacou DN, Coben JH: Errors in emergency medicine: Research strategies. Acad Emerg Med 2000;7:1201.

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Section VIII - Psychiatric and Behavioral Disorders Chapter 108 – Thought Disorders Robert S. Hockberger John R. Richards

PERSPECTIVE Although unusual or bizarre behavior dates back more than 3000 years, no detailed descriptions of behavior resembling modern schizophrenia can be found before 1800. In the 1800s, Morel introduced the term dementia praecox to describe a progressive deterioration of mental functioning and behavior with onset in adolescence to early adult life.[1] In 1911 Bleuler detailed the specifics of this disorder, which he termed schizophrenia, or “split-mindedness.”[2] Early authorities differed in their views regarding the pathophysiology of the disorder. Early treatments for schizophrenia included ice water immersion, the use of barbiturates or insulin to induce prolonged narcosis or coma, seizure induction with pentylenetetrazol (Metrazole), electroconvulsive therapy, and frontal leukotomy.[3] The effectiveness of these treatments was marginal at best, and until more recent times most schizophrenic patients were relegated to lifelong institutionalization. Modern-era pharmacotherapy of schizophrenia, principally with chlorpromazine and haloperidol, began in the early 1950s. This treatment proved so successful that, by the 1960s, most psychiatrists believed that schizophrenia could be successfully managed in the outpatient setting. In 1965, the Community Mental Health Centers Act initiated the release of medicated schizophrenic patients into the community.[4] Unfortunately, inadequate family support, the unavailability of jobs and low-cost housing, and the lack of funding for social services and outpatient psychiatric care left these individuals isolated without the tools needed for resocialization. This situation has improved little during the past 40 years, and currently 20% to 40% of homeless people in the United States have major mental illness.[5] The emergency department serves as the primary entry point into the mental health care system for many of these individuals and is the only source of treatment for many chronically ill mental patients.

PRINCIPLES OF DISEASE Schizophrenia is currently viewed as a heterogenous disorder that results from the interaction of biologic and environmental factors. Studies involving adopted twins whose biologic parents have schizophrenia demonstrate a strong genetic basis for the disorder. Although the overall incidence of schizophrenia in the general population is approximately 1%, it increases to almost 10% in first-degree biologic relatives of individuals with the disorder.[6] Research on drugs that mimic schizophrenic-like psychoses, as well as drugs that alleviate the disorder, implicates involvement of the dopaminergic, serotonergic, cholinergic, and glutamatergic systems in the pathophysiology of schizophrenia.[] Evidence increasingly suggests that schizophrenia is a neurodevelopmental disorder resulting from the influence of environmental factors on genetically predisposed individuals. Disruptions in fetal brain development, caused by perinatal hypoxia, poor nutrition, influenza infection, and other insults, may set the stage for development of schizophrenia decades later.[1] Models of schizophrenia have suggested that two or more insults to brain development are required over the life span rather than only one early-life event.[11] New imaging techniques have documented structural brain abnormalities, most of which appear to be developmental rather than degenerative, in many patients with schizophrenia.[7] Evidence supports the existence of a progressive continuum of psychotic illness.[] The continuum begins with unipolar depression, progressing to bipolar illness, then to schizoaffective psychoses, and finally to schizophrenia, depending on the extent of the developmental defect.

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CLINICAL FEATURES Overt signs of schizophrenia usually become manifest during adolescence or early adult life. If questioned carefully, however, many patients describe a childhood marked by few interpersonal relationships and a sense, on the part of themselves and others, that they were withdrawn and somewhat eccentric.

Phases of Schizophrenia The development of schizophrenia almost invariably passes through three phases.[14] The premorbid phase is characterized by the development of “negative” symptoms that cause deterioration from a previous level of personal, social, and intellectual functioning. Typically, patients progressively withdraw from social interactions and neglect personal appearance and hygiene. It becomes increasingly difficult for them to function at work and school and, ultimately, in their home environment. The active phase is usually precipitated by a stressful event that results in the development of “positive” symptoms such as active delusions, hallucinations, and bizarre behavior. Patients may become agitated or exhibit a hypervigilant withdrawal state characterized by rocking or staring. It is during this phase that they are most likely to be brought to the emergency department by family, friends, coworkers, or the police. The residual phase resembles the premorbid phase in that patients are left with impaired social and cognitive ability, marked by bizarre ideation or vague delusions and accompanied by peculiar behavior, poor personal hygiene and grooming, and social isolation. Most schizophrenic patients require a sheltered environment to function adequately. Despite a wide spectrum of severity, the general course for most patients is one of gradual deterioration with periodic episodes of psychotic decompensation, often precipitating another visit to the emergency department.

Criteria for Schizophrenia The clinical criteria for the diagnosis of schizophrenia are outlined in the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) ( Box 108-1 ).[14] (1) The patient must exhibit two or more of the following symptoms: delusions, hallucinations, disorganized speech, grossly disorganized or catatonic behavior, and negative symptoms such as flattening of affect, poverty of speech, or inability to perform goal-directed activities. (2) There must be a sharp deterioration from the patient's prior level of functioning (work, school, self-care, or interpersonal relations), and there must be continuous signs of disturbance (including prodromal symptoms) for at least 6 months. (3) The diagnoses of schizoaffective disorder and mood disorder with psychotic features must be excluded. (4) Most important for emergency physicians, the presence of medical conditions that can mimic or cause psychotic symptoms must be excluded. Such conditions include substance abuse, the side effects of some medications, and certain medical disorders ( Boxes 108-2 and 108-3 ). BOX 108-1 Summary of DSM-IV Criteria for Schizophrenia

A.

Presence of two (or more) characteristic symptoms for 1 month (or more) unless treated 1. Delusions 2. 3. 4. 5.

B. C.

Hallucinations Disorganized speech (derailment or incoherence) Grossly disorganized or catatonic behavior Negative symptoms: affect flattening, alogia (poverty of speech), avolition (unable to perform goal-directed activities) Note: only one symptom above is required if delu-sions are bizarre or hallucinations consist of a running commentary.

Sharp deterioration from prior level of functioning (i.e., work, self-care, interpersonal relations) Continuous signs of disturbance for 6 months (or more)

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D. E.

Schizoaffective disorder and mood disorder when psychotic features have been ruled out Not caused by substance abuse, medication, or a general medical condition

Modified from Diagnostic and Statistical Manual of Mental Disorders, ed 4-TR, Washington, DC, 2000, American Psychiatric Association. BOX 108-2 Pharmacologic Agents that May Cause Acute Psychosis

Antianxiety Agents Alprazolam Chlordiazepoxide Clonazepam Clorazepate Diazepam Ethchlorvynol

Antibiotics Isoniazid Rifampin

Anticonvulsants Ethosuximide Phenobarbital Phenytoin Primidone

Antidepressants Amitriptyline Doxepin Imipramine Protriptyline Trimipramine

Cardiovascular Drugs Captopril Digitalis Disopyramide Methyldopa Procainamide

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Propranolol Reserpine

Miscellaneous Drugs Antihistamines Antineoplastics Bromides Cimetidine Corticosteroids Disulfiram Heavy metals

Drugs of Abuse Alcohol Amphetamines Cannabis Cocaine Hallucinogens Opioids Phencyclidine Sedative-hypnotics BOX 108-3 Medical Disorders that May Cause Acute Psychosis

Metabolic Disorders Hype rcalc emia Hype rcar bia Hypo glyc emia Hypo natre mia Hypo xia

Inflammatory Disorders Sarc oido sis Syst

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emic lupu s eryth emat osus Tem poral (gian t cell) arteri tis

Organ Failure Hep atic ence phal opat hy Ure mia

Neurologic Disorders Alzh eime r's dise ase Cere brov ascu lar dise ase Enc epha litis (incl udin g HIV) Enc epha lopat hies Epile psy Hunti ngto n's dise ase

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Multi ple scler osis Neo plas ms Nor malpres sure hydr ocep halu s Parki nson 's dise ase Pick' s dise ase Wils on's dise ase

Endocrine Disorders Addi son' s dise ase Cus hing' s dise ase Pan hypo pituit aris m Para thyro id dise ase Post partu m psyc hosi s Rec

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urre nt men strua l psyc hosi s Syde nha m's chor ea Thyr oid dise ase

Deficiency States Niaci n Thia mine Vita min B12 and folat e

Delusions The DSM-IV defines delusions as “erroneous beliefs that usually involve a misinterpretation of perceptions or experiences.”[14] The delusions seen with schizophrenia are most often persecutory, religious, or somatic. They most often involve loss of control over the mind or body, such as having one's thoughts stolen, feeling that one is being manipulated by some outside force, or the belief that one's internal organs are rotting away.

Hallucinations A hallucination is a sensory experience that does not exist, except in the mind of the person experiencing it. Although the hallucinations seen with schizophrenia can involve any sensory modality (auditory, visual, olfactory, gustatory, or tactile), auditory hallucinations (hearing voices) that are pejorative or threatening are especially common.

Disorganized Speech Patients with schizophrenia experience loosening of associations; that is, their thoughts shift randomly from one topic to another without a logical connection. Their speech often shows lack of content or not saying much when talking. Neologisms (nonsense words invented by the patient) and perseverations (frequently repeated words or phrases) are common. Occasionally, the person's speech may be so severely disorganized that it is totally incoherent, termed word salad.

Grossly Disorganized or Catatonic Behavior As a result of their delusions, hallucinations, and disorganized thinking, schizophrenic patients have great difficulty formulating and producing goal-directed behavior. They are often found wandering about, disheveled, malnourished, apparently talking to themselves, and exhibiting unpredictable and untriggered agitation, such as shouting or swearing. It is this behavior that usually prompts family members, friends, or the police to bring them to the emergency department. Patients exhibiting catatonia appear to be completely unaware of their environment, maintain a rigid posture, and resist efforts to be moved.

Negative Symptoms

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Three negative symptoms—flattening of affect, alogia, and avolition—account for a significant degree of the morbidity associated with schizophrenia. Patients with a flattened affect exhibit little facial expressiveness, eye contact, or body language. Alogia, or poverty of speech, is manifested by brief, laconic, empty replies to questioning. Avolition is characterized by an inability to initiate and persist in goal-directed activities. The emergency physician must be cautious in using the presence of negative symptoms to support a diagnosis of schizophrenia because similar symptoms can be produced by severe depression, chronic environmental understimulation, and treatment with neuroleptic medications.

DIAGNOSTIC STRATEGIES Patients with Known Psychiatric Disorders Patients with known psychiatric disorders who present with a mild to moderate exacerbation of their symptoms secondary to noncompliance with neuroleptic medication do not require extensive laboratory evaluation.[15] Because some of these patients may have coexisting substance abuse or undiagnosed medical disorders, a complete history and physical examination, along with urine toxicology studies, are indicated for most patients.[] Patients exhibiting severe exacerbation of symptoms accompanied by marked agitation, violent behavior, or significantly abnormal vital signs should receive more extensive evaluation.

Patients without Known Psychiatric Disorders Schizophrenia is a clinical diagnosis (see Box 108-1 ). Unfortunately, many toxicologic and medical disorders can mimic schizophrenia. Patients with the apparent new onset of psychosis and those with known psychiatric disorders who experience a severe exacerbation of symptoms or exhibit signs or symptoms of organic disease should receive a comprehensive medical evaluation to exclude toxicologic and medical disorders.[]

DIFFERENTIAL CONSIDERATIONS Medical Disorders Certain medications and medical disorders may affect thought processes, causing persons to exhibit abnormal behavior (see Boxes 108-2 and 108-3 ). This behavior may range from mild personality changes to apparent acute psychosis, even in the absence of an underlying psychiatric disorder.[1] Factors that should alert the emergency physician to a medical disorder include (1) history of substance abuse or a medical disorder requiring medication, (2) patient's age greater than 35 years without previous evidence of psychiatric disease, (3) recent fluctuation in behavioral symptoms, (4) hallucinations that are primarily visual in nature, (5) presence of lethargy, (6) abnormal vital signs, and (7) poor performance on cognitive function testing, particularly orientation to time, place, and person. These and other factors may be helpful in differentiating functional (psychiatric) from organic (medical) causes of abnormal behavior and can be organized for easy recall into the mnemonic MADFOCS ( Table 108-1 ).[23] Table 108-1 -- Factors in Differentiating Organic and Functional Psychosis: “MADFOCS” Organic Functional Memory deficits Activity

Distortions Feelings Orientation Cognition

Some other findings

Recent impairment Psychomotor retardation Tremor Ataxia Visual hallucinations Emotional lability Disoriented Islands of lucidity Perceives occasionally Attends occasionally Focuses Age >40 Sudden onset Physical examination often abnormal Vital signs may be abnormal

Remote impairment Repetitive activity Posturing Rocking Auditory hallucinations Flat affect Oriented Continuous scattered thoughts Unfiltered perceptions Unable to attend Age 37°C) and cold-reacting (37°C) antibodies.[66] BOX 119-12 Diseases Associated with Autoimmune Hemolytic Anemia

Neoplasms Malig nant: chro nic lymp hocy tic leuk emia , lymp hom a, myel oma, thym oma, chro nic myel oid leuk emia Beni gn: ovari an terat oma, der moid cyst

Collagen Vascular Disease Syst emic lupu s eryth emat osus

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Peri arteri tis nodo sa Rhe umat oid arthri tis

Infections Myc opla sma Syph ilis Mala ria Bart onell a Virus : mon onuc leosi s, hepa titis, influ enza , coxs acki eviru s, cyto meg alovi rus

Miscellaneous Thyr oid disor ders, ulcer ative coliti s Drug imm une

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react ions Warm-reacting antibodies are characterized by a higher incidence in younger patients (30 to 60 years of age), predominance in women, variable complement fixation, and a positive direct antiglobulin test for IgG. Cold-reacting antibodies, or cold agglutinins, are seen predominantly in men and older patients (50 to 80 years of age) and with IgM complement fixation. They may also be found in patients with infectious mononucleosis and Mycoplasma infection, as well as lymphoma. Hemolysis may be intravascular and extravascular, and the direct antiglobulin test is positive for complement.[66] Clinically, a patient with immune hemolytic anemia has the signs and symptoms of anemia and, often, splenomegaly. Spherocytosis and reticulocytosis are noted in the blood smear. The direct antiglobulin test is positive in 90% of cases. The strength of the direct antiglobulin test does not correlate with the severity of the hemolysis because the Coombs' reaction is a different antibody function than hemolysis or stimulation of reticuloendothelial sequestration. In patients with newly diagnosed, reticulocytopenic or severe hemolytic anemia, the emergency physician may need to institute transfusion therapy. Compatible blood may be almost impossible to find because the antibody can react with almost all donors. The most compatible donor cells in terms of the ABO and Rh systems should be transfused with the knowledge that they will be no more compatible than the patient's own blood cells. Prednisone or its equivalent in a dose of 60 to 100 mg should be given orally or intravenously. It is believed to produce an improvement in 60% of patients with warm antibody reactions. Splenectomy and immunosuppressive therapy are also effective in treating these reactions. Cold agglutinin hemolytic anemia may be self-limited, as after infectious mononucleosis. Other forms respond well to cold avoidance, variably to immunosuppressive agents, but poorly to steroids and splenectomy. Death commonly results from uncontrolled hemolysis, the underlying primary disorder, and pulmonary embolism.[] Drug-induced hemolytic anemia may be difficult to diagnose. The emergency physician should know the drugs most often associated with this Coombs'-positive phenomenon and realize that this test is sometimes positive only in the drug's presence. Common drugs and mechanisms of action are listed in Box 119-13 .[67]

Extrinsic Mechanical Causes. Hemolysis may be caused by trauma to RBCs. The peripheral smear may demonstrate schizocytes or fragmented cells, which should immediately raise the suspicion of traumatic injury (see Figure 119-7 ). Microangiopathic hemolytic anemia, cardiac trauma, and “march” hemoglobinemia are the most commonly encountered forms of traumatic hemolysis. BOX 119-13 Drugs Associated with Immune Hemolytic Anemia

Hapton type with antibodies to the drug 1. Com plem ent-fi xing antib ody: quini dine, quini ne, phen aceti n, etha cryni c acid, p

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-ami nosa licyla te, sulfa drug s, oral hypo glyc emic agen ts 2. Non – com plem ent-fi xing antib ody: peni cillin dosa ges great er than 20 millio n U/da y Autoimmune type with antibodies to the RBC membrane: d-Methyldopa, l-dopa, mefenamic acid, chlordiazepoxide Cephalosporins at dosages greater than 4 g/day may cause hemolysis by direct membrane injury Microangiopathic hemolytic anemia is a form of microcirculatory fragmentation by threads of fibrin deposited in the arterioles. An underlying disease is inevitably present. It may be found in renal lesions such as malignant hypertension and preeclampsia, vasculitis, thrombotic thrombocytopenic purpura, disseminated intravascular coagulation, and vascular anomalies. The signs and symptoms are those of intravascular hemolysis. Treatment is directed at the causative disease. Cardiac trauma to RBCs results from increased turbulence. It may be found in patients with prosthetic valves, traumatic arteriovenous fistula, aortic stenosis, and other left-sided heart lesions. Surgical correction may be necessary. Supportive therapy with an iron supplement is usually required. March hemoglobinemia is a form of trauma caused by breaking of intravascular RBCs by repetitive pounding. Soldiers, marathon runners, and anyone with repetitive striking against a hard surface may incur

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this problem. Reassurance and a change in the patient's pattern of activity are the recommended therapy.[]

Environmental Causes. Hemolysis may be seen in cases of severe burns, freshwater drowning, and hyperthermia. Toxic causes of hemolysis have been documented to be of animal origin, such as brown recluse spider and some snake bites; vegetable origin, such as castor beans and certain mushrooms; and mineral origin, such as copper. Certain infections are associated with hemolytic states. Malaria, Bartonella, and Clostridium sepsis are three well-known causes.

Abnormal Sequestration. Hypersplenism may be caused by any disease that enlarges the spleen or stimulates the reticuloendothelial system. An unfortunate cycle can be set up in which the enlarged spleen traps more blood components and grows larger. It is usually seen as splenomegaly with pancytopenia and marrow hyperactivity.[51] Chromium-labeled RBCs may demonstrate increased trapping in the spleen. Therapy for symptomatic or severe disease is splenectomy. Adults usually tolerate splenectomy well, but children should be approached conservatively because the risk of postsplenectomy life-threatening sepsis is increased significantly.[69]

POLYCYTHEMIA Definition Polycythemia is a term commonly used for erythrocytosis (i.e., increased number of RBCs). This disorder is seen occasionally in emergency medicine but rarely in a life-threatening manner that requires emergency intervention.

Pathophysiology Erythropoiesis is controlled by the kidney-produced glycoprotein hormone erythropoietin. It is activated in the liver and regulates the committed erythropoietic stem cell. Its major stimulant is tissue hypoxia. Neoplastic dysfunction of bone marrow may also result in an elevated absolute RBC count. The major complication of polycythemia is related to the increase in blood viscosity associated with increased RBC numbers. As the hematocrit rises past 60%, viscosity increases in an almost exponential manner. This condition increases the possibility of reduced tissue flow, thrombosis, and hemorrhage. This hazard is usually blunted to a degree by an associated increase in blood volume and some viscosity-reducing vascular dilatation.[]

Clinical Features The history may range from only mild headaches to a full-blown syndrome of hypervolemia (vertigo, dizziness, blurred vision, headache), hyperviscosity (venous thrombosis), and platelet dysfunction (epistaxis, spontaneous bruising, and gastrointestinal bleeding). On physical examination, the skin and mucous membrane manifestations of the elevated RBC count are often readily observed. Plethora, engorgement, and venous congestion are commonly noted ( Figure 119-10 ). Other systems to be examined include the fundus for venous congestion, the abdomen for evidence of splenomegaly, and the cardiopulmonary system for signs of congestive heart failure. Uterine, central nervous system, renal, and hepatic tumors should be sought. All are associated with secondary polycythemia. An elevated RBC count, usually greater than the hematocrit, defines the disorder. It results in a low MCV, usually related to low serum iron and iron stores. Specific laboratory testing is discussed in the section on differential diagnosis.[71]

Figure 119-10 Polycythem ia vera. Facial plethora and conjunctival suffusion in a 40-year-old wom an (Hb, 19.5 g/dL). ((From Hoffb rand AV, Pettite JE: Color Atlas of Clinical Hem atology, 3rd ed. London, Mosb y, 2000, p 248.)Elsevier Inc.)

Differential Diagnosis Polycythemia is classified as apparent, primary, or secondary ( Box 119-14 ). Apparent polycythemia is a

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decrease in plasma volume such as found with dehydration. The RBC volume does not exceed the upper limit of normal. Although a questionable diagnostic entity, “stress” polycythemia is the tendency for an elevated hematocrit and is found in overweight, hypertensive, and overstressed middle-aged men. Increased cigarette smoking with its associated increased carboxyhemoglobin level is considered to be partially responsible. The symptoms are minimal, and treatment is confined to moderation, weight loss, and blood pressure control. The risk of vascular occlusive complications is minimal. The hematocrit is usually less than 60% and RBC mass measurements are normal.[] BOX 119-14 Classification of Polycythemia

A. B. C.

Apparent polycythemia Primary polycythemia vera Secondary polycythemia 1. Appropriately increased erythropoietin caused by tissue hypoxia a. Con genit al heart dise ase with a rightto-lef t shun t b. Pul mon ary dise ase (e.g., bron chial -type chro nic obstr uctiv e pulm onar y dise ase) c. Carb oxyh emo globi nemi a d. High -altit

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2.

ude accli mati zatio n e. Decr ease d tissu e oxyg en relea se from nem oglo bino pathi es with high oxyg en-af finity Inappropriate autonomous erythropoietin production a. Ren al origi n: carci nom a, hydr onep hrosi s, cyst b. Othe r lesio ns: uteri ne fibroi ds, hepa toma of adre nal origi n, cere bella r hem

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c.

D. E.

angi oma Con genit al over prod uctio n

Pure or essential erythrocytosis AIDS and zidovudine treatment

Primary polycythemia vera is a myeloproliferative disorder found predominantly in middle-age or older patients. It may have all the clinical components of polycythemia. Initial symptoms are reported in up to 30% of patients. The most common problems are thrombotic episodes (cerebrovascular accident, myocardial infarction, deep vein thrombosis), bleeding, and bruising. Primary polycythemia vera is a disease that involves all cell lines—hematopoietic stem, erythroid, granulocytic, and megakaryocytic. The diagnostic criteria used by the Polycythemia Vera Study Group are listed in Box 119-15 . BOX 119-15 Diagnostic Criteria for Polycythemia Vera[*]

Category A Increased RBC mass In men: >36 mL/k g In wom en: >32 mL/k g Normal arterial oxygen saturation (>92%) Splenomegaly

Category B Thro mbo cyto sis: plate lets >400 ,000/ mm [ 3]

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Leuk ocyt osis: WB C coun t >12, 000/ mm [ 3]

(with no fever or infec tion) Leuk ocyt e alkali ne phos phat ase scor e >100 Vita min B12 >900 pg/m L, unbo und vita min B12 – bindi ng capa city 400 mg/dL, white blood cell count < 10 mL) is virtually diagnostic of Guillain-Barré syndrome.[] Early in the course of an acute presentation of generalized weakness, the history and physical examination may suggest several processes, and definitive diagnosis is often not possible in the emergency department.[ 2]

EMPIRIC MANAGEMENT The immediate life threats associated with acute presentations of weakness are an inability to maintain or protect the upper airway, inadequate strength to breathe, and circulatory collapse resulting from autonomic instability. Initial empiric management consists of repeated assessment beyond initial stabilization of the patient for airway protective reflexes and for adequacy of ventilatory effort (see Figure 12-1 ). Most decisions about intubation can be made based on clinical assessment ( Box 12-3 ). Patients with neuromuscular weakness have an intact respiratory drive, and the decrease in tidal volume is offset by an increase in respiratory rate. Because of a subjective sense of dyspnea at low tidal volumes, patients often maintain arterial partial pressure of carbon dioxide (Paco2) in the range of 35 mm Hg, and a critically low vital capacity develops. When the Paco2 begins to increase in these circumstances, abrupt respiratory failure is imminent. Rapid sequence intubation is the preferred approach to the airway in the absence of identified difficult airway markers, but if a progressive denervation syndrome is suspected, succinylcholine should be avoided because of the potential for hyperkalemia. Intravenous access should be established to support circulation as needed.[3] A thorough search for a tick should be performed, especially in the hair. Tick removal is rapidly curative in cases of tick paralysis.[8] BOX 12-3 Indications for Intubation in Patients with Weakness and Ventilatory Insufficiency

Seve re fatig ue Inabil ity to prote ct airw ay or hand le secr etion s Rapi dly risin g Pac o2 Hypo xemi a desp ite supp leme ntal

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O2 FVC < 12 mL/k g NIF< 20 cm H2O

Note: If paralytics are used to facilitate intubation, depolarizing agents should be avoided because of the potential for hyperkalemia. FVC, forced vital capacity; NIF, negative inspiratory force.

DEFINITIVE MANAGEMENT When the diagnosis is known, specific therapies can be applied. Specific antitoxins exist for botulism and diphtheria and can shorten the course of the disease and avoid the need for intubation in the case of botulism.[9] Potassium supplements can be given orally or intravenously if hypokalemia is a contributing cause. Good results have been obtained with plasma exchange and intravenous immunoglobulin G in Guillain-Barré syndrome. Consultation with a neurologist or intensivist helps direct the application of these therapies. Steroids have no role in the management of Guillain-Barré syndrome.[] Most cases of myasthenia present to the emergency department with the diagnosis already established, but exacerbations of the weakness may be seen and present a diagnostic challenge to determine if the weakness is due to a myasthenic crisis or a cholinergic crisis caused by cholinesterase inhibitor therapy. About 20% of patients with myasthenia gravis experience a myasthenic crisis that requires intubation and mechanical ventilation. Although a Tensilon (edrophonium chloride) test may help distinguish between myasthenic and cholinergic crises, the interpretation of this test is complex and best left to an experienced neurologist. Most cholinergic crises occur superimposed on an underlying myasthenic crisis, and in questionable cases it is best to protect the airway, support ventilation, and withdraw all anticholinergic medications.[]

DISPOSITION Most patients with complaints of weakness in the emergency department have nonspecific, non-neuromuscular problems and are simply reporting subjective weakness that is neither focal nor progressive. A thorough assessment, including directed ancillary testing, allows most of these patients to be discharged with follow-up care planning through a primary physician. Patients with known neuromuscular problems who are in the emergency department for exacerbations or complications should be treated in consultation with their primary physician or a neurologist. Most of these patients can be discharged with prearranged follow-up. Patients with new-onset neuromuscular problems usually are admitted for definitive studies. Selected patients with limited manifestations of disease may be discharged after consultation and planned follow-up with a neurologist. In cases in which toxin-mediated paralyses, such as botulism, are suspected, patients should be hospitalized in an intensive care setting for close ventilatory monitoring and support. Consultation with a clinical toxicologist or regional poison center is advisable.

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KEY CONCEPTS {, {, {, {, {,

Anemia in the elderly often occurs as an exacerbation of preexisting comorbid diseases. Anemia of uncertain etiology should be thoroughly evaluated. If the patient has no adverse hemodynamic consequences, the evaluation can proceed on an outpatient basis. One of the most important, but often overlooked studies in the evaluation of suspected hemolytic anemia is the peripheral blood smear. Patients with sickle cell disease who come to the emergency department are most commonly having a true crisis and are not simply exhibiting drug-seeking behavior. The white blood cell determination in the emergency department has poor sensitivity and specificity for disease.

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Marx: Rosen's Emergency Medicine: Concepts and Clinical Practice, 6th ed., Copyright © 2006 Mosby, Inc.

REFERENCES 1. Williams MD, Wheby MS: Anemia in pregnancy. Med Clin North Am1992;76:631. 2. Izaks GJ, Westendorp RG, Knook DL: The definition of anemia in older persons. JAMA1999;281:1714. 3. Mansouri A, Lipschitz DA: Anemia in the elderly patient. Med Clin North Am1992;76:619. 4. Spivak JL, Eichner ER: The Fundamentals of Clinical Hematology, 3rd ed. Baltimore, Johns Hopkins University Press, 1993. 5. Hillman RS, Ault KA: Normal erythropoiesis. In: Hillman RS, Ault KA, ed.Hematology in Clinical Practice, 3rd ed. New York: McGraw-Hill; 2002: 6. Bayless PA: Selected red cell disorders. Emerg Med Clin North Am1993;11:481. 7. Barber AE, Shires GT: Cell damage after shock. New Horiz1996;4:161. 8. Rodgers KG: Cardiovascular shock. Emerg Med Clin North Am1995;13:793. 9. Balducci L: Epidemiology of anemia in the elderly: Information on diagnostic evaluation. J Am Geriatr Soc 2003;51:2. 10. Strobach RS, Anderson SK, Doll DC, Ringenberg QS: The value of the physical examination in the diagnosis of anemia. Arch Intern Med1988;148:831. 11. Jain R: Use of blood transfusion in management of anemia. Med Clin North Am1992;76:727. 12. Hillman RS, Ault KA: Clinical approach to anemia. In: Hillman RS, Ault KA, ed.Hematology in Clinical Practice, 3rd ed. New York: McGraw-Hill; 2002: 13. Welborn JL, Meyers FJ: A three-point approach to anemia. Postgrad Med1991;89:179. 14. Bessman JD, Gilmer PR, Gardner FH: Improved classification of anemias by MCV and RDW. Am J Clin Pathol1988;80:322. 15. Fairbanks VR: Laboratory testing for iron status. Hosp Pract1991;26:17. 16. Brown RG: Determining the cause of anemia: General approach, with emphasis on microcyctic hypochromic anemias. Postgrad Med1991;89:161. 17. Andrews NC: Disorders of iron metabolism. N Engl J Med1999;341:1986. 18. Brittenham GM: Disorders of iron metabolism: Iron deficiency and overload. In: Hoffman R, ed. Hematology: Basic Principles and Practice, 2nd ed. New York: Churchill Livingstone; 1995: 19. Olivieri NF: The b-thalassemias. N Engl J Med1999;341:99. 20. Giardina PJ, Hilgartner MW: Update on thalassemia. Pediatr Rev1992;13:55. 21. Brittenham GM: Efficacy of deferoxamine in preventing complications of iron overload in patients with thalassemia major. N Engl J Med1994;31:567. 22. Lucarelli G, Giardini C, Angelucci E: Bone marrow transplantation in the thalassemias. In: Winter JN, ed. Blood Stem Cell Transplantation, Boston: Kluwer Academic; 1997: 23. Beutler E: Hereditary and acquired sideroblastic anemias. In: Beutler E, ed.Williams Hematology, 6th ed. New York: McGraw-Hill; 2001: 24. Damon LE: Anemias of chronic disease in the aged: Diagnosis and treatment. Geriatrics1992;47:47. 25. Lipschitz DA: The anemia of chronic disease. J Am Geriatr Soc1990;38:1258. 26. Means RT, Krantz SB: Progress in understanding the pathogenesis of the anemia of chronic disease. Blood1992;80:1639. 27. Hoffbrand V, Provan D: ABC of clinical haematology. Macrocytic anaemias. BMJ1997;314:430. 28. Stabler SP, Allen RH, Savage DG, Lindenbaum J: Clinical spectrum and diagnosis of cobalamin deficiency. Blood1990;76:871. 29. Babior BM: The megaloblastic anemias. In: Beutler E, ed.Williams Hematology, 6th ed. New York: McGraw-Hill; 2001: 30. Young NS: Acquired aplastic anemia. Ann Intern Med2002;136:534. 31. Young NS: Acquired aplastic anemia. JAMA1999;282:271. 32. Humphries JE: Anemia of renal failure: Use of erythropoietin. Med Clin North Am1992;76:711. 33. Santhosh-Kumar CR, Kolhouse JF: Hemolytic anemias. In: Wood ME, Bunn RA, ed. Hematology/Oncology Secrets, Philadelphia: Hanley & Belfus; 1999: 34. Leonard KA, Klein HG: Acute hemolytic disorders. In: Bell WR, ed.Hematologic and Oncologic Emergencies, New York: Churchill Livingstone; 1993: 35. Tabbara IA: Hemolytic anemias: Diagnosis and management. Med Clin North Am1992;76:649.

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36. Nydegger UE, Kazatchkine MD, Mieschner PA: Immunopathologic and clinical features of hemolytic anemia due to cold agglutinins. Semin Hematol1991;28:66. 37. Jacobasch G, Rapoport SM: Hemolytic anemias due to erythrocyte enzyme deficiencies. Mol Aspects Med1996;17:143. 38. Valentine WN, Paglia DE: Erythroenzymopathies and hemolytic anemia. J Lab Clin Med1990;115:12. 39. Beutler E: Glucose-6-phosphate dehydrogenase deficiency. In: Beutler E, ed.Williams Hematology, 6th ed. New York: McGraw-Hill; 2001: 40. Palek J, Jarolim P: Hereditary spherocytosis, elliptocytosis, and related disorders. In: Beutler E, ed. Williams Hematology, 6th ed. New York: McGraw-Hill; 2001: 41. Bunn HF: Pathogenesis and treatment of sickle cell disease. N Engl J Med1997;337:762. 42. Embury SH: Sickle cell disease. In: Hoffman R, ed.Hematology: Basic Principles and Practice, 2nd ed. New York: Churchill Livingstone; 1995: 43. Sickle Cell Disease: Screening Diagnosis, Management and Counseling in Newborns and Infants, AHCPR Publication 93-0562, Rockville, Md, U.S. Department of Health and Human Services, 1993. 44. Chen H: Resource Manual for Hemoglobinopathies, Columbus, Division of Maternal and Child Health, Ohio Department of Health, 1992. 45. Platt OS: Mortality in sickle cell disease. N Engl J Med1994;330:1639. 46. Platt OS: Pain in sickle cell disease: Rates and risk factors. N Engl J Med1991;325:11. 47. Serjeant GR: Sickle Cell Disease, 2nd ed. Oxford, Oxford University Press, 1992. 48. Kravis E, Fleisher G, Ludwig S: Fever in children with sickle cell hemoglobinopathies. Am J Dis Child 1992;16:1075. 49. Steingart R: Management of patients with sickle cell disease. Med Clin North Am1992;76:669. 50. Nagel RL, Lawrence C: The distinct pathobiology of sickle cell–hemoglobin C disease: Therapeutic implications. Hematol Oncol Clin North Am1991;5:433. 51. Hargis CA, Claster S: Acute chest syndrome in sickle cell disease. Crit Decisions Emerg Med1997;11:1. 52. Gladwin MT, Schechter AN, Shelhamer JH, Ognibene FP: The acute chest syndrome in sickle cell disease. Am J Respir Crit Care Med1999;159:1368. 53. Brugnara C: Therapy with oral clotrimazole induces inhibition of the Gardos channel and reduction of erythrocyte dehydration in patients with sickle cell disease. J Clin Invest1996;97:1227. 54. de Franceschi L: Oral magnesium supplements reduce erythrocyte dehydration in patients with sickle cell disease. J Clin Invest1997;100:1847. 55. Charache S, Terrin ML, Moore RD: Effect of hydroxyurea on the frequency of painful crisis in sickle cell anemia. N Engl J Med1995;332:1317. 56. Nagel RL: F reticulocyte response in sickle cell anemia treated with recombinant human erythropoietin: A double-blind study. Blood1993;81:9. 57. Perrine SP: Sodium butyrate enhances fetal globin gene expression in erythroid progenitors of patients with Hb SS and beta thalassemia. Blood1989;74:454. 58. Walters MC: Collaborative multicenter investigation of marrow transplantation for sickle cell disease: Current results and future directions. Biol Blood Marrow Transplant1997;3:310. 59. Vermylen C, Cornu G: Hematopoietic stem cell transplantation for sickle cell anemia. Curr Opin Hematol 1997;4:377. 60. Charache S, Koshy M, Milner PF: Care of patients with sickle cell anemia in the adult emergency department. In: Bell WR, ed.Hematologic and Oncologic Emergencies, New York: Churchill Livingstone; 1993: 61. Wayne AS, Kevy SW, Nathan DG: Transfusion management of sickle cell disease. Blood1993;81:1109. 62. Vichinsky EP: A comparison of conservative and aggressive transfusion regimens in the perioperative management of sickle cell disease. N Engl J Med1995;333:206. 63. Adams-Graves P: RheothRx (poloxamer 188) injection for the acute painful episode of sickle cell disease: A pilot study. Blood1997;286:2099. 64. Orringer EP: Purified poloxamer 188 for treatment of acute vaso-occlusive crisis of sickle cell disease: A randomized controlled trial. JAMA2001;245:2099. 65. Kickler TS, Ness PM: Blood component therapy. In: Bell WR, ed.Hematologic and Oncologic Emergencies, New York: Churchill Livingstone; 1993: 66. Engelfriet CP, Overbeeke MA, von dem Borne AE: Autoimmune hemolytic anemia. Semin Hematol 1992;29:3. 67. Salama A, Mueller-Eckardt C: Immune-mediated blood cell dyscrasias related to drugs. Semin Hematol 1992;29:54. 68. Eichner ER: The anemia of athletes. Phys Sports Med1986;14:122. 69. Erslev AJ: Hypersplenism and hyposplenism. In: Beutler E, ed.Williams Hematology, 6th ed. New York: McGraw-Hill; 2001: 70. Hinshelwood S, Bench AJ, Green AR: Pathogenesis of polycythemia vera. Blood Rev1997;11:224. 71. Landaw SA: Polycythemia vera and other polycythemic states. Clin Lab Med1990;10:857. 72. Messinezy M, Pearson TC: Apparent polycythemia: Diagnosis, pathogenesis, and management. Eur J

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Haematol1993;51:125. 73. Djulbegovic B, Habley T, Joseph G: A new algorithm for the diagnosis of polycythemia. Am Fam Physician1991;41:113. 74. Conley CL: Polycythemia vera. JAMA1990;263:2481. 75. Beutler E: Polycythemia vera. In: Beutler E, ed.Williams Hematology, 6th ed. New York: McGraw-Hill; 2001: 76. Wehmeier A, Daum I, Jamin H, Schneider W: Incidence and clinical risk for bleeding and thrombotic complications in myeloproliferative disorders. Ann Hematol1991;63:101. 77. Berk PD, Wasserman LR, Fruchtman SM, Goldberg JD: Treatment of polycythemia vera: A summary of clinical trials conducted by the Polycythemia Vera Group. In: Wasserman LR, Berk PD, Berlin NI, ed. Polycythemia Vera and the Myeloproliferative Disorders, Philadelphia: WB Saunders; 1995: 78. Erslen AJ: Secondary polycythemia (erythrocytosis). In: Beutler E, ed.Williams Hematology, 5th ed. New York: McGraw-Hill; 1995: 79. Landolfi R: Efficacy and safety of low-dose aspirin in polycythemia vera. N Engl J Med2004;350:114. 80. Hillman RS, Ault KA: Normal myelopoiesis. In: Hillman RS, Ault KA, ed.Hematology in Clinical Practice, 3rd ed. New York: McGraw-Hill; 2002: 81. Werman HA, Brown CG: White blood cell and differential counts. Emerg Med Clin North Am1986;4:41. 82. Shapiro MF, Greenfield S: Complete blood counts and leukocyte differential counts. Ann Intern Med 1987;105:65. 83. McCarthy DA: Leukocytosis induced by exercise. BMJ1987;295:636. 84. Dale DC: Neutrophilia. In: Beutler E, ed.Williams Hematology, 6th ed. New York: McGraw-Hill; 2001: 85. Faderl S: The biology of chronic myeloid leukemia. N Engl J Med1999;341:164. 86. Goldman JM, Melo JV: Chronic myeloid leukemia—Advances in biology and new approaches to treatment. N Engl J Med2003;349:1451. 87. Bunin N, Pui CH: Differing complications of hyperleukocytosis in children with acute lymphoblastic or acute nonlymphoblastic leukemia. J Clin Oncol1985;3:1590. 88. Kipps TJ: Lymphocytosis and lymphocytopenia. In: Beutler E, ed.Williams Hematology, 6th ed. New York: McGraw-Hill; 2001: 89. Cheson BD: National Cancer Institute–sponsored Working Group guidelines for chronic lymphocytic leukemia: Revised guidelines for diagnosis and treatment. Blood1996;87:4990. 90. Pui CH: Childhood leukemia. N Engl J Med1995;332:1618. 91. Mauer AM: Acute lymphocytic leukemia. In: Beutler E, ed.Williams Hematology, 6th ed. New York: McGraw-Hill; 2001: 92. Frontiera M, Myers AM: Peripheral blood and bone marrow abnormalities in the acquired immunodeficiency syndrome. West J Med1987;147:157. 93. Groopman JE: Management of the hemolytic complications of human immunodeficiency virus infection. Rev Infect Dis1990;12:931. 94. Hughes WT: 1997 guidelines for the use of antimicrobial agents in neutropenic patients with unexplained fever. Clin Infect Dis1997;25:551. 95. Maher DW: Filgrastim in patients with chemotherapy-induced febrile neutropenia: A double-blind placebo-controlled trial. Ann Intern Med1994;121:492. 96. American Society of Clinical Oncology recommendations for the use of hematopoietic colony-stimulating factors : Evidence-based clinical practice guidelines. J Clin Oncol1994;12:2471. 97. Badgett RG, Hansen CJ, Rogers CS: Clinical usage of the leukocyte count in emergency department decision making. J Gen Intern Med1990;5:198. 98. Da Silva O, Ohlsson A, Kenyon C: Accuracy of leukocyte indices and C-reactive protein for diagnosis of neonatal sepsis: Critical review. Pedatr Infect Dis J1995;14:362. 99. Callaham M: The white blood count in the emergency department. Crit Decisions Emerg Med 1988;3(30):1. 100. Young GP: CBC or not CBC, that is the question. Ann Emerg Med1986;15:367. 101. Shapiro MF, Greenfield S: The complete blood count and leukocyte differential count: An approach to their rational application. Ann Intern Med1987;106:65.

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Chapter 120 – Disorders of Hemostasis Timothy G. Janz Glenn C. Hamilton

PERSPECTIVE Hemostasis is the process of blood clot formation and represents a coordinated response to vessel injury. It requires an orchestrated response from platelets, the clotting cascade, blood vessel endothelium, and fibrinolysis. Thrombin-stimulated clot formation and plasmin-induced clot lysis are closely related and regulated. This dynamic process is often viewed in phases: formation of a platelet plug, propagation of the coagulation cascade, formation of a clot, and fibrinolysis of the clot. Most hemostatic abnormalities are acquired and result from drugs (e.g., aspirin or warfarin [Coumadin]), from associated disease (e.g., hepatic insufficiency), or from iatrogenic causes (e.g., multiple transfusions).

PATHOPHYSIOLOGY Hemostasis depends on normal function and integration of the vasculature, platelets, and the coagulation pathway.

Vasculature Vascular integrity is maintained by a lining of nonreactive overlapping endothelial cells supported by a basement membrane, connective tissue, and smooth muscle. These cells are important in maintaining a barrier to macromolecules and, when injured, in contributing to the metabolic response and local vasoconstriction. The vascular wall is an important contributor to hemostasis.[1] The endothelium contributes to both clot formation and regulation by producing substances such as von Willebrand factor (vWF), antithrombin III, heparin sulfate, prostacyclin, nitric oxide, and tissue factor pathway inhibitor.

Platelets Platelets have multiple and ever-expanding roles in our understanding of hemostasis. They are complex cytoplasmic fragments released from bone marrow megakaryocytes under the control of thrombopoietin. Platelets contain lysosomes, granules, a trilaminar plasma membrane, microtubules, and a canalicular system. Granules are an important component of hemostasis and contain platelet factor 4, adhesive and aggregation glycoproteins, coagulation factors, and fibrinolytic inhibitors. Each participates in the process of coagulation. The platelet's role is termed primary hemostasis, and it serves as the initial defense against blood loss. A fibrin clot that incorporates coagulation factors usually reinforces a platelet clot. Platelet activity is summarized in Box 120-1 . Any of the steps listed may be absent, altered, or inhibited by inherited or acquired disorders.[] BOX 120-1 Role of Platelets in Hemostasis

Adhesion to subendothelial connective tissue: collagen, basement membrane, and noncollagenous microfibrils; serum factor VIII (von Willebrand) permits this function; adhesion creates the initial bleeding arrest plug Release of adenosine diphosphate, the primary mediator and amplifier of aggregation; release of thromboxane A, another aggregator and potent vasoconstrictor; release of calcium, serotonin, epinephrine, and trace thrombin Platelet aggregation over the area of endothelial injury

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Stabilization of the hemostatic plug by interaction with the coagulation system: Platelet factor 3, a phospholipid that helps accelerate certain steps in the coagulation system Platelet factor 4, a protein that neutralizes heparin Pathway initiation and acceleration by thrombin production Possible secretion of active forms of coagulation proteins Stimulation of limiting reactions of platelet activity

Coagulation Pathway The coagulation pathway is a complex system of checks and balances that results in controlled formation of a fibrin clot. Factors have been given standard Roman numerals matching their order of discovery ( Box 120-2 ).[7] BOX 120-2 Coagulation Factors

I. II. III. IV. V. VI. VII. VIII. IX. X. XI. XII. XIII.

Fibrinogens Prothrombin Tissue thromboplastin Calcium Labile factor (proaccelerin) Not assigned Proconvertin Antihemophilic A factor Antihemophilic B factor (plasma thromboplastin component, Christmas factor) Stuart-Prower factor Plasma thromboplastin antecedent Hageman factor (contact factor) Fibrin-stabilizing factor

A simplified version of the coagulation pathway is presented in Figure 120-1 . The clotting cascade is traditionally depicted as consisting of intrinsic and extrinsic pathways. The intrinsic pathway is initiated by exposure of blood to a negatively charged surface, such as a glass surface in the activated partial thromboplastin clotting time. The extrinsic pathway is activated by tissue factor exposed at the site of vessel injury or thromboplastin. Both pathways converge to activate factor X, which then activates prothrombin to thrombin. The primary physiologic event that initiates clotting is exposure of tissue factor at the injured vessel site. Tissue factor is a critical cofactor that is required for activation of factor VII. Activated factor VII activates factor X directly, as well as indirectly by activating factor IX.

Figure 120-1 Coagulation pathway.

Because of limited amounts of tissue factor and rapid inactivation by tissue factor pathway inhibitor, the extrinsic pathway initiates the clot process. Sustained generation of thrombin and clot formation depends on the intrinsic pathway through activation of factor IX by activated factor VII, which helps explain the bleeding problems associated with hemophilia.[] Intrinsic, extrinsic, and common pathways must function normally for hemostasis to occur, and each may be evaluated with laboratory tests.[] The clinically important groups of coagulation factors are as follows:

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1.

2. 3.

Thrombin-sensitive factors contributing to the metabolic response and local vasoconstriction: I, V, VIII, XIII Vitamin K–sensitive factors: II, VII, IX, X Sites of heparin activity: IIa, IXa, Xa (major site), XIa, platelet factor 3

Thrombin-sensitive factors are activated by thrombin and may give rise to a bleeding disorder if defective synthesis occurs. Vitamin K–sensitive factors may also cause bleeding from defective synthesis, as occurs with liver disease and warfarin anticoagulants. Heparin in combination with antithrombin III affects the coagulation pathway at multiple sites.[]

Coagulation Control All the components of the coagulation reaction are necessary to prevent excessive bleeding. Hemostasis is a balance between the excessive bleeding state and thrombosis. Once coagulation is initiated, controls are necessary to prevent local or generalized thrombosis. These controls include the following[]: 1.

2.

3.

4.

5.

Removal and dilution of activated clotting factors via blood flow, which also mechanically opposes growth of the hemostatic plug Modulation of platelet activity by endothelialgenerated nitric oxide and prostacyclin Removal of activated coagulation components by the reticuloendothelial system Regulation of the clotting cascade by antithrombin III, protein C, protein S, and tissue factor pathway inhibitor Activation of the fibrinolytic system

CLINICAL FEATURES Prehospital The prehospital treatment of bleeding problems has no special concerns. Local pressure and volume repletion are the mainstays of therapy for blood loss. The prehospital team must be aware that inherited coagulopathies may complicate any medical or traumatic problems and that acquired forms can develop rapidly. Patients who do not respond quickly to the usual measures of hemostasis either in the field or in the emergency department should be considered to have a potential bleeding disorder.

History and Physical Examination An outline of the history and physical examination is presented in Box 120-3 . The history alone may be useful in differentiating between platelet and coagulation factor abnormalities. Platelet disorders are usually manifested as acquired petechiae, purpura, or mucosal bleeding and are more common in women. Coagulation problems are commonly congenital, are characterized by delayed deep muscle or joint bleeding, and are seen more often in men. BOX 120-3 Clinical Evaluation of a Bleeding Patient

History Nature of bleeding

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Pete chia e Purp ura Ecc hym osis Signi fican t blee ding epis odes Sites of bleeding Skin Muc osa: oral or nasa l Mus cle Gast roint estin al Geni touri nary Joint s Patterns of bleeding Rec ent onse t or lifelo ng Freq uenc y and seve rity Spo ntan eous or after injur y Chall enge s to

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hem osta sis: tooth extra ction , oper ative proc edur es Asso ciati on with medi catio n, parti cular ly aspir in Medications Associated diseases Ure mia Liver dise ase Infec tion Malig nanc y Previous transfusion Family history

Physical Examination Vital sign s Skin: natur e of blee ding, sign s of liver dise ase Muc

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osa: oral or nasa l Lym phad enop athy Abdo men: liver size and shap e, sple nom egal y Joint s: sign s of previ ous blee ding Othe r sites of bloo d loss: pelvi c, recta l, urina ry tract

Ancillary Evaluation A definitive diagnosis depends on laboratory evaluation. Tests pertinent to the emergency department are discussed in the following sections and listed in Box 120-4 . BOX 120-4 Coagulation Studies

CBC and sme ar (ED TA— purpl e top)

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Plate let coun t (ED TA— purpl e top) Blee ding time Prot hro mbin time (citra te— blue top) Parti al thro mbo plast in time (citra te— blue top) Othe r coag ulati on studi es: fibrin ogen level, thro mbin time, clot solu bility, facto r level s, inhibi tor scre ens As nece ssar y: elect rolyt

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es, gluc ose, BUN , creat inine , type and cros smat ch

BUN, blood urea nitrogen; CBC, complete blood count; EDTA, ethylenediaminetetraacetic acid.

Complete Blood Count and Blood Smear The complete blood count assesses the degree of anemia associated with the bleeding episode. Reductions in hemoglobin and hematocrit often lag behind the actual loss of red blood cells (RBCs) in acute hemorrhage because of a slow equilibration time. The peripheral blood smear may demonstrate schistocytes or fragmented RBCs in disseminated intravascular coagulation (DIC). Teardrop-shaped or nucleated RBCs may reflect myelophthisic disease. A characteristic white blood cell morphologic condition is seen with thrombocytopenia associated with infectious mononucleosis, folate or vitamin B12 deficiency, or leukemia.[19]

Platelet Count The platelet count may be estimated from the smear. Normally, one platelet is present per 10 to 20 RBCs. Often, the count is automated, the normal range being 150,000 to 400,000/mm3. Platelet counts less than 100,000/mm[3] define thrombocytopenia. With normal function, the bleeding time increases in direct relation to a decrease in the platelet count below 100,000/mm3. Levels below 20,000/mm[3] may be associated with serious spontaneous hemorrhage. However, the count gives no information about the functional capability of platelets.[20]

Bleeding Time The bleeding time is the best test for both vascular integrity and platelet function that can be performed in the emergency department. The test is performed after making two standard incisions 1 mm deep and 1 cm long on the volar aspect of the forearm with a template while it is under 40–mm Hg pressure via a blood pressure cuff. The time is measured from the incision to the moment when the blood oozing from the wound is no longer absorbed by filter paper. A normal time is 8 minutes, a time of 8 to 10 minutes is borderline, and a time longer than 10 minutes is typically abnormal. Because of the high incidence of drug-induced platelet dysfunction, it is important to ask the patient about medications, particularly aspirin. The test is independent of the coagulation pathways.[] As mentioned previously, the bleeding time is prolonged with platelet counts below 100,000/mm3, but such prolongation does not represent platelet dysfunction. However, a prolonged bleeding time associated with platelet counts greater than 100,000/mm[3] suggests impaired function.

Prothrombin Time The prothrombin time (PT) tests the factors of the extrinsic and common pathways. The patient's anticoagulated plasma is combined with calcium and tissue factor prepared from rabbit or human brain tissue. Sensitivity to factor deficiencies depends on the source of the tissue factor. The PT detects deficiencies in fibrinogen, prothrombin, factor V, factor VII, and factor X. It is typically used to test the extrinsic pathway. A normal control sample is simultaneously run, and the clotting times of both are recorded. The time in seconds is usually given over the normal control time, for example, 12.5/11.5. A PT 2 seconds or more over the control time can be considered significant. Results are usually reported as the International Normalized Ratio (INR), which compensates for differences in sensitivity of various thromboplastin reagents to the effects of warfarin. The test is helpful in monitoring the use of coumarin anticoagulants, and the time may be prolonged in patients with liver disease and other abnormalities of vitamin K–sensitive factors.[22]

Partial Thromboplastin Time

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The partial thromboplastin time (PTT) tests the components of the intrinsic and common pathways, that is, essentially all factors but VII and XIII in the entire clotting cascade. In this test a phospholipid source and a contact-activating agent (kaolin) are added to anticoagulated citrate plasma. After an incubation period that allows factor XII to become activated, calcium is added and the clotting time is recorded. A normal control sample is run simultaneously. Normal ranges may vary, and each hospital laboratory should be checked. The average time is 25 to 29 seconds. The sensitivity of the test varies from factor to factor, but factor levels must usually be less than 40% before the PTT is prolonged. The test may be altered by clotting factor inhibitors of external origin (e.g., heparin) or internal origin (e.g., anti-VIII antibody). Inappropriately high values may occur if the plasma is too turbid or icteric. The activated PTT is most sensitive to abnormalities in the sequence of the coagulation cascade that precedes activation of factor X.[]

Fibrinogen Fibrinogen is present in sufficient concentration to be measured directly. Because it is the final coagulation substrate, its level reflects the balance between production and consumption. It may be decreased by hypoproduction, as in severe liver disease, or by overconsumption, as in DIC. Low levels or altered function increase the PT, PTT, and thrombin clotting time. Because fibrinogen is an acute phase reactant, certain conditions, including malignancy, sepsis, inflammation, and pregnancy, may alter interpretation of the test result.

Thrombin Time Measurement of the thrombin clotting time bypasses the intrinsic and extrinsic pathways by directly converting fibrinogen to fibrin. It is a useful screening test for both qualitative and quantitative abnormalities of fibrinogen and inhibitors such as heparin and fibrin split products.[26]

Clot Solubility The result of clot solubility testing may be the only abnormality in disorders involving factor XIII deficiency and some abnormal fibrinogen. A washed clot is incubated in acetic acid or urea. If the clot is not properly cross-linked, it dissolves.[12]

Factor Level Assays Factor levels are determined either by bioassay, in which the ability of the sample of plasma to normalize controlled substrate-deficient plasma is evaluated, or by immunologic assay. Inhibitor screening tests reveal antibodies in plasma that prolong the normal plasma clotting time when mixed.[]

DIFFERENTIAL DIAGNOSIS AND MANAGEMENT When a bleeding disorder is diagnosed or suspected, the assessment initially includes stabilization, which may necessitate volume, RBC, and coagulation factor replacement. If the disorder is known, clinical complications associated with its underlying pathophysiologic condition must be considered. If the disorder is unknown, a rapid differential diagnosis must be made. A clinically useful scheme approaches bleeding disorders in terms of three constituents: vascular integrity, platelets, and coagulation factors. This differential diagnostic approach can be further divided into inherited and acquired disorders.

Vascular Disorders Vascular disorders have signs and symptoms similar to those of thrombocytopenic states. The inherited forms are rare. Acquired forms are usually associated with connective tissue changes or endothelial damage. The differential diagnosis of vascular disorders is listed in Box 120-5 .[27] BOX 120-5 Differential Diagnosis of Vascular Disorders

Inherited Disorders of connective tissue Pse udox anth oma

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elast icum Ehle rs-D anlo s synd rom e Oste ogen esis impe rfect a Disorders of blood vessels Hem orrh agic telan giect asia

Acquired Scurvy (vitamin C deficiency) Simple or senile purpura Purpura secondary to steroid use Vascular damage Infec tion (me ning ococ cemi a) Azot emia (he moly tic-ur emic synd rom e) Hypo xemi a Thro mbot ic

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thro mbo cyto peni c purp ura Snak ebite Dys prote inem ic purp ura

Platelet Disorders General Approach Most platelet abnormalities occur in women and are acquired. The bleeding source is usually capillary, with resultant cutaneous and mucosal petechiae or ecchymosis. Epistaxis, menorrhagia, and gastrointestinal bleeding are common initial symptoms. The bleeding is generally mild and occurs immediately after surgery or dental extractions. Preceding trauma does not usually cause the bleeding incident. Petechiae and purpura may be noted on physical examination, and superficial ecchymoses may be found around a venipuncture site. Deep muscle hematomas and hemarthroses are not aspects of the clinical picture. The bleeding time is prolonged, and the platelet count may be low, normal, or high. The differential diagnosis of platelet disorders is listed in Box 120-6 . BOX 120-6 Differential Diagnosis of Platelet Disorders

Thrombocytopenia Decreased production Decr ease d meg akar yocy tes seco ndar y to drug s, toxin s, or infec tion Nor mal meg akar yocy tes with meg alobl astic hem

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atop oiesi s or here ditar y origi n Platelet pooling and splenic sequestration Increased destruction Immunologic Rela ted to colla gen vasc ular dise ase, lymp hom a, leuk emia Drug relat ed Infec tion Post trans fusio n Idiop athic (auto imm une) thro mbo cyto peni c purp ura Mechanical Diss emin ated intra vasc ular coag ulati on Thro mbot

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ic thro mbo cyto peni c purp ura Hem olytic -ure mic synd rom e Vasculitis Dilutional secondary to massive blood transfusion

Thrombocytopathy Adhe sion defe cts such as von Wille bran d's dise ase Rele ase defe cts: acqu ired and drug relat ed Aggr egati on defe cts such as in thro mba sthe nia

Thrombocytosis

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Autonomous (primary thrombocythemia ) Reactive (secondary thrombocythemia ) Iron defic ienc y Infec tion/i nfla mm atory Trau ma Non hem atolo gic mali gnan cy Post sple nect omy Reb ound from alco hol, cytot oxic drug thera py, folat e/vit amin B12 defic ienc y

Thrombocytopenia Decreased Production Thrombocytopenia from decreased bone marrow production is usually caused by the effects of chemotherapeutic drugs, myelophthisic disease, or direct bone marrow effects of alcohol or thiazides.

Splenic Sequestration Splenic sequestration is rare and seen primarily with hypersplenism resulting from hematologic malignancy, portal hypertension, or disorders involving increased splenic RBC destruction, such as hereditary spherocytosis or autoimmune hemolytic anemia.[28]

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Increased Destruction Immune Thrombocytopenia. Thrombocytopenia associated with increased peripheral destruction of platelets and shortened platelet survival caused by an antiplatelet antibody is seen in a number of diseases. In most cases a cause is identifiable. Collagen vascular diseases, particularly systemic lupus erythematosus, may cause an antiplatelet antibody– related platelet decrease. Similar associations have been noted with leukemia and lymphoma, particularly lymphocytic lymphoma. All evaluations of suspected immune thrombocytopenia should include a complete blood count, peripheral smear, antinuclear antibody test, and bone marrow examination.[29] A number of drugs have been associated with thrombocytopenia of immunologic origin. Quinine and quinidine are common offenders that affect platelets through an “innocent bystander” mechanism. The platelet is coated with a drug-antibody complex, complement is fixed, and intravascular platelet lysis occurs. Because of its relatively high frequency, heparin is an important cause of drug-induced thrombocytopenia in hospitalized patients. Platelets are activated by the formation of an IgG-heparin complex. Low molecular-weight heparin may be associated with less thrombocytopenia than standard, unfractionated heparin is; however, both forms of heparin demonstrate cross-reactivity.[30] Heparin-induced thrombocytopenia (HIT) is a serious immune-mediated side effect associated with heparin. HIT occurs in 1% to 5% of patients receiving unfractionated heparin and in less than 1% of those receiving low-molecular-weight heparin. It usually occurs within 5 to 7 days of heparin treatment. Thrombus develops in approximately half the patients with HIT. The thrombotic complications can lead to loss of a limb in up to 20% and mortality in as many as 30%. The diagnosis should be suspected in the presence of absolute thrombocytopenia or a greater than 50% reduction in platelets after the initiation of heparin. The most specific diagnostic tests for HIT are serotonin release assays, heparin-induced plateletaggregation assays, and solid-phase immunoassays. Elevated platelet-associated IgG levels are commonly present, but this finding is less specific or sensitive than the other diagnostic tests. More concerning to the emergency physician is delayed-onset HIT. This form of HIT occurs a median of 14 days after the initiation of heparin, but it has been reported to occur up to 40 days after starting heparin. Arterial or venous thrombosis typically develops in patients with HIT after receiving heparin. Treatment of thrombotic complications in these patients involves the use of direct thrombin inhibitors, such as lepirudin or argatroban.[] Digitoxin, sulfonamides, phenytoin, heparin, and aspirin are other problem drugs. The patient has usually ingested the medication within 24 hours. An idiopathic thrombocytopenic purpura (ITP) type of syndrome has been reported in intravenous cocaine users.[34] Clinical trials with platelet glycoprotein IIbIIIa antagonists suggest that intravenous glycoprotein IIb-IIIa inhibitors may confer an increased risk for associated thrombocytopenia, independent of heparin therapy.[35] The platelet count may fall below 10,000/mm[3] and be complicated by serious bleeding. Laboratory testing may confirm the presence of antibody, especially with the use of quinine and quinidine. After stopping administration of the drug, the platelet count improves slowly over a period of 3 to 7 days. A short course of corticosteroid therapy such as prednisone in a dose of 1 mg/kg with rapid tapering may facilitate recovery.[] Postinfectious immune thrombocytopenia is usually associated with viral diseases such as rubella, rubeola, and varicella. Although many cases associated with sepsis have a mechanical origin, some immune mechanisms have been demonstrated.[36] Posttransfusion thrombocytopenia is a rare disorder that causes a precipitous fall in platelets approximately 1 week after the transfusion. In 90% of cases, its origin is linked to the 98% of the population carrying a PLAI antigen on platelets. When transfused into a PLAI antigen–negative patient, the PLAI antibody accompanying this antigen destroys the recipient's platelets without the PLAI antigen. The platelet count often falls precipitously below 10,000/mm3, with a significant risk for major bleeding. Intracranial hemorrhage occurs in approximately 10% of such cases. Patients are usually middle-aged women with a history of pregnancy who may have been previously sensitized to the PLAI antigen during pregnancy. Despite the fact that 2% of blood recipients are mismatched with respect to this antigen, it is fortunately a rare occurrence. Plasma exchange therapy is an effective antidote.[]

Idiopathic Thrombocytopenic Purpura. Idiopathic (autoimmune) thrombocytopenic purpura should be considered after other causes have been excluded. ITP is associated with an IgG antiplatelet antibody that has proved difficult to detect. The two clinically important forms are acute and chronic.[]

Page 2604

The acute form of ITP is seen most often in children 2 to 6 years of age. A viral prodrome commonly occurs within 3 weeks of its onset. The platelet count falls, usually to less than 20,000/mm3. The course is self-limited, with a greater than 90% rate of spontaneous remission. Morbidity and mortality are low, although full recovery may take several weeks. Treatment is supportive, and steroid therapy does not alter the disease course.[] The more chronic form of ITP is primarily an adult disease found three times more often in women than men. Its onset is insidious, without a prodrome, and it is manifested as easy bruising, prolonged menses, and mucosal bleeding. The patient may have petechiae or purpura, and platelet counts between 30,000/mm[ 3] and 100,000/mm[3] are common. Splenomegaly is unusual in either acute or chronic ITP. Bleeding complications are of unpredictable frequency and severity, although long-term mortality is approximately 1%. [] The course is one of waxing and waning severity, and spontaneous remission is rare. Associated diseases, such as lymphoma and systemic lupus erythematosus, must be ruled out before the diagnosis can be made. Quantitative laboratory tests of antiplatelet antibody may differentiate between patients who will favorably respond to therapy and those who will not. Hospitalization is recommended during the initial evaluation because the differential diagnosis is complex and the risk of bleeding is significant. Treatment usually includes corticosteroids, splenectomy, and in refractory cases, immunosuppressive therapy such as with cyclophosphamide, azathioprine, or vincristine. Plasmapheresis, androgens, immune globulin, anti-Rh(D), danazol, and colchicine have all met with varied success. Platelet transfusions are used only to control life-threatening bleeding because of increased antiplatelet antibody titers and short-lived hemostatic effect. Though rare, life-threatening bleeding should be treated with platelet transfusions, intravenous immune globulin (1 g/kg), and methylprednisolone (30 mg/kg IV). Otherwise, care is supportive. The use of all nonessential drugs should be stopped, particularly those that might inhibit platelet function, such as aspirin.[] A similar pattern of thrombocytopenic purpura has been reported in sexually active homosexual men. Although the clinical findings and response to therapy mimic ITP, the mechanism is believed to be nonspecific deposition of immune complexes and complement rather than antiplatelet IgG.[44]

Nonimmune Thrombocytopenia. Nonimmune platelet destruction is usually consumptive or mechanical. Consumption occurs as part of the process of intravascular coagulation, although it may be seen at sites of significant endothelial loss. Thrombotic thrombocytopenic purpura (TTP), hemolytic-uremic syndrome, and vasculitis all initiate platelet destruction through endothelial damage.[] The most striking difference between the first two is the age at onset and the prognosis.

Thrombotic Thrombocytopenic Purpura. The pathologic state of TTP is the result of subendothelial and intraluminal deposits of fibrin and platelet aggregates in capillaries and arterioles. Hemolytic-uremic syndrome is considered to be very similar to TTP; however, the former is associated with less central nervous system and more renal involvement than TTP is. Although the initiating event is unclear, prostacyclin and abnormal platelet aggregation are believed to play a central role in pathogenesis of the disease. The disease may affect patients of any age or sex, but the majority are 10 to 40 years of age and 60% of cases occur in women. Most cases of TTP are idiopathic. However, TTP can be associated with medications. Quinine is the most common drug associated with the disease. The antiplatelet drugs ticlopidine and clopidogrel, which are used in a variety of cardiovascular disorders, have also been associated with TTP. It is classically seen as the constellation of thrombocytopenic purpura, microangiopathic hemolytic anemia, fluctuating neurologic symptoms, renal disease, and fever, but only 40% of cases have the classic pentad. The platelet count ranges from 10,000/mm[3] to 50,000/mm3, and generalized purpura and bleeding complaints are common. Anemia is universal, with hematocrit levels commonly less than 20%. The hemolysis may cause jaundice or pallor, and the blood smear characteristically contains numerous schistocytes and fragmented RBCs. Neurologic symptoms include stroke, seizures, paresthesias, altered levels of consciousness, and coma, all of which characteristically fluctuate in severity. The renal component varies from hematuria and proteinuria to acute renal failure. Fever is present in 90% of patients. Untreated, the disease follows a progressive and fatal course, with 80% mortality 1 to 3 months after diagnosis. Therapy has included corticosteroids, splenectomy, anticoagulation, exchange transfusion, and dextran. However, plasma exchange with fresh frozen plasma (plasmapheresis) is the current treatment of choice. Over the last several years, the aggressive use of plasma exchange has reduced the mortality rate

Page 2605

from 90% to 17%. In addition to plasma exchange, initial therapy may also include steroids such as prednisone and antiplatelet agents such as aspirin and dipyridamole (Persantine). Splenectomy, immune globulin, vincristine, and other therapies may have a role in resistant cases. With the exception of life-threatening bleeding, platelet transfusion should be avoided because platelets may cause additional thrombi in the microcirculation.[]

Dilutional Thrombocytopenia Dilutional thrombocytopenia occurs in cases of massive transfusion, exchange transfusion, or extracorporeal circulation. Volume replacement with stored bank blood is platelet poor because platelets have a life span of only 9 days. The number of transfusions directly correlates with the degree of thrombocytopenia. Current transfusion practice is to monitor platelet counts for every 10 U of RBCs and transfuse once the platelet count approaches 50,000/mm3.[51]

Thrombocytopathy Knowledge of abnormal platelet function as a clinical disorder has grown rapidly in recent years. The drug-induced form may be one of the most commonly seen causes of abnormal bleeding.[52] Defects may occur at any level of platelet function, including adhesion, release, and aggregation.

Adhesion Defects The representative adhesion disorder is von Willebrand's disease, which is more a factor VIII problem than a platelet deficiency. Platelets are normal in terms of their morphologic condition, number, release, and aggregation. The abnormal adhesion results not from the platelet but from an endothelium-based plasma deficiency of a factor VIII component (vWF) that permits platelet adhesion.[]

Release Defects Release defects include “storage pool” syndromes in which release is normal but amounts of adenosine diphosphate, calcium, and serotonin are decreased. Release defects may be congenital or acquired, as in systemic lupus erythematosus, alcoholism, or lymphoma. Drugs induce the most common release problem. Aspirin and related drugs block the enzyme cyclooxygenase, which participates in thromboxane A2 formation. Decreased release of thromboxane A2 results in decreased aggregation and less local vasoconstriction. Both may contribute to an increased risk of bleeding. Testing for this risk has been suggested by development of the postaspirin bleeding time as a screening test for hemostatic disorders. Aspirin is unique in that it permanently poisons this reaction for the life of the platelet in dosages of only 300 to 600 mg. Phenylbutazone and indomethacin affect function only while measurably circulating. A similar problem may occur in patients with uremia or dysproteinemia and as a rare inherited form.[]

Aggregation Defects Primary aggregation defects are associated with the rare recessive trait thrombasthenia. This platelet membrane abnormality may be detected by the lack of clot retraction during a 2-hour clot retraction test.[21]

Platelet Transfusions Most platelet function disorders are not treated by platelet transfusion because its efficacy is questionable and alloimmunization may occur. Platelet transfusions are commonly indicated for primary bone marrow disorders (e.g., aplastic anemia or acute leukemia). Assessing the risk for spontaneous bleeding by using platelet counts is an imprecise science. Less mature platelets associated with peripheral consumption or sequestration are less likely to allow spontaneous hemorrhage than are those associated with primary bone marrow involvement. An estimate of functionality is combined with the platelet count for a better predictor of primary hemostasis potential. At counts below 50,000/mm3, a variable degree of risk exists, especially that associated with trauma, ulcers, or invasive procedure. At counts higher than 50,000/mm3, hemorrhage caused by platelet deficiency is unlikely. The transfusion threshold for platelets in trauma is not well defined and may be as high as 75,000/mm[3] to 80,000/mm3. Spontaneous bleeding in the absence of surgery, trauma, or other risk factors may occur in patients with platelet counts less than 10,000/mm3.[56]

Thrombocytosis Thrombocytosis may be discovered in the emergency department. The reactive form is considered benign. The differential diagnosis (see Box 120-6 ) should be considered when confronted with a platelet count higher than 600,000 to 1,000,000mm3. The primary or autonomous state may be associated with bleeding or thrombosis. It is often an associated finding in patients with polycythemia vera, myelofibrosis, or chronic myelogenous leukemia. Suspected autonomous thrombocytosis requires a full hematologic evaluation.[]

Page 2606

Disorders of the Coagulation Pathway The coagulation system accomplishes secondary hemostasis through a complex enzymatic cascade. The clinically significant disorders have a number of characteristic features that help differentiate them from platelet disorders, including the following[18]: 1.

2.

3.

4.

5.

The bleeding source is often an intramuscular or deep soft tissue hematoma from small arterioles. The congenital form of the disease occurs predominantly in men, often as a sex-linked inheritance. Bleeding may occur after surgery or trauma but is delayed in onset up to 72 hours. Epistaxis, menorrhagia, and gastrointestinal sources of bleeding are rare, whereas hematuria and hemarthrosis are common in severe cases. The bleeding time is normal except in patients with von Willebrand's disease.

The PT and PTT are the basic laboratory diagnostic tools for the evaluation of coagulation disorders and can be used to organize the approach to their diagnosis.[18]

Abnormal Prothrombin Time and Other Tests Normal An elevated PT reflects an extrinsic pathway abnormality mediated through deficiency of factor VII. The hereditary form is caused by a rare autosomal recessive gene. The acquired form is commonly seen as a manifestation of vitamin K deficiency, coumarin use, or liver disease. Because factor VII has the shortest half-life (3 to 5 hours) of the coagulation factors, it is the first to manifest a deficiency when its active form is underproduced. The PT is a sensitive gauge of hepatic function and the efficacy of coumarin administration. INRs calculate the prothrombin ratio raised to the power of an international sensitivity index for specific thromboplastin reagents. It is recommended with most warfarin therapy that the INR be maintained between 2.0 and 3.0.[]

Abnormal Partial Thromboplastin Time and Other Tests Normal Two groups of inherited disorders manifest an isolated elevation in the PTT. The first group consists of the contact factors (e.g., XII [Hageman factors]), prekallikrein (Fletcher factor), and high-molecular-weight kinogen. They cause a benign disorder in which the PTT is elevated but the patient has no bleeding diathesis. These deficiencies exist as isolated laboratory abnormalities, and thus they should not be invoked as a cause of the patient's bleeding problem. They may be specifically assayed when a precise diagnosis is necessary.[] The second group causes significant bleeding problems resulting from deficiencies of factors within the intrinsic coagulation system. They are the most common inherited abnormalities of the entire clotting system. Deficiencies of factors VIII, IX, and XI account for 99% of inherited bleeding disorders. Patients with active life-threatening bleeding who are suspected of having a congenital bleeding disorder can be supported with fresh frozen plasma, 15 mL/kg, while diagnostic studies are being performed. The risk of viral transmission of hepatitis B or C or human immunodeficiency virus must be considered. In a patient with a prolonged PTT and a lifelong history of bleeding, the most important test in initiating the differential diagnosis is a factor VIII assay. This test measures the ability of the patient's plasma to correct the prolonged PTT of plasma deficient in factor VIII. This ability is compared with that of normal plasma and the result is given as a percentage of normal. The test measures the procoagulant activity of factor VIII but does not discriminate between abnormal activity resulting from abnormal factor VIII or low levels of normal factor VIII. The two forms of this deficiency are hemophilia A and von Willebrand's disease.[]

Hemophilia A

Page 2607

Hemophilia A is caused by a variant form of factor VIII that is present in normal levels but lacks a clotpromoting property. The incidence is 60 to 80 persons per million population. Of cases, 70% have been found to have a sex-linked recessive nature; that is, the disease is carried on the X chromosome at location Xq28. Factor VIII circulates in plasma in very low concentration and is normally bound to vWF. The source of factor VIII production is uncertain, but the liver is thought to be a significant source because hemophilia A can be corrected by liver transplantation. A female carrier mating with a normal man would be predicted to pass the disease to half her sons. Likewise, a male hemophiliac would have all normal sons and all carrier daughters. The remaining 25% to 30% of cases of the disease are believed to result from a spontaneous genetic abnormality. The familial form has a remarkable consistency of severity from generation to generation, although the degree of severity has considerable variation. This severity may be directly related to the level of factor VIII coagulant (factor VIII:C) activity. Cases with less than 1% activity are severe, with a tendency toward spontaneous bleeding. Cases with 1% to 5% activity are moderate, with rare spontaneous bleeding but increased problems with surgery or trauma. Cases with 5% to 10% activity and above are considered mild, with little risk of spontaneous bleeding but still with hazards after trauma and surgery. A number of hemophiliacs may have activity above 10% but have few problems unless stressed. The PTT may lack sensitivity for this group because it is significantly prolonged only at factor VIII:C levels less than 35% to 40%.[] The disease is seen as a disorder of secondary hemostasis with a characteristic pattern of bleeding. Bleeding can occur anywhere, but deep muscles, joints, the urinary tract, and intracranial sites are the most common. Recurrent hemarthrosis and progressive joint destruction are major causes of morbidity in hemophilia. Intracranial bleeding is the major cause of death in all age groups of hemophiliacs. Mucosal bleeding such as epistaxis and oral bleeding or menorrhagia is rare unless the disease is associated with von Willebrand's disease or platelet inhibition, such as with aspirin use. Gastrointestinal bleeding is rare unless peptic ulcer disease is also present. Trauma is a common initiator of bleeding in all stages of severity. This potential hazard must be viewed expectantly in all hemophiliacs because late bleeding may occur, usually by 8 hours but potentially up to 1 to 3 days after trauma.[]

Management of Hemophilia A Comprehensive management of hemophilia involves a team effort of physicians, specialized nurses, physical therapists, social workers, the patient, and the patient's family. The therapeutic responsibility of the emergency physician consists of three areas: preparation for and identification of the problem, initial evaluation, and admission of new bleeders; replacement therapy for bleeding episodes; and anticipation of potential life threats and admission of known bleeders for observation in selected circumstances. At one time, treatment of hemophilia-associated bleeding was a relatively common emergency medicine activity, but since 1975, hemophilia home therapy has increasingly been instituted. Therefore, many hemophiliacs now come to the emergency department only with complicated problems or trauma-related difficulties, and most are knowledgeable about their disease.[]

Preparation. In preparing for the problem, the emergency physician should have updated information covering disease processes and current therapy. A cooperative effort should be made between the emergency department and the hematology service to generate a file of known hemophiliacs in the area who are monitored at the hospital. The file should include the primary physician, diagnosis, factor VIII activity level, blood type, presence of antihemophilic factor antibodies, and time of last hospitalization. A protocol should be developed for ordering and administering factor VIII.

Replacement Therapy. The accepted therapy for hemophilia A is factor VIII replacement with cryoprecipitate or factor VIII:C concentrates. These concentrates are exposed to heat treatment or solvent-detergent mixtures to decrease transmission of hepatitis B, hepatitis C, and human immunodeficiency virus. In the past, the concentrate was made from fractionated freeze-dried antihemophilic factor and contained 250 to 1500 IU of factor VIII:C in a reconstituted volume. Factor VIII is also produced by recombinant DNA techniques and is considered by some to be the replacement product of choice. Recombinant-derived factor VIII is comparable to plasma-derived factor VIII in terms of characteristics and control of bleeding, but it has no discernible side effects. Factor VIII:C concentrates are commonly used in severe hemophilia and for home use. Cryoprecipitate is the cold precipitable protein fraction derived from fresh frozen plasma thawed at 1°C to 6°C. It was once the mainstay of hemophilia A therapy and may be used when noninfectious factor VIII concentrates are not available.[] Plasma-derived replacement therapies pose some risk for hepatitis C and hepatitis B. Persistent hepatitis B

Page 2608

surface antigen occurs in the blood of 5% of hemophiliacs, whereas the anti-B surface antigen is found in 80%. This problem has been overshadowed by the association of acquired immunodeficiency syndrome with hemophilia. The association is related to blood product use, and although the total number is low, the incidence is high—3.6 per 1000 hemophilia A patients.[] Therapy for a bleeding episode includes a number of considerations: the circumstances in which factor VIII is given, the dosage, the timing of maintenance, the duration of the dosage, the presence of antibodies, and the means of gauging effectiveness. Tables 120-1 and 120-2 include guidelines for the recommended treatment in a variety of circumstances. Most important, the emergency physician should believe patients who say that they are bleeding and institute early therapy.[] Table 120-1 -- Recommended Factor VIII Therapy for Specific Problems in Hemophilia Type of Bleeding

Initial Dosage

Duration

Comment

Abrasion

None

None

Lac erati on

Usually none; if necessary, treat as minor

None

Treat with local pressure and topical thrombin Local pressure and anesthetic with epinephrine may benefit; watch 4 hours after suturing, reexamine in 24 hours

Minor bleeding (12.5 mg/kg)

Single-dose coverage May need hospitalization for observation; repeat may be necessary for suture removal

Skin

Superficial Deep

Nasal epistaxis

Spontaneous

Traumatic

Usually none; may None need to be treated as mild bleeding Moderate bleeding (25 Up to 5–7 days mg/kg)

Uncommon; consider platelet inhibition; treat in usual manner Trauma-related bleeding can be significant

Oral Mucosa or tongue bites Traumatic (laceration) or dental extraction

Soft tissue/muscle hematomas

Usually none; treat as Single dose Commonly seen minor if persists Moderate (25 U/kg) to Single dose; may need Saliva rich in fibrin lytic severe (50 U/kg) more activity; oral e-aminocaproic acid (Amicar) may be given at 100 mg every 6 hours for 7 days to block fibrinolysis; check contraindications; hospitalize patients with severe bleeding Moderate (25 U/kg) to 2–5 days May be complicated by severe (50 U/kg) local pressure on nerves or vessels (e.g., iliopsoas, forearm, calf)

Hemarthrosis Early

Mild (12.5 U/kg)

Single dose

Treat as earliest

Page 2609

Type of Bleeding

Late or unresponsive cases of early hemarthrosis

Initial Dosage

Mild to moderate (25 U/kg)

Hematuria

Mild (12.5 U/kg)

Major bleeding

Major bleeding (50 U/kg)

Duration

Comment

symptom (pain); knee, elbow, ankle more common 3–4 days Arthrocentesis rarely necessary and only with 50% level coverage; immobilization is critical point of therapy 2–3 days Urokinase, the fibrinolytic enzyme, is in urine; with persistent hematuria an organic cause should be ruled out 7–10 days or 3–5 days In head trauma, after bleeding ceases therapy should be given prophylactically; early CT scan of head recommended for all

Gastrointestinal severe bleeding Neck/sublingual Retroperitoneal Intra-abdominal Major trauma Head injury (see text) Central nervous system bleeding (see text) Surgical procedure

Table 120-2 -- Dosage of Factor VIII (Antihemophilic Factor) Bleeding Risk

Mild Moderate Severe

Desired Factor VIII Level (%) 5–10 20–30 50 or greater

Initial Dose (U/kg)

12.5 25 50

Stan dard Calc ulati on 1.

Patie nt's plas ma volu

Page 2610

Bleeding Risk

2.

3.

Desired Factor VIII Level (%)

Initial Dose (U/kg)

me (50 mL/k g× weig ht in kg) × (Des ired level of facto r VIII [perc ent]) – (Pre sent level of facto r VIII [perc ent]) = Num ber of units for initial dose In eme rgen cy thera py, the pres ent level of facto r VIII is assu med to be zero One unit is the activi ty of the coag

Page 2611

Bleeding Risk

4.

5.

Desired Factor VIII Level (%)

Initial Dose (U/kg)

ulati on facto r pres ent in 1 mL of nor mal hum an plas ma Bec ause the half-l ife of facto r VIII is 8 to 12 hour s, the desir ed level is main taine d by givin g half the initial dose ever y8 to 12 hour s Cryo preci pitat e is assu med to have 80 to 100 U of facto r

Page 2612

Bleeding Risk

Desired Factor VIII Level (%)

Initial Dose (U/kg)

VIII:C per bag; facto r VIII:C conc entra tes list the units per bottl e on the label

The response to therapy can be monitored by clinical improvement, a decreasing PTT, and optimally, serial factor VIII:C activity levels. The infusion of 1 U of factor VIII per kilogram increases factor VIII levels by 2%. The lack of a response to factor VIII administration should raise the question of circulating antibodies. All hemophiliacs should be screened for the development of these antihemophilic factor antibodies when they are given in-hospital therapy or if they become refractory to home therapy. The 7% to 20% of patients in whom these IgG antibodies develop usually have a severe deficiency necessitating multiple factor VIII transfusions. The treatment may be complex, and hospitalization is necessary. A variety of therapies have been considered, including “overwhelming” factor VIII doses, exchange plasmapheresis, immunosuppressive therapy, and the infusion of prothrombin complexes containing activated clotting factors. Other recommended therapies include porcine factor VIII, which has less cross-reactivity with the human product, and probably in the future, recombinant activated factor VII.[] Acquired IgG antihemophilic factor antibodies may exist in nonhemophiliac patients. They can occur in the postpartum period, as immunologic reactions to penicillin or phenytoin, and in association with systemic lupus erythematosus, rheumatoid arthritis, or inflammatory bowel disease. The diagnosis is made by the occurrence of an acquired hemophilia-like syndrome with positive antibody titers in the appropriate setting. The “lupus anticoagulant” is unique in that it may be associated with an increased risk for thrombosis, as well as a hemorrhagic diathesis.[] Desmopressin acetate has been shown to increase levels of factors VIII:C and VIII:Ag in patients with hemophilia A and in some with von Willebrand's disease. It is given intravenously at 0.3 p-g/kg per dose. Benefits are primarily noted in patients with mild to moderate disease and last for 4 to 6 hours.[]

Prophylaxis. The anticipation of delayed bleeding in patients with hemophilia may necessitate admission and observation for a variety of trauma-related injuries. Candidates for prophylactic admission are patients with deep lacerations; those with soft tissue injuries in areas where the pressure from a developing hematoma could be destructive, such as in the eye, mouth, neck, back, and spinal column; and patients with a history of major trauma forces without injury. Head trauma is potentially life threatening to hemophiliacs, and central nervous system bleeding is the major cause of death for patients in all age groups. Studies find a 3% to 13% risk of intracranial hemorrhage, yet no patient given replacement therapy within 6 hours had intracranial bleeding. It is recommended that head trauma patients have factor VIII therapy initiated to a 50% activity level and be admitted, as a minimum, for 24 hours of observation. All patients with anything but the most trivial head trauma should undergo computed tomography of the head and factor VIII therapy to at least a 50% activity level. In any patient with an altered level of consciousness or focal neurologic signs, factor VIII therapy should be started immediately and a computed tomography scan performed.[] Obviously, all these patients are treated in joint consultation with their primary physician and hematologist.

Page 2613

Gene therapy represents a potential development in the treatment of hemophilia. With cloning of the genes encoding factor VIII, the possibility exists for either a partial or complete cure of hemophilia. The goal of gene therapy is not to restore factor levels to normal but rather to convert from a severe to a mild phenotype and dramatically improve clinical outcomes. Early studies are encouraging. Although genetic testing and counseling are currently available, no genetic therapies for hemophilia A are available at present.[]

von Willebrand's Disease To understand von Willebrand's disease, it is helpful to review the nomenclature used to refer to factor VIII in some centers. Factor VIII has at least three activities. First is its antihemophilic, or coagulant, activity, VIII:C. All references to factor VIII in this chapter thus far have been to this activity. A second activity supports platelet adhesion and in vitro aggregation with the antibiotic ristocetin; it is called von Willebrand factor activity, or VIII/vWF. A third component reacts with rabbit antibodies to factor VIII. It is termed the factor VIII antigen, or VIII:Ag, and relates to the measured plasma level rather than the activity of factor VIII. The antigen and cofactor activity for platelet function are structurally related.[] Von Willebrand's disease has both decreased factor VIII:Ag levels and decreased VIII:C activity secondary to underproduction. The patient's platelets are normal in number, morphologic condition, and other functions, but in the absence of circulating factor VIII/vWF, their adhering properties are diminished. Von Willebrand's disease is the most common hereditary bleeding disorder, with an estimated prevalence of 1%. The disease occurs in 5 to 10 persons per million population as an autosomal dominant trait with a variable penetrance pattern. A rare X-linked inheritance has been described.[] Manifestations of von Willebrand's disease are usually milder and less crippling than those of hemophilia. The factor VIII:C level is in the 6% to 50% range. Bleeding sites are predominantly mucosal (e.g., epistaxis) and cutaneous. Hemarthroses are rare, but menorrhagia and gastrointestinal bleeding are common. Laboratory differentiation from hemophilia A includes an abnormal bleeding time, a decreased level of factor VIII:Ag, and abnormal platelet aggregation with ristocetin.[85] In patients with severe disease, replacement therapy with factor VIII in the form of intermediate purity factor VIII concentrate is the method of choice. The initial dose is 20 to 30 IU/kg every 12 hours to keep vWF levels at 50% or to control bleeding. A unique response to the transfusion of plasma components in patients with von Willebrand's disease is the stimulation of a progressive increase in VIII:C activity that lasts 12 to 40 hours. After the initial dose, fewer units are necessary, and longer dosage schedules may be followed by a clinical response and a combination of factor VIII:C activity and serial bleeding times. In extreme circumstances without alternatives, fresh frozen plasma may be used. A factor VIII concentrate (Humate-P) has also demonstrated sufficient VIII/vWF to treat the disease.[] Drug therapy with desmopressin is of benefit in patients with mild to moderately severe von Willebrand's disease. It is most useful in a specific type of the disease and should not be given without previous consultation with a hematologist.[]

Hemophilia B (Christmas Disease) Hemophilia B is a deficiency of factor IX activity. Its genetic pattern and clinical findings are indistinguishable from those of hemophilia A, but its incidence is only a fifth that of hemophilia A. Factor IX is a vitamin K– dependent glycoprotein. Its deficiency is diagnosed by a factor IX assay, usually after the factor VIII:C assay is found to be normal. The replacement schedule for factor IX is similar to that for hemophilia A, but a purified factor IX concentrate or recombinant factor IX preparation is used. The plasma prothrombin complex (factors II, VII, IX, and X) and fresh frozen plasma are also useful, but they pose a higher risk of viral transmission and venous or arterial thrombosis. The maintenance dosage schedule is increased to every 24 hours because of the longer half-life of factor IX.[] Similar to hemophilia A, gene testing and counseling are available. Gene therapy in animals has demonstrated promising results, and preliminary results from a human study suggest that the severity of hemophilia B can be altered and improved by gene manipulation.[]

Miscellaneous Coagulation Disorders A number of other disorders may be caused by a deficiency in the common coagulation pathway. An altered fibrinogen level or abnormal function is a relatively common cause. Patients with this deficiency also have an abnormal thrombin time. The inherited forms are rare. The acquired forms have been related to fibrin-blocking substances and hypofibrinogenemia, which are found most often in cases of DIC and dysfibrinogenemia associated with macroglobulinemia, multiple myeloma, and hepatoma. In the context of emergency medicine, fibrinogen's most important role relates to its activity in DIC.

Page 2614

The other components of the common pathway (factors II, V, and X) have rare inherited deficiencies. The acquired forms are far more common and relate to vitamin K deficiency (decreased factor II, VII, IX, and X activity), warfarin use (same factors as with vitamin K deficiency), hepatic insufficiency (potentially all factors except VIII), and massive transfusion of stored blood (low in factors V and VIII and platelets).

Disseminated Intravascular Coagulation DIC is a relatively common acquired coagulopathy. Its ubiquitous nature, multiple origins, and potentially devastating sequelae, balanced by an effective mode of therapy, make early diagnosis of this hematologic process critical. It is most often encountered in the critical care setting. Hemostasis is achieved by a fine balance between procoagulants and inhibitors and thrombus formation and lysis. The balance may be disturbed by pathologic processes that result in an out-of-control coagulation and fibrinolytic cascade within the systemic circulation. The following occurs in this abnormal clotting sequence: 1.

2.

3. 4.

5.

6.

Platelets and coagulation factors are consumed, especially fibrinogen and factors V, VIII, and XIII. Thrombin is formed, and it overwhelms its inhibitor system and acts to accelerate the coagulation process and directly activate fibrinogen. Fibrin is deposited in small vessels in multiple organs. The fibrinolytic system by means of plasmin may lyse fibrin and impair thrombin formation. Fibrin degradation products are released and affect platelet function and inhibit fibrin polymerization. Coagulation inhibition levels (e.g., antithrombin III, protein C, and tissue factor pathway inhibitor) are decreased.

The clinical consequence of these processes is the life-threatening combination of a bleeding diathesis from loss of platelets and clotting factors, fibrinolysis, and fibrin degradation product interference; small vessel obstruction and tissue ischemia from fibrin deposition; and RBC injury and anemia from fibrin deposition. The condition must be suspected in any patient in whom purpura, a bleeding tendency, and signs of organ injury, particularly the central nervous system and kidney, develop in the appropriate clinical setting. This broad description is further confused clinically by the variable acuteness and intensity of intravascular clotting, the effectiveness of fibrinolysis, and other systemic manifestations of the initiating disease.[] The clinical diagnosis is necessarily supported by laboratory tests. The tests recommended in Table 120-3 usually confirm the presence of DIC. Other tests (e.g., specific degradation products of fibrin and fibrinogen) can confirm the diagnosis. These tests are rarely available in the emergency department. Table 120-3 -- Laboratory Diagnosis of Disseminated Intravascular Coagulation Test Finding Pathophysiology Peripheral smear

Low platelets, schistocytes, RBC fragments

Platelet count PT PTT

Low (usually 15 00 U/L) Adva nced dise ase with abdo mina l invol vem ent Pree xistin g renal dysf uncti on Post treat ment renal failur e Acidi c urine Con centr ated urine Pree xistin g volu me depl etion Youn g Biochemical hallmarks of this syndrome include hyperuricemia (DNA breakdown), hyperkalemia (cytosol breakdown), and hyperphosphatemia (protein breakdown). Hypocalcemia develops secondary to hyperphosphatemia. Acute renal failure, cardiac dysrhythmias, neuromuscular symptoms, and sudden death from hyperkalemia or hypocalcemia may ensue.

Clinical Features Symptoms are related to the underlying malignancy and hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia. Hyperuricemia with resultant urate nephropathy is the most commonly recognized metabolic cause of renal insufficiency.[] The kidney provides the primary mechanism for excretion of uric acid, potassium, and phosphate. Rapid proliferation of tumor cells may exceed the removal rate of the respective substances, resulting in increased levels. In fact, increased quantities of these substances have been observed in patients undergoing rapid

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lysis of chemosensitive tumors. The integrity of renal function is a critical factor in determining the degree of metabolic derangements. In patients with preexisting renal insufficiency, the metabolic derangements of acute tumor lysis are more likely to be severe. However, even when renal function appears normal at the start of treatment, the rapid lysis of certain tumors may overwhelm the excretory capacity of the kidney. Similarly to hyperuricemia, hyperphosphatemia may cause renal failure. A possible mechanism is precipitation of calcium phosphate within the kidney.[] Hyperkalemia, along with a contributing hypocalcemia, may result in life-threatening ventricular dysrhythmias. Hypocalcemia may also cause neuromuscular instability with muscle cramps and occasionally tetany. Confusion and convulsions have also been described in case reports.[]

Management Because of the life-threatening complications associated with acute tumor lysis, patients at high risk for developing the syndrome should be treated with prophylactic measures as soon as possible. Chemotherapy should be delayed, if possible, until metabolic disturbances, especially prerenal azotemia and hyperuricemia, are corrected. Initial management is aimed at the control of preexisting hyperuricemia with hydration, allopurinol, and alkalinization of the urine to a pH greater than 7. Diuretics are added if necessary, and frequent monitoring of electrolytes, calcium, and phosphorus is essential. Most articles agree that it is wise to alkalinize the urine as a prophylactic measure against hyperuricemia, but caution is advised should hyperphosphatemia and hypocalcemia develop. Under these circumstances, alkali therapy may exacerbate manifestations of hypocalcemia such as tetany.[] Although alkalinization increases the solubility of uric acid, the primary means of uric acid control is hydration and diuresis to maintain adequate urinary flow.[] If tumor lysis syndrome develops, hemodialysis should be considered as early as possible as a potentially lifesaving measure. This therapy is effective in lowering uric acid, potassium, and phosphate levels as well as in controlling uremic symptoms. See the suggested criteria for instituting hemodialysis in Box 121-5 . BOX 121-5 Criteria for Instituting Hemodialysis

Seru m pota ssiu m >6m Eq (6m mol/ L) Seru m uric acid >10 mg/d L (590 p-m ol/L) Seru m creat inine >10 mg/d

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L (880 p-m ol/L) Seru m phos phor us >10 mg/d L (pho spha te >3.2 mm ol/L) or rapid ly risin g To redu ce volu me overl oad Sym ptom atic hypo calc emia The prognosis is good in the absence of renal failure. If renal failure exists and hemodialysis of 5 to 7 days is necessary, the prognosis is grave. With aggressive management, the incidence of renal and metabolic complications of cytoreductive therapy may be decreased.

HYPERVISCOSITY SYNDROME Viscosity is the resistance that a liquid exhibits to the flow of one layer over another. Excessive elevations in certain paraproteins, marked leukocytosis, or erythrocytosis can result in elevated serum viscosity and the development of significant sludging, decreased perfusion of the microcirculation, and vascular stasis. The outcome of these pathophysiologic events is the development of hyperviscosity syndrome (HVS). This development deserves urgent medical therapy to forestall or reverse the effects of sludging in the microcirculation of the CNS, visual system, and cardiopulmonary system.[24]

Pathophysiology The most common causes of HVS include the dysproteinemias. The most common is Waldenstrm's macroglobulinemia, which accounts for 85% to 90% of all HSV cases. Multiple myeloma, the next most common cause, is responsible for 5% to 10% of cases. Other etiologies include cryoglobulinemia, a benign hyperglobulinemia of the immunoglobulin M (IgM)-IgG type, and leukemias.[] The blastic phase of chronic myelogenous leukemia, chronic granulocytic leukemia, and the blast cell crisis of acute lymphoblastic and nonlymphoblastic leukemias also commonly cause HVS.[] Other more benign causes include leukemoid reaction, polycythemia vera, and the accumulation of abnormal hemoglobins in sickle cell disease. The incidence of HVS in Waldenstrm's macroglobulinemia is approximately 20%, in IgG myeloma approximately 4.2%, and in IgA myeloma as high as 25%.[25]

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The inherent physiochemical properties of the dysproteinemias along with extremely high concentrations of these proteins seem to predispose to the development of hyperviscosity. Paradoxically, HVS has also been reported in kappa light chain disease owing to a greater tendency to form unstable, highly polymerized circulating aggregates. The etiologic factor most responsible for HVS in the leukemias appears to be leukocytosis with white blood cell (WBC) counts in excess of 100,000, usually accompanied by blast forms exceeding 100,000 in the peripheral smear. The clinical manifestations of HVS become most apparent when the serum viscosity relative to water is greater than 4 to 5, normal serum viscosity relative to water being 1.4 to 1.8.[]

Clinical Features A symptomatic triad of bleeding, visual disturbances, and neurologic manifestations is a classical presentation of HVS. Visual disturbances, and on occasion visual loss, may occur with retinopathy characterized by venous engorgement (e.g., “sausage link” or “boxcar” segmentation), which is also seen in the bulbar conjunctiva; microaneurysms; hemorrhages; exudates; and occasionally papilledema. Persistent bleeding diatheses from mucosal surfaces, especially nasal mucosa, the gastrointestinal tract, and sites of minor surgery or trauma, even in the presence of a normal platelet count are common. Other clinical findings encompass myriad neurologic disturbances, including headache, dizziness, jacksonian and generalized seizures, somnolence, lethargy, coma, auditory disturbances (including hearing loss), and hypotension. Constitutional symptoms of fatigue, anorexia, and weight loss that are nonspecific early on are commonly associated with the underlying malignancy or with numerous electrolyte disturbances related to the underlying malignant process. Cardiopulmonary findings, including acute respiratory failure and hypoxemia, congestive heart failure, myocardial infarction, and valvular abnormalities, have all been reported. Renal insufficiency and failure may be complications of the syndrome.[] The laboratory evaluation of the patient with suspected HVS should include coagulation, renal, electrolyte, and differential white count profiles. Serum and urine protein electrophoresis should be done with all suspected dysproteinemias, with the diagnosis supported by a large spike on the serum electrophoresis. A clue to the presence of hyperviscosity may be the inability of the laboratory to perform chemical tests on the blood because of the serum stasis and increased viscosity that jams analyzers. In multiple myeloma significant hypercalcemia may also occur, and with high M protein fractions a factitious hyponatremia may be present. The diagnosis may also be entertained when a patient is brought to the emergency department in a stupor or coma and anemia and rouleaux formation are found on the peripheral smear.[27] Because HVS is often a presenting characteristic of dysproteinemias and leukemias with blastic transformation and because a history of previously documented disease is often absent, this syndrome must be considered in patients with unexplained somnolence and coma.

Management Emergency leukapheresis or plasmapheresis is the definitive treatment. Temporizing measures provided by the emergency physician should focus on adequate rehydration and diuresis. An immediate temporizing measure in a patient with frank coma and an established dysproteinemia is a two-unit phlebotomy with replacement of the patient's red blood cells with physiologic saline.[] After plasmapheresis or leukapheresis has adequately alleviated the clinical findings, chemotherapeutic modalities can be used.

HYPERURICEMIA Pathophysiology Hyperuricemia, defined as a serum uric acid concentration exceeding 7 to 8 mg/dL, is a serious and well-known consequence of certain malignant disorders, which, if recognized early, can result in a significant decrease in morbidity for the cancer patient. The major source is cell breakdown, and its major excretory pathway is renal. The pathogenesis of hyperuricemia results from either increased production or decreased excretion of uric acid, or both. Increased production of uric acid commonly results from rapid dissolution of neoplastic tissues following chemotherapy or radiation therapy of undifferentiated lymphomas or lymphoblastic lymphomas and with acute lymphoblastic leukemias. In addition, hyperuricemia may be seen with multiple myeloma and occasionally with disseminated metastatic carcinoma. With massive release of precursors, uric acid levels rise precipitously and may become as high as 15 to 20 mg/dL. As a result, uric acid crystals form in the highly concentrated and acidified urine of the distal tubules. Intrarenal obstruction follows, and acute renal failure ensues.[] Chronic, moderately elevated levels of the serum uric acid may result in renal colic, obstructive uropathy, or chronic renal failure. Either uric acid renal calculi or interstitial deposits of sodium urate develop. This situation is associated with neoplastic overproduction of uric acid precursors. Polycythemia vera, myeloid

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metaplasia, mast cell disease, and chronic granulocytic leukemia are often associated with this type of hyperuricemia. Decreased excretion may be a result of underlying renal insufficiency or of precipitation of urates in the renal tubules, parenchyma, or ureters with subsequent development of renal insufficiency and further reduction in excretion of uric acid. Three types of renal diseases are attributable to hyperuricemia: acute hyperuricemic nephropathy, uric acid nephrolithiasis, and gouty nephropathy.

Clinical Features Hyperuricemia can occur with or without symptoms. Symptoms may be associated with the underlying malignancy. Hyperuricemia precipitated or worsened by therapy of these diseases may occur as an isolated metabolic disturbance or may be accompanied by other manifestations of the tumor lysis syndrome. If an underlying neoplastic disease has been diagnosed, hyperuricemia should be sought and treated before renal damage develops. In patients with urate stones and hyperuricemia, examination of the peripheral blood may provide evidence of an underlying myeloproliferative disorder. Acute oliguria after chemotherapy or radiation therapy suggests the diagnosis of hyperuricemia, and the uric acid level in the blood often far exceeds that associated with acute renal failure. A number of benign diseases are associated with hyperuricemia that may coexist with neoplasia. These include hereditary gout, hyperparathyroidism, psoriasis, sarcoidosis, and renal failure of any cause. From a therapeutic standpoint, however, the finding of hyperuricemia obviates the importance of the primary cause; the therapy is the same. The long-term administration of certain drugs may lead to elevation of the serum uric acid level. Various diuretics, including thiazides and furosemide, are important examples.[]

Management When possible, hyperuricemia should be treated before chemotherapy or radiation therapy, especially with bulky tumors or if the serum uric acid level is borderline or increased. If a uric acid elevation of more than 9 mg/dL is found, allopurinol, fluids, and alkalinization of the urine should be initiated. If possible, this regimen should be started a day or two before the initiation of chemotherapy or radiation treatment. Patients with histories of gouty arthritis should also receive colchicine, 0.6 mg orally twice a day, to avoid the acute attacks that can be associated with allopurinol administration. Patients should be kept well hydrated. Alkalinization of the urine with oral sodium bicarbonate may help prevent nephropathy. In patients with acute distal tubular uric acid obstruction, management includes the administration of allopurinol, together with the fluid and electrolyte management used in other forms of acute renal failure. If hyperuricemia is secondary to malignancy, cytolytic therapy should be stopped. Allopurinol in dosages of 300 to 600 mg/day usually causes a decrease in the serum uric acid level in approximately 3 days, and its administration should be started 2 or 3 days before cytolytic therapy, if time permits. Hydration is vital in maintaining a urine output above 2 L/day. Alkalinization to keep the urine pH above 7 can be accomplished by administering sodium bicarbonate, 100 mEq/day. Diuretics are to be used as needed. Acetazolamide (Diamox) in doses of 1 g/day usually alkalinizes the urine temporarily until allopurinol becomes effective. If oliguria occurs, mannitol may be started with 12.5 g of a 20% solution given intravenously over 3 minutes to keep urine output more than 250 mL/hr. The dose of mannitol is limited to 100 g per 24 hours to avoid clinical features resembling those of water intoxication. If these measures fail, peritoneal dialysis or hemodialysis or flushing the ureters through retrograde catheters may be considered. Urate oxidase is currently being studied for treatment of hyperuricemia. Urate oxidase is a nonhuman proteolytic enzyme that catalyzes the enzymatic oxidation of uric acid into allantoin, a metabolite that is 5 to 10 times more soluble in urine than uric acid. The primary advantage of urate oxidase is its rapid onset of action. Although commercially available in Europe, urate oxidase has not yet become the standard of care in the United States. A recombinant DNA version is in clinical trials and appears to be well tolerated and a potent uricolytic agent.[] Clearly, prevention of this complication is far better than treatment. The cancer patient who comes to the emergency department with renal colic warrants careful evaluation for hyperuricemia. The prognosis depends on the underlying malignancy and degree of renal failure.[]

HYPERCALCEMIA Hypercalcemia occurs in approximately 20% to 40% of cancer patients and is the most common life-threatening metabolic disorder associated with cancer.[30] It affects multiple organ systems and induces a variety of pathophysiologic events that may be more immediate threats to life than the cancer itself. Two mechanisms have been proposed to explain the development of hypercalcemia associated with malignancy. The first mechanism affects patients with metastatic bone involvement. The hypercalcemia is

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most likely associated with the release of calcium and phosphate caused by associated osteolysis. The second mechanism affects patients with no bone disease. A variety of tumor-produced hormone-like substances have been associated with the development of hypercalcemia, including parathyroid hormone, prostaglandins, and peptides, all of which affect bone turnover. Hypercalcemia is a common feature of many malignancies but most often complicates cancer of the breast, lung, head, and neck as well as multiple myeloma and leukemia. Bone metastases are not a prerequisite for hypercalcemia and, when present, do not necessarily cause hypercalcemia. Of patients who are hypercalcemic from squamous cell lung cancer, only one in six has bone metastases. In small cell lung carcinoma; hypercalcemia is almost never seen despite the presence of bone marrow metastases in 20% to 50% of cases. A complex interaction of various substances (parathyroid hormone, prostaglandins, peptides, steroids, osteoclastic factors) appears to be the result of both increased bone synthesis and degradation. The exception is multiple myeloma, in which bone destruction is accompanied by minimal bone synthesis. Other entities that cause hypercalcemia are listed in Box 121-6 .[] BOX 121-6 Nonneoplastic Causes of Hypercalcemia

Hype rpar athyr oidis m Hype rthyr oidis m Ren al insuf ficie ncy (diur etic phas e of acut e renal failur e, after trans plant ation , seco ndar y hype rpar athyr oidis m) Drug s (thia zide diure tics,

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lithiu m, and calci um carb onat e) Hype rvita mino sis (A and D) Acut e adre nal insuf ficie ncy Imm obiliz ation (Pag et's dise ase, fract ure, para plegi a) Acro meg aly Myxe dem a Milkalkali synd rom e Sarc oido sis Beni gn mon oclo nal gam mop athy Rare r still are factit

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ious hype rcalc emia , idiop athic hype rcalc emia of infan cy (with elfin facie s), famil ial hypo calci uric hypo calc emia , and hype rcalc emia from pheo chro moc ytom a or perio stitis

Clinical Features There is little correlation between serum calcium levels and the presence and severity of symptoms. Acute hypercalcemia results in marked CNS effects ranging from personality changes (depression, paranoia, lethargy, somnolence) to coma. With chronic hypercalcemia, symptoms include a history of anorexia, nausea, vomiting, constipation, polyuria, polydipsia, memory loss, and a shortened QT interval on the electrocardiogram. The symptoms, signs, and complications of hypercalcemia are summarized in Box 121-7 . BOX 121-7 Common Signs and Symptoms of Hypercalcemia in Malignancy

General Itchi ng

Neurologic Fatig ue, mus

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cle wea knes s, hypo refle xia, letha rgy, apat hy, distu rban ces of perc eptio n and beha vior, stup or, com a

Renal Poly uria, poly dipsi a, renal insuf ficie ncy

Gastrointestinal Anor exia, naus ea, vomi ting, cons tipati on, abdo mina l pain

Cardiovascular

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Hype rtens ion, dysr hyth mias , digit alis sens itivity In patients with carcinoma, any of these symptoms should suggest the diagnosis of hypercalcemia, but the emergency physician should be particularly suspicious of hypercalcemia in any cancer patient with lethargy or a change in mental status. Many may also have electrolyte abnormalities such as hypokalemia and dehydration. Thus, evaluation of serum electrolytes should accompany the measurement of serum calcium, phosphorus, albumin, and alkaline phosphate. In general, a serum calcium level above 14 mg/dL constitutes a medical emergency. In chronic hypercalcemia, one may see patients with blood calcium levels as high as 15 mg/dL with only mild symptoms. With an acute onset, one can see patients comatose at a level of only 12 to 13 mg/dL.[] Many nononcologic conditions can result in hypercalcemia. The most common are hyperparathyroidism and Paget's disease of bone ( Figure 121-2 ). Clinical features include a long history of hypercalcemia symptoms, particularly renal stones. Chronic changes on bone films, such as subperiosteal reaction and cysts or a “ground glass” appearance of the skull, suggest hyperparathyroidism. Diagnosis of Paget's disease rests on biopsy results. Vitamin D excess, milk-alkali syndrome, and adrenal insufficiency are other common causes in the differential diagnosis of hypercalcemia.[] The acute onset of severe hypercalcemia or chronic exposure of the renal tubules to elevated calcium levels may reduce the glomerular filtration rate and renal blood flow, resulting in acute renal failure.[23]

Management The therapeutic modalities used in the treatment of hypercalcemia are numerous, but they should always be used in conjunction with therapy of the underlying malignant disease. The exception to this is breast cancer, in which hormone therapy should be stopped until hypercalcemia is regulated.

Figure 121-2 Skull radiograph showing Paget's disease of bone.

The treatment depends on the clinical status of the patient and on the calcium level in the blood, but the general principles of treatment include treating the cancer when possible, encouraging ambulation, correcting dehydration, increasing calcium excretion, decreasing calcium removal from bone, and reducing calcium intake. If serum calcium levels are below 14 mg/dL and the patient has normal mental status, oral rehydration and ambulation may suffice. Normal saline solution can be administered if the oral intake is not sufficient. If the serum phosphate level is not elevated, oral phosphates may be used cautiously. Monobasic and dibasic sodium phosphate (Phospho-Soda), 5 mL by mouth two or three times daily, is usually tolerated with mild to no diarrhea. Saline rehydration and diuresis stimulates renal tubular excretion of calcium and is the most important initial component of the emergency management of hypercalcemia. Dehydration should be corrected within 1 to 2 hours with normal saline solution. When urine flow is adequate, furosemide, 40 to 60 mg intravenously (IV), may be given to increase excretion of calcium. Although the calciuric effect of furosemide is modest, it is

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also useful in preventing fluid overload in patients predisposed to cardiac failure. Careful attention to fluid input and output to ensure that the patient remains euvolemic is necessary. Calcitonin may be effective in doses of 4 to 8 IU/kg intramuscularly (IM). This treatment, although relatively safe when renal function is normal, is not generally part of the initial emergency management of hypercalcemia. If prostaglandin production is suspected, as in renal cancer, indomethacin or aspirin may be given, although its theoretic appeal exceeds its practical value. Fifty percent of hypercalcemic cancer patients also have hypokalemia. Serum potassium levels should be monitored every 4 hours and potassium chloride (20 to 40 mEq) supplemented IV or orally as necessary to prevent severe hypokalemia.[] If the serum calcium level is greater than 14 mg/dL or significant symptoms are present, more aggressive management should be undertaken. Continuous cardiac monitoring in the emergency department is necessary and central venous or pulmonary artery pressure monitoring may be required. Intravenous phosphates, although they can effectively lower the serum calcium level through precipitation of inorganic calcium phosphate salts in bone, are not recommended in view of their serious complications, which include widespread visceral calcifications, shock, and renal failure. In the 5 years following approval by the Food and Drug Administration, bisphosphonates have become the treatment of choice for management of cancer-induced hypercalcemia, supplanting all other pharmacologic approaches except corticosteroids. Bisphosphonates are analogues of pyrophosphate and powerful inhibitors of bone resorption. Several agents are now available including clodronate, pamidronate, and ibandronate with other more potent bisphosphonates in development. Pamidronate, 90 mg, given as an infusion over 4 to 24 hours effectively and safely achieves normocalcemia within a few days (mean 4 days) in more than 90% to 95% of patients.[] Zolendronate, a new third-generation bisphosphonate, appears to be more effective treatment than pamidronate in preliminary trials. It has been shown to normalize calcium faster and for longer periods of time. Zolendronate can be administered as 1- to 4-mg doses given over a few minutes IV. Mithramycin given as 25 p-g/kg IM once every 4 to 5 days is not generally part of the initial emergency management of hypercalcemia and has been supplanted in most cases by the bisphosphonates. Prednisone, 60 to 80 mg/day, or other corticosteroids may be effective within a few days to a week. Prednisone is more useful for long-term treatment than for acute control. Corticosteroids are particularly valuable in breast carcinoma, myeloma, and lymphoma. They should not be initiated without oncologic consultation because they are chemotherapeutic agents for these malignancies.

NEOPLASTIC CARDIAC TAMPONADE Although cardiac tamponade resulting from neoplasm is rarely seen in the emergency department, it is an important clinical problem because it can occur abruptly and result in the death of a patient with a tumor that may be responsive to treatment with a resultant complete remission or significantly prolonged partial remission. The decompensated state of cardiac function comes from a marked rise in intrapericardial pressure caused by accumulation of fluid within the pericardial sac resulting from malignancy or from pericardial thickening with scar formation, which results in a thick constrictive neoplastic encasement. This condition needs to be recognized early to allow fluid decompression or pericardiectomy in order to avoid circulatory compromise and death of the patient. Signs and symptoms are partially affected by the rapidity of development. In the era prior to diagnostic ultrasonography, this medical-oncologic emergency was often unrecognized. In one early series before ultrasonography, the diagnosis was missed by the first physician in 11 of 17 patients and a number of times was missed by more than a single examiner.[36] In most instances, pericardial effusion is accompanied by signs and symptoms that presage the development of the clinical picture of tamponade including dyspnea, apprehension, anxiety, and chest pain. In rare instances, tamponade may be the first manifestation of the malignancy, solid tumor, or leukemia. Any patient in the emergency department with a history of cancer, shortness of breath, and hypotension should be suspected of having pericardial tamponade. The diagnoses of pulmonary embolism, congestive heart failure, and anxiety can be mistakenly made in this setting.

Etiology The most common cause of neoplastic pericardial tamponade is malignant pericardial effusion, often associated with postirradiation pericarditis, fibrosis, and effusion. Only rarely does a tumor or radiation fibrosis cause a neoplastic constrictive pericarditis with resultant tamponade. In most reported cases, cardiac tamponade represents a clinical progression of neoplastic or postirradiation pericarditis. Neoplastic pericarditis can result from any number of benign, malignant, primary, or secondary tumors of the pericardium or mediastinum.[] The most common benign tumors of the pericardium or mediastinum are

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fibromas, angiomas, and teratomas. Pericardial mesothelioma can have a clinical course characterized by rapid accumulation of massive quantities of bloody pericardial fluid, eventually leading to tamponade. Secondary involvement of the pericardium may result from either direct invasion from structures or metastases from a distant primary tumor. These metastases are usually multiple rather than solitary lesions. The tumors most commonly associated with pericardial involvement include those of the lung and breast, leukemia, Hodgkin's and non-Hodgkin's lymphomas, melanomas, gastrointestinal primary tumors, and sarcomas.[] Clinically recognizable symptoms or signs of pericardial disease are difficult to appreciate before death. Less than 30% of patients with autopsy-proven malignant pericardial disease were diagnosed before death.[] Radiation pericarditis has been a well-known complication of radiotherapy since the introduction of modern megavoltage techniques. The cardiac effects of radiotherapy may manifest themselves immediately with acute pericarditis or be delayed for months to years, although the majority develop effusion within the first year. The acute forms are inflammatory or effusive, usually self-limited, and subside without residual constriction; the chronic effusive and constrictive types may lead to tamponade and death.[40] Neoplastic constrictive pericarditis, although rare, may be caused by invasion of the pericardium by metastatic lesions or indirectly by the complication of radiation therapy with resultant fibrous thickening of the pericardium. Each of these entities can progress to cardiac tamponade because of thickening by tumor or radiation fibrosis, resulting in a decrease in the distensibility of the pericardium, thus reaching the critical point of cardiopulmonary decompensation earlier, despite smaller volumes of slowly accumulating effusion. The symptoms and signs of neoplastic and radiation pericarditis mimic those of pericarditis of other causes, and because of the usual insidious onset of the effusion of fibrous pericardial thickening, the condition might be attributed to the underlying malignancy and not suspected until the full-blown picture of cardiac tamponade develops.

Pathophysiology The severity of cardiac tamponade and eventual cardiopulmonary decompensation depend on the rate of development of pericardial fluid accumulation, the fluid volume, and the rate of compression of the heart. Clinically, the progressive elevation of intrapericardial pressure interferes with ventricular expansion and results in a decrease in the cardiac volume. There is a rapid rise of intracardiac chamber pressures with subsequent transmission of this pressure peripherally in pulmonary and vena caval beds. In an effort to maintain cardiac output, various compensatory mechanisms come into play (tachycardia, peripheral vasoconstriction, decrease in renal flow with resultant increase in blood volume by sodium and water retention), all to maintain arterial pressure and venous return. When these compensatory mechanisms fail to maintain cardiac output, ventricular end diastolic pressure increases and subsequent circulatory collapse is impending. The signs and symptoms parallel these pathophysiologic changes. The most common symptoms include extreme anxiety and apprehension, a precordial oppressive feeling, or actual retrosternal chest pain with dyspnea of varying degrees. True orthopnea and paroxysmal nocturnal dyspnea are uncommon, but when they occur the patient assumes a variety of positions to get relief from the chest pain and the dyspnea. Other prominent symptoms include cough, hoarseness, hiccups, and occasional gastrointestinal manifestations such as dysphagia, nausea, vomiting, and epigastric or right upper quadrant abdominal pain that is probably the result of visceral congestion.[]

Clinical Features In contrast, patients with severe tamponade are acutely ill and may appear ashen, pale, or markedly diaphoretic with an impaired consciousness ranging from mildly confused to unresponsive. Rapid, shallow, and occasionally labored breathing may be present along with peripheral cyanosis and distended jugular veins. Seizures have been reported. Striking facial plethora and a full neck secondary to edema (Stokes' collar) have also been seen in SVCS. Pulses are soft and easily compressible. The systolic blood pressure is usually low, with a decreased pulse pressure, although normal systolic, diastolic, and pulse pressures have been reported with moderate degrees of tamponade. Kussmaul's signs (quiet heart sounds, an enlarged cardiomediastinal silhouette, tachycardia, and most notably pulsus paradoxus) are extremely useful findings in the physical evaluation of tamponade. One must remember that with significant hypotension, atrial septal defect, and aortic insufficiency, pulsus paradoxus may be absent and an unreliable finding. Ascites, hepatomegaly, peripheral edema, and mottling are other findings that reflect the elevation in venous pressure and decrease in cardiac output.[]

Diagnostic Strategies The electrocardiogram may demonstrate low voltage and the nonspecific findings of pericardial effusion,

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sinus tachycardia, ST elevation, and nonspecific ST-T wave changes. Electrical alternans with 1:1 total atrial-ventricular complexes has been considered almost pathognomonic of cardiac tamponade. Approximately two thirds of patients with neoplastic pericarditis who have tamponade caused by massive pericardial effusion also exhibit pulsus alternans. The alternation customarily disappears soon after removal of a small volume of fluid, but it can also disappear spontaneously or be observed in attendance with a fluid increase.[40] Radiographic signs of tamponade suggestive of pericardial effusion include an enlarged cardiac silhouette with clear lung fields and normal vascular pattern, although a normal chest radiograph does not exclude tamponade. The typical “water bottle” appearance of the heart on a plain radiograph is often present. Echocardiography is the simplest and most sensitive of diagnostic tests and can be done at the bedside immediately for confirmation of pericardial effusion. Therapeutic intervention with echocardiography equipment can then guide the pericardiocentesis. Thoracic CT scanning has also become an important diagnostic tool in diagnosing pericardial effusions.[] The diagnosis of cardiac tamponade should be suspected in any cancer patient with dyspnea. Highly suggestive symptoms include clouded sensorium, thready pulse, pulsus paradoxus exceeding 50% of the pulse pressure, low systolic pressure, engorged neck veins, a falling pulse pressure below 20 mm Hg, and electrical alternans. There is an uncommon yet pathognomonic sinusoidal variation in QRS size secondary to the pendular effect of the heart swinging in the fluid medium of the pericardial sac.[43] In this setting, sudden death may occur and pericardiocentesis should be performed as soon as possible.

Management In the emergency department, the only lifesaving treatment for tamponade that is effective is immediate removal of the pericardial effusion by pericardiocentesis. The procedure carries some risk, including induction of cardiac dysrhythmias and hemorrhage from an injured coronary vessel. Aspiration of as little as 50 to 100 mL of fluid has been shown to alleviate the pathologic process temporarily.[] Removal of the maximal amount of fluid is advisable, along with insertion of an indwelling catheter, during the first pericardiocentesis because fluid may reaccumulate during the first 24 hours. When the pericardial fluid has been obtained, it must be sent for biochemical and cytologic analysis. Other types of supportive therapy may be needed during the evaluation process while preparing for pericardiocentesis, such as intravenous hydration with normal saline and oxygen therapy. When the patient has been stabilized, additional therapeutic interventions should be planned and initiated by the appropriate admitting services because reaccumulation of effusion in neoplastic tamponade is not easily managed on a short-term basis. Pericardial windows, radiotherapy, intrapericardial chemotherapy, and pericardiectomy may be justified.[] The prognosis of neoplastic cardiac tamponade is dependent on the underlying type and extent of cancer. The presence of total electrical alternans is an adverse prognostic sign, even when the alternans disappears with pericardiocentesis. Despite a poor prognosis for patients with cancers such as melanoma or non–small cell lung cancer, some patients with treatmentresponsive lymphomas have had long-term survival after neoplastic cardiac tamponade.

NEUROLOGIC EMERGENCIES Of all patients with cancer, 15% to 20% have neurologic complications.[45] Neurologic symptoms are occasionally the presenting complaint in patients with systemic cancer, but more often symptoms develop in patients known to have cancer. In both settings it is necessary to initiate both an appropriate workup and emergency intervention. Neurologic emergencies in cancer patients include cerebral herniation, seizures, epidural spinal cord compression, CNS infections, and reversible toxic or metabolic encephalopathies. Treatment is needed within minutes to hours after the patient arrives at the emergency department to prevent permanent neurologic dysfunction or death.

Cerebral Herniation Pathophysiology Cerebral herniation occurs when the ICP increases locally within the skull from an expanding mass lesion. The increase produces a shift of brain substance in the direction of least resistance caudally through the tentorial opening and the foramen magnum. Causes of cerebral herniation in cancer patients commonly include primary or metastatic brain tumors and intracerebral hemorrhage. Less common causes include subdural hematoma, brain abscess, acute hydrocephalus, and radiation-induced brain necrosis.[46] Primary brain tumors account for approximately one half of intracranial tumors. Metastatic brain tumors are seen

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most commonly in lung, breast, colon, kidney, and testicular cancer and in patients with choriocarcinoma and malignant melanoma.[]

Clinical Features Three distinct herniation syndromes have been described: uncal, central, and tonsillar herniation. In uncal herniation a lateral mass displaces the temporal lobe, which compresses the upper brainstem. A rapid loss of consciousness is seen in conjunction with unilateral pupillary dilatation and ipsilateral hemiparesis. Central herniation usually results from slowly expanding, multifocal lesions that cause a downward and lateral shift of the diencephalon and upper pons. A slowly decreasing level of consciousness, small reactive pupils, and Cheyne-Stokes respirations, without focal signs, are seen clinically. Central herniation is sometimes mistaken for toxic or metabolic encephalopathy because of the lack of focal signs. A history of headache or focal neurologic complaints or any lateralizing findings mandates the acquisition of a CT scan to rule out a herniating mass lesion before lumbar puncture. Tonsillar herniation is produced by a large posterior fossa mass that pushes the cerebellar tonsils through the foramen magnum, compressing the medulla and resulting in a rapidly decreasing level of consciousness, occipital headache, vomiting, hiccups, hypertension, meningismus, and abrupt changes in the respiratory pattern.[]

Management When the clinical diagnosis of cerebral herniation is made, emergency management is mandatory before the cause can be established. Intubation with hyperventilation to a carbon dioxide partial pressure (pco2) of 25 to 30 mm Hg temporarily lowers the ICP by producing cerebral vasoconstriction. This should be avoided if possible but may be necessary for brief periods in response to reversible, acute neurologic deterioration. Excessive or prolonged hyperventilation may cause paradoxical vasodilation and should be avoided. Mannitol, 1 g/kg IV, should be given and may be repeated in 4 to 6 hours. Dexamethasone, 12 to 24 mg IV, has not been shown to improve outcome or reduce ICP acutely in severe head injury[] but is often administered in patients with raised ICP or impending herniation caused by CNS malignancy because of the effect of corticosteroids on reducing cerebral edema associated with the neoplastic process. A CT scan of the brain should be obtained as soon as emergency stabilization is accomplished. Epidural or subdural hematoma and hydrocephalus usually require surgery, whereas abscess and metastases are usually managed with antibiotics and antineoplastics or radiation, or both, respectively. When stabilization and an initial diagnosis have been made, neurologic or neurosurgical consultation and prompt admission to an intensive care unit are mandatory.[]

Seizures Seizures are common in patients with cancer. Their immediate management is necessary to prevent physical injury, increased ICP, and risk of aspiration. Seizures increase the brain's metabolic requirements and lead to increased cerebral blood flow. This may precipitate increased ICP in susceptible patients. Seizures may be due to brain metastases, toxic or metabolic disturbances (usually hyponatremia or uremia), vascular problems (especially intracerebral hemorrhage or subdural hematomas), and infections. Diagnostic laboratory studies should include a CBC, electrolytes, glucose level, blood urea nitrogen (BUN), calcium and magnesium levels, liver function tests, coagulation studies, and appropriate cultures. A head CT scan should be done and followed by a lumbar puncture, when indicated.[] The therapy for seizures depends on the specific cause and the patient's clinical status. For example, a single hypoglycemic or hypoxic seizure usually requires only correction of the underlying metabolic defect. Patients with a single seizure whose workup reveals a chronic problem (e.g., a cerebral metastasis) require anticonvulsants and therapy specific for the malignancy. A loading dose of phenytoin (15 to 18 mg/kg IV) may be given followed by oral maintenance. Prolonged single seizures or repetitive seizures require more aggressive treatment, including diazepam, 5 to 10 mg IV, or lorazepam, 1 to 2 mg IV, followed by IV phenytoin. Active airway and ventilatory management is essential. A bedside fingerstick glucose level should be obtained immediately. Thiamine and naloxone are not routinely indicated. In addition, when repetitive seizures have occurred, management of the underlying cause should be initiated rapidly and the patient admitted to an intensive care unit.[]

Epidural Spinal Cord Compression Principles of Disease Epidural spinal cord compression from metastatic cancer is common, serious, and potentially treatable. It is most often caused by lymphoma or lung, breast, or prostate carcinoma. With the exception of lymphoma, which extends through the intervertebral foramina from paravertebral lymph nodes, these tumors metastasize to the vertebral body and extend into the spinal canal to compress the spinal cord. Less

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common causes of spinal cord compression in patients with cancer include melanoma, myeloma, renal cell carcinoma, vertebral subluxation, spinal epidural hematomas, and intramedullary metastasis. Acute myelopathy in patients with cancer may also be caused by radiation, paraneoplastic necrotizing myelitis, a ruptured intervertebral disk, and meningeal carcinomatosis with spinal cord involvement. Most cases (68%) of epidural cord compression occur in the thoracic spine, 15% occur in the cervical spine, and 19% in the lumbosacral spine.[51]

Clinical Features Back pain, either local or radicular, is the initial symptom in 95% of patients with epidural metastasis. It may be acute in onset or develop insidiously over weeks to months and usually predates other symptoms. The pain may increase during physical examination with spinal percussion, neck flexion, Valsalva's maneuver, or straight leg raising and is usually located at the level of the tumor.[] Other symptoms are usually present at the time of diagnosis and may include weakness (75% of patients) and autonomic or sensory symptoms (50% of patients). Fifty percent of patients are not ambulatory at the time of diagnosis. The neurologic examination usually reveals symmetrical weakness with either flaccidity and hyporeflexia (if the diagnosis is made very early) or spasticity and hyperreflexia (if the diagnosis is made later).

Diagnostic Strategies Plain films show evidence of tumor in the vertebral body in 70% to 90% of patients with vertebral metastases.[] Immediate myelography or MR imaging is indicated if the plain films are abnormal, regardless of whether the neurologic examination is abnormal or is consistent with spinal cord compression or what the findings on plain x-ray films are. In cases with questionable findings on plain films of the spine, tomograms, coned-down views, or a CT scan may reveal bone metastases not otherwise appreciated. Myelography can demonstrate a complete or near-complete obstruction of contrast dye flow at the level of vertebral body involvement. MR imaging has emerged as the procedure of choice for intramedullary metastases and has also replaced myelography, which is associated with significant morbidity related to lumbar puncture and dye insertion at multiple levels (including cisternal puncture), to demonstrate the length of the compression or skip lesions along the spinal cord.[]

Management Because minimal weakness at the time of presentation may progress to profound, irreversible weakness over several hours, treatment should be started immediately. In the emergency department, a loading dose of dexamethasone, 10 to 100 mg IV, followed by 4 to 24 mg every 6 hours for 3 days to reduce cord edema is initiated at the time of diagnosis. Immediate oncology and radiation oncology consultations should be obtained. Although corticosteroids are routinely administered to patients with suspected spinal cord compression, high-dose corticosteroids, such as dexamethasone 100 mg, have been associated with complications and their use is controversial.[53] Radiation treatment is the usual therapy and can be initiated after steroid treatment. The prognosis depends on the radiosensitivity of the tumor, the location of the compression, the pretreatment performance status, and the rate of decompensation. Surgery is indicated only if the diagnosis is in doubt, if a tissue diagnosis is required, if the spine is unstable, or when radiation to the involved area has already been given in maximal doses.[] Intramedullary metastases are similar in presentation and treatment to epidural cord compression but are associated with a very poor prognosis. Epidural hematomas have been described in patients with thrombocytopenia or a coagulopathy as a complication of lumbar puncture. A rapidly progressive paraparesis and back pain are seen. MR imaging or myelography can establish the diagnosis; the treatment is surgical decompression. Platelet transfusions may limit progression in the emergency department.[]

Central Nervous System Infections Principles of Disease Patients with cancer are susceptible to a variety of CNS infections. These patients may have impaired immune responses secondary to their underlying disease or treatment with steroids, chemotherapy, splenectomy, or irradiation. Most CNS infections occur in patients with leukemia, lymphoma, or head and neck cancer. Patients with head and neck cancer are susceptible (in addition to the reasons discussed) because of fistula formation and tumor invasion, which allows organisms access to the CNS. Important CNS infections include meningitis, brain abscess, and encephalitis. These often have similar presentations, making their differentiation in the emergency department difficult.

Clinical Features Meningitis is characterized by fever, headache, and altered mental status. Meningismus is often absent. The

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diagnosis of meningitis in patients with cancer is often delayed because the manifestations of the disease are attributed to other processes: fever to systemic infection, headache to cerebral metastases, and altered mental status to a toxic or metabolic encephalopathy.

Diagnostic Strategies All cancer patients with fever and an altered mental status require a lumbar puncture, which should be preceded by a head CT scan if cerebral metastases are suspected.[] In addition, thrombocytopenia and coagulopathy should be considered and either ruled out or treated appropriately with platelet transfusions or fresh frozen plasma, respectively, before a lumbar puncture is done. Platelet transfusion is usually reserved for patients with platelet count less than 10,000/mL. The fluid obtained should be sent for a cell count and differential cell count, Gram's stain, India ink stain, protein and glucose levels, bacterial and fungal cultures, cryptococcal antigen level, and cytologic examination. The absence of WBCs in the CSF does not rule out meningitis, especially in neutropenic patients. The likely organisms responsible for meningitis vary with the underlying disease and the peripheral WBC count.

Differential Considerations Brain abscess is usually seen in patients with leukemia or head and neck tumors and accounts for 30% of CNS infections in cancer patients.[46] Patients have symptoms of elevated ICP (headache, vomiting, and papilledema), lateralizing findings, and a source of infection.[] Fever is usually present. Head CT scanning characteristically demonstrates an ill-defined mass early in the course of an abscess, with the classical well-defined mass with a low-density center and a contrast enhancing ring seen later. Edema and mass effect are common. A lumbar puncture is not helpful in making the diagnosis and may precipitate cerebral herniation. Organisms that cause abscess include gram-negative rods, Aspergillus and Phycomycetes species, and Toxoplasma gondii. Emergency management includes high-dosage antibiotics. If herniation develops, immediate steps to reduce the ICP, followed by emergency surgery, are indicated. Encephalitis is rare in patients with cancer and is most often caused by herpes zoster or T. gondii. The presenting complaints are usually headache, fever, and altered mental status. The CT scan is commonly normal but may show diffuse edema, whereas the lumbar puncture may show pleocytosis with an elevated protein level but no demonstrable organism. It is difficult to distinguish encephalitis from meningitis in the emergency department, but the overall clinical picture in both diseases mandates hospital admission for further evaluation.

Management However, empirical broad spectrum antibiotic coverage should be initiated for all patients with a thirdgeneration cephalosporin (ceftriaxone or ceftazidime) and vancomycin. Ampicillin may be added when there is suspicion of Listeria. Ceftazidime with or without an aminoglycoside is generally selected when the likelihood of infection with Pseudomonas is high. Neutropenic patients (polymorphonuclear WBC count 200 mg/dL), ketonemia (>1:2 dilutions), and acidemia (pH < 7.3). DKA can be caused by any condition that reduces insulin availability or activity or that increases glucagon. DKA occurs most often in type 1 diabetic patients with little or no endogenous insulin; however, its occurrence in patients with type 2 diabetes, particularly obese African Americans, is not as rare as once thought. DKA in these patients results from increased lipolysis, and the breakdown of free fatty acids leads to production of ketoacids. Precipitating events usually include infections, surgery, and emotional or physical stressors.

Isoniazid and Iron Toxicity Isoniazid is a common, important, but potentially lethal medication used for the treatment of tuberculosis. Clinicians must be aware that ingestions of greater than 40 to 60 mg/kg pose a danger of not only recurrent seizures but also life-threatening metabolic acidosis (as a result of the lactate-producing seizure activity). Treatment involves pyridoxine administration to control seizures and hemodialysis to reduce both intravascular drug concentration and acidemia. Elevated AG metabolic acidosis from iron ingestion is a direct result of mitochondrial poisoning and uncoupled oxidative phosphorylation. Metabolic acidosis is typically appreciated in phase I of toxicity, usually within 6 hours of ingestion. It becomes quite apparent in phase III, signaling impending hepatic failure and shock. Effective treatment depends on early recognition and administration of deferoxamine.

Lactic Acidosis There are two forms of lactic acid, the “l” form and the “d” form. The “l” form is most common and is the traditional form measured when obtaining serum lactate levels. A product of anaerobic metabolism, lactic acidosis develops when an imbalance exists between lactic acid production and subsequent conversion by the liver and kidney. Thus, lactic acidosis is a marker of hypoperfusion and ongoing shock as hypoperfusion, hypoxemia, hypermetabolic states or some combination of these results in an increase in serum lactate.[14] The “d” form has recently gained attention because of an increasing number of patients with small-bowel resection or gastric bypass surgery.[15] d-Lactic acidosis is characterized by episodes of encephalopathy and acidemia. Development of short-gut syndromerequires ingestion of a large carbohydrate load, carbohydrate malabsorption with increased delivery of carbohydrates to the large bowel, prominent lactobacilli, diminished colonic motility, and impaired d-lactic acid metabolism. Nucleoside analogue reverse transcriptase inhibitors (e.g., zidovudine and stavudine) for human immunodeficiency virus have also been shown to induce lactic acidosis. The syndrome that results from the mitochondrial toxicity of these agents can manifest with severe lactic acidosis, hepatic steatosis, and a high rate of mortality.[16] Initial measurement of metabolic acidosis (serum lactate levels), compared with the traditional carboxyhemoglobin levels, might better indicate the severity of carboxyhemoglobin toxicity and better predict hyperbaric treatment requirements.[17] Metformin, currently considered the initial drug of choice for overweight patients with type 2 diabetes mellitus, is a biguanide derivative that is pharmacologically related to phenformin hydrochloride, which was withdrawn from the U.S. market in 1976 (owing to a high incidence of lactic acidosis). Studies support the clinical experience of metformin-induced lactic acidosis as well.[18] Metforminis believed to induce lactic acidosis, especially in the patient with renal insufficiency, by reducing pyruvate dehydrogenase activity and enhancing anaerobic metabolism. A serum creatinine concentration greater than 1.5 mg/dL, congestive heart failure requiring medications, acute or chronic metabolic acidosis, or exposure to iodinated contrast agents within 48 hours are considered absolute contraindications to the drug.

Salicylates Salicylates' first toxic effect on acid-base balance results from direct stimulation of the respiratory center, increasing minute ventilation and inducing hypocapnia. In the early presentation of salicylate toxicity,

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respiratory alkalosis is often the only acid-base disturbance appreciated. Salicylates can also cause metabolic acidosis by uncoupling oxidative phosphorylation and inhibiting the dehydrogenase enzymes of the Krebs cycle.

Normal Anion Gap Metabolic Acidosis Metabolic acidosis with a normal AG is caused by either an excessive loss of HCO[3] or an inability to excrete H+ and can be remembered with the mnemonic F-USED CARS (see Box 122-4 ). Any condition that causes excessive loss of intestinal fluid distal to the stomach can cause a normal AG metabolic acidosis. Normal AG metabolic acidosis is primarily a bicarbonate wasting condition and in 95% of cases results from diarrhea. Other possible, although less common, causes include tube drainage and skin fistulae, with loss of HCO3-rich intestinal, biliary, or pancreatic fluids. Ureterosigmoidostomy (surgical insertion of ureters into the sigmoid colon) produces a hyperchloremic acidosis because of loss of HCO[3] in exchange for the reabsorption of Cl−. Patients with renal failure develop an inability to excrete their dietary H+ load; the severity is proportional to the degree of reduction in the GFR. Patients with renal tubular acidosis type 1 are unable to secrete H+ at the distaltubule, whereas impairment of HCO[3] reabsorption at the proximaltubule is the defect in renal tubular acidosis type 2. Calculation of the urinary anion gap(UAG = [Na+ − K+] − Cl−) may be helpful; a negative urinary anion gap suggests gastrointestinal loss of bicarbonate, whereas a positive urinary anion gap suggests altered urinary acidification, indicating a renal tubule abnormality. Other causes of normal AG metabolic acidosis include hyperparathyroidism, medications such as carbonic anhydrase inhibitors (e.g., acetazolamide [Diamox], mafenide acetate [Sulfamylon]) and spironolactone, and hyperalimentation with excess arginine, lysine, or chloride.

Physiologic Compensation The body responds to acidemia by utilizing four buffering systems: (1) extracellular bicarbonate−carbonic acid system, (2) intracellular blood protein system, and (3) renal and (4) respiratory compensation systems (see Figure 122-2 ). The first two processes minimize the initial H+ concentration while the kidneys eliminate excessive H+ in the urine, reabsorb HCO3, and restore acid-base homeostasis. The CNS responds to increased H+ concentration, through direct stimulation of the chemoreceptors in the medulla oblongata, by stimulating the respiratory center. This results in an increase in alveolar ventilation, producing a compensatory elimination of Paco2 and elimination of excess H+. It may take 12 to 24 hours to achieve a maximal respiratory response to a sustained metabolic acidosis. When the arterial pH is 7.10 or less, the minute ventilation can reach 30 L/min. This type of prolonged and prominent hyperventilation, Kussmaul's respiration, is characteristic of metabolic acidosis. In response to metabolic acidosis, H+ ions are excreted by the kidney while HCO[3] is reabsorbed. The rate-limiting reaction (the synthesis of H2CO 3 from CO2 and H2O) is catalyzed by carbonic anhydrase. Therefore, inhibitors of this enzyme can create a metabolic acidosis by preventing the renal excretion of H+. The excretion of H+ requires buffering with HPO−4 or NH3, with ammonium playing the largest role. This buffering is called titratable acidity. The kidney responds to an increased H+ load by the augmentation of cellular NH3 production and consequently NH+4 excretion. In summary, H+ ions are acutely buffered by extracellular and intracellular mechanisms. However, these mechanisms are not potent enough to correct acidosis sufficiently. Acidemia will stimulate the CNS ventilatory center, and the Paco2 will be reduced secondary to Kussmaul's respiration. With continued and chronic acidemia, the kidneys will secrete H+ (as NH+4 and H2PO−4) and reabsorb HCO−3 in an attempt to neutralize the acidosis.

Management In treating patients with metabolic acidosis, primary efforts should be directed at restoring their homeostatic mechanisms. The clinician must treat the patient, using laboratory markers only as a guide. Active correction of the pH depends on the severity of the acid-base imbalance, the cause, the patient's compensatory capabilities, and the potential harm caused by therapy. Most patients with metabolic acidosis

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do not require aggressive attempts at pH manipulation. For many, the causality is easily discernible, and treatment involves stabilization of homeostatic mechanisms. For example, metabolic acidosis after a seizure resolves within approximately 15 minutes. Rather than administration of sodium bicarbonate (NaHCO3), immediate treatment would involve termination of the seizure activity, maintenance of the airway, and provision for acid-base normalization by ventilatory loss of CO2. Therapy with NaHCO3 has some inherent complications, and rapid NaHCO3 replacement can result in paradoxical CNS intracellular acidosis, impaired oxygen delivery, hypokalemia, hypocalcemia, “overshoot” alkalosis, hypernatremia, volume overload, and hyperosmolality. Bicarbonate penetration into the CNS across the blood-brain barrier is very slow; consequently, intravenous HCO[3] therapy alkalinizes the plasma much faster than the CNS. As the serum pH increases, the peripheral chemoreceptors will decrease minute ventilation, raising Paco2 in an attempt to normalize the serum pH. CO2, which rapidly diffuses across the blood-brain barrier, will rise intracerebrally, and the CNS will become more acidotic despite alkalinization of the plasma. This inverse reaction is referred to as paradoxical CNS acidosis. Much discussion surrounds this phenomenon and intravenous bicarbonate use. Buffer therapy during out-of-hospital cardiac arrest had little to no benefit in one study, regardless of the arterial pH.[19] The only prospective, randomized, controlled study failed to demonstrate any difference between the bicarbonate and control groups.[20] Furthermore, alkali therapy can lead to ECF volume overload (especially in patients with congestive heart failure) and hypokalemia, which may lead to respiratory muscle weakness and inability to hyperventilate if it is severe. Administration of loop diuretics may prevent or treat this complication, but if adequate diuresis cannot be established, emergent dialysis may be necessary. Because NaHCO3 imparts a significant sodium load on the patient, several low-sodium buffers have been developed. Unfortunately, none have proven to be clinically more efficacious than NaHCO3.[21] Because of the inherent complications associated with bicarbonate replacement, a rule of thumb is to treat patients who have a pH less than 7.1 with NaHCO3 1 mEq/kg.[22] Another formula available to assist in determining the adequate dose is the following:

Half should be replaced initially and further NaHCO3 therapy should be determined by patient response and laboratory parameters. Patients with normal AG metabolic acidosis have a greater loss of HCO[3] than those with an increased anion gap, and therefore the clinician may have a lower threshold for replacement.

METABOLIC ALKALOSIS Metabolic alkalosis is produced by conditions that increase HCO[3] or reduce H+. This usually requires either the loss of H+ or the retention of HCO3. The diagnosis requires knowledge of the Paco2, because elevation of the plasma HCO[3] may be secondary to renal compensation of a chronic respiratory acidosis.

Etiology Metabolic alkalosis is usually caused by an increase in HCO[3] reabsorption secondary to volume, potassium, or chloride loss ( Box 122-5 ). Loss of H+ and Cl− from aggressive vomiting and nasogastric suctioning can also lead to HCO[3] retention. Renal impairment of HCO[3] excretion, especially in the setting of alkali therapy, can lead to a significant metabolic alkalosis. BOX 122-5 Causes of Metabolic Alkalosis

Volume-Contracted (Saline-Responsive) Vomi ting/ gastr ic sucti on Diur

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etics Ion-d efici ent baby form ula Colo nic aden oma s

Normal Volume/Volume-Expanded (Saline-Resistant) Prim ary aldo stero nism Exog enou s mine raloc ortic oids (licor ice, che wing toba cco) Aden ocar cino ma Bartt er's synd rom e Cus hing' s dise ase Ecto pic adre noco rticot ropic hor mon e An ECF volume reduction can increase the plasma HCO[3] concentration when combined salt and water

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losses occur, typically in patients using diuretics. This state forces a contraction of the ECF around a constant plasma HCO3, creating a relative excess in HCO[3] concentration; this is known as contraction alkalosis. Metabolic alkalosis can be caused by hypokalemia as H+ is shifted intracellularly in exchange for the osmotic movement of K+ extracellularly. There is also an increase in renal H+ secretion and HCO[3] reabsorption. The net effect is ECF alkalosis with paradoxical intracellular acidosis, which is easily reversed with potassium therapy. Primary hyperaldosteronism, hyperreninism, licorice ingestion, Cushing's syndrome, and congenital adrenal hyperplasia are associated with mineralocorticoid excess. This leads to an increased Na+ reabsorption in the distal tubule with its accompanying H+ and K+ secretion to maintain electroneutrality.

Physiologic Compensation Although somewhat less predictable, acute compensation of metabolic alkalosis involves the respiratory center, and chronic compensation involves the renal system. During acute compensation, chemoreceptors controlling ventilation respond to an increased pH by inducing hypoventilation, thus increasing Paco2 and forming H+, which lowers the pH back to normal. A Paco2 of greater than 55 mm Hg is unlikely to be caused by simple respiratory compensation of metabolic alkalosis,[23] and this value should alert the clinician to a ventilation disorder complicating the picture. Chronic compensation for metabolic acidosis results from the kidney excreting excess HCO[3] in the urine. In patients with renal failure, impairment in renal HCO[3] excretion results in sustained metabolic alkalosis.

Management Clinicians can easily treat the simple loss of H+ from aggressive vomiting or nasogastric suction. For more complicated causes, however, management can be directed by measurement of the urinary chloride, which helps classify metabolic alkalosis into saline-responsive or saline-resistant.

Saline-Responsive Alkalosis Patients with saline-responsive alkalosis have a urinary chloride level less than 10 mEq/L. Treatment is directed toward correcting the urinary excretion of HCO3. Administration of NaCl and KCl suppresses both renal acid excretion and renal HCO[3] excretion. NaCl and KCl should be considered for patients with mild to moderate saline-responsive alkalosis. In patients who are severely volume depleted, consultation for admission and administration of intravenous mineral acids (e.g., arginine monohydrochloride) may be necessary. In edematous states for which saline therapy may be contraindicated, acetazolamide will increase the excretion of NaHCO3, treating both the alkalosis and the edema. In renal failure patients, severe metabolic alkalosis should be treated with dialysis.

Saline-Resistant Alkalosis Patients with saline-resistant alkalosis have a urinary chloride level greater than 10 mEq/L. In mineralocorticoid excess, hypokalemia and increased secretion of aldosterone lead to excessive renal excretion of H+ and a reabsorption of HCO3. Treatment can be successful with potassium replacement by reversing the intracellular shift of H+. This reduction of cellular H+ also enhances HCO[3] excretion. Additional therapy can be directed toward reducing mineralocorticoid activity (e.g., administering spironolactone, an aldosterone antagonist).

MIXED ACID-BASE DISORDERS Double and triple primary acid-base disturbances are common. Traditionally, mixed disorders have been difficult to evaluate in the emergency department.[24] However, recent literature provides some guidelines for ascertaining the mixed disorder and its causes. Clues to the presence of a mixed acid-base disturbance can either be historical (e.g., polydrug ingestion) or clinical, with varied chemistry and arterial blood gas findings that differ from those anticipated. From that point, the “three-step approach of Haber” is useful because it involves a logical, easily remembered, rules-based approach that can be applied clinically.[25] Step 1 involves measuring the pH. It is necessary to first assess whether the patient has an acidemia (pH < 7.36) or alkalemia (pH > 7.44). The human body almost never fully compensates for any primary acid-base disturbance except for chronic respiratory alkalosis. Step 2 requires the clinician to calculate the AG. Box 122-3 lists possible causes of an AG greater than 15

Page 2665

mEq/L, and Box 122-4 lists possible causes for a case in which the AG is normal but the patient has a metabolic acidosis. Step 3 involves calculating the delta gap(p3G = deviation of AG from normal − deviation of HCO[3] from normal) to help resolve the possibility of a mixed acid-base disorder or further differentiate an elevated AG metabolic acidosis. Values for the p3G are all gaussian, and therefore the mean value should be near zero.[26] An expected normal range for the p3G would be 0 ± 6. A positive p3G (−6 or greater) is almost always caused by high AG acidosis and a primary metabolic alkalosis. DKA or AKA with severe vomiting, lactic acidosis in the setting of chronic diuretic use, and renal disease with vomiting are clinical examples. A negative p3G (−6 or less), on the other hand, can be of varied clinical representation. Most often there is either a mixed high AG and normal AG acidosis, or a high AG acidosis with chronic respiratory alkalosis and a compensating hyperchloremic acidosis. Clinically, these patients often have severe underlying metabolic disease with ongoing toxic ingestion (e.g., profound hypermagnesemia, hyponatremia, or hypercalcemia in patients with lithium toxicity) or chronic lung disease, acute lactic acidosis, and furosemide use. Other algorithms and relationships in these disorders can also assist in rapid interpretation of mixed acid-base disturbances ( Box 122-6 ). BOX 122-6 Relationships in Acid-Base Disturbances

Respiratory Acidosis

Acute 1.

HCO − 3

incre ases 1 mEq /L (ran ge, 0.251.75) for ever y 10mm Hg incre ase in Pco2 . 2.

pH drop s 0.08 for ever y 10mEq /L rise in HCO

Page 2666

− 3.

Chronic (>5 days of hypercapnia) HCO − 3

incre ases 4 mEq /L for ever y 10mm Hg incre ase in Pco2 (±4). Limit of com pens ation : bicar bona te will rarel y exce ed 45 mEq /L.

Metabolic Acidosis Note: It may take 12 to 24 hours for maximal respiratory response to develop. 1. Pac o2 = (1.5 × HCO − 3) + 8±2 2. Pac o2 is

Page 2667

3.

4.

5.

equi vale nt to last two digit s of pH (i.e., if Pco2 is 20, pH shou ld be 7.20) . DPc o2 = 1− [1.3 × (HC O −3)] For pure anio n gap acid osis, the rise in anio n gap shou ld be equa l to the fall in bicar bona te conc entra tion (i.e., p3ga p shou ld equa l 0). For pure non– anio

Page 2668

n gap (hyp erchl ore mic) acid osis, the fall in bicar bona te shou ld be equa l to the rise in chlor ide conc entra tion (i.e., bicar b= chlor ide). Limit of compensation: Paco2 will not fall below 10 to 15 mm Hg.

Respiratory Alkalosis

Acute HCO − 3

drop s1 to 3.5 mEq /L for ever y 10mm Hg drop in Pco2 . Limit of

Page 2669

com pens ation : bicar bona te is rarel y belo w 18 mEq /L.

Chronic (renal compensation starts within 6 hours and is usually at a steady state by 1½ to 2 days) HCO − 3

drop s2 to 5 mEq /L for ever y 10mm Hg drop in Pco2 . Limit of com pens ation : bicar bona te is rarel y belo w 12 to 14 mEq /L.

Metabolic Alkalosis 1.

Pco2 = 0.9 (HC O −3)

Page 2670

2.

+9 Pco2 incre ases 0.6 mm Hg for each 1-m Eq/L incre ase in HCO − 3. Limit of com pens ation : Pco2 rarel y exce eds 55 mm Hg.

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Page 2671

Use of this content is subject to the Term s and Conditions of the MD Consult web site.

Marx: Rosen's Emergency Medicine: Concepts and Clinical Practice, 6th ed., Copyright © 2006 Mosby, Inc.

KEY CONCEPTS {, {,

{,

Changes in serum pH are dealt with by three compensatory systems: (1) the physiologic buffers, (2) the lungs, and (3) the kidneys. Bicarbonate is present in large quantities and can be controlled by the lungs and kidneys, making it the major contributor to the maintenance of acid-base balance and the primary system to handle the acute load of organic acidemia. Respiratory acidosis is defined as decreased pH that results from pulmonary CO2 retention. This CO 2 retention leads to excess H2CO 3 production and acidemia.

{,

Increased minute ventilation is the primary cause of respiratory alkalosis, characterized by decreased Paco2 and increased pH.

{,

Metabolic acidosis can be caused by one of three mechanisms: (1) increased production of acids, (2) decreased renal excretion of acids, or (3) loss of alkali. The causes of metabolic acidosis can be divided into those that create an elevation in the anion gap and those that do not.

{,

Metabolic alkalosis is usually caused by an increase in HCO−3 reabsorption secondary to volume, potassium, or chloride loss. Contraction alkalosis can result from extracellular volume reduction, with a consequent increase in the plasma HCO−3 concentration, when combined salt and water losses occur. This typically occurs in patients using diuretics. Determination of a mixed acid-base disorder requires knowledge of the pH, calculation of the AG, and calculation of the delta gap.

{,

{,

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Bookmark URL: /das/book/view/60636217-2/1365/319.html/top

Page 2672

Use of this content is subject to the Term s and Conditions of the MD Consult web site.

Marx: Rosen's Emergency Medicine: Concepts and Clinical Practice, 6th ed., Copyright © 2006 Mosby, Inc.

REFERENCES 1. LoVecchio F, Jacobson S: Approach to generalized weakness and peripheral neuromuscular disease. Emerg Med Clin North Am1997;15:605. 2. Bolton CF: The changing concepts of Guillain-Barré syndrome. N Engl J Med1995;333:1415. 3. Abrunzo TJ, Bowman MJ: Acute presentation of muscle weakness. Pediatr Emerg Med Rep1999;4:29. 4. Cheng BC: Predictive factors and long-term outcome of respiratory failure after Guillain-Barré syndrome. Am J Med Sci2004;327:336. 5. Lawn ND: Anticipating mechanical ventilation in Guillain-Barré syndrome. Arch Neurol2001;58:893. 6. Miller JD, Quillian W, Cleveland WW: Nonfamilial hypokalemic periodic paralysis and thyrotoxicosis in a 16-year-old male. Pediatrics1997;100:412. 7. Sladky JT: Guillain-Barré syndrome in children. J Child Neurol2004;19:191. 8. Felz MW, Smith CD, Swift TR: A six-year-old girl with tick paralysis. N Engl J Med2000;342:90. 9. Robinson RF: Management of botulism. Ann Pharmacother2003;37:127. 10. van Koningsveld R: Effect of methylprednisolone when added to standard treatment with intravenous immunoglobulin for Guillain-Barré syndrome: Randomized trial. Lancet2004;363:192. 11. Hughes RA: Practice parameter: Immunotherapy for Guillain-Barré syndrome: Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology2003;61:736. 12. Keesey JC: Clinical evaluation and management of myasthenia gravis. Muscle Nerve2004;29:484. 13. Younger DS: Medical therapies in myasthenia gravis. Chest Surg Clin N Am2001;11:329. 14. Bedlack RS: How to handle myasthenic crisis: Essential steps in patient care. Postgrad Med 2000;107:211.

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REFERENCES 1. Salem MM, Mujais SK: Gaps in the anion gap. Arch Intern Med1992;152:1625. 2. Kissoon N: Comparison of the acid-base status of blood obtained from intraosseous and central venous sites during steady and low-flow states. Crit Care Med1993;21:1765. 3. Brandenburg MA: Comparison of arterial and venous blood gas values in the initial emergency department evaluation of patients with diabetic ketoacidosis. Ann Emerg Med1998;31:459. 4. Harrison AM: Comparison of simultaneously obtained arterial and capillary blood gases in pediatric intensive care unit patients. Crit Care Med1997;25:1904. 5. Davis JW, Shackford SR, Hollbrook TL: Base deficit as a sensitive indicator of compensated shock and tissue oxygen utilization. Surg Gynecol Obstet1991;173:473. 6. Narins RG, Emmett M: Simple and mixed acid-base disorders: A practical approach. Medicine 1980;59:161. 7. Kassirer JP: Serious acid-base disorders. N Engl J Med1974;291:773. 8. Kazmaier S: Effects of respiratory alkalosis and acidosis on myocardial blood flow and metabolism in patients with coronary artery disease. Anesthesiology1998;89:831. 9. Landon M: Acid-base disorders during pregnancy. Clin Obstet Gynecol1994;37:16. 10. Chabli R: Diagnostic use of anion and osmolal gaps in pediatric emergency medicine. Pediatr Emerg Care1997;13:204. 11. Baud FJ: Elevated blood cyanide concentrations in victims of smoke inhalation. N Engl J Med 1991;325:1761. 12. McGarry JD, Foster DW: Diabetic ketoacidosis. In: Rifkin H, Raskin P, ed.Diabetes Mellitus, American Diabetic Association; 1981: 5:185 13. Kamijima M: Metabolic acidosis and renal tubular injury due to pure toluene inhalation. Arch Environ Health1994;49:410. 14. Bernardin G: Blood pressure and arterial lactate levels are early indicators of short-term survival in human septic shock. Intensive Care Med1996;22:17. 15. Uribarri J, Oh MS, Carrol HJ: D-lactic acidosis: A review of clinical presentation, biochemical features and pathophysiologic mechanisms. Medicine1998;77:73. 16. Gerard Y: Symptomatic hyperlactatemia: Emerging complication of antiretroviral therapy. AIDS 2000;14:2723. 17. Turner M, Esaw M, Clark RJ: Carbon monoxide poisoning treated with hyperbaric oxygen: Metabolic acidosis as a predictor of treatment requirements. J Accid Emerg Med1999;16:96. 18. Misbin RI: Lactic acidosis in patients with diabetes treated with metformin. N Engl J Med1998;338:265. 19. Dybvik T, Strand T, Steen PA: Buffer therapy during out-of-hospital cardiopulmonary resuscitation. Resuscitation1995;29:89. 20. Levy MM: An evidence-based evaluation of the use of sodium bicarbonate during cardiopulmonary resuscitation. Crit Care Clin1998;14:457. 21. Offenstandt G: Alkali therapy in the treatment of acute metabolic acidosis. Minerva Anestesiol 1999;65:202. 22. Cummins R: Advanced Cardiac Life Support, 1997-1999, Dallas, Scientific Publishing, 1997. 23. Weinberger SE, Schwartzstein RM, Weiss JW: Hypercapnia. N Engl J Med1989;321:1223. 24. Schreck DM, Zacharias D, Grunau CF: Diagnosis of complex acid-base disorders: Physician performance versus the microcomputer. Ann Emerg Med1986;15:164. 25. Haber RJ: A practical approach to acid-base disorders. West J Med1991;155:146. 26. Wrenn K: The delta gap: An approach to mixed acid-base disorders. Ann Emerg Med1990;19:1310.

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Chapter 123 – Electrolyte Disturbances Michael A. Gibbs Vivek S. Tayal

PERSPECTIVE Abnormalities of serum electrolyte levels generally cannot be diagnosed by the history and physical examination alone. Severe electrolyte disturbances can be fatal, however, and some disorders may produce no symptoms or nonspecific clinical manifestations until life-threatening effects occur.

SODIUM Normal Physiology Water makes up approximately 60% of body weight and is distributed in three compartments: the intracellular space, the interstitial space, and the intravascular space. The intracellular space makes up approximately two thirds of total body water, with the remaining one third in the interstitial space and intravascular space. The concentration of sodium, the predominant extracellular cation, governs the movement of water among these three compartments. When the extracellular sodium concentration decreases, water shifts to the intracellular space to restore osmotic equilibrium. When the extracellular sodium concentration rises, water shifts out of the intracellular space. Under normal conditions, sodium leaks passively into cells down a concentration gradient and is transported back out of the cell by the sodium-potassium adenosine triphosphatase (Na+,K+-ATPase) pump. Sodium homeostasis and water balance are under the hormonal regulation of the renin-angiotensin system and antidiuretic hormone, respectively. Renin, an enzyme produced by the kidney, is released in response to decreases in circulating intravascular volume. Renin catalyzes the production of angiotensin I, which is then converted to angiotensin II in the lung. Angiotensin IIstimulates the production of aldosterone, a mineralocorticoid hormone produced by the zona glomerulosa of the adrenal glands. Aldosteroneenhances sodium reabsorption and potassium excretion in the distal nephron. Antidiuretic hormone(ADH, vasopressin, arginine vasopressin) is synthesized in the hypothalamus and secreted from the posterior pituitary. ADH is released primarily in response to rises in serum osmolality but also to decreases in intravascular volume or arterial pressure. Volume depletion is the most potent stimulus for ADH production, and with decreases in plasma volume, ADH may be secreted even in the face of hypotonicity. ADH enhances renal water reabsorption by increasing tubular water permeability. Other factors that may stimulate ADH release include angiotensin, catecholamines, opiates, caffeine, stress, hypoglycemia, and hypoxia.

Hyponatremia Principles of Disease Hyponatremia is defined as a serum sodium concentration of less than 135 mEq/L. Hyponatremia can be classified into three categories based on the patient's clinical volume status: (1) hypovolemic hyponatremia, (2) euvolemic hyponatremia, and (3) hypervolemic hyponatremia ( Box 123-1 ). When assessing the patient with a low serum sodium level, it is also important to consider the possibility of sampling errors (e.g., phlebotomy from a venous site proximal to an infusion of hypotonic solution), as well as pseudohyponatremia and redistributive hyponatremia. BOX 123-1 Causes of Hyponatremia

Sampling error Pseudohyponatremia

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Hyperlipemia Hyperproteinemia Redistributive type Hyperglycemia Mannitol Hypovolemic type Renal losses Gastrointestinal Third-space losses Excessive sweating Addison's disease Euvolemic type SIADH Psychogenic polydipsia Hypervolemic type Congestive heart failure Hepatic cirrhosis Nephrotic syndrome

SIADH, syndrome of inappropriate secretion of antidiuretic hormone.

Pseudohyponatremia Pseudohyponatremia refers to a falsely low serum sodium measurement in patients whose plasma contains excessive protein or lipid. The relative percentage of water in plasma is reduced. Flame photometry, which determines sodium content per unit of plasma, shows an artifactually low sodium level, although both the total sodium content and the serum osmolarity remain within the normal range. Measurement of the serum sodium by direct potentiometry avoids this problem.[1]

Redistributive Hyponatremia Redistributive hyponatremia is caused by osmotically active solutes in the extracellular space that draw water from the cell, diluting the serum sodium concentration. Common situations causing such hyperosmolar states include hyperglycemia (e.g., diabetic ketoacidosis) and parenteral administration of mannitol or glycerol for the management of intracranial hypertension or glaucoma. The measured serum sodium in patients with hyperglycemia can be corrected by adding approximately 1.6 mEq/L for every 100-mg/dL rise in the serum glucose over 100 mg/dL.

Hypovolemic Hyponatremia Hypovolemic hyponatremia results from the loss of water and sodium with a greater relative loss of sodium. Typical causes include vomiting, diarrhea, gastrointestinal suction or drainage tubes, fistulas, and “third spacing” of fluids (e.g., burns, intra-abdominal sepsis, bowel obstruction, pancreatitis). Causes specifically attributable to renal losses include diuretic use, mineralocorticoid deficiency, renal tubular acidosis, and salt-wasting nephropathy. When sodium losses are sufficient to decrease the glomerular filtration rate (GFR) significantly, the amount of filtrate delivered to the loop of Henle (where free water is generated) is decreased, and little free water appears in the urine. Also, because ADH is released in response to intravascular volume deficits despite hypotonicity, hyponatremia may be maintained even in patients whose GFR would otherwise be adequate to excrete excess free water. Hypovolemic hyponatremia can also be worsened when fluid losses are replaced with hypotonic fluids.

Euvolemic Hyponatremia The many causes of euvolemic hyponatremia include the syndrome of inappropriate secretion of ADH (SIADH), defined as the secretion of ADH in the absence of an appropriate physiologic stimulus. Its hallmark is an inappropriately concentrated urine despite the presence of a low serum osmolality and a normal circulating blood volume. Causes of SIADH include central nervous system (CNS) disorders, pulmonary disease, drugs, stress, pain, and surgery ( Box 123-2 ). Before the diagnosis of SIADH can be confirmed, other potential causes of euvolemic hyponatremia (e.g., hypoadrenalism, hypothyroidism, renal failure)

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should be ruled out. Psychogenic polydipsiais a rare cause of euvolemic hyponatremia. This is most often seen in patients with psychiatric disorders who consume large volumes of water, usually in excess of 1 L/hr, overwhelming the capacity of the kidneys to excrete free water in the urine.[2] In contrast to SIADH, the urine in patients with psychogenic polydipsia is maximally dilute. BOX 123-2 Causes of Syndrome of Inappropriate Secretion of Antidiuretic Hormone

CNS disease Brai n tumo r, infar ction , injur y, or absc ess Meni ngiti s Enc epha litis Pulmonary disease Pne umo nia Tube rculo sis Lung absc ess Pul mon ary aspe rgillo sis Drugs Exog enou s vaso pres sin Diur etics Chlo rpro pami de Vincr

Page 2678

istin e Thior idazi ne Cycl opho spha mide

CNS, central nervous system.

Hypervolemic Hyponatremia Hypervolemic hyponatremia results when sodium is retained but retention of water exceeds that of sodium. This is seen in edematous states such as congestive heart failure, hepatic cirrhosis, and renal failure. In these conditions, decreased effective renal perfusion causes the secretion of both ADH and aldosterone. This leads to increased tubular reabsorption of both sodium and water, decreased delivery of water to the distal nephron, and inability to produce hypotonic urine.

Clinical Features The signs and symptoms of hyponatremia depend on the rapidity with which the serum sodium concentration declines, as well as on its absolute level. The acutely hyponatremic patient is almost always symptomatic when the serum sodium level falls below 120 mEq/L, whereas patients with chronic hyponatremia may tolerate much lower levels. Very young and very old patients typically develop symptoms with lesser decreases in the serum sodium level. The primary symptoms of hyponatremia are related to the CNS, including lethargy, apathy, confusion, disorientation, agitation, depression, and psychosis. Focal neurologic deficits, ataxia, and seizures have been reported.[3] Other nonspecific signs and symptoms include muscle cramps, anorexia, nausea, and weakness.

Diagnostic Strategies The urinary sodium concentration can be a useful tool in the assessment of the patient with hyponatremia. Patients with hypovolemic hyponatremia caused by renal sodium wasting typically have an inappropriately high urinary sodium concentration (>20 mEq/dL); those with extrarenal sodium wasting and intact renal sodium-conserving mechanisms have a low urinary sodium concentration (5.0 mg/dL) is rare in patients with normal renal function because the kidneys readily excrete an excess phosphate load. True hyperphosphatemia can result from decreased phosphate clearance, an increased endogenous phosphate load, or an increased exogenous load ( Box 123-16 ). BOX 123-16 Causes of Hyperphosphatemia

I.

Pseudohyperphosphatemia A. Para prote inem ia B. Hype rlipid emia C. Hem olysi s D. Hype rbilir ubin emia

II.

Renal A.

B.

Acute and chronic renal failure Increased renal tubular reabsorption 1. Hypo parat hyroi dism 2. Thyr otoxi cosi s 3. Exce ss vita min D admi nistr

Page 2726

ation III.

Cellular injury A. Rha bdo myol ysis B. Tum or lysis synd rom e C. Hem olysi s

IV.

Increased intake A. Pho spha te ene mas or laxati ves B. Intra veno us or oral phos phat e admi nistr ation

Pseudohyperphosphatemia represents a spurious elevation of inorganic phosphate measurements caused by interference with analytical methods. Causes include paraproteinemia (e.g., multiple myeloma), hyperlipidemia, hemolysis, and hyperbilirubinemia. Renal failureis the most common cause of hyperphosphatemia.[74] The serum phosphate level typically remains normal until the creatinine clearance falls below 30 mL/min.[85] Hyperphosphatemia is usually mild unless an exogenous phosphate load is given. Hyperphosphatemia may also occur in patients with normal renal function when renal phosphate resorption is increased, as occurs with PTH deficiency, and in the setting of thyrotoxicosis or excessive vitamin D administration. Hyperphosphatemia can also occur with large endogenous phosphate loads, as with extensive cell damage, which causes phosphate to be released into the extracellular space. This may occur in the setting of rhabdomyolysis, tumor lysis syndrome, or hemolysis.[86] Patients with these disorders often develop renal failure, impairing phosphate excretion and further increasing serum levels. Hypophosphatemia may also result from exogenous loads, as with intravenous, oral, or rectal phosphate administration. Infants, elderly persons, and patients with preexisting renal insufficiency are particularly vulnerable.[]

Clinical Features The clinical signs of hyperphosphatemia reflect the associated hypocalcemia that results when excess serum phosphate binds with calcium and precipitates in tissues. Signs of neuromuscular hyperexcitability (e.g., paresthesias, hyperreflexia, tetany, seizures) and myocardial depression (e.g., hypotension, bradycardia, left ventricular dysfunction) predominate. Tissue deposition of calcium phosphate may result in

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acute heart block and death.

Management The emergency treatment of hyperphosphatemia involves supportive care and treatment of symptomatic hypocalcemia. In patients with normal renal function, infusion of isotonic saline increases phosphate clearance. The administration of dextrose and insulin drives phosphate into cells, temporarily lowering the serum level. Aluminum-containing antacids are the mainstay of the prevention of hyperphosphatemia in patients with chronic renal failure.[91] Although these are usually not administered in the emergency department, their use is reasonable in the management of hyperphosphatemia after a large overdose of exogenous phosphate. When hyperphosphatemia poses a threat to life, hemodialysis or peritoneal dialysis should be considered, especially in patients with renal failure.

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KEY CONCEPTS {, {,

{,

{,

{, {, {,

{,

The primary symptoms of hyponatremia are related to the CNS, including lethargy, apathy, confusion, disorientation, agitation, depression, and psychosis. Treatment of hyponatremia is based on severity of symptoms, estimated duration of illness, and patient's volume status. Patients with acute hyponatremia are usually symptomatic (e.g., severe weakness, diminished consciousness, seizures) when the serum sodium level falls below 120 mEq/L, whereas patients with chronic hyponatremia can tolerate much lower levels. Acute hyponatremia may be corrected at rates of up to 1 to 2 mEq/L/hr, and chronic hyponatremia should be corrected at a rate not greater than 0.5 mEq/L/hr. In general, the serum sodium level should not be increased by more than 10 mEq/L in a 24-hour period. Oral therapy for hypokalemia is preferable to intravenous therapy because of the risk of inducing hyperkalemia through the intravenous route. However, patients with prominent symptoms (e.g., dysrhythmias) and those who are unable to tolerate oral supplements should receive intravenous potassium replacement. The ECG can provide valuable clues to the presence of hyperkalemia (e.g., peaked T waves, loss of P waves, QRS widening). Treatment of hyperkalemia includes cardiovascular monitoring, administration of calcium for hemodynamic instability, lowering of serum potassium, and correction of the underlying disorder. Treatment of hypercalcemia (intravenous fluids, furosemide, osteoclastic inhibitors such as bisphosphonates [etidronate, pamidronate], plicamycin, calcitonin, glucocorticoids, and gallium nitrate) should be initiated in patients with significant symptoms (e.g., severe dehydration, alteration of consciousness, dysrhythmias) or when the calcium level is above 14 mg/dL. The goals of therapy are normalization of volume status, enhancement of renal calcium elimination, diminution of osteoclastic activity, and treatment of the underlying disorder. In hypomagnesemia, although the serum magnesium level often inaccurately reflects total body stores, magnesium supplementation should be considered when the level is less than 1.2 mg/dL. Intravenous magnesium therapy should be instituted for patients with significant symptoms (e.g., seizures, dysrhythmias).

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34. Kaye TB: Hypercalcemia: How to pinpoint the cause and customize therapy. Postgrad Med1995;97:153. 35. Pimentel L: Medical complications of oncologic disease. Emerg Med Clin North Am1993;11:407. 36. Walls J, Bundred N, Howell A: Hypercalcemia and bone resorption in malignancy. Clin Orthop 1995;312:51. 37. Broadus AE: Humoral hypercalcemia of cancer: Identification of a novel parathyroid hormone-like peptide. N Engl J Med1988;319:556. 38. Kao PC: Parathyroid hormone-related peptide in plasma of patients with hypercalcemia and malignant lesions. Mayo Clin Proc1990;65:1399. 39. Budayr AA: Increased serum levels of a parathyroid hormone-like protein in malignancy-associated hypercalcemia. Ann Intern Med1989;111:807. 40. Burtis WJ: Immunocytochemical characterization of circulating parathyroid hormone-related protein in patients with humoral hypercalcemia of cancer. N Engl J Med1990;322:1106. 41. Rizzato B, Fraioli P, Montemurro L: Nephrolithiasis as a presenting feature of chronic sarcoidosis. Thorax1995;50:555. 42. Connin CC: Precipitation of hypercalcemia in sarcoidosis by foreign sun holidays: Report of four cases. Postgrad Med J1990;66:307. 43. Sato M, Grasser W: Effect of diphosphonates on isolated rat osteoclasts as examined by reflected light microscopy. J Bone Miner Res1991;5:31. 44. Singer FR: Treatment of hypercalcemia of malignancy with intravenous etidronate: A controlled multicenter study. Arch Intern Med1991;151:471. 45. Singer FR: Role of the bisphosphonate etidronate in the therapy of cancer-related hypercalcemia. Semin Oncol1990;17:34. 46. Fitton A, McTavish D: Pamidronate: A review of its pharmacological properties and therapeutic efficacy in resortive bone disease. Drugs1991;41:289. 47. Gucalp R: Comparative study of pamidronate disodium and etidronate disodium in the treatment of cancer-related hypercalcemia. J Clin Oncol1992;10:134. 48. Levine MM, Kleeman CR: Hypercalcemia: Pathophysiology and treatment. Hosp Pract1987;22:73. 49. Whang R, Ryder KW: Frequency of hypomagnesemia and hypermagnesemia. JAMA1990;263:3063. 50. Olinger ML: Disorders of calcium and magnesium metabolism. Emerg Med Clin North Am1989;7:795. 51. Martin BJ, Black J, McLelland AS: Hypomagnesemia in elderly hospital admission: A study of clinical significance. Q J Med1991;78:177. 52. Whang R, Hampton EM, Whang DD: Magnesium homeostasis and clinical disorders of magnesium deficiency. Ann Pharmacother1994;28:220. 53. Ryan MP: Interrelationship of magnesium and potassium homeostasis. Miner Electrolyte Metab 1993;19:290. 54. Hamill-Ruth RJ, McGory R: Magnesium repletion and its effect on potassium homeostasis in critically ill adults: Results of a double-blind, randomized, controlled study. Crit Care Med1996;24:38. 55. Ramsey LE, Yeo WW, Jackson PR: Metabolic effects of diuretics. Cardiology1994;2:48. 56. Elisaf M: Acid-base and electrolyte abnormalities in alcoholic patients. Miner Electrolyte Metab 1994;20:274. 57. Ragland G: Electrolyte abnormalities in the alcoholic patient. Emerg Med Clin North Am1990;8:761. 58. Al-Ghamdi SM, Cameron EC, Sutton RA: Magnesium deficiency: Pathophysiologic and clinical overview. Am J Kidney Dis1994;24:737. 59. Kurzel RB: Serum magnesium levels in pregnancy and preterm labor. Am J Perinatol1991;8:119. 60. Cameron JD: Serum magnesium as affected by drugs. Clin Chem1989;35:506. 61. Shah GM, Kirschenbaum MA: Renal magnesium wasting associated with therapeutic agents. Miner Electrolyte Metab1991;17:58. 62. Millane TA, Ward DE, Camm AJ: Is hypomagnesemia arrhythmogenic?. Clin Cardiol1992;15:103. 63. Salem M: Hypomagnesemia is a frequent finding in the emergency department in patients with chest pain. Arch Intern Med1991;151:2185. 64. Rasmussen JS: Magnesium deficiency in patients with ischemic heart disease with and without acute myocardial infarction uncovered by an intravenous loading test. Arch Intern Med1988;148:329. 65. ISIS-4: A randomised factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58,050 patients with suspected acute myocardial infarction. ISIS-4 (Fourth International Study of Infarct Survival) Collaborative Group. Lancet1995;345:669. 66. Quereshi TI, Melonakos TK: Acute hypermagnesemia after laxative use. Ann Emerg Med1996;28:552. 67. Gerald SK, Hernadez C, Khayam-Bashi H: Extreme hypermagnesemia caused by an overdose of magnesium-containing cathartics. Ann Emerg Med1988;17:728. 68. Woodard JA: Serum magnesium concentration after repetitive magnesium cathartic administration. Am J Med1990;8:297. 69. Clark BA, Brown RS: Unsuspected morbid hypermagnesemia in elderly patients. Am J Nephrol 1992;12:336. 70. Mosseri M: Electrocardiographic manifestations of combined hypercalcemia and hypermagnesemia. J

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Electrocardiol1990;23:235. 71. Ferdinandus J, Pederson JA, Whang R: Hypermagnesemia as a cause of refractory hypotension. Ann Intern Med1991;141:669. 72. Zwerling H: Hypermagnesemia-induced hypotension and hypoventilation. JAMA1991;266:2374. 73. Yucha CB, Toto KH: Calcium and phosphorus derangements. Crit Care Clin1994;6:747. 74. Peppers MP, Gehelo M, Desai H: Hypophosphatemia and hyperphosphatemia. Crit Care Clin1991;7:201. 75. Thatte L: Review of the literature: Severe hyperphosphatemia. Am J Med Sci1995;310:167. 76. Itescu S, Haskell LP, Tannenberg AM: Thiazide-induced clinically significant hypophosphatemia. Clin Nephrol1987;27:161. 77. Kurtin P, Kouba J: Profound hypophosphatemia in the course of acute renal failure. Am J Kidney Dis 1987;10:346. 78. Bohannon NJ: Large phosphate shifts with treatment for hyperglycemia. Arch Intern Med1989;149:1423. 79. Brady HR: Hypophosphatemia complicating bronchodilator therapy for acute severe asthma. Arch Intern Med1989;10:2367. 80. Laaban JP: Hypophosphatemia complicating management of acute severe asthma. Ann Intern Med 1990;112:68. 81. Davis SV, Olichwier KK, Chakko SC: Reversible depression of myocardial performance in hypophosphatemia. Am J Med Sci1988;295:183. 82. Gravelyn TR: Hypophosphatemia-associated respiratory muscle weakness in a general inpatient population. Am J Med1988;84:870. 83. Lentz RD, Brown DM, Kjellstrand CM: Treatment of severe hypophosphatemia. Ann Intern Med 1989;89:941. 84. Lloyd CW, Johnson CE: Management of hypophosphatemia. Clin Pharm1988;7:123. 85. Sirmon MD, Kirkpatrick WG: Acute renal failure: What to do until the nephrologist comes. Postgrad Med 1990;87:55. 86. Vachvanichsanong P: Severe hyperphosphatemia following acute tumor lysis syndrome. Med Pediatr Oncol1995;24:63. 87. Biarent D: Acute phosphate intoxication in seven infants under parenteral nutrition. J Parenter Enteral Nutr1992;16:558. 88. Fass R, Do S, Hixson LJ: Fatal hyperphosphatemia following Fleet Phospho-Soda in a patient with colonic ileus. Am J Gastroenterol1993;88:929. 89. Korzets A: Life-threatening hyperphosphatemia and hypocalcemic tetany following the use of Fleet enemas. J Am Geriatr Soc1992;40:620. 90. DiPalma JA: Biochemical effects of oral sodium phosphate. Dig Dis Sci1996;41:749. 91. Ghazali A: Management of hyperphosphatemia in patients with renal failure. Curr Opin Nephrol Hypertens1993;2:566.

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Marx: Rosen's Emergency Medicine: Concepts and Clinical Practice, 6th ed., Copyright © 2006 Mosby, Inc.

Chapter 124 – Diabetes Mellitus and Disorders of Glucose Homeostasis Rita K. Cydulka Jeffrey Pennington

PERSPECTIVE Diabetes mellitus is the most common endocrine disease. It comprises a heterogeneous group of hyperglycemic disorders characterized by high serum glucose and disturbances of carbohydrate and lipid metabolism. Acute complications include hypoglycemia, diabetic ketoacidosis, and hyperglycemic hyperosmolar nonketotic coma. Long-term complications include disorders of blood vessels, especially the microvasculature. The cardiovascular system, eyes, kidneys, and nerves are particularly susceptible to complications. Despite the discovery of insulin more than 75 years ago by Banting and Best,[1] the incidence of severe debilitating complications, including arteriosclerosis, renal failure, retinopathy, and neuropathy, remains high. The Diabetes Control and Complications Trial proved that tight blood glucose control reduces the risk of these late sequelae.[2] Patients with diabetes mellitus incur emergency department costs three times higher and are admitted to the hospital four times more often than nondiabetic patients.

PRINCIPLES OF DISEASE Normal Physiology Maintenance of the plasma glucose concentration is critical to survival because plasma glucose is the predominant metabolic fuel used by the central nervous system (CNS). The CNS cannot synthesize glucose, store more than a few minutes' supply, or concentrate glucose from the circulation. Brief hypoglycemia can cause profound brain dysfunction, and prolonged severe hypoglycemia may cause cellular death. Glucose regulatory systems have evolved to prevent or correct hypoglycemia.[3] The plasma glucose concentration is normally maintained within a relatively narrow range, between 60 and 150 mg/dL, despite wide variations in glucose that occur after meals and exercise. Glucose is derived from three sources: intestinal absorption from the diet; glycogenolysis, the breakdown of glycogen; and gluconeogenesis, the formation of glucose from precursors, including lactate, pyruvate, amino acids, and glycerol. After glucose ingestion, the plasma glucose concentration increases as a result of glucose absorption. Endogenous glucose production is suppressed. Plasma glucose then rapidly declines to a level below the baseline.

Insulin Insulin receptors on the beta cells of the pancreas sense elevated blood glucose and trigger insulin release into the blood. For incompletely understood reasons, glucose taken by mouth evokes more insulin release than parenteral glucose. Certain amino acids induce insulin release and even cause hypoglycemia in some patients. Sulfonylurea oral hypoglycemic agents work, in part, by stimulating the release of insulin from the pancreas. The number of receptor sites helps determine the sensitivity of the particular tissue to circulating insulin. The number and sensitivity of receptor sites are also the primary factors in the long-term efficacy of the sulfonylurea oral hypoglycemic agents. Receptor sites are increased in glucocorticoid deficiency and may be relatively decreased in obese patients. Under normal circumstances, insulin is rapidly degraded through the liver and kidney. The half-life of insulin is 3 to 10 minutes in the circulation. Whereas insulin is the major anabolic hormone pertinent to the diabetic disorder, glucagon plays the role of the major catabolic hormone in disordered glucose homeostasis. Although most tissues have the enzyme systems required to synthesize and hydrolyze glycogen, only the liver and kidneys contain glucose-6-phosphatase, the enzyme necessary for the release of glucose into the

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circulation. The liver is essentially the sole source of endogenous glucose production. Renal gluconeogenesis and glucose release contribute substantially to the systemic glucose pool only during prolonged starvation. The hepatocyte does not require insulin for glucose to cross the cell membrane. However, insulin augments both the hepatic glucose uptake and storage needed for the process of energy generation and glycogen and fat synthesis. Insulin inhibits hepatic gluconeogenesis and glycogenolysis.[4] Muscle can store and use glucose, primarily through glycolysis to pyruvate, which is reduced to lactate or transaminated to form alanine. Lactate released from muscle is transported to the liver, where it serves as a gluconeogenic precursor. Alanine may also flow from muscle to liver. During a fast, muscle can reduce its glucose uptake, oxidize fatty acids for its energy needs, and, through proteolysis, mobilize amino acids for transport to the liver as gluconeogenic precursors. Adipose tissue can also use glucose for fatty acid synthesis for oxidation to form triglycerides. During a fast, adipocytes can also decrease their glucose use and satisfy energy needs through the p -oxidation of fatty acids. Other tissues do not have the capacity to decrease glucose use on fasting and therefore produce lactate at relatively fixed rates. Glucose transport across the fat cell membrane also requires insulin. A large percentage of the adipocyte glucose is metabolized to form p -glycerophosphate, required for the esterification of fatty acids to form triglycerides. Although most insulin-mediated fatty acid synthesis occurs in the liver, a very small percentage occurs in fat cells, using the acetyl coenzyme A generated by glucose metabolism. Very low levels of insulin are required to inhibit intracellular lipolysis while stimulating the extracellular lipolysis required for circulating lipids to enter the fat cell.

Glucose Regulatory Mechanisms Maintenance of the normal plasma glucose concentration requires precise matching of glucose use and endogenous glucose production or dietary glucose delivery. The regulatory mechanisms that maintain systemic glucose balance involve hormonal, neurohumoral, and autoregulatory factors. Glucoregulatory hormones include insulin, glucagon, epinephrine, cortisol, and growth hormone. Insulin is the main glucose-lowering hormone. Insulin suppresses endogenous glucose production and stimulates glucose use. Insulin is secreted from the beta cells of the pancreatic islets into the hepatic portal circulation and has important actions on the liver and the peripheral tissues. Insulin stimulates glucose uptake, storage, and use by other insulin-sensitive tissues such as fat and muscle.[3] Counterregulatory hormones include glucagon, epinephrine, norepinephrine, growth hormone, and cortisol. When glucose is not getting into the cells because of either a lack of food intake or lack of insulin, the body perceives a “fasting state” and releases glucagon, attempting to provide the glucose necessary for brain function. In contrast to the fed state, in the fasted state the body metabolizes protein and fat. Glucagon is secreted from the alpha cells of the pancreatic islets into the hepatic portal circulation. Glucagon lowers hepatic levels of fructose 2,6-biphosphate, resulting in decreased glycolysis and increased gluconeogenesis, an effect that may be enhanced by ketosis.[5] Glucagon increases the activity of adenyl cyclase in the liver, thereby increasing glycogen breakdown to glucose and further increasing hepatic gluconeogenesis. Glucagon acts to increase ketone production in the liver. Thus, whereas insulin is an anabolic agent that reduces blood glucose, glucagon is a catabolic agent that increases blood glucose. Glucagon is released in response to hypoglycemia as well as to stress, trauma, infection, exercise, and starvation. It increases hepatic glucose production within minutes, although transiently. Epinephrine both stimulates hepatic glucose production and limits glucose use through both direct and indirect actions mediated through both p - and p -adrenergic mechanisms. Epinephrine also acts directly to increase hepatic glycogenolysis and gluconeogenesis. It acts within minutes and produces a transient increase in glucose production but continues to support glucose production at approximately basal levels thereafter. Norepinephrine exerts hyperglycemic actions by mechanisms similar to those of epinephrine, except that norepinephrine is released from axon terminals of sympathetic postganglionic neurons. Growth hormone initially has a plasma glucose–lowering effect. Its hypoglycemic effect does not appear for several hours. Thus, growth hormone release is not critical for rapid glucose counterregulation; this is also true for cortisol. Over the long term, both growth hormone and cortisol may also increase glucose production.

Types of Diabetes The National Diabetes Data Group (NDDG) defines four major types of diabetes mellitus: type 1 diabetes mellitus, type 2 diabetes mellitus, gestational diabetes, and IGT/IFG ( Box 124-1 ).[6] The 1997 NDDG report

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discontinued the use of the terms “insulin-dependent diabetes mellitus” and “non–insulin-dependent diabetes mellitus” because they are confusing and clinically inaccurate. The group also recommended that arabic numerals 1 and 2 be used to replace roman numerals I and II in the designation of types “one” and “two.”[6] BOX 124-1 Classification of Diabetes Mellitus and Other Categories of Glucose Intolerance

Diabetes Mellitus Type 1 (or type I, formerly “insulin-dependent”) Immune mediated Idiopathic Type 2 (or type II, formerly “non–insulin-dependent”) Other specific types Genetic defects of beta cell function Genetic defects in insulin action Diseases of exocrine pancreas Endocrinopathies Drug or chemical induced Infections Uncommon forms of immune-mediated diabetes Other genetic syndromes sometimes associated with diabetes

Gestational Diabetes Mellitus

Impaired Glucose Tolerance Impaired fasting glucose From American Diabetes Association: Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 20:1183, 1997.

Type 1 Diabetes Mellitus Type 1 (or I) diabetes is characterized by abrupt failure of production of insulin with a tendency to ketosis even in the basal state. Parenteral insulin is required to sustain life. From 85% to 90% of patients with type 1 diabetes demonstrate evidence of one or more autoantibodies implicated in the cell-mediated autoimmune destruction of the beta cells of the pancreas. Strong human leukocyte antigen (HLA) associations are also found in type 1 diabetes. The autoimmune destruction has multiple genetic predispositions and may be related to undefined environmental insults.[6]

Type 2 Diabetes Mellitus Patients with type 2 (or II) diabetes may remain asymptomatic for long periods and show low, normal, or elevated levels of insulin because of insulin resistance. Ketosis is rare in type 2. Patients have a high incidence of obesity. No association exists with viral infections, islet cell autoantibodies, or HLA expression. Hyperinsulinemia may be related to peripheral tissue resistance to insulin because of defects in the insulin receptor.[7] Defects in muscle glycogen synthesis have an important role in the insulin resistance that occurs in type 2. A subgroup of patients who develop type 2 before 25 years of age have a mutation in the glucokinase gene and on chromosome 7.[8]

Gestational Diabetes Gestational diabetes “mellitus” is characterized by an abnormal oral glucose tolerance test (OGTT) that occurs during pregnancy and either reverts to normal during the postpartum period or remains abnormal. The clinical pathogenesis is thought to be similar to that of type 2. The clinical presentation is usually nonketotic hyperglycemia during pregnancy.

Impaired Glucose Tolerance

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A fourth category is impaired glucose tolerance (IGT) and its analogue, impaired fasting glucose (IFG). This group is composed of persons whose plasma glucose levels are between normal and diabetic and who are at increased risk for the development of diabetes and cardiovascular disease. The pathogenesis is thought to be related to insulin resistance.[6] Presentations of IGT/IFG include nonketotic hyperglycemia, insulin resistance, hyperinsulinism, and often obesity. IGT/IFG differs from the other classes in that it is not associated with the same degree of complications of diabetes mellitus. Many of these patients even spontaneously develop normal glucose tolerance. The emergency physician, however, should not be complacent about the patient with IGT because the decompensation of this group into the category of diabetes mellitus is 1% to 5% per year.[]

Epidemiology The prevalence of diabetes is difficult to determine because many standards have been used. The NDDG, using the 75-g OGTT as the diagnostic criterion, estimates the prevalence as 6.6%, with 11.2% of the population having IGT.[3] These figures are probably too high because most subjects diagnosed with IGT or diabetes by OGTT never develop diabetes.[3] The true prevalence of the disease is probably 6.3% of the population.[11] Approximately 5% to 10% of these patients have type 1, and 90% to 95% have type 2.[3] Some groups have a much higher rate of diabetes, such as the Pima Native Americans, who have a 40% rate of type 2; however, diabetes mellitus is significantly more prevalent in whites than in nonwhites.[12] The peak age of onset of type 1 diabetes is 10 to 14 years. Approximately 1 of every 600 schoolchildren has this disease. In the United States the prevalence of type 1 is approximately 0.26% by age 20 years, and the lifetime prevalence approaches 0.4%. The annual incidence among persons from birth to 16 years of age in the United States is 12 to 14 per 1 million population. The incidence is age dependent, increasing from near-absence during infancy to a peak occurrence at puberty and another small peak at midlife.[13] The morbidity in diabetes is related mostly to its vascular complications. A mortality of 36.8% has been related to cardiovascular causes, 17.5% to cerebrovascular causes, 15.5% to diabetic comas, and 12.5% to renal failure.

Pathophysiology and Etiology Type 1 diabetes results from a chronic autoimmune process that usually exists in a preclinical state for years.[4] The classical manifestations of type 1, hyperglycemia and ketosis, occur late in the course of the disease, an overt sign of beta cell destruction. The most striking feature of long-standing type 1 diabetes is the near-total lack of insulin-secreting beta cells and insulin, with the preservation of glucagon-secreting alpha cells, somatostatin-secreting delta cells, and pancreatic polypeptide–secreting cells. Although the exact cause of diabetes remains unclear, research has provided many clues. Studies of the pathogenesis of diabetes mellitus have demonstrated that the cause of the disordered glucose homeostasis varies from individual to individual.[] This cause may determine the presentation in each patient. Individual patients are currently not studied for the source of their disease except on an experimental basis. The goals of the work in progress, however, are to identify who is susceptible to the development of diabetes and to prevent diabetic emergencies and sequelae or to prevent expression of the disease. A genetic basis for diabetes is suggested by the association of type 1 with certain HLA markers and by the findings of numerous twin and family studies.[] Families who move from areas with a low frequency of type 1 diabetes to areas with a high frequency have an incidence of disease similar to that in the areas where they reside; this suggests an environmental basis for diabetes. An autoimmune cause has been clearly demonstrated in many type 1 diabetic patients. Islet cell amyloid has also been associated with diabetes. In both types a variety of viruses have been implicated, most notably congenital rubella, Coxsackie B virus, and cytomegalovirus. Research has identified two groups of cellular carbohydrate transporters in cell membranes. Sodium-linked glucose transporters are found primarily in the intestine and kidney. The glucose transporter (GLUT) proteins are found throughout the body and transport glucose by facilitated diffusion down concentration gradients. The GLUT-4 transporter, found primarily in muscle, is insulin responsive, and a signaling defect in the protein may be responsible for insulin resistance in some diabetic patients.[17]

CLINICAL FEATURES

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Type 1 The patient with type 1 diabetes is usually lean, younger than 40 years of age, and ketosis prone. Plasma insulin levels are absent to low; plasma glucagon levels are high but suppressible with insulin, and patients require insulin therapy when symptoms appear. Onset of symptoms may be abrupt, with polydipsia, polyuria, polyphagia, and weight loss developing rapidly. In some cases the disease is heralded by ketoacidosis.[3] A myriad of problems related to type 1 diabetes may prompt an emergency department visit, including acute metabolic complications such as diabetic ketoacidosis and late complications such as cardiovascular or circulatory abnormalities, retinopathy, nephropathy, neuropathy, foot ulcers, severe infections, and various skin lesions.

Type 2 The patient with type 2 diabetes is usually middle aged or older, overweight, with normal to high insulin levels. Insulin levels are lower than would be predicted for glucose levels, however, leading to a relative insulin deficiency, probably because of an insulin secretory defect.[3] All type 2 patients demonstrate impaired insulin function related to poor insulin production, failure of insulin to reach the site of action, or failure of end-organ response to insulin. As with type 1 diabetes, research suggests distinct subgroups of patients under the classification of type 2 diabetes. Although most adult patients are obese, 20% are not. Nonobese patients form a subgroup with a different disease, more similar to type 1. Another subgroup comprises young persons with maturity-onset diabetes.[8] They have an autosomal dominant inheritance of their disease, are usually not obese, and have a relatively mild course of disease. Symptoms tend to begin more gradually in type 2 diabetes than in type 1. The diagnosis of type 2 is often made because of an elevated blood glucose found on routine laboratory examination. Glucose may be controlled by dietary therapy, oral hypoglycemic agents, or insulin, depending on the individual. Decompensation of disease usually leads to hyperosmolar nonketotic coma rather than ketosis. Type 2 diabetes is increasingly being diagnosed in children and adolescents.[18]

DIAGNOSTIC STRATEGIES Serum Glucose As a rule, any random plasma glucose level greater than 200 mg/dL, a fasting plasma glucose concentration greater than 140 mg/dL, or a 2-hour postload OGTT is sufficient to establish the diagnosis of diabetes. In the absence of hyperglycemia with metabolic decompensation, these criteria should be confirmed by repeated testing on a different day.[6] A value of 150 mg/dL is likely to distinguish diabetic from nondiabetic patients more accurately. Formal OGTTs are unnecessary except during pregnancy or in patients suspected of having diabetes who do not meet the criteria for a particular classification. The World Health Organization and NDDG provide protocols for performance of the OGTT.

Glycosylated Hemoglobin Measurement of glycosylated hemoglobin (HbA1c) is one of the most important ways to assess the level of glucose control. Elevated serum glucose binds progressively and irreversibly to the amino-terminal valine of the hemoglobin p -chain. The HbA 1cmeasurement provides insight into the quality of glycemic control over time. Given the long half-life of red blood cells, the percentage of HbA1c is an index of glucose concentration of the preceding 6 to 8 weeks, with normal values approximately 4% to 6% of total hemoglobin, depending on the assay used.[19] Levels in poorly controlled patients may reach 10% to 12%. Measurement of glycated albumin can be used to monitor diabetic control over 1 to 2 weeks because of its short half-life but is rarely used clinically. The American Diabetes Association (ADA) recommends at least biannual measurements of HbA1c for the follow-up of all types of diabetes.[19] The ADA currently sets an HbA1c of less than 7% as a treatment goal.[20]

Urine Glucose Urine glucose measurement methods are basically of two types: reagent tests and dipstick tests. The reagent tests (e.g., Clinitest) are copper reduction tests. They are somewhat more cumbersome and expensive than dipstick methods, use tablets that are very caustic and dangerous if accidentally ingested, and may be affected by many substances ( Box 124-2 ). BOX 124-2 Substances Interfering with Copper Reduction Tests (False-Positive Results)

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Asco rbic acid Cep halor idine Cep halot hin Dilut e urine Gent isic acid (aspi rin) Gluc uroni c acid conj ugat es Hom ogen tisic acid Isoni azid Lact ose in preg nant wom en Levo dopa Meta xalo ne (Skel axin) meta bolit e Meth yldo pa Peni cillin Prob enec id Red ucin

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g suga rs Salic ylate s Stre ptom ycin From Contemp Pharm Pract 3:224, 1980.

Dipstick tests generally use glucose oxidase, which may also be affected by different substances ( Box 124-3 ). Dipsticks are inexpensive and convenient but may vary in their sensitivity and strength of reaction to a given concentration of glucose. Dipstick interpreta-tion can vary significantly, depending on the observer and the type of lighting. Both falsely high and falsely low urine glucose readings can also occur.[21] With the “plus” system, one-plus, two-plus, three-plus, and four-plus have different implications about urine glucose concentrations, depending on the brand of dipstick. Using reflectance colorimeters to read dipsticks increases accuracy. Urine glucose tests must be interpreted loosely because many factors can affect their results. BOX 124-3 Substances Interfering with Glucose Oxidase Tests

False-Positive Results Chlo ride gluc ose hypo chlor ite

False-Negative Results Asco rbic acid Aspir in Biliru bin Cata lase Cate chol Cyst eine 3,4Dihy drox yphe nyla cetic acid

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Epin ephri ne Ferr ous sulfa te (Feo sol) Gent isic acid Glut athio ne Hom ogen tisic acid Hydr ogen pero xide Pero xide 5-Hy drox yind ole aceti c acid 5-Hy drox ytryp tami ne 5-Hy drox ytryp toph an L-Do pami ne Levo dopa Mera llurid e injec tion Meth yldo pa (Aldo met) Sodi um

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bisul fate Tetr acyc line (with vita min C) Uric acid From Contemp Pharm Pract 3:224, 1980.

Urine Ketones Urine ketone dipsticks use the nitroprusside reaction, which is a good test for acetoacetate but does not measure p -hydroxybutyrate. Although the usual acetoacetate/p -hydroxybutyrate ratio in diabetic ketoacidosis is 1:2.8, it may be as high as 1:30, in which case the urine dipstick does not reflect the true level of ketosis. When ketones are in the form of p -hydroxybutyrate, the urine ketone dipsticks may infrequently yield negative reactions in patients with significant ketosis.

Dipstick Blood Glucose Dipsticks for testing blood glucose are clearly a more accurate means of monitoring blood glucose than urine dipsticks but also may be inaccurate. Hematocrits below 30% or above 55% cause unduly high or low readings, respectively, and a number of the strips specifically disclaim accuracy when used for neonates. Sensitivity of dipsticks to a variety of factors varies with the particular brand. The largest errors are in the hyperglycemic range. Dipstick readings rarely err more than 30 mg/dL when actual concentrations are below 90 mg/dL. Although specific glucose concentrations may not be accurately represented, blood glucose dipsticks are useful in estimating the general range of the glucose value. Reflectance meters increase the accuracy of the dipstick blood glucose determination. If maximum accuracy is desired, however, the emergency physician should normally order a laboratory blood glucose determination. Patients' subcutaneous insulin regimens must be closely managed by their primary physician or endocrinologist, tailored to achieve optimal glycemic control based on HbA1c measurements. Patients are also able to individualize their insulin regimen by using an insulin pump. The insulin pump requires the patient to insert a new plastic hub subcutaneously approximately every 3 days. The delivery tubing from the palm-sized pump is inserted into the hub, ensuring a reliable infusion of insulin. The pump can be dynamically programmed by the patient to deliver sufficient insulin to metabolize the carbohydrates consumed. Use of the pump obviously requires the patient to develop substantial skill.

HYPOGLYCEMIA Hypoglycemia is a common problem in patients with type 1 diabetes, especially if tight glycemic control is practiced, and may be the most dangerous acute complication of diabetes. The estimated incidence of hypoglycemia in diabetic patients is 9 to 120 episodes per 100 patient-years.[] As aggressive efforts continue to keep both fasting and postprandial glucose within the normal range, the incidence of hypoglycemia may increase. The most common cause of coma associated with diabetes is an excess of administered insulin with respect to glucose intake. Hypoglycemia may be associated with significant morbidity and mortality. Severe hypoglycemia is usually associated with a blood sugar level below 40 to 50 mg/dL and impaired cognitive function.[25]

Principles of Disease Protection against hypoglycemia is normally provided by cessation of insulin release and mobilization of counterregulatory hormones, which increase hepatic glucose production and decrease glucose use. Diabetic patients using insulin are vulnerable to hypoglycemia because of insulin excess and failure of the counterregulatory system.[3] Hypoglycemia may be caused by missing a meal, increasing energy output, or increasing insulin dosage. It can also occur in the absence of any precipitant ( Box 124-4 ). Oral hypoglycemic agents have also been

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implicated in causing hypoglycemia, both in the course of therapy and as an agent of overdose. BOX 124-4 Precipitants of Hypoglycemia in Diabetic Patients

Addi son' s dise ase Akee fruit Anor exia nerv osa Anti mala rials Decr ease in usua l food intak e Etha nol Facti tious hypo glyc emia Hep atic impa irme nt Hype rthyr oidis m Hypo thyro idis m Incre ase in usua l exer cise Insuli n Islet cell

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tumo rs Malf uncti onin g, impr operl y adju sted, or incor rectl y used insuli n pum p Maln utriti on Old age Oral hypo glyc emic s Over aggr essi ve treat ment of diab etic keto acid osis and hype rglyc emic hype ros mola r nonk etoti c com a Pent amid ine Phe nylb utaz

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one Prop ranol ol Rec ent chan ge of dose or type of insuli n or oral hypo glyc emic Salic ylate s Sep sis Som e antib acter ial sulfo nylur eas Wor seni ng renal insuf ficie ncy Hypoglycemia without warning, or hypoglycemia unawareness, is a dangerous complication of type 1 diabetes probably caused by previous exposure to low blood glucose concentrations.[25] Even a single hypoglycemic episode can reduce neurohumoral counterregulatory responses to subsequent episodes.[] Other factors associated with recurrent hypoglycemic attacks include overaggressive or intensified insulin therapy, longer history of diabetes, autonomic neuropathy, and decreased epinephrine secretion or sensitivity.[25] The Somogyi phenomenon is a common problem associated with iatrogenic hypoglycemia in the type 1 diabetic patient. The phenomenon is initiated by an excessive insulin dosage, which results in an unrecognized hypoglycemic episode that usually occurs in the early morning while the patient is sleeping. The counterregulatory hormone response produces rebound hyperglycemia, evident when the patient awakens. Often, both the patient and the physician interpret this hyperglycemia as an indication to increase the insulin dosage, which exacerbates the problem.[28] Instead, the insulin dosage should be lowered or the timing changed.

Clinical Features Symptomatic hypoglycemia occurs in most adults at a blood glucose level of 40 to 50 mg/dL. The rate at which glucose decreases, however, as well as the patient's age, gender, size, overall health, and previous hypoglycemic reactions, also contributes to symptoms. Signs and symptoms of hypoglycemia are caused by excessive secretion of epinephrine and CNS dysfunction and include sweating, nervousness, tremor, tachycardia, hunger, and neurologic symptoms ranging from bizarre behavior and confusion to seizures and

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coma.[22] In patients with hypoglycemia unawareness, the prodrome to marked hypoglycemia may be minimal or absent. These individuals may rapidly become unarousable without warning. They may have a seizure or show focal neurologic signs, which resolve with glucose administration.

Diagnostic Strategies The cardinal laboratory test for hypoglycemia is blood glucose. It should be obtained, if possible, before therapy is begun. As noted, dipstick readings are very helpful in permitting rapid, reasonably accurate blood glucose estimates before therapy. Laboratory testing should address any suspected cause of the hypoglycemia, such as ethanol or other drug ingestion. If factitious hypoglycemia is suspected, testing for insulin antibodies or low levels of C peptide may be helpful.

Management In alert patients with mild symptoms, consumption of sugar-containing food or beverage orally is often adequate ( Box 124-5 ). In other patients, after blood is drawn for glucose determination, one to three ampules of 50% dextrose in water (D50W) should be administered intravenously while the airway, breathing, and circulation of resuscitation are being completed. Augmentation of the blood glucose level by administering an ampule of D50W may range from less than 40 to more than 350 mg/dL.[29] These therapeutic steps are appropriately performed in the field if prehospital care is available. If alcohol abuse is suspected, thiamine should also be administered. D50W should not be used in infants or young children because venous sclerosis can lead to rebound hypoglycemia. In a child younger than 8 years it is advisable to use 25% (D25W) or even 10% dextrose (D10W). D25W may be prepared by diluting D50W 1:1 with sterile water. The dose is 0.5 to 1 g/kg body weight or, using D25W, 2 to 4 mL/kg. BOX 124-5 Summary of Treatment for Hypoglycemia

1.

2.

Suspect hypoglycemia. Check serum glucose; obtain sample before treatment. If clinical suspicion of hypoglycemia is strong, proceed before laboratory results are available. Correct serum glucose. If patient is awake and cooperative, administer sugar-containing food or beverage PO. If patient is unable to take PO: 25-7 5g gluc ose as D50 W

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(1-3 amp ules) IV Child ren: 0.5-1 g/kg gluc ose as D25 W IV (2-4 mL/k g)

Neonates: 0.5-1 g/kg glucose (1-2 mL/kg) as D10W If unable to obtain IV access: 1-2 mg gluc agon IM or SC; may repe at q20 min Child ren: 0.02 5-0.1 mg/k g SC or IM; may repe at q20 min If intravenous (IV) access cannot be rapidly obtained, 1 to 2 mg of glucagon may be given intramuscularly or subcutaneously.[30] The onset of action is 10 to 20 minutes, and peak response occurs in 30 to 60 minutes. It may be repeated as needed. Glucagon may also be administered intravenously; 1 mg has an effect very similar to that of one ampule of D50W. Glucagon is ineffective in causes of hypoglycemia in which glycogen is absent, notably alcohol-induced hypoglycemia. Families of type 1 diabetic patients are often taught to administer intramuscular glucagon at home. Of the families so instructed, only 9% to 42% actually inject the glucagon when indicated.[31] Intranasal glucagon may become more widely accepted.[32] Prehospital care providers and emergency physicians should seek a history of glucagon administration because it alters initial blood glucose readings. All patients with severe hypoglycemic reactions require aspiration and seizure precautions. Although the response to IV glucose is generally rapid, older patients may require several days for complete recovery.

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Overdoses of oral hypoglycemic agents pose special problems because the hypoglycemia induced tends to be prolonged and severe. The hypoglycemia may be delayed in onset by as much as 24 hours and may recur more than 72 hours later. Chlorpropamide is particularly troublesome in this respect. Thus, patients with overdose of oral hypoglycemic agents should have a minimum observation period of 24 hours and more if hypoglycemia is recurrent. Patients with overdose of oral hypoglycemic agents often require constant infusion of D10W to maintain a normal serum glucose. When therapy for hypoglycemia has been given, a careful history must be taken to determine the cause.

Disposition Type 1 diabetic patients with brief episodes of hypoglycemia uncomplicated by other disease may be discharged from the emergency department if a cause of the hypoglycemia can be found and corrected by instruction or medication. All patients should be given a meal before discharge to ensure the ability to toler-ate oral feedings and to begin to replenish glycogen stores in glycogen-deficient patients. Patients who are discharged should receive short-term follow-up for ongoing evaluation. Patients with hypoglycemia caused by oral agents should be observed in the hospital because of the high likelihood of recurrent hypoglycemia.

Nondiabetic Patients Hypoglycemia in the nondiabetic patient may be classified as postprandial or fasting ( Box 124-6 ). The most common cause of postprandial hypoglycemia is alimentary hyperinsulinism, such as that seen in patients who have undergone gastrectomy, gastrojejunostomy, pyloroplasty, or vagotomy. Fasting hypoglycemia is caused when there is an imbalance between glucose production and use. The causes of inadequate glucose production include hormone deficiencies, enzyme defects, substrate deficiencies, severe liver disease, and drugs. Causes of overuse of glucose include the presence of an insulinoma, exogenous insulin, sulfonylureas, drugs, endotoxic shock, extrapancreatic tumors, and a variety of enzyme deficiencies. BOX 124-6 Causes of Hypoglycemia

Postprandial Alim entar y hype rinsu linis m Fruc tose intol eran ce Gala ctem ia Leuc ine sens itivity

Fasting

Underproduction of Glucose Hormone deficiencies Hypo

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pituit aris m Adre nal insuf ficie ncy Cate chol amin e defic ienc y Gluc agon defic ienc y Enzyme defects Substrate deficiency Maln utriti on Late preg nanc y Liver disease Drugs

Overuse of Glucose Hyperinsulinism Insuli nom a Exog enou s insuli n Sulfo nylur eas Drug s Sho ck Tumors Emergency treatment is similar to that of hypoglycemia in the diabetic patient. The determination of inpatient versus outpatient evaluation of hypoglycemia in a nondiabetic patient should be based upon the suspected cause and the nature of the episode (i.e., factors such as severity, persistence, and recurrence),

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DIABETIC KETOACIDOSIS Principles of Disease Pathophysiology Diabetic ketoacidosis (DKA) is a syndrome in which insulin deficiency and glucagon excess combine to produce a hyperglycemic, dehydrated, acidotic patient with profound electrolyte imbalance ( Figure 124-1 ).[ 33] All derangements producing DKA are interrelated and are based on insulin deficiency. DKA may be caused by cessation of insulin intake or by physical or emotional stress despite continued insulin therapy.

Figure 124-1 Syndrom e of diabetic ketoacidosis. BUN, blood urea nitrogen; FFA, free fatty acids; TG, total glucose concentration.

The effects of insulin deficiency may be mimicked in peripheral tissues by a lack of either insulin receptors or insulin sensitivity at receptor or postreceptor sites. When the hyperglycemia becomes sufficiently marked, the renal threshold is surpassed and glucose is excreted in the urine. The hyperosmolarity produced by hyperglycemia and dehydration is the most important determinant of the patient's mental status.[34] Glucose in the renal tubules draws water, sodium, potassium, magnesium, calcium, phosphorus, and other ions from the circulation into the urine. This osmotic diuresis combined with poor intake and vomiting produces the profound dehydration and electrolyte imbalance associated with DKA ( Table 124-1 ). Exocrine pancreatic dysfunction closely parallels endocrine beta cell dysfunction, producing malabsorption that further limits the body's intake of fluid and exacerbates electrolyte loss. Table 124-1 -- Average Fluid and Electrolyte Deficits in Severe Diabetic Ketoacidosis (per Kilogram Body Weight) Weight

Water (mL/kg)

Sodium (mEq/L) Potassium (mEq/L)

Chloride (mEq/L)

Phosphorus (mEq/L)

20 kg

70–80

8–10

5–7

6–8

3

In 95% of patients with DKA, the total sodium level is normal or low. Potassium, magnesium, and phosphorus deficits are usually marked. As a result of acidosis and dehydration, however, the initial reported values for these electrolytes may be high. Hypokalemia may further inhibit insulin release. The cells, unable to receive fuel substances from the circulation, act as they do in starvation from other causes. They decrease amino acid uptake and accelerate proteolysis such that large amounts of amino acids are released to the liver and converted to two-carbon fragments. Adipose tissue in the patient with DKA fails to clear the circulation of lipids. Insulin deficiency results in activation of a hormone-sensitive lipase that increases circulating free fatty acid (FFA) levels. Long-chain FFAs, now circulating in abundance as a result of insulin deficiency, are partially oxidized and converted in the liver to acetoacetate and p -hydroxybutyrate. This alteration of liver metabolism to oxidize FFAs to ketones rather than the normal process of reesterification to triglycerides appears to correlate directly with the altered glucagon/insulin ratio in the portal blood. Despite the pathologic glucagon-mediated increased production of ketones, the body acts as it does in any form of starvation, to decrease the peripheral tissue's use of ketones as fuel. The combination of increased ketone production with decreased ketone use leads to ketoacidosis. The degree of ketosis has been related to the magnitude of release of the counterregulatory hormones

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epinephrine, glucagon, cortisol, and somatostatin. Glucagon is elevated fourfold to fivefold in DKA and is the most influential ketogenic hormone. It is believed to affect ketogenesis by reducing the concentration of malonyl coenzyme A and by inhibiting glycolysis. Epinephrine, norepinephrine, cortisol, growth hormone, dopamine, and thyroxin have all been shown to enhance ketogenesis indirectly by stimulating lipolysis. Because propranolol and metyrapone can block the effect of counterregulatory hormones, they have been successfully used to inhibit the development of DKA in patients with frequent episodes not otherwise treatable. Acidosis plays a prominent role in the clinical presentation of DKA. The acidotic patient attempts to increase lung ventilation and rid the body of excess acid with Kussmaul's respiration. Bicarbonate (HCO3) is used up in the process. Current evidence suggests that acidosis compounds the effects of ketosis and hyperosmolality to depress mental status directly. Acidemia is not invariably present, even with significant ketoacidosis. Ketoalkalosis has been reported in diabetic patients vomiting for several days and in some with severe dehydration and hyperventilation. The finding of alkalemia, however, should prompt the consideration of alcoholic ketoacidosis, in which this finding is much more common.

Etiology Most often, DKA occurs in patients with type 1 diabetes and is associated with inadequate administration of insulin, infection, or myocardial infarction (MI). DKA can also occur in type 2 patients and may be associated with any type of stress, such as sepsis or gastrointestinal (GI) bleeding. Approximately 25% of all episodes of DKA occur in patients whose diabetes was previously undiagnosed.[]

Diagnostic Strategies History Clinically, most patients with DKA complain of a recent history of polydipsia, polyuria, polyphagia, visual blurring, weakness, weight loss, nausea, vomiting, and abdominal pain. Approximately one half of these patients, especially children, report abdominal pain, which may mimic that in acute inflammation of the abdomen. In children this pain is usually idiopathic and probably caused by gastric distention or stretching of the liver capsule; it resolves as the metabolic abnormalities are corrected. In adults, however, abdominal pain more often signifies true abdominal disease.

Physical Examination Physical examination may or may not demonstrate a depressed sensorium. Typical findings include tachypnea with Kussmaul's respiration, tachycardia, frank hypotension or orthostatic blood pressure changes, the odor of acetone on the breath, and signs of dehydration.[36] An elevated temperature is rarely caused by DKA itself and suggests the presence of sepsis.

Laboratory Tests Initial tests allow preliminary confirmation of the diagnosis and immediate initiation of therapy ( Table 124-2 ). Subsequent tests are made to determine more specifically the degree of dehydration, acidosis, and electrolyte imbalance and to reveal the precipitant of DKA. Table 124-2 -- Typical Laboratory Values in Diabetic Ketoacidosis (DKA) and Hyperglycemic Hyperosmolar Nonketotic Coma (HHNC) DKA HHNC Glucose (mg/dl) Sodium (mEq) Potassium (mEq)

Bicarbonate (mEq) BUN (mg/dL) Serum ketones

>350 low 130s

>700 140s

∼4.5–6.0

∼5

15 >50 Absent

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DKA

HHNC

BUN, blood urea nitrogen.

On the patient's arrival at the emergency department, serum and urine glucose and ketones, electrolytes, and arterial blood gases (ABGs) should be checked. Glucose is usually elevated above 350 mg/dL; however, euglycemic DKA (blood glucose 25%

Depth

CELLULITIS Perspective Cellulitis is a soft tissue infection of the skin and subcutaneous tissue usually characterized by erythema, swelling, and tenderness. Cellulitis can be acute, subacute, or, on rare occasions, chronic. Trauma, or breaks in the protective cutaneous skin layer, may be a predisposing cause, but hematogenous and lymphatic dissemination can account for its sudden appearance in previously normal skin.

Principles of Disease and Clinical Features The signs and symptoms of cellulitis are generally pain or tenderness, erythema that blanches on palpation, swelling of the involved area, and local warmth. Without therapy, it will spread in a radial fashion both distally and proximally with associated swelling. Cellulitis occurs most often in the lower extremities, then upper extremities, and the face. Staphylococcus aureus and Streptococcus pyogenes are by far the most

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commonly isolated organisms.[1] In children, Haemophilus influenzae may cause facial cellulitis, although anaerobic and oral mucosa flora play a role in facial and orbital cellulitis. Risk factors for cellulitis include lymphedema, a portal of entry, venous insufficiency, and obesity. Interestingly, diabetes mellitus, alcohol misuse, and smoking are not associated with increased risk.[2] Ludwig's angina is a cellulitis of the submandibular spaces bilaterally. This deep soft tissue infection caused by oral flora may quickly result in respiratory distress by causing swelling and subsequent elevation of the floor of the mouth and the tongue. Odontogenic infection, especially of the second and third lower molars, is the most common origin of Ludwig's angina. Approximately 80% of patients offer a history of recent dental work or tooth pain.[] Cellulitis around the perineum is often due to anaerobes or fecal flora and may spread rapidly through the soft tissues, producing a necrotizing fasciitis. In general, the bacterial cause of cellulitis is a reflection of the bacteria found on the skin or mucous membranes of the anatomic site involved.

Differential Considerations Other conditions simulate the appearance of bacterial cellulitis, including arthropod and marine envenomation, the inflammatory response to foreign bodies, healing or postsurgical wounds, chemical or thermal burns, septic or inflammatory joints, dermatitis, and the arthritides. Differentiation, especially if the process is early and localized, may be difficult. In nonbacterial cellulitis, the inflammation tends to stay localized and is often less tender to palpation. In bacterial cellulitis, lymphangitis and local lymphadenopathy may be seen. Fluctuance, if present, signifies abscess formation. Fever is uncommon and should prompt the physician to consider secondary bacteremia or systemic involvement. With local involvement, vital signs, other than a slight tachycardia, are usually normal. Unless there is systemic involvement, white blood cell counts are usually normal or mildly elevated with little or no shift to the left. One exception is H. influenzae B in children. This cellulitis is usually associated with high fever and white blood cell counts greater than 15,000/mm3, with a left shift.[6] Fortunately, the incidence of such infections in children has decreased with the advent of an effective vaccine.

Diagnostic Strategies Bacterial cultures of material obtained by direct needle aspiration of the area of cellulitis, either in the area of greatest erythema intensity or at the leading edge, are not helpful when no purulence is present. A recent study of needle aspiration of cellulitis indicated that only about 10% of the time is the causative bacteria identified.[7] Blood cultures of patients with cellulitis are also not helpful, except in cases of H. influenzae B cellulitis, which are associated with bacteremia in children more than two thirds of the time.[] Soft tissue radiographs and ultrasonograms may be useful to detect radiopaque foreign bodies, including glass. Computed tomography or magnetic resonance imaging scans are reserved for instances in which deep space infections or abscesses are suspected. For most localized infections, no radiographic procedures are indicated.

Management The time-honored treatment for cellulitis includes immobilization, elevation, heat or warm moist packs, analgesics, and antibiotics. Studies do not document any difference in morbidity or resolution with this regimen versus the use of antibiotics alone. When managing a patient with cellulitis, the emergency physician must attempt to identify the cause. Trauma, puncture wounds, breaks in the skin, lymphatic or venous stasis, immunodeficiency, and foreign bodies are all predisposing factors. Hematogenous or contiguous spread from nearby infected tissue is an uncommon cause. Most patients will respond to appropriate oral antimicrobial agents. Cellulitis in the area of edema from venous or lymphatic stasis is often difficult to manage and may need aggressive parenteral antibiotic therapy. Secondary bacterial overgrowth occurs commonly in these circumstances.

Disposition Localized cellulitis of an extremity in an immunologically intact, afebrile patient can be treated on an outpatient basis with oral antibiotics. Follow-up is indicated within 24 to 48 hours if the erythematous area is not diminishing in size or if fever or systemic symptoms develop. In general, antistaphylococcal agents should be selected for outpatient management ( Table 135-2 ), as such agents will treat the most common skin organisms that cause cellulitis. Inpatient management with parenteral antibiotics and closer observation are indicated in patients with systemic toxicity, and with severe infections involving significant portions of an extremity (particularly the hands and feet), the head and neck, or the perineum. Inpatient management is

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also often required for adequate treatment of significant cellulitis of the lower limb and hand. Patients whose cellulitis continues to worsen after 48 to 72 hours of appropriate outpatient therapy should be treated with parenteral antibiotics. All patients with cellulitis must be monitored closely to ensure that the process is resolving. Patients who are immunocompromised, including those who are diabetic, alcoholic, on chemotherapy or steroid therapy, asplenic, or at extremes of age require aggressive monitoring and treatment. Table 135-2 -- Oral Therapy of Superficial Soft Tissue Infections Agent Dose Group A Streptococcus Penicillin V (phenoxymethylpenicillin) First-generation cephalosporin Erythromycin Azithromycin Clarithromycin

250–500 mg qid 250–500 mg qid 250–500 mg qid 500 mg × 1 dose then 250 mg qd × 4 500 mg bid

Staphylococcus aureus (not MRSA * )+ Dicloxacillin Cloxacillin First-generation cephalosporin Erythromycin (variable effectiveness) Azithromycin Clarithromycin Clindamycin Amoxicillin/clavulanate Ciprofloxacin Haemophilus influenzae Amoxicillin/clavulanate Cefaclor Trimethoprim (TMP)/sulfamethoxazole (SMX) Azithromycin Clarithromycin

125–500 mg qid 250–500 mg qid 250–500 mg qid 250–500 mg qid 500 mg × 1 dose then 250 mg qd × 4 500 mg bid 150–450 mg qid 875/125 mg bid or 500/125 mg tid 500 mg bid 250–500 mg tid 250–500 mg tid 160 mg TMP/800 mg SMX bid 500 mg × 1 dose then 250 mg qd × 4 500 mg bid

+

Methicill in-resist ant strains require treatme nt with alternat e antibioti cs such as vancom ycin, linezolid , daptom ycin, and

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Agent

Dose others. Combin ation therapie s may be necess ary. There is no clearly accepte d therapy for vancom ycin resistan t strains; combin ations of the above drugs with other antimicr obials may be effectiv e. Singledrug therapy should be avoided to decrea se the develop ment of resistan ce.

*

Methicillin-resistant Staphlococcus aureus.

Patients do not have a simple cellulitis if they have a fever, hypotension, confusion, crepitus, or bullae formation of the involved soft tissues. These patients may be septic, with infectious seeding to other sites such as blood, bone, lung, solid organs, or brain. They may have deep soft tissue infections necessitating aggressive surgical debridement. If an infection spreads to deeper tissues, either directly or through lymph or blood with distal seeding, the initially localized superficial infection can quickly evolve into a severe systemic illness. Patients with these symptoms should be hospitalized and evaluated for deep soft tissue infections and systemic bacteremia.[9]

SPECIAL TYPES OF CELLULITIS Periorbital (Preseptal) and Orbital Cellulitis Perspective

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Cellulitis of the central face involving the area of the orbits must be treated aggressively. The venous drainage of that area is through communicating vessels into the brain via the cavernous sinus. Streptococcal species are currently the most common infecting organisms. The incidence of cellulitis from H. influenzae has decreased from previous prominence due to the advent of an effective vaccine.[]

Principles of Disease and Clinical Features Periorbital (preseptal) cellulitis is an infection lying anterior to the orbital septum. It is usually associated with swelling of the eyelid, discoloration of the orbital skin, redness, and warmth. Conjunctival ecchymosis and injection with occasional discharge, fever, and leukocytosis are present. Vision, extraocular movements, pupillary findings, and optometric examination findings are normal. Orbital cellulitis tends to have similar but more severe symptoms than preseptal cellulitis. Patients with orbital cellulitis may have proptosis, decreased ocular mobility, ocular pain, and tenderness on eye movement. Retro-orbital gas or abscess formation increases the severity of these findings and results in decreased visual acuity; it can be detected with computed tomography or magnetic resonance imaging. Both orbital and periorbital cellulitis tend to be associated with young age and to be unilateral. Sinusitis is the leading cause, with up to 81% of cases having coexisting sinus infections.[10] Other causes include penetrating or abrading skin trauma, facial fractures, and preexisting vascular or pustular periocular skin infections. Less common causes are chemical agents and dental infections.

Diagnostic Strategies Differentiation of periorbital (preseptal) from orbital cellulitis is an important clinical decision that affects management and prognosis. If orbital cellulitis is suspected, a computed tomography scan of the orbit is the most useful aid to determine retro-orbital involvement.[12] Sinus and orbital x-ray films tend to be less specific.[13] Causative organisms now are predominantly streptococcus species, but S. aureus, H. influenzae, and anaerobes are also occasionally identified.[] Blood cultures and lumbar punctures are indicated in those patients with high fevers or those showing signs of meningismus or sepsis.

Management Early periorbital (preseptal) cellulitis may be followed on an outpatient basis for the first 24 to 48 hours of antibiotic therapy, with daily follow-up to determine whether resolution is occurring. A broad-spectrum antistaphylococcal agent will provide appropriate coverage. Treatment for orbital cellulitis includes hospitalization, intravenous antibiotics, and, in some cases, incision and drainage. Up to 50% of more serious infections require surgery. Indications include clinical deterioration on antibiotics, the presence of a foreign body as the cause of the infection, and the presence of an abscess.[] Broad-spectrum antibiotic coverage of H. influenzae, S. aureus, S. pyogenes, and anaerobes is indicated.[]

Streptococcal Cellulitis Principles of Disease and Clinical Features Streptococcal cellulitis, often termed ascending cellulitis, is usually seen after surgery or trauma but can occur with no predisposing event. The cause may be as subtle as a break in the skin around the web of the fingers or toes. Ascending cellulitis usually progresses rapidly with prominent lymphangitic streaking and a swollen extremity. Untreated patients can quickly become toxic.

Management Treatment includes the use of an antistreptococcal agent along with elevation of the involved extremity and warm soaks.

Erysipelas Principles of Disease and Clinical Features Erysipelas is an acute superficial cellulitis characterized by a sharply demarcated border surrounding skin that is raised, deeply erythematous, indurated, and painful. It usually involves the dermis, lymphatics, and most of the superficial subcutaneous tissue. Erysipelas most often occurs in the very young and in 50- to 60-year-olds and is associated with small breaks in the skin, nephrotic syndrome, and postoperative wounds. Patients usually appear toxic, with a prodrome of fever, chills, and malaise preceding the eruption of a bright red cellulitis predominantly on the lower extremities or on the face. Streptococci are the predominant pathogenic organism in erysipelas, including S. pyogenes (58-67%), S. agalactiae (3-9%), and S. dysgalactiae (14-25%). Other bacteria are also found in some patients, such as S. aureus, Pseudomonas, and enterobacteria. The leg is involved in erysipelas 90% of the time, but the arm (5%), the

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face (2.5%), and the thigh can also be involved.[15]

Management Treatment of erysipelas includes elevation of the infected part, treatment of the portal of entry, if any, and antibiotic therapy. Penicillin G continues to be a standard treatment, but amoxicillin can also be used for 10 to 20 days. Macrolides, cephalosporins, and fluoroquinolones have been shown to be more effective but should be reserved for complicated cases.[15]

Staphylococcal Cellulitis Principles of Disease and Clinical Features Staphylococcus aureus produces various toxins that result in local and systemic effects. Tissue invasion, blister formation, and inflammation are caused by toxins such as alpha toxin, hyaluronidase, fibrinolysin, various proteases, and pyrogenic toxin superantigens.[16] Staphylococcal cellulitis is usually an indolent infection. The patient often appears less toxic than with streptococcal cellulitis, and the lesions usually appear more localized and are more likely to result in the formation of an abscess.

Management Antistaphylococcal agents are indicated, along with heat, immobilization, elevation, and incision and drainage if an abscess is present.

Staphylococcal Scalded Skin Syndrome Principles of Disease and Clinical Features Staphylococcal scalded skin syndrome, also called staphylococcal epidermal necrolysis, is caused by an exfoliative toxin produced by phage group II, type 71 staphylococci. This toxin acts on the zona granulosa of the skin to produce a superficial separation that results in widespread painful erythema and blistering of the skin. The syndrome usually occurs in children between the ages of 6 months and 6 years. The mortality rate is approximately 3% in children but reaches 50% in adults and up to 100% in adults with underlying systemic disease.[] Mucous membranes are usually not involved. Nikolsky's sign, the easy separation of the outer portion of the epidermis from the basal layer when pressure is exerted, is often present. The skin lesion is characterized by the formation of bullae and vesicles leading to the loss of large sheets of superficial epidermis. The resultant appearance is that of scalded skin.

Differential Considerations The primary differential diagnosis is toxic epidermal necrolysis. Toxic epidermal necrolysis is a full-thickness epidermal necrosis that starts on acral sites and involves mucous membranes. There is also usually a history of drug ingestion with toxic epidermal necrolysis, and Nikolsky's sign is positive only on the lesions. In staphylococcal scalded skin syndrome, unaffected skin also has a positive Nikolsky's sign. Staphylococcal scalded skin syndrome usually responds to antibiotics. Toxic epidermal necrolysis has no curative treatment and is associated with up to a 50% rate of mortality.[19]

Diagnostic Strategies The diagnosis is based on clinical, histologic, and microbiologic findings, including (1) a clinical pattern of tenderness, erythema, desquamation, or bullae formation; (2) histopathologic evidence of intraepidermal cleavage through the stratum granulosum; (3) isolation of an exfoliative exotoxin producing S. aureus, and (4) the absence of pemphigus foliaceus by immunofluorescence.[19] Blister fluid and the skin are usually sterile because this syndrome is toxin generated. S. aureus may be cultured from mucous membrane sites such as the oral and nasal cavity.

Management Treatment of staphylococcal scalded skin syndrome includes adequate hydration, management of fluid and electrolyte balance, and treatment with systemic antibiotics such as a penicillinase-resistant penicillin.[16]

Haemophilus influenzae Cellulitis Principles of Disease and Clinical Features Haemophilus influenzae cellulitis is usually seen in children younger than 5 years of age and occurs primarily on the face or the extremities. The skin often appears red with a violaceous tinge.[20] The patient appears acutely ill, often with a high fever, a white blood cell count greater than 15,000, and a high incidence (75-90%) of positive blood cultures. With widespread H. influenzae B immunization, there has been a dramatic decrease in the incidence of H. influenzae skin infections.

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Management Treatment is parenteral antibiotics with a second- or third-generation cephalosporin followed by ampicillin/clavulanic acid for a total of 10 to 14 days.[20]

Gram-Negative and Anaerobic Cellulitis Gram-negative and anaerobic cellulitis usually occur in the immunocompromised patient. Cellulitis is seen most often around mucous membranes, primarily the perineum and in chronic wounds that are not kept clean and thus become superinfected. The diagnosis requires culturing the causative organism. Aggressive debridement and broad-spectrum antimicrobial coverage are indicated.

TOXIC SHOCK SYNDROME Staphylococcal Toxic Shock Syndrome Perspective Toxic shock syndrome often occurs in menstruating women who use vaginal tampons. Although prevalent in the early 1980s, the incidence of toxic shock syndrome has decreased remarkably since highly absorbent tampons were withdrawn from the market. Today, toxic shock syndrome occurs in patients of both sexes who have focal soft tissue staphylococcal infections; nonmenstrual causes are more prevalent.

Principles of Disease and Clinical Features In menstruating women with toxic shock syndrome, S. aureus is isolated more than 90% of the time. The clinical manifestations are mainly due to the exfoliative exotoxin produced by S. aureus. This is the same exotoxin produced in bullous impetigo, but toxic shock syndrome results from systemic circulating exotoxin, whereas the localized blistering in bullous impetigo is caused by a direct S. aureus inoculum. The exotoxin in both cases has exquisite specificity in causing loss of desmosome-mediated cell adhesion within the superficial epidermis only.[19] Other clinical features include fever, a “sunburn/sandpaper” rash, hypotension, and abnormalities in at least three organ systems. Mucosal inflammation, myalgia, profuse watery diarrhea, and changes in mental status are common ( Box 135-1 ). Differential diagnosis includes Rocky Mountain spotted fever, streptococcal scarlet fever, Kawasaki syndrome, and leptospirosis.[16] BOX 135-1 Toxic Shock Syndrome: Criteria for Diagnosis

Fever of 38.9° C (102° F) or higher Rash (diffuse macular erythema) that resembles the rash of scarlet fever Desquamation of skin 1 to 2 weeks after onset of disease Hypotension (systolic blood pressure less than 90 mm Hg, orthostatic drop of 15 mm Hg or more, or orthostatic dizziness of syncope) Clinical or laboratory abnormalities in

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at least three organ systems: Gast roint estin al: naus ea and vomi ting, diarr hea Mus cular : myal gia or creat ine phos phok inas e at least two time s nor mal level Muc ous me mbr ane: vagi nal, orop hary ngea l, or conj uncti -val hype remi a Ren al: bloo d urea nitro gen or creat inine level at

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least twic e nor mal or pyuri a great er than five cells per highpow er field Hep atic: biliru bin, seru m trans amin ases at least twic e nor mal level Hem atolo gic: thro mbo cyto peni a, 15 points) 39%. Thus, the greater the number of risk factors, the more likely a patient is to die during the hospitalization. Table 136-1 -- Mortality in Emergency Department Sepsis (MEDS) Prediction Rule Risk Factor

Odds Ratio for Death

MEDS score

Terminal illness (death within 30 days)

6.1

6 points

Tachypnea or hypoxia

2.7

3 points

2.7

3 points

Platelet count 5%

2.3

3 points

Age >65 years

2.2

3 points

Pneumonia

1.9

2 points

Nursing home resident

1.9

2 points

Altered mental status

1.6

2 points

Septic shock 3

DIAGNOSTIC STRATEGIES The use of diagnostic testing in patients with sepsis syndromes or suspected syndromes serves two

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purposes. Diagnostic studies are used both to identify the type and location of the infecting organisms and to define the extent and severity of the infection to assist in focusing therapy. As a result, the diagnostic approach must be tailored to the particular patient.

Hematology The white blood cell count is a marker of inflammation and activation of the inflammatory cascade. Leukocytosis is associated with infection and is incorporated in the consensus definition of sepsis; however, it is often insensitive and nonspecific, limiting its absolute utility in the emergency department. The febrile neutropenic patient has been shown to be at increased risk for severe infection. Thus a white blood cell count less than 500 cells/mm[3] should prompt admission, isolation, and empiric intravenous antibiotics in most chemotherapy patients. A bandemia (>10% bands on a peripheral smear) represents the release of immature cells from the bone marrow and is considered to be a sign of infection and inflammation; it is part of the consensus sepsis definition. Like the white blood cell count, it is an imperfect indicator of infection. The hemoglobin and hematocrit should be obtained to ensure adequate oxygen delivery in shock. Patients should be maintained with a hematocrit greater than 30% and hemoglobin greater than 10 g/dL. Platelets are an acute-phase reactant and may be elevated in the presence of infections. Conversely, a low platelet count has been found to be a significant predictor of bacteremia in patients with shock.[] Thrombocytopenia, elevated prothrombin time, an elevated activated partial thromboplastin time, decreased fibrinogen, and increased fibrin split products are associated with DIC and severe sepsis syndrome.

Chemistry Electrolyte abnormalities should be identified and corrected. Low bicarbonate level suggests acidosis and inadequate perfusion. An elevated anion gap acidosis in the setting of sepsis syndrome commonly represents lactic acidosis or diabetic ketoacidosis, but other causes need to be ruled out. A high creatinine level is indicative of renal dysfunction or failure, which, if due primarily to sepsis, indicates organ failure and a worse prognosis. Calcium, magnesium, and phosphorus levels should be checked. The presence of an elevated lactate level is associated with inadequate perfusion, shock, and a poorer prognosis.[69] The presence of lactic acidosis identifies patients who are in organ failure and could benefit from aggressive resuscitation.[70] A multicenter prospective study of intensive care unit patients showed an overall 3-day mortality rate of 59% for patients with lactic acidosis. An arterial blood gas assessment may be helpful in identifying and classifying acid-base disturbances. Metabolic acidosis suggests inadequate tissue perfusion. A low PO2, specifically a PaO2 less than 75 mm Hg, is part of the consensus sepsis syndrome's definition. Liver function tests can be used to identify liver failure or dysfunction. An elevated bilirubin level may sug-gest the gallbladder as a cause of sepsis. An elevated amylase and lipase level may represent pancreatitis as the cause of noninfectious SIRS.

Microbiology Obtaining proper blood, sputum, urine, cerebrospinal fluid (CSF), and other tissue culture samples is important in guiding therapy. Although usually not helpful in the acute emergency department setting, culture samples should be obtained before or soon after the administration of antibiotics in the patient with sepsis syndrome. The initiation of antibiotic therapy should not be delayed while waiting for culture samples to be obtained. One well-designed prospective study suggests the following factors as predictive of a positive blood culture: fever greater than 38.3°C, the presence of a rapidly (1 week) therapy, flumazenil can be used and reverses coma within 1 to 2 minutes. Despite a return of normal mentation and protective airway reflexes, the therapeutic benefit of flumazenil is limited with a single dose, and respirations may remain depressed. The short half-life when compared with some benzodiazepine agents often leads to re-sedation within 45 to 60 minutes after administration. Repeat doses can be given safely to reverse the recurrent effects of the longer acting benzodiazepines. It is administered as a 0.2-mg dose in the first minute followed by 0.2-mg doses every minute until a response is obtained or a total dose of 1 mg is given. The need for tracheal intubation may be eliminated with a continuous intravenous flumazenil drip. The empiric use of physostigmine is not indicated. Physostigmine specifically reverses anticholinergic effects and has nonspecific analeptic activities. A response to physostigmine does not confirm the diagnosis of anticholinergic poisoning because the induced cholinergic action may provoke arousal nonspecifically in other conditions. Thyroxine may be given in comatose patients with characteristic findings consistent with myxedematous skin changes, mild hypothermia, bradycardia, and pseudomyotonic stretch reflexes (delayed relaxation phase). Treatment must be initiated based on clinical diagnosis because delaying for laboratory confirmation places the patient at significant risk. Steroids usually are given in advance because the potential for a combined adrenal and thyroid insufficiency exists. Antibiotics should be considered in all patients with coma of unknown cause, particularly if fever or hypothermia is present. The key is early administration. Antibiotics administered before a lumbar puncture have little effect on cerebrospinal fluid cell count, differential, glucose, and protein for 68 hours. Blood cultures reveal the pathogen in 80% of patients with meningitis. Broad-spectrum antibiotics that cross the blood-brain barrier (e.g., third-generation cephalosporins) should be administered when the blood cultures are obtained. The actual risk of tonsillar herniation caused by a lumbar puncture in patients with a mass lesion or subarachnoid hemorrhage is unresolved. If meningitis is clinically probable, antibiotics should be started before the lumbar puncture and before the patient is sent for head CT scanning. If an overdose is suspected, the empiric treatment of a potential toxic ingestion is indicated. The administration of 1 g/kg of activated charcoal through a nasogastric tube after airway protection is a benign and potentially beneficial intervention that should be performed in all cases in which poisoning is strongly suspected. Gastric lavage is not beneficial beyond 1 hour postingestion, but the retrieval of pill fragments confirms the diagnosis of poisoning and helps direct the evaluation and management. The definitive diagnosis of depressed mental status is often uncertain in the emergency department. The patient's neurologic examination should be serially reassessed and aggressive assessment pursued until the final diagnosis is established, and definitive treatment and disposition are secured.

DISPOSITION Patients with reversible causes of coma, such as hypoglycemia or heroin overdose, may be discharged after a period of observation and sustained consciousness. Even after normal mentation can be restored with antidotes, however, if the duration of action of the offending action exceeds that of the antidote, as with methadone or certain oral hypoglycemics, admission to the hospital is warranted. Patients with alcohol or other CNS depressants may be safely observed in the emergency department and discharged when they are sober. Patients with all other causes of coma are admitted to the hospital for observation and definitive treatment.

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Marx: Rosen's Emergency Medicine: Concepts and Clinical Practice, 6th ed., Copyright © 2006 Mosby, Inc.

Section II - Toxicology Chapter 145 – General Approach to the Poisoned Patient Ken Kulig

PERSPECTIVE Most poisoned patients seen in the emergency department are adults with acute, oral drug overdoses. Other common clinical scenarios include accidental poisoning in children; parenteral drug abuse; chronic poisoning, usually from environmental, industrial, and agricultural chemical exposure; medication reactions or interactions; and envenomation. Management requires both a general approach and specific actions directed at the particular toxin or toxins involved, as outlined in the various chapters in this section. Clinical studies have modified the management of poisoned patients, such as the use of gastric decontamination, but much of the toxicology literature, especially with unusual poisonings, remains case based.

INITIAL APPROACH TO THE POISONED PATIENT With rare exception, the priorities of care for a poisoned patient are identical to those for all patients coming to the emergency department. Patients who are contaminated with an agent that might injure health care personnel require decontamination before treatment to avoid disabling the hospital staff or the entire health care facility. Except for specific lifesaving antidotes against certain toxins, most poisoned patients require only supportive therapy for recovery. The initial workup should determine whether a specific patient has been exposed to an agent for which an antidote (or other specific treatment) exists.[1] A thorough poisoning history and toxicologic physical examination are followed by the selective use of laboratory tests. After initial stabilization of a critically ill patient, specific antidote therapy is administered while a detailed history and physical examination are performed. Hypoglycemia must always be considered in a patient with altered mental status or seizures and should be evaluated by bedside glucose testing rather than empiric administration of hypertonic glucose solution.[2] Naloxone can be given to patients with respiratory depression while preparations are made to secure the airway because a positive response may obviate the need for intubation. Flumazenil is not indicated in an undifferentiated overdose patient, and its use should be limited to confirmed acute benzodiazepine overdose in a patient known to not be a regular benzodiazepine user (e.g., an adolescent who impulsively ingests a parent's benzodiazepine). Indiscriminate use may force a chronic benzodiazepine user into severe benzodiazepine withdrawal. Likewise, the patient may have ingested tricyclic antidepressants or other drugs likely to cause seizures. In either case, the use of flumazenil can carry a substantial risk of seizures. Patients with benzodiazepine overdose respond well to supportive care. Thiamine should be administered when dextrose is given to nutritionally compromised, alcoholic patients with altered mental status (100 mg in the maintenance intravenous line is sufficient and safe).[3] A complete overdose history is required, particularly when the ingested agent is unknown or the patient is suicidal ( Box 145-1 ). Valuable clues often come from unexpected sources, such as the patient's previous medical records, the pharmacy where prescriptions were filled, or the prescribing physician as listed on the patient's prescription bottles. Field personnel, whenever possible, should bring the patient's medications to the hospital with them. If the ingested agent is a hazardous chemical (e.g., pesticide) that might endanger hospital personnel, it should be brought to the hospital in an airtight container or secured at the scene. Precise product identification information must be ascertained so that a hazardous materials reference system can be consulted. When it is suspected that the contents of the container are not the original product, the substance should be checked against the product label. It is easy to confuse the different types of chemical agents with similar names found in many homes, and some may have specific properties that

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affect treatment. In rare cases, overdose patients may deliberately attempt to deceive caregivers by hiding the ingested agents. BOX 145-1 Obtaining an Overdose History

{, {,

{,

{, {,

{,

Obtain all prescription bottles and other containers when possible. Perform a pill count. Be sure that the bottles contain the medications listed. Identify any unknown tablets. Contact the prescribing physician(s) or the pharmacy as listed on the bottles to determine previous overdoses or other medications that the patient may have available. Identify underlying medical and psychiatric disorders and medication allergies. Review past medical records. Talk to the patient's family and friends in the emergency department. If necessary, call the patient's home to ask questions of others. The persons providing the important elements of the history should be identified in the chart. Search the patient's belongings for drugs or drug paraphernalia. A single pill hidden in a pocket, for example, may provide the most important clue to the diagnosis. Have family members (or the police) search the patient's home, including the medicine cabinet, clothes drawers, closets, and garage: such searches may also provide clues that make the diagnosis. This has the added benefit of involving the family in the patient's care. Always look for track marks on the patient. Consider body packing or body stuffing.

Vital signs, including pulse oximetry, are important in the diagnosis of poisoning and should be measured accurately and repeated as indicated. At least one measurement of temperature must always be included. Respirations should be counted, not estimated. A cardiac monitor or 12-lead electrocardiogram should be evaluated for QRS and QT intervals, morphology, and rhythm. The physical examination in a comatose patient should ensure that concomitant treatable conditions (e.g., intracranial hemorrhage, central nervous system [CNS] infection) are not missed. Focal neurologic findings could be possible indicators of intracranial catastrophe or severe head trauma. The pupillary examination may give misleading information. Some opioid agonists, especially propoxyphene and pentazocine, may not produce the characteristic miosis of opioid intoxication. When multiple drugs are ingested, the expected pupillary findings related to any particular agent may be modified or absent. Physical stigmata of intravenous drug use (track marks) should be sought in both usual (e.g., antecubital fossa) and unusual (e.g., under the tongue, top of the feet) locations. A critical condition of unknown cause may be a result of “body packing” or “body stuffing,” complicated by rupture of packets of cocaine, heroin, or amphetamines (see Chapter 152 ). Rectal, vaginal, and radiographic examination of the abdomen should be performed in these circumstances. Other important physical findings are evidence of aspiration or noncardiogenic pulmonary edema on chest auscultation. Bowel sounds may be increased or decreased if agents affecting the cholinergic nervous system have been ingested. A rectal examination to detect melena or hematochezia may also provide evidence of suicidal ingestion of anticoagulant medication. Unusual odors of the patient's breath, skin, clothing, vomitus, or nasogastric aspirate may also provide useful diagnostic clues ( Table 145-1 ).[4] The absence of such odors, however, should not be taken as evidence that the agents listed are not present. Table 145-1 -- Odors in Overdose History Odor

Possible intoxicant

Bitter almonds Carrots Fishy Fruity Garlic

Cyanide Water hemlock (cicutoxin) Zinc or aluminum phosphide Ethanol, acetone, isopropyl alcohol, chlorinated hydrocarbons (e.g., chloroform) Arsenic, dimethyl sulfoxide (DMSO), organophosphates, yellow phosphorus, selenium, tellurium

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Glue Pears Rotten eggs Shoe polish Wintergreen

Toluene, other solvents Chloral hydrate, paraldehyde Disulfiram, hydrogen sulfide, N-acetylcysteine, dimercaptosuccinic acid (DMSA) Nitrobenzene Methyl salicylate

TOXIC SYNDROMES AND ANTIDOTES The term toxidrome refers to a constellation of physical findings that can provide important clues to narrow the differential diagnosis.[1] The general rules outlined here have many exceptions, and polydrug overdoses may result in overlapping and confusing mixed syndromes. Nevertheless, this approach may confirm the history, provide the clinician with a starting point for management, and suggest useful laboratory tests. The most common toxidromes are the anticholinergic syndrome, sympathomimetic syndrome, opioid/sedative/ethanol syndrome, and cholinergic syndrome ( Table 145-2 ). Table 145-2 -- Common Toxic Syndromes (Toxidromes) Anticholinergic Common signs

Common causes

Sympathomimetic Common signs

Common causes

Opioid/Sedative/Ethanol Common signs

Common causes

Cholinergic Common signs

Common causes

Delirium with mumbling speech, tachycardia, dry flushed skin, dilated pupils, myoclonus, slightly elevated temperature, urinary retention, decreased bowel sounds. Seizures and dysrhythmias may occur in severe cases Antihistamines, antiparkinsonians, atropine, scopolamine, amantadine, antipsychotics, antidepressants, antispasmodics, mydriatics, muscle relaxants, many plants (e.g., jimson weed, Amanita muscaria) Delusions, paranoia, tachycardia (or bradycardia with pure a-agonists), hypertension, hyperpyrexia, diaphoresis, piloerection, mydriasis, hyperreflexia. Seizures, hypotension, and dysrhythmias may occur in severe cases Cocaine, amphetamine, methamphetamine and its derivatives, over-the-counter decongestants (phenylpropanolamine, ephedrine, pseudoephedrine). In caffeine and theophylline overdoses, similar findings, except for the organic psychiatric signs, result from catecholamine release Coma, respiratory depression, miosis, hypotension, bradycardia, hypothermia, pulmonary edema, decreased bowel sounds, hyporeflexia, needle marks. Seizures may occur after overdoses of some narcotics (e.g., propoxyphene) Narcotics, barbiturates, benzodiazepines, ethchlorvynol, glutethimide, methyprylon, methaqualone, meprobamate, ethanol, clonidine, guanabenz Confusion, central nervous system depression, weakness, salivation, lacrimation, urinary/fecal incontinence, gastrointestinal cramping, emesis, diaphoresis, muscle fasciculations, pulmonary edema, miosis, bradycardia/tachycardia, seizures Organophosphate and carbamate insecticides,

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Anticholinergic physostigmine, edrophonium, some mushrooms Modified from Kulig K: Initial management of ingestions of toxic substances, N Engl J Med 326:1677, 1992.

The anticholinergic syndrome occurs frequently because many common medications and plants have anticholinergic properties. Anticholinergic CNS poisoning causes mild temperature elevation and acute delirium with mumbling speech and typical “picking movements” of the fingers. Suppression of cholinergic inhibition of the heart rate leads to tachycardia. Inhibition of the secretory functions of the integument causes dry mouth and skin, and the face is typically flushed. Unopposed sympathetic drive of the ciliary apparatus causes wide papillary dilation. Most patients recover with supportive therapy, but the delirium may last a day or more. Physostigmine may be a useful antidote in carefully selected patients and quickly resolves the delirium. It should not be used with a possible cyclic antidepressant overdose where it is associated with asystole. The sympathomimetic syndrome is usually seen after acute or chronic abuse of cocaine, amphetamines, or decongestants (e.g., phenylpropanolamine). Patients may be delusional; amphetamine, in particular, may cause complicated, intricate, and paranoid delusions. Seizures may occur, and the postictal state can contribute to the altered mental status. Blood pressure is usually elevated, the pulse is rapid (except with pure p -adrenergic agonists such as phenylpropanolamine, which can cause reflex bradycardia), the pupils are dilated, and piloerection may be seen. In massive overdoses of sympathomimetic agents, cardiovascular collapse can occur with the development of shock and wide-complex dysrhythmias. This clinical picture can mimic that of overdose of cardioactive drugs or cyclic antidepressants. In contrast to the diaphoresis seen with anticholinergic syndrome, the skin in sympathomimetic syndrome is dry. All sedative/hypnotic agents, when taken in sufficient dosage, cause general anesthesia with a complete loss of awareness and reflex activity. The CNS depressant (opioid/sedative/ethanol) syndrome is the most common toxic syndrome seen in the emergency department, and a depressed sensorium is its hallmark. Mixing agents in this class (e.g., ethanol and benzodiazepines) is common. As the drugs are absorbed at higher doses, the patient becomes increasingly obtunded, the deep tendon reflexes diminish, and finally, the vital signs deteriorate as medullary drive of respiration and cardiovascular function is attenuated. Respiratory depression is particularly pronounced with opioid overdose, and the respiratory rate is often diminished before decreases in blood pressure or pulse occur. The diagnosis of opioid overdose is confirmed by the use of naloxone (Narcan) or nalmefene (Revex) in adequate doses.[] Naloxone has an elimination half-life of 1.1 hours, whereas that of nalmefene is 10.8 hours. Nalmefene is especially useful when the offending opioid has a very long elimination half-life itself (e.g., methadone, with a half-life of 15 to 40 hours).[5] Close observation, investigation of alternative causes of depressed mental status when suggested by the clinical course, and airway intervention when indicated are the keys to successful management. The cholinergic syndrome is uncommon, but important to recognize because lifesaving treatment is available. Cholinergic syndrome causes the patient to be “wet,” as opposed to the anticholinergic syndrome, which causes the patient to be “dry.” The wetness is manifest by profuse sweating and excessive activity of virtually the entire exocrine system, often accompanied by vomiting, diarrhea, and urinary incontinence. The mnemonic “SLUDGE” is used to recall the specific elements of the syndrome: salivation, lacrimation, u rination, defecation, gastrointestinal cramping, and emesis. The CNS (e.g., confusion, coma, seizures) and the skeletal muscles (e.g., weakness, fasciculations) can also be involved. The pupils are often miotic. Cholinergic syndrome is most frequently caused by organophosphate or carbamate pesticide exposure, which may be through unsuspected dermal contamination. Anticholinergic agents are also the foundation of “nerve agents” such as sarin, which was used in the Tokyo subway attack. Recognition of the syndrome led to the use of atropine and cholinesterase regenerators, with a subsequent good outcome in many patients.[7] Serotonin syndrome ensues when there is a drug interaction involving the selective serotonin reuptake inhibitors (SSRIs) or an overdose of an SSRI.[8] Fluoxetine (Prozac), sertraline (Zoloft), paroxetine (Paxil), fluvoxamine (Luvox), and citalopram (Celexa) are commonly used SSRIs. Other drugs that are serotonin reuptake inhibitors (SRIs) also inhibit the reuptake of other neurotransmitters and are therefore not specific. These drugs include venlafaxine (Effexor), nefazodone (Serzone), and mirtazapine (Remeron). Drug interactions between many drugs can cause the serotonin syndrome described in Chapter 159 . These drugs include the SSRIs, SRIs, monoamine oxidase inhibitors (MAOIs), tryptophan, sympathomimetics,

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tricyclic and other antidepressants, meperidine, dextromethorphan, and lithium. Because of the long-lasting effects of the SSRIs, the syndrome can occur when one of the active agents is ingested even weeks after use of an SSRI has been discontinued. Serotonin syndrome is characterized by altered mental status, fever, agitation, tremor, myoclonus, hyperreflexia, ataxia, incoordination, diaphoresis, shivering, and sometimes diarrhea.[8] The diagnosis relies on the drug history, and it is difficult to distinguish serotonin syndrome from an overdose of cocaine, lithium, or MAOIs; the neuroleptic malignant syndrome; or thyroid storm. Patients may deteriorate slowly and become critically ill after an apparently benign manifestation. As possible toxidromes are investigated, the use of specific antidotes should be considered ( Table 145-3 ). Table 145-3 -- Antidotes Used in the Emergency Department Toxin Used For Antidote Acetaminophen

N-acetylcysteine

Anticholinergics

Physostigmine

Arsenic, lead, and mercury

BAL D-Penicillamine

Benzodiazepines

Flumazenil

Black widow spider bite

Latrodectus antivenin

p -Blockers

Glucagon Insulin and glucose

Calcium channel blockers

Calcium

Glucagon Insulin and glucose

Cyanide, hydrogen sulfide

Sodium thiosulfate Sodium nitrate

Digitalis glycosides

Digoxin-specific Fab fragments

Ethylene glycol

Fomepizole

Dose and Comments 140 mg/kg po, then 70 mg/kg q4h for up to 17 doses or 150 mg/kg IV load over 1 hr with 50 mg/kg over 4 hr followed by 100 mg/kg over 16 hr 1–2 mg IV in adults, 0.5 mg in children over 2 min for anticholinergic delerium, seizures, or dysrhythmias 3–5 mg/kg IM only 20–40 mg/kg/day; 500 mg tid in adults; may cross-react with penicillin in allergic patients 0.2 mg, then 0.3 mg, then 0.5 mg, up to 5 mg; not to be used if patient has signs of TCA toxicity; not approved for use in children, but probably safe 1 vial by slow IV infusion is usually curative; may cause anaphylaxis 5–10 mg in adults, then infusion of same dose per hour 10 U insulin with dextrose 25 g initially, then 0.1–1.0 U/kg/hr, 10–30 g/hr 1 g calcium chloride IV in adults, 20 –30-mg/kg/dose in children, over a few minutes with continuous monitoring. Repeat as needed 5–10 mg in adults, then infusion of same dose per hour 10 U insulin with dextrose 25 g initially, then 0.1–1.0 U/kg/hr with 10–30 g/hr 50 mL of 25% (12.5 g; 1 ampule) in adults; 1.65 mL/kg IV in children 10 mL of 3% (300 mg; 1 ampule) in adults; 0.33 mL/kg slowly IV in children 10–20 vials if patient in ventricular fibrillation; otherwise dose based on serum digoxin concentration or amount ingested 15 mg/kg × 1, then 10 mg/kg q12h

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Toxin Used For

Antidote

Hydrofluoric acid

Pyridoxine Thiamine Calcium gluconate

Iron

Deferoxamine

Isoniazid, hydrazine, and monomethylhydrazine

Pyridoxine

Lead

DMSA (succimer)

EDTA

Methanol

Folate or leucovorin Ethanol

Fomepizole

Methemoglobin-forming agents

Methylene blue

Opioids

Nalmefene Naloxone

Organophosphates and carbamates

Atropine

Protopam

Rattlesnake bite

Cro-Fab antivenin

Serotonin syndrome

Cyproheptadine

Sulfonureas

Octreotide

Tricyclic antidepressants

Bicarbonate

Valproic acid

Carnitine

Dose and Comments × 4, until ethylene glycol < 20 mg/dL. Adjust dose during dialysis 100 mg IV daily 100 mg IV 3.5 g in 5 oz of KY jelly topical; apply liberally to affected skin 15 mg/kg/hr IV; higher doses reported to be safe 5 g in adults, 1 g in children, if ingested dose unknown; antidote may cause neuropathy in very large doses Reported useful for arsenic and lead as well; one 100-mg capsule per 10-kg body weight tid for 1 wk then bid, with chelation breaks 75 mg/kg/day by continuous infusion; watch for nephrotoxicity, best done in hospital 50 mg IV q4h in adults while patients has serious toxicity Loading dose, 10 mL/kg of 10%; maintenance dose, 0.15 mL/kg/hr of 10%; double rate during dialysis 15 mg/kg × 1, then 10 mg/kg q12h × 4, until methanol < 20 mg/dL. Adjust dose during dialysis 1–2 mg/kg IV, one 10-mL dose of 10% solution (100 mg) is typical for an adult without anemia 2 mg; much longer half-life than naloxone 2 mg; less to avoid narcotic withdrawal, more if inadequate response; same dose in children Test dose, 1–2 mg IV in adults, 0.03 mg/kg in children; titrate to drying of pulmonary secretions Loading dose, 1–2 g IV in adults, 25–50 mg/kg in children; adult maintenance, 500 mg/hr or 1–2 g q4–6h 5 vials minimum dose by infusion in normal saline; increases in rate dependent on patient tolerance; may cause anaphylaxis 4 mg PO as needed; no parenteral form available; antidote may cause anticholinergic effects 50 p-g SC q12h, 5–10 p-g/kg/24 hr IV 44–88 mEq in adults, 1–2 mEq/kg in children; best used by IV push and not by slow infusion 100 mg/kg IV or PO loading dose with 25 mg/kg q6h

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Toxin Used For

Antidote

Dose and Comments

BAL, British anti-Lewisite; DMSA, dimercaptosuccinic acid; EDTA, ethylenediaminetetraacetic acid; TCA, tricyclic antidepressant.

TOXICOLOGY LABORATORY A toxicology screen (usually urine, sometimes blood and urine, and occasionally including gastric contents) only rarely results in identification of the ingested agent for three major reasons. first, the laboratory does not even attempt to screen for many substances, even commonly ingested agents that are capable of causing critical illness ( Box 145-2 ).[9] BOX 145-2 Drugs, Chemicals, and Groups Not Detected by a Comprehensive Toxicology Screen

Am moni a Anes theti c gase s Antib iotic s Antic oagu lants p Bloc kers Bora tes Bro mide s Cau stics /corr osiv es Colc hicin e Cya nide Digit alis glyc osid es Disul

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firam Ergo t alkal oids Ethyl ene glyc ol Fent anyl and its deriv ative s Fluor ides H2 anta goni sts Hallu cino gens (e.g., LSD ) Herb icide s Hou seho ld prod ucts Hypo glyc emic s Inse ct repel lents Isoni azid Laxa tives Lithi um Meta ls Mon oami ne oxid ase inhibi tors

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Most antih ypert ensi ves Most cardi ac medi catio ns Mus cle relax ants Mus hroo ms New er antid epre ssan ts (e.g., fluox etine , sertr aline , paro xetin e, bupr opio n, busp irone ) Nitra tes/n itrite s NSAI Ds Para quat Pesti cide s Phe nol Plant s Solv ents Thyr oid hor

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mon e Vita mins

NSAIDs, nonsteroidal anti-inflammatory drugs. Second, the urine screen is often performed soon after the ingestion, when the drug concentration is too low for a positive result. Even the drug responsible for life-threatening symptoms (e.g., tricyclic antidepressant) may be negative on the urine screen soon after ingestion. Other drugs, such as p~-hydroxybutyrate, need to be collected in the first urine sample to be detected. Third, drugs found on screening may not be those responsible for the initial symptoms, especially if the drugs are not quantified (e.g., benzodiazepines, cocaine parent compound). In such cases, a positive screen may not relate to the patient's current findings and symptoms. Drugs with a large volume of distribution or high fat solubility may be detected in urine for a long time after the last dose. Cocaine metabolites may be detected for days and marijuana for weeks after the last exposure. In addition, the results of toxicology screens are not usually available until many hours after most of the important treatment decisions are made. Screening results rarely change the clinical management of patients.[9] Toxicology screens are often very expensive ($300 or more), and their use is not warranted in most routine drug overdoses. Alternatives to a full toxicology screen include obtaining (1) discrete drug levels (e.g., acetaminophen, which should be considered in almost all adult intentional ingestions), (2) a qualitative urine screen for drugs of abuse, or (3) no toxicology tests.[] Several commercial urine testing kits have a rapid turnaround time, primarily for drugs of abuse. The full toxicology screen is most useful in patients who are critically ill for an unknown reason when identification of an otherwise unsuspected toxin may change management. Electrolyte levels help identify metabolic acidosis by the carbon dioxide content (“bicarbonate level”), which should be repeated if low to ensure that the acidosis is resolving. A persistent, unexplained metabolic acidosis should prompt urine examination for oxalate crystals (suggestive of ethylene glycol poisoning,) a serum salicylate level, and methanol and ethylene glycol levels. Arterial blood gas measurement is rarely helpful. A normal arterial blood gas or electrolyte measurement does not rule out such ingestion because metabolic acidosis is delayed and does not appear until after metabolism of the acids from ethylene glycol/methanol or until after erratic and slow absorption of salicylate. Rhabdomyolysis is evaluated, when indicated, with a urinary dipstick for blood (myoglobin) and determination of serum creatine kinase. Rhabdomyolysis and its treatment are discussed in Chapter 125 . Noncardiogenic pulmonary edema on a chest radiograph suggests opioid or salicylate overdose. Selective abdominal radiographs can detect smuggled packets. Some drugs are radiopaque (e.g. heavy metals, phenothiazines, potassium, calcium, and chlorinated hydrocarbons such as chloral hydrate), but radiography is rarely helpful in the evaluation of a poisoned patient except to monitor the decontamination of iron, lead, or body packets.[11]

DECONTAMINATION Gastric decontamination rarely affects the clinical outcome in poisoned patients.[] In the occasional situations in which decontamination may be helpful, activated charcoal (AC) may be beneficial if given early after an ingestion or for drugs that may have delayed emptying, including drugs with an anticholinergic effect, opioids, sustained-release drugs, or drug packets in “body stuffers.” For patients who are initially seen hours after ingestion, AC is usually unnecessary and should not be given. Administration of AC only in the small number of circumstances in which it is truly indicated also avoids rare complications such as pulmonary aspiration of the charcoal slurry.[] If charcoal is used, 50 g of an oral slurry of AC is usually sufficient. If the patient is obtunded or uncooperative and the benefits of AC administration are thought to outweigh the risks (principally aspiration), intubation should be considered, and the AC can be administered through a nasogastric tube. A cathartic such as sorbitol is often used to speed AC transit through the gut, but cathartics have never been shown to be of benefit and, in general, should be avoided. Agents that do not adsorb to charcoal include ions (e.g., acids and alkalies, lithium, borates, bromides), hydrocarbons, metals (e.g., iron), and ethanol.

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Whole-bowel irrigation with a polyethylene glycol solution may be useful in certain cases of severe, recent ingestion of lithium or metals such as iron or lead or in patients with massive ingestion of sustained-release formulations of highly toxic drugs. Whole-bowel irrigation has also been used to aid in the evacuation of drug packets from body packers.[15] Gastric lavage is rarely, if ever, indicated (and should be considered only when a patient is seen within a few minutes [less than an hour] after the ingestion of a highly toxic substance [e.g., calcium channel blocker, cyclic antidepressant]). Gastric lavage has not been shown to improve the clinical course or outcome of most poisoned patients.[16] In the rare circumstances in which gastric lavage is performed, a large (30-French or greater) orogastric tube is used, and specially designed lavage systems with large-bore tubes are available for this purpose. In 2004, the Federal Drug Administration withdrew approval of syrup of ipecac because of its abuse by patients with bulimia. Exposure of the eye to caustic chemicals and irritants requires immediate irrigation with large amounts of water or readily available fluid, as outlined in Chapter 151 . Exposure to a gas does not require decontamination because the patient and rescuers are not at risk once the patient is removed from the toxic environment. The exception is when the patient's skin or clothing is contaminated with a liquid that is evaporating. The most important intervention to limit dermal exposure is to remove all clothing as soon as possible

DISPOSITION AND CONSULTATION The decision to admit a patient is not difficult when the patient manifests serious toxicity. When the patient is minimally symptomatic but has ingested a potentially dangerous substance, the decision is more difficult. Identification of a agent that causes a particular risk for the patient, especially cardiovascular instability, seizures, or respiratory depression, generally mandates admission to the hospital or to an observation unit in the emergency department. A 6-hour period of observation for a minimally symptomatic patient is usually sufficient, except for some extended-release preparations. Patients with cardiac dysrhythmia, conduction disturbance, altered mental status requiring intubation, or the need for frequently titrated agents (e.g., pressors) should be admitted to the intensive care unit or a monitored inpatient unit. If the patient is acutely suicidal, a sitter or secure environment may be required. Poison control centers and medical toxicologists can provide specific, current advice, especially for more esoteric or unfamiliar poisons. Consultation with a medical toxicologist is particularly helpful when an uncommon agent has been ingested, the patient is not following the anticipated clinical course, or specific interventions such as administration of antibody therapy or dialysis are contemplated.

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KEY CONCEPTS {, {, {, {, {,

A thorough history from many sources is the key to toxicologic diagnosis. Common toxidromes should guide judicious use of antidotes. Minimally symptomatic patients do not benefit from toxicology screening or extensive laboratory investigation. Good supportive care is the key to management. Activated charcoal is rarely indicated in overdose, and other methods of gut decontamination (gastric lavage, whole-bowel irrigation) are virtually never helpful. Activated charcoal may decrease absorption of many drugs, but its use should be carefully weighed against potential complications.

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REFERENCES 1. Kulig K: Initial management of ingestion of toxic substances. N Engl J Med1992;326:1677. 2. Hoffman RS, Goldfrank LR: The poisoned patient with altered consciousness: Controversies in the use of a “coma cocktail.”. JAMA1995;274:562. 3. Wrenn K, Murphy F, Slovis C: A toxicity study of parenteral thiamine hydrochloride. Ann Emerg Med 1989;18:867. 4. Goldfrank L: Teaching the recognition of odors. Ann Emerg Med1982;11:684. 5. Glass PJ, Jhaver RM, Smith LR: Comparison of potency and duration of action of nalmefene and naloxone. Anesth Analg1994;78:536. 6. Doyon S, Roberts JR: Reappraisal of the “coma cocktail.”. Emerg Med Clin North Am1994;12:301. 7. Suzuki T: Sarin poisoning in a Tokyo subway. Lancet1995;345:980. 8. Boyer EW, Shannon M: The serotonin syndrome. N Engl J Med2005;352:1112. 9. Kulig K: The appropriate utilization of toxicology screens. Cost-Effective Diagnostic Testing in Emergency Medicine, Dallas: American College of Emergency Physicians; 2000: 10. Mahoney JD: Quantitative serum toxic screening in the management of suspected drug overdose. Am J Emerg Med1990;8:16. 11. Craig SA: Radiology. In: Ford MD, ed.Clinical Toxicology, Philadelphia: WB Saunders; 2001: 61-72. 12. Chyka PA, Seger D: Position statement: Single-dose activated chavcoal. American Academy of Clinical Toxicology; European Association of Poisons Centres and Clinical Toxicologists. J Toxicol Clin Toxicol 1997;35:721. 13. Bond GR: The role of activated charcoal and gastric emptying in gastrointestinal decontamination: A state-of-the-art review. Ann Emerg Med2002;39:273. 14. Osterhoudt KC: Activated charcoal in a pediatric emergency department. Pediatr Emerg Care 2004;20:493. 15. Tennenbein M: Position statement: Whole bowel irrigation. American Academy of Clinical Toxicology; European Association of Poisons Centres and Clinical Toxicologists. J Toxicol Clin Toxicol1997;35:753. 16. Vale JA: Position statement: Gastric lavage. American Academy of Clinical Toxicology; European Association of Poisons Centres and Clinical Toxicologists. J Toxicol Clin Toxicol1997;35:711.

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Chapter 146 – Acetaminophen Kenneth E. Bizovi Robert Hendrickson

PERSPECTIVE Acetaminophen is one of the most common analgesic-antipyretic medications. More hospitalizations occur after acetaminophen overdose than after overdose of any other pharmaceutical agent.[1] In addition to recognized acetaminophen overdose, the widespread availability and the multitude of combination products make acetaminophen toxicity a concern in cases of unknown ingestion, drug abuse, and therapeutic misadventures. Despite established protocols for assessment and management of acute acetaminophen exposure, variations in treatment strategies exist, and controversy remains regarding indications, route, and duration of antidotal treatment. The indications and endpoints for treatment after chronic excessive acetaminophen exposure are almost completely undefined, and the importance of ethanol use, malnutrition, drug interactions, and individual differences in metabolism remains unresolved.[2]

PRINCIPLES OF DISEASE Most acetaminophen absorption occurs within 2 hours, even after overdose. Peak plasma concentrations generally occur within 4 hours. Once acetaminophen is absorbed, hepatic metabolism normally accounts for up to 90% of its elimination. Acetaminophen is primarily metabolized in the liver through three routes: (1) conjugation with glucuronide (40-67%), (2) conjugation with sulfate (20-46%), or (3) oxidation via the cytochrome P450 (CYP450) mixed-function oxidase system (CYP2E1, CYP1A2, and CYP3A4)[3] with subsequent conjugation ( Figure 146-1 ).

Figure 146-1 Acetam inophen (APAP) m etabolism and N-acetylcysteine (NAC) m echanism s of action. NAC1 enhances sulfation; NAC2 serves as a glutathione (GSH) precursor; NAC3 is a GSH substitute; NAC4 m ay reduce system ic toxicity. NAPQI, N-acetyl-p-benzoquinoneim ine. ((Modified from Sm ilkstein MJ. Acetam inophen. In Goldfrank LR, et al (eds): Goldfrank's Toxological Em ergencies, 6th ed, Stam ford, Conn, Appleton & Lange, 1998, p 547.)Appleton & Lange)

The oxidation of acetaminophen by CYP450 subfamilies, predominantly CYP2E1[] results in the formation of the highly reactive electrophile, N-acetyl-p-benzoquinoneimine (NAPQI).[3] NAPQI combines rapidly with glutathione and other thiol-containing compounds, forming nontoxic conjugates, which are eliminated in urine. When NAPQI formation exceeds glutathione supply, free NAPQI binds to hepatocyte intracellular proteins, causing toxicity. Inducers (e.g., ethanol, isoniazid, anticonvulsants) and inhibitors (e.g., cimetidine) of CYP450 enzymes may affect the NAPQI formation, but their clinical significance is controversial. Renal injury may occur with or without hepatic injury[6] and may be mediated by the presence of CYP450 enzyme species[] and the activation of prostaglandin synthase within the kidneys.[] Most oxidative metabolism is concentrated in hepatic zone III, which is affected most via acetaminophen toxicity. In cases of severe toxicity, necrosis can extend into zones I and II, destroying the entire liver

Page 3468

parenchyma. The sequelae of severe acetaminophen toxicity are those of fulminant liver failure, rather than direct acetaminophen effects, and the pathophysiology of these complex multisystem problems is well described (see Chapter 89 ).[11] As treatment for acetaminophen toxicity, N-acetylcysteine (NAC) serves as both a glutathione precursor and a glutathione substitute (see Figure 146-1 ). In addition, NAC may decrease NAPQI formation by augmenting nontoxic sulfation.[12] Unlike its early acetaminophen-specific actions, other NAC mechanisms are suggested by the surprising finding that intravenous NAC improves survival in patients with acetaminophen-induced fulminant hepatic failure, even long after completion of acetaminophen metabolism.[ 13] Possible mechanisms include improving oxygen delivery and uptake by tissues, changes in hepatic microcirculation, scavenging of reactive species, and diminishing cerebral edema.[14] The ability of NAC to ameliorate multiorgan failure suggests that extrahepatic mechanisms not specific to acetaminophen are of benefit.

CLINICAL FEATURES The progression of acetaminophen-induced hepatic injury occurs in four stages. Stage 1 is the preinjury period, usually the first 24 hours after ingestion. Nonspecific symptoms, including nausea, vomiting, anorexia, diaphoresis, and malaise, are common in the first 8 hours after ingestion, usually resolving thereafter. Patients may be asymptomatic during this stage. Stage 2 is the onset of liver injury, usually 24 hours after ingestion but possibly 12 to 36 hours after overdose. In extraordinary cases, liver injury is evident as early as 8 hours after ingestion. Signs and symptoms of hepatic injury include nausea, vomiting, and right upper quadrant and epigastric pain or tenderness. Stage 3 is maximum liver injury, usually 3 to 4 days after ingestion, with a wide variety of clinical manifestations, depending on severity of the injury. Signs and symptoms of hepatic injury can persist or progress. Fulminant hepatic failure can develop during this stage, with encephalopathy, coma, and clinical evidence of coagulopathy. Patients with hepatic failure sometimes develop hypoglycemia and metabolic acidosis. Death with hepatic failure can occur from hemorrhage, adult respiratory distress syndrome, sepsis, multiorgan failure, or cerebral edema.[] The risk of renal injury increases with severity of hepatic injury, occurring in less than 2% of patients without hepatotoxicity and in 25% of patients with severe hepatotoxicity.[] Stage 4 is the recovery period. Hepatic enzymes return to baseline by 5 to 7 days but may take longer with severe hepatic injury. Complete histologic resolution of hepatic insult can take months. Regeneration of the liver is complete, without chronic hepatic dysfunction.[19]

DIAGNOSTIC STRATEGIES The primary goals of patient assessment after acetaminophen exposure are to identify risk for acetaminophen-induced hepatotoxicity and to initiate timely treatment with NAC. The history and physical examination establish potential risk of toxicity, but because early symptoms are unreliable indicators of toxicity, and late symptoms occur long after NAC should be started, laboratory evaluation is essential. Once a patient is determined to be at risk for acetaminophen toxicity, treatment with NAC should be initiated. Additional diagnostic testing of these patients involves evaluation for hepatic injury and hepatic failure in select patients. Acetaminophen exposures can be categorized as acute or chronic. Acute overdose is usually considered to be a single ingestion, arbitrarily defined as occurring within a single 4-hour period.[2] All other repeated ingestions of greater than recommended doses are considered to be chronic exposure. The initial management of most single acute overdoses in adults is well established. Liver failure and death are completely preventable if NAC is administered early after ingestion.[20] Factors that complicate evaluation and management decisions after acute exposures include inability to establish the time of ingestion, presentation longer than 24 hours after ingestion, new formulations of acetaminophen, age younger than 5 years, and pregnancy. Management of chronic excessive acetaminophen dosing is much more controversial and includes widely accepted approaches to uncomplicated acute overdose, as well as our approach to complicated acute and chronic acetaminophen exposures ( Boxes 146-1 and 146-2 ). BOX 146-1 Risk Assessment and Treatment Recommendations for Acute Acetaminophen Ingestion

Page 3469

I.

Laboratory evaluation A. Serum acetaminophen concentration 4 hours after ingestion or as soon as possible thereafter B. Aspartate transaminase (AST) measurement if: 1. Patient has signs or symptoms of hepatic injury. 2. 3. C.

Acetaminophen concentration is on or above nomogram treatment line. Time of ingestion is completely unknown.

Prothrombin time, electrolytes, glucose, blood urea nitrogen, and creatine kinase if AST greatly elevated

II. N-acetylcysteine (NAC) treatment if: A. Acetaminophen concentration is on or above nomogram treatment line. B. AST is elevated. C.

Acetaminophen concentration is greater than 10 p-g/mL, and time of ingestion is unknown. [*]

* NAC treatm ent should not be delayed m ore than 8 hours after ingestion. If the patient presents after this tim e, NAC should be started as soon as possible.

BOX 146-2 Risk Assessment and Treatment Recommendations for Chronic Acetaminophen Ingestion[*]

I.

Indications for laboratory evaluation A. Signs or symptoms of hepatic injury B. Children 1. Inge stion of >75 mg/k g in 24-h our perio d asso ciate d with acut e febril e illnes s, maln ouris hme nt, or chro

Page 3470

2.

C.

Adults 1.

nic use of medi catio ns that indu ce CYP 450 syst em (e.g., antic onvu lsant s, isoni azid) Inge stion of >150 /kg in 24-h our perio d Inge stion of >4 g in 24-h our perio d asso ciate d with maln ouris hme nt, chro nic alco hol cons umpt ion, or chro nic use of medi

Page 3471

2.

II. III.

catio ns that indu ce CYP 450 syst em (e.g., antic onvu lsant s, isoni azid) Inge stion of >7.5 g in 24-h our perio d

Laboratory evaluation: acetaminophen concentration, AST Risk classification A. Higher risk 1. Acetaminophen concentration twi ce nor mal b. AST >nor mal; patie nt sym ptom atic 2.

Acetaminophen concentration >10 p-g/mL and as expected for appropriate dose[ †]

a.

3.

AST >nor mal

Acetaminophen concentration greater than expected for

Page 3472

appropriate dose[ †]

B.

Low risk 1.

2.

Acet amin ophe n conc entra tion 100 msec) and negative inotropic effects. [] Impaired excitation-contraction coupling within myocardial cells and diminished release of calcium from sarcoplasmic calcium stores decrease contractility.[8] p 1-Adrenoreceptor blockade can result in vasodilation in all vascular beds, causing hypotension from decreased preload and afterload. p 1-Blockade can decrease systemic vascular resistance, widen pulse pressure, and decrease pupillary size. BOX 149-1 Major Pharmacodynamic Effects of Cyclic Antidepressents (CAs)

1. 2. 3. 4.

Sodium channel blockade (quinidine-like membrane-stabilizing effects) p

1-Adrenoreceptor

blockade

Inhibition of reuptake of biogenic amines (e.g., norepinephrine, serotonin) Muscarinic receptor blockade (anticholinergic effects)

Page 3513

5. 6. 7.

Histamine receptor blockade (antihistaminic effects) Potassium efflux blockade Indirect GABAA antagonism caused by binding at picrotoxin receptor

Serotonin and norepinephrine reuptake inhibition within the central nervous system (CNS) predisposes to agitated delirium and seizures. Peripheral inhibition of catecholamine reuptake results in increased circulating catecholamines and initial hypertension.[10] Eventual metabolism of peripheral catecholamines by catechol O-methyltransferase results in late hypotension and bradycardia. Anticholinergic and antihistaminic effects are associated with peripheral autonomic nervous system antimuscarinic effects ( Box 149-2 ) and CNS effects of delirium, seizures, sedation, and coma ( Box 149-3 ).[1] Potassium efflux blockade prolongs phase 3 of the myocardial action potential, repolarization, resulting in an increased duration of the Q-T interval. This increases the risk for developing torsades de pointes. CAs promote CNS excitation and seizures because of their indirect inhibition of p~-aminobutyric acid (GABA), the primary cerebral inhibitory neurotransmitter. CAs bind to the picrotoxin site of the GABAA receptor-chloride ionophore complex. BOX 149-2 Peripheral Nervous System Effects of Cyclic Antidepressants

Anticholinergic Tach ycar dia caus ed by vago lysis Hype rther mia Mydr iasis Anhy drosi s Red skin Decr ease d bow el soun ds Ileus Urin ary reten tion Dist ende d

Page 3514

blad der

p 1-Blockade Refl ex tach ycar dia Miosi s or midr ange pupil s (inhi bitio n of dilat ory radia l mus cle of iris) BOX 149-3 Central Nervous System Effects of Cyclic Antidepressants

Excitation Agita tion Deliri um Myo cloni c jerks Hype rrefle xia Clon us Seiz ures Hype rther mia

Inhibition Sed

Page 3515

ation Com a

Clinical Features CA poisoning initially presents with anticholinergic symptoms, including sinus tachycardia and early hypertension (see Chapter 148 ). Severe poisoning is characterized by subsequent convulsions, coma, and cardiovascular collapse. CA toxicity should be considered in all patients with a decreased level of consciousness and prolonged QRS complex. Mental status changes do not predict the occurrence of seizures, and 23% of patients are awake and alert immediately before a seizure.[11] Hypotension caused by CA poisoning can occur with or without QRS prolongation (>100 msec).[12] Hypotension can result from myocardial depression or peripheral vasodilation. Catastrophic cardiovascular collapse closely follows seizures in 13% of patients with CA-induced seizures.[11] Cardiovascular collapse is attributed to lactic acidosis, which impairs myocardial sodium conduction. Patients can deteriorate rapidly, and even patients with trivial signs of poisoning on presentation can have a 50% mortality rate.[13] Most serious complications develop within 30 to 60 minutes of presentation, usually while in the emergency department.[12] Because of rapid deterioration, death rates of 44% have been reported for patients en route to the hospital, many of whom were initially awake and alert with normal sinus rhythm.[13] CAs also can cause cardiogenic or noncardiogenic pulmonary edema. Amoxapine has fewer cardiac effects but a greater incidence of seizures. The tetracyclic maprotiline has more cardiac and CNS effects than TCAs.

Diagnostic Strategies A history of CA overdose is the most helpful diagnostic indicator. A dose greater than 10 mg/kg or 1000 mg in an adult should be considered life-threatening. Patients who have an anticholinergic toxidrome, decreased level of consciousness, QRS prolongation (>100 msec), or rightward deviation of the terminal 40-msec QRS axis (R wave in aVR >3 mm or R/SaVR ratio of ≥0.7) should be considered to have CA poisoning until proved otherwise ( Figure 149-2 ).[] With QRS prolongation greater than 100 msec in the limb leads, 30% of patients experience seizures; for prolongation greater than 160 msec, 50% develop dysrhythmias. CAs can induce an electrocardiogram (ECG) pattern consistent with the Brugada syndrome, a genetic disorder resulting in sodium channel dysfunction. A right bundle branch block and ST segment elevation in the right precordial leads (V1 through V3) are seen.[16] CA toxicity is not fully excluded with normal ECG findings.

Figure 149-2 Electrocardiogram (ECG) changes in cyclic antidepressant poisoning. A, ECG of a 24-year-old woman who ingested 2.5 g of desipram ine shows ventricular bigem iny, right axis deviation, wide QRS complex, long Q-Tc interval, and right deviation of term inal 40-m sec QRS vector in lim b leads, with prom inent R wave in aVR. B, ECG of sam e patient after receiving bolus and continuous intravenous infusion of sodium bicarbonate shows sinus tachycardia, 90-degree axis, slight prolongation of QRS and Q-Tc intervals, and persistent right axis deviation of terminal 40 m sec in lim b leads. C, ECG of sam e patient 25 hours after ingestion and 4 hours after termination of sodium bicarbonate infusion shows persistent but im proved sinus tachycardia, norm alization of QRS axis and width, norm alization of Q-Tc interval, and resolution of prom inent R wave in aVR.

Quantitative serum toxicology tests for CAs are not usually available in a timely fashion and do not predict adequately the degree of toxicity. Qualitative laboratory tests may document only exposure. Neither serum toxicology tests nor laboratory tests are useful for clinical decision making. Diagnosis, treatment, and disposition are determined on a clinical basis and with ECG and cardiac monitoring.[] Determining which patients require admission has been simplified with a management algorithm for CA overdose (see Figure 149-1 ).

Differential Considerations

Page 3516

The differential diagnosis of CA poisoning is extensive and includes intoxications by anticholinergic, psychiatric, and cardiac medications, especially type I antidysrhythmics. Many conditions cause sinus tachycardia and hypotension with a wide pulse pressure; however, QRS widening, seizures, or coma suggests CA poisoning.

Management Treatment begins with assessment of airway and breathing. Endotracheal intubation should be performed if the patient is exhibiting a markedly decreased level of consciousness or if the level of consciousness is rapidly deteriorating. Respiratory depression, with attendant hypoxia and hypercarbia, significantly increases morbidity and mortality of CA poisoning. Patients with overdoses severe enough to require admission to the intensive care unit (ICU) have a high incidence of airway and breathing complications, with aspiration pneumonitis reported in 13% to 18% of patients.[17] The initial benign appearance of the patient's presentation may be deceptive; rapid deterioration with cardiac dysrhythmias, generalized seizures, and death can occur despite appropriate management. Ventilatory support to avoid respiratory acidosis is crucial because acidosis inhibits conductance through fast sodium channels. Any patient with a significant CA overdose should have continuous pulse oximetry. Arterial blood gas determination or capnography may be helpful when ventilatory function is questionable despite normal oxygen saturations on pulse oximetry. Patients assessed clinically to be ventilating adequately have been shown to have low minute volumes, hypoxia, and acidosis. Gastric lavage and administration of activated charcoal within 60 minutes from time of significant ingestion is theoretically appealing, but there is no evidence that gastrointestinal decontamination improves clinical outcome. Physostigmine is contraindicated in CA overdose. Seizures, cardiac arrest, and death have occurred when physostigmine has been used in CA overdose.[18] No clinically effective method exists to change the metabolism or distribution of CAs. Hypertension is usually mild and transient and requires no treatment (see Table 149-3 ). Treatment of hypotension begins with isotonic crystalloids. If the QRS is greater than 100 msec, and the patient is symptomatic, with hypotension or a dysrhythmia, or if the patient is acidemic, intravenous sodium bicarbonate (NaHCO3) also should be administered.[19] NaHCO3 produces an alkaline pH and provides a sodium load and hypertonicity that increase sodium conductance through myocardial fast sodium channels.[ 8] Hyperventilation and hypertonic sodium chloride also enhance sodium conduction.[20] Hypertonic sodium chloride has been used for hypotension with QRS widening caused by CA-induced cardiotoxicity unresponsive to standard therapies.[21] Table 149-3 -- Cardiovascular Complications of Cyclic Antidepressant Toxicity and Treatments Mechanism: Cause Complication

Cardiac

Hypertension (early and transient) Posit ive chro notro pism : antic holin ergic vago lytic effec ts Posit ive inotr opis m: incre

Peripheral Treatment Vascular Initial Not indicated vasoconstri ction: increased circulating catecholami nes caused by reuptake inhibition

Page 3517

Mechanism: Cause Complication

Cardiac

Peripheral Vascular

Treatment

ased circu latin g cate chol amin es caus ed by reupt ake inhibi tion Hypotension

Negative inotropism: fast sodium channel inhibition with impairment of excitation-contraction coupling

Sinus tachycardia Posit ive chro notro pism : antic holin ergic vago lytic effec ts

Vasodilation : a1 -adrenorece ptor blockade

IV isoto nic cryst alloid IV NaH CO 3 if QRS >100 mse c Nore pine phrin e or dopa mine

Reflex Not indicated tachycardia: p 1 adrenorece ptor blockade

Posit ive chro notro pism : incre

Page 3518

Mechanism: Cause Complication

Cardiac

Peripheral Vascular

Treatment

ased circu latin g cate chol amin es caus ed by reupt ake inhibi tion Ventricular tachycardia (monomorphic) Negative dromotropism: fast sodium channel inhibition with QRS prolongation

IV NaH CO 3 Sync hroni zed cardi over sion Over drive paci ng

Ventricular tachycardia (polymorphic) (torsades de pointes)

Bradydysrhythmias (late and uncommon)

Negative dromotropism: fast sodium channel inhibition with QRS prolongation and resultant Q-T prolongation, and potassium efflux inhibition Neg ative dro motr opis m: fast sodi um chan nel inhibi tion

Magnesium sulfate for torsades de pointes

ACLS algorithm for bradycardia

Neg ative chro notro pism : impa

Page 3519

Mechanism: Cause Complication

Cardiac

Peripheral Vascular

Treatment

ired auto mati city from thres hold volta ge elev ation and slowi ng of phas e4 depo lariz ation QRS prolongation, Q-T prolongation

Negative dromotropism: fast sodium channel inhibition (potassium efflux inhibition), PR prolongation, rightward terminal 40-msec QRS axis deviation

IV NaHCO3 for symptomatic QRS prolongation

IV NaHCO3, intravenous sodium bicarbonate; ACLS, advanced cardiac life support.

Serum alkalinization is clinically effective in decreasing CA-induced intraventricular conduction delays. The major effect of increasing pH seems to be increased sodium conductance through myocardial sodium channels rather than the increase in plasma protein binding.[8] NaHCO3 is administered by intravenous boluses of 1 to 2 mEq/kg until hypotension improves and the QRS narrows to 100 msec, or until serum pH increases to a maximum of 7.50 to 7.55. After obtaining the desired endpoint with intravenous NaHCO3 boluses, the emergency physician can consider initiating continuous isotonic intravenous infusion by adding three ampules of 8.4% NaHCO3 (50 mEq/ampule, 100 mOsm/ampule) to 1 L of 5% dextrose in water. The initial intravenous infusion is started at a usual maintenance rate for intravenous fluids, based on the patient's weight. This initial NaHCO3 infusion rate often must be maintained for at least 4 to 6 hours before the rate can be decreased. For a hypertonic continuous intravenous solution, four ampules of 8.4% NaHCO3 can be added to 1 L of 5% dextrose in water. This infusion is occasionally necessary for refractory hypotension with a prolonged QRS or refractory ventricular dysrhythmias. Excess NaHCO3 and saline can worsen heart failure. Excessive alkalemia from combined use of hyperventilation and NaHCO3 can result in complications, including death.[22] Repeat boluses and continuous intravenous infusion should be guided by serial measurements of arterial pH and QRS duration. When symptoms were refractory, hypertonic sodium chloride administered as an intravenous bolus was used to treat hypotension and wide QRS interval with ventricular ectopy in an adult.[21] If hypotension does not resolve, norepinephrine or dopamine is recommended.[8] High-dose dopamine (20 to 30 p-g/kg/min) and norepinephrine (0.1 to 1 p-g/kg/min) may be necessary for the direct p 1-agonist effect.[23] For inotropic support alone, dobutamine is controversial.[8]

Page 3520

Sinus tachycardia is usually well tolerated and does not require specific therapy. p -Receptor antagonists and physostigmine are contraindicated.[19] Wide-complex tachycardia is not always ventricular tachycardia and can represent sinus tachycardia with aberrant conduction. Determining the specific type of wide-complex rhythm is unnecessary because treatment in either case is intravenous NaHCO3.[8] Lidocaine has not been consistently effective.[24] Phenytoin has been shown to increase the frequency and duration of episodes of ventricular tachycardia and is not recommended as an antidysrhythmic agent.[25] Type IA antidysrhythmics (quinidine, disopyramide, procainamide) and type IC antidysrhythmics (flecainide, moricizine, propafenone) are contraindicated because they also inhibit fast sodium channels. A transvenous pacemaker and overdrive pacing can be used for CA-associated polymorphic ventricular tachycardia (torsades de pointes) not responsive to magnesium. Bradydysrhythmias are rare and late in CA overdose. CA poisoning can result in increased threshold requirements for ventricular pacing and decrease electric cardioversion and defibrillation effectiveness. Q-T prolongation, PR prolongation, and rightward terminal 40-msec QRS axis deviation do not mandate specific therapy.[] Treatment with NaHCO3, hypertonic sodium chloride, and hyperventilation does not resolve completely Q-T prolongation, which involves not only sodium channel blockade, but also protracted repolarization from potassium efflux blockade. Treatment of neurologic complications of CA poisoning includes early intubation with mechanical ventilation for coma (see Table 149-2 ). Benzodiazepines should be used for agitation because they do not have the anticholinergic or cardiac conduction effects of some antipsychotic medications. Status epilepticus or prolonged seizures account for 20% to 30% of the seizures caused by CAs.[] These seizures usually respond to intravenous lorazepam or diazepam.[11] Seizures refractory to other benzodiazepines have terminated with intravenous midazolam boluses of 2.5 to 10 mg and continuous intravenous infusions.[27] Table 149-2 -- Treatment of Neurologic Complications of Antidepressant Poisoning Complication Treatment Coma

Seizures

Hyperthermia

Endotracheal intubation Mechanical ventilation Supportive care Lorazepam or diazepam Phenobarbital, continuous intravenous midazolam infusion, or propofol Cessation of seizures with benzodiazepines and phenobartital Neuromuscular blockade with vecuronium during phenobarbital loading General anesthesia with continuous EEG monitoring Evaporative cooling Ice water bath

EEG, electroencephalogram.

If benzodiazepines fail to terminate prolonged or repetitive seizures, phenobarbital may be administered in a loading dose of 20 mg/kg, given at a rate of up to 50 mg/min in adults or up to 1 mg/kg/min in children. Propofol also has been used to treat refractory seizures successfully.[28] A loading dose of 2.5 mg/kg is followed by continuous infusion of 25 to 200 p-g/kg/min.[28] Phenytoin may cause more and longer episodes of ventricular tachycardia.[25] If maximal doses of benzodiazepines, phenobarbital, or propofol are ineffective, neuromuscular blockade and general anesthesia with continuous electroencephalogram monitoring are recommended to prevent rhabdomyolysis and hyperthermia caused by excessive muscle activity. Flumazenil is contraindicated, even if benzodiazepines are known coingestants.[] Flumazenil counteracts

Page 3521

the anticonvulsant activity of the coingested benzodiazepines. Seizures, ventricular tachycardia, and ventricular fibrillation can occur when flumazenil is used in mixed benzodiazepine/CA overdoses.[30] Life-threatening hyperthermia (rectal temperature >40° C) is best treated with control of seizures and neuromuscular blockade. A nondepolarizing neuromuscular blocker (e.g., rocuronium) is recommended if rhabdomyolysis and hyperkalemia with ECG changes are present. Evaporative cooling should be used until core temperature reaches 38.5° C. Forced diuresis, hemodialysis, and hemoperfusion are not indicated because CAs have large volumes of distribution, are highly bound to plasma proteins, and are minimally eliminated by the kidneys.

Disposition Patients with known or suspected CA overdoses require 6 hours of observation with continuous cardiac monitoring and pulse oximetry. After 6 hours of observation, patients may be discharged for psychiatric evaluation if they do not develop (1) ventilatory insufficiency, (2) desaturation on pulse oximetry, (3) QRS greater than 100 msec, (4) sinus tachycardia greater than 120 beats/min, (5) dysrhythmias, (6) hypotension, (7) decreased level of consciousness, (8) seizures, or (9) abnormal or inactive bowel sounds. Patients who exhibit any of these findings should be admitted to an ICU (see Figure 149-1 ).[]

SELECTIVE SEROTONIN REUPTAKE INHIBITORS SSRIs approved in the United States for treatment of depression are fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft), citalopram (Celexa), and escitalopram (Lexapro). Fluvoxamine (Luvox) is approved in the United States for treating obsessive-compulsive disorder.

Principles of Disease SSRIs are well absorbed from the gastrointestinal tract and reach peak plasma concentrations 3 to 8 hours after therapeutic doses. Controlled-release paroxetine reaches peak serum concentration 6 to 10 hours after ingestion. Because SSRIs have no significant anticholinergic effects, they are less likely than CAs to have delayed absorption. SSRIs are highly lipophilic, are extensively bound to plasma proteins, and have large volumes of distribution (12 to 97 L/kg).[31] SSRIs are metabolized predominantly by the liver. The elimination half-life is about 15 hours for fluvoxamine, about 1 day for paroxetine and sertraline, 27 hours for escitalopram, 35 hours for citalopram, and 1 to 4 days for fluoxetine. Fluoxetine, sertraline, citalopram, and escitalopram have active metabolites that increase the duration of their effect. Fluoxetine is demethylated to its clinically active metabolite, norfluoxetine, with a half-life of 4 to 9 days.[31] The long half-lives of the SSRIs and their active metabolites explain the long interval necessary between stopping SSRI treatment and beginning MAOI treatment to avoid the life-threatening serotonin syndrome. MAOI therapy should not be initiated until at least 5 weeks after stopping fluoxetine and for at least 2 weeks after stopping the other SSRIs. Likewise, none of the SSRIs should be used for at least 2 weeks after stopping MAOI treatment. Minimal amounts of SSRIs are eliminated in the urine as unchanged drugs; forced diuresis is of no benefit. Enterochromaffin cells of the gastrointestinal tract contain 90% of the total serotonin in adults. Most remaining serotonin is in platelets and the CNS. In the CNS, serotonin is involved with mood, depression, anxiety, obsession, compulsion, perception of pain, migraine headaches, sleep, circadian rhythms, temperature regulation, and regulation of blood pressure.[32] Serotonin's roles in the periphery involve regulating gastrointestinal motility and facilitating hemostasis by promoting vasoconstriction and platelet aggregation. The antidepressant effects of SSRIs are thought to be due to the blockade of presynaptic reuptake of serotonin at the 5-hydroxytryptamine type 1 (5-HT1) autoreceptors, resulting in increased intrasynaptic serotonin.

Clinical Features Overdose The signs, symptoms, morbidity, and mortality of SSRI poisoning are much less than for CA poisoning. The organ systems most affected by excessive serotonin are the gastrointestinal tract, cardiovascular system, and CNS ( Table 149-4 ). Overdose can cause sedation, agitation, tremor, hyperreflexia, tachycardia, bradycardia, nausea, vomiting, abdominal pain, facial flushing, and dizziness. More severe overdoses can cause seizures and cardiac toxicity. The frequency of severe symptoms increases with coingestants.[33] Table 149-4 -- Clinical Manifestations of Acute Fluoxetine Overdoses in Adults

Page 3522

Neuromuscular System Manifestations

% Cardiovascular System Manifestations

% Gastrointestina l System Manifestations

%

Drowsiness

21 Sinus 22 Nausea 6 tachycardia Tremor 8 Hypertension 6 Emesis 6 Euphoria 2 Trigeminy 2 Abdominal pain 2 Headache 2 Junctional 2 rhythm From Borys DJ, et al: Acute fluoxetine overdose: A report of 264 cases. Am J Emerg Med 10:115, 1992.

Fluoxetine About 45% of adults and 90% of children who overdose on fluoxetine alone develop no symptoms.[] Common symptoms of fluoxetine overdose include agitation, anxiety, restlessness, confusion, and hypomania.[36] Other milder symptoms are tachycardia, drowsiness, tremor, nausea, and vomiting. In children, 5% develop diarrhea, and 5% develop sleepiness.[3] Q-Tc prolongation, torsades de pointes, QRS widening, ventricular bigeminy, ventricular tachycardia, and seizures, with delayed onset 10 hours after ingestion, have been observed with fluoxetine overdose.[]

Fluvoxamine Tachycardia, bradycardia, hypotension, ECG abnormalities, seizures, liver function abnormalities, coma, and death have been reported with fluvoxamine.[36] Status epilepticus and refractory hypotension also have been described with fluvoxamine toxicity.[39]

Citalopram Gastrointestinal upset; mild CNS changes, such as dizziness and somnolence; and mild autonomic symptoms, such as tachycardia, are observed with ingestions of citalopram less than 600 mg.[40] Q-Tc prolongation has been observed after an ingestion of 400 mg.[40] At higher doses, Q-Tc prolongation, QRS widening, ventricular fibrillation, seizures, and death have been reported.[] Seizures have been reported to start 14 hours after a citalopram and fluoxetine overdose.[43]

Escitalopram Limited information is available about this new drug. In one review, ingestion of 600 mg was associated with only minor effects, including drowsiness, agitation, and tachycardia. No seizures were reported.[44]

Sertraline and Paroxetine Mild symptoms after sertraline or paroxetine overdose are similar to symptoms with other SSRIs. Seizures and death have been reported with large doses of sertraline.[] In general, deaths attributed to SSRI overdose usually are associated with polydrug poisonings involving significant coingestants.[]

Serotonin Syndrome Serotonin syndrome is a constellation of signs and symptoms manifesting autonomic, neuromuscular, and mental status changes ( Box 149-4 ).[] Various drugs increase serotonin concentrations and serotoninergic neurotransmission ( Box 149-5 ). Serotonin syndrome can occur when (1) a serotoninergic agent is added to an established medication regimen, (2) the dose of a serotoninergic agent is increased, or (3) high but usually therapeutic doses of a serotoninergic agent are taken.[47] Sternbach[48] suggested diagnostic criteria for the serotonin syndrome ( Box 149-6 ); these also could include signs and symptoms of severe disease, such as muscle rigidity, clonus, hypertension, and tachycardia.[47] The Hunter criteria are diagnostic decision rules for diagnosis of serotonin toxicity ( Box 149-7 ).[49] BOX 149-4 Clinical Manifestations of Serotonin Toxicity

Neuromuscular

Page 3523

Agita tion Akat hisia Anxi ety Ataxi a Bilat eral Babi nski sign s Clon us Com a Conf usio n Deliri um Diap hore sis Dys arthri a Eup horia Hea dach e Hype rrefle xia Hype rther mia Hypo mani a Inso mnia Mani a Mydr iasis Myo clon us Nyst agm us Piloe

Page 3524

recti on Rha bdo myol ysis Rigid ity Seiz ures Shiv ering Tre mor

Cardiovascular Cuta neou s flush ing Hype rtens ion Hypo tensi on Sinu s tach ycar dia Vent ricul ar tach ycar dia (rare )

Gastrointestinal Abdo mina l cra mps Diarr hea Saliv ation BOX 149-5

Page 3525

Drugs Associated with Serotonin Toxicity Incr eas e Ser oto nin

Incr eas e Ser oto nin

Synt Rel hesi eas s e Amp heta min es

L-Tr ypto pha n[*] Dec reas e Ser oto nin Deg rada tion (Mo noa min e Oxi das e Inhi bito rs)

Coc aine Cod eine Dext rom etho rpha n Fenf lura min e Levo dop a Pent azo cine Res erpi ne Dec reas e Ser oto nin Reu ptak e Amp heta min es

Amp Car

Page 3526

Incr eas e Ser oto nin

Incr eas e Ser oto nin

heta min e met aboli tes[*] Clor gylin e[*]

bam aze pine

Cital opra m Cycl ic antid Ipro epre niazi ssa d[*] nts Isoc arbo xazi Coc d[*] aine Dext Mocl rom obe etho mid rpha e[*] n Parg Fluo yline xetin e [*] Phe Fluv nelzi oxa ne min e Sele Mep gilin eridi e ne Tran Meth ylcy ado pro ne min Paro e xetin e Sert ralin e Traz odo ne Venl afaxi ne Direct or

Page 3527

Incr eas e Ser oto nin

Incr eas e Ser oto nin

Indirect Serotoni n Receptor Agonists Bus piro ne Elec troc onvu lsive ther apy Lithi um LSD and othe r indol es[*] Mescaline and other phenylalky lamines[*] Sum atrip tan *

Not m ark eted in the Unite d State s.

BOX 149-6 Sternbach's Diagnostic Criteria for Serotonin Syndrome

1.

Adding a serotoninergic agent to a patient's established medication regimen or increasing the dose of a patient's serotoninergic

Page 3528

2.

3.

4.

agent. At least three of the following signs and symptoms: a. Agita tion b. Ataxi a c. Diap hore sis d. Diarr hea e. Hype rrefle xia f. Hype rther mia g. Ment al statu s chan ges (e.g., conf usio n, hypo mani a) h. Myo clon us i. Shiv ering j. Tre mor A neuroleptic has not been started or increased in dosage before the onset of the above signs and symptoms. Other etiologies have been ruled out, such as infections, intoxications, metabolic derangements, and withdrawal.

From Sternbach H: The serotonin syndrome. Am J Psychiatry 148:705, 1991. BOX 149-7

Page 3529

Hunter Serotonin Toxicity Criteria: Decision Rules In the presence of a serotonergic agent: 1.

2.

3.

IF (spo ntan eous clon us = yes) THE N serot onin toxici ty = YES ELS E IF (indu cible clon us = yes), AND [(agit ation ) OR (diap hore sis = yes)] THE N serot onin toxici ty = YES ELS E IF (ocul ar clon us = yes) AND [(agit ation = yes) OR (diap hore sis = yes)] THE N serot onin toxici

Page 3530

4.

5.

6.

ty = YES ELS E IF (tre mor = yes) AND (hyp errefl exia = yes) THE N serot onin toxici ty = YES ELS E IF (hyp erton ic = yes) AND (tem perat ure > 38° C) AND [(ocu lar clon us = yes) OR (indu cible clon us = yes)] then serot onin toxici ty = YES ELS E serot onin toxici ty = NO

From Dunkley EJC, et al: The Hunter serotonin toxicity criteria: Simple and accurate diagnostic decision rules serotonin toxicity. QJM 96:635, 2003.

Page 3531

Diagnostic Strategies A history of SSRI dosage increase, SSRI overdose, or SSRI use with an incompatible drug is the most helpful diagnostic indicator. Urine and blood toxicology tests for SSRIs are neither readily available nor clinically useful.

Differential Considerations The differential diagnosis of SSRI poisoning includes intoxications and pathologic conditions that cause sinus tachycardia, hypertension or hypotension, gastrointestinal upset, and seizures. In addition to these signs and symptoms secondary to SSRI overdose, SSRIs can produce serotonin syndrome (see Boxes 149-6 and 149-7 ). CNS and other infections, intoxications (e.g., methamphetamine, cocaine, other sympathomimetics), metabolic derangements (e.g., thyroid storm), sedative-hypnotic withdrawal, and strychnine poisoning should be considered in the differential diagnosis of serotonin syndrome. Clinically, serotonin syndrome can be difficult to distinguish from neuroleptic malignant syndrome. A history of precipitating medication use (SSRI versus neuroleptic), more rapid onset of symptoms, and presence of clonus helps differentiate serotonin syndrome from neuroleptic malignant syndrome ( Table 149-5 ). Table 149-5 -- Comparison of Serotonin Toxicity and Neuroleptic Malignant Syndrome Factor

Serotonin Toxicity

Neuroleptic Malignant Syndrome

Dopamine antagonists

No

Yes

Serotonin agonists

Yes

No

Onset of symptoms

Within minutes to hours

Usually over days to weeks, may occur immediately

Hyperthermia, altered level of consciousness, autonomic dysfunction, muscle rigidity

Present in varying degrees

Almost universal for each sign

Leukocytosis, metabolic acidosis

Unusual

Very common

Elevated creatine kinase

Present in varying degrees

Very common

Hyperreflexia, myoclonus

Present in varying degrees

Unusual

Treatment

Benzodiazepines, cyproheptadine Bromocriptine

Resolution of symptoms

Resolution of symptoms begins but not complete in < 24 hours; usually 24–48 hours to complete

Usually over days to weeks

Management Activated charcoal may be considered, but is of no proven benefit and should not be used if there is risk of aspiration. Hemodialysis and hemoperfusion are not indicated because SSRIs have large volumes of distribution and are highly bound to plasma proteins.[31] Forced diuresis is not indicated because minimal amounts of SSRIs and their active metabolites are eliminated in the urine. Cardiovascular complications of serotonin toxicity include hypertension, sinus tachycardia, hypotension, and, rarely, ventricular dysrhythmias (see Box 149-4 ).[47] Hypertension and tachycardia are usually mild and transient and require no treatment.[3] Hypotension is treated with intravascular volume repletion with isotonic crystalloids. Vasopressors are rarely necessary. Ventricular dysrhythmias should be treated with standard antidysrhythmic agents (e.g., lidocaine) ( Table 149-6 ).[3] QRS prolongation in the setting of flu-oxetine toxicity narrowed with intravenous NaHCO3 treatment.[37] Table 149-6 -- Treatment of Cardiovascular Coplica-tions of Selective Serotonin Reuptake Inhibitor Overdose and Serotonin Toxicity Complication Treatment Hypertension

Not usually indicated

Page 3532

Complication

Hypotension Sinus tachycardia Ventricular tachycardia

Bradydysrhythmias (rare)

Treatment Sodium nitroprusside if clinical signs of hypertensive emergency Intravenous isotonic crystalloid, then norepinephrine or dopamine Not usually indicated ACLS algorithm for ventricular tachycardia (lidocaine, synchronized cardioversion) IV NaHCO3 if symptomatic with wide QRS complex ACLS algorithm for bradycardia

ACLS, advanced cardiac life support; IV NaHCO3, intravenous sodium bicarbonate.

Neurologic complications of SSRI overdose and serotonin syndrome are treated similarly to neurologic complications of CAs (see Table 149-2 ). The mainstay of therapy is benzodiazepines. Cyproheptadine, methysergide, chlorpromazine, and propranolol have been proposed as therapies, but have inconsistent instead of multiple effects. They have been used in isolated case reports of serotonin syndrome; however, none of these should be considered a proven therapy or diagnostic modality.[] Consultation with a medical toxicologist or regional poison center may be advisable before initiating therapy with these agents. Cyproheptadine is available as a convenient liquid that can be given through a nasogastric tube, beginning with an adult dose of 4 to 8 mg followed by 4-mg doses every 1 to 4 hours as needed to a maximum of 32 mg/day. For children, 0.25 mg/kg/day is given in divided doses every 6 hours to a maximum of 12 to 16 mg/day depending on the child's age and weight. For children 2 to 6 years old, 2-mg doses can be given to a maximum of 12 mg/day based on the child's weight. For children 7 to 14 years old, 4-mg doses can be given to a maximum of 16 mg/day. Complications are rare, but cyproheptadine should be avoided in anticholinergic overdoses. Methysergide is not available as a liquid preparation.

Disposition Patients with known or suspected SSRI overdose should have a 6-hour observation period with cardiac monitoring. Asymptomatic patients who have not overdosed on citalopram may receive psychiatric evaluation and disposition. ECG abnormalities and seizures have been reported later in the course of citalopram overdoses. These overdoses warrant a longer observation period of up to 12 hours.[43] Patients with known or suspected serotonin syndrome should be admitted to a monitored inpatient unit for 24 hours of observation. The clinical course and treatment of serotonin syndrome is less defined than that of SSRI overdose. Serotonin syndrome can be fatal and may require ICU admission for potential complications (e.g., ventricular tachycardia, hypotension, coma, hyperthermia, rhabdomyolysis).

MISCELLANEOUS ANTIDEPRESSANTS Bupropion (Wellbutrin, Zyban), trazodone (Desyrel), venlafaxine (Effexor), and mirtazapine (Remeron) are the four antidepressants approved by the U.S. Food and Drug Administration that constitute the miscellaneous category. Serzone was withdrawn because of liver toxicity. The structures and mechanisms of action of the miscellaneous antidepressants are unique and unrelated to the CAs, SSRIs, and MAOIs.

Bupropion Bupropion is available in immediate-release, sustained-release, and newer extended-release formulations. A sustained-release formulation of bupropion is approved for use in smoking cessation. Bupropion is well absorbed from the gastrointestinal tract, reaches peak concentrations in 2 hours for immediate-release formulations, and has a maximal serum concentration of metabolites at 3 to 4 hours. The sustained-release peak concentration occurs at 3 hours for the parent compound and at 5 to 6 hours for the metabolites. The extended-release parent compound peak concentration occurs at 5 hours and at 7 to 8 hours for the metabolites. Bupropion is highly lipophilic, is extensively bound to plasma proteins, has a large volume of distribution (20 to 30 L/kg), and is metabolized predominantly by the liver. It has a half-life of 10 to 21 hours. Bupropion has three metabolites; two are active and clinically significant, with half-lives longer than 20 hours. Bupropion inhibits dopamine reuptake and enhances dopaminergic neurotransmission. To a lesser extent,

Page 3533

bupropion also enhances noradrenergic neurotransmission by inhibition of norepinephrine reuptake.[2]

Clinical Features Bupropion's most significant toxic effect is seizure activity, which occurs not only with overdose, but also when the maximal daily dose is exceeded.[51] At the recommended daily dose of 450 mg of immediate-release bupropion, the seizure incidence is 0.4%.[52] Incidence increases to 4% with dosages of 450 to 600 mg/day.[1] The incidence of seizure with the sustained-release formulation is 0.1%. Seizures cannot be predicted from ECG or cardiac monitoring, and there is no correlation between seizures and the presence of other symptoms.[53] Patients who overdose on bupropion alone do not usually develop hypotension or coma, but concomitant overdose with benzodiazepines can lead to coma or respiratory failure. The rare deaths associated with bupropion overdose usually involve coingestants.[54] Deaths due to bupropion alone have been reported, however.[55] Tachycardia, vomiting, agitation, lethargy, tremor, confusion, and drowsiness are the most common symptoms in adults and teenagers; vomiting is the most common symptom in children ( Table 149-7 ).[55] Seizures are usually single and self-limited, but about 5% of patients develop status epilepticus.[ 55] Delayed onset of seizures has been recorded, including one case with seizure onset 32 hours after ingestion of a sustained-release product.[56] Another case of a delayed seizure occurred at 19 hours after an overdose of Zyban, a sustained-release bupropion formulation.[57] These seizures were thought to be caused by the slow-release nature of the parent product and accumulation of its active metabolites.[57] Cardiovascular complications, including hypotension, bradycardia, intraventricular conduction delays, asystole, and death, have been reported.[56] A pharmacobezoar was noted in one fatal sustained-release bupropion overdose.[56] Table 149-7 -- Clinical Manifestations of Bupropion Overdose Neuromuscular % Cardiovascular % Gastrointestina System System l System Manifestations Manifestations Manifestations

%

Lethargy

41 Sinus 43 Emesis 14 tachycardia Tremors 24 Other 0 dysrhythmias Seizures 21 Hypertension 0 Confusion 14 Hypotension 0 Lightheadedness 10 Conduction 0 delays (e.g., wide QRS) Hallucinations 9 Coma 0 Modified from Spiller HA, et al: Bupropion overdose: A three year multi-center retrospective analysis. Am J Emerg Med 12:43, 1994.

Management Bupropion-induced seizures should be treated with an intravenous benzodiazepine (e.g., lorazepam, diazepam). Patients who have recurrent seizures or status epilepticus should be loaded with phenobarbital. Phenytoin is not indicated. ECG conduction delays (e.g., QRS/Q-Tc prolongation) have resolved without specific treatment.[53] Activated charcoal has no proven clinical efficacy and is not indicated in an isolated bupropion ingestion, considering the often benign course and the risk of aspiration during a seizure. Forced diuresis, hemodialysis, and hemoperfusion have no role for enhanced elimination. Patients with an immediate-release bupropion overdose require 8 hours of observation because seizures have occurred 8 hours after this overdose in the absence of other signs and symptoms.[51] With a sustained-release preparation, observation should be at least 12 hours. Because of limited data about overdose with the extended-release formula, a 24-hour observation period seems reasonable. All of these observation periods

Page 3534

should be extended if patients are otherwise symptomatic or experience a seizure during the observation period because of the risk of subsequent seizures.

Trazodone Trazodone is well absorbed from the gastrointestinal tract, reaches peak concentration in 1 to 2 hours, is extensively bound to plasma proteins, and is metabolized predominantly by the liver. The half-life of trazodone is about 6 hours.[] The major action of trazodone is inhibition of reuptake of serotonin, but it is not an SSRI.[2] It does not have antimuscarinic or antihistaminic effects.[] Other pharmacodynamic effects include p 1-adrenoreceptor blockade, inhibition of norepinephrine reuptake, and postsynaptic serotonin2 -receptor blockade.[2] Hypotension in trazodone overdose is caused by p 1-adrenoreceptor blockade.[58] Trazo-done overdoses are less toxic than CA and MAOI overdoses.[]

Clinical Features Clinical presentation of trazodone overdose is similar to SSRI overdose.[58] Cardiac toxicity has been reported with trazodone, but is rare. Trazodone also has been implicated in serotonin syndrome.[] The most common manifestations of trazodone overdose are orthostatic hypotension with lightheadedness, drowsiness, lethargy, ataxia, nausea, and vomiting.[58] There are isolated reports of priapism, respiratory arrest, prolonged Q-Tc, ventricular dysrhythmias including torsades de pointes, bradycardia, hypotension, seizures, coma, and death. When trazodone overdose occurs with coingestants, morbidity and mortality are increased.[]

Management Hypotension responds to boluses of intravenous crystalloids and usually does not require vasopressors.[58] Rare ventricular dysrhythmias with trazodone overdose should be treated with standard advanced cardiac life support therapy. Neurologic complications of trazodone poisoning are treated similarly to neurologic complications of CAs (see Table 149-2 ). There is no proven efficacy of activated charcoal, and this is usually a more benign ingestion. Based on the pharmacokinetic data, forced diuresis, hemodialysis, and hemoperfusion have no role. After 6 hours of observation, asymptomatic overdose patients can receive psychiatric evaluation and disposition.

Venlafaxine Venlafaxine is well absorbed from the gastrointestinal tract, reaches peak concentrations in 2 hours, has a large volume of distribution (about 7.5 L/kg), and undergoes extensive hepatic metabolism to form the active metabolite O-desmethylvenlafaxine (ODV). The half-life of venlafaxine is about 5 hours, and the half-life of ODV is about 11 hours.[1] The extended-release preparation, Effexor XR, reaches a peak concentration 6 to 7 hours after therapeutic dosing.[56] Venlafaxine and ODV inhibit reuptake of serotonin to a greater extent than norepinephrine and dopamine.[] There is a dose-dependent blockade of sodium channels.[56]

Clinical Features Most venlafaxine overdose patients are asymptomatic. Somnolence and sinus tachycardia are the most common symptoms.[56] Seizures and prolonged Q-Tc are rarer.[56] Neuromuscular signs and symptoms were most common in one study, but patients recovered without permanent sequelae ( Table 149-8 ).[61] Table 149-8 -- Clinical Manifestations of Venlafaxine Overdose Clinical Manifestations Drowsiness Tremor Seizures Responsive only to pain Unresponsive Lightheadedness Nervousness Headache From Setzer SC, et al: Acute venlafaxine overdose: A multicenter study. J Toxicol Clin Toxicol 33:496, 1995.

% 39 5 5 4 3 3 1 1

Page 3535

Seizures, life-threatening hypotension, QRS and Q-Tc prolongation, and death from venlafaxine overdose have been reported, but occur more often in combination with coingestants.[] Venlafaxine may not be as safe in overdose, however, as other serotoninergic drugs.[] Massive venlafaxine overdose has resulted in arrhythmogenic death.[63] Serotonin syndrome has occurred when venlafaxine was used with MAOIs.[]

Management Standard supportive care is the foundation of venlafaxine overdose treatment. There is no antidote. Cyproheptadine has been used in serotonin syndrome associated with venlafaxine. The rare instances of hypotension are treated successfully with intravenous fluids, dopamine, and norepinephrine.[62] Benzodiazepines have been effective for venlafaxine-associated seizures. Forced diuresis, hemodialysis, and hemoperfusion have no role. After 6 hours of observation, asymptomatic overdose patients can receive psychiatric evaluation and disposition.

Mirtazapine Mirtazapine is well absorbed from the gastrointestinal tract, reaches peak concentrations within 2 hours after therapeutic doses, and is highly protein bound. It is extensively metabolized in the liver to one active and two inactive metabolites. The elimination half-life of mirtazapine is 20 to 40 hours; the half-life for the active demethylated metabolite, normirtazapine, is about 19 hours.[] Mirtazapine blocks presynaptic p 2-adrenergic receptors, increasing release of 5-HT and norepinephrine.[] Mirtazapine blocks 5-HT2 and 5-HT3 receptors with high potency but has little effect on 5-HT1 receptors; this results in fewer gastrointestinal effects compared with SSRIs.[] To a lesser extent, mirtazapine antagonizes H1 (histaminic), muscarinic, and peripheral p 1-adrenergic receptors; this can cause sedation, tachycardia, and hypotension.[2] Mirtazapine has fewer anticholinergic, antihistaminic, and antiadrenergic effects than CAs.

Clinical Features In the few cases reported, somnolence, dizziness, anxiety, confusion, moderate hypotension, slight increase in systolic blood pressure, and mild tachycardia have occurred and resolved without specific treatment. No seizures or significant ECG changes have been reported in isolated mirtazapine overdoses, and all reported patients have recovered fully.[] Sedation, tachycardia and cognitive disorganization have been observed, but without permanent sequelae.[36]

Management Hypotension may require intravenous fluids. A 6-hour observation period is reasonable.

MONOAMINE OXIDASE INHIBITORS Many drugs inhibit monoamine oxidases (MAOs).[1] Five drugs with significant MAO inhibition are marketed in the United States: the antidepressants phenelzine and tranylcypromine, the antiparkinsonian agent selegiline, the antimicrobial furazolidone, and the antineoplastic procarbazine ( Box 149-8 ).[1] MAOIs are well absorbed from the gastrointestinal tract, reach peak concentrations in 0.5 to 2.5 hours, are extensively bound to plasma proteins, and have relatively large volumes of distribution.[69] Tranylcypromine and selegiline have active metabolites that include significant amounts of amphetamine and methamphetamine.[ 70] Minimal amounts of MAOIs are eliminated in the urine as unchanged drugs. BOX 149-8 FDA-Approved and Other Monoamine Oxidase Inhibitors (MAOIs) FDA, Food and Drug Administration; MAOI, monoamine oxidase inhibitor.

MAOI Antidepressants Phe nelzi ne (Nar

Page 3536

dil) Tran ylcyp romi ne (Par nate)

Antimicrobial Fura zolid one (Fur oxon e)

Antiparkinsonian Sele giline (Eld epryl )

Antineoplastic Proc arba zine (Mat ulan e)

Not Marketed in United States Brof aro mine Cim oxat one Clor gylin e Ipron iazid Isoc arbo xazi d Meb

Page 3537

anaz ine Mocl obe mide Niala mide Parg yline Safr azin e The MAO isoenzymes, MAO-A and MAO-B, inactivate direct-acting, endogenous, biogenic amines, such as epinephrine, norepinephrine, and serotonin. The MAO isoenzymes also inactivate indirect-acting exogenous biogenic amines, such as tyramine.[] Effects of MAOIs include (1) inhibition of MAO; (2) MAOI effect on indirect sympathomimetics, such as amphetamine and methamphetamine, with the potential for enhanced CNS and peripheral nervous system sympathomimetic toxicity; (3) eventual depletion of nor-epinephrine stores; and (4) inhibition of pyridoxine phosphokinase and pyridoxine (vitamin B6)-containing enzymes ( Box 149-9 ).[] BOX 149-9 Monoamine Oxidase Inhibitors Grouped by Inhibitory Activity MAO-A, monoamine oxidase type A; MAO-B, monoamine oxidase type B.

Irreversible Nonselective Inhibitors of MAO-A and MAO-B Fura zolid one Ipron iazid Isoc arbo xazi d Meb anaz ine Niala mide Phe nelzi ne Proc arba zine Safr azin e Tran ylcyp romi ne

Relatively Selective MAO-A Inhibitors

Page 3538

Reversible Brof aro mine Cim oxat one Mocl obe mide

Irreversible Clor gylin e

Relatively Selective MAO-B Inhibitors

Reversible Non e

Irreversible Parg yline Sele giline

Clinical Features The three presentations of MAOI toxicity are (1) MAOI overdose, (2) MAOI-food or MAOI-beverage interactions, and (3) MAOI-drug interactions.[69] These three presentations are differentiated by precipitating events, time to onset of symptoms, duration of symptoms, and major sign and symptom complexes ( Table 149-9 ). All three presentations involve excessive sympathetic activity. The most common cardiovascular complications of interactions between foods, beverages, or drugs and MAOIs are hypertension and tachycardia. Reflex bradycardia can occur with severe hypertension. Table 149-9 -- Three Major Types of Monoamine Oxidase Inhibitor Toxicity Toxicity Onset Duration Major Symptom Complexes MAOI overdose

Delayed for hours

Days

MAOI-food or MAOI-beverage interaction MAOI-drug interaction

Minutes to hours

Hours

Minutes to hours

Hours to days

CNS sympathomimetic storms CNS and PNS sympathomimetic storms CNS and PNS sympathomimetic storms; serotonin syndrome

Page 3539

Toxicity

Onset

Duration

Major Symptom Complexes

MAOI, monoamine oxidase inhibitor; CNS, central nervous system; PNS, peripheral nervous system.

Overdose The clinical course of severe MAOI overdose occurs in four phases: (1) asymptomatic or latent, (2) neuromuscular and cardiovascular excitation with sympathetic hyperactivity, (3) CNS depression and cardiovascular collapse with hypotension and bradycardia late in severe overdoses, and (4) secondary complications caused by previous phases.[69] Onset of signs and symptoms after acute overdose usually occurs in 6 to 12 hours, but may be delayed 24 hours. Symptoms in acute MAOI overdose last for days ( Table 149-10 ). Table 149-10 -- Clinical Manifestations of Acute Monoamine Oxidase Inhibitor Overdose Neuromuscular System % Cardiovascular System Manifestations Manifestations

%

Agitation 67 Sinus tachycardia 67 Mydriasis 58 Hypertension 17 Rigidity 58 Hypotension 17 Hyperthermia 50 Coma 50 Hyperreflexia 33 Nystagmus 33 Writhing 25 Seizures 17 Hallucinations 8 Papilledema 8 From Meredith TJ, Vale JA: Poisoning due to psychotropic agents. Adverse Drug React Acute Poisoning Rev 4:83, 1985.

Seizures, coma, and muscular rigidity impair patients' abilities to keep airways patent, decrease ventilatory drive, and can produce rigid chest walls. Seizures, agitated delirium, myoclonus, muscular rigidity, and hyperthermia can result in rhabdomyolysis.[69] An overdose of 2 mg/kg (170 mg in an adult) can be lethal. Occasionally, hypotension, bradycardia, and asystole have been reported late in severe poisonings.[69] Initial release of norepinephrine can result in a decrease in the amount available for subsequent discharge from presynaptic vesicles. This situation may explain late CNS depression and cardiovascular collapse after earlier stimulatory phases of MAOI overdose.[69] Another potential cause of late bradycardic dysrhythmias is hyperkalemia from rhabdomyolysis. Long-term use of phenelzine has been associated with a sensorimotor peripheral neuropathy, probably from pyridoxine depletion.[]

Monoamine Oxidase Inhibitor-Food or Monoamine Oxidase Inhibitor-Beverage Interactions Onset of sympathetic signs and symptoms with MAOI-food or MAOI-beverage interactions occurs in minutes to hours because ingested tyramine acts on the adrenal medulla to release endogenous biogenic amines ( Box 149-10 ). These interactions last only a few hours because of tyramine's short duration of

Page 3540

action. BOX 149-10 Foods and Beverages Associated with Monoamine Oxidase Inhibitor Toxicity

Foods Aged , ferm ente d, pickl ed, smo ked, or tend erize d meat s and fish Aged chee ses Dec ayed or spoil ed food s Broa d bean s Fava bean s Bea n curd Sau erkra ut Yeas t and meat extra cts Ripe avoc ados Gins eng Cho colat e

Page 3541

Figs Raisi ns Ban anas Soy sauc e Miso soup

Undistilled Alcoholic Beverages Ales Beer s Win es Sher ry Ver mout h

Monoamine Oxidase Inhibitor-Drug Interactions Signs and symptoms of MAOI-drug interactions are sympathetic storm or the serotonin syndrome and begin minutes to hours after ingesting precipitating drugs (see Boxes 149-4 to 149-7 and Table 149-9 ). Most MAOI-drug interactions occur in patients who are taking MAOIs regularly on an ongoing basis and ingest incompatible drugs, such as indirect-acting and mixed-acting (direct/indirect-acting) sympathomimetics, methylxanthines, antidepressants, opioids (e.g., meperidine), and other drugs that can cause serotonin syndrome ( Box 149-11 ). These drugs produce excessive concentrations of endogenous biogenic amines that are not degraded because of MAO inhibition. Duration of MAOI-drug interactions is hours to days, depending on the precipitant's duration of effect, half-life, and formulation (e.g., sustained release, delayed release). BOX 149-11 Drugs That Interact with Monoamine Oxidase Inhibitors to Produce Toxicity

Sympathomimetics

Indirect Acting Amp heta mine s Bret yliu m Coc aine Fenfl ura mine Gua nethi dine

Page 3542

Keta mine Meth yldo pa Meth ylph enid ate Pem oline Phe ncyc lidine Phe nter mine Phe nylpr opan olam ine Pse udoe phed rine Res erpin e Rito drine Tyra mine

Indirect Acting Mixed (Direct/Indirect Acting) Dop amin e Eph edrin e Mep hent ermi ne Meta rami nol

Methylxanthines Amin ophy lline

Page 3543

Caff eine Oxtri phylli ne Theo phylli ne

Serotonin Toxicity See Box 1495

Differential Considerations A history of MAOI ingestion is the most helpful diagnostic indicator. Urine and blood toxicology tests for MAOI levels are not readily available and are of little clinical value. The differential diagnosis of MAOI poisoning includes illnesses (e.g., thyroid storm, meningitis) and sympathomimetic intoxications (e.g., cocaine, amphetamines, theophylline, nicotine). Hypertensive emergencies, malignant hyperthermia, and heatstroke also are considerations in the differential diagnosis. Effects of MAO inhibition persist for weeks after cessation of MAOIs because MAO enzyme activity must be regenerated by synthesis of new MAO isoenzymes. Significant potential for MAOI toxicity can persist long after the drug has left the body.

Management There is no antidote for MAOI toxicity, and forced diuresis, hemodialysis, and hemoperfusion are not effective.[69] Sinus tachycardia does not require treatment. p -Blockers can cause unopposed p 1 -adrenoreceptor stimulation of the peripheral vasculature with vasoconstriction and worsening of the hypertension. p -Blockers also can exacerbate the hypotension and bradycardia that can occur later in severe MAOI poisonings. Calcium channel blockers also are relatively contraindicated because of the potential for hypotension and bradycardia.[69] Hypertension associated with MAOI toxicity can range from mild to life-threatening hypertensive emergencies. Mild hypertension does not require treatment. Hypertension with signs of impending or ongoing target-organ damage or with reflex bradycardia mandates treatment with sodium nitroprusside or phentolamine; both have rapid onset, easy titratability, and rapid resolution of effect when stopped, if hypotension develops later. An initial 5-mg bolus (adults) or 0.02 mg/kg to 0.1 mg/kg (children) of phentolamine is given over 1 minute.[69] The initial intravenous bolus can be repeated at 5- to 10-minute intervals as needed to lower the blood pressure to the desired range, followed by a phentolamine infusion to maintain the pressure. The initial dose of nitroprusside is 0.3 p-g/kg/min, titrated to effect with a maximum rate of 10 p-g/kg/min. Sodium thiosulfate can be used with continuous infusions of nitroprusside to prevent cyanide toxicity. Reflex bradycardia is a beneficial compensatory response to significant, acute hypertension and decreases cardiac output; bradycardia should not be treated, unless it is associated with significant hypotension. Hypotension caused by MAOI toxicity usually occurs late in severe intoxications. If hypotension is associated with bradycardia, intravenous atropine should be administered until the bradycardia and hypotension resolve or a vagolytic dose of atropine has been reached (3 mg in adults or 0.04 mg/kg in children, with a minimum dose of 0.1 mg in children). Hypotension without bradycardia should be treated with intravenous isotonic crystalloids. A pacemaker is necessary for symptomatic bradycardia with accompanying hypotension that does not respond to atropine or agents such as epinephrine, dobutamine, or norepinephrine.[69] Initially a transcutaneous pacemaker can be used. Symptomatic, treatment-resistant bradycardia is often prolonged, however, and a transvenous pacemaker is optimal. Lidocaine is the drug of choice for ven-tricular dysrhythmias associated with MAOI toxicity. Bretylium is contraindicated in patients taking MAOIs and during acute MAOI toxicity because it releases endogenous biogenic amines. Neurologic complications of MAOI toxicity are treated similarly to neurologic complications of CA toxicity (see Table 149-2 ). Dantrolene, 2.5 mg/kg intravenously initially and repeated every 6 hours for 24 hours,

Page 3544

seemed to be useful in a phenelzine overdose accompanied by life-threatening hyperthermia.[74] Intravenous benzodiazepines may be used to control agitation.

Disposition The severity of acute MAOI overdoses is easily underestimated because signs and symptoms usually are not evident during the first 6 to 12 hours and may be delayed in onset for 24 hours. Patients with significant MAOI overdose or suspected serotonin syndrome should be observed for 24 hours. Symptomatic patients with known or suspected MAOI interactions with food, beverages, or drugs should be admitted to an ICU for at least 24 hours. Patients with suspected food or drug interactions can be discharged if they remain asymptomatic for 6 hours.

DISCONTINUATION SYNDROME Discontinuation syndromes with MAOIs, CAs, SSRIs, and various atypical antidepressants including venlafaxine and mirtazapine have been described.[75] A discontinuation syndrome has not yet been described for citalopram.[36] Symptoms depend on the agent and its mechanism of active action. With some SSRIs, insomnia, nausea, headache, sensory disturbances, hyperarousal, anxiety, agitation, tachycardia, and tremor have been reported.[75] Restarting the drug and instituting a gradual taper over days to weeks generally reverses the discontinuation syndrome. Augmenting a drug that has a short half-life with another that has a long half-life may help to overcome the discontinuation syndrome.[75] Confusion and psychotic symptoms caused by stopping MAOIs may require hospital admission, restarting the MAOI, or treating with an antipsychotic medication.[75] Atropine and benztropine can help treat CA discontinuation symptoms because these symptoms reflect cholinergic rebound.[75] A neonatal discontinuation syndrome, after in utero exposure to an SSRI in the third trimester of pregnancy, was described.[75] Symptoms included irritability, constant crying, shivering, increased tonus, eating and sleeping difficulties, and seizures.[76] Signs and symptoms began within a few days after birth and have lasted 1 month.[76]

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KEY CONCEPTS • • • • • • • • • • •

• •

A patient with CA poisoning can deteriorate quickly. When in doubt, it is better to perform endotracheal intubation to prevent aspiration, hypoxia, or hypercarbia that can increase significantly the morbidity and mortality of CA poisoning. NaHCO3 treats cardiac conduction abnormalities and negative inotropic effects of CA poisoning that result in ventricular dysrhythmias and hypotension with a wide QRS complex. The case-fatality rate for SSRI overdose is much lower than for CA overdose. If serotonin syndrome is suspected, the patient should be admitted to a monitored unit for 24 hours of observation. Medication lists should be scrutinized for serotonin-enhancing drugs, and medications such as meperidine should be avoided in patients with SSRI overdose. Although the case-fatality rate for overdoses with miscellaneous antidepressants is much lower than for CA overdoses, fatal poisoning can occur, even without coingestants. Bupropion poisoning should be considered when seizures occur. Trazodone toxicity should be considered in a patient with priapism. If MAOI overdose is suspected or diagnosed, admission for 24 hours of observation is indicated, even if the patient is initially asymptomatic. Differential considerations of MAOI toxicity include etiologies for hyperthermia, altered mental status, and muscular rigidity, such as meningitis, thyroid storm, neuroleptic malignant syndrome, malignant hyperthermia, and heatstroke. Hyperthermia must be treated aggressively to limit morbidity and mortality. The source of a food, beverage, or drug interaction with an MAOI should be identified to avoid recurrence and future complications.

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REFERENCES 1. Baldessarini RJ: Drugs and the treatment of psychiatric disorders: Depression and anxiety disorders. In: Hardman JG, ed.Goodman and Gilman's the Pharmacological Basis of Therapeutics, 10th ed. New York: McGraw-Hill; 2001: 2. Stahl SM: Basic pharmacology of antidepressants: Part 1. Antidepressants have seven distinct mechanisms of action. J Clin Psychiatry1998;59:5. 3. Borys DJ: Acute fluoxetine overdose: A report of 264 cases. Am J Emerg Med1992;10:115. 4. Stoner SC: Antidepressant overdoses and resultant emergency department services: The impact of SSRIs. Pharmacol Bull1997;33:667. 5. Phillips S: Fluoxetine vs. tricyclic antidepressants: A prospective multicenter study of antidepressant overdoses. J Emerg Med1997;15:439. 6. Tokarski GF, Young MJ: Criteria for admitting patients with tricyclic antidepressant overdose. J Emerg Med1988;6:121. 7. Banahan BF, Schelkun PH: Tricyclic antidepressant overdose: Conservative management in a community hospital with cost-saving implications. J Emerg Med1990;8:451. 8. Pentel PR, Benowitz NL: Tricyclic antidepressant poisoning: Management of arrhythmias. Med Toxicol 1986;1:101. 9. Heard K: Tricyclic antidepressants directly depress human myocardial mechanical function indeprendent of effects on the conduction system. Acad Emerg Med2001;8:1122. 10. Schwartz R, Esler M: Catecholamine levels in tricyclic antidepressant self-poisoning. Aust N Z J Med 1974;4:479. 11. Ellison DW, Pentel PR: Clinical features and consequences of seizures due to cyclic antidepressant overdose. Am J Emerg Med1989;7:5. 12. Shannon M, Merola J, Lovejoy FH: Hypotension in severe tricyclic antidepressant overdose. Am J Emerg Med1988;6:439. 13. Callaham M, Kassel D: Epidemiology of fatal tricyclic antidepressant ingestion: Implications for management. Ann Emerg Med1985;14:1. 14. Foulke G, Albertson T: QRS interval in tricyclic antidepressant overdosage: Inaccuracy as a toxicity indicator in emergency settings. Ann Emerg Med1987;16:160. 15. Emerman C, Connors A, Burma G: Level of consciousness as a predictor of complications following tricyclic overdose. Ann Emerg Med1987;16:326. 16. Goldgran-Toledano D, Sideris G, Kevorkian J: Overdose of cyclic antidepressants and the Brugada syndrome. N Engl J Med2002;346:1591. 17. Roy TM: Pulmonary complications after tricyclic antidepressant overdose. Chest1989;96:852. 18. Pentel P, Peterson CD: Asystole complicating physostigmine treatment of tricyclic antidepressant overdose. Ann Emerg Med1980;9:588. 19. Shannon M, Liebelt EL: Toxicology reviews: Targeted management strategies for cardiovascular toxicity from tricyclic antidepressant overdose: The pivotal role for alkalinization and sodium loading. Pediatr Emerg Care1998;14:293. 20. Bessen HA, Niemann JT: Improvement of cardiac conduction after hyperventilation in tricyclic antidepressant overdose. J Toxicol Clin Toxicol1986;23:537. 21. McKinney PE, Rasmussen R: Reversal of severe tricyclic antidepressant induced cardiotoxicity with intravenous hypertonic saline solution. Ann Emerg Med2003;42:20. 22. Wrenn K, Smith BA, Slovis CM: Profound alkalemia during treatment of tricyclic antidepressant overdose: A potential hazard of combined hyperventilation and intravenous bicarbonate. Am J Emerg Med 1992;10:553. 23. Vernon DD: Efficacy of dopamine and norepinephrine for treatment of hemodynamic compromise in amitriptyline intoxication. Crit Care Med1991;19:544. 24. Bain DJG, Turner T: Imipramine poisoning. Arch Dis Child1971;46:887. 25. Callaham M, Schumaker H, Pentel P: Phenytoin prophylaxis of cardiotoxicity in experimental amitriptyline poisoning. Pharmacol Exp Ther1988;245:216. 26. Olson KR: Seizures associated with poisoning and drug overdose. Am J Emerg Med1993;11:565.

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27. Kumar A, Black TS: Intravenous midazolam for the treatment of refractory status epilepticus. Crit Care Med1992;20:483. 28. Merigian KS, Browning RG, Leeper LV: Successful treatment of amoxapine induced refractory status epilepticus with propofol (Diprivan). Acad Emerg Med1995;2:128. 29. Mordel A: Seizures after flumazenil administration in a case of combined benzodiazepine and tricyclic antidepressant overdose. Crit Care Med1992;20:1733. 30. Geller E: Risks and benefits of therapy with flumazenil (Anexate) in mixed drug intoxications. Eur Neurol 1991;31:241. 31. Preskorn SH: Clinically relevant pharmacology of selective serotonin reuptake inhibitors: An overview with emphasis on pharmacokinetics and effects on oxidative drug metabolism. Clin Pharmacokinet 1997;32:1. 32. Briley M, Moret C: Neurobiological mechanisms involved in antidepressant therapies. Clin Neuropharmacol1993;16:387. 33. Whyte IM, Dawson AH, Buckley NA: Relative toxicity of venlafaxine and selective serotonin reuptake inhibitors in overdose. QJM2003;96:369. 34. Myers LB, Krenzelok EP: Paroxetine (Paxil) overdose: A pediatric focus. Vet Hum Toxicol1997;39:86. 35. Spiller HA, Morse S, Muir C: Fluoxetine ingestion: A one year retrospective study. Vet Hum Toxicol 1990;32:153. 36. Goldberg JF: New drugs in psychiatry. Emerg Med Clin North Am2000;18:211. 37. Graudins A, Vossler C, Wang R: Fluoxetine-induced cardiotoxicity with response to bicarbonate therapy. Am J Emerg Med1997;15:501. 38. Braitberg G, Curry S: Seizure after isolated fluoxetine overdose. Ann Emerg Med1995;26:234. 39. Hahn I: Fluvoxamine overdose producing status epilepticus [abstract]. J Toxicol Clin Toxicol2000;38:573. 40. Catalano G: QTc interval prolongation associated with citalopram overdose: A case report and literature review. Clin Neuropharmacol2001;24:158. 41. Personne M, Persson H, Sjöberg G: Citalopram toxicity. Lancet1997;350:518. 42. Grundemar L: Symptoms and signs of severe citalopram overdose. Lancet1997;349:1602. 43. Grover J, Caravati EM: Right bundle branch block and delayed seizure associated with citalopram and fluoxetine ingestion [abstract]. J Toxicol Clin Toxicol2001;39:491. 44. Lindgren KN: Escitalopram, a review of adverse effects in overdose reported to select regional poison centers. J Toxicol Clin Toxicol2003;41:658. 45. Buckley NA, McManus PR: Fatal toxicity of serotoninergic and other antidepressant drugs: Analysis of United Kingdom mortality data. BMJ2002;325:1332. 46. Lau GT, Horowitz Z: Sertraline overdose. Acad Emerg Med1996;3:132. 47. Mills KC: Serotonin syndrome: A clinical update. Crit Care Clin1997;13:763. 48. Sternbach H: The serotonin syndrome. Am J Psychiatry1991;148:705. 49. Dunkley EJC: The Hunter serotonin toxicity criteria: Simple and accurate diagnostic decision rules for serotonin toxicity. QJM2003;96:635. 50. Bodner RA: Serotonin syndrome. Neurology1995;45:219. 51. Spiller HA: Bupropion overdose: A three-year multi-center retrospective analysis. Am J Emerg Med 1994;12:43. 52. Dunner DL: A prospective safety surveillance study for bupropion sustained-release in the treatment of depression. J Clin Psychiatry1998;59:366. 53. Paris PA, Saucier JR: ECG conduction delays associated with massive bupropion overdose. J Toxicol Clin Toxicol1998;36:595. 54. Harris CR, Gualtieri J, Stark G: Fatal bupropion overdose. J Toxicol Clin Toxicol1997;35:321. 55. Belson MG, Kelley TR: Bupropion exposures: Clinical manifestations and medical outcome. J Emerg Med2002;23:223. 56. Buckley NA, Faunce TA: “Atypical” antidepressants in overdose: Clinical considerations with respect to safety. Drug Saf2003;26:539. 57. Falkland M: Bupropion SR in overdose: Subsidized poisoning. J Toxicol Clin Toxicol2002;40:275. 58. Gamble DE, Peterson LG: Trazodone overdose: Four years of experience from voluntary reports. J Clin Psychiatry1986;47:544. 59. Goeringer KE, Raymon L, Logan BK: Postmortem forensic toxicology of trazodone. J Forensic Sci 2000;45:850. 60. Patat A: Absolute bioavailability and electroencephalographic effects of conventional and extended-release formulations of venlafaxine in healthy subjects. J Clin Pharmacol1998;38:256. 61. Setzer SC: Acute venlafaxine overdose: A multicenter study. J Toxicol Clin Toxicol1995;33:496. 62. Kokan L, Dart RC: Life-threatening hypotension from venlafaxine overdose. J Toxicol Clin Toxicol 1996;34:559. 63. Cumpston K, Chao M, Pallasch E: Massive venlafaxine overdose resulting in arrhythmogenic death. J Toxicol Clin Toxicol2003;41:659. 64. Daniels RJ: Serotonin syndrome due to venlafaxine overdose. Hum Exp Toxicol1997;16:14.

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65. Caccia S: Metabolism of the newer antidepressants: An overview of the pharmacological and pharmacokinetic implications. Clin Pharmacokinet1998;34:281. 66. De Boer T: The pharmacologic profile of mirtazapine. J Clin Psychiatry1996;57:19. 67. Holzbach R: Suicide attempts with mirtazapine overdose without complications. Biol Psychiatry 1998;44:925. 68. Bremner JD, Wingard P, Walshe TA: Safety of mirtazapine in overdose. J Clin Psychiatry1998;59:233. 69. Linden CH, Rumack BH, Strehlke C: Monoamine oxidase inhibitor overdose. Ann Emerg Med 1984;13:1137. 70. Youdim MBH: Tranylcypromine (Parnate) overdose: Measurement of tranylcypromine concentrations and MAO inhibitory activity and identification of amphetamines in plasma. Psychol Med1979;9:377. 71. McDaniel KD: Clinical pharmacology of monoamine oxidase inhibitors. Clin Neuropharmacol1986;9:207. 72. Goodheart RS, Dunne JW, Edis RH: Phenelzine associated peripheral neuropathy: Clinical and electrophysiologic findings. Aust N Z J Med1991;21:339. 73. Heller CA, Friedman PA: Pyridoxine deficiency and peripheral neuropathy associated with long-term phenelzine therapy. Am J Med1983;75:887. 74. Kaplan RF: Phenelzine overdose treated with dantrolene sodium. JAMA1986;255:642. 75. Haddad PM: Antidepressant discontiunuation syndromes, clinical relevance, prevention and management. Drug Saf2001;24:183. 76. Nordeng H: Neonatal withdrawal syndrome after in utero exposure to selective serotonin reuptake inhibitors. Acta Paediatr2001;90:288.

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Chapter 150 – Cardiovascular Drugs David J. Roberts Cardiovascular drugs rank among the most common causes of poisoning fatalities, both in children (third leading cause) and in adults (fifth leading cause). Of the scores of cardiovascular drugs, three—digitalis, propranolol, and verapamil—account for the majority of fatalities.

DIGITALIS Perspective Digitalis is derived from the foxglove plant ( Figure 150-1 ). Despite centuries of experience with digitalis, chronic and acute poisonings remain common. Dr. Benjamin Rush wrote in 1797, ‘I suspect the cases in which [digitalis preparations] were useful to have been either so few or doubtful and that the cases they had done harm were so much more numerous and unequivocal as justly to banish them from the Materia Medica.’[1] Medication errors and toxic effects account for the most common causes (44%) of preventable iatrogenic cardiac arrests.[2] Digoxin is the most common offending drug, and although its use is now generally limited to treatment of congestive heart failure and atrial fibrillation, digitalis remains a commonly prescribed drug in the United States.

Figure 149-1 The foxglove plant, from which digitalis is derived.

Principles of Disease Pathophysiology In therapeutic doses, digitalis has two effects: (1) increasing the force of myocardial contraction to increase cardiac output in patients with heart failure; and (2) decreasing atrioventricular (AV) conduction to slow the ventricular rate in atrial fibrillation. The biochemical basis for its first effect is an inhibition of membrane sodium-potassium adenosine triphosphatase (ATPase), which increases intracellular sodium and calcium and increases extracellular potassium. At therapeutic doses, the effects on serum electrolyte levels are minimal. With toxic levels, digitalis paralyzes the Na-K pump, potassium cannot be transported into cells, and serum potassium can rise as high as 13.5 mEq/L.[3] Because intracellular levels of calcium are already high, administering calcium, a common treatment for hyperkalemia, can be dangerous in the digitalis-intoxicated patient. Digitalis exerts direct and indirect effects on sinoatrial (SA) and AV nodal fibers. At therapeutic levels, digitalis indirectly increases vagal activity and decreases sympathetic activity. At toxic levels, digitalis can directly halt the generation of impulses in the SA node, depress conduction through the AV node, and increase sensitivity of the SA and AV nodes to catecholamines. Catecholamines, whether endogenous or administered by physicians to treat bradydysrhythmias or hypotension, probably play an important role in digitalis toxicity. It is unclear how much iatrogenic interventions may contribute to digitalis toxicity. Because bradydysrhythmias and tachydysrhythmias can appear and alternate in the same patient, administering one class of drugs to treat tachycardias may later contribute to more refractory bradycardias and AV block.

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Digitalis also exerts three primary effects on Purkinje's fibers: (1) decreased resting potential, resulting in slowed phase 0 depolarization and conduction velocity; (2) decreased action potential duration, which increases sensitivity of muscle fibers to electrical stimuli; and (3) enhanced automaticity resulting from increased rate of phase 4 repolarization and delayed after depolarizations. These mechanisms account for the most common manifestation of digitalis toxicity, an increase in premature ventricular contractions. At toxic extremes, these effects result in a dangerous sensitivity to mechanical and electrical stimulation. Iatrogenic interventions with pacemaker catheters and cardioversion can result in asystole, ventricular tachycardia, and ventricular fibrillation.[4] Unlike most cardiovascular drugs, digitalis can produce virtually any dysrhythmia or conduction block, and bradycardias are as common as tachycardias ( Box 150-1 ). Unfortunately, none is peculiar to digitalis, and they can all occur in the setting of ischemic and other heart disease in the absence of digitalis. Digitalis intoxication remains a clinical rather than an electrocardiographic diagnosis. BOX 150-1 Dysrhythmias Associated with Digitalis Toxicity AV, atrioventricular; PVC, premature ventricular contraction.

Nonspecific PVCs, especially bigeminal and multiform First-, second- (Wenckebach), and third-degree AV block Sinus bradycardia Sinus tachycardia Sinoatrial block or arrest Atrial fibrillation with slow ventricular response Atrial tachycardia Junctional (escape) rhythm AV dissociation Ventricular bigeminy and trigeminy Ventricular tachycardia Torsades de pointes Ventricular fibrillation

More Specific, but not Pathognomonic Atrial fibrillation with slow, regular ventricular rate (AV dissociation) Nonparoxysmal junctional tachycardia (rate 70 to 130 beats/min) Atrial tachycardia with block (atrial rate usually 150 to 200 beats/min) Bidirectional ventricular tachycardia The volume of distribution (Vd), or apparent body volume into which digoxin distributes, is 5 L/kg for adults but varies from 3.5 L/kg in premature infants to 16.3 L/kg in older infants.[5] This indicates that only a small fraction of digitalis remains in the intravascular space, and the drug is highly concentrated in cardiac tissue. The myocardial-to-serum ratio at equilibrium ranges from 15:1 to 30:1.[6] The Vd for digitoxin is 0.5 L/kg. The elimination half-life of digoxin, which is primarily excreted in the urine, is 30 hours, and the half-life of digitoxin, which is metabolized in the liver, is 7 days.[6] Whereas digoxin undergoes only a small enterohepatic circulation, that for digitoxin is large, and multiple-dose charcoal treatment is clearly indicated for the latter. Protein binding varies from 25% for digoxin to 95% for digitoxin.[6] Both significant protein binding and a large volume of distribution suggest that hemodialysis, hemoperfusion, and exchange transfusion are ineffective. The long half-lives suggest that temporizing measures such as pacemakers, atropine, and antidysrhythmic

Page 3551

drugs might in the end cost more time, money, and lives than simply giving Fab fragments initially. Multiple drugs and disease states can negatively alter absorption, volume of distribution, protein binding, and elimination and render the heart more susceptible to digitalis toxicity. The factors listed in Box 150-2 are especially important in evaluating suspected cases of chronic intoxication. BOX 150-2 Factors Associated with Increased Risk of Digitalis Toxicity

Renal insufficiency Heart disease Con genit al heart dise ase Isch emic heart dise ase Con gesti ve heart failur e Myo cardi tis Electrolyte imbalance Hypo kale mia or hype rkale mia Hypo mag nese mia Hype rcalc emia Alkalosis Hypothyroidism Sympathomimeti c drugs Cardiotoxic coingestants p Bloc kers

Page 3552

Calci um chan nel bloc kers Tricy clic antid epre ssan ts Drug interactions Quin idine , amio daro ne Eryt hro myci n Vera pami l, diltia zem, nifed ipine Capt opril Elderly woman

Clinical Features The symptoms and signs of digitalis intoxication are nonspecific. The most common symptoms—reported in more than 80% of cases—are nausea, anorexia, fatigue, and visual disturbance, but a variety of gastrointestinal, neurologic, and ophthalmic disturbances have been linked to digitalis ( Box 150-3 ). One should consider digitalis intoxication in any patient on maintenance therapy who develops consistent symptoms, especially with new conduction disturbances or dysrhythmias. BOX 150-3 Noncardiac Symptoms of Digitalis Intoxication in Adults and Children

General Wea knes s Fatig ue Malai se

Gastrointestinal

Page 3553

Nau sea and vomi ting Anor exia Abdo mina l pain Diarr hea

Ophthalmologic Blurr ed or sno wy visio n Phot opho bia Yello w-gr een chro mato psia (also red, brow n, blue) Tran sient ambl yopi a, diplo pia, scot omat a, blind ness

Neurologic Dizzi ness Hea dach e

Page 3554

Conf usio n, disor ienta tion, deliri um Visu al and audit ory hallu cinat ions Para noid ideat ion, acut e psyc hosi s Som nole nce Abno rmal drea ms Pare sthe sias and neur algia Apha sia Seiz ures Significant differences exist between acute and chronic intoxication ( Table 150-1 ). Chronic poisoning has an insidious onset and is accompanied by a higher mortality rate. In cases of chronic intoxication, the LL50 (the level with a 50% mortality) is only 6 ng/mL.[7] The LL50 for acute intoxication is not known, but it is certainly much higher, especially in children. Chronically intoxicated patients almost always have underlying heart disease, which contributes to both morbidity and mortality. Table 150-1 -- Chronic Versus Acute Digitalis Intoxication Chronic

Acute

Higher mortality (LL50 = 6 ng/mL)

Lower mortality

Potassium level normal or low Ventricular dysrhythmias more common Usually elderly patients Often need Fab fragment therapy Underlying heart disease increases morbidity and mortality

Potassium level normal or high Bradycardia and atrioventricular block more common Usually younger patients Often do well without Fab (caution: many exceptions) Absence of heart disease decreases morbidity and mortality

Page 3555

Chronic

Acute

Diagnostic Strategies It is the steady state, rather than peak level, that correlates with tissue toxicity and is used to calculate antidote dosages. Peak levels after an oral dose of digoxin occur in 1.5 to 2 hours, with a range of 0.5 to 6 hours.[] Steady-state serum concentrations are not achieved until after distribution, or 6 to 8 hours after a dose or overdose, and may be only one fourth to one fifth of the peak level. Serum steady-state digoxin levels of 1.6 to 3.0 ng/mL are equivocal; that is, levels as low as 1.6 ng/mL have been associated with toxicity, and patients with levels up to 3.0 ng/mL can be asymptomatic.[9] A level drawn too soon after the last maintenance dose will falsely suggest toxicity, especially in cases of chronic intoxication, in which significant morbidity and mortality can occur at levels of 2 to 6 ng/mL.[7] After an acute massive overdose in a patient who is rapidly becoming symptomatic, however, it may be impractical to wait 6 to 8 hours for the first reading.[] It is unlikely that early levels exceeding 10 to 20 ng/mL will fade to clinical insignificance at 6 to 8 hours after ingestion. Patients taking digitalis therapeutically often take diuretics as well, and they often have low serum and total body potassium levels. The acutely poisoned patient, in contrast, may have life-threatening hyperkalemia, and empiric potassium administration is contraindicated.

Differential Considerations No sign or symptom, including dysrhythmias, is unique to digitalis poisoning, so the differential diagnosis is broad. Intrinsic cardiac disease as well as other cardiotoxic drugs must be considered. Central nervous system (CNS) depression or confusion may be secondary to various drugs and toxins as well as infection, trauma, inflammation, and metabolic derangements. Visual disturbances, which should be binocular, are often not reported by the patient, and the clinician should ask directly about them. Gastrointestinal disturbances are common and nonspecific and may be misdiagnosed as gastritis, enteritis, or colitis.

Management With the availability of digoxin-specific Fab fragment antibodies (Digibind and DigiFab), all other therapies, except for mild cases, must be considered temporizing. There is no evidence to support gastric emptying for the treatment of digoxin overdose. Oral overdoses can be treated with activated charcoal if it can be administered within 1 hour of ingestion, but no improvement in outcome has been proven. Similarly, although not proven to improve outcome, multidose charcoal has historically been used for digitoxin tox-icity because of its prominent 26% enterohepatic circulation. The benefit, if any, of multidose charcoal may largely be irrelevant with the widespread availability of antidigoxin antibody treatment as a specific antidote.

Electrolyte Correction Potassium replacement is one of the first steps taken to treat chronic intoxication. In cases of chronic intoxication, often exacerbated by hypokalemia, most authorities recommend raising the serum potassium level to 3.5 to 4 mEq/L. Potassium can be administered orally (which is safer) or intravenously. Infusing potassium intravenously more rapidly than 10 to 40 mEq/hr is dangerous. In cases of acute poisoning, when serum potassium may begin to rise rapidly after 1 to 2 hours, potassium should be withheld, even if mild hypokalemia is measured initially. A serum potassium level greater than 5 mEq/L warrants consideration of digitalis antibody treatment. If digitalis antibodies are not immediately available, severe hyperkalemia must be treated with infusions of glucose, insulin, and sodium bicarbonate. Calcium, as noted earlier, should be avoided. Many patients on diuretic therapy are also magnesium depleted, even when the serum magnesium level is normal. If significant magnesium depletion is suspected, 1 to 2 g of magnesium sulfate can be given over 10 to 20 minutes (child: 25 mg/kg), followed by a constant infusion of 1 to 2 g/hr. Patients must be closely monitored for respiratory depression, which is usually preceded by progressive loss of deep tendon reflexes. Hypermagnesemia can exacerbate digitalis toxicity, but magnesium has been reported to reverse digoxin-induced tachydysrhythmias. It is prudent to infuse magnesium slowly and stop the infusion if heart block or bradycardia develops. Avoid magnesium in patients with renal failure. The role of magnesium in bradydysrhythmias and conduction blocks is less clear but probably dangerous because hypermagnesemia can actually impair impulse formation and AV conduction.

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Atropine Atropine is generally used for severe bradycardia and advanced AV block, with mixed results. Generally, an external or transvenous pacemaker should be readied when bradycardia or AV block appears.

Pacing Transvenous pacing has been a mainstay of treatment for several decades, but the catheter may induce ventricular tachydysrhythmias in a myocardium made irritable by digitalis. Iatrogenic accidents of cardiac pacing are frequent (14/39, 36%) and often fatal (5/39, 13%).[12] It may be safer to temporize with an external rather than a transvenous pacemaker while waiting for Fab fragments to take effect. Cardioversion and defibrillation can also be dangerous, with asystole after attempts to treat tachydysrhythmias. Lower energy settings, such as 25 to 50 J, may be less hazardous.

Carotid Sinus Massage Carotid sinus massage is dangerous in the setting of digitalis toxicity and may result in bradyasystole and cardiac arrest.

Phenytoin and Lidocaine Phenytoin and lidocaine are believed to be the safest of the antidysrhythmic drugs for controlling tachydysrhythmias in the setting of digitalis intoxication. Phenytoin may enhance AV conduction. Phenytoin has been infused at 25 to 50 mg/min to a loading dose of 10 to 15 mg/kg. Lidocaine can be given initially at a dosage of 1 to 3 mg/kg over several minutes, followed by an infusion of 1 to 4 mg/min (30 to 50 p-g/kg/min).[ 13] Most other cardiac drugs (isoproterenol, procainamide, amiodarone, p -blockers, calcium antagonists) may worsen dysrhythmias or depress AV conduction. Digoxin immune Fab fragments are the preferred therapy for dysrhythmias.

Fab Fragments The rate of mortality before Fab fragment therapy was 23% despite all of the interventions decribed.[] Fab fragment treatment is well established in both chronic and acute poisonings with a 90% response rate.[] Nonresponders usually received too little antibody or received it too late. Other nonresponders were compromised by underlying heart or multisystem disease. Digitalis antibodies are derived from sheep immunized with digoxin. Because the more antigenic Fg fragments are discarded, allergic reactions are less than 1% and routine skin testing is uneccessary.[] Reactions have included erythema, urticaria, and facial edema, all of which have responded to the usual treatment. Other adverse reactions to Fab fragment neutralization of digitalis include hypokalemia, exacerbation of congestive heart failure, or increase in ventricular rate with atrial fibrillation. Because of its expense, Fab fragment treatment is best reserved for cases of life-threatening toxicity rather than for routine or prophylactic administration. The primary indication for antibody treatment in cases of acute poisoning is hyperkalemia with a serum potassium level greater than 5.5 mEq/L or electrocardiographic changes. Although toxicity increases with greater body load, there is no clear correlation with amount ingested, especially in children, and many patients with large ingestions or high serum levels become only mildly symptomatic.[5] Fab fragment therapy should be used before transvenous pacing, which carries significant risk. The median time to initial response is 19 minutes after completion of the Fab infusion, but complete resolution of digitalis-toxic rhythms may require hours.[] Late administration of Fab fragments has resuscitated 54% of patients who have suffered cardiac arrest.[] This antidote should be considered whenever hemodynamic compromise attends a digitalis-toxic dysrhythmia or heart block ( Box 150-4 ).[20] BOX 150-4 Recommendations for Administration of Digitalis Antibody Fragments

Adults 1.

Seve re ventr icula

Page 3557

2.

3.

4.

5.

r dysr hyth mias Prog ressi ve and hem odyn amic ally signi fican t brad ydys rhyth mias unre spon sive to atrop ine Seru m pota ssiu m great er than 5 mEq /L Rapi dly prog ressi ve rhyth m distu rban ces or risin g seru m pota ssiu m level Co-i nges tion of cardi otoxi

Page 3558

6.

7.

c drug such as p -b lock ers, calci um chan nel bloc kers, or tricy clic antid epre ssan ts Inge stion of plant kno wn to cont ain cardi ac glyc osid es plus seve re dysr hyth mias (rare ) Acut e inge stion great er than 10 mg plus any one of facto rs 1 throu gh 6 abov e

Page 3559

8.

Stea dy-st ate seru m digo xin great er than 6 ng/m l plus any one of facto rs 1 throu gh 6 abov e

Children 1.

Inge stion of great er than 0.1 to 0.3 mg/k g or stea dy-st ate digo xin great er than 5 ng/m L plus rapid ly prog ressi ve sym ptom s or sign s of digit

Page 3560

2.

3.

alis intoxi catio n or pote ntiall y life-t hreat enin g dysr hyth mias or cond uctio n bloc ks or seru m pota ssiu m great er than 6 mEq /L Co-i nges tion of other cardi otoxi c drug s with addit ive or syne rgisti c toxici ty Inge stion of plant kno wn to cont ain cardi ac

Page 3561

glyc osid es plus seve re dysr hyth mias (rare ) Current formulas for calculating Digibind dosages are found in the package insert. There are at least three approaches. The first is empiric. A patient has a history of digitalis ingestion, consistent symptoms, and life-threatening dysrhythmias. There is no time to assess serum digoxin levels, either at 1 hour or in steady state. In such a situation, 10 vials should be administered over 30 minutes through a 0.22-p-m filter for the average acute ingestion, and 4 to 6 vials for the average chronic ingestion. In patients in cardiac arrest, 20 vials of Digibind can be administered undiluted by intravenous bolus. The second approach uses a simple calculation when the ingested dose is known with reasonable certainty. One vial of Digibind contains 38 mg of Fab fragments, which bind 0.5 mg of digoxin or digitoxin ( Box 150-5 ). A third approach is to base the dosage on the steady-state serum digoxin or digitoxin level after 6 to 8 hours ( Boxes 150-6 and 150-7 ). Once Fab fragments have been administered, it is no longer fruitful to measure digitalis levels for up to 1 week because most assays will measure both bound and unbound drug, with values greater than 100 ng/mL common. Newer methods can measure free digoxin, but it is more meaningful to follow the patient clinically. BOX 150-5 Sample Calculation of Digibind Based on Ingested Dose of Digoxin or Digitoxin[*]

Cas e: A toxic 40-y earold wom an has inge sted 50 0.25mg digo xin table s Body load = amo unt inge sted × 0.8 (bioa vaila bility of digo xin

Page 3562

table ts) = 12.5 mg × 0.8 = 10 mg Dos e of Digib ind (in vials )= 10 mg ÷ 0.5 mg boun d per vial = 20 vials * Form ula from GlaxoSm ithKline 2005.

BOX 150-6 Sample Calculation of Digibind Based on Steady-State Digoxin Concentration[*]

Cas e: A toxic 4-ye ar-ol d child weig hing 20 kg has a digo xin level of 16 ng/m L8 hour s after inge stion of an unkn own num ber of digo xin

Page 3563

table ts Dos e (in num ber of vials )= (ser um digo xin conc entra tion × weig ht in kg) ÷ 100 = (16 × 20) ÷ 100 = appr oxim ately 3 vials * Form ula from GlaxoSm ithKline 2005; assum es Vd = 5 L/kg.

BOX 150-7 Calculation Based on Steady-State Digitoxin Concentration[*]

Cas e: A toxic 70-y earold man weig hing 80 kg has a digit oxin level of 200 ng/m L (ther apeu

Page 3564

tic = 10 to 35 ng/m L) Dos e (in num ber of vials )= (ser um digit oxin conc entra tion × weig ht in kg) ÷ 1000 = (200 × 80) ÷ 1000 = 16 vials * Form ula from GlaxoSm ithKline 2005, Vd = 5 L/kg.

Pediatric Considerations Children at greatest risk are those on chronic digitalis therapy for heart disease. Children with healthy hearts have been known to tolerate massive acute oral ingestions without digitalis antibody treatment.[12] This excludes therapeutic errors, children taking digitalis therapeutically, and children with heart disease. Dosage calculation and administration errors probably account for more pediatric digitalis intoxication and death than accidental oral ingestion. Therapeutic errors—especially accidental intravenous overdoses—are often catastrophic, with death within 1 to 4 hours. Signs and symptoms in children with digitalis poisoning are somewhat different ( Table 150-2 ). Somnolence or obtundation is more common than in adults.[] A CNS depression, in the absence of a history, might lead the clinician to suspect narcotic or sedative-hypnotic overdose, or even nontoxicologic causes such as head injury, metabolic disorder, or CNS infection. Vomiting is probably more common than in adults. Conduction disturbances and bradycardias are more common than ventricular dysrhythmias in children, especially in cases of acute ingestion.[] Table 150-2 -- Age Differences in Digitalis Intoxication Adult Toxic at lower levels Nausea, fatigue, and visual disturbances most common Tachydysrhythmias as common as blocks and bradydysrhythmias Allergic reactions to Fab fragments uncommon (90 mm Hg diastolic) Sensorium Alert and oriented

57.4 57

45.9

Page 3652

Findings

Percentage

Acute brain syndrome 36.9 Unconscious 10.6 Lethargy/stupor 6.6 Behavior Violent 35.4 Agitated 34 Bizarre 28.8 Hallucinating/delusional 18.5 Mute and staring 11.7 Nudism 3.3 No behavioral effects 3.5 Motor Signs Generalized rigidity 5.2 Grand mal seizures 3.1 Localized dystonias 2.4 Facial grimacing 1.7 Athetosis 1.3 Cholinergic Signs Profuse diaphoresis 3.9 Bronchospasm 2.1 Pupils ≤1 mm 2.1 Hypersalivation 1.7 Bronchorrhea 0.6 Anticholinergic signs Pupils ≥4 mm 6.2 Urinary retention 2.4 Abnormal Vital Signs Tachycardia (>100/min) 30 Hypothermia (38.9° C [102° F]) 2.6 Cardiac arrest 0.3 Hypotension 1.6 From McCarron MM, et al: Acute phencyclidine: Incidence of clinical find-ings in 1,000 cases. Ann Emerg Med 10:5, 1981.

Behavior may be bizarre, lethargic, agitated, confused, or violent. A blank or catatonic stare is common. Vertical, horizontal, and rotatory nystagmus is often present. Moderate hypertension and tachycardia may be present. Pupils usually are midsized and reactive, although there may be miosis or mydriasis. Bizarre posturing, grimacing, and writhing may be seen.[82] Other variable findings include ataxia, muscle rigidity, increased deep tendon reflexes, increased secretions, bronchospasm, hyperthermia, and convulsions. The percentage of violent patients ranges from 10% to 40% for PCP, and controlling these patients may be the most challenging problem in the emergency department. “Superhuman” strength is possible because of the dissociative action of PCP. Patients have broken police handcuffs, fracturing bones in doing so, and have performed other destructive actions not normally possible. Although mild hypertension in PCP intoxication is common, hypertension requiring antihypertensive treatment is rare. Severe hypertension with PCP overdose has been reported to cause intracerebral hemorrhage, but not as commonly as with cocaine or amphetamine.[83]

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Hyperthermia can range from mild to life-threatening. Core temperatures of PCP victims can exceed 40° C and often go undetected for prolonged periods in the emergency department. Severe hyperthermia with temperatures greater than 42° C resembles heatstroke and often is associated with multiple organ damage.[ 84] Particularly susceptible organs are the kidneys, liver, heart, and brain. High-output congestive heart failure has been reported.[84] The presumed mechanism is muscle damage from seizures, extreme muscular activity such as struggling against restraints, or prolonged immobility. Rhabdomyolysis and acute myoglobinuric renal failure are the most common serious medical complications. Renal function returns after several weeks in most cases. Among the most lethal complications of PCP are respiratory depression, apnea, and cardiac arrest.[82] Although dextromethorphan has activity at opioid receptors, the typical triad of opioid intoxication (miosis, respiratory depression, and mental status depression) generally is not encountered.[88] Similar to meperidine, dextromethorphan intoxication may result in mydriasis through paralysis of the ciliary body.[89] More typical clinical findings as a result of misuse are lethargy, agitation, slurred speech, ataxia, diaphoresis, hypertension, and nystagmus.[90] With higher doses, nausea and vomiting is common, and intoxication resembles that of LSD with euphoria and hallucinations. Dystonic reaction has been reported in a child after therapeutic administration.[79]

Diagnostic Strategies Most hospital laboratories can perform urine screening for PCP. These tests are frequently bedside or point-of-care evaluations with rapid results. Many radioimmunoassays now can detect urinary PCP with a detection limit of 5 ng/mL. Urine is positive for 2 to 4 days after PCP use, but this can extend for more than 1 week after chronic exposure. Serum screening for PCP is of little clinical benefit because levels correlate poorly with symptoms. Several substances may cross-react with urine screens for PCP, including dextromethorphan owing to its structural similarity. Chlorpromazine, methadone, ketamine, and diphenhydramine also may cross-react with some assays.[91] Rhabdomyolysis can be diagnosed with elevated creatinine phosphokinase (CPK) or a positive urine test for occult blood (orthotoluidine test) with few or no red blood cells, pigmented granular casts in the urine, and urine positive for myoglobin. Because dextromethorphan typically is formulated as a hydrobromide salt, chronic use may result in spurious hyperchloremia with a low or negative anion gap. This is due to interference of chloride analysis by the bromide ion in the autoanalyzer.[92]

Differential Considerations PCP, ketamine, and dextromethorphan intoxications can mimic such diverse entities as head trauma, meningitis, catatonia, or heatstroke. Sympathetically mediated vital sign changes can be found in numerous other agents, including cocaine, amphetamine, and LSD. Antimuscarinic compounds, such as diphenhydramine, benztropine, and tricyclic antidepres-sants, also can simulate the tachycardia and altered mentation found with PCP or ketamine. Salicylate poisoning, thyrotoxicosis, and sepsis should be considered. Meningitis, intracerebral hemorrhage, and viral encephalitis all can present with altered mental status of unclear etiology. Even with a urine screen positive for PCP, the diagnosis is not certain unless a definitive history of recent PCP, ketamine, or dextromethorphan use is obtained and other conditions have been eliminated.

Management Prehospital Life-threatening complications, such as apnea or seizures, should be stabilized before transport. The threat of violence to prehospital care providers from patients with PCP poisoning makes it dangerous, or impossible, for only two or three prehospital care providers to restrain these patients until additional help arrives. Oxygen and glucose testing should be deferred until the patient is controlled. Violent patients under the influence of PCP may have traumatic injuries.

Emergency Department Patients with PCP toxicity can have unpredictable, violent behavior or sudden life-threatening complications, such as cardiac arrest or seizures. Violent behavior, although possible, is less common with ketamine. Most patients with minor intoxication are alert, oriented, and neurologically normal after 4 to 6 hours.[83] All patients with signs of trauma or struggle should be evaluated for injuries. Reliable assessments of these individuals are difficult, and sedation and restraint are often necessary before diagnostic tests or examinations are undertaken. Chemical sedation or restraint usually is preferred to physical force in cases of PCP or ketamine

Page 3654

intoxication. Although mental status may not be as reliable after chemical sedation, the benefits of protecting the staff and patient in this manner far outweigh the disadvantages. Haloperidol, 5 to 20 mg intramuscularly or intravenously, or droperidol, 2.5 to 10 mg intramuscularly or intravenously (using appropriate precautions as per the Food and Drug Administration black box warning), is usually an effective means of chemical restraint in these patients. These agents may antagonize CNS receptor sites that are responsible for much of the violent behavior in these individuals. Benzodiazepines, such as lorazepam, 2 to 4 mg intravenously or intramuscularly, or diazepam, 5 to 10 mg intravenously, may be used in aggressive dosages to calm patients with all types of sympathomimetic poisonings. A well-coordinated team may be needed to apply hard restraints simultaneously to all four extremities and the body. Comatose patients or patients with a questionable airway should be empirically intubated to ensure adequate ventilation. Although PCP intoxication can cause mild hypotension, profound hypotension is probably the result of trauma or a mixed-drug ingestion, and the patient should be resuscitated with fluids. Seizures should be treated with intravenous benzodiazepines (diazepam or lorazepam). Phenobarbital, 20 mg/kg intravenously, should be used for refractory seizures. Tachycardia does not require additional treatment except for sedation. Hyperthermia (temperature >40° C) is common in severe cases of PCP poisoning. All patients with significant symptoms, psychosis, or violent behavior should have rectal temperatures measured. Individuals with elevated temperatures should be treated aggressively with active cooling measures. Renal status and CPK should be monitored to detect rhabdomyolysis and myoglobinuric renal failure. Urinary acidification has been used in the past to trap PCP in urine and aid elimination, but its use has been abandoned because of the large volume of distribution of the drug (6 L/kg), the insignificant renal clearance of the drug (10%), and the potential adverse impact of acid urine on myoglobin in renal tubules that is often present after PCP intoxication. Activated charcoal is of no value in acute intoxication, but a standard oral dose of 50 g should be administered when body stuffing is suspected. Dextromethorphan poisoning can be managed with supportive care and measures to prevent injury to the patient. Sedation with a benzodiazepine may be needed when the patient is agitated. The patient should improve over 4 to 6 hours. Because many dextromethorphan cough and cold preparations also contain acetaminophen, levels should be measured routinely.

Disposition For nonviolent patients with PCP intoxication, a quiet holding room is ideal for observation, with 4 to 6 hours of observation. If patients have never been hyperthermic and have no signs of trauma, laboratory or other diagnostic tests are not needed. If hyperthermia or trauma is witnessed or suspected, urinalysis, CPK, and the appropriate radiographs should be considered before discharge. Patients with violent behavior or obtundation often require admission to the hospital, where close observation and treatment of potential life-threatening complications can be accomplished. Serial chemistry evaluations, including serum creatinine and CPK, should be monitored. Most of these patients can be medically cleared the next day.

KEY CONCEPTS {,

Hallu cino gens inclu de man y type s of drug s with differ ent asso ciate d effec

Page 3655

{,

{,

{,

ts. Diag nosi s and man age ment are base d prim arily on the histo ry and phys ical exa mina tion. Rea ssur ance and supp ortiv e care suffi ce for most patie nts. Aggr essi ve seda tion is nece ssar y in agita ted and viole nt patie nts.

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REFERENCES 1. Schultes RE, Hofmann A: The Botany and Chemistry of Hallucinogens, 2nd ed. Springfield, Ill, Charles C Thomas, 1980. 2. Wasson RC: Soma, Divine Mushroom of Immortality, New York, Harcourt Brace, 1968. 3. Gertsch JH, Wood C: Case report: An ingestion of Hawaiian Baby Woodrose seeds associated with acute psychosis. Hawaii Med J2003;62:127. 4. Schwartz RH, Smith DE: Hallucinogenic mushrooms. Clin Pediatr1988;27:70. 5. Cuomo MJ, Dyment PG, Gammino VM: Increasing use of “ecstasy” (MDMA) and other hallucinogens on a college campus. J Am Coll Health1994;42:271. 6. Gessner PK, Page IH: Behavioral effects of 5-methoxy-N,N-dimethyltryptamine, other tryptamines and LSD. Am J Physiol1962;203:167. 7. Weil AT: Bufo alvarius: A potent hallucinogen of animal origin. J Ethnopharmacol1994;41:1. 8. Shulgin AT: N,N-Diisopropyltryptamine (DIPT) and 5-methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT): Two orally active tryptamine analogs with CNS activity. Commun Psychopharmacol1980;4:363. 9. Meatherall R: Foxy, a designer tryptamine hallucinogen. J Anal Toxicol2003;27:313. 10. Jacobs BL: How hallucinogenic drugs work. Am Sci1987;75:386. 11. Glennon RA: Evidence for 5-HT 2 involvement in the mechanism of action of hallucinogenic drugs. Life Sci1985;35:2506. 12. Smythies JR: On the molecular mechanism of action of hallucinogens. In: Stillman R, Willette R, ed.The Psy-chopharmacology of Hallucinogens, Elmsford Park, NY: Pergamon Press; 1978: 23-27. 13. Grinspoon L, Bakasar J: Psychedelic Drugs Reconsidered, New York, Basic Books, 1979. 14. Sloviter R: A common mechanism for lysergic acid, indolealkylamine and phenethylamine hallucinogens: Serotonergic medication of behavioral effects in rats. J Pharmacol Exp Ther1980;214:231. 15. Freedman DX: LSD: The bridge from human to animal. In: Jacobs BL, ed.Hallucinogens: Neurochemical, Behavioral and Clinical Perspectives, New York: Raven Press; 1984: 203-226. 16. Jacobs BL: Postsynaptic serotonergic action of hallucinogens. In: Jacobs BL, ed.Hallucinogens: Neurochemical, Behavioral and Clinical Perspectives, New York: Raven Press; 1984: 183-202. 17. Hoolister LE: Effects of hallucinogens in humans. In: Jacobs BL, ed.Hallucinogens: Neurochemical, Behavioral and Clinical Perspectives, New York: Raven Press; 1984: 19-33. 18. Klock JC: Coma, hyperthermia and bleeding associated with massive LSD overdose, a report of eight cases. J Toxicol Clin Toxicol1975;8:191. 19. Peroutka SJ: Incidence of recreational use of 3,4 methylenedimethoxymethamphetamine (MDMA, ecstasy) on an undergraduate campus. N Engl J Med1987;317:1542. 20. Nichols DE: Differences between the mechanism of action of MDMA, MBDB, and the classic hallucinogens: Identification of a new therapeutic class: Entactogens. J Psychoactive Drugs1986;18:305. 21. Texas Commission on Alcohol and Drug Use : Texas Commission of Alcohol and Drug Use 1996 Texas School Survey: Grades 7-12, Austin, Tex, Texas Commission of Alcohol and Drug Use, 1997. 22. Leverant R: MDMA reconsidered. J Psychoactive Drugs1986;18:373. 23. Riedlinger TJ, Riedlinger JE: Psychedelic and entactogenic drugs in the treatment of depression. J Psychoactive Drugs1994;26:41. 24. Peroutka SJ, Newman H, Harris H: Subjective effects of 3,4-methylenedioxymethamphetamine in recreational users. Neuropsychopharmacology1988;1:273. 25. Voorspoels S: Resurgence of a lethal drug: Paramethoxyamphetamine deaths in Belgium. J Toxicol Clin Toxicol2002;40:203. 26. Byard RW: Death and paramethoxyamphetamine—an evolving problem. Med J Aust2002;176:496. 27. Ling LH: Poisoning with the recreational drug paramethoxyamphetamine (“death”). Med J Aust 2001;174:453. 28. Bergman R: Navajo peyote use: Its apparent safety. Am J Psychiatry1971;128:51. 29. Shulgin AT, Sargent T, Naranjo C: The chemistry and psychopharmacology of nutmeg and of several related phenylisopropylamines. Psychopharmacol Bull1967;4:13. 30. Sangalli BC, Chiang W: Toxicology of nutmeg abuse. J Toxicol Clin Toxicol2000;38:671. 31. Sjoholm A, Lindberg A, Personne M: Acute nutmeg intoxication. J Intern Med1998;243:329.

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32. Cowen PJ: Serotonin receptor subtypes: Implications for psychopharmacology. Br J Psychiatry 1991;12(Suppl):7. 33. Rudnick G, Wall SC: The molecular mechanism of [3,4-methylenedioxy-methamphetamine (MDMA)]: Serotonin transporters are targets for MDMA-induced serotonin release. Proc Natl Acad Sci U S A 1992;89:1817. 34. Ricaurte GA: (+) 3,4-Methylenedioxymethamphetamine selectively damages serotonergic neurons in nonhuman primates. JAMA1988;260:51. 35. Kleven MS, Woolverton WL, Seiden LS: Evidence that both intragastric and subcutaneous administration of methylenedioxymethylamphetamine (MDMA) produce serotonin neurotoxicity in rhesus monkeys. Brain Res1989;488:121. 36. Ricaurte GA: Toxic effects of MDMA on central serotonergic neurons in the primate: Importance of route and frequency of drug administration. Brain Res1988;446:165. 37. McCann UD, Ricaurte GA: Lasting neuropsychiatric sequelae of (+) methylenedioxymethamphetamine (“ecstasy”) in recreational users. J Clin Psychopharmacol1991;11:302. 38. Malberg JE, Seiden LS: Small changes in ambient temperature cause large changes in 3,4-methylenedioxymethamphetamine (MDMA)-induced serotonin neurotoxicity and core body temperature in the rat. J Neurosci1998;18:5086. 39. Farfel GM, Seiden LS: Role of hyperthermia in the mechanism of protection against serotonergic toxicity: II. Experiments with methamphetamine, p-chloroamphetamine, fenfluramine, dizocilpine and dextromethorphan. J Pharmacol Exp Ther1995;272:868. 40. O'Connor A: Death from hyponatraemia-induced cerebral oedema associated with MDMA (“Ecstasy”) use. N Z Med J1999;112:255. 41. Henry JA: Low-dose MDMA (“ecstasy”) induces vasopressin secretion. Lancet1998;351:1784. 42. Holden R, Jackson MA: Near-fatal hyponatraemic coma due to vasopressin over-secretion after “ecstasy” (3,4-MDMA). Lancet1996;347:1052. 43. Brown C, Osterloh J: Multiple severe complications from recreational ingestion of MDMA (“ecstasy”). JAMA1987;258:780. 44. Verebey K, Alrazi J, Jaffe JH: The complications of “ecstasy” (MDMA). JAMA1988;259:1649. 45. Smilkstein MJ, Smolinske SC, Rumack BH: A case of MAO inhibitor/MDMA interaction: Agony after ecstasy. J Toxicol Clin Toxicol1987;25:149. 46. Dowling GP, McDonough III IIIET, Bos RO: “Eve” and “ecstasy”: A report of five deaths associated with the use of MDEA and MDMA. JAMA1987;257:1615. 47. Randall T: Ecstasy-fueled “rave” parties become dances of death for English youths. JAMA 1992;268:1505. 48. Kunsman GW: Application of Syva EMIT and Abbott TDX amphetamine immunoassays to the detection of 3,4-methylenedioxyamphetamine (MDMA) and 3,4-methyleneethoxyamphetamine (MDEA) in the urine. J Anal Toxicol1990;14:149. 49. Schwartz RH, Miller NS: MDMA (ecstasy) and the rave: A review. Pediatrics1997;100:705. 50. Logan AS: Survival following “ecstasy” ingestion with a peak temperature of 42 degrees C. Anaesthesia 1993;48:1017. 51. Padkin A: Treating MDMA (“ecstasy”) toxicity. Anaesthesia1994;49:259. 52. Chadwick IS: Ecstasy, 3-4 methylenedioxymethamphetamine (MDMA), a fatality associated with coagulopathy and hyperthermia. J R Soc Med1991;84:371. 53. Nahas GG: Cannabis: Toxicological properties and epidemiological aspects. Med J Aust1986;145:82. 54. Mason AP, McBay AJ: Cannabis: Pharmacology and interpretation of effects. J Forensic Sci1985;30:615. 55. Taylor FM: Marijuana as a potential respiratory carcinogen. South Med J1988;81:1213. 56. Wall ME: Metabolism, disposition, and kinetics of delta-9-tetrahydrocannabinol in men and women. Clin Pharmacol Ther1983;34:352. 57. Ohlsson A: Plasma delta-9-tetrahydrocannabinol concentration and clinical effects after oral and intravenous administration and smoking. Clin Pharmacol Ther1980;28:409. 58. Hawks RL: The constituents of cannabis and the disposition and metabolism of cannabinoids. In: Hawks RL, ed.Analysis of Cannabinoids: NIDA Research Monograph 42, Rockville, Md: NIDA; 1982: 125-137. 59. Heishman SJ: Acute and residual effects of marijuana: Profiles of plasma TCH levels, physiological, subjective and performance measures. Pharmacol Biochem Behav1990;37:561. 60. Huestis MA: Pharmacology and toxicology of marijuana. Ther Drug Monit1993;14:131. 61. Janowsky DS: Simulated flying performance after marijuana intoxication. Aviat Space Environ Med 1976;47:124. 62. Renier S, Messi G, Orel P: Acute cannabis poisoning in a female child. Minerva Pediatr1994;46:335. 63. Weinberg D, Lande A, Hilton N: Intoxication from accidental marijuana ingestion. Pediatrics1983;71:848. 64. Macnab A, Anderson E, Susak L: Ingestion of cannabis: A cause of coma in children. Pediatr Emerg Care1989;5:238. 65. Ellis GM: Excretion patterns of cannabinoid metabolites after last use in a group of chronic uses. Clin

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Pharmacol Ther1985;38:572. 66. Cone EJ: Passive inhalation of marijuana smoke: Urinalysis and room air levels of delta-9-tetrahydrocannabinol. J Anal Toxicol1987;11:89. 67. Otten EJ: Marijuana. In: Goldfrank LR, ed.Toxicologic Emergencies, 7th ed. New York: McGraw Hill; 2002: 1054-1058. 68. Valdes LJ: Salvia divinorum and the unique diterpene hallucinogen, Salvinorin (Divinorin) A. J Psychoactive Drugs1994;26:277. 69. Hold KM: Alpha-thujone (the active component of absinthe): Gamma-aminobutyric acid type A receptor modulation and metabolic detoxification. Proc Natl Acad Sci U S A2000;97:3826. 70. Arnold WN: Absinthe. Sci Am1989;260:112. 71. Weisbord SD, Soule JB, Kimmel PL: Poison online—acute renal failure caused by oil of wormwood purchased through the Internet. N Engl J Med1997;337:825. 72. Crider R: Phencyclidine: Changing abuse patterns. NIDA Res Monogr1986;64:163. 73. Siegel RK: Phencyclidine and ketamine intoxication: A study of four populations of recreational users. In: Peterson RC, Stillman RC, ed.Phencyclidine (PCP) Abuse: An Appraisal (Department of Health, Education and Welfare Pub. No. [ADM] 78-728), Washington, DC: US Government Printing Office; 1978: 119-147. 74. Baker SD, Borys DJ: A possible trend suggesting increased abuse from Coricidin exposures reported to the Texas Poison Network: Comparing 1998 to 1999. Vet Hum Toxicol2002;44:169. 75. Banerji S, Anderson IB: Abuse of Coricidin HBP cough and cold tablets: Episodes recorded by a poison center. Am J Health Syst Pharm2001;58:1811. 76. Javitt DC, Zukin SR: Recent advances in the phencyclidine model of schizophrenia. Am J Psychiatry 1991;148:1301. 77. Cook CE: Phencyclidine and phenylcyclohexane disposition after smoking phencyclidine. Clin Pharmacol Ther1982;31:635. 78. Young JD, Crapo LM: Protracted phencyclidine coma from an intestinal deposit. Arch Intern Med 1992;152:859. 79. Graudins A, Fern RP: Acute dystonia in a child associated with therapeutic ingestion of a dextromethorphan containing cough and cold syrup. J Toxicol Clin Toxicol1996;34:351. 80. Schneider SM: Dextromethorphan poisoning reversed by naloxone. Am J Emerg Med1991;9:237. 81. Skop BP: The serotonin syndrome associated with paroxetine, an over-the-counter cold remedy, and vascular disease. Am J Emerg Med1994;12:642. 82. McCarron MM: Acute phencyclidine intoxication: Incidence of clinical findings in 1,000 cases. Ann Emerg Med1981;10:238. 83. McCarron MM: Phencyclidine intoxication. Dig Emerg Med Care1985;5:4. 84. Barton CH: Rhabdomyolysis and acute renal failure associated with phencyclidine intoxication. Arch Intern Med1980;140:568. 85. Burns RS, Lerner SE: Phencyclidine deaths. J Am Coll Emerg Physicians1978;7:135. 86. Burns RS, Lerner SE, Corrado R: Phencyclidine: States of acute intoxication and fatalities. West J Med 1975;123:345. 87. Schwartz RH, Einhorn A: PCP intoxication in seven young children. Pediatr Emerg Care1986;2:238. 88. Wolfe TR, Caravati EM: Massive dextromethorphan ingestion and abuse. Am J Emerg Med1995;13:174. 89. Pender ES, Parks BR: Toxicity with dextromethorphan-containing preparations: A literature review and report of two additional cases. Pediatr Emerg Care1991;7:163. 90. Nordt SP: “DXM”: A new drug of abuse?. Ann Emerg Med1998;31:794. 91. Osterloh JD, Snyder JW: Laboratory principles and techniques to evaluate the poisoned or overdosed patient. In: Goldfrank LR, ed.Toxicologic Emergencies, 6th ed. Stamford, Conn: Appleton & Lange; 1998: 63-75. 92. Ng YY: Spurious hyperchloremia and decreased anion gap in a patient with dextromethorphan bromide. Am J Nephrol1992;12:268.

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Chapter 155 – Heavy Metals Larissa I. Velez Kathleen A. Delaney

IRON Iron is an essential metal that can be extremely toxic, either after an overdose or from accumulation in disease states. The acute ingestion of iron is especially hazardous to children.[1] More than 100 iron-containing preparations are listed in the Physicians' Desk Reference, and many more are available as nonprescription drugs. Most iron exposures result from the ingestion of a pediatric multivitamin formulation (usually minimally toxic) by a child younger than 6 years of age. Life-threatening poisonings in children are associated with ingestion of more potent adult preparations, often prescribed to the mother during pregnancy. Serious iron ingestions in adults are usually the result of suicide attempts.[]

Principles of Disease Pharmacology Iron is an essential cofactor in the function of hemoglobin, myoglobin, many cytochromes, and catalytic enzymes.[] Iron absorbed from the intestine is bound to transferrin. Under normal conditions, only 15% to 35% of the iron-binding capacity of transferrin is utilized. Following a significant iron overdose, transferrin becomes completely saturated and the excess iron circulates as free iron in the serum. This unbound iron is directly toxic to target organs.[] Transferrin levels vary considerable among individuals and are affected by disease states. The total iron-binding capacity (normal, 300-400 p-g/dL) provides a crude measure of the extent of saturation of transferrin and the possibility of free unbound iron. Serum iron levels are normally in the range of 50 to 150 p-g/dL. The toxicity of an iron compound depends primarily on the amount of elemental iron it contains, which in turn depends on the formulation ( Table 155-1 ). The total amount of elemental iron ingested can be approximated by multiplying the estimated number of tablets ingested by the fraction of elemental iron contained in the tablet. Ingestion of less than 20 mg/kg of elemental iron usually causes no symptoms. Ingestion of 20 to 60 mg/kg results in mild to moderate symptoms, and more than 60 mg/kg may lead to severe morbidity. Although the dose of elemental iron associated with 50% mortality (LD50) is reported to be 200 to 250 mg/kg, doses as small as 130 mg of elemental iron have been lethal in children.[7] Table 155-1 -- Common Iron Preparations Compound

Percentage of Elemental Iron

Ferrous sulfate

20

Ferrous fumarate

33

Ferrous gluconate

12

Ferric pyrophosphate

30

Ferrocholinate

14

Ferroglycine sulfate

16

Ferrous sulfate, dried

33

Ferrous carbonate, anhydrous

38

Carbonyl iron

100

Pathophysiology

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Iron has two distinct toxic effects: (1) direct caustic injury to the gastrointestinal mucosa and (2) impairment of intracellular metabolism that primarily affects the heart, liver, and central nervous system (CNS). The caustic effects of iron on the gut cause vomiting, diarrhea, and abdominal pain. Hemorrhagic necrosis of gastric or intestinal mucosa can lead to bleeding, perforation, and peritonitis.[] Unbound (free) iron moves into cells and localizes near the mitochondrial cristae, resulting in uncoupling of mitochondrial oxidative phosphorylation and impairment of adenosine triphosphate synthesis. Cellular injury from iron is also associated with the production of free radicals that injure cell membranes by lipid peroxidation.[] Iron increases capillary permeability and induces both arteriolar and venodilation. It is also directly toxic to the myocardium. These effects, combined with severe gastrointestinal fluid losses, lead to the development of shock.[] In addition, hydration of the iron molecule creates an excess of unbuffered protons, which contributes to the production of metabolic acidosis.[] Cardiovascular collapse and death may ensue from this multitude of effects.

Clinical Features The clinical effects of acute iron poisoning are described in five stages.[8] Phase I reflects the corrosive effects of iron on the gut. Vomiting occurs within 80 minutes of ingestion in more than 90% of symptomatic cases of ingestion. Diarrhea follows and gastrointestinal bleeding is common. Phase II represents an apparent (but not complete) recovery that lasts less than 24 hours but can extend up to 2 days. Most patients recover after this point. Phase III is characterized by the recurrence of gastrointestinal symptoms, severe lethargy or coma, anion gap metabolic acidosis, leukocytosis, coagulopathy, renal failure, and cardiovascular collapse. Serum iron levels may be normal during this phase, reflecting distribution into the tissues. Phase IV, characterized by fulminant hepatic failure, occurs 2 to 5 days after ingestion. This is relatively rare but usually fatal.[11] Phase V, the consequence of healing of the corrosive gastrointestinal mucosal effects, is characterized by pyloric or proximal bowel scarring, sometimes associated with obstruction.[] Metabolic derangements due to iron poisoning include hypoglycemia, leukocytosis, and severe lactic acidosis from hypoperfusion and interference with cellular respiration. Early coagulation defects are probably related to the direct effects of iron on vitamin K–dependent clotting factors.[12] Later, these coagulation defects are due to hepatic failure. Elevated aspartate and alanine transaminases, and bilirubin levels and hypoglycemia are other markers of hepatotoxicity.[11]

Diagnostic Strategies The presence of gastrointestinal symptoms suggests a potentially serious ingestion, whereas their absence is reassuring. A serum iron level measured at its peak, 3 to 5 hours after ingestion, is the most useful laboratory test to evaluate the potential severity of an iron overdose. Sustained-release or enteric-coated preparations may have erratic absorption, so a second level 6 to 8 hours after ingestion should also be checked. Peak serum iron levels of less than 350 p-g/dL are generally associated with minimal toxicity, 350 to 500 p-g/dL with moderate toxicity, and greater than 500 p-g/dL with severe toxicity ( Table 155-2 ).[3] Because iron is rapidly cleared from the serum and deposited in the liver, iron levels may be deceptively low if measured too late after a substantial ingestion. Table 155-2 -- Toxicity of Iron by Amount Ingested and Peak Serum Levels Elemental iron (mg/kg) Peak serum iron (mg/Dl) 60

>500 Severe

Although a negative radiograph does not rule out the presence of iron from chewable, liquid, and completely dissolved iron compounds, most nonchewable iron tablets are radiopaque, and the presence of tablets on a radiograph correlates with the severity of the ingestion ( Figure 155-1 ).[]

Page 3663

Figure 155-1 Radiopaque iron tablets seen on abdom inal radio-graph. ((From Craig SA: Radiology. In: Ford MD, Delaney KA, Ling LJ, Erickson T (eds): Clinical Toxicology. Philadelphia, WB Saunders, 2001, p 62.)Elsevier Inc.)

Management Gastric Emptying Iron is not bound to activated charcoal, and neither gastric lavage nor ipecac effectively removes large amounts of pills. Iron tablets clump together as their outer coatings dissolve. Gastrotomy has been required to remove iron from the stomach, but the success of whole-bowel irrigation generally obviates the need to consider surgery for purposes of decontamination.[15] For significant ingestions, especially when tablets are identified on the abdominal radiograph, whole-bowel irrigation with a polyethylene glycol electrolyte lavage solution (PEG-ELS) (CoLyte, NuLytely, GoLYTELY) is indicated. The solution is either taken orally or administered through a nasogastric tube.[] The usual rate of administration of PEG-ELS is 20 to 40 mL/kg/hr in young children and 1.5 to 2 L/hr for teenagers or adults, continued until the rectal effluent is clear and there is no radiographic evidence of pill fragments. This technique has been used in children, adolescents, and pregnant women without serious complications or electrolyte disturbances.[] Common side effects include nausea, vomiting, abdominal cramping, and bloating. Whole-bowel irrigation is contraindicated in the presence of bowel obstruction or ileus. Hemodialysis and hemoperfusion are not effective in removing iron, due to its large volume of distribution. Exchange transfusions should be considered in severely symptomatic patients with serum iron levels exceeding 1000 p-g/dL.[18]

Deferoxamine Deferoxamine binds with iron to form a water-soluble compound, ferrioxamine, which can be renally excreted or dialyzed. One hundred milligrams will chelate 9.35 mg of elemental iron.[7] Deferoxamine may also limit the entrance of iron into the cell and chelate intracellular iron. Because of its short half-life, it is administered as a continuous infusion at a dose of 15 mg/kg/hr for up to 24 hours. Rapid administration of deferoxamine can lead to hypotension, which is treated by reducing the rate of the infusion and slowly increasing it to the desired rate. Pregnancy is not a contraindication for deferoxamine. The presence of ferrioxamine turns the urine a “vin rosé” color, which reflects the excretion of chelated iron. Historically, the deferoxamine challenge test, which relied on detection of this color change, was used to diagnose the presence of free iron in the serum. The color change is difficult to detect, especially when the urine is dilute, resulting in false-negative results even in cases of serious poisoning. Falsely low serum iron values also occur in the presence of deferoxamine, so serum iron should be measured before its administration.[19]

Disposition The asymptomatic patient with an ingestion of less than 20 mg/kg of elemental iron can be observed without further therapy. If the patient remains asymptomatic after 6 hours of observation, discharge is recommended.[2] The patient who has ingested more than 20 mg/kg of elemental iron, or has pills visible on an abdominal radiograph, and is asymptomatic or exhibits evidence of mild toxicity should receive whole bowel irrigation. Abdominal radiographs can verify adequate gastrointestinal emptying. The serum iron should be checked 3 to 5 hours after ingestion, and a second iron level 6 to 8 hours after ingestion should be decreasing. Moderate gastrointestinal toxicity can be expected with peak levels of 300 to 500 p-g/dL. Patients with an iron level greater than 500 p-g/dL or patients with any systemic signs of toxicity require chelation with deferoxamine. If peak levels are below 300 p-g/dL, are not rising, and no symptoms develop over 6 hours of observation, the patient can be discharged home. When serum iron levels are not available on an immediate basis, elevations of the serum glucose level and

Page 3664

leukocyte count are helpful markers of early toxicity. If results of both these tests are normal, no signs or symptoms of toxicity occur over the 6-hour period, and the abdominal radiographs do not show pills in the gastrointestinal tract, the patient can be sent home.

LEAD The use of lead in human endeavors dates back more than 5000 years, and its toxic effects have been recognized for at least 2000 years. In 370 bc, Hippocrates attributed severe abdominal pain in a metal extractor to “lead colic.” In the 1970s, the addition of lead to household paints and gasoline was banned in the United States. Lead poisoning, a disease of industrialization, is the most common toxicologic problem of environmental origin in the United States.[] Exposure usually results from ingestion or inhalation or, less often, from direct skin contact with organic lead compounds or from retained bullets.[22] Approximately 3 to 4 million children (1 in 20) in the United States have toxic blood lead levels (BLLs).[] Lead-based paint is still found in 30 million homes in the United States.[23] Other sources of toxic lead ingestions include curtain weights, buckshot, fishing weights, lead-contaminated soil or water, bootleg whiskey (“moonshine”), food or beverages stored or prepared in lead-soldered cans, lead-glazed pottery, and lead crystal decanters. Herbal and folk remedies, including numerous products imported from Asia and Mexico, contain dangerous amounts of lead.[24] Children typically present to the emergency department (1) following an ingestion of lead, (2) symptomatic with a possible exposure history, or (3) referred for management of a toxic BLL. Lead toxicity in adults most often results from inhalational exposure in the workplace, as well as from hobbies and related activities. More than 3 million workers in the United States are estimated to be at risk for toxic lead exposure in industries such as lead smelting, battery manufacture, radiator repair, bridge and ship construction or demolition, soldering or welding, cable or tin can production, stained glass manufacture, lead-glazed or crystal pottery making, glass production, firing range operation, and lead-based paint abatement.[] Hobbies at risk include making glazed pottery, target shooting at indoor firing ranges, soldering lead, smelting lead in the preparation of buckshot and fishing sinkers, repairing cars or boats, and remodeling homes. Lead toxicity should be considered in adults with compatible symptoms associated with these exposures.

Principles of Disease Pharmacology There is no known biologic need for lead. Its absorption is highest in malnourished children (about 40%) and in pregnant women.[25] Although 90% to 95% of lead is stored in cortical bone and teeth, it is also found in the brain, liver, and kidneys. About 75% of the absorbed lead is eliminated renally, with the remainder through the skin, hair, sweat, nails, and gastrointestinal tract.[20]

Pathophysiology Lead binds to sulfhydryl groups and other ligands, interfering with critical enzymatic reactions.[20] Its toxic effects are most prominent in the hematopoietic, neurologic, and renal systems.[25] Anemia, the classic manifestation of toxicity in the hematopoietic system, may be either normochromic or hypochromic. The severity of the anemia correlates directly with BLLs. Inhibition of heme biosynthesis results in the accumulation of heme precursors, such as p3-aminolevulinic acid and protoporphyrin.[25] In the peripheral nervous system, the motor axons are the principal target, with segmental demyelination and axonal degeneration resulting in peripheral neuropathies.[21] Wrist drop and footdrop are characteristic of adult lead poisoning. Lead toxicity causes neuropsychiatric disorders. In children, elevated BLLs are associated with decreased intelligence (IQ) scores, hyperactivity, decreased attention span, overaggressive behavior, learning disabilities, criminal behavior, and subclinical sensorineural hearing loss.[] Adults and children with acute toxicity may present with lead encephalopathy associated with increased capillary permeability and cerebral edema.[27] Lead poisoning has also been correlated with hypertension.[32] Lead nephropathy is characterized by fibrosis in the proximal tubules, with relative sparing of the glomeruli. Hyperuricemic gout (“saturnine gout”) can result from increased reuptake of uric acid by the tubular cells. Acute lead poisoning results in “lead colic,” cramping abdominal pain with nausea, vomiting, constipation, and occasionally, diarrhea.[27]

Clinical Features

Page 3665

Chronic mild lead poisoning is slow in onset and nonspecific in symptoms. The diagnosis is suspected by obtaining an accurate and comprehensive history of exposure to lead. Acute exposure to lead often results in symptomatic poisoning. The characteristic symptoms and signs of acute toxicity include abdominal colic, malaise, nausea, vomiting, constipation, fatigue, anemia, peripheral neuropathy, renal impairment, hepatic dysfunction, and CNS dysfunction. The CNS toxicity can range from mild headache or personality changes to full-blown encephalopathy with coma, convulsions, and papilledema. Permanent neurologic and behavioral sequelae can occur in patients who have acute lead encephalopathy.[20]

Diagnostic Strategies The most informative biomarker is a BLL.[] The Centers for Disease Control and Prevention has defined a chronic BLL of greater than 10 p-g/dL as toxic for a child. Acute exposure can result in levels up to 100 p-g/dL ( Table 155-3 ).[35] Other ancillary data include findings on complete blood cell count; serum glucose, blood urea nitrogen, creatinine, and electrolyte level measurements; urinalysis; and, with acute lead ingestion, liver function tests. Lead-containing paints and objects are radiopaque when present in sufficient quantities, and radiographs can confirm acute ingestion and monitor the effectiveness of whole-bowel irrigation. In cases of altered mental status, seizures, or coma, a computed tomography scan of the head will show cerebral edema associated with acute lead encephalopathy and rule out other causes for these symptoms. In children, plain radiographs of the wrist and knees may show a characteristic “lead band” or “lead line” of increased metaphyseal activity seen with chronic exposures. Table 155-3 -- Serum Lead Levels and Symptomatology Symptoms Level (p-g/dL) 10

Adults None

Children Decreased intelligence Decreased hearing Decreased growth

20

Increased protoporphyrin Decreased nerve conduction velocity No symptoms

Increased protoporphyrin

30

Increased blood pressure Decreased vitamin D metabolism Decreased hearing

40

Peripheral neuropathies Nephropathy

Decreased hemoglobin synthesis

Infertility (men) 50

Decreased hemoglobin synthesis

Lead colic

70

Anemia

Anemia Encephalopathy Nephropathy

100

Encephalopathy

Death

Management Acute Lead Encephalopathy Acute lead encephalopathy can be rapidly fatal. The initial goals in management are to identify and treat all life-threatening conditions, followed by efforts to prevent further exposure to lead, minimize absorption of acutely ingested lead, enhance its elimination, and prevent or reverse cellular pathology. Standard measures to control cerebral edema, including intubation and neurosurgical consultation for invasive monitoring of intracranial pressure, are indicated. When poisoning is associated with ingestion or if radiopacities are seen on the radiograph, decontamination with gastric lavage and whole-bowel irrigation is indicated.[] Activated charcoal does not bind lead.

Page 3666

Chelation Therapy The use of chelation in cases of acute lead poisoning is guided by the patient's clinical status and the BLL. Any patient with a BLL greater than 70 p-g/dL, or with protracted gastrointestinal symptoms or CNS toxicity from an acute lead exposure, will require parenteral chelation therapy. For these seriously poisoned patients, dimercaprol (or British antilewisite) should be the first chelator given. The dosage is 3 to 5 mg/kg (25 mg/kg/day), given by deep intramuscular injection every 4 hours for 2 days, followed by another dose every 4 to 6 hours for 2 more days, and then every 4 to 12 hours for up to 7 days. Dimercaprol forms complexes that undergo both renal and biliary excretion. Adverse reactions to dimercaprol include nausea, vomiting, urticaria, pyrexia, hypertension, and hemolysis in patients with glucose-6-phosphate dehydrogenase deficiency.[38] Since dimercaprol is diluted in peanut oil, it is contraindicated in patients allergic to peanuts. Dimercaprol is followed by calcium disodium ethylenediaminetetraacetic acid (CaNa2EDTA), a highly effective lead chelator. Because of concerns that the chelated lead can cross the blood-brain barrier and worsen the encephalopathy, the first dose of CaNa2EDTA is administered with the second dose of dimercaprol. The dosage of CaNa2EDTA for patients with acute lead encephalopathy is 75 mg/kg/day or 1500 mg/m2/day given intravenously or intramuscularly in two to four divided doses, with a maximum daily dose of 1 g in children and 2 g in adults. Adverse reactions include renal tubular injury and chelation of other metals, especially iron and zinc. CaNa2EDTA should be given only with adequate urine flow or with hemodialysis in the patient with renal failure.[39] The need for parenteral chelation therapy in asymptomatic or minimally symptomatic children is guided by the BLL. A BLL of more than 69 p-g/dL mandates hospitalization and parenteral chelation therapy.[] For less seriously poisoned patients, the dosage of CaNa2EDTA is 50 mg/kg/day or 1000 mg/m2/day, given in two to four divided doses for up to 5 days. Serum lead levels of 45 to 69 p-g/dL in patients without vomiting or CNS symptoms can be managed in the outpatient setting using oral succimer (2,3-dimercaptosuccinic acid, DMSA, Chemet).[] The initial dose of DMSA is 10 mg/kg every 8 hours for 5 days, then 10 mg/kg every 12 hours for 14 days. The most common adverse reactions include nausea, vomiting, diarrhea, and transient elevations in liver transaminase levels. Although DMSA has been approved only for children, it is also used in adults.[] Oral d-penicillamine should be used only in patients who do not tolerate succimer. The usual oral dose of d-penicillamine is 25 mg/kg every 6 hours for 5 days. d-Penicillamine is less efficacious than succimer and has more adverse reactions. Penicillin allergy is a contraindication to the use of d-penicillamine. The key to managing chronic lead toxicity is the identification and reduction of sources of primary exposure. Any patient treated on an outpatient basis must be discharged to a lead-free environment. A BLL between 20 and 44 p-g/dL in a patient who is asymptomatic or minimally symptomatic requires a more aggressive medical and environmental evaluation. The current evidence indicates no need for chelation for children with a BLL lower than 45 p-g/dL.[42] Children with lead levels of 10 to 19 p-g/dL require family counseling about the symptoms and sources of lead exposure and careful follow-up, with frequent screening of BLLs. The treatment of adults with chronic poisoning is less aggressive than for children. If gastrointestinal symptoms or CNS problems are present, hospitalization with parenteral chelation therapy is indicated. In the asymptomatic adult or the adult with only mild clinical problems, the only intervention needed is cessation of exposure. Workers with serum lead levels greater than 60 p-g/dL must be removed from work and should not be allowed to return until levels are below 40 p-g/dL.

Disposition Patients who have ingested a single lead foreign body (e.g., fishing sinker) will usually pass it harmlessly.[43] If the foreign body remains in the gastrointestinal tract after 2 weeks, removal should be considered to prevent lead toxicity. Patients who are significantly symptomatic after an acute lead exposure and children with a BLL of 69 p-g/dL or greater require hospitalization and chelation therapy, as outlined previously. Patients discharged home on oral chelation therapy should not return to a contaminated environment. The health department should conduct an environmental assessment so that the primary source of lead exposure can be identified and further exposure prevented. Follow-up should be arranged with an experienced pediatrician, toxicologist, or occupational medicine physician. Basic education about hand washing, good nutritional habits, and multivitamin supplementation is also indicated.

ARSENIC

Page 3667

Arsenic (As), a tasteless, odorless substance that looks like sugar, has an infamous history as an agent of homicide. Arsenic has also been implicated in many incidences of epidemic poisoning. At present, arsenic exposure is primarily environmental and occupational. It is found in smelters and electric power plants that burn arsenic-rich coal. It is used in industry as a wood preservative and in the production of glass and microcircuits. Inorganic arsenicals are also used in rodenticides, fungicides, insecticides, paint, and tanning agents, and as defoliants in the cotton industry. Arsenic is still used for medicinal purposes in the treatment of trypanosomiasis, amebiasis, and leukemia.[44] It has also been found as a contaminant in herbal remedies and drugs such as opium. There are widespread reports of chronic arsenic poisoning associated with contaminated drinking water in underdeveloped countries. Arsenic poisoning should be suspected if compatible symptoms occur with the use of these products or these possible exposures.

Principles of Disease Pharmacology Arsenic has no metabolic or biologic function. The elemental metal is poorly water soluble and is considered nontoxic. Of the two inorganic forms, trivalent arsenite (As3+) is highly lipid soluble and is 5 to 10 times more toxic than the pentavalent arsenate (As5+) form. Trivalent arsenic has a lower gastrointestinal absorption but is well absorbed by the skin. Pentavalent arsenic is water soluble and readily absorbed from the gastrointestinal tract. Absorbed arsenic is bound by hemoglobin, leukocytes, and plasma proteins. It is cleared from the intravascular compartment within 24 hours and concentrates in the liver, kidneys, spleen, lungs, and gastrointestinal tract. Arsenic crosses the placenta and can accumulate in the fetus. Its affinity for sulfhydryl groups in keratin makes arsenic detectable in the hair, skin, and nails. Arsine (AsH3), a colorless and almost odorless gas, is extremely toxic. It is immediately lethal at 250 ppm.[45] The excretion of arsenic and its metabolites occurs mainly through the kidneys.

Pathophysiology Arsenic disrupts cellular energy production by binding avidly to sulfhydryl groups, inhibiting critical enzymes such as lactate dehydrogenase and glyceraldehyde-3-phosphate dehydrogenase, a critical step in glycolysis. It also disrupts oxidative phosphorylation by replacing phosphorus in the formation of high-energy phosphate bonds (arsenolysis).[44]

Clinical Features Acute exposure to arsine gas is characterized by severe hemolysis that is associated with renal tubular injury. Gastrointestinal symptoms are common, and CNS and liver dysfunction can occur. The mortality rate is 25% to 30%. Exchange transfusions have been used to remove arsine, which is tightly bound to the erythrocytes. Urinary alkalinization can decrease renal deposition of hemoglobin. Chelation is not useful for arsine exposures. Acute gastrointestinal effects—nausea, vomiting, abdominal pain, and diarrhea—predominate as the initial manifestations of acute exposure to arsenic salts.[] These symptoms can be so severe as to result in hematemesis and hematochezia. Within 30 to 60 minutes of exposure, patients complain of a metallic or garlicky taste in the mouth. The patient can also develop encephalopathy with seizures and coma, acute respiratory distress syndrome and respiratory failure, and dysrhythmias associated with cardiac conduction disturbances.[] In cases of severe poisoning, cardiovascular collapse and death ensue. Less common complications include hepatitis, rhabdomyolysis, hemolytic anemia, renal failure, unilateral facial nerve palsy, pancreatitis, pericarditis, pleuritis, and fetal demise ( Box 155-1 ).[51] The syndrome may be misdiagnosed as gastroenteritis or sepsis. BOX 155-1 Acute Effects of Arsenic Poisoning

Gastrointestinal Viole nt gastr oent eritis Hem atem

Page 3668

esis/ hem atoc hezi a Jaun dice Pan creat itis Dys phag ia Hep atom egal y

Cardiovascular Third spac ing with shoc k Sinu s/ve ntric ular tach ycar dia Prol onge d QT inter val, ST depr essi on, T wav e inver sion Tors ades de point es Peri cardi tis

Respiratory

Page 3669

Res pirat ory failur e Adult respi rator y distr ess synd rom e (AR DS) Pul mon ary ede ma Pne umo nia

Renal Prot einur ia Hem aturi a Olig uria Ren al failur e

Neurologic Hea dach e Dro wsin ess Deliri um Com a Enc

Page 3670

epha lopat hy Seiz ures Weeks to months after the initial symptoms, chronic effects of arsenic poisoning appear. These include characteristic lines in the nails (Mees' lines), painful sensorimotor neuropathy, and hyperkeratosis of the palms and soles.[44] Arsenic poisoning should also be considered in any patient with a history of severe or recurrent gastroenteritis and unexplained dermatologic lesions associated with peripheral neuropathy. Finally, arsenic is a known human carcinogen.[44]

Diagnostic Strategies Normal arsenic levels are 5 p-g/L or less in blood or less than 50 p-g/day in a 24-hour urine collection. Any urine level above 100 p-g/day or 50 p-g/L necessitates treatment. A spot urine sample may be falsely low because urinary excretion of arsenic is intermittent. Seafood contains arsenobetaine, which can increase urinary arsenic excretion to as high as 1700 p-g/L.[52] Arsenobetaine, however, does not result in arsenic toxicity. Other laboratory results may raise the suspicion of arsenic poisoning. Anemia, leukocytosis or leukopenia, and erythrocyte basophilic stippling are seen in the complete blood cell count. The results of renal function tests may be abnormal. Proteinuria, hematuria, and pyuria are also seen. The alanine transaminase, aspartate transaminase, and bilirubin levels may be elevated. In cases of chronic arsenic poisoning, the serum and urine arsenic levels may be undetectable, and hair and nail specimens can confirm the diagnosis. Arsenic in the gastrointestinal tract is radiopaque and can show up on a radiograph, although sensitivity is limited by arsenic's rapid absorption.[53]

Management The initial management should address life-threatening conditions with aggressive supportive management of shock, dysrhythmias, and seizures. Activated charcoal does not bind arsenic and should be considered only if a serious co-ingestion is suspected. Orogastric lavage or whole-bowel irrigation should be considered for very recent ingestions or if radiopaque material is visualized on an abdominal radiograph. Hemodialysis removes arsenic in the setting of acute renal failure.[50] With a known history in a symptomatic patient, chelation should start as early as possible without waiting for laboratory confirmation of the arsenic levels. Intramuscular dimercaprol is the preferred chelator in patients who are critically ill. DMSA is a water-soluble analogue of dimercaprol that can be given orally.[54] d-Penicillamine has a high side effect profile, and its ability to chelate arsenic is inferior to that of dimercaprol and DMSA.

MERCURY Mercury is a silvery white metal, familiar to most as the only liquid metal at room temperature. It has been mined in Spain for more than 2500 years in the form of cinnabar (HgS) and has been used for many medical purposes as an antiparasitic, a diuretic, a cathartic, and an antiseptic.[55] Significant poisoning in the home has occurred when small amounts of spilled mercury, such as that contained in a sphygmomanometer, were aerosolized by vacuuming, or when mercury was heated on the kitchen stove to extract gold from ore.[] Various other sources of mercury have resulted in intoxication ( Box 155-2 ). Because of its many uses in the manufacture of batteries, polyvinyl chloride, and latex paint, mercury is a common pollutant of air and water, which has led to restrictions in the consumption of fish caught in many local waters.[58] BOX 155-2 Sources of Mercury

Elemental Spill from mer

Page 3671

curycont ainin g devi ces Gast roint estin al expo sure from ruptu red Cant or or Miller -Abb ott tube Inhal ation al expo sure in the work plac e/ho me Delib erate injec tion or inge stion Acci dent al inge stion

Salts Acci dent al disk batte ry inge stion Delib erate inge stion

Page 3672

Laxa tive abus e

Organic Oral/ der mal expo sure to mer curo chro me or thim eros al Rep eate d injec tions of drug s cont ainin g thim eros al as a pres ervat ive Expo sure from occu patio nal or agric ultur al acci dent s Wat er/so il pollu tion Con sum

Page 3673

ption of cont amin ated seaf ood Expo sure to paint cont ainin g mer cury

Principles of Disease Pharmacology The most familiar form of mercury is elemental mercury or metallic mercury, also known as “quicksilver.” A common route of exposure to elemental mercury is the inhalation of volatilized vapor. Aspiration of elemental mercury and intentional sub-cutaneous and intravenous injections also cause poisoning.[59] After inhalation, 74% of the metallic mercury is retained in the lungs. This can result in severe pneumonitis and acute respiratory distress syndrome. Aspiration of elemental mercury results in primary pulmonary toxicity, in addition to CNS and renal toxicities. Elemental mercury is not absorbed by the gastrointestinal tract, and ingestion does not normally lead to toxicity. Injected elemental mercury is slowly absorbed from the site of tissue deposition. Inorganic mercury salts have two different valences, Hg+ (mercurous) and Hg++ (mercuric). Ingestion of either salt leads to significant gastrointestinal and renal toxicity. The organic mercury compounds are categorized as either short chain (alkyl) or long chain (aryl). The major route of exposure to this type of mercury is through ingestion. These compounds are also readily absorbed through the skin. These organic forms classically result in delayed neurotoxicity with prominent ataxia, tremor, dysarthria, and tunnel vision.

Pathophysiology Mercury binds covalently to sulfhydryl groups, disturbing cellular enzyme functions. Nephrotoxicity results from both direct damage and an immune reaction in the kidney.[57] The skin changes associated with mercury poisoning are also caused by an immune reaction. Mercury increases catecholamine levels by inhibition of catechol O-methyltransferase, resulting in hypertension and tachycardia.[60] Atrophy of the cerebellum, postcentral gyri, and calcarine areas of the brain correlate with the symptoms of visual field constriction, ataxia, and sensory disturbances, respectively.

Clinical Features The clinical manifestations of mercury poisoning depend on the acuity of the exposure, route of exposure, and chemical form of mercury. The inhalation of metallic mercury vapor results in a rapid onset of shortness of breath, fever, and chills that progresses to respiratory distress and pneumonitis.[] Aspiration of liquid metallic mercury during medical procedures results in tracheobronchial hemorrhage.[62] The acute ingestion of inorganic salts typically causes a corrosive gastroenteritis with third spacing and hemorrhage. Patients complain of a metallic taste in the mouth and may have a grayish discoloration of the mucous membranes. Massive fluid loss results in shock and acute tubular necrosis. The manifestations of subacute or chronic inorganic mercury poisoning are neurologic (neurasthenia and erethism), renal (ranging from proteinuria to the nephrotic syndrome), and gastrointestinal (metallic taste, gingivostomatitis, loose teeth, burning sensation in mouth, hypersalivation, nausea).[] Exposure to organic mercury compounds does not generally cause acute toxicity. Neurologic symptoms progress slowly over weeks to months. The neurologic and teratogenic effects of chronic exposure to methyl mercury were well illustrated by the tragedy inflicted on the population of Minamata, Japan, by the contamination of fish through the release of mercury into the water. Slowly progressive and fatal CNS injury

Page 3674

was described following a single apparently minor topical exposure to dimethylmercury in a laboratory researcher ( Table 155-4 ).[] Table 155-4 -- Mercury Intoxication Syndromes Type of Mercury/Route of Exposure Inhalation of metallic mercury

Aspiration of metallic mercury Subacute/chronic inhalation of metallic mercury

Ingestion of inorganic mercury salts

Subacute/chronic inhalation of inorganic mercury Methylmercury

Signs/Symptoms Hypoxemia Respiratory distress, ARDS Dyspnea, chest tightness Fever, chills Burning in mouth and throat Nausea, vomiting Bloody diarrhea Renal tubular necrosis Aspiration pneumonitis ARDS Metal fume fever Neuropsychiatric symptoms Renal dysfunction Skin changes Severe hemorrhagic gastroenteritis, shock, hypovolemia, third spacing Acute tubular necrosis in 24 hours, with albuminuria and hematuria Neurasthenia, erethism, acrodynia Delayed neurologic problems (ataxia, tremor, dysarthria), visual field constriction, hearing loss, spasticity, hyperreflexia

ARDS, acute respiratory distress syndrome.

Diagnostic Strategies Measurement of urine mercury levels is the most helpful test in confirming exposure and monitoring the effectiveness of chelation. For organic mercury compounds, which undergo little urinary excretion, serum levels must be used to confirm the diagnosis. “Normal” mercury levels are considered to be less than 10 p-g/L in the blood or less than 20 p-g/L in the urine. Blood levels greater than 35 p-g/L and urine levels greater than 150 p-g/L require intervention.[61] No information is available on chelation at levels between 20 and 150 p-g/L. Injected metallic mercury is radiopaque on plain radiographs.

Management Initial management in the acutely poisoned patient should be aggressive support and decontamination. Gastric lavage with protein-containing solutions (e.g., milk, egg whites) may be beneficial in the decontamination of the gastrointestinal tract following ingestion of mercury salts. Charcoal binds very little mercury and is not recommended. Ingested metallic mercury is generally harmless unless its passage is impaired by entrapment in a diverticulum or the appendix. For acute inhalational exposures, the patient should be removed from the source and supportive management provided. There is no role for antibiotics or steroids. Suction and postural drainage are indicated in cases of acute aspiration of metallic mercury. Self-injection of metallic mercury often requires surgical debridement.[59] For mercury spills, sand or mercury decontamination kits that contain calcium polysulfide, which converts

Page 3675

mercury to mercuric sulfide, should be used. Absorbable surfaces such as carpets should be removed. Help can be obtained from the local hazardous materials (HazMat) team. Attempts to remove mercury by vacuuming can volatilize the mercury and precipitate acute inhalational toxicity. Small spills, such as the contents of a thermometer, can be scooped up with a stiff card, placed in a baggie, and ideally disposed of as hazardous waste. Mecury placed in household trash is incinerated and contributes to water pollution and fish contamination.

Chelation Therapy Chelating agents have thiol groups that compete with the enzyme's sulfhydryl groups that bind mercury after its absorption. BAL is used for clinically significant acute inorganic mercury intoxication. Because it increases brain mercury levels in patients with methyl mercury poisoning, BAL is contraindicated for patients with organomercurial poisoning. Although DMSA is not currently approved by the U.S. Food and Drug Administration for this indication, it is used for both acute and chronic mercury poisoning and may be the best chelator for methyl mercury. d-Penicillamine is also used. It should be administered only after thorough gastrointestinal decontamination because mercury absorption from the intestinal lumen is enhanced by the penicillamines.

Disposition In general, in cases of acute intoxication, the most toxic forms are the inorganic mercurials. Suicidal patients with such ingestions require decontamination and admission for supportive treatment. Patients who self-inject metallic mercury often need surgical debridement. Most asymptomatic individuals can be followed closely with urinary testing as outpatients.

KEY CONCEPTS {,

Most inge sted meta ls caus e seve re gastr ointe stina l pain and eme sis.

{,

Chel ation with acut e iron inge stion is guid ed by sym ptom s and two seru m

Page 3676

iron level s mea sure d betw een 3 and 8 hour s after inge stion . {,

Patie nts with sym ptom atic acut e lead expo sure s requi re imm ediat e chel ation . Asy mpto mati c or mini mall y sym ptom atic child ren with elev ated BLL s requi re clos e follo w-up and poss

Page 3677

ible outp atien t chel ation . Pare ntera l chel ation is indic ated in child ren with lead level s great er than 69 p-g/d L. {,

Patie nts with a poss ible chro nic heav y meta l expo sure and com patib le sym ptom s shou ld have furth er inve stiga tion and clos e follo w-up

Page 3678

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REFERENCES 1. Charney E: A fatal case of ferrous sulfate poisoning. JAMA1961;178:326. 2. Mills KC, Curry SC: Acute iron poisoning. Emerg Med Clin North Am1994;12:397. 3. Fine JS: Iron poisoning. Curr Probl Pediatr2000;30:71. 4. Olenmark M: Fatal iron intoxication in late pregnancy. J Toxicol Clin Toxicol1987;25:347. 5. van Eijk HG, de Jong G: The physiology of iron, transferrin, and ferritin. Biol Trace Elem Res1992;35:13. 6. Whitten CF, Brough AJ: The pathophysiology of acute iron poisoning. Clin Toxicol1971;4:585. 7. Robotham JL, Lietman PS: Acute iron poisoning: A review. Am J Dis Child1980;134:875. 8. Banner Jr JrW, Tong TG: Iron poisoning. Pediatr Clin North Am1986;33:393. 9. Gezernik W, Schmaman A, Chappell JS: Corrosive gastritis as a result of ferrous sulphate ingestion. S Afr Med J1980;57:151. 10. Aisen P, Cohen G, Kang JO: Iron toxicosis. Int Rev Exp Pathol1990;31:1. 11. deCastro FJ, Jaeger R, Gleason Jr JrWA: Liver damage and hypoglycemia in acute iron poisoning. Clin Toxicol1977;10:287. 12. Evensen SA: Acute iron intoxication with abruptly reduced levels of vitamin K-dependent coagulation factors. Scand J Haematol1982;29:25. 13. Chyka PA, Butler AY: Assessment of acute iron poisoning by laboratory and clinical observations. Am J Emerg Med1993;11:99. 14. Ng RC, Perry K, Martin DJ: Iron poisoning: Assessment of radiography in diagnosis and management. Clin Pediatr (Phila)1979;18:614. 15. Tennebein M, Wiseman N, Yatscoff RW: Gastrotomy and whole bowel irrigation in iron poisoning. Pediatr Emerg Care1991;7:286. 16. Tenenbein M: Whole bowel irrigation in iron poisoning. J Pediatr1987;111:142. 17. Kaczorowski JM, Wax PM: Five days of whole-bowel irrigation in a case of pediatric iron ingestion. Ann Emerg Med1996;27:258. 18. Movassaghi N, Purugganan GG, Leikin S: Comparison of exchange transfusion and deferoxamine in the treatment of acute iron poisoning. J Pediatr1969;75:604. 19. Wythe E, Osterloh J, Becker C: The reliability of serum iron levels after deferoxamine treatment: An in vitro study. Vet Hum Toxicol1986;28:478. 20. Paloucek FP: Lead poisoning. Am Pharm1993;NS33:81. 21. Landrigan PJ, Todd AC: Lead poisoning. West J Med1994;161:153. 22. Akhtar AJ, Funnye AS, Akanno J: Gunshot-induced plumbism in an adult male. J Natl Med Assoc 2003;95:986. 23. Markowitz G, Rosner D: “Cater to the children”: The role of the lead industry in a public health tragedy, 1900-1955. Am J Public Health2000;90:36. 24. Tait PA: Severe congenital lead poisoning in a preterm infant due to a herbal remedy. Med J Aust 2002;177:193. 25. Markowitz M: The diagnosis and treatment of childhood lead poisoning. Resident Staff Physician 1997;3:27. 26. Lidsky TI, Schneider JS: Lead neurotoxicity in children: Basic mechanisms and clinical correlates. Brain 2003;126:5. 27. Nevin R: How lead exposure relates to temporal changes in IQ, violent crime, and unwed pregnancy. Environ Res2000;83:1. 28. Needleman HL, Gatsonis CA: Low-level lead exposure and the IQ of children: A meta-analysis of modern studies. JAMA1990;263:673. 29. Needleman HL: The long-term effects of exposure to low doses of lead in childhood: An 11-year follow-up report. N Engl J Med1990;322:83. 30. Wang CL: Relationship between blood lead concentrations and learning achievement among primary school children in Taiwan. Environ Res2002;89:12. 31. Canfield RL: Intellectual impairment in children with blood lead concentrations below 10 microg per deciliter. N Engl J Med2003;348:1517. 32. Cheng Y: Bone lead and blood lead levels in relation to baseline blood pressure and the prospective

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development of hypertension: The Normative Aging Study. Am J Epidemiol2001;153:164. 33. Gordon JN, Taylor A, Bennett PN: Lead poisoning: Case studies. Br J Clin Pharmacol2002;53:451. 34. Graziano JH: Validity of lead exposure markers in diagnosis and surveillance. Clin Chem1994;40:1387. 35. Harvey B, Campbell CC, Dolbeare CN: Center for Disease Control and Prevention. Managing blood lead levels among young children: Recommendations from the Advisory Committee on Childhood Lead Poisoning Prevention, Atlanta, CDC, 2002. Available at: http://www.cdc.gov.ezproxy.hsclib.sunysb.edu/nceh/lead/ACCLPP/recommend.htm (Accessed 3/6/2005). 36. McNutt TK: Bite the bullet: Lead poisoning after ingestion of 206 lead bullets. Vet Hum Toxicol 2001;43:288. 37. Roberge RJ, Martin TG: Whole bowel irrigation in an acute oral lead intoxication. Am J Emerg Med 1992;10:577. 38. American Academy of Pediatrics Committee on Drugs : Treatment guidelines for lead exposure in children. Pediatrics1995;96:155. 39. Chisolm Jr JrJJ: Safety and efficacy of meso-2,3-dimercaptosuccinic acid (DMSA) in children with elevated blood lead concentrations. J Toxicol Clin Toxicol2000;38:365. 40. Safety and efficacy of succimer in toddlers with blood lead levels of 20-44 microg/dL, Treatment of Lead-Exposed Children (TLC) Trial Group. Pediatr Res2000;48:593. 41. Torres-Alanis O, Garza-Ocanas L, Pineyro-Lopez A: Effect of meso-2,3-dimercaptosuccinic acid on urinary lead excretion in exposed men. Hum Exp Toxicol2002;21:573. 42. Rogan WJ: The effect of chelation therapy with succimer on neuropsychological development in children exposed to lead. N Engl J Med2001;344:1421. 43. Durback LF, Wedin GP, Seidler DE: Management of lead foreign body ingestion. J Toxicol Clin Toxicol 1989;27:173. 44. Ratnaike RN: Acute and chronic arsenic toxicity. Postgrad Med J2003;79:391. 45. Teitelbaum DT, Kier LC: Arsine poisoning: Report of five cases in the petroleum industry and a discussion of the indications for exchange transfusion and hemodialysis. Arch Environ Health1969;19:133. 46. Heyman A: Peripheral neuropathy caused by arsenical intoxication: A study of 41 cases with observations on the effects of BAL (2,3,dimercapto-propanol). N Engl J Med1956;254:401. 47. Cullen NM, Wolf LR, St Clair D: Pediatric arsenic ingestion. Am J Emerg Med1995;13(4):432. 48. Bolliger CT, van Zijl P, Louw JA: Multiple organ failure with the adult respiratory distress syndrome in homicidal arsenic poisoning. Respiration1992;59:57. 49. Beckman KJ: Arsenic-induced torsade de pointes. Crit Care Med1991;19:290. 50. Mathieu D: Massive arsenic poisoning: Effect of hemodialysis and dimercaprol on arsenic kinetics. Intensive Care Med1992;18:47. 51. Roses OE: Mass poisoning by sodium arsenite. J Toxicol Clin Toxicol1991;29:209. 52. Arbouine MW, Wilson HK: The effect of seafood consumption on the assessment of occupational exposure to arsenic by urinary arsenic speciation measurements. J Trace Elem Electrolytes Health Dis 1992;6:153. 53. Hilfer RJ, Mandel A: Acute arsenic intoxication diagnosed by roentgenograms: Report of a case with survival. N Engl J Med1962;266:663. 54. Shum S: Chelation of organoarsenate with dimercaptosuccinic acid. Vet Hum Toxicol1995;37:239. 55. Sunderman FW: Perils of mercury. Ann Clin Lab Sci1988;18:89. 56. Rennie AC: Mercury poisoning after spillage at home from a sphygmomanometer on loan from hospital. BMJ1999;319:366. 57. Kazantzis G: Mercury exposure and early effects: An overview. Med Lav2002;93:139. 58. Kulig K: A tragic reminder about organic mercury. N Engl J Med1998;338:1692. 59. Soo YO: Subcutaneous injection of metallic mercury. Hum Exp Toxicol2003;22:345. 60. Wossmann W: Mercury intoxication presenting with hypertension and tachycardia. Arch Dis Child 1999;80:556. 61. Taueg C: Acute and chronic poisoning from residential exposures to elemental mercury: Michigan, 1989-1990. J Toxicol Clin Toxicol1992;30:63. 62. Zimmerman JE: Fatality following metallic mercury aspiration during removal of a long intestinal tube. JAMA1969;208:2158. 63. Rosenman KD: Sensitive indicators of inorganic mercury toxicity. Arch Environ Health1986;41:208. 64. Nierenberg DW: Delayed cerebellar disease and death after accidental exposure to dimethylmercury. N Engl J Med1998;338:1672. 65. Clarkson TW, Magos L, Myers GJ: The toxicology of mercury: Current exposures and clinical manifestations. N Engl J Med2003;349:1731.

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Chapter 156 – Hydrocarbons David C. Lee

PERSPECTIVE Human exposure to hydrocarbons is one of the most frequently reported poisonings, accounting for more than 60,000 cases annually, with most treated in an outpatient setting.[] The cases of patients with hydrocarbon exposures who present to the emergency department generally can be classified into four types, as follows: 1. 2.

3. 4.

Accidental ingestion involving children younger than 5 years. This is the most common scenario causing fatality and usually involves significant pulmonary injury. Intentional inhalational abuse of a volatile hydrocarbon. Recreational abuse has been a medical problem ever since solvent inhalation became popular during the late 1800s. Fatalities typically occur within distinct demographic groups (e.g., American Indians, homosexual males, teenagers).[] Accidental inhalational or dermal exposure to hydrocarbons in the household or workplace. Massive oral ingestion of hydrocarbons in a suicide attempt.

PRINCIPLES OF DISEASE Pharmacology Hydrocarbons are a diverse group of organic compounds that contain hydrogen and carbon ( Table 156-1 ). Most hydrocarbons are byproducts of crude oil and are therefore called petroleum distillates (e.g., gasoline). Some products, such as turpentine, are derived from pine oil, not petroleum. Hydrocarbons are also classified by their structure. The two main categories are straight-chain hydrocarbons (aliphatic; e.g., propane) and those containing a benzene ring structure (aromatic; e.g., toluene). Hydrocarbons can also have multiple nonorganic side chains—for example, halogenated hydrocarbons such as carbon tetrachloride. Hydrocarbons are commonly used as the solvent base for many toxic chemicals, such as insecticides and metals, which in turn can cause a separate type of poisoning. Although the range of toxicity of hydrocarbon varies widely, most human exposures are confined to petroleum distillates. Table 156-1 -- Spectrum of Hydrocarbon Toxicity Type Example Use Aliph atic petrol eum distill ates

Methane Propane Butane Gasoline Kerosene Mineral spirits Mineral oil Naphtha Mineral seal oil Diesel oil

Fuels Exist as gases Liquid fuels Solvents Furniture polish Degreasers Multiple uses in chemical industry

Pathophysiology Asphyxiants causing hypoxia and CNS depression Abused inhalants Pneumonitis when aspirated Abused inhalants CNS depression from fumes n-Hexane causes

Comments Sudden death from intentional inhalation Viscosity and volatility determine spectrum of toxicity Mineral seal oil has high aspiration potential Poor gastrointestinal

Page 3683

Type

Example

Use

n-Hexane

Pathophysiology peripheral neuropathy

absorption

Inhaled toluene causes renal tubular acidosis Benzene causes aplastic anemia, leukemia

Arom atic petrol eum distill ates

Toluene Xylene Benzene

Used in plastics, pharmaceutical, rubber, chemical, and solvent industries In patients, degreasers

Highly volatile, lung aspiration Absorbed from gastrointestinal tract Abused inhalants

Woo d distill ates

Turpentine Pine oil

Solvent Household disinfectants

Well absorbed from gastrointestinal tract CNS toxicity

Methylene chloride Chloroform Carbon tetrachloride Trichloroethylene Freon Methylbromide Lindane DDT

Solvents Cleaning fluids Degreasers Fire extinguishers Paint strippers Fumigants

Multisystem toxicity (CNS, renal, hepatic, cardiac) Inhalant abuse Highly lipid soluble

Phenol Creosols

Disinfectants Used in chemical industry

Halog enate d hydro carbo ns

Relat ed chem icals

Comments

Very corrosive

Gastrointestinal/CNS toxicity

Methylene chloride metabolized to carbon monoxide Carbon tetrachloride is radiopaque Insecticides absorbed through skin

Phenol causes severe skin burns

CNS, central nervous system; DDT, Dichlorodiphenyltrichloroethane.

Pathophysiology Acute hydrocarbon toxicity usually affects three main target organs: the lungs, the central nervous system (CNS), and the heart. Although certain hydrocarbons can enter the body through the skin or gastrointestinal tract, hydrocarbons cause the most acute damage in the lungs. Despite the thousands of different types of hydrocarbons, their potential for acute toxicity depends mainly on the following four characteristics[4]: 1.

2. 3. 4.

Viscosity, or the capacity to resist flow. Low viscosity allows a substance to spread rapidly; thus, the lower the viscosity, the higher the toxicity. Viscosity is measured in Saybolt seconds universal (SSU), and substances with an SSU of less than 60 have the highest potential risk of aspiration. For example, lubricants and mineral oil have high viscosity and low toxicity, whereas furniture polish has low viscosity and high risk of aspiration. Volatility, or the capacity for a liquid to turn into a gas. High volatility enables a substance to displace alveolar oxygen. Butane and gasoline are hydrocarbon types with high volatility. Surface tension, or the capacity for a substance to collect on a liquid surface. Low surface tension enables a substance (e.g., turpentine) to disperse easily. Chemical side chains, which often increase toxicity. These toxic side chains include heavy metals (e.g., arsenic), halogens (e.g., carbon tetrachloride), and aromatic structures (e.g., toluene).

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Pulmonary Disease Fatalities usually occur after an ingestion that is accompanied by an aspiration. Animal studies have shown that pulmonary toxicity is caused by aspiration rather than by gastrointestinal absorption with hematogenous spread. A small amount of hydrocarbon in the trachea can be devastating, whereas a much larger amount in the stomach can be benign.[] Lung injury is mediated through several mechanisms. First, most hydrocarbons are poorly water soluble and can penetrate into the lower airways, producing bronchospasm and an inflammatory response. Second, volatilized hydrocarbon can displace oxygen in the alveolar space. Third, hydrocarbon can inhibit surfactant function, leading to alveolar instability and collapse. Fourth, hydrocarbon can damage pulmonary alveoli and capillaries causing hyperemia, diffuse hemorrhagic exudative alveolitis with granulocytic infiltration, microabscesses, and lipoid pneumonias. These effects cause alveolar dysfunction, ventilation/perfusion mismatch, hypoxemia, and respiratory failure.[]

Central Nervous System Certain hydrocarbons can cause CNS depression (e.g., toluene, benzene, gasoline, butane, and chlorinated hydrocarbons). These hydrocarbons can have a narcotic-like effect and cause euphoria, disinhibition, confusion, and obtundation. With an isolated single exposure, patients usually have a rapid onset of intoxication and rapid recovery. For these reasons, substance abusers seek these hydrocarbons for recreational use. Inhalation of these substances avoids hepatic first-pass metabolism and generates high concentrations in the CNS. Chronic use of inhaled hydrocarbons can cause peripheral neuropathy, cerebellar degeneration, neuropsychiatric disorders, chronic encephalopathy, and dementia.[] More than 50% of patients who abuse toluene for more than 10 years have cerebrocortical atrophy with histologic changes, including loss of neurons, diffuse gliosis, and axonal degeneration.[11]

Cardiac Hydrocarbons can cause sudden death, typically with sudden physical activity during or after intentional inhalation. These compounds are thought to produce myocardial sensitization to endogenous and exogenous catecholamine, which precipitates ventricular dysrhythmias and myocardial dysfunction. This is particularly true for halogenated and aromatic hydrocarbons (e.g., trichloroethylene found in paper correction fluid).[12]

Other Systems Various hydrocarbons have been reported to be toxic to other organ systems. Recognized syndromes include toluene-induced renal tubular acidosis, benzene-induced bone marrow toxicity and leukemia, methylene chloride–induced carbon monoxide poisoning, and chlorinated hydrocarbon–induced centrilobular hepatic necrosis and renal failure.[] Direct skin exposure of certain hydrocarbons can cause extensive chemical burns. Hydrocarbons are often used as solvents for other chemicals that may have significant inherent toxicity.

CLINICAL FEATURES There are four typical presentations of acute hydrocarbon exposures. The first scenario is a toddler who has ingested an unknown quantity of a hydrocarbon. One third of these patients will have drunk from a reused beverage container storing hydrocarbon.[9] Patients with significant life-threatening poisonings usually have early respiratory symptoms, including cyanosis, coughing, grunting, noisy respirations, or repeated bouts of vomiting. These findings suggest aspiration. A patient may initially have mild symptoms and then develop tachypnea, dyspnea, bronchospasm, wheezing, rales, and fever within 6 hours.[] A change in mental status may be a manifestation of hypoxia or hypercapnia but may also be a direct CNS effect of hydrocarbons. In extreme cases, patients present with frank respiratory failure. Additives or solutes in the hydrocarbon base can produce other symptoms (e.g., seizures from camphorated hydrocarbons, cyanosis from nitrite-induced methemoglobinemia). Pesticides are a classic example of such a toxic substance that is often placed in a hydrocarbon base. With pesticide exposures, it can be difficult to distinguish acute respiratory distress induced by hydrocarbon aspiration from bronchorrhea induced by organophosphate exposure. The second scenario is the solvent-abusing adolescent or adult. In extreme cases, these patients can be in cardiac arrest. Prehospital care providers often describe an individual who has inhaled solvents, performed some type of physical activity, then suddenly collapsed. This is thought to result from cardiac sensitization by endogenous catecholamines and the ensuing development of dysrhythmias. Paraphernalia is often found,

Page 3685

including plastic bags used for “bagging” (pouring hydrocarbon in a bag or container, then inhaling deeply) or a hydrocarbon-soaked cloth used for “huffing” (inhaling through a saturated cloth). Other paraphernalia include gasoline containers, multiple butane lighters, and spray paint cans. These patients often have a distinctive odor because almost all these hydrocarbons are volatile. They may have paint or a rash over the mouth and nose (glue-sniffer's rash) ( Figure 156-1 ). These patients can also present to the emergency department with CNS intoxication, euphoria, agitation, hallucinations, confusion, and bizarre behavior, which may progress to CNS depression and convulsions. Drug abusers who chronically inhale hydrocarbons may not be brought to medical attention specifically for treatment of their drug abuse but rather for behavioral problems or nonspecific medical symptoms caused by their abuse. The long-term chronic abuser may clinically appear similar to the long-term “skid-row” alcoholic, with peripheral neuropathy, cerebellar degeneration, and encephalopathy.[3]

Figure 156-1 Typical presentation of paint sniffer (“huffer”) with paint around the face and sedation. ((Courtesy of Chris Tom aszewski, MD, Carolinas HealthCare System.))

A third common scenario is the accidental dermal or inhaled (nonaspiration) respiratory exposure to hydrocarbons in the workplace or home. This is rarely life threatening, and most patients do not seek medical care. Most are asymptomatic or have transient nonspecific symptoms, such as headache, dizziness, or nausea. Symptoms resolve with fresh air and removal from the offending environment.[] Patients with significant respiratory exposure may have persistent pulmonary complaints and physical findings, such as coughing, wheezing, and cyanosis. Patients with significant acute dermal exposures may report pain and have evidence of chemical burns consisting of erythema, swelling, blistering, and dermal destruction. A fourth scenario is the rare patient who intentionally ingests or intravenously injects a hydrocarbon in a suicide attempt. These patients can be difficult to treat because hydrocarbons are often used in combination with other substances. In the absence of aspiration or co-ingestion of another toxic substance, the massive oral ingestion of most commonly available hydrocarbons is not associated with significant morbidity or mortality.

DIAGNOSTIC STRATEGIES The diagnosis of hydrocarbon poisoning is made on clinical grounds. Prehospital providers, family, and bystanders should be encouraged to bring the offending agent to the emergency department. The local poison control center can help identify and verify the agent. Laboratory identification of hydrocarbons is time-consuming and unhelpful in the emergency department management. Signs of a significant exposure include tachypnea, tachycardia, wheezing, and hypoxemia. Patients with a significant hydrocarbon exposure should have a chest radiograph taken. Radiographic changes can occur within 30 minutes of ingestion and may identify pathologic lesions not recognized by auscultation in more than 50% of patients ( Figure 156-2 ).[ 14] Continuous pulse oximetry and arterial blood gas measurement may also be helpful. Patients who chronically abuse hydrocarbons can be similar to the intoxicated chronic alcoholic and require close scrutiny to exclude underlying or secondary diseases. For example, chronic toluene sniffing can cause acid-base disorders, so measurement of acid-base, electrolytes, blood urea nitrogen, and creatinine levels and urinalysis should be performed.

Figure 156-2 Chest radiograph of a patient with hydrocarbon ingestion 6 hours after exposure.

Page 3686

DIFFERENTIAL CONSIDERATIONS In the most common fatal pediatric scenario, the child who ingests and then aspirates hydrocarbons, the physician should ensure that no other toxic substances are involved. Organophosphate, salicylate, and paraquat poisonings can mimic the symptoms of hydrocarbon aspiration. These poisonings mandate gastrointestinal decontamination and antidotal therapy, whereas hydrocarbon poisoning requires only good supportive care. In the recreational abuser, multiple drugs of abuse may be present. Behavioral disorders and confusion can result from hypoxia and respiratory compromise as well as from the drugs. In the chronic abuser, it can be difficult to differentiate between functional and organic confusional states.

MANAGEMENT Because hydrocarbons can cause sudden decompensation in pulmonary, cardiac, and CNS functions, patients should be monitored with cardiac monitors and pulse oximeters in a well-observed area. In patients with severe aspiration, early intubation for airway control and positive airway pressure has been advocated to minimize aspiration risks and counteract hydrocarbon-induced alveoli collapse.[4] However, no studies have proven this to be more beneficial than standard respiratory care. High-frequency jet ventilation and extracorporeal membrane oxygenation have been used to treat children with respiratory failure secondary to aspiration.[] Surfactant therapy has also been considered in these cases, but its benefit has not been proven. Corticosteroids and antibiotics have not been shown to be beneficial in cases of hydrocarbon aspiration, but the differentiation between bacterial and chemical pneumonia is difficult.[4] The aphorism, “the safest place in the body for hydrocarbons is the duodenum,” holds true for most hydrocarbons regardless of the volume ingested. Routine gastrointestinal decontamination such as gastric lavage should be avoided. This reflects the high toxicity of hydrocarbon to the lungs and the low toxicity of most hydrocarbons to the gastrointestinal tract, with low potential for systemic gastrointestinal absorption. A common complication of aggressive decontamination after the ingestion of a benign hydrocarbon is aspiration, which converts a relatively nontoxic ingestion to a toxic aspiration. In special cases, aggressive gastrointestinal decontamination is indicated because of the inherent toxicity of the hydrocarbon or the toxicity of additives to the hydrocarbon. A mnemonic to describe most of these cases is CHAMP: camphor, which can cause seizures and status epilepticus; halogenated hydrocarbon, which can cause dysrhythmias and hepatotoxicity; aromatic hydrocarbon, which can cause bone marrow suppression and cancer; metals (arsenic, mercury, lead); and pesticides, which can cause cholinergic crises, seizures, and respiratory depression. The mode of decontamination is also controversial.[] In most cases of hydrocarbon ingestion or inhalation, close observation, supportive care, and monitoring are the cornerstones of management. There are no specific antidotes for hydrocarbon poisoning. Epinephrine and isoproterenol should be avoided unless required for cardiac resuscitation. Theoretically, exogenous catecholamine can cause dysrhythmias in hydrocarbon-sensitized myocardium.[] Other p -adrenergic agonists (e.g., metaproterenol, albuterol) have not been well explored. Patients should be kept calm and sedated, if necessary, to prevent excess catecholamine release. Dermal exposures of certain hydrocarbons can cause extensive burns. Exposed patients should be decontaminated immediately. Contaminated clothing should be removed, and the skin should be washed with soap and copious lukewarm water.

DISPOSITION Patients with exposures to known, relatively benign hydrocarbons should receive appropriate decontamination and undergo a 4- to 6-hour period of observation. Patients who have ingested unknown hydrocarbons and do not have symptoms initially should be monitored for a minimum of 6 hours. A reassessment at the last hour of observation can include pulse oximetry, arterial blood gas measurements, and chest radiography. The presence of any signs or symptoms at this time suggests hospital admission and further observation. Asymptomatic patients with accidental exposures to hydrocarbons can be discharged after a period of observation with appropriate follow-up. Patients who have ingested hydrocarbons and have cough, difficulty breathing, or shortness of breath suggestive of aspiration should be admitted for a minimum of 24 hours for observation. Patients who present after an episode of recreational hydrocarbon inhalation should be observed for 4 to 6 hours. Patients who chronically abuse hydrocarbons often go to the emergency department for behavioral problems or nonspecific symptoms caused by their drug addiction. All patients in this category should be offered drug addiction counseling.

Page 3687

KEY CONCEPTS {,

{,

{,

{,

Aspir ation is the majo r effec t from inge sted hydr ocar bons . Rout ine gastr ointe stina l deco ntam inati on of hydr ocar bons shou ld be avoi ded. Asy mpto mati c patie nts shou ld be obse rved for dela yed sym ptom s for a mini mu m of 4 hour s. Solv ent-a busi ng

Page 3688

{,

patie nts are at risk for sudd en cardi ovas cular colla pse and shou ld be kept calm and quiet . Patie nts expo sed to hydr ocar bon vapo rs reco ver rapid ly with fresh air and rem oval from the expo sure.

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REFERENCES 1. Machado B, Cross K, Snodgrass WR: Accidental hydrocarbon ingestion cases telephoned to a regional poison center. Ann Emerg Med1988;17:804. 2. Watson WA: 2002 annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med2003;21:353. 3. Linden C: Volatile substances of abuse. Emerg Med Clin North Am1990;8:559. 4. Ellenhorn M: The hydrocarbon products. In: Ellenhorn MJ, ed.Medical Toxicology, Diagnosis and Treatment of Human Poisoning, 2nd ed. Baltimore: Williams & Wilkins; 1997: 1420-1426. 5. Gerarde HW: Toxicological studies on hydrocarbons. IX. The aspiration hazard and toxicity of hydrocarbons and hydrocarbon mixtures. Arch Environ Health1963;6:329. 6. Richardson J, Pratt-Thomas H: Toxic effects of varying doses of kerosene administered by different routes. Am J Med Sci1951;221:531. 7. Gross P, McNerney JM, Babyak MA: Kerosene pneumonitis: An experimental study with small doses. Am Rev Respir Dis1963;88:656. 8. Ohwada A: Exogenous lipoid pneumonia following ingestion of liquid paraffin. Intern Med2002;41:483. 9. Truemper E, Reyes de la Rocha S, Atkinson SD: Clinical characteristics, pathophysiology, and management of hydrocarbon ingestion: Case report and review of the literature. Pediatr Emerg Care 1987;3:187. 10. Hormes JT, Filley CM, Rosenberg NL: Neurologic sequelae of chronic solvent vapor abuse. Neurology 1986;36:698. 11. Schikler KN, Seitz K, Rice JF, Strader T: Solvent abuse associated cortical atrophy. J Adolesc Health Care1982;3:37. 12. Anene O, Castello FV: Myocardial dysfunction after hydrocarbon ingestion. Crit Care Med1994;22:528. 13. Press E: Cooperative Kerosene Poisoning Study: Evaluation of gastric lavage and other factors in the treatment of accidental ingestion of petroleum distillate products. Pediatrics1962;29:648. 14. Zucker AR, Berger S, Wood LD: Management of kerosene-induced pulmonary injury. Crit Care Med 1986;14:303. 15. Scalzo AJ: Extracorporeal membrane oxygenation for hydrocarbon aspiration. Am J Dis Child 1990;144:867. 16. Bysani GK, Rucoba RJ, Noah ZL: Treatment of hydrocarbon pneumonitis: High frequency jet ventilation as an alternative to extracorporeal membrane oxygenation. Chest1994;106:300. 17. Ng RC, Darwish H, Stewart DA: Emergency treatment of petroleum distillate and turpentine ingestion. Can Med Assoc J1974;111:537. 18. Beamon RF, Siegel CJ, Landers G, Green V: Hydrocarbon ingestion in children: A six-year retrospective study. JACEP1976;5:771.

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Chapter 157 – Inhaled Toxins Lewis S. Nelson Robert S. Hoffman Airborne toxins produce local noxious effects on the airways and lungs, and the respiratory tract can also serve as a portal of entry for systemic poisons. Inhalational exposure can be covert and indolent (as in occupational exposure to asbestos or urban exposure to photochemical smog) or fulminant and obvious. The circumstances and location of the exposure, presence of combustion or odors, and number and condition of victims assist in the diagnosis. Despite the array of possible toxic inhalants, identification of a specific inhalant is generally unnecessary because therapy is based primarily on the clinical manifestations ( Table 157-1 ). Table 157-1 -- Common Inhaled Toxins Inhalant Acrolein Ammonia Carbon dioxide

Source/Use

Combustion Fertilizer, combustion Fermentation, complete combustion, fire extinguisher Carbon monoxide Incomplete combustion, methylene chloride Chloramine Mixed cleaning products (hypochlorite bleach and ammonia) Chlorine Swimming pool disinfectant, cleaning products Chlorobenzylidenemalononitrile Tear gas (Mace) / chloroacetophenone Hydrogen chloride Tanning and electroplating industry Hydrogen cyanide Combustion of plastics, acidification of cyanide salts Hydrogen fluoride Hydrofluoric acid Hydrogen sulfide Methane Methylbromide Nitrogen Nitrous oxide Noble gases (e.g., helium) Oxides of nitrogen Oxygen Ozone

Predominant class Irritant, highly soluble Irritant, highly soluble Simple asphyxiant; systemic effects Chemical asphyxiant Irritant, highly soluble Irritant, intermediate solubility Pharmacologic “irritant”

Irritant, highly soluble Chemical asphyxiant

Irritant, highly soluble; systemic effects Decaying organic matter, oil industry, Chemical asphyxiant; irritant, mines, asphalt highly soluble Natural gas, swamp gas Simple asphyxiant Fumigant Chemical asphyxiant Mines, scuba divers (nitrogen narcosis, Simple asphyxiant; systemic decompression sickness) effects Inhalant of abuse, whipping cream, racing Simple asphyxiant fuel booster Industry, laboratories Simple asphyxiant Silos, anesthetics, combustion Irritant, intermediate solubility Medical use, hyperbaric conditions Irritant, free radical; systemic effects Electrostatic energy Irritant, free radical

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Phosgene Phosphine Smoke (varying composition)

Combustion of chlorinated hydrocarbons Hydration of aluminum or zinc phosphide (fumigants) Combustion

Sulfur dioxide

Photochemical smog (fossil fuels)

Irritant, poorly soluble Chemical asphyxiant Variable, but may include all classes Irritant, highly soluble

SIMPLE ASPHYXIANTS Perspective The vast majority of simple asphyxiations are workplace related and typically occur during the use of liquefied gas or airline respirators or while working in confined spaces.[1] With catalytic converters, most deaths related to the intentional inhalation of automotive exhaust result from simple asphyxiation and not carbon monoxide poisoning.[2]

Principles of Disease Simple asphyxiants are typically inert and produce toxicity by displacing oxygen and lowering the fraction of inspired oxygen (FIO2). Exposed patients remain asymptomatic if the FIO2 is normal. Carbon dioxide and nitrogen, both constituents of air, produce narcosis at elevated levels, but their predominant toxic effect is simple asphyxiation.

Clinical Features Acute effects occur within minutes of onset of asphyxia and are the manifestations of hypoxia. A fall in the F IO2 from normal, 0.21 (i.e., 21%), to 0.15 results in autonomic stimulation (e.g., tachycardia, tachypnea, dyspnea) and cerebral hypoxia (e.g., ataxia, dizziness, incoordination, confusion). Dyspnea is not an early finding because hypoxemia is not as potent a stimulus for this sensation as hypercarbia. Lethargy from cerebral edema is expected as the FIO2 falls below 0.1 (10%), and life probably cannot be sustained at an F [3] IO2 below 0.06 (6%). Since removal from exposure terminates the hypoxia and results in clinical improvement, most patients present with resolving symptoms. However, failure to improve suggests complications of ischemia (e.g., seizures, coma, cardiac arrest) and is associated with a poor prognosis.

Diagnostic Strategies and Differential Considerations A consistent history, an appropriate spectrum of complaints, and rapid resolution on removal from exposure are generally sufficient to make the diagnosis. Minimally symptomatic or asymptomatic patients do not require chest radiography or arterial blood gas (ABG) analysis. Definitive diagnosis ultimately requires scene investigation by a trained and suitably outfitted team. Determination of the exact nature of the gas is of limited clinical value but may have important public health implications. Since the presenting complaints offered by most exposed patients are nonspecific and protean (e.g., dizziness, syncope, dyspnea), the differential diagnosis is extensive.

Management and Disposition Management rarely requires specific therapy other than removal from exposure, supportive care, and possibly administration of supplemental oxygen. Neurologic injury or cardiorespiratory arrest should be managed with standard resuscitation protocols. Patients with manifestations of mild poisoning who recover after removal from the exposure can be observed briefly and discharged. Patients at risk for complications of hypoxia, such as those presenting with significant symptoms (e.g., coma) or with exacerbating medical conditions (e.g., cardiac disease) should be observed for the development or progression of posthypoxic complications.

KEY CONCEPTS {, {,

Any gas can be a simple asphyxiant if it displaces sufficient oxygen from the breathable air. Appropriate therapy for asphyxiation includes removal from exposure, administration of oxygen, and supportive care.

PULMONARY IRRITANTS

Page 3693

Perspective The pulmonary irritant gases are a large group of agents that produce a common toxicologic syndrome when inhaled in moderate concentrations. Although many of these agents can be found in the home, significant poisoning from consumer products is uncommon because of restrictions designed to reduce their toxicity. Still, catastrophes such as the 1984 release of methyl isocyanate in Bhopal, India, which resulted in more than 2000 fatalities and 250,000 injuries, remain as a rare environmental risk. On a different scale, industrialization has increased ambient levels of sulfur dioxide, ozone, and oxides of nitrogen. These irritant gases frequently exacerbate chronic pulmonary disease.

Principles of Disease Irritant gases dissolve in the respiratory tract mucus and alter the air-lung interface by invoking an irritant or inflammatory response. When dissolved, most of the gases produce an acid or alkaline product, but several generate oxygen-derived free radicals that produce direct cellular toxicity ( Figure 157-1 ). Pulmonary irritants are grouped by their water solubilities (see Table 157-1 ).

Figure 157-1 Sam ple reactions of pulm onary irritants reacting with water in the lung.

Clinical Features Highly water-soluble gases have their greatest impact on the mucous membranes of the eyes and upper airway. Exposure results in immediate irritation, with lacrimation, nasal burning, and cough. Although their pungent odors and rapid symptom onset tend to limit significant exposure, massive or prolonged exposure can result in life-threatening laryngeal edema, laryngospasm, bronchospasm, or acute lung injury (ALI), formerly known as “noncardiogenic pulmonary edema.”[4] Poorly water-soluble gases do not readily irritate the mucous membranes, and some have pleasant odors (e.g., phosgene's odor is similar to that of hay). Since there are no immediate symptoms, prolonged breathing in the toxic environment allows the substance to reach the alveoli. Even moderate exposure causes irritation of the lower airway, alveoli, and parenchyma and causes pulmonary endothelial injury after a 2- to 24-hour delay. Initial symptoms consistent with ALI may be mild, only to progress to overt respiratory failure and acute respiratory distress syndrome over the ensuing 24 to 36 hours.[5] Gases with intermediate water solubility tend to produce clinical syndromes that are a composite of the other gases, depending on the extent of exposure. Massive exposure is most often associated with rapid onset of upper airway irritation and more moder-ate exposure with delayed onset of lower airway symptoms.[6]

Diagnostic Strategies and Differential Considerations The evaluation of upper airway symptoms is usually done through physical examination but may require laryngoscopy. After exposure, swelling may occur rapidly or may be delayed, so a normal oropharyngeal or laryngeal evaluation may not exclude subsequent deterioration. Radiographic and laboratory studies have little role in the evaluation of upper airway symptoms. Oxygenation and ventilation are assessed by serial chest auscultation and pulse oximetry, supplemented by chest radiography and ABGs in patients with cough, dyspnea, hypoxia, or abnormal findings on physical examination. No clinical tests can identify the specific irritant, and identification is not generally necessary for patient care, although knowing the causative agent may allow reduction of the observation period. Bronchospasm, cough, chest tightness, and acute conjunctival irritation frequently follow allergen exposure, but the history generally suggests the diagnosis. ALI occurs after many physiologic insults, including trauma and sepsis, again highlighting the need for accurate history taking.

Management Signs of upper airway dysfunction (e.g., hoarseness, stridor) mandate direct visualization of the larynx and immediate airway stabilization, if necessary. Given the potential rapidity of airway deterioration, early and frequent reassessment should be performed.

Page 3694

Bronchospasm generally responds to inhaled p -adrenergic agonists; the role of ipratropium is not yet defined. Other than as a standard treatment for a comorbid condition, such as asthma, there is no clear indication for corticosteroids.[7] Nebulized 2% sodium bicarbonate solution can provide symptomatic relief in patients exposed to chlorine or hydrogen chloride gas.[6] Because the inflammatory cascade is not altered, however, the component of lung injury mediated by free radicals probably continues. Thus, delayed deterioration predictably occurs based on the nature of the exposure. Patients receiving inhalational bicarbonate therapy therefore require extensive discharge instructions or admission to the hospital. Diagnosis of ALI or acute respiratory distress syndrome indicates the need for aggressive supportive care, including manipulations of the patient's airway pressures (e.g., continuous positive airway pressure, positive end-expiratory pressure). Exogenous surfactant and nitric oxide may have a beneficial role in toxin-induced acute respiratory distress syndrome, despite little support for its use in other forms of the syndrome.

Disposition Patients exposed to highly water-soluble agents can be discharged if they are asymptomatic or improve with symptomatic therapy. After exposure to intermediate or poorly water-soluble agents, asymptomatic patients should be observed for increasing dyspnea for several hours before final disposition. Patients with substantial exposure to these agents or those in high-risk situations (e.g., underlying pulmonary disease, extremes of age, poor follow-up) should be observed for 24 hours and may require hospitalization. All patients should be instructed to return if symptoms recur.

KEY CONCEPTS {,

{,

Highl y wate r-sol uble agen ts prod uce rapid irritat ion and pred omin antly uppe r respi rator y tract sym ptom s. Poor ly wate r-sol uble agen ts often prod uce dela

Page 3695

yed lowe r respi rator y tract findi ngs.

SMOKE INHALATION Perspective Annually, 4000 persons are injured or die in residential fires in the United States. Many of these casualties do not suffer serious cutaneous burns, but rather die from smoke inhalation. This is a variant of irritant injury in which heated particulate matter and adsorbed toxins injure normal mucosa, similar to other irritant gases. Although carbon monoxide and cyanide are often discussed with the smoke inhalation syndrome because of their common origin, these are systemic, not pulmonary, toxins.

Principles of Disease Even at temperatures between 350° C and 500° C, air has such a low heat capacity that it rarely produces lower airway damage. However, the greater heat capacities of steam (approximately 4000 times that of air) or heated soot suspended in air (i.e., smoke) can transfer heat and cause injury deep within the respiratory tract. The nature of the fuel determines the composition of its smoke, and since fires involve variable fuels and burning conditions, the character of fire smoke is almost always undefined to the clinician. Irritant toxins produced by the fire are adsorbed onto carbonaceous particles that deposit in the airways. The irritant substances damage the mucosa through mechanisms similar to the irritant gases, including acid generation and free radical formation.

Clinical Features Most smoke-associated morbidity and mortality relate to respiratory tract damage. Thermal and irritant-induced laryngeal injury may produce cough or stridor, but these findings are often delayed. Soot and irritant toxins in the airways can produce initial cough, dyspnea, and bronchospasm. Subsequently, a cascade of airway inflammation results in acute lung injury and failure of pulmonary gas exchange. The time between smoke exposure and the onset of clinical symptomatology is highly variable and dependent on the degree and nature of the exposure. Singed nasal hairs and soot in the sputum suggest substantial exposure but are not sufficiently sensitive or specific to be practical. Carbon monoxide (CO) inhalation should be considered in these patients. Patients who are exposed to filtered or distant smoke (e.g., in a different room) or to relatively smokeless combustion (e.g., engine exhaust) inhale predominantly CO, cyanide, and metabolic poisons and do not suffer irritant exposure.

Diagnostic Strategies and Differential Considerations Early death is caused by asphyxia, airway compromise, or metabolic poisoning (e.g., CO). Airway patency should be evaluated early, optimally with fiberoptic laryngoscopy. Signs of alveolar filling or hyperinflation on chest radiography, abnormal flow-volume loop or diffusing capacity for carbon monoxide on pulmonary function testing, or abnormal distribution and clearance of radiolabeled gas on ventilation scans can help predict lower airway injury.[8] Metabolic acidosis, particularly when associated with a serum lactate level greater than 10 mmol/L, suggests concomitant cyanide poisoning.[9] Oxygenation should be assessed by co-oximetry because ABG analysis and pulse oximetry may be inaccurate in CO-poisoned patients. With the obvious exposure history, the differential diagnosis is limited. Although it is often unclear whether inhalational injuries are thermal or irritant, the differentiation is clinically irrelevant. CO and cyanide should be considered in every case.

Management The acute management of victims of smoke inhalation is identical to that of other irritant inhalational injuries. Rapid assessment of the airway and early intubation are critical because deterioration may be precipitous.

Page 3696

Inhaled p agonists are widely used, but without evidence supporting their benefit. Optimal supportive care and maintenance of adequate oxygenation (e.g., suctioning, pulmonary toilet) are the most important aspects of care. Bronchoscopy with bronchoalveolar lavage is frequently recommended to clear debris and toxins from the distal airways. Corticosteroids, whether inhaled or systemic, are not indicated and potentially harmful in patients with cutaneous burns.[10] Ibuprofen, antioxidants, exogenous surfactant, and high-frequency ventilation yield variably improved survival in experimental and clinical trials; none is generally considered as standard care. Antibiotics should be used only in patients with suspected infection.

Disposition After the airway is examined and stabilized, patients with worrisome clinical findings (e.g., hoarseness, respiratory distress) and those with identifiers of substantial exposure (e.g., closed-space exposure, carbonaceous sputum) should be admitted to a critical care unit or transferred to a burn center. This decision will vary based on local resources, such as hospital capabilities or availability of a burn referral center.

KEY CONCEPTS {,

{,

Smo ke inhal ation injur y is typic ally irrita nt in natur e. Early visu aliza tion of the airw ay is critic al. Early intub ation prior to deter iorati on is critic al if dam age is pres ent.

CYANIDE AND HYDROGEN SULFIDE Perspective Hydrogen cyanide (prussic acid) is a gas with many commercial uses, particularly in synthetic fiber manufacture and fumigation, in addition to its intentionally poisonous role in capital punishment. Hydrogen cyanide is occasionally noted to have the odor of bitter almonds. Cyanide in its salt form (e.g., sodium or

Page 3697

potassium) is important in the metallurgic (e.g., jewelry) and photographic industries and is dramatically safer to work with because of its low volatility. Cyanide salts do not have an odor under dry conditions. When cyanide salts are dissolved in water, hydrogen cyanide can leave the surface, particularly under acidic conditions. Cyanide is generated in vivo from precursors (cyanogens) such as amygdalin, found in apricot and other Prunus species pits, and from nitriles, a group of chemicals with many commercial uses. Hydrogen sulfide (H2S) poisoning most often occurs in petroleum refinery and sewage storage tank workers. Occasionally, well-intentioned would-be rescuers become victims, emphasizing the need for proper training and equipment. Hydrogen sulfide has a noxious odor similar to rotten eggs, which becomes unnoticeable with extremely high concentrations or prolonged exposure (olfactory fatigue).[11]

Principles of Disease Gaseous cyanide is rapidly absorbed after inhalation and is immediately distributed to the oxygen-utilizing body tissues. Inhibition of oxidative metabolism by binding to complex IV of the electron transport chain within mitochondria occurs within seconds. The poisoned tissue rapidly depletes its adenosine triphosphate reserves and ceases to function ( Figure 157-2 ). Cyanide has no evident effect on other oxygen-binding enzyme systems, most notably hemoglobin. This is probably explained by the oxidation state of its iron moiety; cyanide binds only to oxidized iron (Fe+++), whereas deoxyhemoglobin contains reduced iron (Fe++).

Figure 157-2 The com plete m etabolism of a m olecule of glucose to energy is com plex but occurs in two broad steps. The first step, anaerobic glycolysis, which occurs in the absence of oxygen, generates pyruvate, NADH, and adenosine triphosphate (ATP). Pyruvate then enters the Krebs cycle to create potential energy in the second step, through the reduction of NAD+ to NADH and FADH to FADH2. Sim ilarly, fatty acid m etabolism and protein m etabolism produce FADH2 and NADH, which also m ust be converted to ATP. These conversions occur in the mitochondrial m em brane, where oxidative phosphorylation is linked to the electron transport chain, the last phase of which involves the transfer of electrons to molecular oxygen to form water. Cyanide (CN), hydrogen sulfide (H2), and carbon monoxide (CO) bind to and inhibit the last step, the Fe3+-containing cytochrome aa3 in com plex IV, preventing further oxidation of NADH. This in turn hinders the Krebs cycle, since the required regeneration of NAD+ does not occur, and glucose m etabolism is forced to end at pyruvate. For energy production to continue, NADH donates its electrons to pyruvate, creating lactate, and sufficient NAD+ is regenerated for glycolysis to progress. Ultim ately, energy failure and end-organ dam age occur. CoA, coenzym e A; FAD, flavin adenine dinucleotide; NAD, nicotinam ide adenine dinucleotide.

Hydrogen sulfide exerts its toxic effects both as a pulmonary irritant and as a cellular poison.[11] Its deadly metabolic effects are produced by a mechanism identical to that for cyanide poisoning. However, hydrogen sulfide's spontaneous dissociation from the mitochondria is rapid, allowing patients to survive after brief exposure.

Clinical Features Tissue hypoxia occurs within seconds to minutes, depending on the route and nature of the exposure. Dysfunction of the heart and the central nervous system, the organ systems most sensitive to hypoxia, is characteristic of cyanide poisoning, manifesting as coma, seizures, cardiovascular collapse, and severe metabolic acidosis. Cyanosis is not characteristic but can be present in profoundly poisoned patients. Given the extreme toxicity of cyanide, mild acute poisoning is uncommon. Patients with acute hydrogen sulfide poisoning have similar clinical manifestations, although many are recovering by the time of arrival in the emergency department. Since cyanide and hydrogen sulfide prevent tissue extraction of oxygen from the blood, the oxygen content of venous blood remains high, approaching that of arterial blood. Clinically, this may appear as the “arterialization,” or brightening, of venous blood to resemble arterial blood. A comparison of the measured venous (ideally but impractically mixed venous) and arterial oxygen contents may assist in the diagnosis of cyanide poisoning.[12] Patients surviving cyanide or hydrogen sulfide poisoning may have persistent[13] or delayed-onset neurologic syndromes identical to those noted in patients with CO poisoning or cardiac arrest.

Diagnostic Strategies and Differential Considerations

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Obtaining a serum cyanide level is generally too slow for emergency department use but can be useful for confirmation and documentation purposes. Technology exists for immediate cyanide determination but is not widely available. Rapid tests for hydrogen sulfide are not available, but the presence of blackened copper coins in the pockets of victims may be a clue to the diagnosis. In practice, the diagnosis must be based on the circumstances of exposure and a corroborative physical examination. Pulse oximetry and ABG analysis are accurate in cases of isolated cyanide or hydrogen sulfide poisoning. An increased anion gap metabolic acidosis and elevated serum lactate level are usually present. A lactate level greater than 10 mmol/L in a fire victim is highly predictive of cyanide poisoning.[9] Carboxyhemoglobin levels frequently correlate with the presence of cyanide poisoning but may take too long to obtain and may falsely exclude patients exposed to combustion products of substances that generate only cyanide (e.g., certain plastics). Rapid cardiovascular collapse, ventricular dysrhythmias, and seizures are typical. Coma, acidosis, or hemodynamic instability in a fire victim should suggest cyanide poisoning, but each of these findings is also consistent with severe CO poisoning.[9] This differentiation is important given the implication of cyanide treatment.

Management Patients exposed to cellular poisons, including hydrogen cyanide and hydrogen sulfide, require individualized and specific therapy. The diagnosis can usually not be confirmed, and therapy is almost always empiric but should not be delayed in patients with suspected acute cyanide poisoning. In uncertain situations, the cyanide antidote kit, or at least the thiosulfate component for victims exposed to fires, should be administered immediately.

Hydrogen Cyanide Although the exact mechanism of the cyanide antidote kit is controversial, the accepted goal of therapy is to reactivate the cytochrome oxidase system by providing an alternative, high-affinity source of ferric ions (Fe +++ ) for cyanide to bind. The kit has three components, each of which is helpful in treating cyanide poisoning. Although the best results are likely attained when the entire kit is used, this may be impractical or dangerous, particularly for prehospital providers. Since animal models and clinical evidence in humans demonstrate that sodium thiosulfate in combination with oxygen and sodium bicarbonate offers substantial protection, this should be the initial therapy administered by paramedics and during mass poisoning events. At all times, aggressive resuscitation measures including 100% oxygen and intravenous fluids should be provided simultaneously. Methemoglobin (MetHb) formation is the goal of the first two parts of the kit. Amyl nitrite pearls are broken and held under the patient's nose or at the intake port of the ventilatory apparatus. Caution should be taken to minimize the provider's exposure to this volatile nitrite, as dizziness, hypotension, or syncope may occur after substantial inhalation. Because these inhalers are relatively inefficient at inducing methemoglobinemia, intravenous sodium nitrite is preferred and should be administered as soon as intravenous access is established. The adult dose is 300 mg (10 mL of a 3% solution) given over 2 to 4 minutes. This dosage is calculated on average total hemoglobin, and dosing instructions for anemic patients and children are supplied with the kit. Sodium nitrite is a vasodilator, and hypotension may complicate a rapid infusion. Nitrites predictably generate MetHb levels of 8%; there is no need to attain the 25% MetHb levels quoted in the past. Cyanide has a high affinity for MetHb and readily leaves cytochrome oxidase to form cyanomethemoglobin. Both free serum cyanide and cyanomethemoglobin are converted by sulfur transferase (rhodanese) to thiocyanate, which is renally eliminated. Rhodanese simultaneously regenerates MetHb, which can detoxify additional cyanide. Since the rate of rhodanese function increases with the availability of sulfur donor, the last part of the antidote kit is the sulfur-containing compound sodium thiosulfate. The adult dose is 12.5 g IV, which is provided as 50 mL of a 25% solution. Generally, few, if any, adverse effects are associated with proper doses. Extreme caution must be used in the administration of the nitrite component cyanide antidote kit to fire victims with possible simultaneous CO and cyanide poisoning. Each cyanide antidote kit contains enough to treat two adults or one adult twice. The need to administer a second dose depends on the response to the first treatment and may be common in patients with ingestions of cyanide salts or cyanogenic compounds. Patients with oral cyanide exposure require prolonged therapy and aggressive gastrointestinal decontamination because of ongoing absorption. Hyperbaric oxygen therapy has been advocated but is of no proven benefit and is not routinely indicated. In selected cases, when immediately available, its apparent value may lie in its ability to superoxygenate plasma and tissues, thus permitting higher levels of methemoglobinemia, particularly when CO poisoning is also present.

Hydrogen Sulfide

Page 3699

Since the bond between hydrogen sulfide and cytochrome oxidase is rapidly reversible, removal from exposure and standard resuscitative techniques are usually sufficient to reverse hydrogen sulfide toxicity. The nitrite portion of the cyanide antidote kit to create MetHb is suggested for use in patients with severe or prolonged toxicity.[11] Sodium thiosulfate is unnecessary because hydrogen sulfide is not detoxified by rhodanese. There is no role for hyperbaric oxygen therapy in cases of hydrogen sulfide toxicity.

Disposition All patients with symptomatic cyanide or hydrogen sulfide poisoning should be admitted to a critical care unit and observed for complications of tissue hypoxia. All patients should be followed for delayed neuropsychiatric symptoms.

KEY CONCEPTS {,

An effec tive antid ote exist s for cyan ide pois onin g and must be admi niste red early .

{,

The sodi um thios ulfat e porti on of the cyan ide antid ote kit is safe for empi ric admi nistr ation in any case in whic h

Page 3700

{,

cyan ide pois onin g is cons idere d poss ible. Patie nts with hydr ogen sulfi de pois onin g gene rally resp ond to rem oval from expo sure and ventil atory supp ort.

CARBON MONOXIDE Perspective Carbon monoxide is the most common cause of acute poisoning death and the most common cause of fire-related death.[14] CO is generated through incomplete combustion of virtually all carbon-containing products. Structure fires (e.g., wood), clogged vents for home heating units (e.g., methane), and use of gasoline-powered generators indoors are examples of the myriad means through which patients are poisoned by CO. Appropriate public health authorities (e.g., fire department, Department of Health officials) should be informed immediately about any potential public health risks that are identified during the care of a CO-exposed patient.

Principles of Disease Carbon monoxide interacts with deoxyhemoglobin to form carboxyhemoglobin (COHb), which cannot carry oxygen. Hemoglobin binds carbon monoxide tightly and forms a complex that is only slowly reversible. This allows the exposed individual to accumulate CO, even with exposure to low ambient concentrations. Although this is the classically described mechanism of CO poisoning, it is relevant only to patients who are profoundly CO poisoned. This is because a simple reduction in oxygen carrying capacity due, for example, to anemia would not be expected to result in similar symptoms. However, and relevant to the management of pregnant patients, the affinity of fetal hemoglobin for CO is even greater than that of adult hemoglobin, suggesting that the fetal exposure exceeds that predicted by maternal COHb levels.[15] In addition to preventing the binding of oxygen to hemoglobin, CO also shifts the oxyhemoglobin dissociation curve to the left, interfering with the ability of normal hemoglobin to release its bound oxygen to tissues. CO also affects cellular oxygen utilization at the tissue level. In muscle, CO binds myoglobin, preventing its normal function and causing atraumatic rhabdomyolysis. CO also inhibits the final cytochrome complex involved in mitochondrial oxidative phosphorylation, similarly to cyanide. This results in a switch to anaerobic

Page 3701

metabolism and ultimately cellular death. Delayed-onset neurologic complications may be a manifestation of the hypoxic insult, although reperfusion injury and lipid peroxidation related to platelet-induced nitric oxide release may play a significant role.[16] By altering the platelet-associated nitric oxide cycle, the microvascular endothelium of the central nervous system undergoes free radical-mediated injury, resulting in localized inflammation and dysfunction. Animal models and human reports suggest that loss of consciousness during CO exposure may be necessary, and is certainly a risk factor, for the development of delayed neurologic sequelae.[17]

Clinical Features Severe CO toxicity and cyanide poisoning have identical clinical presentations: altered mental status, including coma and seizures; extremely abnormal vital signs, including hypotension and cardiac arrest; and metabolic acidosis. Unlike cyanide poisoning, however, mild CO poisoning occurs frequently, with headache, nausea, vomiting, dizziness, myalgia or confusion, and other signs of hypoxia. The neurologic assessment in these patients may yield normal findings or may demonstrate focal findings or subtle perceptual abnormalities. The often-touted cherry-red skin color is a postmortem finding and is not noted in living patients. Delayed neurologic sequelae are a well-documented phenomenon after CO exposure, although their frequency varies from 12% to 50%, depending on their definition and with the sensitivity of the test used for their detection.[18] Patients develop a variety of neurologic abnormalities after an asymptomatic period ranging from 2 to 40 days.[17] The delayed neurologic effects can be divided into those with readily identifiable neurologic syndromes (e.g., focal deficits, seizures) and those with primarily psychiatric or cognitive findings (e.g., apathy, memory deficits). Although the latter form of delayed neurologic sequelae requires formal neuropsychiatric testing for detection, the impact of these abnormalities on the patient's daily function may be significant. Since the majority of CO poisoned patients survive, prevention of delayed neurologic and neuropsychiatric sequelae is the predominant goal of therapy.

Diagnostic Strategies and Differential Considerations Suspicion of CO poisoning relies on the history and physical examination findings. Co-oximetry, an inexpensive and readily available spectrophotometric laboratory method that can distinguish between the normal hemoglobins and COHb (and MetHb), confirms exposure to carbon monoxide. Other laboratory tests only exclude other diagnoses. Severity of poisoning may not correlate with COHb levels; prolonged exposure to low levels can result in fatality with low COHb, but a brief, high-concentration exposure can produce a high COHb level with minimal symptoms. The ABG measurement cannot be used as a diagnostic test for CO poisoning other than to identify the presence of a metabolic acidosis and a normal partial pressure of oxygen (PO2). CO does not affect the amount of oxygen dissolved in the serum. Since the PO2, a measure of dissolved oxygen, is normal in patients with CO poisoning, the calculated oxygen saturation will be normal even in the presence of substantial CO poisoning. The pulse oximeter is also inadequate for the detection of CO poisoning, since COHb is essentially misinterpreted as oxyhemoglobin. Mild to moderate CO poisoning is a difficult diagnosis to establish clinically, and patients are easily misdiagnosed as having a benign headache syndrome or viral illness. CO poisoning should be suspected in every patient with persistent or recurrent headache, especially if a group of people have similar symptoms or if the headache improves shortly after the person leaves an exposure site. Patients with severe CO poisoning present with coma or cardiovascular collapse, both of which have a broad toxicologic, metabolic, infectious, medical, and traumatic differential diagnosis. Many diagnoses are excluded by the medical history, physical examination, or standard laboratory testing. Given the relatively protean manifestations of CO poisoning, when seriously considered, it should be excluded by co-oximetry of a venous blood sample. Misdiagnosis can be catastrophic, particularly if the patient returns to the poisoned environment.

Management Treatment begins with oxygen therapy, which serves two purposes. First, the half-life of COHb is inversely related to the PO2; it can be reduced from approximately 5 hours on room air to 1 hour by providing supplemental 100% oxygen. Hyperbaric oxygen therapy further reduces the half-life to approximately 40 minutes. Altering the kinetics of COHb is only applicable to patients with extremely elevated COHb levels (i.e., >50%). Even then, few patients can be treated rapidly enough that enhanced CO clearance by

Page 3702

hyperbaric oxygen would be lifesaving. Second, under hyperbaric oxygen conditions, a sufficient PO2 can be achieved to sustain life in the absence of adequately functioning hemoglobin, but this is also relevant only to situations in which the COHb is extremely elevated. Thus, the primary indication for hyperbaric oxygen is to prevent delayed neurologic sequelae. Risk factors that predict the development of delayed neurologic sequelae include age and loss of consciousness. The controversy over the benefit of hyperbaric oxygen is related to the fact that for the vast majority of patients, hyperbaric oxygen is not administered as a lifesaving therapy, but rather to prevent or minimize the development of delayed neurologic sequelae. Thus, a benefit is not identified immediately (as with life and death) but rather requires close follow-up and sophisticated testing. Hyperbaric oxygen is associated with a reduction in the rate of neurologic delayed neurologic sequelae from approximately 12% without hyperbaric oxygen to less than 1%.[17] When hyperbaric oxygen administration is delayed more than 6 hours after exposure, its efficacy appears to decrease,[19] suggesting the need for rapid decision making. Similarly, evidence suggests that hyperbaric oxygen therapy positively affects the development of the neuropsychiatric delayed neurologic sequelae after CO poisoning.[] A recent randomized, double-blind study found that hyperbaric oxygen was superior to normobaric oxygen at reducing the incidence of neuropsychiatric delayed neurologic sequelae at both 6 weeks and 1 year postpoisoning.[20] However, it is not universally accepted that hyperbaric oxygen is useful in pre-venting the development of neuropsychiatric delayed neurologic sequelae. A 1999 Australian study that compared hyperbaric oxygen to normobaric oxygen suggested that there was no benefit of hyperbaric oxygen on the development of neuropsychiatric delayed neurologic sequelae.[21] In this study, however, the majority of patients were suicidal and presumably depressed, a condition that interferes with performance on the neuropsychiatric testing needed to differentiate the two groups of patients. In addition to other methodologic flaws in the study (e.g., mean delay to hyperbaric oxygen of more than 6 hours, atypical hyperbaric regimen, unusual randomization protocol, limited neuropsychiatric testing), the alternative to hyperbaric oxygen suggested by this study is continuous 100% oxygen for 3 or 6 days. This therapeutic alternative is likely to be poorly accepted by both patients and the medical community. Given the implications of poor tissue oxygenation due to the presence of COHb, many practitioners suggest that any patient with a neurologic abnormality or cardiovascular instability (e.g. syncope, altered mental status, myocardial ischemia, dysrhythmias) is a candidate for hyperbaric oxygen therapy.[] This consideration should be relatively independent of the patient's COHb level, which correlates only weakly with toxicity. Patients with prolonged low-level exposure develop a “soaking” phenomenon, in which extremely high tissue concentrations of CO occur without the patient ever having high COHb levels. In addition to using hyperbaric oxygen therapy in those patients with obvious signs of tissue hypoxia, some institutions have set an arbitrary conservative COHb level of 25% at which asymptomatic or minimally symptomatic patients will be referred for hyperbaric oxygen therapy. Some institutions use COHb levels of 40%, and others refrain from specifying a number. Special consideration is given for pregnancy because of the higher oxygen affinity of fetal hemoglobin and lower fetal PO2. Because fetal CO poisoning is associated with dysfunction and death, and hyperbaric oxygen therapy appears safe in pregnancy, many institutions have lowered the standard for initiating hyperbaric oxygen therapy in a pregnant patient to a COHb level of 15%.[24] Further study is still needed to define the optimal duration, pressure, and frequency of hyperbaric oxygen therapy. In particular, although previous studies suggested that there is no benefit to multiple hyperbaric oxygen sessions, the study by Weaver and associates utilized three sessions and may ultimately become the de facto standard therapy. Patients with elevated COHb levels who do not require hyperbaric oxygen therapy should be treated with normobaric oxygen therapy delivered by a tight-fitting nonrebreather face mask, at least until the symptoms resolve and the COHb levels fall. The total duration of such therapy is undefined, and while 3 days was suggested in one study,[21] most mildly CO-poisoned patients probably require no more than 6 hours of therapy.[25]

Simultaneous Carbon Monoxide and Cyanide Poisoning (Fire Victim) Concurrent toxicity from CO and cyanide is widely reported and a major factor in the mortality associated with exposure to fire smoke.[] Smoke inhalation victims who present with coma and metabolic acidosis can have severe CO poisoning, cyanide poisoning, or both. Nitrite-induced methemoglobinemia, which further reduces the tissue oxygen delivery, may be detrimental to patients with elevated COHb levels. Sodium thiosulfate, administered alone, is shown experimentally to be beneficial, safe, and without the risk of

Page 3703

hypotension or decrease of oxygen-carrying capacity engendered by MetHb.[27] A standard dose of 12.5 g should be given to all adult smoke inhalation victims with coma, hypotension, acidosis, or cardiovascular collapse in whom cyanide poisoning cannot be rapidly excluded (1.65 mL/kg of 25% sodium thiosulfate in children). If the COHb level is known to be low and the patient has persistent acidosis or hemodynamic instability, the complete cyanide antidote kit, including the nitrites, can be administered. Patients with high COHb levels undergoing therapy in a hyperbaric oxygen chamber can receive nitrite therapy while pressurized, with little concern of decreasing the oxygen-carrying capacity.

Disposition The decision to transfer a patient to a hyperbaric oxygen facility must consider the time delay to therapy, patient issues (e.g., burns, age), and potential transport-related complications.[28] At a minimum, prolonged oxygen therapy should be administered, although the benefit of this remains undefined. Hyperbaric oxygen should be administered to all patients with consequential CO poisoning, which includes patients with syncope or altered mental status independent of COHb level and patients with elevated COHb concentrations independent of clinical findings. The specific level depends on the availability of a hyperbaric chamber and local standards, as does the decision to provide hyperbaric oxygen therapy for patients with mild symptoms (e.g., headache, dizziness). All patients exposed to CO require close follow-up to evaluate for delayed sequelae.

KEY CONCEPTS {,

{,

Carb on mon oxid e pois onin g is com mon and has impo rtant publi c healt h impli catio ns. Carb on mon oxid e pois onin g can be obsc ure and shou ld be corr obor ated with

Page 3704

co-o xime try whe n com mon occu pant s or famil ies pres ent with head ache and vagu e flulik e sym ptom s. {,

Bec ause the role of hype rbari c oxyg en thera py in CO pois onin g is contr over sial, cons ultati on with a hype rbari c oxyg en facilit y or pois on contr ol syst em

Page 3705

may be helpf ul in signi fican t toxici ty.

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Marx: Rosen's Emergency Medicine: Concepts and Clinical Practice, 6th ed., Copyright © 2006 Mosby, Inc.

Preface to the First Edition From the vision and foresight of a few physicians who perceived the need for a unique, disciplined, sensitive approach to the identification and stabilization of patients threatened with loss of life or limb, emergency medicine has rapidly developed into an exciting, academically recognized medical specialty. This textbook is dedicated to those who have accepted its responsibilities, challenges, and excitements. We have attempted to define in depth the material on which our practice is based. There have been a number of efforts to write about emergencies, but we believe that this is the first to call solely on those people who themselves practice the specialty. In every chapter theory and knowledge pertinent to the practice of emergency medicine are presented. This book is not an easy one; it was written based on published literature, not anecdote or prejudice. In many instances where the data are not available, both sides are presented with a suggested practice. The book is intended for all with a serious interest in or a need to know emergency medicine, including those who do not practice full-time emergency medicine, as well as the dedicated specialists who do. The book is organized into two main sections trauma and nontrauma. This division is artificial but does correspond to the first major decisions made in patient evaluations, because trauma usually affects individual anatomic structures whereas nontrauma is more likely to affect systems. Despite this artificial separation, long and detailed discussion and instruction to authors concerning content and style ensued. We realize that we could not tap all available talent for contributions to the book, but we have made an effort to represent different schools of thought and regions of the country. There are deliberate omissions; for example, we elected not to include any procedures. There was not enough room to create an atlas, but it was our desire to cover the chosen topics in detail. No effort has been made to address administration, management, disaster planning, or technical requirements of emergency medicine supplies or design. Prehospital care has been included only as it relates to individual topics, not as suggested protocol or from the vantage point of technician training programs. It would be impossible to write a book this long and present nothing controversial. In fact we ourselves find sections we cannot totally accept, but in the process of working with multiple authors, we cannot with intellectual honesty put ideas into their material. We have, however, achieved our goal of presenting an in-depth vision of emergency medicine written by specialists in emergency medicine. We hope you will find the reading of this book as stimulating and enjoyable as we have found its creation. PETER ROSEN FRANK J. BAKER II G. RICHARD BRAEN ROBERT H. DAILEY RICHARD C. LEVY

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REFERENCES 1. Engel J, Starkman S: Overview of seizures. Emerg Med Clin North Am1994;12:895. 2. Huff JS: Emergency department management of patients with seizures: A multicenter study. Acad Emerg Med2001;8:62. 3. Hirtz D: Practice parameter: Treatment of the child with the first unprovoked seizure: Report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology2003;60:166. 4. Bui TT: Infant seizures not so infantile: First-time seizures in children under six months of age presenting to the ED. Am J Emerg Med2002;20:518. 5. Schmidt D: Syncopes and seizures. Curr Opin Neurol1996;9:78. 6. Morrell MJ: Differential diagnosis of seizures. Neurol Clin1993;11:737. 7. American College of Emergency Physicians : Clinical policy for the initial approach to patients presenting with a chief complaint of seizure who are not in status epilepticus. Ann Emerg Med1997;29:706. 8. Cereghino JJ: Treating repetitive seizures with a rectal diazepam formulation: A randomized study. Neurology1998;51:1274. 9. D'Onofrio G: Lorazepam for the prevention of recurrent seizures related to alcohol. N Engl J Med 1999;340:915. 10. Ramsey RE, DeToledo J: Intravenous administration of fosphenytoin: Options for the management of seizures. Neurology1996;46(Suppl 1):S17. 11. Uthman BM, Wilder BJ, Ramsey RE: Intramuscular use of fosphenytoin: An overview. Neurology 1996;46(Suppl 1):S24. 12. Quigg M, Shneker B, Domer P: Current practice in administration and clinical criteria of emergent EEG. J Clin Neurophysiol2001;18:162. 13. Haafiz A, Kissoon N: Status epilepticus: Current concepts. Pediatr Emerg Care1999;15:119. 14. Hanhan UA, Fiallos MR, Orlowski JP: Status epilepticus. Pediatr Clin North Am2001;48:683. 15. Lowenstein DH, Alldredge BK: Status epilepticus. N Engl J Med1998;338:970. 16. Smith BJ: Treatment of status epilepticus. Epilepsy2001;345:631. 17. Alldredge BK: The comparison of lorazepam, diazepam, and placebo for the treatment of out of hospital status epilepticus. N Engl J Med2001;345:631. 18. Sharma S: The role of emergent neuroimaging in children with new-onset afebrile seizures. Pediatrics 2003;111:1. 19. French JA: Efficacy and tolerability of the new antiepileptic drugs I. Treatment of new onset epilepsy. Neurology2004;62:1252.

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REFERENCES 1. Gill JR, Ely SF, Hua S: Environmental gas displacement: Three accidental deaths in the workplace. Am J Forens Med Pathol2002;23:26. 2. Shelef M: Unanticipated benefits of automotive emission control: Reduction in fatalities by motor vehicle exhaust gas. Sci Total Environ1994;146/147:93. 3. DeBehnke DJ: The hemodynamic and arterial blood gas response to asphyxiation: A canine model of pulseless electrical activity. Resuscitation1995;30:169. 4. Kollef MH, Schuster DP: The acute respiratory distress syndrome. N Engl J Med1995;332:27. 5. Bernard GR: The American-European Consensus Conference on ARDS: Definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med1994;149:818. 6. Traub SJ, Hoffman RS, Nelson LS: Case report and literature review of chlorine gas toxicity. Vet Hum Toxicol2002;44:235. 7. Wang J, Zhang L, Walther SM: Inhaled budesonide in experimental chlorine gas lung injury: Influence of time interval between injury and treatment. Intensive Care Med2002;28:352. 8. Lin WY, Kao CH, Wang SJ: Detection of acute inhalation injury in fire victims by means of technetium-99m DTPA radioaerosol inhalation lung scintigraphy. Eur J Nucl Med1997;24:125. 9. Baud FJ: Elevated blood cyanide concentrations in victims of smoke inhalation. N Engl J Med 1991;325:1761. 10. Nieman GF, Clark WR, Hakim T: Methylprednisolone does not protect the lung from inhalation injury. Burns1991;17:384. 11. Reiffenstein RJ, Hulbert WC, Roth SH: Toxicology of hydrogen sulfide. Annu Rev Pharmacol Toxicol 1992;32:109. 12. Johnson RP, Mellors JW: Arteriolization of venous blood gases: A clue to the diagnosis of cyanide poisoning. J Emerg Med1988;6:401. 13. Snyder JW: Occupational fatality and persistent neurological sequelae after mass exposure to hydrogen sulfide. Am J Emerg Med1995;13:199. 14. Girman JR: Causes of unintentional deaths from carbon monoxide poisoning in California. West J Med 1998;168:158. 15. Longo LD: The biological effects of carbon monoxide on the pregnant woman, fetus and newborn infant. Am J Obstet Gynecol1977;129:69. 16. Thom SR, Fisher D, Manevich Y: Roles for platelet-activating factor and *NO-derived oxidants causing neutrophil adherence after CO poisoning. Am J Physiol Heart Circ Physiol2001;281:H923. 17. Choi IS: Delayed neurologic sequelae in carbon monoxide intoxication. Arch Neurol1983;40:433. 18. Thom SR: Delayed neuropsychiatric sequelae following CO poisoning. Ann Emerg Med1994;23:612. 19. Goulon M: Intoxication oxy carbonee et anoxic aique par inalation de gay de charbon et d'hydvocarbure. Ann Med Interne (Paris) J Hyperbaric Med1969;1986;1201:335.23.[English translation.] 20. Weaver LK: Hyperbaric oxygen for acute carbon monoxide poisoning. N Engl J Med2002;347:1057. 21. Scheinkestel CD: Hyperbaric or normobaric oxygen for acute carbon monoxide poisoning: A randomized controlled clinical trial. Med J Aust1999;170:203. 22. Hardy KR, Thom SR: Pathophysiology and treatment of carbon monoxide poisoning. J Toxicol Clin Toxicol1994;32:613. 23. Gorman D, Drewry A, Huang YL, Sames C: The clinical toxicology of carbon monoxide. Toxicology 2003;187:25. 24. Elkharrat D: Acute carbon monoxide intoxication and hyperbaric oxygen in pregnancy. Intensive Care Med1991;17:289. 25. Raphael JC: Trial of normobaric and hyperbaric oxygen for acute carbon monoxide intoxication. Lancet 1989;2:414. 26. Alarie Y: Toxicity of fire smoke. Crit Rev Toxicol2002;32:259. 27. Ivankovich AD: Cyanide antidotes and methods of their administration in dogs: A comparative study. Anesthesiology1980;52:210. 28. Sloan EP: Complications and protocol considerations in carbon monoxide-poisoned patients who require hyperbaric oxygen therapy: Report from a ten-year experience. Ann Emerg Med1989;18:629.

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Marx: Rosen's Emergency Medicine: Concepts and Clinical Practice, 6th ed., Copyright © 2006 Mosby, Inc.

Chapter 158 – Lithium Keith K. Burkhart

PERSPECTIVE Lithium has been recommended as an antidepressant since the 1870s but fell into disfavor because of its side effects. In 1949, Cade advocated lithium for acute mania, and its effectiveness for bipolar mood disorders became well recognized. In the 1940s, lithium chloride was used as a salt substitute, but the U.S. Food and Drug Administration banned its use until 1970 because of fatalities from this practice. Because of its effectiveness, however, lithium remains a mainstay for the treatment of bipolar disorders. Studies are underway to determine whether the suicide rate is lower in patients prescribed lithium, so there is the possibility that increased use of this drug will be seen in the future. Unfortunately, fatalities continue to occur because lithium has such a narrow therapeutic window.

PRINCIPLES OF DISEASE The mechanism for lithium's antipsychotic effect is not fully understood. Competition at the sodium-potassium pump has been proposed. Changes in catecholamine and serotonergic neurotransmission may result from its cellular alterations. With more serotonergic drugs on the market, lithium therapy also places patients at risk for many drug interactions, especially the serotonin syndrome ( Table 158-1 ). Table 158-1 -- Drug Interactions that Result in Lithium Toxicity Agent

Action

ACE inhibitors Angiotensin II receptor blockers Antibiotics Spectinomycin, tetracycline, metronidazole, levofloxacin Benzodiazepines Clonazepam, diazepam Carbamazepine Diuretics: thiazide and loop p -Methyldopa Monoamine oxidase inhibitors NSAIDs Olanzapine Phenothiazines SSRIs

Increase Li level Increase Li level Increase Li level

Serotonin agonists[*]

Serotonin syndrome

Enhance Li toxicity Enhance Li toxicity Increase Li level Enhance toxicity Serotonin syndrome Increase Li level Enhance Li toxicity Enhance Li toxicity Serotonin syndrome

ACE, angiotensin-converting enzyme; Li, lithium; NSAIDs, nonsteroidal anti-inflammatory drugs; SSRIs, selective serotonin reuptake inhibitors. *

For exam ple, buspirone, m eperidine, m irtazapine, nefazodone, tram adol, trazodone, and venlafaxine.

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Lithium is a group IA alkali metal smaller than, but similar to, sodium and potassium. Lithium carbonate is the most commonly prescribed formulation; the typical dose for adults is 600 to 1200 mg/day. Immediate-release and sustained-release preparations are available. In cases of acute overdose, peak serum levels usually occur within 2 to 6 hours for immediate-release preparations, but not until 6 to 24 hours and even days for some sustained-release products. Lithium has a slow alpha phase of distribution. Although the volume of distribution approximates total body water, 0.7 L/kg, lithium moves slowly across cellular membranes. Lithium's elimination from cells is also slow, with a half-life of 24 ± 12 hours. Therefore, patients can present severely toxic with levels in the therapeutic range (0.6-1.2 mEq/L). During recovery from chronic lithium toxicity, serum levels can become undetectable, but symptoms may persist. Lithium elimination is almost entirely renal. Lithium is actively reabsorbed in the proximal tubule and to a lesser extent in the thick ascending limb and collecting duct. During volume loss or sodium depletion, the kidney increases reabsorption of sodium and lithium. Therefore, febrile illnesses, vomiting from any cause and especially gastroenteritis, and heat-related fluid losses can precipitate lithium toxicity. Excessive daily doses or renal insufficiency with stable doses can also lead to elevated lithium levels. In addition, chronic poisoning is commonly seen in patients with nephrogenic diabetes insipidus, patients older than 50 years of age, and those with thyroid dysfunction.[1] A number of drug interactions have been reported (see Table 158-1 ). Many enhance the renal absorption of lithium. Lithium also has been implicated in precipitating the serotonin syndrome when used concomitantly with many psychiatric drugs, including cyclic antidepressants, the monoamine oxidase inhibitors, and possibly the atypical antipsychotic olanzapine (see Chapter 159 ).[2] Another report describes lithium intoxication after levofloxacin therapy.[3] Table 158-2 -- Comparison of Acute and Chronic Lithium Toxicity Acute

Chronic

Cause

Overdose

Sodium loss or volume depletion

Presenting symptoms

Asymptomatic or gastrointestinal symptoms

Gastrointestinal and neurologic symptoms

Whole-bowel irrigation

Helpful acutely

Ineffective

Consider dialysis

Neurologic symptoms or levels > 4 mEq/L

Neurologic symptoms or levels > 2.5 mEq/L

CLINICAL FEATURES Patients present with either acute overdose or chronic toxicity from slowly increasing lithium levels ( Table 158-2 ). Most acutely poisoned patients first have nausea, vomiting, abdominal cramping, and sometimes diarrhea. Typical progression of acute toxicity includes neuromuscular signs. Headache has been described as a manifestation of lithium intoxication.[4] Tremulousness, dystonia (e.g., cogwheel rigidity), hyperreflexia, and ataxia usually precede agitation, confusion, dysarthria, lethargy, coma, and seizures. Cardiovascular complications from acute toxicity are rare but can include ventricular dysrhythmias, sinus arrest, and asystole.[5] Lithium substitution for potassium is a presumed mechanism. Chronic poisonings manifest primarily with neurologic signs and symptoms. Lethargy and confusion develop first, and if unrecognized, patients often continue their lithium regimen. Coma and status epilepticus can result if early symptoms are not recognized. Many severely poisoned patients develop permanent neurologic sequelae, including cognitive impairment, sensorimotor peripheral neuropathy, and cerebellar dysfunction.[] Electrocardiographic changes are common in cases of chronic poisoning. T wave changes predominate and include flattening, nonspecific ST-T wave changes, and inversion. These changes can persist for weeks after toxicity. Conduction defects include prolonged PR, QRS, and QTc intervals. Renal toxicity is a common manifestation of chronic lithium intoxication. Lithium inhibits arginine vasopressin (antidiuretic hormone), impairing sodium and water conservation. Increased parathyroid levels may explain this inhibition.[8] Diabetes insipidus develops from both therapeutic use and toxicity. The replacement of free water at rates of 1 L per hour is sometimes required. Many chronically poisoned patients are severely dehydrated. Because of underlying diabetes insipidus from therapy, some patients drink gallons of water a

Page 3712

day. Any illness that interferes with this water consumption can aggravate or precipitate lithium toxicity. Lithium has an antithyroid effect. Myxedema coma has been reported as a complication of toxicity. The central nervous system effects of hypothyroidism and lithium toxicity are similar. Hypothyroidism may diminish the neuromuscular manifestations of lithium toxicity.

DIAGNOSTIC STRATEGIES Any patient with a history of bipolar disorder or taking lithium who presents to the emergency department should be evaluated for lethargy, increased tremor, and dehydration from lithium toxicity. Symptomatic patients should have their lithium levels checked. After an acute ingestion, toxicity develops from sustained elevated lithium levels. The ingestion of immediate-release formulations can produce dramatically elevated initial levels that subsequently fall quickly without the development of significant toxicity. The patient who has ingested sustained-release preparations, however, may present with an initially therapeutic level, only to develop sustained elevations that lead to severe life-threatening toxicity days later. Because of the delay to signs and symptoms, patients must be cared for in facilities where lithium levels can be measured immediately. Diagnostic testing should include assessment of electrolytes and renal function. A low anion gap may suggest, but is not typical for, lithium toxicity. Sodium depletion may be identified as well as renal dysfunction. Thyroid functions should also be checked, especially in the chronically poisoned patient.

DIFFERENTIAL CONSIDERATIONS Acute gastroenteritis symptoms are common to many drug overdoses, including acute lithium intoxication. A thorough history of possible exposures may be the only initial clue to the diagnosis of lithium intoxi-cation before neurologic symptoms develop. The broad differential diagnoses of ataxia, neuromuscular rigidity, altered mental status including central nervous system depression, and seizures must include lithium toxicity.

MANAGEMENT Severely lithium-poisoned patients in coma or with seizures may require urgent airway interventions and anticonvulsant therapy with benzodiazepines, phenobarbital, and propofol as necessary. A recent report, however, describes a patient who had electroencephalographic evidence for status epilepticus that did not respond to lorazepam therapy.[9] Patients with chronic lithium toxicity are often volume depleted. Although frank hypotension is unusual, fluid resuscitation is needed and should include normal saline. The goal of saline administration is to restore glomerular filtration, normalize urine output, and enhance lithium clearance. Forced diuresis does not assist in lithium clearance. Once the patient is stabilized, methods to prevent absorption should be considered. In acute overdose, induced emesis should be avoided. Most patients will already be vomiting, which may interfere with other decontamination procedures. As with most elemental cations, activated charcoal is of little benefit for patients with lithium toxicity, except in the case of co-ingestants. Gastric lavage is of little, if any, benefit, most likely failing a risk-benefit analysis. Whole-bowel irrigation with polyethylene glycol electrolyte lavage solution (PEG-ELS) is effective in preventing absorption from extended-release lithium and is theoretically useful in cases involving immediate-release formulations.[10] Adult patients should drink or receive PEG-ELS by nasogastric tube, approximately 1.5 L of solution per hour until effluents are clear. Adjunctive antiemetic therapy may be required. Serial levels are still necessary, because not all pills are cleared by PEG-ELS. During the whole-bowel irrigation procedure, absorption of tablets that are not eliminated may be slowed or prevented. Falling levels have occurred during whole-bowel irrigation, only to rise again when the procedure is stopped. Cationic exchange resins such as sodium polystyrene sulfonate are effective in reducing the absorption of lithium. Although multiple doses of sodium polystyrene sulfonate have been suggested in animal models, further human study is needed. Care must be taken to avoid severe life-threatening hypokalemia from sodium polystyrene sulfonate. Lithium is readily dialyzed because of its small molecular weight, water solubility, and lack of protein binding. Although dialysis dramatically shortens the plasma half-life, outcome studies have not demonstrated its benefit in chronic toxicity. Dialysis should be used in the case of an acute overdose with decreased levels of consciousness, seizures, and renal failure and in symptomatic patients with levels greater than 4.0 mEq/L. Asymptomatic patients with higher levels have been managed without dialysis. For cases of chronic toxicity, dialysis is helpful in symptomatic patients with levels greater than 2.0 mEq/L. In critically ill patients, continuous arteriovenous and venovenous hemofiltration have been used.

DISPOSITION

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Patients with any symptom more than a tremor require hospital admission. Asymptomatic patients with increasing lithium levels require admission for monitoring of serial levels after ingestions. Most patients should be admitted to an institution where dialysis, if indicated, can be performed. An observation unit is not helpful because symptoms are delayed up to 24 hours after the peak serum levels of an acute poisoning. Chronically poisoned patients with neurologic signs, including seizures, myoclonus, hyperexcitability, or decreased level of consciousness, should be admitted to the critical care unit.

KEY CONCEPTS {,

Con sider lithiu m toxici ty in the patie nt with alter ed ment al statu s, neur omu scul ar hype rexci tabilit y, myo clon us, hype rrefle xia, rigidi ty, or seiz ures.

{,

Leve ls shou ld be chec ked in all patie nts recei ving lithiu m who pres ent with

Page 3714

medi cal sym ptom s. Con ditio ns or medi catio ns that lead to dehy drati on or renal insuf ficie ncy can preci pitat e chro nic toxici ty. {,

Dialy sis shou ld be cons idere d for lithiu m level s great er than 2.0 mEq /L in sym ptom atic patie nts with chro nic toxici ty or for patie nts with decr ease

Page 3715

{,

{,

d level of cons ciou snes s or seiz ure. Early whol e-bo wel irriga tion after acut e inge stion may prev ent lithiu m toxici ty and the need for dialy sis. Lithi um level s may rebo und after the proc edur e is stop ped. Lithi um is a com mon com edic ation in the serot onin synd rom e.

Page 3716

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REFERENCES 1. Oakley PW, Whyte IM, Carter GL: Lithium toxicity: An iatrogenic problem in susceptible individuals. Aust N Z J Psychiatry2001;35:833. 2. Haslett CD, Kumar S: Can olanzapine be implicated in causing serotonin syndrome?. Psych Clin Neurosci2002;56:533. 3. Takahashi H, Higuchi H, Shimizu T: Severe lithium toxicity induced by combined levofloxacin administration. J Clin Psychiatry2000;61:949. 4. Bigal ME, Bordini CA, Speciali JG: Daily headache as a manifestation of lithium intoxication. Neurology 2001;57:1733. 5. Apte S, Langston W: Permanent neurologic deficits due to lithium intoxication. Ann Neurol1983;13:453. 6. Lang EJ, Davis SM: Lithium neurotoxicity: The development of irreversible neurological impairment despite standard monitoring of serum lithium levels. J Clin Neurosci2002;9:308. 7. Bartha L, Marksteiner J, Bauer G: Persistent cognitive deficits associated with lithium intoxication: A neuropsychological case description. Cortex2002;38:743. 8. Carney SL, Ray C, Gillies-Alastair HB: Mechanism of lithium-induced polyuria in the rat. Kidney Int 1996;50:377. 9. Gansaeuer M, Alsaadi T: Lithium intoxication mimicking clinical and electrographic features of status epilepticus: A case report and review of the literature. Clin Electroencephalogr2003;34:28. 10. Smith S, Ling L: Whole-bowel irrigation as a treatment for acute lithium overdose. Ann Emerg Med 1991;20:536.

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Chapter 159 – Antipsychotics Mary A. Wittler Eric J. Lavonas

PERSPECTIVE The antipsychotic medication chlorpromazine was first used effectively for the treatment of psychosis in France in 1952 and in the United States and Canada in 1954. The term neuroleptic, historically used because of the high degree of sedation produced by earlier antipsychotic drugs, is no longer appropriate because newer agents cause little sedation. The term antipsychotic is now preferred. U.S. poison control centers report more than 5000 exposures to phenothiazines and 25,000 exposures to atypical antipsychotics annually, resulting in 11 (phenothiazines) and 78 (atypical anti-psychotics) deaths.[1]

PRINCIPLES OF DISEASE Antipsychotic medications are used to treat agitation and psychosis caused by schizophrenia, mania, acute idiopathic psychosis, alcohol withdrawal hallucinosis, and Alzheimer's disease. Antipsychotic medications are often divided into three broad categories based on their receptor profiles, clinical effects, and adverse effects ( Table 159-1 ). All antipsychotic medications effectively treat the positive symptoms of psychotic disorders; they reduce hallucinations, control agita-tion, and aid in restructuring disordered thinking. In general, the low-potency neuroleptics are the most sedating at usual clinical doses. Movement disorders, including extrapyramidal syndromes and tardive dyskinesia (TD), are significant problems with low-potency and high-potency neuroleptics. In addition to producing less sedation and fewer movement disorders, the atypical antipsychotic agents assist with the negative symptoms of psychotic disorders, such as flat affect, avolition, social withdrawal, and impoverished thought and speech. Although neuroleptic malignant syndrome (NMS) has occurred with all agents, it occurs least with the atypical antipsychotics. Table 159-1 -- Selected Antipsychotic Agents Approved or Nearing Approval for Use in the United States Medicati on

Receptors Blocked

Clinical Effects

Adverse Effects

Low potency Chlorpro mazine Chlorprot hixene Fluphena zine Hydroxyzi ne Mesoridaz ine Molindone Perphena zine Prochlorp erazine Prometha

Dopamine D2 (moderate affinity in mesolimbic and nigrostriatal areas) Acetylcholine muscarinic (generally strong affinity) Histamine H1 (strong affinity) p -Adrenergic (moderate affinity) Dopamine D1, D3, D4, D5 (variable affinity)

Control positive symptoms of psychotic disorders:

Extrapyramidal syndromes (common)

Hallucinations

Tardive dyskinesia (common)

Delusions

Sedation (common)

Agitation

Orthostatic hypotension (common)

Disordered thoughts

Anticholinergic symptoms (common): Dry mouth Blurred vision Impaired sweating Constipation

Page 3719

zine Thioridazi ne

Weight gain Urinary retention Angle-closure glaucoma

High potency Droperidol Dopamine D2 (strong Control positive symptoms affinity in mesolimbic and of psychotic disorders nigrostriatal areas) Haloperid Acetylcholine muscarinic, ol histamine H1. p -adrenergic (weak affinity) Loxapine Dopamine D1, D3, D4, D5 (variable affinity)

Extrapyramidal syndromes (common) Tardive dyskinesia (common)

Sedation, orthostatic hypotension, and anticholingeric symptoms (uncommon in usual clinical doses)

Pimozide Thiothixen e Trifluoper azine Atypical Clozapine Serotonin 5-HT2A (strong) Control positive symptoms Extrapyramidal syndromes and of psychotic disorders tardive dyskinesia (uncommon) Olanzapin Dopamine D2 (mild to e moderate affinity, selective for mesolimbic areas) Quetiapin Dopamine D1, D3, D4, D5 Control negative symptoms e of psychotic disorders: (variable affinity) Risperido ne Ziprasidon e

Social withdrawal Flattened affect Decreased activity

Aripiprazo le[*] *

Paucity of speech Pseudodementia

Aripiprazole has partial agonist activity at dopam ine D2 and serotonin 5-HT1A receptors and antagonist activity at serotonin 5-HT2A receptors.

Anatomy and Physiology Antipsychotic drugs block dopamine receptors in several areas of the brain, including the cerebral cortex, basal ganglia, limbic system, hypothalamus, and chemoreceptor trigger zone. Traditional antipsychotic agents reduce the positive symptoms of schizophrenia by blocking the dopamine D2 receptor subtype in the mesolimbic region of the brain. Blockade of D2 receptors in the nigrostriatal brain region produces the undesired extrapyramidal movement disorders, and blockade of D2 receptors in the mesocortical brain region impairs cognition and worsens the negative symptoms of schizophrenia. D2 Atypical antipsychotic agents block D2 and serotonin (5-hydroxytryptamine type 2A [5-HT2A]) receptors. These agents selectively bind D2 receptors in the mesolimbic areas of the brain, with less effect on nigrostriatal D2 receptors resulting in fewer extrapyramidal effects. The 5-HT2A receptor antagonism is thought to reduce extrapyramidal effects and improve the negative symptoms of schizophrenia. Antipsychotic medications also block other receptor types (see Table 159-1 ). The antiemetic effects of prochlorperazine, promethazine, and droperidol result from blockade of dopamine receptors in the chemoreceptor trigger zone of the medulla. Hydroxyzine reduces itching by blocking histamine (H1) receptors. Prochlorperazine and droperidol are theorized to abort migraine headaches by

Page 3720

prevent-ing dopamine-mediated meningeal artery vasodilation. Chlorpromazine can treat severe hiccups. Haloperidol is used for certain movement disorders, including Tourette's syndrome and Huntington's chorea.

Pathophysiology Extrapyramidal symptoms (EPS) can be divided into two groups based on the time of development after initiating drug therapy. Acute EPS include dystonia, akathisia, and parkinsonism. These adverse effects are caused by blockade of nigrostriatal D2 receptors and are reduced by muscarinic receptor antagonism. The delayed-onset syndromes, including TD and tardive dystonia, develop after prolonged use of antipsychotic medications, most likely because chronic dopamine receptor blockade in the nigrostriatal area leads to D2 receptor upregulation and hypersensitivity to dopamine.[3] NMS, an idiosyncratic reaction to antipsychotic medication, is thought to result from neuroregulatory dysfunction secondary to D2 receptor blockade in the substantia nigra and hypothalamus. The phenothiazines possess quinidine-like effects, resulting in Q-T prolongation and potential dysrhythmias in overdose.[] Thioridazine and mesoridazine have the greatest risk of cardiac toxicity.[6] The butyrophenones can prolong cardiac repolarization, potentially causing torsades de pointes. Partial blockade of the delayed inward rectifier potassium current prolongs phase 3 of the cardiac action potential.[7] The atypical antipsychotics produce less cardiotoxicity than the traditional agents, although most potentially cause repolarization abnormalities in therapeutic dosing or overdose.[] Clozapine produces agranulocytosis in approximately 0.4% of patients even after strict adherence to labeling requirements.[9] Seizure occurs uncommonly with antipsychotic drugs, but is a risk with clozapine, perhaps related to anticholinergic effects.[10] The atypical antipsychotics have been associated with altered glucose metabolism and diabetes, especially clozapine and olanzapine, but the cause of this has not been established.

CLINICAL FEATURES Acute Overdose In overdose, antipsychotic medications produce signs and symptoms that are exaggerations of the clinical effects. Most patients develop symptoms within a few hours. Central nervous system (CNS) depression is universally present, ranging from mild sedation and confusion to coma, loss of brainstem reflexes, and respiratory depression. Pupils can be of any size. Mild orthostatic hypotension is a common finding secondary to p -adrenergic blockade. The most common cardiac rhythm is sinus tachycardia with a normal QRS duration. If QRS prolongation is present, coingestion of another drug should be suspected. Significant Q-T prolongation can occur, predisposing to torsades de pointes.[] Overdose with low-potency antipsychotics can cause an anticholinergic delirium. EPS has been reported with the traditional and atypical antipsychotics. Atypical antipsychotic overdose is similar to overdose with the traditional antipsychotics. Clozapine, olanzapine, quetiapine, and risperidone overdoses are characterized by CNS depression and tachycardia.[] Miosis may be present, potentially mimicking opioid toxicity.[19] Extremity twitching is common. With the exception of clozapine, seizures rarely occur in overdose. Q-Tc prolongation has been reported in overdose, particularly with ziprasidone.[] The clinical significance of Q-Tc prolongation and the risk of torsades are not known, however. Acute EPS has been reported for risperidone overdose. There are no reports of aripiprazole overdose published to date. Adverse effects during therapeutic use include headache, agitation, akathisia, somnolence, and dyspepsia. Aripiprazole does not seem to prolong the Q-Tc in therapeutic dosing.[22]

Acute Extrapyramidal Syndromes Acute dystonia manifests as involuntary motor tics or spasms that most often involve the facial, neck, back, or limb muscles. Dystonic reactions usually develop within the first several doses of treatment. Oculogyric crisis, characterized by continuous rotatory eye movements, also has been reported. Laryngeal dystonia is a rare but life-threatening form of dystonia that manifests as throat tightening, difficulty breathing or swallowing, or a choking sensation.[23] Akathisia, a subjective feeling of restlessness associated with objective motor restlessness, is often mistaken for worsening agitation, leading incorrectly to an increase in antipsychotic dose. Akathisia usually develops within the first few days of treatment. In one clinical study, 40% of patients administered 10 mg of intravenous haloperidol developed akathisia within 1 hour of the dose, and the syndrome is often seen in

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migraine headache patients treated with prochlorperazine. A parkinsonian syndrome of bradykinesia, masked facies, shuffling gait, muscular rigidity, and resting tremor frequently develops during the first weeks of therapy with low-potency and high-potency neuroleptic-antipsychotic agents. Perioral tremor (rabbit syndrome), in which lip and nose movements resemble those of a rabbit, also can develop after prolonged therapy.[25]

Tardive Dyskinesia TD is a chronic movement disorder induced by prolonged use of antipsychotic medication. Typical signs of TD include quick, involuntary movements of the face (blinking, grimaces, tongue movements, chewing), extremities, or trunk. Twenty percent of patients treated with long-term traditional antipsychotics are affected. The risk of development is much lower with the atypical antipsychotics. Although anticholinergic agents may reduce the symptoms of TD, the disorder is frequently permanent and difficult to treat. Reducing the antipsychotic dose or changing to an atypical agent should be considered. TD improves in many patients switched to clozapine, but further clinical trials are needed to study all atypical antipsychotic agents.[] Respiratory dyskinesia, a variant of TD, is characterized by orofacial dyskinesia, dyspnea, dysphonia, and respiratory alkalosis. This chronic disorder often goes undiagnosed and can cause repeated bouts of aspiration pneumonia.

Neuroleptic Malignant Syndrome NMS, the most serious extrapyramidal effect, typically develops during the first 2 weeks of drug therapy but has occurred in patients on stable drug regimens. Risk factors include rapid drug loading, high dosage, increase in dosage, high-potency antipsychotics, parenteral formulations, dehydration, and previous episodes of NMS.[28] Other medications may contribute to NMS, including lithium, which inhibits dopamine secretion, and withdrawal from dopaminergic agents used to treat Parkinson's disease.[] NMS develops in 0.02% to 12.2% of patients treated with the traditional antipsychotics.[28] The atypical antipsychotic agents, including clozapine, risperidone, olanzapine, and quetiapine, have been associated with NMS.[30] Table 159-2 lists the diagnostic criteria for NMS. Other features of NMS include sialorrhea, dysarthria, opisthotonus, dyskinesia, metabolic acidosis, liver function elevations, sodium imbalance, dehydration, elevations in serum catecholamines, coagulopathy, generalized slowing on the electroencephalogram, pulmonary embolism, and renal failure.[28] Multiple case reports discuss atypical presentations that lack full diagnostic criteria for NMS.[30] Table 159-2 -- Diagnostic Criteria and Clinical Features of Neuroleptic Malignant Syndrome Criteria/Features Prevalence A. Development of severe muscle rigidity and Rigidity: 97% elevated temperature associated with the use of a Fever: 98% neuroleptic/antipsychotic medication B. Two (or more) of the following are present: 1. Diaphoresis 98% 2. Dysphagia 3. Tremor 4. Incontinence 5. Change in level of consciousness ranging from 97% confusion to coma 6. Mutism 7. Tachycardia 88% 8. Elevated or labile blood pressure 61% 9. Leukocytosis 98% 10. Laboratory evidence of muscle injury (e.g., 95% elevated CK) C. Symptoms in criteria A and B are not caused by another substance (e.g., phencyclidine), a neurologic or other general medical condition (e.g., viral encephalitis), or another mental disorder (e.g., mood disorder with catatonic features). Modified from American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th

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ed (TR). Washington, DC, 2000; American Psychiatric Association, prevalence data from Caroff SN, Mann SC: Neu-roleptic malignant syndrome. Med Clin North Am 77:185, 1993.

Most patients develop the cardinal features of altered mental status, muscle rigidity, autonomic nervous system instability, and hyperthermia within 3 days. The signs of NMS may develop gradually, however, and in any order.[31] Agitation, often mistaken for worsening psychosis, may occur first. Physicians should consider discontinuing antipsychotic drugs in a patient who has developed one or more of the major manifestations of NMS. Most episodes resolve within 2 weeks after cessation of the offending medication, but some cases have lasted 6 months.[32]

Cardiac Repolarization Abnormalities and Dysrhythmias Q-T prolongation and torsades de pointes are well-described adverse effects of thioridazine, mesoridazine, droperidol, sertindole, and high-dose intravenous haloperidol.[] Therapeutic doses of oral haloperidol, chlorpromazine, pimozide, and ziprasidone also have been associated with Q-T prolongation.[35] In a clinical study, ziprasidone prolonged the Q-T interval more than risperidone, olanzapine, or quetiapine. Q-T prolongation should be considered a “class effect” of all antipsychotic medications. Whenever possible, antipsychotic medications should not be prescribed concomitantly with other drugs known to prolong the Q-T interval. Atrioventricular nodal block is a rare reported complication of overdose with chlorpromazine, thioridazine, and other older neuroleptics.[36]

Agranulocytosis Clozapine produces agranulocytosis, with 75% of occurrences developing within the first 18 weeks after initiation of therapy, peaking at 3 months. The concomitant use of other bone marrow–suppressing agents (e.g., carbamazepine) should be avoided. Clozapine administration must be halted if the total white blood cell count decreases to less than 3000 cells/mm[3] or if the absolute neutrophil count is less than 1500 cells/mm3. Agranulocytosis has not been reported after an acute overdose. Olanzapine, whose chemical structure is similar to clozapine, has been associated with neutropenia and agranulocytosis. All patients recovered after discontinuation of olanzapine.[37]

Seizures Antipsychotic medications can lower the seizure threshold and induce epileptiform electroencephalogram abnormalities in many asymptomatic patients. Antipsychotic-induced seizures are rare, however. An exception is clozapine, which causes a dose-related increased risk of seizures (approximately 5% at high doses). Antipsychotics can be prescribed for patients with known seizure disorders.[38]

DIFFERENTIAL CONSIDERATIONS Differential diagnostic considerations include a broad list of agents and clinical conditions that produce altered mental status, orthostatic hypotension, anticholinergic syndrome, seizure, Q-T prolongation, or torsades de pointes. Although the signs of NMS are similar to serotonin syndrome and heatstroke, the etiologies of these conditions are quite different ( Table 159-3 ). Malignant hyperthermia should be considered in patients receiving inhalational anesthetics or succinylcholine. Table 159-3 -- Differential Diagnosis of Neuroleptic Malignant Syndrome Pathologic Differentiating Disease[*] Mechanism Factor Time Course Neuroleptic Impaired malignant syndrome thermoregulation in hypothalamus and basal ganglia due to relative lack of dopamine activity

Antipsychotic medication use, muscular rigidity (diagnostic criteria in Table 159-2 )

Treatment

Gradual, progresses Stop offending over several days medication(s)

Hydration Active cooling Intravenous benzodiazepines to relax muscles and

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Disease[*]

Pathologic Mechanism

Serotonin syndrome Excess serotonin and dopamine levels in central nervous system

Heatstroke

Environmental heat stress

Differentiating Factor

Medications (usually a combination) that increase serotonin levels (e.g., SSRIs, MAOIs, dextromethorphan, lithium, meperidine, tramadol, tryptophan); muscular rigidity

Environmental exposure history; muscular rigidity rare

Time Course

Usually rapid after introduction of new medication or increase in dose; can be gradual

Rapid or gradual

Treatment control agitation Neuromuscular blockade (nondepolarizing agents) Controversial: Bromocriptine or amantadine Dantrolene Stop offending medication(s)

Hydration Active cooling Cyproheptadine Hydration

Active cooling Malignant hyperthermia

Genetic instability of sarcoplasmic reticulum, causing massive calcium release after administration of triggering medication

Occurs after administration of inhalational anesthetic or succinylcholine; muscular rigidity

Sudden, provoked Stop anesthetic by administration of anesthetic

Hydration Active cooling Dantrolene

SSRIs, selective serotonin reuptake inhibitors; MAOIs, monoamine oxidase inhibitors. *

Other clinical entities to consider in the diagnosis of these conditions include Addison's syndrom e, central nervous system infection, delirium trem ens, hypocal-cem ia, hypoglycem ia, hyponatrem ia, intracranial hem orrhage, lethal catatonia, poisoning (am phetam ines, anticholinergics, cocaine, nicotine, salicylates, sym -pathom im etics, strychnine, theophylline), sedative-hypnotic drug withdrawal, sepsis, status epilepticus (including nonconvulsive status), tetanus, thalam ic

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infarct, thyroid storm , and psychotic agitation.

DIAGNOSTIC STRATEGIES Blood levels are neither readily available nor helpful in the management of an overdose with antipsychotic medication. As with any patient who presents with altered mental status, blood glucose and pulse oximetry readings should be obtained immediately. Other testing, such as brain computed tomography, lumbar puncture, serum acetaminophen measurement, and electrolyte measurements, may be required depending on the clinical situation. An electrocardiogram should be obtained in all patients with significant antipsychotic medication overdose and in symptomatic patients taking thioridazine, mesoridazine, or droperidol. Patients receiving high-dose intravenous haloperidol or droperidol for sedation require cardiac rhythm monitoring. If Q-T prolongation is present, serum potassium, calcium, and magnesium levels should be measured. Patients who develop NMS, parkinsonism with marked muscle rigidity, or prolonged seizures are at risk for rhabdomyolysis. Measurement of serum creatinine kinase, renal function, and urine myoglobin may be indicated. A chest radiograph should be obtained if aspiration is suspected. Patients taking clozapine or olanzapine who present with infection or fever should be checked for leukopenia.

MANAGEMENT Acute Overdose Treatment is supportive; no specific antidote exists for antipsychotic medication overdose. Endotracheal intubation may be required to prevent aspiration or, less often, to support respiration. Hypotension is generally mild and responds to intravenous crystalloids. A vasopressor with p -adrenergic receptor agonism, such as norepinephrine, may be used if needed. If sedation and miosis suggest opioid intoxication, a trial of naloxone is warranted. Physostigmine and flumazenil are not beneficial and may precipitate seizures.

Acute Extrapyramidal Syndromes Diphenhydramine, 25 to 50 mg intravenously, intramuscularly, or orally, or benztropine, 1 to 2 mg intramuscularly or orally, usually controls dystonic reactions. Benzodiazepines also may be effective. Akathisia can be treated with a lipophilic p -adrenergic blocker (e.g., propranolol), anticholinergic agents, or benzodiazepines.[39] Patients with EPS who respond to diphenhydramine or benztropine should continue on therapy for at least 48 hours to prevent recurrence. Benztropine, diphenhydramine, and the neuroleptic antipsychotic medications all cause anticholinergic effects, so combination therapy may worsen dry mouth, blurred vision, and urinary retention. Reducing the antipsychotic dose or changing to an atypical agent may be necessary.

Q-T Prolongation and Torsades de Pointes Correction of hypokalemia, hypomagnesemia, and hypocalcemia shortens the Q-T interval. Treatment of torsades de pointes includes intravenous magnesium sulfate, overdrive pacing, and possibly isoproterenol (see Chapter 78 ). Administration of other antiarrhythmic drugs that prolong the Q-T interval should be avoided.

Neuroleptic Malignant Syndrome Treatment of NMS revolves around supportive care and discontinuation of the offending medication. Agitation, psychomotor hyperactivity, and muscular rigidity should be treated aggressively with intravenous benzodiazepines. Lorazepam can be administered intravenously, 1 to 2 mg every 3 minutes until muscle rigidity improves, to a maximum dose of 10 mg. In refractory cases or cases at risk of aspiration, rapid sequence intubation, endotracheal intubation, and neuromuscular blockade with a nondepolarizing agent (e.g., vecuronium, pancuronium) are required. Hyperthermia should be managed aggressively with intravenous fluids and active external cooling with mist and fans (see Chapter 139 ). If rhabdomyolysis is present, intravenous hydration and urinary alkalization with sodium bicarbonate may be used to prevent renal damage, although the use of sodium bicarbonate is controversial (see Chapter 125 ). The dopamine agonists bromocriptine and amantadine have been advocated as adjunctive treatments for NMS but do not consistently show a benefit.[] Bromocriptine is administered orally or via nasogastric tube, beginning with 5 mg every 8 hours and titrated to a maximum of 20 mg per dose. The dose of amantadine is 200 mg orally every 12 hours. Response to therapy requires at least 24 hours. Bromocriptine has been linked to stroke, seizure, myocardial infarction, and severe hypertension in lactating or postpartum women, but not during treatment of NMS.[42]

Page 3725

Dantrolene, which inhibits the release of calcium from the sarcoplasmic reticulum, also has been advocated as an adjunctive therapy for NMS. As with the dopaminergic agents, it has no proven benefit.[] Because the muscular rigidity of NMS is proposed to be secondary to dopamine blockade in the CNS rather than a muscle abnormality, dantrolene offers no advantage over benzodiazepines and neuromuscular blockade. Adverse effects after intravenous dantrolene include visual disturbances, dizziness, weakness, and gastrointestinal upset.[43] Pleural effusions, pneumonitis, pericarditis, and hepatitis have been reported with long-term administration.[] Dantrolene can cause hyperkalemia and is contraindicated with verapamil.[47]

DISPOSITION Patients with NMS and overdose patients who develop hypotension, coma, torsades de pointes, or airway compromise should be admitted to a critical care unit. Patients with a prolonged Q-T interval (Q-Tc >460 msec) and all patients with significant ingestions of thioridazine or mesoridazine should receive at least 12 hours of cardiac monitoring. Patients with less severe signs of toxicity should be observed in the emergency department for a minimum of 4 hours from the time of ingestion. Persistent or worsening signs and symptoms mandate hospitalization. Criteria for hospital discharge include return to normal mental status and resolution of any vital sign, metabolic, and electrocardiogram abnormalities.

KEY CONCEPTS {,

Extr apyr amid al mov eme nt disor ders are a com mon com plica tion of antip sych otic medi catio ns.

{,

The most com mon findi ng in antip sych otic over dose is CNS depr essi on. Trea tmen t

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{,

{,

cent ers on supp ortiv e care, airw ay contr ol, and cardi ac moni torin g. Q-T abno rmali ties and torsa des de point es are pote ntial com plica tions from over dose of man y antip sych otic medi catio ns and can occu r with thera peuti c dose s of som e agen ts. NMS is char

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acter ized by alter ed ment al statu s, hype rther mia, mus cular rigidi ty, and auto nomi c insta bility. Aggr essi ve supp ortiv e care inclu des airw ay man age ment , benz odia zepi nes, neur omu scul ar bloc kade , and activ e cooli ng.

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REFERENCES 1. Watson WA: 2002 Annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med2003;21:353. 2. Burns MJ: The pharmacology and toxicology of atypical antipsychotic agents. J Toxicol Clin Toxicol 2001;39:1. 3. Seeman P: Tardive dyskinesia, dopamine receptors, and neuroleptic damage to cell membranes. J Clin Psychopharmacol1998;18:477. 4. Haddad PM, Anderson IM: Antipsychotic-related QTc prolongation, torsades de pointes and sudden death. Drugs2002;62:1649. 5. Reilly JG: QTc-interval abnormalities and psychotropic drug therapy in psychiatric patients. Lancet 2000;355:1824. 6. LeBlaye I: Acute overdosage with thioridazine: A review of the available clinical exposure. Vet Hum Toxicol 1993;35:147. 7. Drolet B: Droperidol lengthens cardiac repolarization due to block of the rapid component of the delayed rectifier potassium current. J Cardiovasc Electrophysiol1999;10:1597. 8. Drici MD: Prolongation of QT interval in isolated feline hearts by antipsychotic drugs. J Clin Psychopharmacol1998;18:477. 9. Honigfeld G: Reducing clozapine-related morbi-dity and mortality: 5 years of experience with the cloz-aril national registry. J Clin Psychiatry1998;59(Suppl 3):3. 10. Welch J, Manschreck T, Redmond D: Clozapine-induced seizures and EEG changes. J Neuropsychiatry1994;6:250. 11. Gajwani P, Pozuelo L, Tesar G: QT interval prolongation associated with quetiapine (seroquel) overdose. Psychosomatics2000;41:63. 12. Hustey F: Acute quetiapine poisoning. J Emerg Med1999;17:995. 13. Brown K: Overdose of risperidone. Ann Emerg Med1993;22:1908. 14. Staffan H, Spigset O, Edwardson H, Bjork H: Prolonged sedation and slowly decreasing clozapine serum concentrations after an overdose. J Clin Psychopharmacol1999;19:282. 15. Sartorius A: High-dose clozapine intoxication. J Clin Psychopharmacol2002;22:91. 16. Harmon T: Loss of consciousness from acute quetiapine overdosage. J Toxicol Clin Toxicol 1998;36:599. 17. Pollak P, Zbuk K: Quetiapine fumarate overdose: Clinical and pharmacokinetic lesions from extreme conditions. Clin Pharmacol Ther2000;68:92. 18. Cohen L: Olanzapine overdose with serum concentrations. Ann Emerg Med1999;34:275. 19. O'Malley G: Olanzapine overdose mimicking opioid intoxication. Ann Emerg Med1999;34:279. 20. Acri A, Henretig F: Effects of risperidone in overdose. Am J Emerg Med1998;16:498. 21. Bryant S: A case series of ziprasidone overdoses. Vet Hum Toxicol2003;45:81. 22. Bowles T, Levin G: Aripiprazole: A new atypical antipsychotic drug. Ann Pharmacother2003;37:687. 23. Modestin J, Krapf R, Boker W: A fatality during haloperidol treatment: Mechanism of death. Am J Psychiatry1981;138:1616. 24. Drotts D, Vinson D: Prochlorperazine induces akathisia in emergency patients. Ann Emerg Med 1999;34:469. 25. Levin T, Heresco-Levy U: Risperidone-induced rabbit syndrome: An unusual movement disorder caused by an atypical antipsychotic. Eur Neuropsychopharmacol1999;9:137. 26. Hubert F, Friedman J: Classification and treatment of tardive syndromes. Neurologist2003;9:16. 27. Tarsy D, Baldessarini RJ, Tarazi FI: Effects of newer antipsychotics on extrapyramidal function. CNS Drugs2002;16:23. 28. Caroff S, Mann S: Neuroleptic malignant syndrome. Med Clin North Am1993;77:185. 29. Pope HG: Apparent neuroleptic malignant syndrome with clozapine and lithium. J Nerv Ment Dis 1986;174:493. 30. Farver D: Neuroleptic malignant syndrome induced by atypical antipsychotics. Expert Opin Drug Saf 2003;2:21. 31. Velamoor VR: Progression of symptoms in neuroleptic malignant syndrome. J Nerv Ment Dis

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1994;182:168. 32. Legras A: Protracted neuroleptic malignant syndrome complicating long-acting neuroleptic administration. Am J Med1988;85:875. 33. Buckely NA: Cardiotoxicity more common in thioridazine overdose than with other neuroleptics. J Toxicol Clin Toxicol1995;33:199. 34. Krahenbuhl S: Case report: Reversible QT prolongation with torsades de pointes in a patient with pimozide intoxication. Am J Med Sci1995;309:315. 35. Taylor D: Ziprasidone in the management of schizophrenia: The QT interval issue in context. CNS Drugs 2003;17:423. 36. Hulisz DT: Complete heart block and torsades de pointes associated with thioridazine poisoning. Pharmacotherapy1994;14:239. 37. Tolosa-Vilella C: Olanzapine-induced agranulocytosis, a case report and review of the literature. Prog Neuropsychopharmacol Biol Psychiatry2002;26:411. 38. Welch J, Manschreck T, Redmond D: Clozapine-induced seizures and EEG changes. J Neuropsychiatry Clin Neurosci1994;6:250. 39. Miller C, Fleischhacker W: Managing antipsychotic-induced acute and chronic akathisia. Pract Drug Saf 2000;22:73. 40. Shalev A, Hermesh H, Munitz H: Mortality from the neuroleptic malignant syndrome. J Clin Psychiatry 1989;50:18. 41. Rosebush PI, Stewart T, Mazurek MF: The treatment of neuroleptic malignant syndrome: Are dantrolene and bromocriptine useful adjuncts to supportive care?. Br J Psychiatry1991;159:709. 42. Webster J: A comparative review of the tolerability profiles of dopamine agonists in the treatment of hyperprolactinaemia and inhibition of lactation. Drug Saf1996;14:228. 43. Wedel DJ, Quinlan JG, Iazzo PA: Clinical effects of intravenously administered dantrolene. Mayo Clin Proc1991;70:241. 44. Mahoney JM, Bachtel MD: Pleural effusion associated with chronic dantrolene administration. Ann Pharmacother1994;28:587. 45. Chan CH: Dantrolene sodium and hepatic injury. Neurology1990;40:1427. 46. Miller DH, Haas LF: Pneumonitis, pleural effusion and pericarditis following treatment with dantrolene. J Neurol Neurosurg Psychiatry1984;47:553. 47. San Juan AC, Wong KC, Port JD: Hyperkalemia after dantrolene and verapamil-dantrolene administration in dogs. Anesth Analg1988;67:759.

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Chapter 160 – Opioids Christina E. Hantsch

PERSPECTIVE Opioid is a term that applies to all natural, synthetic, and semisynthetic agents with morphine-like actions. It is more inclusive than the term opiate, which refers only to natural agents. Both terms are derived from opium, the Greek word for juice in reference to poppy juice. Poppy juice contains more than 20 distinct natural alkaloids with morphine-like activity. The term narcotic refers to any agent that induces sleep and is nonspecific. Although the term narcotic persists, primarily in legal contexts, opioid is more precise and is the correct medical term for the family of agents that act on opiate receptors in the body. Finally, the term endorphin applies to any of the peptides of the three endogenous opioid families: enkephalins, p -endorphins, and dynorphins. [1] Pharmacologic actions of opioids involve the gastrointestinal system, genitourinary system, cardiovascular system, pulmonary system, and central nervous system (CNS) and cause characteristic clinical effects. Sedation and analgesia are the most common therapeutic goals of opioid medications, which are available alone or in combination with other agents (e.g., acetaminophen, salicylates) for these purposes. Additional therapeutic goals of opioids and combination preparations include antitussive and antidiarrheal effects. Misuse of pharmaceutical opioid preparations and use of illicit opioids are significant problems in the United States. In 2001, 404,000 Americans age 12 and older had used heroin; 3.7 million have used heroin at least once.[2] Since the early 1990s, there has been a trend among heroin users toward inhalation rather than injection of heroin, although injection is still the more common route overall.[3] Heroin and morphine are among the mostfrequent drugs reported in drug-related death.[]

PRINCIPLES OF DISEASE Anatomy and Physiology Although opioids have been used for more than 5000 years, receptors and endogenous opioids have been recognized and characterized only since the 1970s.[] Opioids have an incompletely understood physiologic role. Three established receptors, originally named mu, kappa, and delta, but now called OP1 (delta), OP2 (kappa), and OP3 (mu),[5] have been cloned and genetically sequenced. Opioid receptors are distributed throughout the CNS. They are concentrated in pain pathways and in areas associated with the perception of pain (e.g., periaqueductal gray matter, locus ceruleus, limbic system, nucleus raphe magnus).[6] Systemically, opioid receptors are localized in sensory nerve endings, on mast cells, and in the gastrointestinal tract.[] The role of the opioid receptors in pain perception and the analgesic effects of exogenous opioids are discussed in detail in Chapter 187 .

Pathophysiology and Pharmacology Toxicity Opioids are a large group of drugs that include therapeutic agents and illicit substances. Opioid toxicity occurs as an adverse effect of therapeutic use, intentional overdose, or intentional abuse. Although different opioids have receptor preferences in therapeutic or low doses, this specificity is lost at higher doses. In general, opioids are well absorbed after gastrointestinal (oral, rectal) or parenteral administration. Nasal, buccal, pulmonary, and transdermal absorption are effective, depending on the lipid solubility of the specific opioid.[1] Heroin is usually abused through intravenous and subcutaneous routes, but it also is absorbed after nasal administration because it is lipid soluble.[] In general, opioid toxicity is less pronounced but more

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prolonged with oral ingestion than with parenteral administration.[1] Absorption of opioids after oral administration occurs in the small intestine. With therapeutic doses, absorption is complete within 1 to 2 hours. Absorption and clinical effects of toxicity may be prolonged after overdose, however, because gastric emptying is delayed. Most opioids have a large volume of distribution. Clinical effects are influenced by the ease with which and extent to which opioids and their metabolites cross the blood-brain barrier; this also depends on lipid solubility. All opioids undergo hepatic metabolism and renal elimination. Variations in hepatic and renal function are important in opioid toxicity because metabolite activity may contribute to clinical effects and toxicity.[1] Excitatory effects (including seizures) with meperidine are caused primarily by its metabolite, normeperidine. The half-lives of meperidine and normeperidine are prolonged with cirrhosis, and the elimination of normeperidine is decreased with renal insufficiency. The likelihood of excitatory side effects is increased in these clinical settings and after multiple or large doses. The pharmacokinetics of the specific agent involved affect the clinical course of opioid toxicity. Heroin peaks in the serum within 1 minute of intravenous injection, 3 to 5 minutes of intranasal administration, and 10 minutes of subcutaneous injection.[] Heroin's lipophilic nature allows for its rapid transport across the blood-brain barrier into the CNS. In the CNS and in blood, heroin is rapidly hydrolyzed to 6-monoacetylmorphine and then morphine (less lipid soluble). In the liver, morphine undergoes conjugation with glucuronic acid to form more water-soluble compounds that are excreted by the kidneys.[9]

Withdrawal Pharmacokinetics affect the clinical course of opioid withdrawal. Because the half-life of heroin is 0.5 hour, and the half-life of methadone is 15 to 40 hours, withdrawal symptoms occur 4 to 6 hours after discontinuation of heroin compared with 24 to 48 hours after discontinuation of methadone.[] Duration of symptoms is 7 to 10 days and 2 weeks. In addition, the degree of physical dependence that has developed is important. With chronic opioid exposure, cellular adaptation results in upregulation of cyclic adenosine monophosphate (cAMP). When either the exposure is discontinued or an antagonist is administered, the result is a temporary elevation of cAMP levels and increased sympathetic activity above a normal baseline.

CLINICAL FEATURES Toxicity Opioid toxicity is associated with the toxidrome of CNS depression, respiratory depression, and miosis. Other potential findings in opioid toxicity are associated with toxicity from any opioid, but some features are unique to a specific agent or route of exposure.

Neurologic CNS depression is a well-recognized manifestation of opioid toxicity, and hypoxia from CNS depression and respiratory depression causes many neurologic complications. Dysphoria and acute psychosis may occur with an agonist-antagonist opioid. Excitatory effects may occur with opioid toxicity. Hypertonicity, myoclonus, and seizures have been reported with overdose of the synthetic opioids meperidine and propoxyphene. Meperidine-related seizures probably are caused by accumulation of normeperidine, especially after multiple or large doses or in patients with hepatic or renal insufficiency. Seizures also may result from hypoxia with overdose of any opioid. Parkinsonian symptoms in intravenous drug abusers have been attributed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), an unintended side product during synthesis of a meperidine analogue in street laboratories. MPTP injection is associated with focal lesions in the substantia nigra and a syn-drome clinically indistinguishable from idiopathic parkinsonism. The syndrome is irreversible in some patients.[12] Similar syndromes have not been seen with other opioids. Spongiform leukoencephalopathy has been associated with inhalation of heated heroin, a practice known as “chasing the dragon.” Patients present with psychomotor retardation, dysarthria, ataxia, tremor, and other neurologic abnormalities.[13] This syndrome is incompletely understood but is thought to be related to a combination of mitochondrial injury and hypoxia.[14] Serotonin syndrome is a clinical triad of mental status changes, autonomic instability, and neuromuscular changes (see Chapter 149 ). It results from excessive stimulation of CNS serotonin receptors and may be fatal. Most reported cases involve an interaction between a serotoninergic agent and a second agent, usually

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a selective serotonin reuptake inhibitor or a monoamine oxidase inhibitor.[15] Meperidine and dextromethorphan have serotoninergic properties and have been associated with serotonin syndrome.[15]

Respiratory Opioids decrease respiratory rate and tidal volume in a dose-dependent manner by suppression of the sensitivity of the medullary respiratory center to hypercapnia.[] Although it initially remains intact, the hypoxic drive is overridden in severe poisoning or when antagonistic stimuli (e.g., pain) are blocked.[16] Overdose of an agonist-antagonist agent produces less significant respiratory depression, presumably because of OP3 receptor antagonism ( Table 160-1 ).[1] Table 160-1 -- Select Opioid Doses and Associated Respiratory Depression Drug Codeine Dextromethorpha n Dihydrocodeine Diphenoxylate Fentanyl Heroin Hydrocodone Hydromorphone Levorphanol Meperidine Methadone Morphine Oxycodone Oxymorphone Paregoric Propoxyphene *

†

[*]

[*]

Time to Onset of Respiratory Depression[†]

200 700

120 —

Fast Fast

150 300 — 15 100 6 1 250 20 70 30 6 175 600

60 — 0.125 3 — 1.5 2 100 10 10 10 1 — —

Fast Slow (or even more delayed) Very fast Fast Fast Fast Fast Fast Slow (or even more delayed) Fast Fast Fast Fast Fast

Oral Dose (mg) Intramuscular Dose (mg)

Equiv alent to 10 m g of intra m usc ular m orp hine. Varie s with the drug and route of adm i nistra tion. In additi on, the effect s of a dose in

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Oral Dose (mg) Intramuscular Dose (mg)

Drug

[*]

[*]

Time to Onset of Respiratory Depression[†]

any partic ular patie nt depe nd on m ulti ple factor s, inclu ding age, weig ht, and com o rbid condi tions. After IM adm i nistra tion, very fast m ea ns 5 to 30 m inut es, fast m ea ns 15 to 60 m inut es, and slow m ea ns 1 to 4 hour s. After oral adm i nistra tion, these tim e defini tions are appr oxim ately doubl ed.

Bronchospasm has been reported rarely with heroin use in asthmatic and nonasthmatic patients. Bronchospasm occurs most often after inhalational exposure, but other routes also have been implicated. The bronchospasm is often severe, prolonged, and refractory to p -agonist therapy. Patients may require mechanical ventilation for several days. It is unclear whether the heroin, an adulterant, or a combination

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triggers the bronchospasm and whether the response is histamine mediated or the result of direct irritation.[8 ]

Noncardiogenic pulmonary edema may occur with therapeutic opioid use but is much more common after overdose.[17] The capillary leak is likely from a hypoxic event and is not a receptor-mediated phenomenon. If present, symptoms include cough and dyspnea, and physical signs include hypoxemia, rales, rhonchi, and frothy sputum. Manifestations and radiographic findings after heroin-induced noncardiogenic pulmonary edema typically resolve within 36 hours, unless other pathology intervenes.[9] This is not the case with longer acting agents.

Ophthalmologic Miosis is seen in more than 90% of heroin overdoses[18] and results from stimulation of OP3 receptors in the Edinger-Westphal nuclei of the third nerve.[16] Miosis is not typically seen with meperidine, propoxyphene, or diphenoxylate-atropine (Lomotil) overdose. Toxicity from agonist-antagonists (e.g., pentazocine) or multiple agents may not produce miosis.

Cardiovascular Opioids cause mild hypotension and relative bradycardia. Hypotension seems to result from histamine release and can be blocked by the administration of antihistamines (H[1] antagonists).[19] In addition, hypotension is typically orthostatic and resolves with supine positioning. Propoxyphene and its metabolite, norpropoxyphene, cause sodium channel blockade similar to that of type IA antidysrhythmic agents to produce widening of the QRS complex.[20]

Gastrointestinal Nausea and vomiting are common side effects of therapeutic opioid use and are seen with overdose. Several mechanisms contribute to these symptoms, including opioid-induced delayed gastric emptying, direct stimulation of the chemoreceptor trigger zone, and vestibular stimulation. Because several mechanisms are involved, antihistamines and dopamine antagonists (e.g., chlorpromazine) may be effective in treatment.[16] Decreased gastrointestinal motility is a common finding with therapeutic use and overdose of opioids. Severe cases may develop ileus.[1] Increased biliary tract pressures and choledochoduodenal sphincter spasm occur with therapeutic dosing of many opioids, including morphine, meperidine, and codeine.[16] Spasm is not always reproducible within the same patient, but seems related more to individual susceptibility than to a specific agent. Presenting clinical symptoms mimic biliary colic and may respond to naloxone or glucagon.[21]

Genitourinary Opioids can cause urinary retention from urethral sphincter spasm and decreased detrusor tone. alpha;-Adrenergic antagonists may reverse this effect.[16] Glomerulosclerosis and renal amyloidosis are seen in end-stage “heroin nephropathy” of chronic opioid addicts.[22]

Dermatologic Pruritus, flushing, and urticaria occur after administration of certain opioids that release histamine (e.g., morphine) and do not represent a true allergy. Pruritus and erythema often are localized to the area of injection (e.g., along the vein through which the morphine was administered). Although all opioids have the potential to stimulate mast cell degranulation and histamine release, some (e.g., fentanyl) release only clinically negligible amounts of histamine and so have outstanding hemodynamic stability. Symptoms typically are controlled easily with antihistamines.

Metabolic Hypoglycemia can occur after opioid overdose, but the mechanism is unclear. Coingestants, especially ethanol, may contribute to this finding. Hypothermia has been reported, but the mechanism is unclear. Hyperthermia should prompt a search for infectious complications, particularly in intravenous drug users, and for coingestants (e.g., cocaine) or adulterants (e.g., tripelennamine, scopolamine).[23] “Cotton fever” is reported in intravenous drug users who strain suspended drug through cotton balls or cigarette filters to remove particulates. Filters are boiled to extract residual drug when supply is low. Cotton is a known pyrogen and can cause a benign fever in patients who subsequently “shoot the cottons” or inject the extracted residue from the filters.[24]

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Withdrawal Opioid withdrawal occurs in tolerant individuals when opioid use is discontinued or an antagonist is administered. Increased sympathetic discharge and adrenergic hyperactivity are responsible for the clinical symptoms and signs. Although these can be significant, they are typically not life-threatening.[] In contrast to the typical toxidrome of opioid toxicity (CNS and respiratory depression, miosis), withdrawal is associated with CNS excitation, tachypnea, and mydriasis. Pulse and blood pressure also are increased. Neurologic manifestations are prominent in opioid withdrawal. Restlessness, agitation, and anxiety are virtually universal, and seizures rarely may occur. Cognition and mental status are unaffected. Dysphoria and drug craving may be severe and prolonged. Nausea, vomiting, diarrhea, and abdominal cramps are common in withdrawal. They can be significant and lead to dehydration and electrolyte abnormalities. Opioid withdrawal symptoms also may include diffuse myalgias and insomnia. Additional signs are piloerection, yawning, lacrimation, rhinorrhea, and diaphoresis.

DIAGNOSTIC STRATEGIES Toxicity The diagnosis of opioid intoxication is usually based on history and physical examination. Diagnostic studies rarely assist in evaluation of patients suspected of opioid overdose. Other than hypoglycemia, specific abnormalities on standard hematology and chemistry studies are not seen with opioid toxicity. When the patient exhibits hypoxemia and pulmonary rales on examination, a chest radiograph should be obtained to evaluate for noncardiogenic pulmonary edema. In the appropriate circumstances, an abdominal radiograph may identify packets of opioids or other illicit substances in a body packer or body stuffer. There is a case of QRS widening thought to be associated with propoxyphene overdose, but this has not been validated.[20] If cardiac monitoring shows a prolonged QRS, a 12-lead electrocardiogram is advisable. When the patient presents with an oral ingestion of an unknown opioid preparation, acetaminophen and salicylate levels should be checked because many prescription opioids are available in combination products. Likewise, many illicit opioid users are exposed to additional drugs and contaminants.[] Although opiates are detected on most qualitative urine toxicology screens, these are rarely helpful in acute situations. On some assays, several synthetic opioids also are detected because they cross-react or because they are metabolized to opiates, which are then excreted. Other agents, such as fentanyl and its derivatives, are missed on urine screens.[25] Poppy seeds can lead to a positive opiate screen secondary to the presence of morphine and codeine; however, detection of 6-monoacetylmorphine, a specific metabolite of heroin, can confirm heroin use.[25]

Withdrawal As with opioid toxicity, no diagnostic test exists for opioid withdrawal.

DIFFERENTIAL CONSIDERATIONS Toxicity The diagnosis of opioid intoxication is usually obvious, based on history and physical examination, although patients with other intoxications or nontoxicologic conditions may have a similar physical examination. Other drugs that should be considered are clonidine (or a related drug), tramadol, valproic acid, gamma hydroxybutyrate, and sedative-hypnotic agents. The differential diagnosis encompasses all causes of depressed mental status, but the coexistence of miosis and respiratory depression greatly narrows the possibilities.

Withdrawal Opioid withdrawal is usually a straightforward diagnosis, and the patient often reveals it as the chief complaint. Simultaneous intoxication with, or withdrawal from, other classes of agents, especially CNS depressants and stimulants, may be seen.

MANAGEMENT Toxicity Attention to the airway, oxygenation, and ventilation are of particular importance in patients with opioid intoxication because significant CNS and respiratory depression are the most common life-threatening developments. Appropriate interventions include airway protection and ventilatory support if reversal is not achieved with antidote therapy. Patients with noncardiogenic pulmonary edema may require oxygen and positive-pressure modalities, such as bilevel positive airway pressure, continuous positive airway pressure,

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or mechanical ventilation with positive end-expiratory pressure. Circulatory support usually does not require more than a crystalloid infusion. Most opioids have a large volume of distribution and cannot be cleared by dialysis. There are no clinically effective techniques for enhanced elimination of opioids.

Gastrointestinal Decontamination Gastrointestinal decontamination is unnecessary because the antidote can reverse the effects. Whole-bowel irrigation has been advocated to hasten passage of drug packets from body packers or patients with ingestions involving opioid combination products or multidrug ingestions. A single early dose of activated charcoal (1 g/kg in children, 50 to 100 g in adults) may be beneficial in some patients because gastrointestinal motility may be reduced.[26]

Antidote Naloxone, a pure opioid antagonist, is the antidote most frequently used to reverse opioid toxicity. Naloxone has a rapid onset of action. It is ineffective after oral administration secondary to the first-pass effect, but intravenous, subcutaneous, intramuscular, and endotracheal routes can be used. Naloxone acts through competitive binding at opioid receptors and can reverse all the receptor-mediated actions of opioids. Naloxone is indicated for patients with opioid intoxication who have significant CNS or respiratory depression. The initial intravenous dose is 0.4 to 2 mg for adults and children, but 10 mg may be required to obtain a clinical response for synthetic opioids, including return of protective airway reflexes and resolution of hypoventilation and hypoxia. The endotracheal dose is 2 to 2.5 times the intravenous dose. Naloxone can precipitate acute withdrawal in chronic opioid users. In this population, the dose should be started at 0.2 mg and slowly titrated. The duration of action of naloxone is 1 to 2 hours. Consequently, either repeat doses or a continuous infusion of two thirds of the effective initial dose per hour may be required.[1] Naloxone has an excellent safety profile. Noncardiogenic pulmonary edema, hypertension, and dysrhythmia have been reported with use of naloxone after general anesthesia[] and in patients with underlying cardiac or pulmonary disease.[1] Whether the naloxone is the cause of these complications is unproven. Idiosyncratic reactions and sympathetic discharge with precipitation of acute withdrawal have been proposed as explanations. Complete clinical recovery in response to naloxone is strongly suggestive of opioid overdose. Other intoxications may improve to lesser degrees with naloxone therapy, including valproic acid, clonidine, tramadol, captopril, and ethanol. Naloxone has been given to patients who have ingested these agents because of a presentation similar to opioid intoxication or suspicion of a mixed exposure that included opioids. The mechanism of these responses to naloxone is not established. Some of these drugs may have activity at opioid receptors.[27] Nalmefene, another opioid antagonist, has a long half-life (8 to 11 hours) and duration of clinical effect. Intravenous nalmefene has a rapid onset of action in reversing opioid-induced CNS and respiratory depression. Alternate administration routes are oral, subcutaneous, and intramuscular. The initial intravenous dose is 0.5 to 1.5 mg (pediatric dose not established). Higher doses have been used but are associated with increased risk of adverse effects.[] When a clinical response has been achieved with nalmefene, repeat doses or continuous infusions are generally not required; however, the duration of withdrawal symptoms or other rare adverse effects may be longer with nalmefene. Naloxone remains the preferred antidote in patients at risk for withdrawal or other adverse effects and in patients with anticipated short duration of opioid toxicity. Seizures associated with opioid toxicity may resolve with correction of hypoxia or may require administration of benzodiazepines.

Withdrawal Opioid withdrawal is not life-threatening, but the potentially serious manifestations mandate attention to supportive and symptomatic care. When withdrawal is produced by administration of naloxone, the symptoms are of short duration, and replacement opioids should be avoided.[] Other patients with withdrawal can receive opioid replacement or other medications to alleviate symptoms. In addition, fluid and electrolyte replacement is important for patients with dehydration from gastrointestinal symptoms. Methadone, a long-acting opioid, and l-alpha;-acetyl-methadol (LAAM), a newer and even longer acting opioid, are options for opioid replacement to treat or prevent withdrawal in chronic heroin users admitted for other medical conditions, but they are not indicated in the emergency department. One method uses an initial dose of methadone of either 20 mg orally or 10 mg intramuscularly, with an onset of action in 30 to 60 minutes. This initial dose typically controls significant manifestations.[10] Some symptoms, particularly drug craving, may be ongoing and require a subsequent dose after several hours. Maintenance methadone therapy requires doses every 12 to 24 hours and is tapered daily. The starting dose of LAAM is 30 mg orally,

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and the drug is given three times a week.[10] Clonidine, a central alpha;2-agonist, is an option for treatment of opioid withdrawal without opioid replacement.[10] Clonidine controls symptoms by suppressing sympathetic hyperactivity. It also may shorten the duration of withdrawal. The initial dose is 0.1 mg orally. Repeat doses may be given every 30 to 60 minutes; relatively large total doses may be required. As with opioid replacement, clonidine therapy must be titrated to individual clinical response. Hypotension may limit the treatment but is not common in the setting of opioid withdrawal treatment. Patches for transdermal administration of clonidine are available, but onset of action is delayed 24 hours. Oral doses still must be given initially. Buspirone is an azaspirone compound that is used to treat ethanol and nicotine addiction. Studies suggest that it also may be an option to treat withdrawal in opioid addicts, but further investigation is needed.[31]

DISPOSITION Toxicity Patients with manifestations of opioid toxicity usually are treated successfully in the emergency department, sometimes in conjunction with the emergency department observation unit. Patients who receive naloxone should be observed for 2 hours to assess the extent of re-sedation. Stable patients who present after an ingestion but who are asymptomatic can be observed in the emergency department until 4 hours after the ingestion, at which time they can be discharged with appropriate psychiatric evaluation or drug abuse counseling. Patients who have ingested an opioid with a longer half-life or active metabolite and patients with multiple drug ingestions involving an opioid may require longer observation periods. Patients who have a known or potential overdose of diphenoxylate-atropine (Lomotil) should be observed in a monitored unit even if asymptomatic[32]; this includes small children who may have ingested only a single tablet (2.5 mg of diphenoxylate, 0.025 mg of atropine). The metabolite of diphenoxylate, difenoxin, has a longer half-life, is five times more active than diphenoxylate, and may cause delayed and prolonged toxicity. Delayed absorption, caused by each component of Lomotil and enterohepatic recirculation, may contribute as well.[32] Patients who have a known or potential ingestion of packets of illicit opioid drugs should be admitted until the packets are passed. Body packers and body stuffers may remain asymptomatic until one or more of the packets leak. A poison center or medical toxicologist should be consulted if there is uncertainty about the appropriate disposition for a particular patient.

Withdrawal Patients with opioid withdrawal may be managed in the outpatient setting. Clonidine may alleviate some of the symptoms of withdrawal but has a high incidence of postural hypotension. Patients with refractory complications (e.g., vomiting, dehydration, electrolyte abnormalities) and patients with an uncertain diagnosis may require hospitalization. Some patients may need to be detoxified before entering chemical treatment programs. Substance abuse counseling and establishment of outpatient program referral should be completed before discharge.

KEY CONCEPTS {,

Diag nosi s of opioi d intoxi catio n is base d on histo ry, phys ical exa mina

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{,

{,

tion, and resp onse to nalo xone . The opioi d toxid rom e inclu des three pro mine nt findi ngs — CNS depr essi on, respi rator y depr essi on, and mios is— but may not be pres ent in ever y patie nt. Early admi nistr ation of rever sal agen ts and airw ay man age ment

Page 3740

and atten tion to oxyg enati on and ventil ation are cruci al to man age ment of patie nts with opioi d toxici ty. {,

The durat ion of actio n of man y opioi ds, espe cially after over dose , is signi fican tly long er than that of nalo xone . Patie nts resp onsi ve to nalo xone shou ld be obse rved

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for recu rren ce of opioi d toxici ty after the effec t of nalo xone has resol ved. {,

Opio id with draw al synd rom e does not inclu de alter ed cogn ition. Patie nts with kno wn or susp ecte d opioi d with draw al who also have alter ed cogn ition shou ld be eval uate d for anot her etiol

Page 3742

ogy of the alter ed cogn ition.

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REFERENCES 1. Reisene T, Pasternak G: Opioid analgesics and antagonists. In: Hardman JG, Limbird LE, ed.Goodman and Gilman's the Pharmacologic Basis of Therapeutics, 9th ed. New York: McGraw-Hill; 1996: 521-555. 2. National Institute on Drug Abuse : Heroin InfoFacts. Available at: www.drugabuse.gov/pdf/Infofacts/heroin 3. Office of Applied Studies, Substance Abuse and Mental Health Services Administration : The Dasis Report: Heroin—changes in how it is used. Available at: http://oas.samsha.gov/2k1/HeroinRT/HeroinRT.cfm 4. Watson WA: 2002 annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med2003;21:353. 5. Dhawan BN: International Union of Pharmacology XII classification of opioid receptors. Pharmacol Rev 1996;48:567. 6. Pasternak GW: Pharmacological mechanisms of opioid analgesics. Clin Neuropharmacol1993;16:1. 7. Pleuvry BJ: Opioid receptors and their relevance to anaesthesia. Br J Anaesth1993;71:119. 8. Cygan J, Trunsky M, Corbridge T: Inhaled heroin-induced status asthmaticus: Five cases and a review of the literature. Chest2000;117:272. 9. Sporer KA: Acute heroin overdose. Ann Intern Med1999;130:584. 10. Olmedo R, Hoffman RS: Withdrawal syndromes. Emerg Med Clin North Am2000;18:273. 11. Jenkins DH: Substance abuse and withdrawal in the intensive care unit. Surg Clin North Am 2000;80:1033. 12. Ballard PA, Tetrud JW, Langston JW: Permanent human parkinsonism due to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP): Seven cases. Neurology1985;35:949. 13. Hill MD, Cooper PW, Perry JR: Chasing the dragon—neurological toxicity associated with inhalation of heroin vapour: Case report. Can Med Assoc J2000;162:236. 14. Vella S: Acute leukoencephalopathy after inhalation of a single dose of heroin. Neuropediatrics 2003;34:100. 15. Mills KC: Serotonin syndrome: A clinical update. Crit Care Clin1997;13:163. 16. Schug SA, Zech D, Grond S: Adverse effects of systemic opioid analgesics. Drug Saf1992;7:200. 17. Soto J, Sacristan JA, Alsar MJ: Pulmonary oedema due to fentanyl. Anaesthesia1992;47:913. 18. Sporer KA, Firestone J, Isaacs SM: Out-of-hospital treatment of opioid overdoses in an urban setting. Acad Emerg Med1996;3:660. 19. Flacke JW: Histamine release by four narcotics: A double-blind study in humans. Anesth Analg 1987;66:723. 20. Stork CM: Propoxyphene-induced wide QRS complex dysrhythmia responsive to sodium bicarbonate—a case report. J Toxicol Clin Toxicol1995;33:179. 21. Bird KJ: Narcotic-induced choledochoduodenal sphincter spasm reversed by naloxone. Anaesthesia 1986;41:1120. 22. Dubrow A: The changing spectrum of heroin-associated nephropathy. Am J Kidney Dis1985;5:36. 23. Perrone J, Shaw L, DeRoos F: Laboratory confirmation of scopolamine co-intoxication in patients using tainted heroin. J Toxicol Clin Toxicol1999;37:491. 24. Harrison DW, Walls RM: “Cotton fever”: A benign febrile syndrome in intravenous drug abusers. J Emerg Med1990;8:135. 25. Kwong TC: Toxicology. In: McClatchey KD, ed.Clinical Laboratory Medicine, Baltimore: Williams & Wilkins; 1994: 445-467. 26. American Academy of Clinical Toxicology, European Association of Poison Centres and Clinical Toxicologists : Position statements on gastrointestinal decontamination. J Toxicol Clin Toxicol1997;35:695. 27. Chamberlain JM, Klein BL: A comprehensive review of naloxone for the emergency physician. Ann Emerg Med1994;12:650. 28. Johnson C, Mayer P, Grosz D: Pulmonary edema following naloxone administration in a healthy orthopedic patient. J Clin Anesth1995;7:356. 29. Kaplan JL: Double-blind randomized study of nalmefene and naloxone in emergency department patients

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with suspected narcotic overdose. Ann Emerg Med1999;34:42. 30. Chumpa A: Nalmefene hydrochloride. Pediatr Emerg Care1999;15:141. 31. Rose JS: Effects of buspirone in withdrawal from opiates. Am J Addict2003;12:253. 32. McCarron MM, Challoner KR, Thompson GA: Diphenoxylate-atropine (Lomotil) overdose in children: An update. Pediatrics1991;87:694.

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Chapter 161 – Pesticides Cynthia K. Aaron

PERSPECTIVE Pesticides, a generic term to refer to all pest-killing agents, include numerous chemicals intended for use as insecticides, herbicides, rodenticides, fungicides, and fumigants. Many of these chemicals are general protoplasmic poisons affecting a wide range of organisms, including humans. Although space does not allow a comprehensive discussion of each individual chemical that may produce human toxicity, numerous chemical classes are commonly used as pesticides. These classes have associated characteristic clinical pictures that are important to recognize because patients with acute (and occasionally chronic) exposures to these agents come to the emergency department. In addition, many other pesticides with particularly unique and interesting mechanisms of toxic effects are described.

ORGANOPHOSPHATE INSECTICIDES The organophosphate insecticide triethyl pyrophosphate was first synthesized in 1859, but was not used to replace nicotine as a pesticide until World War II. After World War II, these compounds were used as nerve agents in wars, as organophosphorus and carbamate insecticides, and as medicinal agents ( Box 161-1 ). After the negative publicity associated with the organochlorine DDT, organophosphate insecticides soon became some of the most common pesticides for home and industrial use. In the late 1990s and in 2000, with the advent of increased awareness of terrorism, nerve agents have gained prominence as weapons of mass destruction (see Chapter 195 ).[1] BOX 161-1 Acetylcholinesterase Inhibitors Nerve Gases “G” or German agents GA Tabun GB Sarin GD Tabun “V” agents VX Organophosphate Insecticides Acephate Orthene Azinphos-methyl Guthion Bomyl Swat Bromophos Nexion Bromophos-ethyl Nexagan Carbophenothion Trithion Chlorfenvinphos Birlane Chlorpyrifos Dursban, Lorsban Chlormephos Dotan Chlorthiophos Celathion Coumaphos Co-Ral Crotoxyphos Ciodrin Cyanofenphos Surecide

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Cyanophos Cythioate DEF Demeton Demeton-methyl Dialifor Diazinon Dichlofenthion Dichlorvos Dimethoate Dioxathion Disulfoton EPN Ethion Ethoprop Ethyl parathion Etrimfos Famphur Fenamiphos Fenitrothion Fenephosphon Fensulfothion Fenthion Fonofos Formothion Heptenophos Iodofenphos Isofenphos Isoxathion Leptophos Malathion Merphos Methamidophos Methidathion Methyl parathion Mevinphos Monocrotophos Naled Phencapton Phenthoate Phorate Phosalone Phosfolan Phosmet Phosphamidon Phoxim Pirimiphosmethyl Profenofos Propetamphos Propylthiopyrophosphate

Cyanox Proban De-Green Systox Metasystox Torak Spectracide Mobilawn Bidrin Cygon, De-Fend Delnav Di-System Santox Acithion Mocap Parathion Ekamet Warbex, Fanfos Nemacur Agrothion Agritox Dasanit Baytex, Entex Dyfonate Anthio Hostaquick Nuvanol-N Amaze, Oftanol Karphos Phosvel Cythion Folex Monitor Supracide Dalf Phosdrin Azodrin Dibrom G 28029 Tanone Thimet Zolone Cyolane Imidan, Prolate Dimecron Baythion Actellic Curacron Safrotin Aspon

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Prothoate Pyrazophos Pyridaphenthion Quinalphos Schradan Sulfotepp Sulprofos Temephos Terbufos Tetrachlorvinphos Tetraethyl pyrophosphate Thiometon Triazophos Trichlorfon Carbamate Insecticides Aminocarb Aldicarb Bufencarb Carbaryl Carbofuran Dimeton Formetanate Methiocarb Methomyl Oxamyl Pirimicarb Promecarb Propoxur Therapeutic Agents Ambenonium Demecarium Edrophonium Neostigmine Physostigmine Pyridostigmine

Fac Afugan, Curamil Ofunack Bayrusil OMPA Bladafum Dithione Bolstar Abate, Abathion Gounter Gardona, Rabon TEPP Ekatin Hostathion Dylox, Neguvon Matacil Temik Bux Sevin Furadan Snip Fly Bands Carzol, Dicarzol Draza, Mesurol Nudrin, Lannate Vydate Aphox, Pirimor Carbamult Minacide Baygon Mytelase Humorsol Tensilon Prostigmin Antilirium Mestinon

EPN, ethyl-p-nitrophenylthionobenzeneiophosphate; OMPA, octamethyl pyrophosphoramide; TEPP, tetraethyl diphosphate.

Principles of Disease Pharmacology Organophosphorus insecticides are highly lipid soluble and are readily absorbed via dermal, gastrointestinal (GI), and respiratory routes.[2] This lipid solubility results in the storage of organophosphorus compounds in body fat, making possible the gradual or rapid accumulation of toxic systemic levels from repeated low-level exposures. The parent compound and its metabolites are acetylcholinesterase inhibitors, and many parent organophosphorus compounds are less potent than their metabolites (e.g., parathion to paraoxon), resulting in delayed onset of clinical toxicity.

Pathophysiology

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Organophosphorus pesticides work by persistently inhibiting the enzyme acetylcholinesterase, the enzymatic deactivator of the ubiquitous neurotransmitter acetylcholine. Because of the global penetration of organophosphorus compounds, inhibition occurs at tissue sites (true acetylcholinesterase or butyrylcholinesterase and represented by erythrocyte or red blood cell [RBC] cholinesterase) and in plasma (circulating pseudocholinesterase).[] Inhibition of cholinesterase results in the accumulation and subsequent prolonged effect of acetylcholine at a variety of neurotransmitter receptors, including the sympathetic and parasympathetic ganglionic nicotinic sites, postganglionic cholinergic sympathetic and parasympathetic muscarinic sites, skeletal muscle nicotinic sites, and central nervous system sites ( Fig. 161-1 ).[2]

Figure 161-1 Schem atic representation of the autonom ic nervous system (ANS). The ANS com prises the sym pathetic and parasym pathetic nervous system s. The sym pathetic nervous system also is known as the thoracolum bar outflow, where the cell body lies in the spinal cord and the first synapse occurs in the sym pathetic ganglia. The neurotransm itter in this first synapse is acetylcholine (ACh) (preganglionic), and the neurotransm itter in the postganglionic neuron with the target organ is norepinephrine (NE). In the parasym pathetic nervous system (craniosacral outflow), nerves from the m edulla and sacrum use ACh as the neurotransm itter in preganglionic and postganglionic target organs. The ANS is divided further into the m uscarinic and nicotinic receptors, where atropine can block the m uscarinic receptors but not the nicotinic receptors. The neurom uscular junction uses ACh as the effector neurotransmitter. In the brain, ACh is just one of several active neurotransm itters.

Clinical Features Signs and Symptoms The accumulation of acetylcholine results in a classic cholinergic syndrome, manifested by hyperactivity of cholinergic responses at the receptor sites indicated earlier. The clinical syndrome of muscarinic acetylcholinesterase inhibition is commonly called the SLUDGE syndrome ( Box 161-2 ). This syndrome represents postganglionic acetylcholine-induced hollow end-organ general hypersecretion,[2] resulting in clinical findings including miotic pupils, lacrimation, rhinorrhea, sialorrhea, bronchorrhea, vomiting, diarrhea, and urinary incontinence. Bradycardia is commonly mentioned as a classic sign of acetylcholinesterase poisoning, but the increased release of norepinephrine from postganglionic sympathetic neurons precipitated by excess cholinergic activity at sympathetic ganglia may result in normal or even tachycardic heart rates (nicotinic effect). Sympathetic hyperactivity can cause diffuse diaphoresis, although this response is mediated by cholinergic receptors at preganglionic (nicotinic) and postganglionic (muscarinic) sites. The most lethal components of acetylcholinesterase inhibition occur in the brain and neuromuscular junction. A combination of sympathetic stimulation, involvement of the N-methyl-d-aspartate receptor, and enhanced acetylcholine concentrations can lead to seizures.[5] At the neuromuscular junction, excess acetylcholine causes hyperstimulation of the muscles with secondary paralysis. Because the diaphragm is affected, cholinesterase poisoning leads to respiratory arrest.[6] BOX 161-2 SLUDGE Symptoms

S alivat ion L acri mati on U rinar y inco ntine nce

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D efec ation G astro intes tinal cra mps E mesi s

BHC, benzene hexachloride; DDT, dichlorodiphenyltrichloroethane; HCB, hexachlorobenzene. Although the usual clinical picture of acute organophosphorus poisoning is impressive, toxicity from gradual, cumulative exposure may be much more subtle. These patients commonly exhibit vague confusion or other central nervous system complaints; mild visual disturbances; or chronic abdominal cramping, nausea, and diarrhea.[7]

Complications Seizures and pulmonary hypersecretion, or bronchorrhea and bronchoconstriction, are prominent mechanisms of early morbidity and mortality in cases of poisoning from acetylcholinesterase inhibitors. Bronchorrhea is typically, although incorrectly, called noncardiogenic pulmonary edema because the origin of the excessive pulmonary fluids is from airway secretions and does not represent transudation of fluid across the alveolar-capillary membrane. The obstruction of upper and lower airways, the potential intrusion of these bronchial secretions into alveolar sacs, and bronchoconstriction produce hypoxia, which is the primary concern in the initial stages of poisoning.[2] Nicotinic hyperstimulation of skeletal muscle determines the ultimate morbidity and mortality of acetylcholinesterase inhibitors. Signs of skeletal muscle hyperactivity include involuntary twitches, fasciculations, and hyperactive reflexes. Muscle hyperactivity eventually gives way to muscle fatigue and paralysis, including the respiratory musculature and particularly the diaphragm.[] Respiratory insufficiency may be delayed and result in significant morbidity if not anticipated and corrected by mechanical or pharmacologic means. Acetylcholinesterase inhibitors produce direct toxic effects on the central nervous system leading to neurologic signs of confusion, combativeness, seizures, and coma. Status epilepticus may occur in severely poisoned patients. Structural central nervous system damage may occur if seizures are not terminated rapidly.[9]

Diagnostic Strategies Any patient with a full-blown cholinergic syndrome should be treated empirically without waiting for laboratory confirmation of decreased cholinesterase activity. Known or suspected exposure to cholinesterase inhibitors should be confirmed by ordering plasma and erythrocyte (RBC) cholinesterase levels. In acute exposures, the plasma cholinesterase levels fall first, with decreases in RBC cholinesterase levels lagging behind. The RBC cholinesterase level is more indicative of what is occurring at the nerve terminal.[3] Patients with chronic exposures may show only reduced RBC cholinesterase activity, and a normal plasma cholinesterase level may impart a false sense of security. The true reflection of depressed cholinesterase activity is found in the RBC activity, and even a mild acute exposure may result in severe clinical poisoning. RBC cholinesterase levels recover at a rate of 1% per day in untreated patients and take about 6 to 12 weeks to normalize, whereas plasma cholinesterase levels may recover in 4 to 6 weeks. Other studies should be geared toward the evaluation of pulmonary, cardiovascular, and renal function and fluid and electrolyte balance.

Differential Diagnosis Few toxins or other clinical conditions produce the same symptoms as acetylcholinesterase inhibitors. One species of mushroom, Amanita muscaria, historically has been mentioned in the differential diagnosis, but actually contains alkaloids that usually produce an anticholinergic (antimuscarinic) syndrome. A variety of

Page 3750

conditions that induce excessive vagal responses (e.g., inferior wall myocardial infarction) also may produce some signs suggesting acetylcholinesterase inhibition, but other symptoms should make the primary cause apparent.

Management Treatment of poisoning with acetylcholinesterase inhibitors is directed toward four goals: (1) decontamination, (2) supportive care, (3) reversal of acetylcholine excess at muscarinic sites, and (4) reversal of toxin binding at active sites on the cholinesterase molecule. Decontamination should be started in the prehospital phase of care to prevent greater absorption and subsequent toxicity and to protect care providers. Decontamination is particularly important in cases of dermal exposure; removal and destruction of clothing and thorough flushing of exposed skin may limit absorption and subsequent toxicity. Alternatively, dermal decontamination can be done with dry agents, such as military resins or flour or bentonite. Caregivers are at risk for contamination from splashes or handling of contaminated clothing. Treating personnel may be rotated to limit their exposure to the organophosphates.[6] Caretakers should use universal precautions, including eye shields, protective clothing, and nitrile or butyl rubber gloves. In the case of ingestion, GI decontamination procedures are of questionable benefit because of the rapid absorption of these compounds. Profuse vomiting and diarrhea are seen early in ingestion and may limit[10] or negate any beneficial effect of additional GI decontamination.[] Equipment may be washed with a 5% hypochlorite solution to inactivate the cho-linesterase inhibitor. Because morbidity results from airway and respiratory failure, supportive care should be directed primarily toward airway management, including suctioning of secretions and vomitus, oxygenation, and, when necessary, ventilatory support. Succinylcholine can be used for intubation but may have an extremely prolonged duration.[3] It is preferable to use a competitive neuromuscular blocking agent, such as rocuronium, for rapid sequence intubation in these patients, but increased dosing may be necessary. Although some authors have advocated the use of p -blockers to control tachycardia, this may lead to worsening cardiovascular instability.[] Most cardiovascular complications that occur in this setting rarely require specific therapy. The definitive treatment of acetylcholinesterase inhibition starts with the administration of atropine.[2] A competitive inhibitor of acetylcholine at muscarinic receptor sites, atropine reverses the clinical effects of cholinergic excess at parasympathetic end organs and sweat glands. Large doses of atropine may be required.[14] Data suggest that the more rapid the atropinization, the faster control is obtained.[] Suggested dosing is 1 to 2 mg of atropine (0.02 to 0.05 mg/kg) intravenously, with doubling of each subsequent dose every 5 minutes until there is control of mucous membrane hypersecretion and the airway clears.[] If intravenous access is not immediately available, atropine may be administered intramuscularly. Patients may require 200 to 500 mg of atropine intravenously during the first hour, followed by prolonged continuous infusions of 5 to 100 mg/hr to maintain adequate secretion control.[14] Tachycardia and mydriasis may occur at these doses, but they are not indications to stop atropine administration. The endpoint of atropinization is drying of respiratory secretions and easing of respiration. Increasing animal evidence suggests that early rapid atropinization may limit seizure propagation and, in conjunction with diazepam, prevent status epilepticus.[] Atropine is not active at nicotinic sites and does not reverse the skeletal muscle effects (e.g., muscle fatigue and respiratory failure).[] The second part of acetylcholinesterase inhibition treatment is the use of an oxime, such as pralidoxime (2-PAM, Protopam) or obidoxime (Toxigonin), to break up the organophosphate-acetylcholinesterase complex and restore cholinesterase activity at muscarinic and nicotinic sites.[] The usual starting dose of pralidoxime is 1 to 2 g intravenously (pediatric dose 25 to 50 mg/kg); additional doses may be given based on clinical response and serial cholinesterase levels. The medication may be given in a bolus of 1 to 2 g intravenously over 30 to 60 minutes every 4 to 8 hours or 500 mg/hr (pediatric dose 10 to 25 mg/kg/hr).[] The World Health Organization recommends an initial dose of 30 mg/kg followed by 8 mg/kg/hr continued for at least 24 hours or, if an infusion cannot be used, 30 mg/kg every 4 hours.[18] The infusion may be continued for several days with no apparent adverse effects attributable to the pralidoxime; however, rapid administration has led to hypertension, vomiting, and a transient reversible neuromuscular blockade.[19] The ideal dose of pralidoxime should be determined by monitoring the clinical condition of the patient and serial cholinesterase levels; the patient may require higher doses of oxime than recommended here. The World Health Organization–recommended infusion dose of obidoxime is 4 mg/kg followed by 0.5 mg/kg/hr; alternatively, intermittent IV doses of 4 mg/kg, then 2 mg/kg, every 4 hours is given.[18] Pralidoxime and obidoxime can be administered by intramuscular injection.

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It is commonly stated that pralidoxime is useful only within the first 24 hours because of aging of the organophosphate-acetylcholinesterase complex.[2] This truism has been challenged with the acknowledgment that not all organophosphates behave in a similar fashion. Dimethyl and diethyl phosphoryl insecticides react differently at variable rates with acetylcholinesterase and oxime therapy. Many organophosphates are highly lipid soluble and slowly leach out of fat stores for days to weeks, resulting in newly formed complexes that are amenable to treatment with pralidoxime. Pralidoxime also can combine with unbound organophosphates and prevent their subsequent binding to nerve terminals. The aforementioned poison leaching may occur for 6 weeks after an acute exposure, with excellent reversal of the cholinesterase inhibition exhibited clinically and by laboratory measurements of cholinesterase activity. Even with optimal treatment, seriously intoxicated patients may require long-term supportive care, including ventilator support.[] In conjunction with atropine and oxime therapy, patients with agitation, seizures, and coma should be treated with adequate doses of a benzodiazpine after the airway has been secured.[] Although diazepam is most studied, midazolam and lorazepam can be used, with midazolam being the best agent for intramuscular use. Sarin, soman, tabun, and VX are nerve agents that might be used in a terrorist attack. These agents have important differences from the common organophosphorous insecticides. VX is an oily but highly toxic agent with low volatility. It does not readily vaporize, and because its risk of inhalation is low, exposure is predominately percutaneous. The other agents can be mostly dispersed into the air resulting in inhalation. These agents do not require the same extremely large doses of atropine but do require pralidoxime. The U.S. military has preloaded Mark I antidote kits containing two syringes, one with 2 mg of atropine and the other containing 600 mg of pralidoxime for intramuscular use. In mild symptomatic exposures, one kit is given, moderate exposures receive two kits, and severe exposures receive three kits. Any patient who requires three kits or has seizures also receives 10 mg of diazepam intramuscularly or equivalent dosing of another benzodiazepine.[22] Pediatric AtroPens are now available in doses of 0.5 and 1 mg per pen.

Disposition Because of the potential prolonged effects of acetylcholinesterase inhibition, most patients with significant exposures require hospital admission. An occasional person with chronic exposure, depressed cholinesterase levels, and mild visual or GI symptoms may be followed on an outpatient basis. Although the laboratory role is limited, if cholinesterase levels are available, they may be useful for treatment and disposition decisions. Normal or minimally depressed levels in asymptomatic or minimally symptomatic patients may allow discharge with outpatient follow-up after 4 to 6 hours, to ensure that progressive toxicity is not occurring. Patients with severely depressed levels (usually associated with significant symptoms) require admission and close monitoring, usually in an intensive care unit. Patients may develop rebound toxicity several days after apparently satisfactory response to initial treatment. Rebound toxicity may occur for many reasons, including persistent release of organophosphates from lipid stores. There have been reports in the literature of an intermediate syndrome that is purportedly caused by an abnormality at the neuromuscular junction. Review of these case reports suggests, however, that it is likely these patients received inadequate initial treatment or premature discontinuation of treatment.[] The syndrome of delayed neuropathy also has been reported as a different entity from the strict or pure cholinergic effects and affects an axonal enzyme.[6] Cholinesterase levels should be followed daily after pralidoxime is discontinued, with 3 consecutive days of improving cholinesterase levels, before the physician can feel comfortable that most of the toxin has been eliminated.

CARBAMATE INSECTICIDES Carbamate insecticides (see Box 161-1 ) are another class of acetylcholinesterase inhibitors and are differentiated from the organophosphorus compounds by their relatively short duration of toxic effects. Carbamates inhibit acetylcholinesterase for minutes to hours, and the carbamate-cholinesterase binding is reversible.[2] Although the clinical picture of acute carbamate poisoning may closely resemble organophosphate poisoning, the toxic effects are limited in duration; patients may require only decontamination, supportive care, and treatment with adequate doses of atropine. Pralidoxime usually is not needed to treat known carbamate poisoning, and animal studies suggest that pralidoxime administration may produce greater toxicity in cases of carbaryl (Sevin) poisoning.[24] Nevertheless, if doubt exists as to whether a severe poisoning is due to a carbamate or organophosphate, pralidoxime should be administered.

CHLORINATED HYDROCARBON PESTICIDES Dichlorodiphenyltrichloroethane (DDT), the prototype of chlorinated hydrocarbon insecticides, was first used extensively during World War II for the control of typhus and malaria and was used widely in the United States as a general insecticide after the war. Environmental contamination and the development of safer

Page 3752

chlorinated hydrocarbon pesticides led to the banning of DDT in the United States in 1972. The compounds replacing DDT ( Box 161-3 ) are used extensively in agricultural, commercial, and residential pest control. Some, such as chlordane, have come under close scrutiny in recent years.[25] Lindane or p~-hexachlorobenzene (Kwell), a well-known and widely used scabicide, was banned in 2000 for normal human use because of concerns over toxicity. BOX 161-3 Chlorinated Hydrocarbon Pesticides Aldri Aldri n te Drin ox Ben BHC zen e Chlo Chlo rdan rdan e Chlo Kep rdec one one Chlo Acar robe abe nzila n te Chlo DDT roph enot han e Dicl Kelt ofol han e Diel Diel drin drite Dien Pent ochl ac or End Thio osulf dan an Endr Hex in adri n Ethy Pert lan han e Ga Lind mm ane a hexa chlo robe nze ne Hept Rho achl diac

Page 3753

or Meth oxyc hlor Mire x

hlor Marl ate

Dec hlor ane Terp Stro ene ban poly e chlo rinat ed Tox Tox aph akil ene

BHC, benzene hexachloride; DDT, dichlorodiphenyltrichloroethane; HCB, hexachlorobenzene.

Principles of Disease Pharmacology Chlorinated hydrocarbon pesticides are highly lipid soluble. They are readily absorbed through dermal, respiratory, and GI routes.[26] Dermal and GI exposures account for most clinical poisonings, including inappropriate external use of lindane or other compounds and the occasional accidental oral administration of lindane. Because they are so lipid soluble, these compounds are stored in fatty tissues, and repeated small exposures may result in accumulation and eventual clinical toxicity.[27]

Pathophysiology Chlorinated hydrocarbon insecticides primarily affect axonal membranes, resulting in neuronal irritability and excitation. Toxicity occurs in central and pe-ripheral neurons.[28] Chlorinated hydrocarbons induce hepatic microsomal enzymes and produce hepatic tumors in some animal models. This potential carcinogenicity is the basis for the current human health concerns, but is only theoretical at present. Chlorinated hydrocarbon insecticides, including chlorinated hydrocarbon solvents, may sensitize the myocardium to circulating catecholamines and increase susceptibility to ventricular dysrhythmias, such as tachycardia and fibrillation.[ 28]

Clinical Features Signs and Symptoms The primary clinical picture of acute or cumulative toxicity from chlorinated hydrocarbon pesticides is related to their neurotoxicity. Premonitory peripheral signs and symptoms, such as tremor or paresthesias, are unusual, and the first sign of toxicity may be the acute onset of seizure activity.[29] Additional signs include confusion, combativeness, and muscle twitching. Untreated, continued muscle activity can lead to hyperthermia, metabolic acidosis, and rhabdomyolysis with secondary acute tubular necrosis.[30] Because many of these agents are halogenated, ventricular dysrhythmias may occur from catecholamine sensitization and direct myocardial toxic effects. Immediate hepatotoxicity is unlikely without secondary hyperthermia or other metabolic complications.[] Long-term exposure may result in neuropsychiatric complaints.[32] Diagnosis may be difficult in chlorinated hydrocarbon pesticide exposure because the patient may be unable to provide a history. Prehospital personnel are often in the best position to obtain information concerning pesticide availability and use and the situation surrounding the exposure. Another clue is the solvent odor and oily feel of the hydrocarbon solvent containing the highly lipid-soluble chlorinated hydrocarbon pesticides.

Diagnostic Strategies Diagnosis must be confirmed by history or by investigation at the site of the exposure to establish the offending agent with certainty. No specific tests are readily available to confirm the diagnosis of chlorinated hydrocarbon pesticide poisoning. Some reference laboratories can measure fat and plasma levels, but

Page 3754

results are difficult to interpret and seldom are available during the acute phase of toxicity.[] Ancillary laboratory and other studies should be based on the clinical condition, complications, and consideration of alternative diagnoses on an individual basis.

Differential Considerations The differential diagnosis includes virtually every condition that produces seizures. The specific diagnosis depends on obtaining the history of significant acute or chronic chlorinated hydrocarbon pesticide exposure.

Management Skin decontamination with soap and water may reduce toxicity in acute dermal exposure. High lipid solubility results in rapid absorption, and delayed GI decontamination is not of benefit. The exception is the use of repeat doses of cholestyramine (4 g orally every 8 hours) for chlordane ingestions.[] The primary therapeutic objective is seizure control, best accomplished with short-acting benzodiazepines or barbiturates. Recurrent seizures or status epilepticus may require high-dose barbiturates and paralyzing agents (e.g., pancuronium or vecuronium) to prevent secondary morbidity from continuous motor activity in prolonged seizures. The seizure activity is usually self-limiting, lasting only 1 or 2 days even in severe cases. []

Continuous cardiac monitoring during the acute phase is indicated because of the potential for myocardial sensitization. Ventricular dysrhythmias are most likely to occur during seizure activity because of the high circulating catecholamine levels and other metabolic abnormalities present during seizures. Dysrhythmias should be treated with p -adrenergic antagonists, such as propranolol, metoprolol, or esmolol, to reduce the effect of catecholamines on the myocardium. Additional treatment should focus on the complications of prolonged seizure activity, such as aggressive external cooling measures for hyperthermia. Metabolic acidosis is almost always transient and resolves spontaneously without treatment. Rhabdomyolysis and myoglobinuria should be anticipated. Other complications of seizures should be treated as indicated. Because of their high lipid solubility, chlorinated hydrocarbon pesticides are distributed largely in tissues and are not amenable to hemoperfusion, dialysis, or other attempts to enhance elimination.

Disposition Patients who have acute or cumulative chlorinated hydrocarbon pesticide toxicity require hospitalization until their seizures have been controlled, complications have resolved, and they have returned to their neurologic baselines; this usually occurs within 1 or 2 days. Severe complications, such as renal failure from rhabdomyolysis, may prolong the clinical course.

SUBSTITUTED PHENOLS The substituted phenols include dinitrophenol, pentachlorophenol (PCP), and dinitrocresol ( Box 161-4 ). These compounds have been used since the 1930s as insecticides, termiticides, herbicides, and wood preservatives. They currently are used in agricultural, commercial, and residential applications, including over-the-counter preparations for home gardeners. Substituted phenols such as dinitrophenol (DNP) are abused as weight-reduction agents and occasionally appear in illegitimate weight-reduction operations. Ads for DNP are found on the Internet.[36] BOX 161-4 Substituted Phenol Pesticides PCP, pentachlorophenol; DNC, dinitrocresol: DNOC, 2-methyl-4,6-dinitrophenol (dinitro-o-cresol).

Chlorinated Phenols Pentachlorophen ol Dowi cide EC7 PCP Pen

Page 3755

chlor ol Pent acon Pen war Prilto x Sinit uho Triox 2,4-Dichlorophen ol Veg-I -Kill 2,4,6-Trichloroph enol

Nitrophenolic Compounds Dinitrophenol Che mox PE Dinobuton Acre x Des sin Dino fen Dra winol Tala n Dinocap Kara than e Crot otha ne Dinopenton Dinoprop Dinosam DNA P Dinoseb Bas anite Cald ron Che

Page 3756

mox Gen eral Che mse ct DNB P Dinit ro-3 Dyn amyt e Elget ol d8 Geb utox Kilos eb Nitro pone C Pre mer ge 3 Sino x Gen eral Subit ex Unic rop DNB P Dinosulfon Dinoterb Dinoterbon

Nitrocresolic Compounds Dinitrocresol DNC DNO C Che mse ct DNO C Elget ol 30 Nitra dor Selin on

Page 3757

Sino x Trifo cide

Principles of Disease Pharmacology Substituted phenols are readily absorbed through the skin and GI tract, and aerosols may be absorbed through the respiratory tract. There is some potential for cumulative toxicity with repeated exposures, but much less so than with the organophosphorus and chlorinated hydrocarbon pesticides already discussed.

Pathophysiology Substituted phenols produce their toxicity by uncoupling cellular oxidative phosphorylation; this leads to inefficient production of high-energy phosphate substrates and increased cellular use of oxygen, glucose, and water, with subsequent excessive heat production.[37] These compounds are commonly used during the summer when the external heat predisposes users to increased toxicity.[] In addition, nitro-substituted phenols may produce methemoglobinemia.

Clinical Features Patients with substituted phenol toxicity present hypermetabolic and hyperthermic, tachycardic, tachypneic, and profusely diaphoretic. They also may have a relative hypovolemia from insensible excessive fluid losses through sweating and metabolic consumption. Loss of energy production in neurologic tissues results in neurologic changes ranging from confusion to seizures and coma. Renal and hepatic injury are common, and rhabdomyolysis with myoglobinuria is commonly present.[30] Because phenols are generally corrosive, patients with dermal exposures often show evidence of irritation or chemical burn, and some substituted phenols, such as dinitrophenol, produce a characteristic yellow staining of the skin or mucous membranes at the site of absorption. This same staining can be found throughout the internal organs at autopsy.[38] A complication of long-term exposure to these compounds is the formation of cataracts. This condition was common in patients who used substituted phenols as part of a weight-reduction regimen and was partially responsible for banning this substance. The cataracts regress spontaneously after exposure is discontinued.[40]

Diagnostic Strategies Laboratory evaluation of patients with substituted phenol toxicity is aimed at identifying deficiency of aerobic metabolic substrates, including oxygen, glucose, and water. A complete blood count may reveal hemoconcentration and a nonspecific leukocytosis. Electrolyte abnormalities depend on the duration and severity of symptoms, environmental factors, and complications or underlying disease states. Arterial blood gas measurements show varying degrees of acidosis, depending on the extent of anaerobic metabolic activity because of oxidative phosphorylation uncoupling and associated tissue hypoperfusion from dehydration. Serum enzyme determinations document the extent of hepatic, renal, and skeletal muscle injury. The presence of phenolic compounds in the urine of a patient with this clinical picture strongly suggests substituted phenol pesticides as the causative agent.

Differential Considerations Acute toxicity from substituted phenol poisoning is difficult to distinguish initially from typical environmental heat-related emergencies or toxicity from sympathomimetics or salicylates. Continued evidence of hypermetabolic activity and metabolic acidosis after routine cooling measures, rehydration, and other supportive care should lead to a consideration of toxin-induced states. Persistent hyperthermia and acidosis in a weightlifter should trigger concern for DNP abuse. The presence of yellow staining virtually clinches the diagnosis.[38]

Management Initial treatment is directed toward aggressive supportive care with body temperature control; treatment of acidosis; protecting the kidneys, brain, and liver from hyperthermic damage; and providing the basic substrates for excessive metabolic activity: oxygen, glucose, and water.[38] If the chemical exposure is known or recognized, early decontamination of affected sites is important. Therapy should be directed toward prevention or minimization of the associated complications discussed previously.

Disposition

Page 3758

Patients with mild toxicity usually can be stabilized after a few hours and discharged from the emergency department. Patients with significant organ system injury or a high likelihood of complications, such as prolonged or recurrent seizures, significant alteration of consciousness, and rhabdomyolysis, require admission, usually to the intensive care unit.

CHLOROPHENOXY COMPOUNDS The chlorophenoxy pesticides were developed in the early 1940s and hailed as a selective herbicide particularly effective against broad-leaf weeds. This class of herbicide developed a special notoriety during the Vietnam War as Agent Orange, a defoliant used in aerial spraying. Agent Orange consisted of a mixture of 2,4-dichlorophenoxyacetic acid (2,4-D) and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T). 2,4,5-T is virtually always contaminated with isomers of tetrachlorodibenzo dioxin. This concern over dioxin exposure has led to the extensive medical investigations of Vietnam veterans and severe restrictions on the production and use of 2,4,5-T.[41] Because of the relative safety and broad-leaf selectivity of 2,4-D, however, most home gardeners find at least one of the substances listed in Box 161-5 on a shelf in their garages, and some old cans may contain 2,4,5-T or a mixture of both compounds. BOX 161-5 Chlorophenoxy Pesticides

2,4-Dichlorophenoxyacetic Acid (2,4-D) Agro tec Amo xone Aqua -Kle en Chlo roxo ne Crop Ride r Dac amin e 4D DedWee d Des orm one Dico tox Dino xol Dor mon e Emu lsam ine BK Emu lsam ine E-3 Enve

Page 3759

rt DT Este ron 99 Este ron Four Esto ne Fern esta Ferni mine Fern oxon e Ferx one Hed onal Herb idal Law n-Ke ep Litha te Mac ondr ay Mira cle Neta gron e 600 Pen nami ne D Plan otox Plant gard Rho dia Salv o Sup eror mon e Con centr e Sup er D Wee done

Page 3760

Tran sami ne Vertr on ZD Visk o-Rh ap Wee d-BGon Wee dar Wee d-Rh ap Wee d Tox Wee dtrol

2,4,5-Trichlorophenoxyacetic Acid (2,4,5-T) Brus h-Rh ap Dec amin e 4T DedWee d Brus h Killer Este ron 245 Fenc e Ride r Forr on Inver ton 245 Line Ride r Spo ntox Sup er D Wee

Page 3761

done Tor mon a Tran sami ne Trino xol Triox one Veon 245 Vertr on 2T Wee dar Wee done Enve rt T

2,4-D-2,4,5-T Mixturesc Decamine 2D-2T Este ron Brus h Killer Tran sami ne Tribu ton Visk o-Ph ap LV2 D-2T

Principles of Disease Pharmacology Chlorophenoxy compounds may be absorbed through the skin, GI tract, and respiratory tract, but almost all significant poisonings occur as a result of accidental or intentional ingestion. The lipid solubility of these compounds is low, and excretion is fairly rapid, so cumulative toxicity from repeated exposures does not occur.[42]

Pathophysiology Although skeletal muscle is the target organ for chlorophenoxy herbicides, the exact mechanism is obscure. [] Depending on severity, muscular abnormalities may range from generalized muscle weakness to acute rhabdomyolysis. Higher doses also may uncouple oxidative phosphorylation similar to that seen with the substituted phenols.[28]

Clinical Features Similar to most organic pesticides in an organic solvent, the chlorophenoxy herbicides may produce mild,

Page 3762

nonspecific dermal and GI irritation with nausea, vomiting, and GI distress. Large exposures are likely to cause systemic symptoms ranging from diffuse myotonia and muscle fasciculations progressing to rhabdomyolysis, hyperthermia, and a hypermetabolic state with metabolic acidosis consistent with uncoupling of oxidative phosphorylation.[44]

Diagnostic Strategies There are no specific tests for the detection of the chlorophenoxy compounds. Laboratory evaluation should be aimed at evaluating skeletal muscle injury and its complications. Severely poisoned patients require generalized organ system evaluation, including hepatic and renal function, because of the effects of rhabdomyolysis and hyperthermia.

Differential Considerations Differential diagnostic possibilities include other causes of acute myopathy. This manifestation of chlorophenoxy compound toxicity is extremely rare, however, and without a definite history or strong suspicion of exposure, other explanations for acute myopathy should be pursued.

Management Treatment consists of initial skin decontamination, activated charcoal or gastric lavage with early presentation, and basic supportive care. Serious toxic effects develop within 4 to 6 hours after ingestion, and treatment can be directed toward the specific problems of muscle weakness, airway and ventilatory support, and treatment for rhabdomyolysis. Treatment of hyperthermia and acidosis has been discussed previously.

Disposition Asymptomatic or minimally symptomatic patients may be discharged with reassurance after 4 to 6 hours of observation. Patients with significant toxicity should be admitted for close observation and monitoring.

BIPYRIDYL COMPOUNDS The bipyridyl (also called dipyridyl) compounds, paraquat and diquat ( Box 161-6 ), were first investigated in the late 1950s and early 1960s. They are extremely effective contact herbicides that are rapidly inactivated by the surrounding soil in the event of overspray. Paraquat is activated when exposed to sunlight, which led to its use as the herbicide of choice during aerial spraying of marijuana by the U.S. and Mexican governments. After spraying, however, growers simply would harvest the crops before the plants were exposed to enough sunlight to damage the plants, resulting in an apparently healthy harvest but one contaminated with paraquat. The burning of marijuana pyrolyzes paraquat into a nontoxic form, a fact that was lost in the warning messages dispensed by the government at that time.[45] BOX 161-6 Bipyridyl Compounds

Paraquat Crisquat Dextrone X Esgram Gramoxone

Diquat Aqua cide Dext rone Regl one Regl ox Wee dtrin

Page 3763

e-D

Paraquat-Diquat Mixtures Pree glon e Prigl one Wee dol

Principles of Disease Pharmacology Of the two bipyridyl compounds in use, paraquat is the most clinically significant in terms of number of cases and toxic effects, and it is the primary consideration of this discussion. Paraquat use is tightly regulated in the United States but is widespread throughout the world. Diquat is found more easily in the United States and is included in some formulations of Roundup. Paraquat is absorbed through the skin, GI tract, and respiratory tract. Almost all fatal exposures have resulted from the ingestion of paraquat, although a few case reports have involved extensive skin contamination.[46] No fatal cases have been reported from inhalation of paraquat vapor or aerosols, but toxicity has occurred from this route of exposure. Diquat is poorly absorbed through intact skin, and most cases of toxicity result from ingestion.[47]

Pathophysiology Paraquat's toxic effect results from the production of superoxides created during cyclic oxidation-reduction reactions of the compound in tissues. Lipid peroxidation of cellular membranes seems to be one significant pathway of cellular injury.[] Paraquat selectively concentrates in the lungs because of an amine uptake mechanism in alveolar cells. In addition, high concentrations of oxygen significantly increase the extent of paraquat-induced injury, causing the lungs to be the major target organ. The pathophysiologic lesions include direct injury to the alveolar-capillary membrane followed by surfactant loss, adult respiratory distress syndrome, progressive pulmonary fibrosis, and respiratory failure.[50] Paraquat damages other major organ systems by the same cellular membrane effects, including the liver, kidney, heart, and central nervous system. Diquat has similar effects but is not preferentially accumulated in lung tissue.[47]

Clinical Features Both agents are extremely corrosive and cause severe chemical burns of the oropharynx soon after ingestion. Patients who ingest concentrated paraquat frequently die as a result of esophageal perforation and mediastinitis before development of the characteristic progressive pulmonary injury. Patients with dermal paraquat exposures show significant skin irritation, and ocular exposures may produce severe corneal injury.[51] Other signs of GI irritation, such as nausea and vomiting, may occur. The classic finding of paraquat-induced progressive pulmonary injury usually occurs over 1 to 3 weeks, although the clinical course varies considerably with severity of poisoning, involvement of other organ systems, and underlying medical problems.[50] This is not a factor in the emergency department, and the pulmonary injury is not discussed here. In contrast to paraquat, diquat usually spares the lungs but produces similar toxicity in all other organ systems.[47]

Diagnostic Strategies Paraquat is measurable in the blood, and the nomogram provides a fairly accurate prognosis. In the United States, the assay is not readily available, and by the time the results are obtained, nothing more can be done about the eventual outcome in most cases. There is a qualitative bedside test using the reduction of paraquat or diquat in alkalinized urine by sodium dithionite, but the reagent frequently is not available.[44] Studies other than evaluation of caustic GI injury and pulmonary and renal damage should be directed toward secondary effects of the poisoning.

Differential Considerations

Page 3764

A person with acute paraquat or diquat ingestion is likely to present with the initial complaint of an acute corrosive injury; the differential diagnosis should encompass all corrosive agents. Successful therapeutic intervention for paraquat toxicity is extremely time dependent, and patient outcome depends on the history. Any patient who has evidence of pulmonary or other organ injury caused by paraquat exposure is already beyond recovery.

Management The key to successful treatment of an acute paraquat exposure depends almost entirely on aggressive early decontamination measures to limit absorption. Thorough skin cleansing is obvious and straightforward in dermal exposures. Aggressive gastric lavage and administration of activated charcoal may be lifesaving, but these measures must be considered in the context of a corrosive ingestion. Early endoscopy and surgical intervention may be necessary if there is evidence of esophageal perforation and mediastinitis. Although Fuller's Earth and bentonite are recommended as adsorbents in paraquat ingestions, activated charcoal is readily available and has equal, if not greater, efficacy.[52] Although controversial, many toxicologists recommend rapid initiation of charcoal hemoperfusion to lower plasma paraquat levels and to limit pulmonary and other organ system uptake of paraquat. Many also have recommended serial and combined hemoperfusion and hemodialysis, particularly during the first 24 hours after exposure.[] There are multiple suggested treatment protocols for paraquat, such as N-acetyl cysteine and low fraction of inspired oxygen, but no single therapy has proved universally successful.[55]

Disposition Patients who have any significant dermal paraquat exposure and all patients who have ingested paraquat should be hospitalized and started on aggressive enhanced elimination therapy as outlined earlier. These patients should be observed and treated expectantly until paraquat levels are reported to be nonexistent or nontoxic.

PYRETHRINS AND PYRETHROIDS Pyrethrins are naturally occurring insecticides of the yellow Chrysanthemum cinerariifolium and Tanacetum cinerariifolium and are among the oldest known insecticides, first used in the 1800s. Extracts of the dried flowers contain the active compound pyrethrum, which contains six naturally occurring pyrethrins. In addition, numerous synthetic derivatives, pyrethroids, have been produced and have greater chemical stability than the natural pyrethrins ( Box 161-7 ). Type II pyrethroids contain a cyano substituent and are among the more toxic formulations of this class. These present a potential danger to humans, but type II pyrethroids are generally less toxic than many of the other classes already discussed and are being used more commonly. BOX 161-7 Pyrethrins and Pyrethroids

Pyrethrins Pyre thru m extra ct Pyre thrin I Pyre thrin II Cine rin I Cine rin II Jas moli nI

Page 3765

Jas moli n II

Pyrethroids Allet hrin Bart hrin Bioal lethri n Bior esm ethri n Cis meth rin Cym ethri n Cyp erm ethri n Dec amet hrin Delt amet hrin Feno thrin Fenv alera te Fura meth rin Tetr amet hrin

Principles of Disease Pharmacology Because pyrethrins and pyrethroids are most commonly aerosolized, inhalation is the most likely source of exposure. The patient may not be aware of an exposure because pyrethrin and pyrethroid aerosols are used frequently as automated insect sprays in public areas. In these situations, concentrations rarely reach levels likely to produce symptoms in any but the most sensitized patient. Occasional ingestions have been reported, and significant toxicity is possible via this route. Systemic absorption via the dermal route is unlikely, but topical effects are possible. Most pyrethrins and pyrethroids are rapidly metabolized and deactivated in human exposure to the extent that cumulative toxicity is not a problem. Piperonyl butoxide, which is added as an insect “knock-down” agent, may add to the toxicity of the pyrethrum derivatives.

Pathophysiology

Page 3766

Pyrethrins and pyrethroids have a variety of pharmacologic effects in humans and other mammals.[] Clinically the naturally occurring pyrethrins have the ability to cause sensitization and allergic phenomena. This property does not occur with the synthetic pyrethroids. Both classes are associated with sodium channel blockade, slowing the rate of activation of the sodium channel and extending the time the channel is open. In addition, both classes affect p~-aminobutyric acid receptors, inhibiting chloride channel function. Less significant effects include potentiation of nicotinic cholinergic neurotransmission, enhancement of norepinephrine release, and inhibition of calcium adenosine triphosphatase interference with sodium-calcium exchange across membranes.[]

Clinical Features Allergic manifestations, including potentially life-threatening events, may occur after acute inhalation or dermal exposure. Inhalation exposure often occurs with the use of a pyrethrin-based aerosol in an enclosed, poorly ventilated space. Local effects include lacrimation, rhinitis, rhinorrhea, sneezing, throat irritation, and pharyngeal and laryngeal edema. Lower respiratory effects include cough, shortness of breath, chest pain, and wheezing. Skin rashes consistent with a contact or allergic dermatitis have been reported, and photosensitivity may contribute to the dermatologic picture. There is potential for allergic cross-reactivity in patients who are allergic to ragweed. Sodium channel–mediated and p~-aminobutyric acid–mediated chloride channel effects mediate neurologic signs and symptoms. Facial paresthesias have been reported, and seizures have occurred with massive ingestions.[] Nonspecific symptoms, such as headache, fatigue, dizziness, and weakness, have been reported.

Diagnostic Strategies No laboratory tests are available to measure pyrethrins or pyrethroids in a clinical setting.

Differential Considerations The differential diagnosis of the signs and symptoms of pyrethrin or pyrethroid toxicity includes the usual causes of bronchospasm or acute neurologic complications.

Management Decontamination, including removal from a contaminated environment or washing, should be the first step. Definitive treatment is supportive and directed at the respiratory and neurologic complications.

Disposition Disposition of a patient with exposure to pyrethrins depends on the severity of the underlying complications. If discharge from the emergency department is anticipated, the patient should be counseled with regard to the possibility of recurrent allergic phenomena on reexposure.

GLYPHOSATE Glyphosate (Roundup) was introduced as a broad-spectrum nonselective herbicide in 1971 by the Monsanto Agricultural Company (St. Louis, Mo). It is the isopropyl ammonium salt of a noncholinesterase-inhibiting organophosphate herbicide. It is sold mixed with the surfactant polyoxyethylene amine (POEA). Because it is effective on broad-leaf weeds and does not undergo photodecomposition, it is popular in the home market. Newer formulations of Roundup may contain diquat.

Principles of Disease Pharmacology Glyphosate is poorly absorbed through the skin so that most exposures result from ingestion. The concentrated solution is extremely irritating, and patients may vomit with subsequent aspiration. The concentrated solution is provided as 41% glyphosate in 15% POEA. The directions state that it should be diluted to a 1% glyphosate solution.

Pathophysiology Glyphosate is toxic to plants by inhibition of the enzyme 5-enolpyruvylskikimate-3 phosphatase-synthetase in the shikimic acid metabolic pathway. After application of glyphosate on the leaves, it is transported to the roots where the enzyme is active. Humans lack this enzyme and so are much less likely to develop toxicity. Reported toxicity is believed to result largely from the surfactant POEA and may reflect the direct corrosive effect from the amine salt, or it may uncouple oxidative phosphorylation.[58]

Clinical Features

Page 3767

Most ingestions of the dilute solution cause only minimal symptoms, including GI distress. Patients ingesting large volumes of dilute solutions or moderate volumes of concentrated solutions complain of sore throat, nausea, abdominal pain, and fever. They may develop vomiting, diarrhea, respiratory distress, noncardiogenic pulmonary edema, dysrhythmias, shock, coma, and renal failure. Acidosis most likely reflects poor tissue perfusion and cardiovascular compromise.[58] Negative prognostic indicators include shock, acidosis, and persistent hyperkalemia.[58]

Diagnostic Strategies The key element in diagnosis is history of ingestion. Laboratory analysis shows an anion gap metabolic acidosis, hypoxemia, and hyperkalemia. Elevated transaminases may occur in 30% of ill patients, and signs of renal failure may develop in persistent shock states. The electrocardiogram may show ventricular dysrhythmias and secondary signs of hypoxemia.[58]

Differential Diagnosis The differential diagnosis includes most corrosive ingestions. The findings of hyperkalemia and metabolic acidosis may suggest hydrofluoric acid ingestions. A normal ionized calcium level may help rule out hydrofluoric acid exposure. Any cause of aspiration also should be considered. The history is the most useful in the differential diagnosis.

Management Treatment is supportive. The patient may require positive-pressure ventilation to overcome the noncardiogenic pulmonary edema. POEA also may be a direct cardiac depressant; inotropic agents can be useful. Hyperkalemia should be treated in the usual fashion with fluids, medications to shift potassium into the cell (bicarbonate, calcium, p -adrenergic agonists), and enhanced elimination (ion-sequestering resins). If there is a suggestion of significant corrosive ingestion, early endoscopy with placement of stent, high-dose steroids, and laparotomy all may be considered.

Disposition Patients with small ingestions of dilute substances may be observed for 6 hours and discharged if asymptomatic. Patients with complaints consistent with corrosive ingestions require admission and GI evaluation. Any patient with pulmonary complaints requires admission and intensive supportive care.

DEET N,N-diethyl-m-toluamide or N,N-diethyl-3-methylbenzamide (DEET) is not a pesticide but an insect repellent. It is the most widely used chemical insect repellent in the United States. DEET was developed by scientists at the U.S. Department of Agriculture in 1946, patented by the U.S. Army shortly thereafter, and released to the general public in 1957.[59] Now with the prevalence of Lyme disease and other concerning arthropod-borne diseases, the use of DEET has increased greatly. Formulations containing DEET range from 5% to 100%. The U.S. Army routinely used 75% solutions until 1987 but now uses a 35% time-release, polymer-based formulation. The American Academy of Pediatrics suggests that no more than a 10% solution be used on children.[59]

Principles of Disease Pharmacology DEET is lipophilic and can be absorbed through the skin. Skin absorption and toxicity increase with repeated applications, increased ambient temperatures, sweating, and abraded, thin skin. Ingestion may lead to toxicity.[60]

Pathophysiology DEET primarily affects the central nervous system. Its mechanism of action is currently unknown. It may sensitize the skin and cause allergic reactions.

Clinical Features Prolonged skin contact may lead to contact dermatitis, and prolonged contact with high concentrations has led to skin blisters. Patients who have ingested DEET or have repeated skin applications under conditions that enhance absorption have developed liver function test abnormalities and neurologic findings, including en-cephalopathy, seizures, movement disorders, and coma.[60] Most exposures to DEET result in minimal toxicity and should not preclude its use in susceptible populations where significant arthropod-borne diseases are prevalent.[61]

Page 3768

Diagnostic Strategies Exposure history is central to the diagnosis. Although DEET can be detected in urine, most laboratories are not able to do this testing during the acute toxicity phase. An electroencephalogram may be useful in a patient with coma or encephalopathy and seizures.

Differential Diagnosis The differential diagnosis includes conditions that may cause encephalopathy, seizures, and movement disorders. Such conditions may include drug intoxication, infectious causes, drug interactions, and structural defects.

Management Treatment is supportive. If DEET exposure is suspected, the skin should be thoroughly decontaminated. Oils or lipophilic agents should be avoided because they enhance skin absorption. After DEET ingestion, milk products and oil-containing foods should be avoided until the GI tract has been emptied of the offending agent. Seizures should be treated with benzodiazepines.

Disposition Asymptomatic patients who have ingested DEET-containing repellents should be observed for 4 to 6 hours. Patients who develop neurologic symptoms should be admitted and observed.

KEY CONCEPTS {,

All patie nts expo sed to choli nest eras e inhibi tors shou ld be assu med to be der mall y cont amin ated and shou ld be deco ntam inate d. Eme rgen cy depa rtme nt pers onne l

Page 3769

{,

{,

need to be prote cted durin g this proc ess. Morb idity in choli nest eras e inhibi tor expo sure resul ts from early airw ay com pro mise seco ndar y to copi ous secr etion s, statu s epile pticu s, and late respi rator y failur e. Vital sign s in choli nest eras e inhibi tor expo sure may refle

Page 3770

{,

{,

ct brad ycar dia or tach ycar dia, hype rtens ion or hypo tensi on, and mios is or mydr iasis . The clinic al endp oint for atrop ine admi nistr ation is dryin g of airw ay secr etion s. Prali doxi me shou ld be give n to all orga noph osph orus -pois oned patie nts who requi re atrop ine rega

Page 3771

{,

{,

{,

rdles s of time sinc e expo sure. With chlor inate d hydr ocar bon expo sure s, skin deco ntam inati on with prote ction of pers onne l is indic ated. Cate chol amin e admi nistr ation is avoi ded in chlor inate d hydr ocar bon expo sure s if poss ible. Sup porti ve care, temp eratu re contr ol,

Page 3772

{,

{,

and seiz ure contr ol must be aggr essi ve. Sub stitut ed phen ol toxici ty is susp ecte d in hype rmet aboli c patie nts in who m envir onm ental cond ition s are not cond uciv e to heatrelat ed illnes s or in who m salic ylate toxici ty is not a cons idera tion. Rapi d cooli ng and subs trate

Page 3773

{,

{,

{,

provi sion (gluc ose) are the two most impo rtant thera pies in subs titute d phen ol toxici ty. Diag nosi s of chlor ophe noxy com poun d toxici ty depe nds on a histo ry of acci dent al or delib erate inge stion . Trea tmen t of chlor ophe noxy com poun d toxici ty is supp ortiv e. Para quat and diqu

Page 3774

{,

{,

{,

at inge stion s caus ea seve re corr osiv e burn to the GI tract. Rapi d GI deco ntam inati on may be the only hope in para quat and diqu at inge stion s. Whe n pulm onar y and renal dysf uncti on deve lop, the prog nosi s is poor. Pyre thrin and pyret hroid expo sure s are usua

Page 3775

{,

{,

lly beni gn exce pt for mas sive inge stion s. The pred omin ant form of pyret hrin and pyret hroid toxici ty is aller gic. Sma ll inge stion s of dilut e glyp hosa te solut ions are GI irrita nts. Larg e or conc entra ted inge stion s may caus e acid osis, hype rkale mia, and nonc ardio geni c

Page 3776

{,

{,

{,

pulm onar y ede ma. Trea tmen t of glyp hosa te toxici ty is supp ortiv e. DEE T shou ld not be appli ed over abra ded or raw skin. DEE T appli catio ns to child ren shou ld be restri cted to 10% solut ions, shou ld not be used unde r occl usiv e cloth ing, and shou ld be was hed

Page 3777

{,

off com plete ly betw een appli catio ns. Trea tmen t of DEE T expo sure is supp ortiv e.

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REFERENCES 1. The Persian Gulf experience and health. NIH Technology Assessment Workshop Panel. JAMA 1994;272:391. 2. Tafuri J, Roberts J: Organophosphate poisoning. Ann Emerg Med1987;16:193. 3. Selden BS, Curry SC: Prolonged succinylcholine-induced paralysis in organophosphate insecticide poisoning. Ann Emerg Med1987;16:215. 4. Namba T: Poisoning due to organophosphate insecticides: Acute and chronic manifestations. Am J Med 1971;50:475. 5. Johnson PS, Michaelis EK: Characterization of organophosphate interactions at N-methyl-D-aspartate receptors in brain synaptic membranes. Mol Pharmacol1992;41:750. 6. Johnson MK: Evaluation of antidotes for poisoning by organophosphorus pesticides. Emerg Med 2000;12:22. 7. Clark G: Organophosphate insecticides and behavior: A review. Aerospace Med1971;42:735. 8. Gutmann L, Besser R: Organophosphate intoxication: Pharmacologic, neurophysiologic, clinical, and therapeutic considerations. Semin Neurol1990;10:46. 9. Shih TM, Duniho SM, McDonough JH: Control of nerve agent-induced seizures is critical for neuroprotection and survival. Toxicol Appl Pharmacol2003;188:69. 10. Petroianu G, Ruefer R: Poisoning with organophosphorus compounds. Emerg Med (Fremantle) 2001;13:258. 11. Eddleston M, Roberts D, Buckley N: Management of severe organophosphorus pesticide poisoning. Crit Care2002;6:259. 12. Eddleston M, Singh S, Buckley N: Acute organophosphorus poisoning. Clin Evidence2003;9:1542. 13. Sungur M, Guven M: Intensive care management of organophosphate insecticide poisoning. Crit Care 2001;5:211. 14. Golsousidis H, Kokkas V: Use of 19,590 mg of atropine during 24 days of treatment, after a case of unusually severe parathion poisoning. Hum Toxicol1985;4:339. 15. McDonough Jr JrJH: Anticonvulsant treatment of nerve agent seizures: Anticholinergics versus diazepam in soman-intoxicated guinea pigs. Epilepsy Res2000;38:1. 16. Eddleston M: Oximes in acute organophosphorous pesticide poisoning: A systematic review of clinical trials. QJM2002;95:275. 17. Worek F: Reappraisal of indications and limitations of oxime therapy in organophosphate poisoning. Hum Exp Toxicol1997;16:466. 18. Feldmann RJ, Szajewski J: Cholinergic syndrome. In: IPIC INTOX Databank. http://www.intox.org/databank/documents/treat/treate/tr15_e.htm 1998 19. Medicis JJ: Pharmacokinetics following a loading plus a continuous infusion of pralidoxime compared with the traditional short infusion regimen in human volunteers. J Toxicol Clin Toxicol1996;34:289. 20. Dickson EW: Diazepam inhibits organophosphate-induced central respiratory depression. Acad Emerg Med2003;10:1303. 21. Shih T, McDonough Jr JrJH, Koplovitz I: Anticonvulsants for soman-induced seizure activity. J Biomed Sci1999;6:86. 22. Sidell FR, Borak J: Chemical warfare agents: II. Nerve agents. Ann Emerg Med1992;21:865. 23. Senanayake N, Sanmuganathan PS: Extrapyramidal manifestations complicating organophosphorus insecticide poisoning. Hum Exp Toxicol1995;14:600. 24. Kurtz PH: Pralidoxime in the treatment of carbamate in-toxication. Am J Emerg Med1990;8:68. 25. National Academy of Sciences Committee on Toxicology, Commission on Life Sciences : An Assessment of the Health Risks of Seven Pesticides Used for Termite Control, Washington, D.C., National Academy Press, 1982. 26. Feldmann RJ, Maibach HI: Percutaneous penetration of some pesticides and herbicides in man. Toxicol Appl Pharmacol1974;28:126. 27. Hayes Jr JrWJ, Curley A: Storage and excretion of dieldrin and related compounds: Effect of occupational exposure. Arch Environ Health1968;16:155. 28. Hayes Jr JrWJ: Pesticides Studied in Man, Baltimore, Williams & Wilkins, 1982.

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29. Jaeger U: Acute oral poisoning with lindane-solvent mixtures. Vet Hum Toxicol1984;26:11. 30. Curry SC, Chang D, Connor D: Drug- and toxin-induced rhabdomyolysis. Ann Emerg Med1989;18:1068. 31. Stehr-Green PA: An evaluation of serum pesticide residue levels and liver function in persons exposed to dairy products contaminated with heptachlor. JAMA1988;259:374. 32. Kilburn KH: Chlordane as a neurotoxin in humans. South Med J1997;90:299. 33. Aks SE: Acute accidental lindane ingestion in toddlers. Ann Emerg Med1995;26:647. 34. Cohn WJ: Treatment of chlordecone (Kepone) toxicity with cholestyramine: Results of a controlled clinical trial. N Engl J Med1978;298:243. 35. Cable GG, Doherty S: Acute carbamate and organochlorine toxicity causing convulsions in an agricultural pilot: A case report. Aviat Space Environ Med1999;70:68. 36. New York State Department of Health : State health commissioner warns of danger of weight loss product. 2001. Available at: http://www.health.state.ny.us.ezproxy.hsclib.sunysb.edu/nysdoh/commish/2001/dinitrophenols.htm 37. Ilivicky J, Casida JE: Uncoupling action of 2,4-dinitrophenols, 2-trifluoromethylbenzimidazoles and certain other pesticide chemicals upon mitochondria from different sources and its relation to toxicity. Biochem Pharmacol1969;18:1389. 38. Leftwich RB: Dinitrophenol poisoning: A diagnosis to consider in undiagnosed fever. South Med J 1982;75:182. 39. Jorens PG, Schepens PJ: Human pentachlorophenol poisoning. Hum Exp Toxicol1993;12:479. 40. Kurt TL: Dinitrophenol in weight loss: The poison center and public health safety. Vet Hum Toxicol 1986;28:574. 41. Kahn PC: Dioxins and dibenzofurans in blood and adipose tissue of Agent Orange-exposed Vietnam veterans and matched controls. JAMA1988;259:1661. 42. Reifenrath WG, Hawkins GS, Kurtz MS: Percutaneous penetration and skin retention of topically applied compounds: An in vitro-in vivo study. J Pharm Sci1991;80:526. 43. Berwick P: 2,4-dichlorophenoxyacetic acid poisoning in man: Some interesting clinical and laboratory findings. JAMA1970;214:1114. 44. Bradberry SM: Mechanisms of toxicity, clinical features, and management of acute chlorophenoxy herbicide poisoning: A review. J Toxicol Clin Toxicol2000;38:111. 45. Landrigan PJ: Paraquat and marijuana: Epidemiologic risk assessment. Am J Public Health1983;73:784. 46. Smith JG: Paraquat poisoning by skin absorption: A review. Hum Toxicol1988;7:15. 47. Jones GM, Vale JA: Mechanisms of toxicity, clinical features, and management of diquat poisoning: A review. J Toxicol Clin Toxicol2000;38:123. 48. Fukushima T: Mechanism of cytotoxicity of paraquat: I. NADH oxidation and paraquat radical formation via complex I. Exp Toxicol Pathol1993;45:345. 49. Yasaka T: Further studies of lipid peroxidation in human paraquat poisoning. Arch Intern Med 1986;146:681. 50. Smith LL: Mechanism of paraquat toxicity in lung and its relevance to treatment. Hum Toxicol1987;6:31. 51. Manoguerra AS: Full thickness skin burns secondary to an unusual exposure to diquat dibromide. J Toxicol Clin Toxicol1990;28:107. 52. Okonek S: Successful treatment of paraquat poisoning: Activated charcoal per os and “continuous hemoperfusion.”. J Toxicol Clin Toxicol1982;19:807. 53. Proudfoot AT, Prescott LF, Jarvie DR: Haemodialysis for paraquat poisoning. Hum Toxicol1987;6:69. 54. Suzuki K: Effect of aggressive haemoperfusion on the clinical course of patients with paraquat poisoning. Hum Exp Toxicol1993;12:323. 55. Honore P: Paraquat poisoning: “State of the art.”. Acta Clin Belg1994;49:220. 56. Ray DE, Forshaw PJ: Pyrethroid insecticides: Poisoning syndromes, synergies, and therapy. J Toxicol Clin Toxicol2000;38:95. 57. Soderlund DM: Mechanisms of pyrethroid neurotoxicity: Implications for cumulative risk assessment. Toxicology2002;171:3. 58. Ling HL: Clinical presentations and prognostic factors of a glyphosate-surfactant herbicide intoxication: A review of 131 cases. Acad Emerg Med2000;7:906. 59. Fradin MS: Mosquitoes and mosquito repellents: A clinician's guide. Ann Intern Med1998;128:931. 60. Tennenbein M: Severe toxic reactions and death following the ingestion of diethyltoluamide-containing insect repellents. JAMA1987;258:1509. 61. Koren G, Matsui D, Bailey B: DEET-based insect repellents: Safety implications for children and pregnant and lactating women. Can Med Assoc J2003;169:209.

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Chapter 162 – Plants, Mushrooms, and Herbal Medications Richard D. Shih

PERSPECTIVE Botanicals such as plants, herbal products, and mushrooms have a long-standing and important place in medical history. Their use as therapeutic agents has been documented in the earliest of medical writings. The extraction of alkaloids from the opium poppy in the 1800s was a forerunner of modern pharmacology. The general public increasingly is using herbal products for medicinal purposes. Despite the tremendous growth in popularity of herbal products, data on herbal efficacy and toxicity are limited. This chapter does not focus on the medicinal benefits of natural products, but rather the toxicology related to their exposure or utility.

Epidemiology Although plants, mushrooms, and herbal products all are derived naturally, they have different exposure patterns and epidemiology.

Unintentional Childhood Exposure Unintentional childhood exposure occurs most commonly with plants. Approximately 5% of all poison center calls involve plants. Of these, about 75% involve children younger than age 6. Most of these cases involve household plants with a limited amount of plant or toxin ingested resulting in little or no toxicity.

Misidentification of Botanical Natural plant and mushroom gathering for personal ingestion is a popular activity. Mistakes while foraging occur commonly, with the potential for serious toxicity and numerous fatalities. In contrast to uninten-tional childhood exposures, foraging accidents usually involve adults and plants or mushrooms and are associated with a much larger toxin burden because a larger quantity of the botanical is ingested. Another type of botanical misidentification occurs with herbal products when plants used for herbal manufacture are misidentified by the manufacturer and incorrectly packaged and marketed.

Drugs of Abuse Many plants and mushrooms are abused for their mind-altering potential, including hallucinogenic mushrooms and anticholinergic plants, such as jimsonweed.

BOTANICAL IDENTIFICATION Identification of the botanical in question is most useful, but most patients do not have any knowledge of botany or plant identification. The name of the plant or mushroom is often confusing because the scientific name is not typically known, and common names often overlap. Most emergency department personnel cannot identify common plants, such as mistletoe, holly berries, philodendron, and others. Several resources may be helpful, including plant atlases, CD-ROM plant databases, a local botanical expert, botanical garden personnel, or a poison center. With herbal products, the product name or herbal plant may be known. Because of the limited Food and Drug Administration (FDA) regulation, however, the purported herb might have been harvested from the wrong plant or contaminated with other toxic material.

Plants Among more than 100,000 plant exposures reported to U.S. poison centers annually, most plant exposures occur in children (6 hours postingestion): cyclopeptide, gyromitrin, and orelline/orellanine. The cyclopeptide group is responsible for most mushroom-related deaths in the United States. The orelline/orellanine-containing mushrooms have not been reported to cause toxicity in the United States. The cyclopeptide mushrooms contain many species, of which Amanita phylloides is the most well known. Several cyclopeptide toxins have been identified (e.g., amatoxins, virotoxins, phallotoxins) that are thought to be responsible for toxicity.[58] Initial manifestations, such as severe nausea, vomiting, diarrhea, and abdominal cramping, begin 6 to 24 hours postingestion. Hydration and supportive care often lead to relief of symptoms and a relatively quiescent period. Hepatic toxicity followed by other end-organ involvement may ensue over the next several days to weeks. Progressive elevation of hepatic transaminases, jaundice, and hepatic encephalopathy can lead to death. Many cases are misdiagnosed as gastroenteritis. Numerous noninvasive therapies have been suggested, including silibinin, thioctic acid, activated charcoal, high-dose penicillin, dexamethasone, vitamin C, cytochrome c, cimetidine, N-acetyl cysteine, kutkin, and aucubin.[] None of these therapies has been rigorously tested in human-controlled studies. Repetitive administration of activated charcoal seems to be reasonable because of its ability to bind the toxins, availability, and relative safety. Numerous invasive therapies also have been proposed for use in cyclopeptide poisoning, including forced diuresis, hemodialysis, hemoperfusion, hemofiltration, plasmapheresis, and hepatic transplantation.[61] Similar to the noninvasive modalities, it is not clear what efficacy these therapies have. There have been several reports of successful transplantation in severe cases of poisoning[62]; however, it is uncertain what criteria should be used for selecting candidates. Patients developing hepatic signs and symptoms should be considered for transfer to a transplant center. Gyromitrin-containing mushrooms commonly are mistaken for edible mushrooms. The metabolites of this toxin cause GABA neurotransmitter depletion similar to isoniazid toxicity, leading to excitatory CNS effects, such as headaches, agitation, and seizures. Effects also include nausea, vomiting, and possible hepatotoxicity. The onset of symptoms is at least 6 hours after ingestion. Because of its similarity to isoniazid toxicity, pyridoxine has been proposed as an antidote. It is unclear how effective this antidote is, but it is useful for gyromitrin-induced CNS effects because of its availability and safety profile. Orelline/orellanine-containing mushrooms have been found in North America.[63] There have been no reports of toxicity associated with cases in the United States, however, with most reported cases in Europe. Symptoms begin 1 to 2 days after ingestion, with nausea, vomiting, abdominal pain, and headache. Renal toxicity manifests days to weeks after these initial symptoms and can progress to chronic renal failure.

Disposition Initial management is aimed at ruling out mushroom groups associated with early onset of symptoms. If the patient remains asymptomatic after a period of observation, the patient should be discharged with instructions to return if any symptoms manifest over the next 72 hours.

KEY CONCEPTS {,

Plant expo sure s occu r com monl y in child ren and most com monl y

Page 3796

{,

{,

invol ve hous ehol d plant s. Most expo sure s caus e little or no toxici ty. Plant s and mus hroo ms often are inge sted for their mind -alter ing prop ertie s. Misid entifi catio n of plant s and herb al prod ucts is a com mon caus e for plant -indu ced and herb al prod uct– indu ced toxici

Page 3797

{,

{,

ty. Natu ral plant and mus hroo m gath ering for pers onal inge stion is a popu lar activi ty. Mist akes while forag ing occu r com monl y, with the pote ntial for serio us toxici ty and num erou s fatali ties. Herb al medi cine s incre asin gly are bein g used by the gene ral publi

Page 3798

c. Limit ed infor mati on is avail able rega rding the effic acy and toxici ty of thes e prod ucts. {,

In the asse ssm ent of a patie nt expo sed to a mus hroo m, the timin g of initial sym ptom s and the asse ssm ent for asso ciate d sym ptom s cons titute the most impo rtant data need ed to

Page 3799

{,

mak ea differ entia l diag nosi s. A patie nt who has eate n or been expo sed to a wild mus hroo m may have anot her medi cal cond ition actu ally resp onsi ble for the sym ptom s.

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Chapter 17 – Headache Gregory L. Henry Christopher S. Russi

PERSPECTIVE Epidemiology As many as 85% of the U.S. adult population complains of significant headaches at least occasionally and 15% on a regular basis. Headache as a primary complaint represents between 3% and 5% of all emergency department visits. The vast majority of patients who have the primary complaint of headache do not have a serious medical cause for the problem. Tension headache accounts for approximately 50% of patients presenting to the emergency department, another 30% have headache of nonidentified origin, 10% have migraine-type pain, and 8% have headache from other potentially serious causes (e.g., tumor, glaucoma). It is estimated that less than 1% of patients who present to the emergency department with headache have a life-threatening organic disease.[1] The percentages can create a false sense of security, and headache is disproportionately represented in emergency medicine malpractice claims. Although still rare, the most commonly encountered cause of severe sudden head pain is subarachnoid hemorrhage (SAH); approximately 20,000 potentially salvageable cases of SAH present to emergency departments each year. It is estimated that between 25% and 50% of these are missed on the first presentation to a physician.[2] The other significant, potentially life-threatening causes of headache occur even less frequently. Meningitis, carbon monoxide poisoning, temporal arteritis, acute angle closure glaucoma, and increased intracranial pressure often have specific historical elements and physical findings that facilitate their diagnosis.

Pathophysiology The brain parenchyma is insensitive to pain. The pain-sensitive areas of the head include the coverings of the brain—the meninges—and the blood vessels, both arteries and veins supplying the brain, and the various tissues lining the cavities within the skull. The ability of the patient to localize head pain specifically is often poor. Much of the pain associated with headache, particularly with vascular headache and migraines, is mediated through the fifth cranial nerve. Such pain may proceed back to the nucleus and then be radiated through various branches of the fifth cranial nerve to areas not directly involved. A specific inflammation in a specific structure (e.g., periapical abscess, sinusitis, or tic douloureux) is much easier to localize than the relatively diffuse pain that may be generated by tension or traction headaches. Pains in the head and neck may easily overlap. They should be thought of as a unit when considering complaints of headache.

DIAGNOSTIC APPROACH Differential Considerations The differential diagnosis of headache is complex because of the large number of potential disease entities and the diffuse nature of many types of pain in the head and neck region ( Table 17-1 ). However, in evaluating the patient with a headache complaint, the first focus is on excluding intracranial hemorrhage, meningitis, encephalitis, and mass lesions. Carbon monoxide is an exogenous toxin that may be reversible by removing the patient from the source and administering oxygen. It is a rare example of a headache in which a simple intervention may quickly improve a critical situation. On the contrary, returning the patient to the poisoned environment without diagnosis could be lethal. Table 17-1 -- Differential Diagnosis Organ System Critical Diagnoses Neurologic, CNS, vessels

Subarachnoid hemorrhage

Emergent Diagnoses Nonemergent Diagnoses Shunt failure Traction headaches

Migraine, various types Vascular, various types Trigeminal neuralgia

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Organ System

Critical Diagnoses

Emergent Diagnoses Nonemergent Diagnoses Tumor/other masses Subdural hematomas

Carbon monoxide Toxic/metabolic poisoning Environmental Collagen vascular disease Eye/ENT

Posttraumatic Post–lumbar puncture Headaches

Mountain sickness

Temporal arteritis Glaucoma/sinusitis

Dental problems/temporomandibular joint disease

Musculoskeletal Tension headaches Cervical strain Allergy Infectious disease

Bacterial meningitis/encephalitis

Brain abscess

Cluster/histamine headaches Febrile headaches/nonneurologic source of infection

Pulmonary/O2 Anoxic headache Anemia Cardiovascular Unspecified

Hypertensive crisis

Hypertension (rare) Effort-dependent/coital headaches

CNS, central nervous system; ENT, ear, nose, and throat.

Rapid Assessment and Stabilization If the patient presents in a critical state, a fundamental approach to airway, breathing, and circulatory management must supercede any other initial intervention. Included in the primary survey is a focused and rapid assessment of the patient's mental status. For purposes of the initial assessment, headache can be divided into two categories: accompanied by altered mental status and without altered mental status. Whenever a patient's mental status is decreased, it must be initially assumed that brain tissue is being compromised. The principles of care centered on cerebral resuscitation address the seven major causes of evolving brain injury: lack of substrate (glucose, oxygen), cerebral edema, mass lesion intracranially, endogenous or exogenous toxins, metabolic alterations (fever, seizure), ischemia, or elevated intracranial pressure.

Pivotal Findings History The history is the pivotal part of the workup for the patient with headache ( Table 17-2 ). Table 17-2 -- Significant Symptoms Symptom

Finding

Possible Diagnoses

Sudden onset pain Lightning strike or thunder clap with any decreased Subarachnoid hemorrhage mentation, any positive focal finding and/or intractable pain “Worst headache of Associated with sudden onset Subarachnoid hemorrhage their life” Near syncope or Associated with sudden onset Subarachnoid hemorrhage

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syncope Increase with jaw movement Facial pain

Clicking or snapping. Pain with jaw movement Fulminant pain of the forehead and area of maxillary sinus. Nasal congestion. Tender temporal arteries

Forehead and/or temporal area pain Periorbital or Sudden onset with tearing retroorbital pain

1.

2.

3.

4.

Temporomandibular joint disease Sinus pressure or dental infection Temporal arteritis Temporal arteritis or acute angle closure glaucoma

A patient should be asked to describe the pattern and onset of the pain. Patients often relate frequent and recurrent headaches similar to the one they have on this emergency department visit. A marked variance in a headache pattern can signal a new or serious problem. The rate of onset of pain may have significant value. Pain with rapid onset of a few seconds to minutes is more likely to be vascular in origin than pain that developed over several hours or days. Almost all studies dealing with subarachnoid bleeding report that patients have moved from the pain-free state to severe pain within seconds to minutes. The “thunder clap” or “lightning strike” headache is a real phenomenon, and this response to questioning may lead to the correct diagnosis of subarachnoid bleeding, even if the pain is improving at the time of evaluation.[3] The patient's activity at the onset of the pain may be helpful. Certainly, headaches that come on during severe exertion have a relationship to vascular bleeding, but again, there is enough variation to make assignment to any specific cause highly variable. The syndrome of coital or postcoital headache is well known, but coitus is also a common time of onset for SAH. These headaches require the same evaluation on initial presentation as any other exertion-related head pain. If the patient can recall the precise activity in which he or she was engaging at the time of the onset of the headache (e.g., “I was just getting up out of the chair to answer the doorbell”), sudden onset is extremely likely and evaluation for SAH is warranted. If the patient or prehospital personnel can relate a history of head trauma, the differential diagnosis and emergent causes have narrowed significantly. The considerations now focus on epidural and subdural hematoma, skull fracture, and closed head injury (i.e., concussion and diffuse axonal injury). Toxoplasmosis, cryptococcal meningitis, and abscess are considered higher in the differential in patients with a history of human immunodeficiency virus (HIV) or immunocompromised state. Although such entities are rare, it is important to remember this subset of patients may have serious disease without typical signs or symptoms of systemic illness, that is, fever and meningismus.

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5.

6.

7.

8.

9.

The intensity of head pain is difficult to quantify objectively. Almost all patients who present to the emergency department consider their headache to be “severe.” Use of a pain scale of 1 to 10 may help differentiate patients initially but has more value in monitoring their response to therapy. The character of the pain, that is, throbbing, steady, and so forth, although statistically helpful, may not be adequate to differentiate one type of headache from another. The location of head pain is helpful when the patient can identify a specific area. It is useful to have the patient point or try to indicate the area of pain and the emergency physician then properly examine that area. Unilateral pain is more suggestive of migraine or a localized inflammatory process in the skull (e.g., sinus) or soft tissue.[4] Occipital headaches are classically associated with hypertension. Certainly, temporal arteritis, temporomandibular joint disease, dental infections, and sinus infections frequently have a highly localized area of discomfort. Meningitis, encephalitis, SAH, and even severe migraine, although intense in nature, are usually more diffuse in their localization. Exacerbating or alleviating factors may be important. Patients whose headaches rapidly improve when they are removed from their environment may have carbon monoxide poisoning. Most other severe causes of head pain are not rapidly relieved or improved when they get to the emergency department. Intracranial infections, dental infections, and other regional causes of head pain tend not to be improved or alleviated before therapy is given. Associated symptoms and risk factors may relate to the severity of headache but rarely point to the specific causes ( Box 17-1 ). Because head pain is mediated largely through the cranial nerves, outflow through other cranial nerves is common. Nausea and vomiting are completely nonspecific. Migraine headaches, increased intracranial pressure, temporal arteritis, and glaucoma can all be manifested through severe nausea and vomiting, as can some systemic viral infections with headache. Such factors may point toward the intensity of the discomfort but are not specific in establishing the diagnosis. BOX 17-1 Risk Factors Associated with Potentially Catastrophic Illness

1.

Carbon Monoxide Poisoning a. Brea thing in encl osed or confi

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2.

ned spac es with engi ne exha ust or ventil ation of heati ng equi pme nt b. Multi ple famil y me mbe rs with the sam e sym ptom s c. Wint ertim e and work ing arou nd mac hiner y or equi pme nt prod ucin g carb on mon oxid e, furna ces, etc. Subarachnoid Hemorrhage a. Histo ry of

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3.

poly cysti c kidn ey dise ase b. Fami ly histo ry of suba rach noid hem orrh age c. Hype rtens ion — seve re d. Previ ous vasc ular lesio ns in other area s of the body e. Middl e aged Meningitis/Encep halitis/Abscess a. Histo ry of sinu s or ear infec tion or rece nt surgi cal proc edur e b. Gen eral debili tatio n with

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c.

d.

e.

f.

4.

Temporal Arteritis a. b.

c.

decr ease d imm unol ogic syst em funct ion Acut e febril e illnes s— any type Extr eme s of age Impa cted living cond ition s (e.g., milit ary barr acks , colle ge dor mitor ies) Lack of prim ary imm uniz ation s

Age > 50 Fem ales > male s 4:1 Histo ry of other colla

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d.

e.

5.

gen vasc ular dise ases (e.g., syst emic lupu s) Previ ous chro nic meni ngiti s Previ ous chro nic illnes s such as tuber culo sis, para sitic infec tion, fungi

Glaucoma— sudden angle closure a. Not asso ciate d with any usua l or cust oma ry head ache patte rn b. Histo ry of previ ous glau com a c. Age > 30

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d.

e.

6.

10.

Histo ry of pain incre asin g in a dark envir onm ent Hype rtens ion — mild stati stica l asso ciati on

Increased intracranial pressure a. Histo ry of previ ous beni gn intra crani al hype rtens ion b. Pres ence of a cere bros pinal fluid shun t c. Histo ry of cong enita l brain or skull abno rmali ties

A prior history of headache, although helpful, does not rule out current serious problems. It is extremely helpful, however, to know that the patient has had a

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workup for severe disease. Previous emergency department visits, computed tomography (CT) scanning, magnetic resonance imaging, and other forms of testing should be sought. Patients with both migraine and tension headaches tend to have a stereotypical recurrent pattern. Adherence to these patterns is also helpful in deciding the degree to which a patient's symptoms are pursued.

Physical Examination Physical findings associated with various forms of headache are listed in Table 17-3 . Table 17-3 -- Pivotal Findings on Physical Examination Sign Finding General appearance

Alteration of mental status— nonfocal

Alterations of mental status with focal findings

Diagnoses Meni ngiti s/en ceph alitis Sub arac hnoi d hem orrh age Anox ia Incre ased CSF pres sure Intra pare nchy mal blee d Tent orial herni ation Stro ke

Severe nausea/vomiting Incre ased CSF pres sure Acut e angl e

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Sign

Finding

Diagnoses clos ure glau com a Sub arac hnoi d hem orrh age

Vital signs

Hypertension with normal or bradycardia

Incre ased CSF pres sure Sub arac hnoi d hem orrh age Tent orial herni ation Intra pare nchy mal blee d

Tachycardia Anox ia/an emia Febri le head ache Exer tiona l/coit al head ache s Fever Febri le head ache s Meni

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Sign

Finding

Diagnoses ngiti s/en ceph alitis

HEENT

Tender temporal arteries Fundi—loss of spontaneous venous pulsations and/or presence of papilledema

Temporal arteritis Incre ased CSF pres sure Mas s lesio ns

Subhyaloid hemorrhage Subarachnoid hemorrhage Acute red eye (severe ciliary Acute angle closure glaucoma flushing) and poorly reactive pupils Enlarged pupil with third nerve palsy Tent orial pres sure cone Mas s effec t (i.e., subd ural, epid ural, tumo r, intra pare nchy mal hem orrh age) Neurologic

Lateralized motor or sensory deficit

Stro ke (rare ) Sub dural hem atom a, epid ural hem atom a,

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Sign

Finding

Diagnoses hemi plegi c or anes theti c migr aine (rare )

Acute cerebellar ataxia Acut e cere bella r hem orrh age Acut e cere belliti s (mo stly child ren) Che mica l intoxi catio n— vario us type s

CSF, cerebrospinal fluid; HEENT, head, eyes, ears, nose, and throat.

Ancillary Testing The vast majority of headache patients do not require additional testing ( Table 17-4 ). The single largest consistent mistake made by emergency physicians in the workup of the headache patient is believing a single CT scan clears the patient of the possibility of SAH. The CT scan is at least 6% to 8% insensitive in SAH, especially in patients with minor (grade I) SAH, who are most salvageable.[5] The sensitivity of CT scanning for SAH is reduced by nearly 10% if over 12 hours and by almost 20% at 3 to 5 days. The basic approach to integrating CT scanning and lumbar puncture in assessing the headache patient is outlined in Figure 17-1 .[6] When the decision has been made to obtain a CT scan and do a lumbar puncture, short-term sedation of the patient is appropriate as necessary. Table 17-4 -- Diagnostic Adjuncts in Headache Assessment

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Test

Finding

Diagnosis

Erythrocyte sedimentation Significant elevation rate (ESR) ECG Nonspecific ST-T wave changes

Temporal arteritis

Sub arac hnoi d hem orrh age Incre ased CSF pres sure CBC CT—head

Severe anemia Incre ased ventr icula r size Bloo d in suba rach noid spac e Bloo d in epid ural or subd ural spac e Blee ding into pare nchy ma of brain Area s of poor vasc ular flow Stru ctura l/ma ss lesio

Anoxia Incre ased CSF pres sure Sub arac hnoi d hem orrh age Epid ural/ subd ural hem atom a Intra pare nchy mal hem orrh age Pale infar ct Trac tion head ache seco ndar y to mas s effec t

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Test

Finding

Diagnosis n

Lumbar puncture/CSF analysis

Increased pressure Pse udot umo r cere bri Mas s lesio ns Shu nt failur e Incre ased prote in Incre ased RBC s Incre ased WB Cs Posit ive Gra m's stain Decr ease d gluc ose

Tum or/ot her struc tural lesio ns Sub arac hnoi d hem orrh age Infec tion Infec tion Infec tion

CBC, complete blood count; CSF, cerebrospinal fluid; CT, computed tomography; ECG, electrocardiogram; RBC, red blood cell; WBC, white blood cell.

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Figure 17-1 Initial assessm ent and treatm ent of headache. CT, com puted tom ography.

Obtaining cerebrospinal fluid should not delay antimicrobial treatment if intracranial infection is suspected. Intravenous antibiotics should precede lumbar puncture. Any abnormal mental status, signs of increased intracranial pressure, focality, focal findings on the neurologic examination, or any other suspicion of focal intracranial lesion would require CT scanning before lumbar puncture.

DIFFERENTIAL CONSIDERATIONS Certain historical and physical findings can help decide whether the patient falls into an “all clear” or a “warning signal” group. In the warning group, further investigation and testing should be performed on all patients who present with any of the following: (1) sudden onset of headache, (2) “the worst headache ever,” (3) decreased or altered mental status, (4) true meningismus, (5) unexplained abnormal vital signs, (6) focal neurologic deficits on examination, (7) worsening under observation, (8) new onset of headache with exertion, or (9) history of HIV. This group of patients represents those who are at high risk for significant disease. In addition, a group of responsible “all clear signals” indicates patients who do not require further investigation when all are present: (1) previous identical headaches, (2) normal alertness and cognition by both examination and history of the event, (3) normal examination of the neck showing no meningismus, (4) normal vital signs, (5) normal or nonfocal neurologic examination, and (6) improvement under observation or with treatment. Several risk factors for aneurysmal SAH were demonstrated in a case-control study. In a population of 26 cases of known aneurismal SAH, smoking, hypertension, and excessive caffeine intake (>5 cups of coffee daily) showed statistical significance as risk factors in a logistic regression analysis.[7] After initial history taking, physical examination, and stabilization, findings should match the classical atypical patterns of the various potentially critical diseases causing headache. This sequential evaluation and assessment of data are ongoing processes and should be reevaluated when a patient is under observation in the department. Inconsistency in findings may require a rapid review of the situation and rethinking of the diagnosis ( Table 17-5 ).[8] Table 17-5 -- Causes and Differentiation of Potentially Catastrophic Illness Presenting with Nontraumatic Headache Di Pain History Associated Support History Pr Physical Useful Tests Atypical or se Symptoms ev Examination Important as al Aspects e en En ce titi es Ca rb on m on oxi de poi so nin g

Usually gradual, subtle, dull, nonfocal throbbing pain

May wax and wan e as they leav e and enter the invol ved area of carb on

Exposure to Ra No focal engine exhaust, re neurologic old or defective findings. May heating systems, need cognitive most common in testing winter months

Carbon May improve on monoxide level, the way to the cognitive testing hospital. Occurs in groups, may involve entire families or groups of people exposed to the carbon monoxide

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Di Pain History se as e En titi es

Associated Symptoms

Support History Pr Physical ev Examination al en ce

Useful Tests

Atypical or Important Aspects

mon oxid e Thro bbin g may vary cons idera bly Su ba ra ch noi d he m orr ha ge

Sudden onset, “thunder clap” or “lightning strike,” severe throbbing

Me nin giti s/e nc ep hal itis /ab sc es s

Gradual—as general symptoms increase headache increases— nonfocal

Whenever altered mental status is present the outcome is decidedly worse

Decr ease d ment ation pro mine nt, irrita bility pro mine nt With absc ess focal neur ologi c

Un Histo co ry of m poly m cysti on c kidn ey dise ase Histo ry of chro nic hype rtens ion

Frequently decreased mentation— meningismus, increased blood pressure, decreased pulse, decreased spontaneous venous pulsations, rarely subhyaloid hemorrhage

Un Rec co ent m infec m tion on Rec ent facia l or dent al surg ery or other ENT surg ery

Fever—late in course decreased spontaneous venous pulsations

CT Lum bar punc ture

If CT posit ive, imm ediat e invol vem ent of neur osur gery If CT nega tive, lumb ar punc ture

CT Lum bar punc ture

Whe n such infec tion susp ecte d, treat Do not dela y antib iotic s and stero ids awai

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Di Pain History se as e En titi es

Associated Symptoms

Support History Pr Physical ev Examination al en ce

Useful Tests

findi ngs may be pres ent Te m po ral art erit is

Decreased Ofte vision, nausea, vomiting intense n pain —may confuse deve diagnosis lopin g over a few hour s from mild to seve re Virtu ally alwa ys focal in natur e

Ac Sudden in onset Nausea, ute vomiting, an decreased vision gle clo su re gla uc o m a

Inc Gradual, dull, re nonfocal as ed intr

Vomiting, decreased mentation

Atypical or Important Aspects

ting labor atory resul ts Un Tender temporal Sedimentation rate Age co arteries m over m 50 Othe on r colla gen vasc ular dise ases or infla mm atory dise ases

Usually unrelated rapidly progressive

Ra Histo re ry of glau com a Histo ry of pain goin g into dark area

Rapid intervention with medications required—if no relief, immediate surgery may be required

History of CSF shunt or other congenital brain or skull abnormality

Un co m m on

Measurement of “Ste intraocular amy” pressure corn ea Midp ositi on pupil poorl y react ive Acut e red eye Papil lede ma Loss

Shunt failure or CT other cause of Shu significant increased CSF nt funct pressure

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Di Pain History se as e En titi es ac ra nia l pr es su re sy nd ro m es

Associated Symptoms

Support History Pr Physical ev Examination al en ce

of spon tane ous veno us puls ation s

Useful Tests

Atypical or Important Aspects

ion requires stud involvement of neurosurgery y If OK, lumb ar punc ture

C SF , ce re br os pin al flui d; CT , co m put ed to m og ra ph y; EN T, ea r, no se, an d thr oat .

MANAGEMENT Empirical

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Patients with headache represent a spectrum of disease. Patients with headache need to be placed for evaluation according to their symptoms. Clearly, patients with abnormal vital signs or altered mental status require evaluation before patients with less severe symptoms. If history and physical examination point toward potentially lethal causes, however, effort should be made to establish the diagnosis rapidly with ancillary testing. Pain treatment should be started early. The pain medication of choice depends on the particular patient, underlying vital signs, allergies, and general condition; but relief of pain is still an essential part of the physician's job and should have little effect on the workup of the patient.

Specific Specific management for the patient with headache is described in Chapter 101 . The challenge in emergency medicine, however, is to eliminate life-threatening causes of headache and to treat the patient's pain.

DISPOSITION Most patients presenting with headache are discharged from the emergency department with appropriate analgesia and follow-up. These represent patients in the all clear category or those found to have no serious disease after a careful evaluation and testing. Any patients in whom warning findings are noted require more extensive assessment.

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33. De Smet PAGM: Drug therapy: Herbal remedies. N Engl J Med2002;347:2046. 34. Marcus DM, Grollman AP: Botanical medicines—the need for new regulations. N Engl J Med 2002;347:2073. 35. Fugh-Berman A: Herb-drug interactions. Lancet2000;355:134. 36. Pui-Hay But P: Need for correct identification of herbs in herbal poisoning. Lancet1993;341:637. 37. Meggs WJ: Anticholinergic poisoning associated with an herbal tea—New York City, 1994. MMWR Morb Mortal Wkly Rep1995;44:193. 38. Slifman NR: Brief report: Contamination of botanical dietary supplements by Digitalis lanata. N Engl J Med1998;339:806. 39. Vanherweghem JL: Rapidly progressive interstitial renal fibrosis in young women: Association with slimming regimen including Chinese herbs. Lancet1993;341:387. 40. Ko RJ: Adulterants in Asian patent medicine. N Engl J Med1998;339:847. 41. Ernst E: Adulteration of Chinese herbal medicine with synthetic drugs: A systematic review. J Intern Med 2002;252:107. 42. Hill GJ: Lead poisoning due to Hai Be Fen. JAMA1995;273:24. 43. Espinoza EO: Arsenic and mercury in traditional Chinese herbal balls. N Engl J Med1995;333:803. 44. Ries CA, Sahud MA: Agranulocytosis caused by Chinese herbal medicines. JAMA1975;231:352. 45. Nelson L: Aplastic anemia induced by an adulterated herbal preparation. J Toxicol Clin Toxicol 1995;33:467. 46. Capobianco DJ: Proximal-muscle weakness induced by herbs. N Engl J Med1993;329:1430. 47. Diamond J, Pallone PL: Acute interstitial nephritis following use of Tung Shueh pills. Am J Kidney Dis 1994;24:219. 48. Chan TYK, Critchley JAJH: Usage and adverse effects of Chinese herbal medicines. Hum Exp Toxicol 1996;15:5. 49. Wong HCG: Allergic reactions associated with Chinese herbal medicine. Allergy Asthma2000;13:13. 50. Ernst E: Adverse effects of herbal drugs in dermatology. Br J Dermatol2000;143:923. 51. Fugh-Berman A: Herb-drug interactions. Lancet2000;355:134. 52. Smolinske SC: Dietary supplement-drug interactions. J Am Med Womens Assoc1999;54:191. 53. Jacobs J: Serious mushroom poisonings in California requiring hospital admission, 1990 through 1994. West J Med1996;165:283. 54. Lampe KF, McCann MA: Differential diagnosis of poisoning by North American mushrooms, with particular emphasis on Amanita phalloides-like intoxication. Ann Emerg Med1987;16:956. 55. Michelot D, Melendez-Howell LM: Amanita muscaria: Chemistry, biology, toxicology, and ethnomycology. Mycol Res2003;107:131. 56. Schwartz RH, Smith DE: Hallucinogenic mushrooms. Clin Pediatr (Phila)1998;27:70. 57. Michelot D: Poisoning by Coprinus atramentarius. Nat Toxins1992;1:73. 58. Vetter J: Toxins of Amanita phalloides. Toxicon1998;36:13. 59. Montanini S: Use of acetylcysteine as the life-saving antidote in Amanita phalloides (death cap) poisoning: Case report on 11 patients. Arzneimittel-Forschung1999;49:1044. 60. Schneider SM: Cimetidine protection against alpha-amanitin hepatotoxicity in mice: A potential model for the treatment of Amanita phalloides poisoning. Ann Emerg Med1987;16:1136. 61. Aji DY: Haemoperfusion in Amanita phalloides poisoning. J Trop Pediatr1995;41:371. 62. Skaare VK: Mushroom poisoning: An indication for liver transplantation. J Transplant Coor1997;7:141. 63. Horn S: End-stage renal failure from mushroom poisoning with Cortinarius orellanus: Report of four cases and review of the literature. Am J Kidney Dis1997;30:282.

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Marx: Rosen's Emergency Medicine: Concepts and Clinical Practice, 6th ed., Copyright © 2006 Mosby, Inc.

Chapter 163 – Sedative Hypnotics Leon Gussow Andrea Carlson

BARBITURATES Perspective Barbiturates are discussed in do-it-yourself suicide manuals and have been implicated in the high-profile deaths of Marilyn Monroe, Jimi Hendrix, Abbie Hoffman, Margaux Hemingway, and the mass suicide of 39 members of the Heaven's Gate cult in 1997. Although barbiturates are still prescribed for the treatment of seizure disorders, their use as sedatives has declined significantly with the availability of safer alternatives, such as the benzodiazepines. There has been a concomitant decline from approximately 1500 reported barbiturate deaths per year in the 1950s to only nine fatalities in 1998. Barbiturates are addicting, producing physical dependence and a withdrawal syndrome that can be life-threatening. Tolerance to the mood-altering effects of barbiturates develops rapidly with repeated use. Unfortunately, tolerance to the lethal effects does not develop as quickly, and the risk of severe toxicity increases with continued use.

Principles of Disease Barbiturates depress the activity of all excitable cells, especially those in the central nervous system (CNS). They enhance the activity of p~-aminobutyric acid (GABA), the major central inhibitor of nerve excitability. In cases of acute overdose, barbiturates decrease transmission in autonomic ganglia and the activity of the myocardium and gastrointestinal tract. Barbiturates also inhibit the excitatory response to acetylcholine at autonomic neuroeffector and skeletal neuromuscular junctions. The GABAA receptor is a protein complex found on postsynaptic membranes in the CNS. Structurally, it consists of distinct receptor sites for a number of endogenous and exogenous depressive chemicals with sedative and hypnotic properties, surrounding a chloride ion (Cl−) channel ( Figure 163-1 ). GABA opens the chloride channel. The resulting flow of Cl− into the cell increases the negative resting potential, hyperpolarizing and stabilizing the membrane. There are separate receptor sites for barbiturates and for benzodiazepines, and a site that binds GABA, ethanol, and meprobamate. Barbiturates hold Cl− channels longer in an open position, whereas benzodiazepines cause them to open more often. Although barbiturates and ethanol can directly increase Cl− conductance, benzodiazepines require the presence of GABA to affect Cl− flow. This may account for the relative safety of benzodiazepines in comparison with barbiturates.

Figure 163-1 The p~-am inobutyric acid (GABA) receptor com plex. BZ, benzodiazepine binding site; GABA, GABA binding site; ETOH, m epro, barb, binding site for ethanol, meprobam ate, and barbiturates.

Barbiturates produce the gamut of depressive effects, from mild sedation to coma, respiratory arrest, and death. In the early stages of intoxication, some patients experience euphoria. Barbiturates have no analgesic effect and can paradoxically increase the reaction to pain at low doses. Barbiturates act directly on the medulla to produce respiratory depression. In therapeutic doses, this

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respiratory depression mimics that seen in normal sleep. Starting with doses approximately three times therapeutic, the neurogenic, chemical, and hypoxic respiratory drives are progressively suppressed. Laryngospasm can occur at low doses, because airway reflexes are not inhibited until general anesthesia is achieved. Therapeutic oral doses of barbiturates produce only mild decreases in pulse and blood pressure, similar to those seen in sleep. With toxic doses, more significant hypotension occurs from direct depression of the myocardium and pooling of blood in a dilated venous system. Peripheral vascular resistance is usually normal or increased, but since barbiturates interfere with autonomic reflexes, these compensatory changes are inadequate for the decrease in blood pressure. In patients whose reflexes are already maximally stimulated, such as those with heart failure or hypovolemic shock, barbiturates can precipitate severe hypotension. Barbiturates also decrease cerebral blood flow and decrease intracerebral pressure. Although hypnotic doses of barbiturates do not affect gastric emptying, higher doses can decrease gastrointestinal smooth muscle tone and peristaltic contractions. Barbiturates are classified according to their onset and duration of action: (1) ultrashort-acting (onset immediate after intravenous dose, duration minutes), (2) short-acting (onset 10 to 15 minutes after oral dose, duration 6 to 8 hours), (3) intermediate-acting (onset 45 to 60 minutes, duration 10 to 12 hours), and (4) long-acting (onset 1 hour, duration 10 to 12 hours) ( Box 163-1 ). Only long-acting preparations have anticonvulsant effects in doses that do not cause sedation. The highly lipid-soluble, short-acting barbiturates are rapidly absorbed and quickly distributed to tissues with high perfusion, especially the brain, while phenobarbital, the least lipid-soluble barbiturate, has a slow onset. BOX 163-1 Barbiturates

Ultrashort-Acting Methohexital (Brevital) Thiopental (Pentothal)

Short- and Intermediate-Acting Pentobarbital (Nembutal) Secobarbital (Seconal) Amobarbital (Amytal) Aprobarbital (Alurate) Butabarbital (Butisol) Butalbital (Fiorinal)

Long-Acting Phenobarbital (Solfoton, Luminal) Mephobarbital (Mebaral) Short- and intermediate-acting preparations are almost completely metabolized to inactive metabolites in the liver, but 25% of a phenobarbital (long-acting) dose is excreted unchanged through the kidney. Because phenobarbital is a weak acid (pKa 7.2), alkalinizing the urine will increase the amount of drug present in ionized form, minimizing tubular reabsorption. Phenobarbital is 95% ionized at pH 7. Short- and intermediate-acting barbiturates are not significantly affected by pH changes in this range; for example, secobarbital (pKa 7.9) is 98% nonionized at pH 7.4. Barbiturates cross the placenta, and fetal levels approach those of the mother. They are also excreted in breast milk, but at much lower concentrations than those found in maternal plasma. Use during pregnancy is associated with birth defects (category D).

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Clinical Features Mild barbiturate toxicity mimics ethanol intoxication, with drowsiness, slurred speech, ataxia, unsteady gait, nystagmus, emotional lability, and impaired cognition (e.g., memory, judgment, and attention). In cases of severe acute intoxication, CNS depression progresses from stupor to deep coma and respiratory arrest. Although pupils are usually normal or small but reactive, hypoxia can cause pupil dilation and loss of reactivity. Corneal and gag reflexes can be diminished or absent. Muscle tone can be flaccid, with absent reflexes and a positive Babinski sign. Flexor (decorticate) and extensor (decerebrate) posturing can occur in patients comatose from barbiturate intoxication. These neurologic signs are variable and do not always correlate with severity of intoxication or depth of coma. Fluctuating level of consciousness is common. High barbiturate levels depress gastrointestinal motility, delaying drug absorption. However, as the drug is metabolized and blood levels drop, peristalsis and drug absorption increase again and levels rise. The threat to life in cases of severe barbiturate toxicity is respiratory depression. The degree of hypoventilation may not be readily apparent on clinical examination, because respirations can be rapid but shallow. Pulse oximetry is used to assess for hypoxemia. Cheyne-Stokes breathing may precede respiratory arrest. Delayed complications include pneumonia. Hypotension is common in patients with severe intoxication, with a normal or increased heart rate. Barbiturate overdose can be associated with noncardiogenic pulmonary edema. Altered pulmonary capillary permeability can result from hypoperfusion or hypoxia or be a direct effect of the drug. Hypothermia (31° to 36.6° C) occurs in patients with short-acting barbiturate intoxication or can result from exposure in any comatose patient. A withdrawal syndrome includes tremors, hallucinations, seizures, and delirium (similar to the delirium tremens of ethanol withdrawal). However, severe withdrawal occurs only following dependence on short- or intermediate-acting barbiturates (e.g., pentobarbital, secobarbital, amobarbital, and butalbital). Because these drugs have few medical uses, this syndrome is now rare.

Diagnostic Strategies Qualitative and quantitative tests detect barbiturates in urine and blood; however, a positive urine screen establishes the presence of the drug but does not prove that it is present in toxic amounts. The therapeutic level of phenobarbital is 15 to 40 p-g/mL (65 to 172 p-mol/L). A serum level greater than 50 p-g/mL can be associated with coma, especially in a patient who is not a chronic barbiturate user. Levels greater than 80 p-g/mL are potentially fatal. Serial phenobarbital levels may be helpful in monitoring effectiveness of treatment. Because barbiturates other than phenobarbital have high volumes of distribution, serum levels do not accurately reflect CNS concentrations or correlate with clinical severity. In more severe overdose cases, chest radiographs can show noncardiogenic pulmonary edema or pneumonia. Computed tomography of the head can be performed in comatose patients with evidence of trauma, focal neurologic signs, papilledema, or uncertain diagnosis. Other causes of stupor and coma must be considered and ruled out. Since the electroencephalogram may be silent as a result of barbiturate overdose, no patient should be declared “brain dead” if barbiturates are present at therapeutic levels or greater.

Management Barbiturates have no specific antidote, and management is based on supportive care, particularly with respect to the cardiovascular and respiratory systems. Severely intoxicated patients are unable to protect their airway adequately, and ventilatory drive is decreased, with ensuing hypoxemia. Supplemental oxygen may suffice for patients with mild to moderate overdose, but intubation is often required as the patient's level of consciousness becomes progressively depressed with accompanying respiratory depression. When intubation is required, and in the absence of an identified difficult airway, a rapid-sequence technique is preferred, using a barbiturate (sodium pentothal) or benzodiazepine (midazolam) induction agent with succinylcholine for neuromuscular blockade. Long-term paralysis is rarely necessary, and the patient's own ingestion will generally provide sufficient sedation for mechanical ventilation. Cardiovascular support involves careful but adequate fluid replacement to maintain a systolic blood pressure above 90 mm Hg and adequate urine output. Patients must be monitored for signs of fluid overload and pulmonary edema. If vasopressors are necessary, dopamine is preferable to norepinephrine because of its renal vasodilating effects. Active warming should be initiated if the rectal temperature is less than 30° C.

Gastrointestinal Decontamination

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Although there is no evidence proving that activated charcoal reduces the morbidity or mortality of barbiturate overdose, several studies have demonstrated enhanced clearance of specific barbiturates, so charcoal administration is generally recommended. A single dose of activated charcoal (50-100 g for an adult) can be given if ingestion has occurred recently. In addition, multiple doses of activated charcoal will increase the clearance and decrease the half-life of phenobarbital, since it has the longest half-life.[] Multidose activated charcoal may adsorb the drug as it continues to be released from a bezoar and interrupt “enterohepatic” circulation, where phenobarbital is excreted in the bile and then reabsorbed from the gastrointestinal tract. Finally, multidose activated charcoal will bind the drug as it diffuses into the gastrointestinal tract, increasing both the concentration gradient across the gastrointestinal mucosal surface and drug clearance. An adult dose of multidose activated charcoal is 25 g every 2 hours; the pediatric dose is 0.5 g/kg every 2 hours. If vomiting interferes with administering multidose activated charcoal, a smaller dose or antiemetics should be used. Multidose activated charcoal can also be administered slowly through a nasogastric tube. Although alkalinizing the urine with NaHCO3 has been recommended in the past in place of or in addition to multidose activated charcoal for treating phenobarbital overdose, a recent nonrandomized study suggested that multidose activated charcoal alone is most effective at increasing the drug's clearance.[3] The authors hypothesize that alkalinization may interfere with the ability of multidose activated charcoal to clear the drug across the intestinal mucosa. Hemodialysis or charcoal hemoperfusion is rarely needed but may increase clearance of phenobarbital in the presence of renal or cardiac failure, acid-base or electrolyte abnormalities, unstable cardiorespiratory status, or inadequate response to less invasive measures. Because phenobarbital is 40% to 60% protein-bound, hemoperfusion is sometimes advocated over hemodialysis; however, newer, high-efficiency dialyzers using high blood flow rates may provide drug clearance greater than that achieved by hemoperfusion.[4]

Disposition An asymptomatic patient who arrives in the emergency department after ingesting barbiturates should be observed for at least 6 hours and monitored for mental status changes, slurred speech, ataxia, hypotension, and respiratory depression. Onset of symptoms generally occurs within 1 hour. Patients who remain asymptomatic and have no significant complicating co-ingestants or medical problems can be discharged or referred for psychiatric care. Patients who are still symptomatic 6 hours after arrival should be admitted for observation.

BENZODIAZEPINES Perspective Prior to 1950, treatment of anxiety was limited. Meprobamate, synthesized in 1950, ultimately proved no safer than the barbiturates, but its commercial success inspired the development of other nonbarbiturate anxiolytics. With the introduction of chlordiazepoxide in 1960 and diazepam in 1963, benzodiazepines emerged as the principal agents in the treatment of anxiety. Cardiac effects and fatalities from pure benzodiazepine overdose are rare, and respiratory depression is less pronounced than with barbiturates. Additionally, drug-drug interactions involving benzodiazepines are uncommon. Benzodiazepines remain among the most widely prescribed class of drugs ( Table 163-1 ). With nearly 50 individual agents available worldwide, they account for two thirds of all prescriptions for psychotropic drugs.[5 ] Benzodiazepines are the most common prescription drugs used by individuals attempting drug-assisted suicide. Despite such frequent misuse, the vast majority of benzodiazepine overdoses follow a relatively benign clinical course. Children make up 10% of benzodiazepine overdose cases. Table 163-1 -- Benzodiazepines Generic Name

Brand Name

Usual Dose

Oral Peak (hr)

Half-Life (hr) Parent

Metabolite Activity

Alprazolam Clonazepam Clorazepate Chlordiazepoxid e Diazepam

Xanax Klonopin Tranxene Librium

0.25–0.5 mg 0.25–0.5 mg 7.5–15 mg 5–25 mg

1–2 1–2 1–2 0.5–4

6–27 18–50 1–3 5–30

Inactive Inactive Active Active

Valium

2–10 mg

0.5–1

20–50

Active

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Generic Name

Brand Name

Usual Dose

Oral Peak (hr)

Half-Life (hr) Parent

Metabolite Activity

Estazolam Flurazepam Halazepam Lorazepam Midazolam Oxazepam Quazepam Temazepam Triazolam

ProSom Dalmane

1–2 mg 15–30 mg 20–40 mg 0.5–2 mg 0.025–0.1 mg/kg 10–30 mg 7.5–15 mg 7.5–30 mg 0.125–0.25 mg

2 0.5–1 1–3 2–4 1–2 2–4 2 1–2 1–2

8–28 2–3 14 10–20 1.5–3 5–20 39–41 3–19 1.5–5.5

Inactive Active Active Inactive Active Inactive Active Inactive Inactive

Ativan Versed Serax Doral Restoril Halcion

Principles of Disease Benzodiazepines produce sedative, hypnotic, anxiolytic, and anticonvulsant effects by enhancing the inhibitory actions of GABA. Binding of a benzodiazepine to a specific benzodiazepine receptor potentiates GABA effects on the chloride channel at the GABAA receptor, increasing intracellular flux of chloride ions and hyperpolarizing the cell. The net effect is a diminished ability of the nerve cell to initiate an action potential, resulting in inhibition of neural transmission. Three unique benzodiazepine receptors have been identified. The distribution of these receptors varies throughout the central and peripheral nervous systems. Classic benzodiazepines are nonselective, producing a broad range of clinical effects. Newer benzodiazepines interact selectively with a single receptor subtype to achieve a desired result, such as sedation, while minimizing unnecessary effects.

Pharmacokinetics Oral benzodiazepines are rapidly absorbed. Intramuscular use of chlordiazepoxide and diazepam is limited by erratic absorption, but both lorazepam and midazolam are predictably absorbed intramuscularly. Following absorption, benzodiazepines distribute readily. Penetration of the blood-brain barrier is facilitated by their highly lipophilic structure. In plasma, benzodiazepines are highly protein-bound.[5] Metabolism of all benzodiazepines occurs in the liver. Oxazepam, temazepam, and lorazepam are directly conjugated to an inactive, water-soluble glucuronide metabolite that is excreted by the kidney. Other benzodiazepines must first be metabolically converted by the hepatic cytochrome P-450 system. Chlordiazepoxide, diazepam, flurazepam, and clorazepate are metabolized to active derivatives that are then slowly conjugated and excreted. The long elimination half-lives of these intermediates can result in their accumulation in the body with repeated dosing. Triazolam, alprazolam, and midazolam are converted to hydroxylated intermediates that, although active, are very rapidly conjugated and excreted and do not contribute significantly to the drug's overall pharmacologic effect.[5] Cytochrome P-450 processes may be significantly impaired in elderly patients or those with liver disease, leading to prolonged elimination of some benzodiazepines. Co-ingestion of drugs that also undergo cytochrome P-450 metabolism (e.g., cimetidine, ethanol) prolongs the half-lives of these benzodiazepines. The clinical significance of these interactions is unclear.[6]

Clinical Features Central nervous system depression is common in patients with benzodiazepine poisoning and ranges from mild drowsiness to coma. Respiratory depression can be seen with large oral overdoses or with intravenous conscious sedation. The latter is particularly pronounced when the benzodiazepine is combined with an opioid such as fentanyl.[7] Hypotension is uncommon. Other complications include aspiration pneumonia and pressure necrosis of skin and muscles. The vast majority of children develop symptoms within 4 hours of benzodiazepine ingestion. Ataxia is the most common sign of toxicity, occurring in 90% of patients. In children, respiratory depression occurs in less than 10% of cases and hypotension has not been reported. The duration of physical findings averages 18 hours, with a range of 4 to 48 hours.

Diagnostic Strategies

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Rapidly determine the blood glucose level. Qualitative immunoassays for benzodiazepines in urine are readily available but do not aid management decisions. Many of these tests detect only benzodiazepines that are metabolized to oxazepam glucuronide. Therefore, benzodiazepines that do not produce this metabolite (clonazepam, lorazepam, midazolam, alprazolam) are not detected on a urine drug screen.[8] Serum drug concentrations are not routinely available on an emergency basis and do not correlate with clinical severity. The benzodiazepine antagonist flumazenil should not be administered to patients with coma of unknown origin or suspected benzodiazepine overdose. Any possibility of concomitant tricyclic overdose contraindicates flumazenil use.[7]

Differential Considerations Benzodiazepine overdose is usually suspected or diagnosed because of the clinical setting in which the patient presents. Many patients are rousable and can provide supporting information. Because signs and symptoms of benzodiazepine intoxication are nonspecific, atypical findings can be clues to the presence of other conditions. For example, profound coma or cardiopulmonary instability with pure benzodiazepine overdose is rare, and the presence of either should prompt the search for a co-ingestant. Nontoxicologic causes of CNS depression should also be considered.

Management General Respiratory compromise is the primary life threat in benzodiazepine overdose. Initial stabilization, including endotracheal intubation if warranted, must not be delayed by attempts at antidote administration. The vast majority of benzodiazepine overdoses can be managed expectantly. Activated charcoal is generally of no benefit in benzodiazepine overdose cases. Whole-bowel irrigation is unwarranted because sustained-release preparations are rarely used clinically. Neither multidose activated charcoal nor hemodialysis is effective.

Antidote Flumazenil, a nonspecific competitive antagonist of the benzodiazepine receptor, can be used for reversal of benzodiazepine-induced sedation after general anesthesia, conscious sedation, and overdose. Seizures and cardiac dysrhythmias can occur with flumazenil administration.[] Although the majority of these effects are well tolerated, fatalities have been reported.[10] Co-ingestion of drugs with proconvulsant properties is associated with an increased risk of seizures, presumably due to loss of the benzodiazepine's protective anticonvulsant effect when the antagonist is administered. Combined overdose of benzodiazepines with tricyclic antidepressants accounts for 50% of these seizures.[9] Co-ingestants possessing prodysrhythmic properties, such as carbamazepine or chloral hydrate, may increase the likelihood of cardiac effects by a similar mechanism.[7] Other risk factors are summarized in Box 163-2 . A recent observational study found that 12% of patients receiving flumazenil after known pure or mixed benzodiazepine overdose actually had a contraindication to its use.[12] BOX 163-2 Use of Flumazenil

Indications Isola ted benz odia zepi ne over dose in nonh abitu ated user (e.g., acci

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dent al pedi atric expo sure ) Rev ersal of cons ciou s seda tion

Absolute Contraindications Kno wn or susp ecte d co-in gest ant that lowe rs seiz ure thres hold Tricy clic antid epre ssan ts, coca ine, lithiu m, meth ylxan thine s, isoni azid, prop oxyp hene , mon oami ne oxid ase

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inhibi tors, bupr opio n, diph enhy dra mine , carb ama zepi ne, cycl ospo rine, chlor al hydr ate Patie nt takin g benz odia zepi ne for contr ol of a pote ntiall y life-t hreat enin g cond ition (e.g., seiz ures ) Con curr ent seda tive hypn otic with draw al Seiz ure activi ty or myo

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clon us Hype rsen sitivit y to flum azen il or benz odia zepi nes Patie nt with neur omu scul ar bloc kade

Relative Contraindications Chro nic benz odia zepi ne user, not takin g for contr ol of life-t hreat enin g cond ition Kno wn seiz ure disor der not treat ed with benz odia zepi nes Hea d

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injur y Pani c attac ks Alco holic patie nts The initial adult dose of flumazenil is 0.2 mg given intravenously over 30 seconds. A second dose of 0.3 mg may be given, followed by 0.5-mg doses at 1-minute intervals, to a total of 3 mg. Most patients respond to less than 3 mg. In children, the initial dose is 0.01 mg/kg (up to 0.2 mg). Because the duration of action of flumazenil is short (0.7-1.3 hours), resedation occurs in up to 65% of patients and requires either redosing or continuous infusion (0.25-1.0 mg/hr). Although flumazenil reverses benzodiazepine-induced sedation, it does not consistently reverse respiratory depression. In summary, benzodiazepine overdose requires only supportive care (including, in some cases, intubation), and flumazenil should generally not be used because of the risk of precipitating seizures or acute withdrawal. It is most useful in highly selected cases, such as small children with accidental poisoning or others who are known to not be chronic benzodiazepine users. When flumazenil is used, careful monitoring is necessary for persistent respiratory depression and for resedation. Use of flumazenil has not consistently altered outcome, complication rate, number of costly procedures performed, or duration of hospital stay.[12]

Disposition Patients remaining asymptomatic after 4 to 6 hours of emergency department observation may be medically cleared after appropriate psychiatric consultation.

Withdrawal Syndrome Abrupt discontinuation of a benzodiazepine in a chronic user results in a unique constellation of symptoms ( Box 163-3 ). Risk for withdrawal is a function of both the dose of benzodiazepine and the duration of its use. Continuous treatment for more than 4 months is generally required before a patient is at risk for withdrawal. With abrupt discontinuation of a short acting benzodiazepine, the most severe withdrawal symptoms are expected within 2 to 3 days. For longer acting agents, the peak of withdrawal may be delayed up to 7 days.[13 ] Use of flumazenil can precipitate immediate withdrawal symptoms. Treatment of withdrawal consists of reinstitution of long-acting benzodiazepines. If discontinuation of the drug is the ultimate goal, a gradual taper should be performed over several weeks.[13] BOX 163-3 Benzodiazepine Withdrawal Symptoms

Nonspecific Anxi ety, depr essi on, inso mnia , trem or, tach ycar dia, swe ating

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Severe (rare) Visu al hallu cinat ions, deliri um, seiz ures

FLUNITRAZEPAM Flunitrazepam (Rohypnol) has been used in Europe, Asia, and Latin America for insomnia and preoperative sedation since 1975. Although never manufactured or sold in the United States, recurrent reports of its use in “date rape” prompted the U.S. Drug Enforcement Agency to classify flunitrazepam as a Schedule I drug. Flunitrazepam has been an active agent in the illicit drug market, where it is used to alter the effects of other drugs, including heroin and cocaine.[14] Flunitrazepam has 10 times more affinity than diazepam for benzodiazepine2 receptors. Onset of marked CNS depression occurs within 30 minutes. The drug is most frequently ingested with alcohol, producing disinhibition and amnesia. Despite marked CNS depression, patients can usually be aroused with noxious stimuli. The half-life of the drug is 16 to 35 hours, but the resulting coma can be prolonged for up to 48 hours. [14] Despite many years of concern over flunitrazepam as a “date rape” agent, its use in such cases has rarely been documented.[15] Nevertheless, this drug remains easily obtainable outside the United States. Flunitrazepam is not detected on routine urine drug screens but, if needed as evidence, urine should be collected, refrigerated, or frozen and the local or state police crime laboratory contacted to arrange testing. Metabolites of flunitrazepam are detectable in the urine up to 72 hours after exposure.[15]

BUSPIRONE Buspirone (BuSpar) has been approved for treatment of generalized anxiety since 1986. Unlike benzodiazepines, buspirone does not have any significant effect on the actions of GABA. Rather, it acts as a partial serotonin (5-HT1A) agonist. To a lesser extent, it also antagonizes dopamine (D2) receptors. Buspirone has no hypnotic, anticonvulsant, or muscle relaxant effects. The use of buspirone has several advantages over benzodiazepines. The drug causes minimal CNS depression, even in combination with ethanol. Dosage adjustment is not needed for elderly patients. Chronic administration does not cause tolerance. Additionally, dependence does not occur. A withdrawal state after discontinuation has not been reported. Only one case of isolated buspirone overdose has been published. That patient was lethargic and had a tonic-clonic seizure but recovered fully.[16]

ZOLPIDEM AND ZALEPLON Zolpidem (Ambien) and zaleplon (Sonata) differ in structure from both the benzodiazepines and buspirone. They act selectively at the benzodiazepine receptor, producing sedation without many of the other effects seen with benzodiazepines. They have modest anxiolytic, muscle relaxant, and anticonvulsant properties. Significant drug interactions are uncommon. Compared with zolpidem, zaleplon causes less memory loss and sedation at therapeutic doses and is more rapidly eliminated.[17] Transient visual disturbances and hallucinations can occur in patients with normal levels of consciousness with use of both zolpidem and zaleplon. [] Abuse of zolpidem is limited by vomiting, which may occur after a supratherapeutic dose. Both zolpidem and zaleplon have rapid elimination and lack active metabolites.[19] Patients with zolpidem overdose generally do well with supportive care alone. Zolpidem is antagonized by flumazenil. Fatalities from isolated zolpidem overdose are rare; all published cases involve individuals found dead at home. Fatalities are often associated with co-ingestants, particularly other sedative hypnotics or antipsychotics.[20] Drowsiness is by far the most common manifestation of toxicity. Development of coma and respiratory failure are rare, despite overdoses of up to 40 times the normal dose.[21] Zolpidem overdose in children follows a similarly benign course. Drowsiness, ataxia, and hallucinations resolve within 10 hours.[

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22]

Overdose information for zaleplon is limited. In a case series, patients manifested CNS depression and mild hypotension. In one patient, arousal was temporally associated with flumazenil administration.[23] To date, the only published fatality involved a mixed drug intoxication (unknown quantities of zaleplon and butalbital). In this case, the postmortem serum zaleplon concentration was found to be approximately 40 times greater than what is reported following therapeutic use.[24] Adverse effects with therapeutic use include headache, anterograde amnesia, and transient visual hallucinations.[19]

CHLORAL HYDRATE Perspective Deaths related to chloral hydrate overdose were first reported in the medical literature in 1890. Incorrectly thought of as safe, chloral hydrate actually has a low therapeutic ratio and can produce significant, potentially fatal, toxicity. Chloral hydrate use is rare today, but it is still occasionally prescribed as a sedative in the elderly and for sedation in children undergoing medical procedures. The hyprotic oral adult dose is 0.5 to 1.0 g. The toxic oral dose in adults is approximately 10 g and may be as little as 1.5 g in a child.[25] The toxic effects of chloral hydrate include CNS depression, gastrointestinal irritation, cardiovascular instability, hepatitis, and proteinuria. The primary active metabolite of chloral hydrate, trichloroethanol, has a barbiturate-like effect on GABAA receptors and is responsible for most of the CNS depression seen with significant overdose. Chloral hydrate is rapidly absorbed from the gastrointestinal tract and almost immediately metabolized to trichloroethanol by the enzyme alcohol dehydrogenase. Onset of action is 20 to 30 minutes.[26] Trichloroethanol is long-acting, with a half-life (8-12 hours after a single therapeutic dose) that is significantly prolonged after overdose (up to 35 hours) as metabolic pathways become saturated. The combination of chloral hydrate and ethanol (the so-called Mickey Finn) can produce rapid loss of consciousness. Both agents are CNS depressants and potentiate each other's action. Chloral hydrate increases the half-life of ethanol by competitively inhibiting the enzyme alcohol dehydrogenase, and the metabolism of ethanol will generate NADH, a cofactor for the conversion of chloral hydrate to the long-acting trichloroethanol.

Clinical Features Chloral hydrate toxicity causes CNS and respiratory depression, gastrointestinal irritation, and cardiovascular instability and dysrhythmias. The combination of deep coma and cardiac dysrhythmia without hypoxia is characteristic of severe cases. Mild chloral hydrate toxicity can look like intoxication from ethanol or barbiturates, with drowsiness, ataxia, and lethargy. A pearlike odor on the patient's breath or gastric contents may suggest the diagnosis. With more severe toxicity, findings can include miosis, muscle flaccidity, diminished deep tendon reflexes, hypoventilation, hypotension, and hypothermia.[25] Chloral hydrate is corrosive and causes nausea, vomiting, esophagitis, hemorrhagic gastritis and, more rarely, gastrointestinal perforation, gastric necrosis, or esophagitis with stricture formation.[25] Transient hepatic or renal dysfunction can occur. Dysrhythmias from chloral hydrate toxicity correlate with fatal outcome. Chloral hydrate decreases myocardial contractility, shortens the cardiac refractory period, and increases the sensitivity of myocardium to catecholamines. Specific cardiac dysrhythmias include atrial fibrillation, supraventricular tachycardia, ventricular tachycardia, multifocal premature ventricular contractions, torsades de pointes, ventricular fibrillation, and asystole.[26] Hypotension results from inhibition of central neurovascular regulatory centers and impaired myocardial contractility.

Management The management of the patient severely intoxicated with chloral hydrate includes support of cardiorespiratory function. Intubation may be required for airway protection or to support ventilation and oxygenation. Naloxone and flumazenil may precipitate ventricular dysrhythmias.[25] Because chloral hydrate sensitizes myocardium to the effects of catecholamines, epinephrine and norepinephrine should be avoided. Standard antidysrhythmic agents such as lidocaine do not appear effective against chloral hydrate-induced cardiac ectopy. The treatment of choice is a p -blocker. [27] Intravenous propranolol can be given in adult doses of 0.5 mg until ectopy is suppressed, followed by an infusion of 1 to 2 mg/hr, titrated to a heart rate of

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80 to 100 beats per minute. A short-acting agent such as esmolol can also be used. Torsades de pointes should be treated with intravenous magnesium or overdrive pacing. Type I antidysrhythmic agents should be avoided. Unstable patients not responding to conservative therapy can be treated with hemoperfusion or hemodialysis.[25]

OVER-THE-COUNTER SLEEP AIDS Perspective In the past, most over-the-counter (OTC) sleep aids contained a combination of an antihistamine (either methapyrilene or pyrilamine) and scopolamine. Some preparations also contained a bromide. For safety concerns, these products were reformulated in the late 1980s to contain diphenhydramine or doxylamine, now the only two drugs found in nonprescription hypnotics. Many preparations contain acetaminophen or aspirin, added to create a “nighttime” pain reliever ( Table 163-2 ). The availability and frequent use of these agents may explain in part why overdose is so common. Table 163-2 -- Nonprescription Sedative Hypnotics, United States Brand Name Alka-Seltzer PM effervescent tablets

Active Ingredient(s) 38 mg diphenhydramine citrate 325 mg aspirin

Bayer PM Aspirin Plus Sleep

25 mg diphenhydramine hydrochloride

Aid caplets

500 mg aspirin

Excedrin PM tablets, caplets or geltabs

38 mg diphenhydramine citrate 500 mg acetaminophen

Goody's PM powder

38 mg diphenhydramine citrate 500 mg acetaminophen

Nytol QuickCaps caplets

25 mg diphenhydramine hydrochloride

Maximum Strength Nytol QuickGels softgels

50 mg diphenhydramine hydrochloride

Simply Sleep caplets

25 mg diphenhydramine hydrochloride

Sleepinal Night-Time Sleep Aid capsules and softgels

50 mg diphenhydramine hydrochloride

Sominex Night-Time Sleep Aid tablets

25 mg diphenhydramine hydrochloride

Unisom SleepTabs tablets

25 mg doxylamine succinate

Unisom Maximum Strength SleepGels

50 mg diphenhydramine hydrochloride

Principles of Disease Diphenhydramine and doxylamine are antihistamines that also have hypnotic, anticholinergic, and weak local anesthetic properties. They act as competitive antagonists of H1 histamine receptors and cause sedation by inhibiting the actions of acetylcholine on muscarinic receptors in the CNS. Pharmacologic profiles of diphenhydramine and doxylamine are similar. Both are rapidly absorbed, with peak plasma levels occurring at 1 to 2 hours after administration. In the systemic circulation, they are highly protein-bound, with large volumes of distribution. Extensive metabolism occurs in the liver by the cytochrome P-450 system. The elimination half-life for diphenhydramine is 4 hours and for doxylamine 9 hours.

Clinical Features Impaired consciousness is the most frequent finding with diphenhydramine overdose. Somnolence, psychotic behavior, and agitation are common.[28] Anticholinergic effects may be apparent, as noted in Chapter 148 . Apart from a lower incidence of psychosis, doxylamine has toxicity similar to that of diphenhydramine.[29] Seizures and rhabdomyolysis may occur with severe toxicity. Despite recognized membrane-stabilizing effects, serious cardiotoxicity from poisoning with these agents is rare.

Diagnostic Strategies

Page 3835

Some comprehensive urine drug immunoassays will detect diphenhydramine. Quantitative serum levels of diphenhydramine or doxylamine are neither routinely available nor clinically useful. Serum acetaminophen and salicylate concentrations should be measured in patients with OTC sleep aid overdoses, because some preparations contain both a hypnotic and an analgesic. Serum creatine phosphokinase and urinary myoglobin assessments may detect myoglobinuria.

Management Management of mild to moderate toxicity from OTC sleep aid overdose is generally supportive. Prolongation of the QRS interval has been reported after massive diphenhydramine overdoses. This is most likely due to a quinidine-like effect of the drug on the myocardial conduction system. NaHCO3 has been used successfully to overcome this effect, and administration of 1 to 2 mEq/kg intravenously should be considered.[30] In cases of extremely large overdoses, NaHCO3 alone may not be effective. Physostigmine can be used in patients manifesting severe anticholinergic toxicity (e.g., delirium, refractory seizures, cardiac instability) (see Chapter 148 ).

Disposition Patients who remain asymptomatic throughout a 4- to 6-hour emergency department observation can be medically cleared for psychiatric evaluation. Patients with minor sedation or anticholinergic effects can also be cleared when symptoms are clearly resolving. All other patients require inpatient observation in a monitored setting.

p~-HYDROXYBUTYRATE Perspective Originally synthesized in the 1960s, p~-hydroxybutyrate (GHB) was first used as an anesthetic in Europe and Japan. Researchers later discovered that GHB was a naturally occurring metabolite of GABA. Since 1970, GHB has been used to treat narcolepsy and alcohol addiction, as well as alcohol and opiate withdrawal. A 1977 report that GHB may enhance the effects of steroids and the release of growth hormone resulted in marketing of the agent as a natural aid for increasing muscle mass. Numerous reports of adverse effects followed. In 1989, the U.S. Food and Drug Administration called for a voluntary withdrawal of the drug from store shelves. Its sale and manufacture were banned in 1990; however, illicit use of GHB increased along with the emergence of GHB precursors, p~-butyrolactone (GBL) and 1,4-butanediol (1,4-B) ( Box 163-4 ). On February 18, 2000, President Clinton signed “The Hillory J. Farias and Samantha Reid Date-Rape Drug Prohibition Act of 2000,” making GHB a Schedule I controlled substance. Recently, GHB has been approved for the treatment of narcolepsy, under the trade name Xyrem (sodium oxybate, 0.5 mg/mL). When used with a legitimate prescription, it is a Schedule III drug in many states. BOX 163-4 p~-Hydroxybutyrate Street Names

GHB Grie vous bodil y har m GBH Geor gia hom e boy Gib Natu ral slee

Page 3836

p-50 0 Gam maOH Gam ma hydr ate Liqui dX Orga nic Qua alud e Liqui dE Liqui d ecst asy Liqui dG Som atom ax Soa p Salty wate r Sco op Sodi um oxyb ate Easy lay Cher ry ment h Fant asy G-Ri ffick p~-Hydroxybutyrate remains a popular drug of abuse. Recipes for home synthesis are widely available. Some individuals take GHB for its purported muscle-building and fat-burning properties, others for its psychoactive effects. The drug's euphoria-producing properties make it popular at “raves” (large, crowded youth parties with energetic dancing to rhythmic music for many hours).[] Self-treatment of insomnia with GHB has been reported and can cause dependence.[34] The CNS depression, amnesia, and disinhibition that occur with GHB, especially mixed with ethanol, make this combination a potential agent of sexual assault, especially in date rape situations. Chemical precursors to GHB are also commonly abused. GBL is rapidly converted to GHB by plasma lactonases. 1,4-Butanediol is metabolized to p~-hydroxybutyraldehyde by the enzyme alcohol

Page 3837

dehydrogenase, and then to GHB by aldehyde dehydrogenase.[]

Principles of Disease p~-Hydroxybutyrate binds to specific GHB receptors found primarily in the hippocampus, cortex, and striatum; it also binds weakly to GABAB receptors.[37] The drug stimulates dopamine synthesis but inhibits its release, causing dopamine to concentrate in the nerve terminal. With higher doses of GHB, dopamine release is triggered. GHB also has effects through the endogenous opioid system, increasing dynorphin levels, which may explain its euphoria-producing properties. p~-Hydroxybutyrate is available in a powder or granular form that, when dissolved in water, produces a colorless, odorless liquid with a mildly salty taste. Underground home-based laboratories often synthesize liquid GHB by mixing and heating butyrolactone and sodium hydroxide. Careless preparation can result in residual unreacted base, causing significant caustic injury when the liquid is ingested. p~-Hydroxybutyrate is rapidly absorbed. It is lipo-philic and readily enters the CNS. Peak plasma levels occur within 20 to 60 minutes after ingestion.[34] Onset of symptoms is within 15 to 30 minutes of ingestion. Unlike GABA, it readily crosses the blood-brain barrier. The half-life of GHB is 27 minutes but may increase at higher doses. A characteristic feature of GHB intoxication is that the patient may awaken from deep coma suddenly, sometimes with self-extubation. Supportive therapy usually results in complete recovery within 7 hours of ingestion. p~-Butyrolactone is an industrial solvent that is rapidly absorbed after ingestion and metabolized within minutes to GHB by peripheral and hepatic lactonases.[36] It produces a clinical syndrome similar to that of GHB ingestion, but its effects are greater and more prolonged.[] In fact, GBL is more efficient at delivering GHB to the central nervous system than GHB itself.[36] GBL is available under a number of street names ( Box 163-5 ). BOX 163-5 p~-Butyrolactone Street Names

Blue Nitro Enliv en Gam ma G GH Revit alize r GHR E (gro wth hor mon e relea se extra ct) Nitro NRG 3 Ren ewtri ent

Page 3838

Revit alize Plus Revi vara nt Som atoP ro Verv e 5.0 1,4-Butanediol (1,4-B), an aliphatic alcohol normally present in the body in trace amounts, is converted after ingestion to GHB by the enzyme alcohol dehydrogenase.[35] Like GBL, it is used as an industrial solvent. A recent series of cases of 1,4-B toxicity reported nine episodes in eight patients, with two deaths.[36] Clinical findings included dizziness, confusion, unconsciousness, vomiting, incontinence, bradycardia, respiratory depression, myoclonus, and ataxia. When 1,4-B and ethanol are ingested together, ethanol acts as a competitive inhibitor of alcohol dehydrogenase so the toxic effects of 1,4,-B are delayed and prolonged, and the risk of fatality is increased.[36] 1,4,-B is available under a number of street names ( Box 163-6 ). BOX 163-6 Butanediol Street Names

Inner G Pine need le extra ct Pine need le oil Revit alize Plus Sere nity Thun der nect ar Wei ght belt clea ner Zen

Clinical Features Diagnosis of GHB intoxication is based on the history, or retrospectively on the patient's rapid recovery. Signs and symptoms are generally consistent with poisoning by other sedative hypnotic agents. Hypothermia may be noted,[32] as well as Cheyne-Stokes breathing. In the presence of coma, bradycardia with or without hypotension may also be seen, which occasionally responds to stimulation alone.[32] Eye examination may reveal miosis with or without nystagmus. Behavioral changes are most common and range from aggression and delirium to coma.[32] A distinctive feature of GHB intoxication is respiratory depression with apnea, interrupted by periods of agitation and combativeness, especially following attempts

Page 3839

at intubation. Emesis occurs in nearly 50% of cases.[32] Generalized seizures have been reported and may appear as random myoclonic movements of the face and extremities. The severity of the signs and symptoms caused by GHB is dependent on the dose and the concurrent use of alcohol or other psychoactive drugs.[34] The dose-response curve of GHB is steep. An oral dose of 10 mg/kg results in hypotonia and amnesia, whereas 25 mg/kg induces sleep. A dose of 50 to 60 mg/kg produces anesthesia, and higher doses may cause coma associated with bradycardia, respiratory depression, vomiting, and myoclonic activity.

Diagnostic Strategies p~-Hydroxybutyrate is not detected on most urine toxicology screens. If laboratory confirmation is required, gas chromatography–mass spectroscopy must be performed. Because GHB is metabolized to endogenous substances, specimens must be collected early, ideally the first urine sample, to capture the parent compound. The drug is detectable in urine up to 12 hours after ingestion. Poisoning with another sedative hypnotic can produce a clinical picture identical to that seen with GHB. Unique to GHB, however, is the relatively rapid resolution of symptoms. In the absence of a co-ingestant such as ethanol, most patients will awaken within 3 to 4 hours. Nearly all patients recover fully within 8 hours. Thus, the presence of prolonged coma should prompt a search for another cause. Cardiac effects and refractory seizures are uncommon, and either of these findings suggests the presence of an-other agent.

Management Because of the high incidence of emesis in cases of GHB overdose, intubation for airway protection is essential in patients with significant CNS depression. Bradycardia unresponsive to stimulation should be treated with atropine. Treatment of isolated GHB ingestion is supportive. Patients should be protected from self-injury and observed for resolution of symptoms. Although physostigmine had been used to reverse the effects of GHB when used as an anesthetic agent, it does not follow that its use would be safe in the less controlled emergency setting when unknown co-ingestants might be present. Since good supportive therapy is very effective and spontaneous recovery rapid, the use of physostigmine as an antidote to GHB toxicity is not recommended.[35]

Withdrawal Patients who suddenly stop ingestion of GHB or its precursors after chronic, frequent use can experience a severe and potentially life-threatening withdrawal syndrome, similar to withdrawal from other sedatives and hypnotics.[] Because of the short half-life of GHB, symptoms of withdrawal usually begin within several hours of the last dose. The typical patient will have been using these products for weeks or years, and taking them every 1 to 3 hours around the clock in an effort to avoid withdrawal symptoms. Mild withdrawal consistently manifests with anxiety, tremor, and insomnia. This can progress to confusion, delirium, overt psychosis, paranoid ideation, hallucinations (visual, aural, and/or tactile), and autonomic instability. Diagnosis relies on a history of symptoms beginning after abruptly ceasing use of these products, following a period of chronic frequent ingestion. The differential diagnosis includes withdrawal from other sedatives or hypnotics, delirium tremens, sympathomimetic toxicity, serotonin syndrome, neuroleptic malignant syndrome, CNS infection, and thyroid storm. Initial treatment usually begins with high-dose benzodiazepines. However, GHB withdrawal may involve depleted levels of GABA.[38] Since benzodiazepines require the presence of GABA, they may not be effective in controlling GHB withdrawal. Barbiturates, which open chloride channels directly and do not need GABA to be effective, are often required in cases of severe intoxication. Pentobarbital has been used successfully in the treatment of severe GBL withdrawal.[40] These patients often require intensive care unit admission for high-dose sedatives to manage agitation and to monitor fluctuating vital signs. Rhabdomyolysis and severe hyperthermia should be ruled out. Deaths are reported, sometimes many days after presentation and after apparent improvement.[38]

Disposition Because of GHB's short half-life, symptoms sometimes resolve while the patient is still in the emergency department. The patient generally regains consciousness spontaneously. No delayed toxicity is expected. Patients should be counseled about the seriousness of their intoxication because they will be amnesic for the event.

Page 3840

KEY CONCEPTS {,

Most patie nts with barbi turat e intoxi catio n will reco ver with obse rvati on and meti culo us supp ortiv e care. The vast majo rity will not requi re gastr ic lava ge, hem odial ysis, or hem operf usio n.

{,

A urine toxic olog y scre en posit ive for barbi turat es does not

Page 3841

prov e that the patie nt's clinic al cond ition is caus ed by the drug. Qua ntitat ive level s confi rm the diag nosi s. Seru m barbi turat e level s do not nece ssari ly corr elate with dept h of com a or clinic al outc ome. {,

Flum azen il is rarel y indic ated and can be dang erou s.

Page 3842

Admi niste ring flum azen il to rever se cons ciou s seda tion in the eme rgen cy depa rtme nt does not per mit early disc harg e, beca use the patie nt must be moni tored for the occu rren ce of rese datio n. {,

Chlo ral hydr ate– indu ced dysr hyth mia shou ld be treat ed with p -b lock

Page 3843

{,

{,

ade. End otrac heal intub ation to prote ct agai nst eme sis and respi rator y depr essi on shou ld be stron gly cons idere d for patie nts with GHB over dose and signi fican t CNS depr essi on. With draw al from GHB or its prec urso rs can mani fest mildl y with anxi ety, trem or, and inso

Page 3844

mnia , but can prog ress to a seve re synd rom e char acter ized by deliri um and auto nomi c insta bility. Man age ment of this synd rom e often requi res admi ssio n to the inten sive care unit for highdose benz odia zepi nes or barbi turat es.

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Page 3845

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Page 3846

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REFERENCES 1. Frenia ML: Multiple-dose activated charcoal compared to urinary alkalinization for the enhancement of phenobarbital elimination. J Toxicol Clin Toxicol1996;34:169. 2. Pond SM: Randomized study of the treatment of phenobarbital overdose with repeated doses of activated charcoal. JAMA1984;251:3104. 3. Ebid AI: Pharmacokinetics of phenobarbital during certain enhanced elimination modalities to evaluate their clinical efficacy in management of drug overdose. Ther Drug Monitor2001;23:209. 4. Palmer BF: Effectiveness of hemodialysis in the extracorporeal therapy of phenobarbital overdose. Am J Kidney Dis2000;36:640. 5. Chouinard G: Metabolism of anxiolytics and hypnotics: Benzodiazepines, buspirone, zoplicone, and zolpidem. Cell Mol Neurobiol1999;19:533. 6. Tanaka E: Clinically significant pharmacokinetic drug interactions with benzodiazepines. J Clin Pharm Ther1999;24:347. 7. Weinbroum AA: A risk-benefit assessment of flumazenil in the management of benzodiazepine overdose. Drug Saf1997;17:181. 8. Perry HE, Shannon MW: Diagnosis and management of opioid and benzodiazepine-induced comatose overdose in children. Curr Opin Pediatr1996;8:243. 9. Spivey WH: Flumazenil and seizures: Analysis of 43 cases. Clin Ther1992;14:292. 10. Haverkos GP: Fatal seizures after flumazenil administration in a patient with mixed overdose. Ann Pharmacother1994;28:1347. 11. Davis CO, Wax PM: Flumazenil associated seizure in an 11-month-old child. J Emerg Med1996;14:331. 12. Mathieu-Nolf M: Flumazenil use in an emergency department: A survey. Clin Toxoicol2001;39:15. 13. Molle HJ: Effectiveness and safety of benzodiazepines. J Clin Psychopharmacol1999;19:2. 14. Waltzman ML: Flunitrazepam: A review of “Roofies.”. Pediatr Emerg Care1999;15:59. 15. ElSohly MA, Salamone SJ: Prevalence of drugs used in cases of alleged sexual assault. J Anal Toxicol 1999;23:141. 16. Catalano G: Seizures associated with buspirone overdose: Case report and literature review. Clin Neuropharmacol1998;21:347. 17. Drover DR: Comparative pharmacokinetics and pharmacodynamics of short-acting hypnosedatives: Zaleplon, zolpidem and zopiclone. Clin Pharmacokinet2004;43:227. 18. Tsai MJ: A novel clinical pattern of visual hallucinations after zolpidem use. J Toxicol Clin Toxicol 2003;41:869. 19. Weitzel KW: Zaleplon: A pyrazolopyrimidine sedative-hypnotic agent for the treatment of insomnia. Clin Therapeut2000;22:1254. 20. Gock SB: Acute zolpidem overdose: Report of two cases. J Anal Toxicol1999;23:559. 21. Garnier R: Acute zolpidem poisoning: Analysis of 344 cases. J Toxicol Clin Toxicol1994;32:391. 22. Kurta D: Zolpidem (Ambien): A pediatric case series. J Toxicol Clin Toxicol1997;35:453. 23. Hojer J: Zaleplon-induced coma and bluish-green urine: Possible antidotal effect by flumazenil. Clin Toxicol2002;40:571. 24. Moore KA: Mixed drug intoxication involving zaleplon (“Sonata”). Forensic Sci Intern2003;134:120. 25. Stracciolini A: Chloral hydrate. Clin Tox Rev1998;21:1. 26. Sing K: Chloral hydrate toxicity from oral and intravenous administration. J Toxicol Clin Toxicol 1996;34:101. 27. Zahedi A: Successful treatment of chloral hydrate cardiac toxicity with propranolol. Am J Emerg Med 1999;17:490. 28. Koppel C: Clinical symptomatology of diphenhydramine overdose: An evaluation of 136 cases in 1982 to 1985. J Toxicol Clin Toxicol1987;25:53. 29. Koppel C: Poisoning with over-the-counter doxylamine preparations: An evaluation of 109 cases. Hum Toxicol1987;6:355. 30. Clark RF, Vance MV: Massive diphenhydramine poisoning resulting in a wide-complex tachycardia: Successful treatment with sodium bicarbonate. Ann Emerg Med1992;21:318. 31. Williams SR: p~-Hydroxybutyric acid poisoning. West J Med1998;168:187.

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32. Chin RL: Clinical course of p~-hydroxybutyrate overdose. Ann Emerg Med1998;31:716. 33. Li J: A tale of novel intoxication: Seven cases of p~-hydroxybutyric acid overdose. Ann Emerg Med 1998;31:723. 34. Galloway GP: p~-Hydroxybutyrate: An emerging drug of abuse that causes physical dependence. Addiction1997;92:89. 35. Mason PE, Kerns WP: Gamma hydroxybutyric acid (GHB) intoxication. Acad Emerg Med2002;9:730. 36. Zvosek DL: Adverse events, including death, associated with the use of 1,4-butanediol. N Engl J Med 2001;344:87. 37. Wong C: From the street to the brain: Neurobiology of the recreational drug p~-hydroxybutyric acid. Trends Pharmacol Sci2004;25:29. 38. Dyer J: Gamma-hydroxybutyrate withdrawal syndrome. Ann Emerg Med2001;37:147. 39. Schneir AB: A case of withdrawal from the GHB precursors gamma-butyrolactone and 1,4-butanediol. J Emerg Med2001;21:31. 40. Sivilotti MLA: Pentobarbital for severe gamma-butyrolactone withdrawal. Ann Emerg Med2001;38:660.

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PART FIVE - Special Populations Section I - The Pediatric Patient Chapter 164 – General Approach to the Pediatric Patient Robert A. Wiebe

PERSPECTIVE Background Assessment of pediatric patients from the newly born through adolescence offers unique and varied challenges to the emergency care provider. Approximately 30% of all visits to a general emergency department are for issues related to pediatric patients. The vast majority of children in crisis are not seen in pediatric specialty hospitals, but in community hospital emergency departments. Although most pediatric visits to an emergency room are not serious, it is not uncommon to see true emergencies in infants and young children. Serious and life-threatening pediatric emergencies result from a wide variety of causes and require the health care provider to understand the unique anatomic, physiologic, immunologic, and developmental differences that make serious problems often difficult to recognize and the differential diagnosis dependent on the age of the patient. Emergency care does not stop or start in the emergency department. An integrated emergency medical system that is capable of responding to the needs of children is a critical part of pediatric emergency care. Likewise, many critically ill or injured children cannot receive definitive care in small community hospitals. Therefore, a support network that includes interfacility transport resources and definitive care for pediatric patients must be part of an integrated system of emergency care for children. This chapter focuses on the role of the emergency physician in recognizing and assessing children needing emergency care.

Epidemiology According to the National Center for Health Statistics, an estimated 107,490,000 emergency department visits took place during the year 2001; 20.7% were for the care of children younger than 15 years.[1] Less than 50% of these visits were for children triaged as emergent or urgent.[2] The National Hospital Ambulatory Medical Care Survey documented that only 6.4% of 24-hour emergency departments had more than one separate emergency service area. Of emergency departments with more than one emergency service area, a specialty area for the care of children was the most common separate service area. Data suggest that health insurance status is not a significant cause of emergency department overcrowding.[3] The convenience of the emergency department, access without appointment, and lack of understanding by parents of the meaning of an emergency are the major factors related to pediatric nonurgent visits.[4] Respiratory emergencies and trauma are the most common reasons for visits to an emergency department. Table 164-1 lists the 20 most common triage complaints at a pediatric specialty emergency department. Injury is the most common cause of serious morbidity and mortality in children younger than 15 years and is responsible for 13.5 emergency department visits per 100 persons per year. In the pediatric age group, approximately 95% of these visits are for unintentional injuries that are largely predictable and preventable. Although the reasons for pediatric emergency department visits are many and varied, the care of critically ill or injured children should always focus on two physiologic events: shock and respiratory

Page 3849

failure. Table 164-1 -- Chief Pediatric Complaints from Emergency Department Triage Complaint No. of Patients Percentage of Total Visits Fever 19,754 Trauma/injury 11,650 Breathing difficulty 9,979 Upper respiratory symptom 9,004 Vomiting/diarrhea 7,657 Abdominal pain 4,460 Rash 4,287 Ear complaint 3,428 Genitourinary problem 3,235 Soft tissue infection 1,754 Seizure 1,745 Eye complaint 1,712 Sore throat 1,562 Oral/dental complaint 1,236 Headache 1,229 Irritability 780 Chest pain 707 Foreign body 547 Behavior issue 392 Sexual abuse suspected 354 Total visits to triage 102,453 Top 20 visits From Children's Medical Center of Dallas: 2003 ED Triage Statistics.

19.3 11.4 9.7 8.8 7.5 4.4 3.3 3.3 3.2 1.7 1.7 1.7 1.5 1.2 1.2 0.8 0.7 0.5 0.4 0.3 82.6%

PRINCIPLES OF DISEASE Pathophysiology Anatomic and Physiologic Differences Physical assessment of a pediatric patient requires attention to a variety of anatomic, physiologic, and developmental differences that vary with the age of the patient. It is sometimes difficult to separate anatomic and physiologic issues; for example, the large surface area–to–weight ratio in young infants can result in heat loss and temperature instability. Thus, it is important to maintain a neutral thermal environment during the physical assessment and stabilization process. The relatively large head-to-body ratio and the small, weak neck of infants and young children make them particularly prone to head injuries. Blunt trauma to the chest and abdomen often results in injury to internal organs with minimal or no external signs of trauma. The elasticity of growing bones creates unique problems in pediatrics. Soft and pliable growing ribs will bend rather than break and transmit the forces of blunt trauma to the thoracic and upper abdominal organs. The weakest part of growing bones is the physeal plate or growth plate, and this area is injured more frequently than the surrounding ligaments are. In a growing child, sprains are uncommon and physeal fractures result in nearly 20% of pediatric fractures. Recognition of growth plate injuries in children is critical to avoid imbalance in bone growth. Anatomic differences between the pediatric and adult airway are important to understand for appropriate assessment and emergency support of the airway when required. The small airways of infants and young children are more prone to obstruction from secretions, which can result in relatively rapid deterioration ranging from respiratory distress to failure. Simple maneuvers such as deep suction of the upper airway can frequently have dramatic results in improving air movement in small infants. Because infants are often

Page 3850

preferential nose breathers, nasal obstruction from secretions can result in significant airway compromise. An irritable and crying infant may just be learning to mouth breath when the nose is obstructed.

Vital Signs Table 164-2 provides normal ranges of vital signs by age. The normal heart rate varies significantly with age, and the first sign of compensated shock is an increase in heart rate. However, tachycardia is a very nonspecific finding in pediatric patients and may be related to fever, anxiety, pain, or fear. When measuring the heart rate, the quality of the pulse can be extremely helpful, as well as a comparison of the strength of the central and peripheral pulses in the same extremity. The quality of the brachial and radial pulses or the femoral and dorsalis pedis pulses palpated concurrently provides important information to differentiate shock from benign causes of tachycardia. Table 164-2 -- Normal Pediatric Vital Signs for Age[*] Age (yr)

Respiratory Rate (breaths/min)

Heart Rate (beats/min)

12

12–16

60–100

Lower limits of systolic blood pressure † 0–28 days: 60 mm Hg 1–12 months: 70 mm Hg 1–10 years: 70 mm Hg + (2 ¥ age in years) *

†

From Dieckm ann R, Brownstein D, Gausche-Hill M (eds): Pediatric Education for Prehospital Professionals. Sudbury, Mass, Jones & Bartlett, Am erican Academ y of Pediatrics, 2000, pp 43–45. From Am erican Heart Association ECC Guidelines, 2000.

The lack of cooperation by infants and small children can often make determination of blood pressure difficult. Whenever possible, blood pressure should be obtained in an infant or child younger than 3 years; however, time should not be wasted when cooperation is a problem. An alert, crying infant with good peripheral pulses and normal mental status can be assumed to have adequate blood pressure. Infants and young children have excellent compensatory measures for maintaining blood pressure in the presence of significant loss of circulatory volume. Compensatory mechanisms include an increase in heart rate and systemic vascular resistance. When these compensatory mechanisms fail and blood pressure drops below normal, the patient moves from a state of compensated to decompensated shock. The lower limit for acceptable blood pressure in children older than 1 year can be quickly estimated by using the following formula: systolic blood pressure = 70 + (2 × age [in years]). The pulse oximetry waveform can also be used to determine systolic blood pressure. Observing for the return of a plethysmographic waveform of the pulse oximeter as the blood pressure cuff is deflated has been shown to correlate closely with conventional methods of blood pressure measurement.[5] The respiratory rate must be interpreted carefully in infants younger than 12 months. It is not at all unusual for infants to have periodic breathing with episodes of apnea lasting up to 20 seconds. To be considered normal, periodic breathing must not be associated with a drop in heart rate or oxygen saturation. The respiratory rate is dependent on the age of the patient, as well as other physiologic factors. In a febrile infant, the respiratory rate will increase by up to 5 respirations per minute for every degree centigrade in temperature elevation. Either a slow or rapid respiratory rate can be a sign of impending respiratory failure. A normal respiratory rate alone cannot be used to determine adequacy of ventilation. The respiratory rate must be compared with the adequacy of air exchange and work of breathing when assessing ventilation in a pediatric patient. Vital signs at one given point in time may be quite difficult to interpret. Repeated measurement of the

Page 3851

respiratory rate, heart rate, and blood pressure over time will provide a more accurate assessment of a patient's physiologic condition.

Developmental Issues Knowledge of basic behavioral and developmental differences by age is important when assessing a pediatric patient. Table 164-3 summarizes age-related pediatric differences in motor function, problem-solving, language, and social/adaptive milestones during the first 2 years. Table 164-3 -- Developmental Milestones Age Gross Motor Visual-Motor and Problem Solving 1 mo

2 mo

3 mo

4 mo

5 mo

6 mo

7 mo 8 mo

Raises head slightly from prone position, makes crawling movements Holds head in midline, lifts chest off table Supports on forearms in prone position, holds head up steadily Rolls front to back, supports on wrists and shifts weight Rolls back to front, sits supported

Pivots when sitting, pulls to stand, cruises

12 mo

Walks alone

Social and Adaptive

Birth: visually fixes 1 Alerts to sound mo: has tight grasp, follows to midline

Regards face

No longer clenches fist tightly, follows object past midline Holds hands open at rest, follows in circular fashion, responds to visual threat Reaches with arms in unison, brings hands to midline Transfers objects

Smiles socially (after being stroked or talked to) Coos (produces long vowel sounds in musical fashion)

Recognizes parent

Laughs, orients to voice

Enjoys looking around environment

Sits unsupported, Unilateral reach, puts feet in mouth in uses raking grasp supine position Creeps 7–8 mo: inspects objects Comes to sit, crawls

9 mo

Language

Says “ah-goo,” orients to bell (localizes laterally) Babbles

Orients to bell (localized indirectly) “Dada” indiscriminately Uses pincer grasp, “Mama” probes with indiscriminately, forefinger, holds gestures, waves bottle, throws bye-bye, objects understands “no” 10 mo: “Dada” and “Mama” discriminately, orients to bell (directly) 11 mo: 1 word other than “Dada” and “Mama,” follows 1-step command with gesture Uses mature pincer Uses 2 words other grasp, releases than voluntarily, marks paper with pencil “Dada” and “Mama,” immature jargoning (runs several

Reaches for familiar people or objects, anticipates feeding

Recognizes strangers 7–9 mo: finger-feeds

Starts to explore environment, plays gesture games (e.g., patty cake)

Imitates actions, comes when called, cooperates with dressing

Page 3852

Age

15 mo

18 mo

21 mo

Gross Motor

Creeps up stairs, walks backward

Runs, throws objects from standing without falling

Visual-Motor and Problem Solving

Scribbles in imitation, builds tower of 2 blocks in imitation

Scribbles spontaneously, builds tower of 3 blocks, turns 2–3 pages at a time

Squats in play, goes up stairs Walks up and down steps without help

Language unintelligible words together) 13 mo: uses 3 words 14 mo: follows 1-step command without gesture Uses 4–6 words

17 mo: uses 7–20 words, points to 5 body parts, uses mature jargoning (includes intelligible words in jargoning) Uses 2-word combinations

Social and Adaptive

15–18 mo: uses spoon, uses cup independently

Copies parent in tasks (sweeping, dusting), plays in company of other children

19 mo: knows 8 body parts Uses 50 words, 2-word sentences Uses pronouns (I, you, me inappropriately), follows 2-step commands

Builds tower of 5 Asks to have food blocks and to go to toilet 24 mo Imitates stroke with Parallel play pencil, builds tower of 7 blocks, turns pages 1 at a time, removes shoes, pants, etc. Modified from Gunn KL, Nechyba C (eds): The Harriet Lane Handbook, 16th ed. St. Louis, CV Mosby, 2003.

Neonates During the neonatal period and early infancy, normal behavior consists of sleeping, feeding, and crying when hungry or experiencing discomfort. There is little or no eye contact and no social smile. Discomfort is usually nonspecific, and the cause of the irritability or crying may be difficult to interpret.

Infants (12 Months or Younger) As infants grow, they become more interactive and increase their behavioral repertoire such that failure to achieve or loss of specific behavioral milestones can be a sign of serious illness or injury. By 2 to 3 months an infant has a social smile and responds to a friendly voice. Lack of appropriate social interaction can be worrisome. An infant with a glassy-eyed, “nobody home” stare can be easily distinguished from a normal infant who tracks lights or has a smiling face. Beyond 6 months of age, separation (stranger) anxiety is a predictable behavior. A 6-month-old infant will cry when taken from the safety of the caretaker's arms. Infants at this age have little or no understanding of language, but they will certainly respond to a calm and soothing voice. Of concern is a 6-month-old who does not acknowledge your presence. Normal behavior for this age includes any expression of curiosity or anxiety, such as crying. Children older than 6 months should be approached with caution. The emergency physician should anticipate stranger anxiety and examine the patient, whenever possible, in the lap of the caregiver. Distractions such as toys and penlights are useful to provide emotional control of the infant during the examination.

Toddlers (13 Months to 3 Years of Age)

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During the toddler age, as language develops, it is important to talk directly to the child. Praise and reassurance during the examination can go a long way in maintaining control. It is important to realize that toddlers and preschoolers usually have more extensive receptive language even when their expressive language is limited. Misconceptions about illness and injury may be picked up from communications with parents and result in illogical fears.

Preschool Children (4 to 5 Years of Age) Preschool children often fantasize, and such fantasies may result in irrational assumptions and even nightmares. The cause of injuries or illnesses in preschoolers or loved ones may be misinterpreted as being a result of their own misbehavior.

School-Age Children (6 to 12 Years of Age) As children reach school age, it becomes particularly important to explain procedures, answer questions, and address fears and concerns honestly. Privacy and modesty should be respected. Whenever possible, the child should be included in conversations, and historical information should be taken from both the child and parent. The powers of reasoning begin to mature, and a school-age child will often attempt to negotiate control over having painful or distasteful procedures performed. Choices and behavior limits should be given only when they do not compromise care. A child may be given the choice to have blood drawn from the left arm or the right arm or be told that it is OK to cry but that it is important to keep the arm still.

Adolescents (13 to 19 Years of Age) With adolescence comes independence and autonomy. Peer pressure becomes far more important than the behavior boundaries provided by the caretaker. Adolescents are risk takers and often have no fear of danger or injury. They rarely anticipate consequences and may lack common sense. Privacy and confidentiality should always be respected, and it is wise to separate adolescents from the caregiver when ob-taining information and performing the physical examination.

CLINICAL FEATURES Recognition of early and compensated shock may be a challenge to a health care provider forced to multitask in a busy emergency department. An infant in respiratory distress who begins to tire and slip slowly into failure may even be interpreted as improving until it is too late. Surgically correctable problems such appendicitis, intussusception, and volvulus can be difficult to recognize early, and delay in diagnosis will predictably increase morbidity and mortality. Infections that could be life threatening must be diagnosed by the history and physical examination. The clinician cannot rely on a blood count to rule out a serious bacterial illness. The possibility of child abuse should always be considered whenever injuries are inconsistent with the reported cause. Signs of increased intracranial pressure may suggest intracranial bleeding, infection, or tumors.

Pediatric Assessment Triangle A “hands-off” assessment of infants and young children can allow the examiner to gather critical information from a distance before upsetting the child with an invasive physical examination. The pediatric assessment triangle (PAT) offers a sensible, orderly approach that can be used to assess children of all ages, identify abnormal physiology, and define the urgency and need for lifesaving interventions. Before touching the patient, observe the child from a distance for visual and auditory clues. Figure 164-1 defines the three arms of the PAT: appearance, work of breathing, and circulation to the skin. This brief assessment rarely takes more than 30 seconds and adds to the initial discernment of “sick from well” ( Table 164-4 ).[]

Figure 164-1 Pediatric assessm ent triangle.

Table 164-4 -- PAT—Initial Assessment Appearance Work of Breathing Tone

Circulation to the Skin

Abnormal sounds: stridor, grunting, Pallor snoring, wheezing

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Appearance

Work of Breathing

Irritable, interactive Consolable Look/gaze

Circulation to the Skin Mottling Cyanosis Petechiae

Abnormal positioning: sniffing, tripoding, refusal to lie down Speech/cry Retractions Head bobbing Nasal flaring Modified from Dieckmann R, Brownstein D, Gausche-Hill M (eds): Pediatric Education for Prehospital Professionals. Sudbury, Mass, Jones & Bartlett, American Academy of Pediatrics, 2000, pp 36–40. PAT, pediatric assessment triangle.

Appearance From a distance, quickly determine the general appearance of the child. Is the child interacting normally with the environment? When the brain is not being adequately perfused for any reason, irritability is usually the first sign, followed by alternating irritability and lethargy. This situation is typified by an infant who sleeps quietly but, when touched or stimulated, immediately begins to shake and become irritable; when the stimulation is removed, the infant immediately returns to sleep. Alternating lethargy and irritability will progress to lethargy and ultimately coma if the causative condition is not reversed. The glassy-eyed, “nobody home” stare of a septic or brain-injured infant is not difficult to recognize. A high-pitched or cephalic cry is characteristic of any insult to the central nervous system. When in doubt, the parent can usually confirm that the cry is atypical. Simple observation of older children for proper tone, motor movements, and reaction to environmental stimulation is a good assessment of the appearance arms of the PAT. Appearance, when normal, can ensure that ventilation, oxygenation, and brain perfusion are at least adequate.

Work of Breathing Assessment of the work of breathing in infants and young children is best done from a distance. Once an infant begins to cry, it is difficult to make any reasonable interpretation of oxygenation and ventilation or to interpret breath sounds. Listening carefully for audible abnormal airway sounds such as grunting, wheezing, stridor, and snoring can be quickly assessed without the use of a stethoscope. Grunting is an infant's or child's way of providing self-administered positive end-expiratory pressure to recruit collapsed or fluid-filled alveoli. The presence of inspiratory stridor alerts the examiner to upper airway obstruction. Muffled, hoarse, or abnormal speech can occur with trauma to the larynx or from a peritonsillar or peripharyngeal abscess. Assessment of wheezing should determine whether the sounds occur during both inhalation and exhalation and whether there is a prolonged expiratory phase. Observing for abnormal positioning can help determine the cause and severity of airway obstruction. A child assuming the “sniffing position” is attempting to best position the airway to overcome obstruction. Tripoding is often seen with severe respiratory distress in an attempt to maximize use of the accessory muscles of breathing ( Figure 164-2 ). The presence of intercostal, supraclavicular, and substernal retractions indicates an increased work of breathing ( Figure 164-3 ). Infants, for the first several months of life, may normally demonstrate abdominal breathing. Seesaw movements of the chest and abdomen are always abnormal. A child with a retropharyngeal abscess may have torticollis or may just refuse to extend the neck with loss of upward gaze. Nasal flaring and head bobbing can be seen in infants and young children with significantly increased work of breathing ( Figure 164-4 ).

Figure 164-2 Tripod position in a child with airway obstruction.

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Figure 164-3 Intercostal retractions in a child with respiratory distress.

Figure 164-4 Nasal flaring in a child with respiratory distress from lower airway obstruction.

Effortless tachypnea, or rapid respirations with no increased work of breathing, is characteristic of a child in compensated or decompensated shock. It reflects a physiologic response to metabolic acidosis by increasing the respiratory drive and driving the pH toward normal. Irregular respirations in a child with an abnormal appearance may suggest increased intracranial pressure. It is important to remember that as a patient slips from respiratory distress to respiratory failure, work of breathing and the respiratory rate may both decrease. When this occurs, the appearance will change and a decrease in the level of consciousness will be evident.

Circulation to the Skin Visual inspection of the skin can be used to quickly assess peripheral perfusion. Young children have excellent compensatory reserves, and with early and compensated shock, blood is shunted from the skin to vital organs. Compensated shock can be recognized by the presence of pallor. A pale child with a rapid heart rate should always be considered to be in shock until proved otherwise. As cardiac output is further compromised and perfusion to vital organs is decreased, the skin may become mottled. Mottling is manifested by areas of vasoconstriction and vasodilation in a random pattern on the skin. It reflects loss of small vessel integrity and may be similar to what is seen in vital organs during multiple organ system failure. Mottling is usually an ominous sign. It is important to not confuse cutis marmorata with mottling in young infants ( Figure 164-5 ). Cutis marmorata is a lacy marbling of the skin caused by vascular instability. It is a normal finding and is commonly seen in infants in a cool ambient environment. Cyanosis may occur in the late stages of shock or with respiratory failure. Unless the child is cyanotic as a result of chronic primary cardiopulmonary problems or congenital heart disease, the development of cyanosis is an indication of respiratory failure or decompensated shock.

Figure 164-5 Cutis m arm orata (A) and m ottling of the skin (B).

Table 164-5 summarizes how the PAT can be used to interpret specific physiologic abnormalities and the clinical condition of the patient. Table 164-5 -- Interpretation of the Pediatric Assessment Triangle

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Physiologic State

Appearance

Work of Breathing

Circulation to the Skin

Respiratory distress Normal Abnormal Normal Respiratory failure Abnormal Abnormal Normal Compensated shock Normal Normal Abnormal Decompensated shock Abnormal Normal Abnormal Brain injury/dysfunction Abnormal Normal Normal Cardiopulmonary failure Abnormal Abnormal Abnormal Modified from Dieckmann R, Brownstein D, Gausche-Hill M (eds): Pediatric Education for Prehospital Professionals. Sudbury, Mass, Jones & Bartlett, American Academy of Pediatrics, 2000, pp 30–57.

Hands-on Initial Assessment Two critical issues should be remembered when interpreting vital signs in children: first, remember to use age-appropriate standards (see Table 164-2 ); second, changes in vital signs over time are far more important than any single recording. A monitored and sleeping infant with an increasing heart rate cannot be ignored. The initial hands-on assessment should be done in an orderly fashion by performing a stepwise assessment of airway, breathing, and circulation and resolving issues related to each before progressing to the next step. Assessment of neurologic status or disability provides an opportunity for a more detailed objective measure of the child's appearance from the PAT. The Glasgow Coma Scale or its pediatric modification provides methods for assessing disability that can be used to monitor changes in mental status over time. The AVPU (alert, verbal, painful, unresponsive) scale is a simple alternative to assess whether the child is alert, responsive to verbal commands, responsive only to painful stimuli, or unresponsive. Exposure of infants and young children can usually be performed more effectively with the parent's assistance. Make every effort to maintain a neutral thermal environment to avoid unnecessary heat loss during the examination. Modesty can be preserved and cooperation can be improved by exposing body parts one area at a time.

Triage The purpose of triage is to rapidly assess a patient and determine the urgency of evaluation and manage-ment. A number of triage scores have been devised, including the recently developed Canadian Pediatric Triage and Acuity Scale.[*] This triage tool uses a five-level system. Table 164-6 uses a similar triage tool to list the 10 most common signs, symptoms, or problems categorized as triage level I in a busy inner-city emergency department in the United States. A triage level I patient is defined as one in shock or respiratory failure, nonresponsive, or with absent or unstable vital signs. Traumatic injuries rank first for triage level I visits and rank third for triage level II visits. The second most common cause for a triage level I emergency department visit is seizures, which represent 16% of all triage level I visits. Respiratory failure is responsible for nearly 10% of all triage level I emergency department visits, and respiratory distress is the most common cause of triage level II visits. Table 164-6 -- Triage Level I Emergency Department[*] Visits Category No. of Patients Trauma Seizures Respiratory failure Altered consciousness Sepsis Cardiac problem Diabetic ketoacidosis Toxic ingestion SIDS/CPR

369 107 64 19 15 15 11 9 8

Percentage of Level I Visits 56.3 16.3 9.8 2.9 2.3 2.3 1.7 1.4 1.2

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Category

No. of Patients

Percentage of Level I Visits

4

0.6 94.8 64.0

Hypovolemic shock Percentage of total Total level I visits

655

CPR, cardiopulmonary resuscitation; SIDS, sudden infant death syndrome. *

Children's Medical Center of Dallas, 2003; N = 102,453 visits.

Table 164-7 lists the 10 most common causes for triage level II visits. A triage level II patient is one who is considered to be an emergency with a potential threat to life, limb, or function; one who is lethargic, with significant respiratory distress; or one with severe pain. A level II patient requires physician assessment within 15 minutes of arrival to triage. Table 164-7 -- Triage Level II Emergency Department[*] Visits Category

No. of Patients

Percentage of Level II Visits

4,132

33.0

Suspected sepsis/meningitis

881

7.0

Trauma/injury

786

6.3

Sickle cell disease complications

727

5.8

Diabetes complications

447

3.6

Genitourinary complaints

413

3.3

Ventriculoperitoneal shunt complications

388

3.1

Seizures

332

2.6

Hypovolemic dehydration

309

2.5

Respiratory distress

Oncology patient with fever

255 Percentage of total Total level II visits

*

2.0 69.2

12,540

(12.2)

Children's Medical Center of Dallas, 2003; N = 102,453 visits.

* See Canadian Journal of Em ergency Medicine, October 2001, vol 3, no 4 (suppl). www.caep.ca

Clinical Interview The initial contact with the child and parent will often determine the ultimate level of cooperation received and parent satisfaction with the visit. Parents who bring children to an emergency department for care usually perceive that their child has an emergency. Treating a family with respect, gentleness, and kindness goes a long way. Never resent the patient for a visit. If the family has been waiting a long time to see the doctor, start the conversation with a simple apology that expresses regret for the long wait. Introducing oneself to both the parents and child will facilitate a relaxed atmosphere for the interview. Toddlers and early school-age children may be expected to say little during the interview process, but they should be allowed to provide answers to questions when appropriate. In an emergency setting, the chief complaint and present illness are the main focus for information gathering, but the past, family, and social history pertinent to the child's condition must also be explored. It is wise to not begin the interview with “What's the problem?” Parents do not like to consider their children or their conditions as “problems.” A better approach would be “What brings you and your child to the emergency department today?” The “SAMPLE” mnemonic may be used to systematically obtain a focused history ( Box 164-1 ). Signs and

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symptoms that describe the onset and nature of the chief complaint should be detailed. Allergies or drug reactions are recorded with information describing the characteristics of the reaction. Medications that the patient is currently taking are recorded, including the time and amount of the last dose. Past medical problems and special health care needs are detailed, including information about the pregnancy, labor and delivery, and current immunization status. Knowledge of the last food and liquid given is important if sedation, analgesia, airway management, or surgery is necessary. Events leading up to the injury or illness should be recorded. Gentle and soothing conversation throughout the physical examination often improves information gathering and reduces anxiety. The history is generally obtained while performing the secondary assessment. BOX 164-1 Focused “Sample” History

Sign s/sy mpto ms Aller gies Medi catio ns Past medi cal probl ems Last food or liquid Even ts leadi ng to injur y/illn ess Modified from Dieckmann R, Brownstein D, Gausche-Hill M (eds): Pediatric Education for Prehospital Professionals. Sudbury, Mass, Jones & Bartlett, American Academy of Pediatrics, 2000, p 51.

Physical Examination In infants and young children, the physical examination is not a stepwise process. It is neither a head-to-toe nor a toe-to-head evaluation. The examination should be performed in the least traumatic fashion by leaving painful or frightening components until the end and concentrating on high-value components initially. Children in late infancy through the toddler age should be left in the caretaker's lap during the majority of the examination.

Specific Disorders Trauma A careful and detailed secondary trauma survey is necessary to identify subtle, but life-threatening injuries. A systematic approach to pediatric trauma that includes a continuum of care from first responders through emergency department stabilization, interfacility transport, and definitive care will save lives.[8] Attention to assessment of the cervical spine is a critical part of pediatric assessment. Because of the elasticity of the cervical spine in young children, spinal cord injuries without radiographic abnormalities (SCIWORA) can occur. These injuries result in ligamentous instability, which if ignored, may result in significant morbidity or mortality. A history of neck pain, paresthesias, numbness, tingling, or focal neurologic findings must not be

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ignored even if cervical spine films are normal.[9] Because most prehospital emergency medical systems require out-of-hospital providers to transport patients in complete spinal immobilization, it is important to obtain information from the transport professionals before they leave. Was the immobilization simply a precautionary measure? Was the child up, walking, and moving the neck before immobilization? Was there any history of pain, paresthesias, or evidence of neurologic injury? Such information can be helpful in deter-mining whether the child needs radiographic imaging or can be clinically cleared from cervical spine immobilization. As the secondary trauma survey is systematically performed, continued attention to the PAT and primary survey is critical to identify ongoing bleeding or progressing respiratory problems. A pale trauma victim should have vascular access and blood available before or during the secondary survey. Intentional injuries to children still result in more than 1200 deaths per year. Because these injuries are most commonly associated with blunt trauma, it is possible that no external evidence of injury will be apparent.[10] When historical indicators suggest possible child abuse, consultation with child protective services is mandatory. Box 164-2 lists historical indicators that should alert the heath care provider to the possibility of child abuse.[11] Examination of the skin for burns or bruises consistent with child abuse should be a part of any trauma survey. Box 164-3 summarizes bruises typically found in abused infants and children. See Chapter 64 for a more extensive discussion of these issues. BOX 164-2 Historical Indicators of Child Abuse

Unex plain ed dela y in seek ing medi cal care Histo ry does not expl ain the injur y Histo ry chan ges with time Histo ry is not cons isten t with the child' s deve lopm

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ental abiliti es Child has “ma gical ” injuri es BOX 164-3 Bruises Suggestive of Child Abuse

Multiple bruises of different ages Pattern injuries Han d print s Belt mark s Cord loop mark s Line ar mark s from rigid obje cts Bite mark s Unusual distribution of bruises Neck Groi n Inner aspe ct of thigh Restraint marks on wrists or ankles

Medical Disorders Seizures Seizures are a common initial sign in the emergency department. Although most seizures in children are benign and self-limited, assessment must include attention to the airway and ventilation. An actively

Page 3861

convulsing child must be quickly assessed for adequacy of oxygenation and ventilation. A nasal airway properly inserted can dramatically relieve airway obstruction and allow for assisted bag/mask ventilation when appropriate. As a part of the secondary survey, the emergency physician should observe carefully for the character of the seizure and the presence or absence of any focal findings. Fever, central nervous system infections, and brain injury must always be con-sidered in children with seizures and no history of childhood epilepsy. Other less common problems to rule out include intoxication, metabolic derangements, intracranial vascular anomalies, and tumor. Neonatal seizures can be very subtle and difficult to recognize. A seizure in this age group may be manifested as lack of an appropriate response to environmental stimuli, nystagmus, blinking eyes, or any fine repetitive movements.[12]

The Difficult Airway and Airway Obstruction Recognition of a “difficult airway” can be a critically important issue in the assessment of seriously ill and injured children. Although scientific evidence for defining a difficult airway in children is limited, certain critical observations may be helpful. Dysmorphic features or physical conditions in special health care needs children that limit the ability to completely open the mouth or that reduce neck mobility should suggest the possibility of a difficult airway. Although Mallampati grades have not been well studied in children, if the uvula cannot be visualized when opening the mouth, the patient should be considered high risk. Any evidence of upper airway obstruction in a child who is in impending respiratory failure should indicate the need for potential surgical airway support.[13] Scores that quantify the severity of upper and lower airway obstruction and disease are helpful tools to monitor response to therapeutic interventions. An example of a clinical croup score is detailed in Box 164-4 .[ 15] The pediatric asthma severity score seen in Table 164-8 has been shown to be reliable, reproducible, and valid for assessing the severity of acute asthma in children aged 1 to 18 years.[15] BOX 164-4 Clinical Croup Score Stri dor Non 0 e Audi 1 ble with stet hos cop e (at rest) Audi 2 ble with out stet hos cop e (at rest) Retractio ns Non e Mild Mod erat e Sev ere

0 1 2

3

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Stri dor Air Entry Nor 0 mal Dec 1 reas ed Sev 2 erely decr eas ed Cyanosis Non 0 e With 4 agita tion At 5 rest Level of Consciou sness Nor 0 mal Alter 5 ed

From Westley CR, Cotton EK, Brooks JG: Nebulized racemic epinephrine by IPPB for the treatment of croup. Am J Dis Child 132:484, © 1978. Reprinted by permission of Wiley-Liss, a division of John Wiley & Sons, Inc.

Table 164-8 -- Pediatric Asthma Severity Score Clinical Finding Definition 0

1

2

Wheezing

None or mild

Moderate

Normal or mildly diminished

Moderately diminished

Severe wheezing or absent wheezing because of poor air exchange Severely diminished

None or mild

Moderate

Severe

Normal or mildly prolonged

Moderately prolonged

Severely prolonged

Absent

Present

Normal

Depressed

Air entry

Work of breathing

Prolongation of expiration Tachypnea

Mental status

High-pitched expiratory sound heard by auscultation Intensity of inspiratory sounds by auscultation Observed use of accessory muscles, retractions, or in-breathing Ratio of duration of expiration to inspiration Respiratory rate above normal for age Observation of the child's state of

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Clinical Finding

Definition

0

1

2

alertness From Gorelick MH, Stevens MW, Shultz TR, Scribano PV: Performance of a novel clinical score, the Pediatric Asthma Severity Score (PASS), in the evaluation of acute asthma. Acad Emerg Med 11:10, 2004.

Altered Level of Consciousness Altered level of consciousness accounts for approximately 3% of all critical emergency department visits. An orderly approach to the assessment of an altered level of consciousness is important to minimize organ damage and provide timely initial management. Quick assessment of the respiratory pattern can identify the irregular appearance of a Cheyne-Stokes breathing pattern, which consists of alternating periods of hyperpnea, followed by slowing ventilatory effort and periods of apnea. This respiratory pattern is typically found in children with increased intracranial pressure. Midbrain dysfunction will generally cause hyperventilation that is regular and rapid with normal oxygen saturation and low PaCO2. Examination of the eyes is helpful in sorting out causes of an altered level of consciousness. Pupils that are fixed and dilated in an unresponsive patient are always suggestive of serious intracranial pathology and are never seen in patients unresponsive because of metabolic derangements. A unilaterally dilated pupil is usually secondary to increased intracranial pressure from mass lesions causing uncal compression on the third cranial nerve. With significantly increased intracranial pressure, transtentorial herniation will increase pressure on the brainstem and result in asymmetric pupils that become fixed and dilated. The doll's eye reflex can be performed by rapidly rotating the head from side to side while observing for a normal doll's eye response; the eyes of a child with a positive response remain fixed forward as the head is turned. Observe closely for equality of extraocular movements, nystagmus, and deviation of the eyes at rest. Funduscopic examination is helpful in identifying papilledema and retinal hemorrhages. Assessment of motor movements and tone is an important part of the secondary assessment for altered consciousness. Observe closely for symmetry of movements and the presence or absence of abnormal posturing, and assess muscle strength and tone.

Shock Patients with trauma, sepsis, cardiac problems, diabetic ketoacidosis, hypovolemic shock, and ingestion of toxic substances may arrive at the emergency department in shock. The secondary survey will help differentiate causes of the shock state. Assessment of four organ systems in systematic fashion will help determine the etiology and severity of the shock and monitor response to treatment. The heart is the first organ to respond to a shock state and does so with an increased rate. Cardiac output is a function of stroke volume and heart rate, and when stroke volume decreases for any reason, the heart rate will increase. Careful examination of the heart by listening closely for a gallop rhythm, murmurs, indistinct or muffled heart sounds, or any dysrhythmia will help identify cardiogenic shock as the cause. Tachycardia may be absent in patients with distributive shock. In the late stages of decompensated shock, bradycardia will occur as the shock progresses. The second organ to respond to shock is the skin. In addition to the manifestations covered in the PAT, observe for skin temperature and signs of dehydration. The reverse thermometer sign can be of assistance in roughly judging the degree of hypovolemic shock. The examiner assesses skin temperature by running the fingers up the extremity to determine the point of cool/warm demarcation. During resuscitation, as reperfusion of the skin occurs, this point of warm/cold demarcation progresses peripherally. With early septic shock, the skin may appear warm and flushed. Look closely for signs of dehydration, including tenting of the skin, a hollow-eyed appearance, or dry mucous membranes, which suggest hypovolemic shock. Capillary refill must be measured at or above the level of the heart to avoid erroneous results from venous flushing. In a neutral thermal environment, capillary refill longer than 2 seconds will be present in all forms of shock. The third organ that objectively responds to the shock state is the brain. Irritability or a decrease in mental status is consistent with progressing shock. The lungs respond to shock with tachypnea and hyperpnea. Hypovolemic shock will often be manifested as effortless tachypnea when the patient has become acidotic. Cardiogenic shock, distributive shock, and septic shock may also give rise to increased work of breathing, crackles, or wheezing (or any combina-tion of the three).

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Close and repeated monitoring of these four organ systems must be continued throughout the secondary survey and stabilization processes.

Children With Special Health Care Needs Children with special health care needs account for a large number of emergency and urgent emergency department visits. In a child with developmental delay, encephalopathy, or significant neurologic problems, it may be difficult to establish a normal baseline functional level. The caretaker is usually quite experienced and can provide valuable information to assist in assessment. Children with life-sustaining hardware such as ventriculoperitoneal shunts commonly come to the emergency department with nonspecific findings such as vomiting and headache. A behavior change that is recognized by the caretaker is a valuable clue suggestive of shunt obstruction. It is important to engage the parent to assist with baseline information and to seek specialty consultation from providers who are familiar with children who have special health care needs.

DIAGNOSTIC STRATEGIES Noninvasive Monitoring Noninvasive monitoring techniques such as oxygen saturation and end-tidal carbon dioxide measurements have become a routine part of pediatric assessment for a variety of illnesses and injuries. Pulse oximetry provides a valuable noninvasive and continuous measurement of arterial hemoglobin oxygen saturation, which has rapidly become a new “vital sign” for many illnesses. The role of pulse oximetry in monitoring children with respiratory distress and failure has been well defined. The use of pulse oximetry in children with cardiorespiratory problems is a valuable assessment tool and helps the clinician titrate the need for oxygen supplementation and respiratory support. End-tidal carbon dioxide measurement is a noninvasive method of monitoring a variety of critically ill children that helps avoid repeated blood gas analysis. Studies have demonstrated that analysis of exhaled end-tidal CO 2 can be used to monitor respiratory failure and perfusion to peripheral tissues during the resuscitation of patients in shock. Measurement of end-tidal CO2 and pulse oximetry can provide valuable assistance in monitoring children in both shock and respiratory failure and is a critical component of assessing correct placement of a tracheal tube after endotracheal intubation has been performed.

The Pediatric-Ready Emergency Department Emergency department preparedness for the care of children is a special need that requires limited additional resources, but significant professional support and advocacy from both physicians and nursing staff. It is quite clear that the majority of hospitals with emergency departments will serve as pediatric receiving facilities for emergency care independent of size, volume, or availability of comprehensive resources. Hospitals without all the necessary resources must clearly be prepared to stabilize critical pediatric illnesses and injuries within their limitations and ensure timely transfer to facilities with available necessary resources. Guidelines for preparedness for the care of children in the emergency department are available.[16] The availability of protocols and policies that ensure timely transfer of critically ill and injured patients after stabilization is a part of the pediatric assessment process.

KEY CONCEPTS {,

The phys ical and deve lopm ental stag es of grow th in pedi atric patie nts provi

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{,

{,

de chall enge s to the asse ssm ent of child ren in crisi s. An unde rstan ding of agerelat ed deve lopm ental issu es and differ ence s is impo rtant for perfo rmin g an adeq uate pedi atric asse ssm ent. Esta blishi ng good rapp ort with pedi atric patie nts is nece ssar y to get coop erati

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{,

{,

on in perfo rmin g the exa mina tion proc ess. The pedi atric asse ssm ent trian gle provi des a rapid asse ssm ent of seve rity and phys iologi c statu s and will thus provi de a road map for the initial asse ssm ent of all pedi atric patie nts. A neutr al ther mal envir onm ent shou ld be main

Page 3867

taine d durin g the phys ical exa mina tion to avoi d heat loss in infan ts who are critic ally ill. {,

The pres ence of a diffic ult airw ay can be asse ssed in serio usly ill or injur ed child ren by deter mini ng whet her they are able to open their mout hs wide enou gh for visu aliza

Page 3868

{,

{,

tion of the uvul a and nor mall y exte nd and flex their neck . Spe cial need s child ren: The care giver can assi st in deter mini ng base line statu s whe n atte mpti ng to asse ss child ren with spec ial need s who have signi fican t deve lopm ental dela ys. Bew are the

Page 3869

pale child : Pallo r is a cons isten t and obje ctive early sign of shoc k that cann ot be ignor ed, espe cially in thos e with blunt trau ma. {,

Cerv ical spin e: A large head with an elast ic cervi cal spin e may resul t in SCI WO RA. Patie nts with this cond ition may not have any neur ologi c

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defic its, and cervi cal spin e imag es may be nor mal. A histo ry of trans ient pare sthe sia, num bnes s, tingli ng, or any focal neur ologi c findi ngs, even if radio grap hs are nor mal, shou ld be inter prete d in this light. {,

Eme rgen cy depa rtme nt prep ared ness for pedi atric eme

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rgen cies: Guid eline s for havi ng a pedi atricread y eme rgen cy depa rtme nt are avail able throu gh the Ame rican Colle ge of Eme rgen cy Phys ician s and the Ame rican Acad emy of Pedi atric s.

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Marx: Rosen's Emergency Medicine: Concepts and Clinical Practice, 6th ed., Copyright © 2006 Mosby, Inc.

REFERENCES 1. U.S. Department of Health and Human Services, Centers for Disease Control and Prevention. National Center for Health Statistics, Division of Data Services : Available at www.cdc.gov/nchs/fastats/ervisits.htm 2. McCaig LF, Burt CW: National Hospital Ambulatory Medical Care Survey: 2001 emergency department summary. Adv Data2003;335:1. 3. Luo X: Children's health insurance status and emergency department utilization in the United States. Pediatrics2003;112:314. 4. Doobinin KA: Nonurgent pediatric emergency department visits: Care-seeking behavior and parental knowledge of insurance. Pediatr Emerg Care2003;19:10. 5. Gilmore B: Determination of systolic blood pressure via pulse oximeter in transported pediatric patients. Pediatr Emerg Care1999;15:183-186. 6. In: Dieckman R, Brownstein D, Gausche-Hill M, ed.Pediatric Education for Prehospital Professionals, Sudbury, Mass: Jones & Bartlett, American Academy of Pediatrics; 2000: 7. In: Gausche-Hill M, Fuchs S, Yamamoto L, ed.APLS: The Pediatric Emergency Medicine Resource, Sudbury, Mass: Jones & Bartlett American Academy of Pediatrics and American College of Emergency Physicians; 2004: 8. Morrison W, Wright JL, Paidas CN: Pediatric trauma systems. Crit Care Med2002;30(11 Suppl):S448. 9. Patel JC: Pediatric cervical spine injuries: Defining the disease. J Pediatr Surg2001;36:373. 10. Cabinum-Foeller E, Perkin RM: Non-accidental injury: Recognizing child abuse in the pediatric trauma patient. Trauma Rep2003;4:1. 11. Block RW: Child abuse: Controversies and imposters. Curr Probl Pediatr1999;29:253. 12. Haafiz A, Kissoon N: Status epilepticus: Current concepts. Pediatr Emerg Care1999;15:119. 13. Caplan RA: Practice guidelines for management of the difficult airway. An updated report by the American Society of Anesthesiologists Task Force on Management of the Difficult Airway. Anesthesiology 2003;98:1269. 14. Westley CR, Cotton EK, Brooks JG: Nebulized racemic epinephrine by IPPB for the treatment of croup. Am J Dis Child1978;132:484. 15. Gorelick MH: Performance of a novel clinical score, the Pediatric Asthma Severity Score (PASS), in the evaluation of acute asthma. Acad Emerg Med2004;11:10. 16. American College of Emergency Physicians and American Academy of Pediatrics : Care of children in the emergency department: Guidelines for preparedness (policy statement). Ann Emerg Med2001;37:423.

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Use of this content is subject to the Term s and Conditions of the MD Consult web site.

Marx: Rosen's Emergency Medicine: Concepts and Clinical Practice, 6th ed., Copyright © 2006 Mosby, Inc.

Chapter 165 – Fever Roger M. Barkin D. Demetrios Zukin[*] * Material new to this chapter in this edition was prepared by Marianne Gausche-Hill, MD, Departm ent of Em ergency Medicine, Harbor-UCLA Medical Center, Torrance, CA, and is indicated in bracketed italic type.

The evaluation and treatment of fever may vary dramatically with the patient's age and preexisting conditions. Management generally varies by age group: neonates and infants less than 1 month of age, infants 2 to 3 months of age, infants 3 months to 3 years of age, children 3 to 7 years of age, and children 7 to 18 years of age.[] Recommendations reflect the child's chief complaint, underlying conditions, community epidemiology, and anticipated compliance and follow-up. Enhanced flexibility may be used in children over 1 month of age for whom care givers' compliance and communication are anticipated.

PRINCIPLES OF DISEASE Pathophysiology Fever in normal infants and toddlers is a rectal temperature of 38° C (100.4° F) or higher. During the first 3 months of life any fever may have a particularly great clinical importance. An oral temperature above 37° C (98.6° F) reflects a fever in teenagers. The thermoregulatory center in the body lies in the hypothalamus. The use of a rectal thermometer or temperature probe remains the most reliable method of measuring temperature in infants and toddlers; epidemiologic data on fever and most protocols for care are based upon a rectal temperature assessment. Temperature is maintained near normal (euthermia) via physiologic mechanisms (sweating and hyper-ventilation to lower temperature, vasoconstriction and shivering to raise temperature) and environmental measures (seeking shelter from a storm, increasing or decreasing the amount of protective clothing). Complex cascades of circulating interleukins, prostaglandins, and prostacyclin mediate the febrile response to infection. In most cases fever is a sign of infection. Other processes that can lead to an elevated temperature are environmental (e.g., the mild temperature elevation that occurs when an infant is swaddled with too many clothes or the severe fever that occurs in heat stroke), physiologic (e.g., the temperature elevation that normally occurs in school-age children after vigorous running and play), toxicologic (e.g., from aspirin ingestion), and hypothalamic (the abnormal temperature control that may occur secondary to damage to the central nervous system [CNS]).

SPECIAL CONSIDERATIONS [] Occult Bacteremia In the early 1970s, McGowan found a high incidence of bacteremia in infants and toddlers with fever.[3] Children under 36 months of age with a rectal temperature of 39° C (102.2° F) and no obvious source for the fever have an incidence of bacteremia of 3% to 5%. Most do not appear toxic. The most common pathogen is Streptococcus pneumoniae, accounting for more than 85% of the positive cultures. The remaining 15% of infections are Haemophilus influenzae type b, Neisseria meningitidis, Salmonella spp., and other pathogens. H. influenzae type b vaccine has decreased the incidence of this pathogen. A new vaccine for S. pneumoniae may also change the epidemiology. (Reviewer suggests The vaccine for S. pneumoniae [pneumococcal conjugate vaccine] has also decreased the incidence of this pathogen [Black S, Shinefield H, Fireman B, et al. Efficacy, safety, and immunogenicity of heptavalent conjugate pneumococcal vaccine in children. Pediatr Infect Dis J 2001; 19:187-195].) Children 24 to 36 months of age are less likely than younger infants to have bacteremia. Each degree of

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temperature elevation above 39° C (102.2° F) increases the risk of bacteremia. Harper and Fleisher report that those with a temperature of 39.5° to 39.9° C (103° F to 103.8° F) have approximately a 3% incidence of bacteremia, 40° to 40.9° C (104° F to 105.6° F) a 4% risk, and above 41° C (105.8° F) a 10% risk.[5] A drop in temperature after administration of acetaminophen does not reflect any change in risk of developing bacteremia.[12] The greater the white blood cell (WBC) count, the larger the risk of bacteremia. Obtaining a blood culture only in patients with a WBC count above 20,000/mm[3] will fail to identify some infants with bacteremia. This is particularly true with H. influenzae and N. meningitidis bacteremias. In the case of H. influenzae, one third of bacteremic patients have a WBC count under 15,000/mm3. Of patients with meningococcemia who initially appear well enough to go home, more than 50% have a WBC count under 15,000/mm3. Of those with pneumococcal bacteremia only one fourth have a WBC count below 15,000/mm3.[6] With pneumococcal bacteremia, most children become afebrile within 3 or 4 days with or without antibiotic coverage. However, H. influenzae and N. meningitidis may cause persistent bacteremia, pneumonia, meningitis, and sepsis. Approximately 33% of those with meningococcal bacteremia die or de-velop meningitis, compared with 7% experiencing H. influenzae bacteremia and 4% having pneumococcal bacteremia. Children who receive prophylactic antibiotics at the time of their febrile illness appear to do better than those who receive placebo. In retrospective reviews of both H. influenzae and N. meningitidis bacteremias, patients sent home on oral antibiotics did better than those discharged without therapy. Oral amoxicillin hastened defervescence and clinical improvement but failed to prevent major morbid events such as meningitis in a prospective evaluation. Harper compared children who received antibiotics for suspected bacteremia with those who were not treated prior to discharge. Treated children were more likely to be improved and less febrile on follow-up, and had persistent bacteremia or required hospitalization less frequently.[13] Fleisher's examination of 6733 children with temperatures below 39° C (102.2° F) (Reviewer suggests Fleisher's study included children between 3 and 36 months of age with temperatures greater than or equal to 39° C [102.2° F].) compares patients given ceftriaxone 50 mg/kg intramuscularly with subjects given six doses of oral amoxicillin 20 mg/kg. Blood cultures were positive in 195. All five children with definite bacterial infections at follow-up (three meningitis, one pneumonia, and one sepsis) were in the amoxicillin group.[14] Of children with occult pneumococcal bacteremia, 10% to 25% will develop some complication, including 3% to 6% who have meningitis.[15]

Hyperpyrexia

[]

True hyperpyrexia, defined as a temperature greater than 41° C (105.8° F), is an uncommon but serious problem. Extreme elevations of temperature account for fewer than 1% of pediatric visits. The main concern about hyperpyrexia is that it may indicate a serious underlying disease (e.g., meningitis or Kawasaki syndrome). In addition, the high fever itself can threaten the child. Approximately 20% of children with fevers above 41° C (105.8° F) will have convulsions.[18] With fevers above 42° C (107.6° F), direct end-organ damage may occur.[16] Overall, infectious diseases far outweigh all other causes of hyperpyrexia. High fever can follow almost any infectious disease but is particularly common in certain viral infections, such as roseola, rubeola, and enteroviral infections.[18] At temperatures of 39° C (102.2° F) and above, children are at increasing risk for occult bacteremia, as well as localized bacterial infections. This tendency becomes exaggerated at very high temperatures. Children with temperatures greater than 41.1° C (106° F) have a 10% risk of bacterial meningitis, and an additional 7% have bacteremia without meningitis. Marcinak found that of children with fever above 40° C (104° F), 40% had a viral cause and 45% had a bacterial cause.[17] The bacterial illnesses, such as otitis media and sinusitis, tend to be benign. Other reviews, however, show a higher incidence of serious illness in children with extreme elevations of temperature. Press and Fawcett found that 8 of 15 (53%) children with fevers above 41.1° C (106° F) had serious diseases: two with bacterial meningitis, two with bacteremia, two with pneumonia, one with pericarditis, and one with Kawasaki syndrome.[18] Many entities other than infection can cause hyperpyrexia. Temperatures greater than 42° C (107.6° F) are most often noninfectious in origin. Causes of such dramatically elevated temperatures include head injury, ingestion of psychotropic agents, heatstroke, and malignant hyperthermia secondary to anesthetic agents.[16 ]

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An unusual and often fatal illness consisting of profound hyperpyrexia, hemorrhagic shock, and encephalopathy has been reported.[] Children with this illness have sudden temperature spikes to as high as 43.9° C (111° F) and a rapidly progressive deterioration characterized by cerebral edema, shock, azotemia, anemia, and usually death. No etiology, infectious or environmental, has yet been determined. Management should consist of an aggressive search for the etiology of the fever. The fever can generally be controlled with acetaminophen 15 mg/kg every 4 hours or ibuprofen 10 mg/kg every 6 to 8 hours. These agents may sequentially or concurrently be used for slowly responsive fevers. Sponging with lukewarm water may be useful. Hyperpyretic children should all be evaluated with at least a complete blood count (CBC), blood culture, urinalysis, and urine culture. When no source is found, a chest radiograph and a lumbar puncture (LP) should be obtained, unless the patient is smiling and playful once the temperature comes down. Because of the high incidence of bacterial infection, these patients are generally treated parenterally with antibiotics (ceftriaxone 50 mg/kg every 12 hours or cefotaxime 50 mg/kg every 6 hours; plus ampicillin 50 mg/kg every 6 hours if the child is under 3 months of age) pending culture results. Age-specific management considerations discussed in this chapter must also be implemented.

Febrile Seizure Febrile seizures are common but generally benign events occurring in infants, toddlers, and young children. Approximately 2% to 5% of all children are affected. The convulsions are usually generalized and tonic-clonic, last less than 10 to 15 minutes, and occur during the up-slope of the fever curve. The peak incidence occurs between 8 and 20 months of age; febrile seizures are uncommon after 5 to 6 years of age. The main entity in the differential diagnosis is meningitis, which can cause fever and convulsions. In the past, many believed that all patients with febrile seizures required an LP to exclude meningitis. Patients at greatest risk for meningitis are those under 18 months of age, having a seizure in the ED, having a focal or prolonged seizure, and who have seen a physician within the past 48 hours. The American Academy of Pediatrics recommends that an LP should be “strongly considered” in infants under 12 months of age with a first febrile seizure. Most children over 12 to 18 months of age who have brief, generalized convulsions and who appear playful and nontoxic after the postictal period can be treated without an LP. Children experiencing a first-time febrile seizure should have an LP if there are any concerns about follow-up. Prior treatment with antibiotics should inspire enhanced concern.

Fever of Unknown Origin

[21]

The term fever of unknown origin (FUO) is traditionally used to refer to a febrile illness of unknown etiology lasting 14 days or more. Most children with a chief complaint of a febrile illness lasting longer than 2 weeks simply have had two or three febrile illnesses, one after the other. Careful questioning usually reveals a period of relative wellness during the time period in question. Miller's review of 40 children with fevers persisting over 1 month in whom an evaluation was inconclusive revealed that these children usually have a benign course.[22] True prolonged fever is a more serious matter. The causes include inflammatory bowel disease, Hodgkin's disease, other neoplasms, juvenile rheumatoid arthritis, systemic lupus erythematosus, infectious mononucleosis, Kawasaki syndrome, and tropical infections such as malaria. In one study of 100 children with FUO, 62 had infections, 20 had collagen-inflammatory disease, 6 had malignancies, and 12 were undiagnosed.[21] Box 165-1 presents a list of the various causes of FUO. A systematic approach to evaluation is essential, usually in collaboration with appropriate consultants. BOX 165-1 Causes of Prolonged Fever of Unknown Origin

Infection

Bacterial Aden itis End ocar

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ditis Mast oiditi s Occ ult absc ess Pyel onep hritis Sinu sitis Tube rculo sis

Viral Cyto meg alovi rus Hep atitis A, B, or C Infec tious mon onuc leosi s

Chlamydial Lym phog ranul oma vene reu m Psitt acos is

Mycoplasmal Fungal Blast omy cosi

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s Cysti cerc osis Histo plas mosi s

Rickettsial Q fever Roc ky Mou ntain spott ed fever

Parasitic Mala ria Toxo plas mosi s

Collagen Vascular Juve nile rheu mato id arthri tis Lupu s eryth emat osus Regi onal enter itis Rhe umat ic fever Ulce

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rativ e coliti s Vasc ulitis

Malignancy Leuk emia Lym pho ma Neur obla stom a Wil ms' tumo r

Drug-Induced Fever Antib iotic s Antic onvu lsant s Antit uber culo us agen ts Proc aina mide Prop ylthio uraci l Quin idine Seru m sick ness

Miscellaneous

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Acqu ired imm unod efici ency synd rom e (AID S) Cent ral nerv ous syst em and hypo thala mic Envir onm ental Facti tious Fami lial dysa uton omia Kaw asak i synd rom e Pul mon ary emb olus Seri al infec tions Thyr otoxi cosi s

Fever and Petechiae One of the most devastating illnesses in pediatric or adult medicine is overwhelming meningococcal sepsis. Afflicted patients commonly develop a downward spiral of disseminated intravascular coagulation (DIC) and irreversible shock despite aggressive antibiotic administration and treatment in the intensive care unit. Selecting which patients with petechiae are at risk for meningococcal or other bacterial sepsis is not an easy

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task. Several relatively benign viral infections and other conditions can also cause fever and petechiae. Furthermore, early in the course of meningococcal disease the child commonly appears minimally ill. In a study of 190 pediatric patients with fever and petechiae, Baker et al found that 15 had invasive bacterial diseases, half of which were meningitis.[23] The most common invasive pathogen is N. meningitidis, accounting for 13 of the 15 cases. Of those without invasive bacterial disease, the most common documented causes were group A streptococcal pharyngitis (10%), respiratory syncytial virus (RSV), or other viruses (12%). The remaining causes are nonspecific viral syndrome (50%), otitis media (15%), pneumonia (5%), and rare cases of Henoch-Schönlein purpura, acute leukemia, and Rocky Mountain spotted fever. Children with a normal LP, CBC, associated neutrophil and band counts, and a temperature greater than 40°C (Reviewer suggests A temperature less than 40°C.) (104° F) are less likely to have a bacterial infection. Patients with invasive bacterial disease often appear toxic and have elevations of both the WBC count and total band count. Of note, all patients in this study with invasive bacterial diseases had petechiae above and below the nipple line.

CLINICAL FEATURES History Parents should be questioned about the length and duration of the illness, the height of the fever, dosage and frequency of antipyretics, pertinent past medical problems (including immunocompetence, drug allergies, immunization status, recurrent infections), and possible exposure to a communicable disease. Is the patient acting normally at home in terms of feeding, playing, speech (when appropriate), and elimination of feces and urine? Explore whether the child has been exposed to other children with communicable diseases such as chicken pox, measles, viral croup, bacterial pneumonia, or meningitis. In young infants the birth history is relevant. The immunization status should be determined, and when appropriate, a travel history obtained. Has the child displayed symptoms consistent with common causes of pediatric fever? For example, children with otitis media typically rub or pull at the affected ear and appear irritable. Infants and toddlers with stomatitis commonly refuse feedings because of oral inflammation. Those with an upper respiratory infection will have sneezing, nasal discharge, and usually night cough. Pneumonia causes fever, cough, and sometimes grunting, flaring, and retracting. Gastroenteritis usually causes vomiting and diarrhea. Inability to walk in older patients points to cellulitis, osteomyelitis, or arthritis of the lower extremity.

Temperature Determination

[24]

Despite many recent technical advances in temperature measurement, the glass-mercury thermometer remains the gold standard for accuracy. However, the relatively long dwell time (2 to 3 minutes) and the risk of cross-contamination and potential breakage have led many practitioners to use newer technologies. Electronic thermometers are as accurate as glass-mercury. They have the advantages of a shorter dwell time and disposable sheaths. Tympanic membrane (TM) thermometers measure the infrared radiation emitted by the TM, yielding an almost instantaneous temperature reading. Unfortunately, TM thermometers commonly yield a falsely low value.[] In a recent study the TM thermometer was 76% sensitive in detecting fever above 100.4° F but only 57% sensitive for fever of 103° F or above.[25] The correlation between tympanic and rectal temperatures in patients over 3 months of age is good, but the correlation in those under 3 months of age is poor.[28] Many recommend against the use of electronic thermometers in children under 3 to 6 months of age. Technique is important when using the tympanic thermometer; tugging down on the earlobe during measurement improves the accuracy.[29] In older children, eating, drinking, hyperventilating, and smoking can falsely raise or lower the oral temperature.[30] Liquid crystal forehead strips are inconsistent.[31] Axillary temperatures are also unreliable, often being falsely low. One third of patients with fever will have a normal axillary temperature, even with correction. In infants and toddlers the preferred route for taking the temperature is rectal, because most algorithms defining risk of serious illness in this age group are based on the rectal temperature. In older children and adolescents the temperature may be taken by the oral route, if the patient has not recently been eating,

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drinking, or smoking. After the initial rectal or oral temperature is documented, axillary or TM temperatures may be adequate to follow the subsequent course of the fever.

Physical Examination The physical examination is the key to determining the workup of a febrile child. Vital signs should be noted. Tachycardia out of proportion to the degree of fever occurs with dehydration, septicemia, and primary cardiac conditions such as myocarditis and pericarditis. Tachypnea out of proportion to the degree of fever occurs with respiratory infections such as laryngotracheitis, bronchiolitis, and pneumonia. Box 165-2 presents various illnesses to keep in mind during the physical examination. Box 165-3 lists the causes of fever and altered sensorium. BOX 165-2 Common Illnesses to Screen for During the Physical Examination

Meningitis Look for meni ngis mus (unr eliabl e unde r 12 mont hs of age), irrita bility, and alter ed sens oriu m.

Otitis Media Note that just as the foreh ead flush es red in a febril e, scre amin g

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infan t, so does the tymp anic me mbr ane (TM) . Ther efore TM redn ess alon e is not a suffi cient criter ion to mak e the diag nosi s of otitis medi a. In one stud y, none of the infan ts with red TMs but nor mal land mark s had otitis medi a base d on direc t aspir ation of the midd

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le ear.

Upper Respiratory Infection (URI) Nas al cong estio n and nasa l disc harg e are so com mon in child ren that the diag nosi s of URI shou ld not be used to expl ain a high fever until mor e serio us caus es have been ruled out.

Pharyngitis

Kee p in mind that tonsi

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llar hype rtrop hy ( witho ut exud ate or eryth ema ) is a com mon nor mal findi ng in child ren 1½ to 3 year s of age.

Croup and Epiglottitis Both caus e inspi rator y strid or. Child ren with crou p typic ally have a grad ual onse t of sym ptom s over 2 to 3 days , do not appe ar

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syst emic ally toxic , and resp ond to mist or cool air. Child ren with epigl ottiti s gene rally have a mor e rapid onse t of sym ptom s (12 to 24 hour s), appe ar toxic and appr ehen sive, and sit uprig ht, drool ing, with the head tilted forw ard.

Bronchiolitis Whe ezin g and tach

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ypne a are seen in infan ts and toddl ers.

Pneumonia The child will usua lly coug h durin g the exa mina tion and displ ay rales on ausc ultati on. Ausc ultat ory findi ngs of pneu moni a may be abse nt in youn ger child ren.

Appendicitis

Abdo mina l tend erne

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ss and guar ding may be seen . Note that thes e sign s are abse nt as often as pres ent in child ren unde r 3 to 4 year s of age.

Intussusception Inter mitte ntly irrita ble infan t or toddl er, hem e-po sitive stool , and (co mm only but not alwa ys) a palp able abdo mina l mas s are

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seen . Leth argy with alter ed ment al statu s also may be seen .

Septic Arthritis Che ck for rang e of moti on of the joint s and feel for overl ying war mth. Logr oll the leg with the child supi ne. This man euve r will elicit tend erne ss in the case of a septi c hip.

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Meningococcemia Pete chial skin rash (earl y) and purp uric rash (late) are seen .

Chicken Pox This may be diffic ult to diag nose befor e true pox occu rs. Early lesio ns cons ist of a 2to 3-m m clear vesi cle on a 1/2to 3/4-c m eryth emat ous base (“tea rdro p on a

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rose petal ”). Child ren who have defer vesc ence early with rise of temp eratu re on day 4 or rem ain febril e at 5 days or beyo nd shou ld have an in-de pth eval uatio n for bact ere mia, espe cially grou pA strep toco ccus .

Measles Sal mon -colo red mac ulop apul ar exan

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them with coug h, cory za, palp ebral conj uncti vitis, and (earl y) Kopli k spot s may be seen . Strid or may also be pres ent. BOX 165-3 Causes of Fever and Altered Sensorium

Bact erial seps is, other than meni ngiti s Febri le seiz ure Hypo glyc emia , seco ndar y to poor oral intak e plus vomi ting

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and diarr hea Hypo natre mic dehy drati on Intus susc eptio n Meni ngiti s or ence phali tis Shig ella gastr oent eritis Toxi c inge stion Uns uspe cted head trau ma, inclu ding shak en-b aby synd rom e with centr al nerv ous syst em blee ding

BUN, Blood urea nitrogen; WBC/hpf, white blood cells per high-power field; UTI, urinary tract infection; SGOT, serum glutamic oxaloacetic transaminase; SGPT, serum glutamic pyruvic transaminase.

Ancillary

[]

Numerous laboratory tests are available to help differentiate serious from nonserious illness and to help locate the source of infection.

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Despite the guidelines that are presented later, there is tremendous variability among clinicians in the types of diagnostic tests they order. Hospital-based subspecialists are more likely to order diagnostic tests than community-based physicians. Children seen by a physician with more than 10 years of experience are less likely to have tests than those seen by more junior colleagues. The presence of trainees tends to increase the likelihood of doing tests.[]

White Blood Cell Count Both high (>15,000/mm3) and low (1.5 cm in diam eter, usua lly unila teral Exclusion of other diseases with similar findings

Other Clinical and Laboratory Findings

Cardiac findings Pan cardi tis, in the early stag es of dise ase

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Coro nary arter y abno rmali ties, usua lly beyo nd 10 days of onse t of illnes s

Noncardiac findings Mus culo skel etal syst em Arthr itic, arthr algia Gast roint estin al tract Diarr hea, vomi ting Abdo mina l pain Hep atic dysf uncti on Hydr ops of the gallbl adde r Cerv ical

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nerv ous syst em Extr eme irrita bility Asep tic meni ngiti s Res pirat ory tract Pul mon ary infiltr ates Othe r findi ngs Testi cular swell ing Peri pher al gang rene Aneu rysm s of medi umsize d nonc oron ary arteri es

Laboratory findings Neut rophi lia with imm ature form s

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Elev ated eryth rocyt e sedi ment ation rate Posit ive C-re activ e prote in Ane mia Hypo albu mine mia Thro mbo cyto sis Prot einur ia Steril e pyuri a Elev ated seru m trans amin ase * Patients with fever and fewer than four principal clinical features can be diagnosed as having Kawasaki syndrome when coronary artery disease is detected by two-dim ensional echocardiography or coronary angiography. † Many experts believe that in the presence of classic features, the diagnosis of Kawasaki syndrom e can be m ade by experienced practitioners before the fifth day of fever.

MANAGEMENT OF THE FEBRILE CHILD Prehospital Care Because the main concern with a febrile, toxic-appearing child is a serious infection (e.g., meningitis, pneumonia, or meningococcemia) or accompanying dehydration, the focus of the paramedic should be on rapid transport to the ED for evaluation and the early institution of antibiotics. Field interventions such as establishing intravenous access or sponging with tepid water are usually not necessary. The administration of a single dose of acetaminophen (15 mg/kg) to children under 6 years of age, especially those with a history of febrile seizures, is appropriate.

ED CARE [] Infants from Birth to 12 Weeks of Age Neonates and young babies with fever are of special concern. Despite having some protective immunity from maternal antibodies, young infants do not have the immunocompetence of older children, being relatively deficient in immune functions such as chemotaxis, phagocytosis, intracellular killing, and serum

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levels of various immune globulins.[] The evaluation of young infants is complicated by many factors. The first several weeks of life are a period of tremendous developmental change, making a 3-week-old infant very different from an 8-week-old infant, who is in turn very different from a 12-week-old infant. During the first 4 weeks of life, many activities (e.g., sucking, eye opening, and grasping) are reflex in origin and can persist even in the face of serious diseases. In one study, one in nine young babies with serious bacterial infections appeared clinically well even to experienced physicians.[50] Infants with meningitis do not have stiff necks. There are no specific and reliable laboratory studies that can identify or exclude all children with serious disease.[] The causes of infection also change greatly with increasing age. As the infant is discharged from the nursery and exposed to a variety of community-acquired pathogens at home, the spectrum of agents changes from maternal vaginal flora (E. coli, group B streptococci, Listeria monocytogenes, herpes virus, and Chlamydia trachomatis) to community-acquired viruses and bacteria (enterovirus, S. pneumoniae, and H. influenzae). During the first month of life, 73% of cases of bacteremia or bacterial meningitis are due to group B streptococci and 8% to E. coli infections.[52] Fever, especially high fever in young infants, is rare but suggests the possibility of a serious infection.[] The reported incidence of bacterial infection varies, with early reports suggesting that bacteremia may be as common as 12% to 14% during the first 8 weeks of life. Others estimate a lower risk, on the order of 3% to 4%.[53] Combining the data from multiple studies of infants less than 12 weeks of age with a temperature of 38° C (100.4° F) or greater, Baskin estimates the prevalence of serious bacterial infections (including pneumonia, pyelonephritis, and aseptic meningitis) to be approximately 7%, and the incidence of bacteremia or bacterial meningitis to be 2% to 3%.[52]

Clinical and Ancillary Data The relative immaturity of infants under 8 weeks of age makes clinical evaluation difficult at best.[] For example, studies find that the presence of a normal smile is a good predictor of the absence of serious illness in most age groups, but a social smile is not in the developmental repertoire of a 4-week-old infant and may not appear in some infants until 8 weeks of age. Although the absence of certain signs does not rule out disease, their presence indicates infants who are at risk for serious infection. These signs include overall impression of toxicity, abnormal or decreased feeding pattern, irritability, lack of consolability, and pale or mottled skin. High fever has a high correlation with serious illness. However, the lack of fever does not rule out the presence of bacterial or other serious disease. Unfortunately, laboratory evaluation is less helpful in this age group than in older children. Several studies have attempted to demonstrate the efficacy of one test or another, but as yet no single test or combination of tests can prospectively predict the presence or absence of serious illness with assurance.[] During the first week of life, the WBC count is commonly lower in the bacteremic than in the nonbacteremic patient. Overall, the CBC is useful as a guide to the degree of illness. In general, a WBC count either above 15,000/mm[3] or below 5000/mm[3] and increased numbers of immature (band) forms correlate with the presence of serious infection.[]

Evaluation Febrile infants under 8 to 12 weeks of age require a complete septic workup including a CBC with differential, platelet count, blood culture, chest radiograph, urinalysis and urine culture (obtained by catheterization), and LP. In infants 8 to 12 weeks of age with normal feeding, normal activity, a good social smile, excellent follow-up, and a normal CBC, the LP may be omitted.

Management and Admission Criteria Infants from Birth to 4 Weeks of Age Infants under 4 weeks of age with fever require admission for parenteral antibiotics and apnea monitoring until cultures prove negative. Admission is the rule for all infants under 4 weeks of age, even when an identifiable source of fever, such as otitis media, is discovered. Ferrera attempted to apply a modification of the low-risk criteria delineated in Box 165-6 and demonstrated that 3 of 48 meeting these guidelines had

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serious bacterial infections.[56] BOX 165-6 Low-Risk Criteria for Infants 4 to 12 Weeks of Age[] Clinical Criteria Previously healthy Nontoxic clinical appearance No focal bacterial infection (except otitis media) Good social situation Laboratory Criteria WBC count 5000/mm[3] to 15,000/mm[3] with 39°C). Patients may or may not have a cough and often appear relatively toxic with tachypnea disproportionate to the fever. Confined rales or wheezes and localized decreased or tubular breath sounds commonly occur in older children, although the physical examination in a younger child may be completely unrevealing.

Diagnostic Considerations Patients with pneumococcal infections often have a preceding dramatic presentation with high white blood cell (WBC) counts with associated pleural effusion and bacteremia in 10% to 30% of children.[18] Radiographic findings may show an alveolar infiltrate in a patchy or consolidated lobar ( Figure 168-2 ) or subsegmental distribution, although patients with bacterial pneumonia may have an interstitial infiltrate.[17] Bilateral involvement, pleural effusion, pneumatocele, and pneumothorax may occur with more severe disease. Although the WBC count may be normal with bacterial pneumonia, leukocytosis often occurs, sometimes exceeding 20,000/mm3. Uncomplicated bacterial pneumonia often has a rapid response to institution of chemotherapy; a stagnant or worsening clinical picture should prompt further investigation.

Figure 168-2 Radiograph shows pneum ococcal pneum onia with infiltrate in right upper lobe. ((Courtesy of Marianne Gausche-Hill, MD.))

Management Of concern is the emergence of resistance to penicillin and cephalosporins.[19] The clinical significance of resistant pneumococcal pneumonia in children is unclear. At this time, it seems that presentation and outcome of otherwise healthy children with pneumonia secondary to resistant pneumococcus may not differ significantly from the outcome of children with pneumonia secondary to penicillin-sensitive pneumococcus. 19-21 Pneumonia caused by S. pneumoniae may be complicated by empyema, pleural effusion, lung abscess, or necrotizing pneumonia. Since the 1990s, there seems to have been an increase in the incidence of such complications, with one study noting an increase from 22.6% in 1994 to 53% in 1999 in children hospitalized with pneumococcal pneumonia.[22] It does not seem that this increased incidence is related to intermediate resistant organisms. It is unclear if highly resistant organisms play a role.[22] High-dose amoxicillin is recommended for initial outpatient treatment of suspected pneumococcal pneumonia in children younger than 4 years old; a standard dose may be used in older children who are immunocompetent ( Tables 168-1 and 168-2 ). Table 168-2 -- Antibiotics for the Treatment of Bacterial Pneumonia: Daily Dosage Agent

Daily Dosage[*]

Oral Amoxicillin (standard dose) Amoxicillin (high dose)

20–50 mg/kg div tid 80–100 mg/kg div bid

Amoxicillin–clavulanate

25–45 mg/kg div bid[†]

Azithromycin Cefuroxime axetil Clarithromycin Erythromycin Penicillin V

10 mg/kg day 1, then 5 mg/kg q day on days 2–5 30 mg/kg div q12h 15 mg/kg div q12h 40–50 mg/kg div q6h 25–50 mg/kg div q6–8h

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Agent

Daily Dosage[*]

Trimethoprim-sulfamethoxazole Parenteral

8–12 mg/kg div q12h

Ampicillin Ampicillin-sulbactam Cefotaxime Ceftriaxone Cefuroxime

150 mg/kg div q6h 150 mg/kg div q6h 150–200 mg/kg div q8h 100 mg/kg div q12h 150 mg/kg div q8h

Chloramphenicol

50 mg/kg div q6h[‡]

Clindamycin

40 mg/kg div q6h

Gentamicin

5–7.5 mg/kg div q8h[‡]

Methicillin-nafcillin Oxacillin Penicillin G (aqueous)

150–200 mg/kg div q4–6h 200 mg/kg div q4–6h 100,000–400,000 U/d div q4–6h Dosages and intervals m ay differ in neonates.

* †

Use 875-m g tablet, 200-m g or 400-m g chewable tablets or 200 m g/5 m L, 400 m g/5 m L, 600 m g/5 m L suspensions for twice-daily dosing.

‡

Must m onitor serum levels.

Viral Pneumonia Viral pneumonia occurs more commonly in the winter and generally has a gradual onset over several days, often with associated cough, coryza, and low-grade fever. Tachypnea may be the only physical finding; however, retractions, rales, and wheezing are common, with grunting, cyanosis, lethargy, dehydration, and apnea apparent in more severely affected children. The diagnosis of viral pneumonia is often made clinically. Rapid antigen testing may be useful in the diagnosis of RSV or influenza A and B. Other viral agents may be diagnosed with culture of nasopharyngeal secretions. Although in the past the use of viral cultures was limited by the time required to grow viruses, improved culture techniques may yield results within 2 days and prove useful in a patient in whom cause needs to be established. The WBC count is variable, but tends to be less than 15,000/mm[3] with lymphocyte predominance. Radiographic findings typically include hyperinflation and peribronchial thickening with diffuse increase in interstitial findings. Patchy areas of consolidation may be present, representing lobular atelectasis or alveolar pneumonia. Although lobar consolidation and small pleural effusions may occur in viral pneumonia, these findings are more consistent with a bacterial cause. Most viral pneumonias resolve without specific therapy. Because of the likelihood of bacterial superinfection and the difficulty in differentiating between bacterial and viral pneumonia, antibiotics may be prudent in a more severely ill child. Potential complications include dehydration, local progression of the disease, bronchiolitis obliterans, and apnea (most commonly in the first 3 months of life).[29]

Mycoplasmal Pneumonia Mycoplasmal pneumonia accounts for 10% to 20% of all pneumonias and was thought to occur most commonly in 5- to 18-year-olds. It is now clear that it also may play a significant role in younger children.[5] Mycoplasmal pneumonia is rare in infants less than 1 year old.[30] Classically the onset is gradual and insidious, but some patients also may present with abrupt onset of symptoms similar to its bacterial counterpart.[5] Prodromal symptoms include fever, headache, and malaise followed several days later by a nonproductive, hacking cough. Patients also may present with pertussis-like illness. Other symptoms of infection may include hoarseness, sore throat, and chest pain; coryza is unusual. Children with mycoplasmal pneumonia generally appear nontoxic. Patients may have rales, with wheezing occurring less often. Pharyngitis, cervical lymphadenopathy, conjunctivitis, and otitis media occur occasionally. Bullous myringitis, although rare, is believed to be indicative of Mycoplasma.[30] Rash is present in 10% of patients and may be urticarial, erythema multiforme, maculopapular, or vesicular.[31] The course may be complicated by pneumatocele, pleural effusion, pneumothorax, or bronchiectasis. Mycoplasma, typically thought to be a

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benign and self-limited infection, has been shown to play a significant role in exacerbating asthma.[5] Mycoplasma may cause chronic pulmonary structural abnormalities.[5] Physical findings generally are less impressive than the radiographic picture; involvement is usually unilateral and in the lower lobes. The radiographic findings are protean, however, and may show lobar consolidation, scattered segmental infiltrates, or interstitial disease. Pleural effusions may occur, but are uncommon. The WBC count is usually normal; the erythrocyte sedimentation rate tends to be elevated. Laboratory diagnosis is problematic. Although used in the past, bedside cold agglutination testing is a poor indication of infection, especially in patients younger than 12 years old.[30] Infection often is diagnosed clinically and treated empirically. Diagnosis may be confirmed with acute and convalescent antibody titers; however, patients may take 4 to 6 weeks to seroconvert, and some patients may fail to mount an immune response.[5] Culture is not routinely available; polymerase chain reaction diagnosis at this time is available only from research laboratories.[5] Complications are varied but unusual and include hemolytic anemia, myopericarditis, neurologic disease (meningoencephalitis, Guillain-Barré syndrome, transverse myelitis, cranial neuropathy), arthritis, and rash.

Chlamydial Pneumonia C. trachomatis is a common sexually transmitted infection, causing cervical infection in 2% to 30% of pregnant women.[9] It can be transmitted from the genital tract of infected mothers to their newborn infants, resulting in conjunctivitis in 22% to 44% and pneumonia in 5% to 20%.[9] An infant with pneumonia caused by C. trachomatis presents at 3 to 19 weeks old after colonization with the organism at birth. The illness usually begins with nasal congestion followed by cough. In half of cases, conjunctivitis precedes the onset of respiratory symptoms. The infant is often afebrile, alert, and tachypneic, with a repetitive staccato cough. The cough may interfere with feeding or sleeping. It can resemble the paroxysms of pertussis and occasionally precipitates episodes of alarming respiratory distress. Mild retractions and diffuse inspiratory crepitant rales are noted on chest examination, with expiratory wheezing usually absent or minimal. Middle ear abnormalities are present in half of cases. The radiograph usually shows hyperinflation with bilateral and symmetrical diffuse interstitial infiltrates ( Figure 168-3 ). The total WBC count is usually normal but often with an eosinophilia of more than 400/mm3.[ 9] Definitive diagnosis is made by isolating the organism in the tissue culture; diagnostic tests based on polymerase chain reaction are more sensitive than fluorescent antibody stain or tissue culture, but may not be as specific.[13] Although often a mild illness, chlamydial pneumonia may be complicated by apnea and hypoxemia. Treatment with erythromycin may shorten the course; however, the disease tends to be protracted with cough and tachypnea often requiring weeks to clear.

Figure 168-3 Radiograph shows chlam ydial pneum onia in an infant. Note the sym m etrical interstitial infiltrates. ((Courtesy of Michael Diam ent, MD.))

C. pneumoniae is a species of Chlamydia that is antigenically, genetically, and morphologically distinct from other Chlamydia species. C. pneumoniae infection is readily transmitted from person to person. C. pneumoniae may play a role in respiratory tract infections in infants and young children and may cause mild illness or asymptomatic infection in children and adults. As with Mycoplasma, C. pneumoniae may play a much greater role in pediatric pneumonia than previously thought. It also commonly may be present as a mixed bacterial infection.[5] C. pneumoniae has been reported to cause sore throat, fever, headache, pertussis-like cough, pneumonia, and influenza-like illness.[32] Outbreaks have been reported in schools, daycare centers, military camps, adolescents, and families.[33] Infection with C. pneumoniae can trigger acute episodes of wheezing in children with asthma.

Pertussis

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Pertussis, or whooping cough, is a respiratory tract infection seen most commonly in infants younger than 6 months old (38% of cases are in children 12 years old Formulas to calculate the estimated normal blood pressures in children ≥1 year of age:

Minimum acceptable SPBs for age:

Newborn to 1 month old: 1 month to 1 year old: >1 year old to 10 years old: >10 years old:

Heart rate 140 120 100 80

Respiratory rate 40 30 20 15

Estimated systolic blood pressure (SBP): [age in years × 2] + 90 mm Hg Estimated diastolic blood pressure (DBP): 2/3 × [estimated SBP] 60 mm Hg 70 mm Hg [age in years× 2] + 70 mm Hg 90 mm Hg

An accurate blood pressure reading is dependent on using a cuff that covers two thirds of the upper arm or thigh. A cuff that is too narrow will overestimate the patient's true blood pressure and a cuff that is too large will underestimate the true blood pressure. Any child with a suspected cardiac disorder should have blood pressures measured in both arms. If the blood pressure in the left arm is significantly lower than the blood pressure in the right arm, a coarctation of the aorta proximal to the origin of the left subclavian artery should be suspected. Blood pressures must also be measured in the thighs in any child with a suspected aortic coarctation or documented hypertensive blood pressures in the upper extremities. The mere presence of femoral pulses does not clinically rule out the possibility of a coarctation of the aorta. Even with an appropriately sized cuff, the blood pressures in the thighs can be 10 to 20 mm Hg higher than the blood pressures in the upper extremities due to the lack of well-designed blood pressure cuffs for the legs. Therefore, if the measured blood pressure in the lower extremities is lower than the blood pressures in the upper extremities, coarctation of the aorta should be suspected. Pulse oximetry readings that are lower in the legs than in the upper extremities are also suggestive of either a coarctation of the aorta or a right-to-left-shunt across a patent ductus arteriosus.[6]

Cardiac Auscultation The intensity and degree of splitting of the S2 heart sound (which reflects closure of the pulmonic and aortic valves) is extremely important in a pediatric cardiologic evaluation. In normal children, both components (aortic closure and pulmonic closure) of S2 should be heard along the left upper sternal border (the pulmonic area). A widely split and fixed S2 suggests a physiologic problem resulting from either a constant volume overload to the right side of the heart (e.g., atrial septal defect) or a pressure overload to the right side of the heart (e.g., pulmonic stenosis). The classic congenital heart defect that is associated with a widely split and fixed S2 is the atrial septal defect. The intensity of the S2 component may be louder than normal in the child with pulmonary hypertension. The third heart sound (S3), which is best heard along the lower left sternal border or the apex, can be a normal finding in children and young adults. S3 is produced by a rapid filling of the ventricles and is heard during early diastole, just after the S2 sound. A loud S3 is always pathologic and is due to dilated ventricles with decreased compliance (e.g., CHF and large ventricular septal defects). The fourth heart sound (S4) occurs late in diastole, just before the S1 sound. The finding of an S4 is due to a decrease in ventricular compliance or CHF. Cardiac murmurs are produced by turbulent blood flow through the heart. The presence of a cardiac murmur may not be associated with an underlying cardiac defect, however. The location, intensity, quality, timing, and radiation of the murmur deter-mine whether the murmur is suggestive of underly-ing cardiac pathologic condition. Although systolic murmurs can be present without any underlying anatomic abnormalities, diastolic murmurs are always considered pathologic in nature. Some of the other criteria that would suggest an underlying anatomic cardiac abnormality are listed in Box 169-4 . Murmurs may be very

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difficult to appreciate in the noisy emergency department setting, given the degree of tachycardia that is often present even in normal infants. However, the location of the murmur may be a valuable clinical tool in determining the underlying anatomic origin of the murmur ( Box 169-5 ). BOX 169-4 A Pathologic Etiology of a Heart Murmur Should Be Suspected with Any of the Following Criteria

{,

{,

{,

{,

Dias tolic mur mur s Syst olic mur mur s that are loud er than a grad e 3/6, conti nuou s or asso ciate d with a thrill Mur mur s that are asso ciate d with abno rmal heart soun ds (clic ks, rubs, or gallo p rhyth ms) Pres ence

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{,

{,

{,

of cyan osis or respi rator y distr ess Bou ndin g puls es or wea k puls es Abno rmali ties on the ECG An abno rmal cardi ac silho uette , abno rmal pulm onar y vasc ularit y or cardi ome galy on the CXR

BOX 169-5 Auscultation Locations of Common Systolic Murmurs in Children

Left Upper Sternal Border (Pulmonic Area) Pul moni c valvu lar sten osis Atrial sept

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al defe cts (due to an incre ased pulm onic flow) Inno cent pulm onic eject ion mur mur Neo nate pulm onic flow mur mur Pate nt duct us arteri osus (a conti nuou s, “ma chin ery” soun ding mur mur)

Left Lower Sternal Border Inno cent vibra tory Still' s mur mur Vent ricul ar sept al defe cts

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End ocar dial cush ion defe cts Tetr alog y of Fallo t Hype rtrop hic cardi omy opat hy

Apex Inno cent vibra tory Still' s mur mur Mitra l regu rgitat ion Aorti c sten osis Hype rtrop hic cardi omy opat hy

Right Upper Sternal Border (Aortic Area) Aorti c valvu lar sten osis Coar ctati on of the aorta

Page 4018

Murmurs without any underlying anatomic abnormalities or hemodynamic significance are termed innocent or functional murmurs. All innocent murmurs are associated with normal ECGs and normal chest radiographs. Two of the most common innocent murmurs encountered in the pediatric population are the neonatal pulmonic flow murmur (also known as the peripheral pulmonic stenosis murmur) and Still's murmur. The pulmonic flow murmur of the neonate is due to the relative hypoplasia and angulation of the right and left pulmonary arteries at birth. This systolic murmur is best heard at the left upper sternal border with radiation throughout the entire chest, axilla, and back. This murmur usually disappears by 3 to 6 months of age. Persistence of a systolic murmur in the pulmonic area beyond this period should raise the possibility of a pathologic pulmonary arterial stenosis. Another common innocent murmur in children is Still's murmur, which is a systolic murmur that typically occurs in children between 2 and 6 years of age. This systolic murmur is best heard along the left midsternal border. The distinctive quality of this murmur has been described as being “vibratory,” “musical,” “zippy,” and “twanging,” and results from turbulent flow. The distinct quality of this murmur helps to distinguish Still's murmur from a ventricular septal defect murmur, which has a more “harsh” quality. The intensity of Still's murmur can be increased due to fever, excitement, exercise, or anemia.

The Hyperoxia Test In general, infants with a cardiac origin for their cyanosis exhibit a worsening of their cyanosis with crying.[7] Administration of 100% oxygen (also known as the hyperoxia test) can be used as a bedside diagnostic tool to help differentiate between cardiac and pulmonary causes of central cyanosis. This test consists of assessing the rise in arterial oxygenation with the administration of 100% oxygen. The response to 100% oxygen can either be determined by the pulse oximeter or by actually measuring an arterial blood gas. According to one reference, if the patient's oxygen saturation increases by more than 10% or the PaO2 rises by more than 20% to 30%, then the most likely origin for the cyanosis is pulmonary rather than cardiac. If the oxygen saturation does not increase and the cyanosis does not improve with supplemental oxygen, then a cardiac origin for the patient's cyanosis should be suspected.[3] The measured PaO2 in patients with a pulmonary origin for cyanosis should rise well above 200 mm Hg unless the degree of pulmonary disease that is present is severe. PaO2 values that do not rise above 100 mm Hg in cyanotic patients are highly suggestive of a cardiac defect. A PaO2 that remains lower than 100 mm Hg despite 100% oxygen is suggestive of a congenital heart defect with decreased pulmonary blood flow and/or right-to-left shunting. Those congenital heart defects with an increased pulmonary blood flow may exhibit a rise in their PaO2 (up to 150 mm Hg) in response to 100% oxygen.[2] Prolonged administration of 100% oxygen may cause some theoretical problems, such as closing the ductus arteriosus in those infants with critical left heart obstructions or by causing pulmonary vasodilation (which would potentially worsen pulmonary vascular congestion).[2]

Arterial Blood Gases Patients with CHF exacerbations can exhibit respiratory acidosis (low pH and high PaCO2) in addition to a low PaO2. In contrast to this, children with compensated cyanotic congenital heart defects may have a normal pH despite a low PaO2. Patients with congenital heart defects who are not experiencing respiratory failure are unlikely to exhibit elevations in their PaCO2 values. Any cardiac condition that results in inadequate tissue perfusion (i.e., any of the acyanotic congenital heart defects that manifest in CHF) will exhibit a metabolic acidosis with or without a respiratory compensation.

Hemoglobin/Hematocrit Levels and Serum Electrolytes The hemoglobin and hematocrit levels may reveal a compensatory physiologic elevation (i.e., polycythemia) in children with cyanotic congenital heart defects. Any concurrent medical illness or blood loss that produces an acute anemia could potentially precipitate an acute deterioration by compromising the oxygen-carrying capacity in these children with an underlying congenital heart defect. A hematocrit level would also be helpful in evaluating whether a child's pallor is due to CHF or anemia. Serum electrolytes may be helpful when evaluating children with acute dysrhythmias or suspected metabolic acidosis and those children who are on chronic diuretic therapy.

Chest Radiograph ( Figure 169-2 ) The three items to pay special attention to when evaluating the chest radiograph of a child with a known or suspected cardiac disorder are (1) the cardiac size (cardiothoracic ratio), (2) the cardiac shape (silhouette), and (3) the degree of pulmonary vascular markings. The easiest method to determine the heart size in children is to determine the cardiothoracic ratio, which is obtained by relating the largest transverse diameter of the cardiac shadow on the posteroanterior view of the chest radiograph to the widest internal diameter (measured from the inside rib margin to the widest point above the costophrenic angle) of the chest. The

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normal cardiothoracic ratio in children is approximately 50%. The cardiothoracic ratio is not very accurate in newborns and small infants, in whom a good inspiratory view is rarely obtained.[8] A cardiac silhouette that is larger than normal may be due to a shunt lesion, CHF, or a pericardial effusion.[8] An enlarged heart shadow on a chest radiograph more reliably reflects a problem with volume overload rather than pressure overload. Problems with pressure overload are better represented on the ECG.

Figure 169-2 Diagram m atic representations of the anatom y of the chest radiograph. A, Normal heart in a young m an. Posteroanterior projection. Aor, aorta; IVC, inferior vena cava; LAA, left atrial appendage; LPA, left pulmonary artery; LV, left ventricle; PT, pulm onary trunk; RA, right atrium ; RPA, right pulm onary artery; RV, right ventricle; SVC, superior vena cava; Tr, trachea. B, Right lateral projection of a norm al heart in a young m an. IVC, inferior vena cava; LPA, left pulmonary artery; LV, left ventricle; RPA, right pulm onary artery; RV, right ventricle; Tr, trachea.

The cardiac size can be falsely increased in infants because of the presence of the thymus, which can be seen in the mediastinum on the chest radiograph from birth until about 5 years of age. The thymic borders are typically wavy in appearance and sometimes can be seen as the classic “sail sign” along the superior right heart border ( Figure 169-3 ). The thymic shadow may not be radiographically visible in infants during times of physiologic stress but should reappear when the infant recovers.

Figure 169-3 Thym ic shadow dem onstrating the “sail sign” along the right cardiac border (dotted line).

The three classic cardiac silhouettes seen in patients with congenital heart defects are (1) the “boot-shaped” heart of tetralogy of Fallot ( Figure 169-4 ), (2) the “egg-on-a-string silhouette” of transposition of the great vessels, and (3) the “snowman-shaped” or “figure of 8 heart” of total anomalous pulmonary venous return.

Figure 169-4 The classic boot-shaped heart of tetralogy of Fallot.

The degree of pulmonary vascular markings is one of the key factors to consider when working through the differential diagnosis of congenital heart defects. An increase in pulmonary vascularity is present when the pulmonary arteries appear enlarged and extend into the lateral third of the lung fields or if there is an increased vascularity to the lung apices. Another criterion that suggests an increased pulmonary vascularity is if the diameter of the right pulmonary artery in the right hilum on the posteroanterior view of the chest is wider than the internal diameter of the trachea. The differential diagnosis of a cyanotic infant with decreased vascular markings includes tetralogy of Fallot, pulmonary atresia, or tricuspid atresia. The cyanotic infant with increased vascular markings may have transposition of the great vessels, total anomalous pulmonary venous return, or truncus arteriosus. Increased vascular markings in an acyanotic infant are suggestive of an endocardial cushion defect, ventricular septal defect, atrial septal defect, or a patent ductus arteriosus. In a normal left-sided aortic arch, the aorta descends to the left of the midline and displaces the tracheal air

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shadow slightly toward the right of midline above the level of the carina. In contrast to this, the tracheal air shadow may be midline or deviated toward the left in the presence of a right-sided aortic arch.[2] This finding is important to note, since a right-sided aortic arch is found in up to 25% of the children with tetralogy of Fallot.[8] Rib notching secondary to increased collateral blood flow along the intercostal vessels can sometimes be appreciated between the fourth and eighth ribs in older children with undiagnosed coarctation of the aorta but is rarely visualized in children with coarctation of the aorta who are younger than 5 years of age.[8]

Electrocardiogram The ECG findings in infants and children can sometimes be problematic because various components of the ECGs change according to the child's age ( Table 169-3 ).[5] At birth, the muscle mass of the right ventricle is greater than that of the left ventricle. By the end of the first month of life, the left ventricle assumes dominance. By 6 months of age, the left ventricular to right ventricular mass ratio is 2:1, which then reaches the adult ratio of 2.5:1 by adolescence. The durations of the PR interval, QRS complex, and QT intervals all increase with age. Table 169-3 -- Normal ECG Values (PR, QRS, QTc and QRS axes) in Infants and Children[5] Age

PR Interval Average (upper limit)

QRS Duration Average (upper limit)

0–1 month

0.10 (0.12)

0.05 (0.07)

1 month-1 year

0.10 (0.14)

0.05 (0.07)

1–3 years

0.11 (0.15)

0.06 (0.07)

3–8 years

0.13 (0.17)

0.07 (0.08)

8–12 years

0.15 (0.18)

0.07 (0.09)

12–16 years

0.15 (0.19)

0.07 (0.10)

Adult

0.16 (0.21)

0.08 (0.10)

The QTc interval should not exceed: 0.45 seconds in infants 3 years

+60 (+20 to +120)

Adults

+50 (-30 to +105)

Normal T wave axis in infants and children: (+) = upright T wave and (-)= inverted T wave Leads V1 and V2

Lead aVF Leads I, V5, and V6

Birth to 1 day old

±

+

±

1–4 days old

±

+

+

4 days to adolescent

-

-

+

Adolescent to adult

+

+

+

Left axis deviation is present when the QRS axis is less than the lower limit of normal for the child's age and occurs with left ventricular hypertrophy and left bundle branch block. Right axis deviation is present when the QRS axis is greater than the upper limit of normal for the child's age and occurs with right ventricular hypertrophy and right bundle branch block. A “superior” QRS axis (0 degrees to −180 degrees with an S

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wave in aVF greater than the R wave) may be suggestive of an endocardial cushion defect or tricuspid atresia. Some of the more common indications for obtaining an ECG in a pediatric patient include chest pain, dyspnea, syncope, palpitations, and suspected dysrhythmias. Other indications for obtaining an ECG are in those children with known cardiac disorders who present with signs and symptoms that could reflect an acute decompensation of their underlying disorder. A rare but potentially fatal congenital cardiac abnormality that will demonstrate ECG abnormalities (i.e., ischemic changes) is the condition of the anomalous origin of the left coronary artery. These infants have a history of poor feeding, irritability, and failure to thrive, then suddenly present with cardiogenic shock secondary to myocardial ischemia.

Biochemical Markers The utility and clinical accuracy of cardiac biochemical markers such as creatinine phosphokinase MB and cardiac troponin-T in the emergency department setting is currently limited in the pediatric population. Plasma homocysteine levels have been studied recently as a possible link to CHF in adults; however, there are currently no studies regarding plasma homocysteine levels in pediatric cardiac disorders.[9] Several recent studies have evaluated the use of plasma B-type natriuretic peptide levels in the assessment and management of CHF in adults.[10] Studies of B-type natriuretic peptide levels in children have demonstrated a similar correlation of elevated levels in children with CHF, and these also correlated to the clinical symptoms of heart failure and the ejection fraction as measured by echocardiography.[11]

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Marx: Rosen's Emergency Medicine: Concepts and Clinical Practice, 6th ed., Copyright © 2006 Mosby, Inc.

SPECIFIC DISORDERS CONGENITAL HEART DISEASE Perspective The incidence of congenital heart disease (CHD) in the United States has remained fairly constant at approximately 1%, or 8 to 10 cases per 1000 live births. This equates to approximately 32,000 infants born each year with some form of CHD[12] ( Table 169-4 ). Although a large percentage of CHDs are now detected with prenatal ultrasonograms, one recent study also recommended using the pulse oximeter to routinely screen all newborns prior to discharge from the nursery as an additional inexpensive screening tool for CHDs.[13] Table 169-4 -- Incidence of Specific Congenital Heart Defects (CHDs) Defect

Percent of CHD

Acyanotic CHDs Ventricular septal defect (VSD)

20–25%

Atrial septal defect (ASD)

5–10%

Patent ductus arteriosus (PDA)

5–10%

Coarctation of the aorta (CoA)

8%

Pulmonic stenosis (PS)

5–8%

Aortic stenosis (AS)

5%

Cyanotic CHDs Tetralogy of Fallot (TOF)

10%

Transposition of the great arteries (TGA)

5%

Tricuspid atresia (TriA)

1–2%

Total anomalous pulmonary venous return (TAPVR)

1%

Truncus arteriosus (TA)

20 mg/dL and dependent on age) of bilirubin may be associated with neurotoxicity, encephalopathy, and the development of kernicterus. Kernicterus is characterized by yellow staining in areas of the brain, including the basal ganglia. Symptoms begin with poor feeding and lethargy and may progress to muscular rigidity, opisthotonos, seizures, and death. Survivors may have residual problems with coordination, hearing, and learning disabilities.[1] The cornerstone of therapy is phototherapy and exchange transfusion.

Diagnostic Strategies Although physiologic jaundice of the newborn and breast milk jaundice are most common, it is important to identify truly pathologic causes of jaundice. Initial testing requires determination of fractionated levels of total and direct bilirubin. Box 170-1 lists indications for workup in infants presenting with hyperbilirubinemia. Conjugated (direct) hyperbilirubinemia is always pathologic. In such cases, a minimal workup should include a complete blood count (CBC) with peripheral smear and a Coombs' test for immune-mediated major blood group incompatibility. Ill-appearing infants also require tests for finger-stick blood glucose, electrolytes, urine for reducing substances, and serum ammonia to rule out inborn errors of metabolism.[2] BOX 170-1 Indications for Workup in Jaundiced Infants

1.

Jaun dice appe aring withi n 24 hour s of birth

2.

Elev ated direc t (conj ugat ed) biliru

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3.

4.

5.

6.

bin level Rapi dly risin g total seru m biliru bin unex plain ed by histo ry or phys ical exa mina tion Total seru m biliru bin appr oach ing exch ange level or not resp ondi ng to phot other apy Jaun dice persi sting beyo nd age 3 wee ks Sickappe aring infan t

Differential Considerations Birth history should be obtained to elicit any history of trauma because large, resolving hematomas can be associated with jaundice. Family history should focus on other children or relatives with a history of jaundice or genetic or metabolic disorders and any unexplained infant deaths. Tables 170-1 and 170-2 contain full

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lists of differential considerations for jaundiced children. Infants with direct hyperbilirubinemia represent a special subset of patients. All infants with direct hyperbilirubinemia require admission and an evaluation for the cause of the jaundice based on history and presenting signs and symptoms. This evaluation may include any or all of the following: sepsis evaluation, TORCHS titers (toxoplasmosis, rubella, cytomegalovirus, herpes, syphilis), basic metabolic studies, p 1 -antitrypsin, sweat test for cystic fibrosis, ultrasound, nuclear medicine (HIDA/DISIDA) scan, and liver biopsy. In children, hemolytic anemias, infection, and drugs are the most common causes of jaundice. History should focus on travel; exposures; medications; and associated symptoms, such as fever, malaise, weight loss, and fever. Gentle palpation of the liver is useful to estimate size, firmness, and tenderness and to distinguish hepatomegaly from liver inflammation.

Management Treatment of infants with hyperbilirubinemia is based on the prevention of kernicterus. Guidelines for using phototherapy and exchange transfusion have been recommended by the American Academy of Pediatrics ( Figure 170-1 ).[3] Feeding should be continued as much as possible because it stimulates enterohepatic circulation and decreases bilirubin levels. Unless the infant is severely jaundiced, breast-feeding should be continued and supplemented with formula as needed. Infants who are premature or who have significant comorbidity require treatment at lower levels. Phototherapy is often now readily available on an outpatient basis. A

B

Figure 170-1 A, Guidelines for exchange transfusion in infants 35 or more weeks' gestation. Note that these suggested levels represent a consensus of m ost of the com m ittee but are based on lim ited evidence, and the levels shown are approximations. During birth hospitalization, exchange transfusion is recom m ended if the TSB rises to these levels despite intensive phototherapy. For readm itted infants, if the TSB level is above the exchange level, repeat TSB m easurem ent every 2 to 3 hours and consider exchange if the TSB remains above the levels indicated after intensive phototherapy for 6 hours. ((From Am erican Academ y of Pediatrics Clinical Practice Guidelines: Managem ent of hyperb ilirub inem ia in the newb orn infant 35 or m ore weeks of gestation. Pediatrics 114:305, 2004.))

Disposition In general, infants with bilirubin levels greater than 18 to 20 mg/dL require admission and phototherapy. All infants with direct hyperbilirubinemia require admission and workup.

HYPERTROPHIC PYLORIC STENOSIS Perspective Hypertrophic pyloric stenosis (HPS) is the most common cause of infantile gastrointestinal (GI) obstruction beyond the first month of life. HPS occurs in 1 of every 250 live births.[4] Boys are affected at four times the rate of girls. HPS tends to run in families; however, the exact pattern of inheritance is unclear. There is an incidence rate of 1 in 14 if the father was affected; the rate is even higher if the mother was affected.[4] Whites are affected more often than African Americans, and the disease is rare in Asian Americans.

Principles of Disease Infants are born with a normal pylorus and develop hypertrophy only as time progresses. The exact etiology is unknown. As the pylorus continues to hypertrophy, there is progressive gastric outlet obstruction. As vomiting continues, the infant loses hydrogen and chloride ions through emesis of gastric juices. As this metabolic derangement worsens, the kidney attempts to retain hydrogen ions by substituting potassium,

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resulting in a hypochloremic, hypokalemic, metabolic alkalosis.

Clinical Features Infants classically present at 2 to 6 weeks old with gradually progressive emesis that becomes projectile and remains nonbilious. Infants remain vigorous with a ravenous appetite. They rapidly finish an entire feeding only to regurgitate the entire volume in a projectile fashion. In the later stages of the disease, children may exhibit visible waves of abdominal peristalsis in response to intense contractions against an obstruction. Children in the later stages of disease may exhibit marasmus, protein-calorie malnutrition as a result of impaired nutrient absorption.

Diagnostic Strategies Children may have a palpable pylorus, commonly referred to as an “olive” in the right epigastrium, on abdominal examination. Placing a nasogastric tube and emptying the stomach or placing the infant in the prone position often facilitates palpation. Identification of the classic olive on physical examination is pathognomonic, and no further workup is required. HPS may be confirmed by ultrasound or upper GI series. Ultrasound is probably the diagnostic modality of choice, but both modalities have reported accuracies of greater than 95%. Ultrasound examinations reveal a thickened pylorus, which is diagnostic.[5] The upper GI tract has a characteristic “string sign” that results from the contrast material narrowly passing through the pyloric sphincter. In advanced stages with complete obstruction at the pylorus, plain films may reveal a modified “double-bubble sign,” indicating an enlarged body of the stomach and pylorus ( Figure 170-2 ).

Figure 170-2 Plain radiograph of the abdom en revealing a m odified double-bubble sign as seen in advanced stages of hypertrophic pyloric stenosis, in which there is com plete obstruction at the pylorus. The “double bubbles” in this case represent the enlarged body and pyloric portions of the stom ach. ((Courtesy of Mark A. Hostetler, MD))

Differential Considerations Etiologic possibilities vary depending on whether the course of vomiting has been sudden in onset, gradually progressive, or chronic. Details such as the frequency and volume of emesis also are important because they may have important implications on the severity of disease and the potential risk for dehydration or electrolyte disturbance. In infants, other major diagnoses in the differential include gastroesophageal reflux (GER) and malrotation. The age of the child and the timing of vomiting provide important clues as to the etiology. GER classically begins early in life, usually shortly after birth, and remains relatively constant. Pyloric stenosis does not begin until 2 to 3 weeks of age, then becomes increasingly severe and projectile. Acute obstruction of pyloric stenosis causes sudden-onset vomiting, which is rarely, if ever, bilious. In neonates, bilious vomiting requires careful consideration to rule out the possibility of malrotation with volvulus.[6] Many causes of vomiting do not have a true GI origin, including sepsis, increased intracranial pressure, middle ear disturbances, inborn errors of metabolism, pain, medications, and drug intoxications. Differential considerations for vomiting in children vary by age ( Table 170-3 ). Table 170-3 -- Differential Considerations for Vomiting by Age Infancy Mechanical

Gastroesophageal reflux Malrotation with midgut volvulus Pyloric stenosis Intussusception Incarcerated hernia

Childhood

Adolescence

Constipation Incarcerated hernia

Constipation Incarcerated hernia

Meckel's diverticulum Bowel obstruction

Meckel's diverticulum Bowel obstruction

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Infancy

Inflammatory/infectious

Tracheoesophageal fistula Necrotizing enterocolitis Gastroenteritis Sepsis Meningitis Pneumonia

Genitourinary

Otitis media Urinary tract infection

Central nervous system

Hydrocephalus Intracranial hemorrhage Intracranial tumor

Metabolic

Diabetic ketoacidosis Congenital adrenal hyperplasia Urea cycle defects

Other/atypical

Organic acidurias Amino acidopathies Fatty acid oxidation disorders Occult trauma (abuse) Toxic ingestions Munchausen by proxy

Childhood

Gastritis/gastroenteritis Otitis media Appendicitis Pancreatitis Henoch-Schönlein purpura Biliary tract disease Urinary tract infection

Migraine headache Hydrocephalus Intracranial hemorrhage Intracranial tumor Reye syndrome Diabetic ketoacidosis Urea cycle defects

Adolescence

Gastroenteritis Appendicitis Henoch-Schönlein purpura Pancreatitis Gastritis Biliary tract disease Urinary tract infection Pregnancy Testicular/ovarian torsion Migraine headache Hydrocephalus Intracranial hemorrhage Intracranial tumor Glaucoma Diabetic ketoacidosis

Fatty acid oxidation disorders

Sickle cell Toxic ingestions Occult trauma (abuse) Munchausen by proxy

Sickle cell Toxic ingestions Occult trauma (abuse) Munchausen/Munchause n by proxy

Management Treatment consists of fluid and electrolyte replacement and surgical consultation. Fluid resuscitation should begin with a 20 mL/kg bolus of normal saline, followed by additional boluses as necessary to treat signs of shock. When the patient is stable and shows no signs of shock, 5% dextrose and half-normal saline at 1.5 to 2 times maintenance may be administered. Potassium supplementation is often necessary. HPS is a chronic, progressive disease, not an acute ischemic process. Confirmatory radiographic diagnosis with ultrasound may be done on a semiurgent basis as symptoms warrant. Pediatric surgical consultation is mandatory, although usually not emergent. The definitive corrective surgical procedure is the Ramstedt pyloromyotomy and has an excellent track record of safety.[7] More recently, laparoscopic pyloromyotomy has gained increasing acceptance as being safe and effective.[8] Mortality is rare.

Disposition Most children may be admitted to the hospital for rehydration and correction of electrolyte abnormalities, with imaging and surgical consultation done on a semielective basis.

MALROTATION WITH MIDGUT VOLVULUS Perspective

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Malrotation occurs in 1 in 500 live births and has a male predominance of at least 2:1.[9] Of infants with malrotation, approximately 75% eventually develop volvulus, and 75% of these infants present within the first month of life. Ninety percent of patients present within the first year of life, although cases of adult midgut volvulus have been reported.[9] Bilious emesis is the hallmark presentation and occurs in greater than 75% of cases.[] Malrotation with volvulus has a mortality rate of 3% to 15%.[9]

Principles of Disease During embryologic development, the GI tract rotates around the superior mesenteric artery. As it completes the rotation, the duodenum forms a C-loop and is fixed to the retroperitoneum in the left upper quadrant at the ligament of Treitz. The cecum becomes similarly fixed in the right lower quadrant. The duodenum and cecum normally come to reside widely separated and loosely connected by a broad-based mesentery. They are fixed firmly in position by peritoneal attachments called Ladd's bands. In cases of malrotation, the duodenum and the cecum do not rotate completely but end up in close proximity to each other suspended in the midgut region by their vascular attachment containing the superior mesenteric artery. This unusually close proximity of the intervening mesentery results in a short stalk of mesentery that easily twists on itself, resulting in obstruction of the distal duodenum and compression of the superior mesenteric artery. Vascular compression results in ischemia of the bowel and, if not rapidly reversed, necrosis of the bowel wall in 1 to 2 hours.[] Twisting of the pedicle also results in varying degrees of obstruction secondary to Ladd's bands that are malpositioned and straddling the duodenum. Bilious emesis is the hallmark presentation and occurs as a result of severe obstruction. Any pigmented staining of the vomitus suggests the presence of bile. When initially produced, bile is bright yellow and turns green only with time and oxidative exposures. Differential coloring of bile-stained emesis, yellow versus green, is not predictive of surgical pathology.

Clinical Features Infants classically present with sudden-onset bilious emesis and abdominal distention.[13] The obstruction may be relatively high, however; consequently, a distended abdomen may not always be present. Infants usually appear quite ill and may present in shock.[] Infants also may present with a history of intermittent, relatively mild episodes of emesis that suddenly become more intense. Although bilious emesis in a neonate always suggests the possibility of acute obstruction and volvulus, children may present with nonspecific signs, such as abdominal distention or ill appearance.[]

Diagnostic Strategies Diagnostic strategies may include obtaining a plain film of the abdomen, an upper GI series, or a computed tomography (CT) scan of the abdomen. Findings on plain abdominal films may include air-fluid levels suggesting obstruction, dilated loops overlying the liver, and a paucity of small bowel gas distally ( Figure 170-3 ).[12] In addition, a double-bubble sign may be present, representing a dilated stomach and obstructed proximal duodenum. Three different conditions are associated with seeing a double-bubble sign on plain abdominal films. The classic double bubble represents a dilated stomach and obstructed proximal duodenum and is seen in duodenal atresia and malrotation with midgut volvulus. Duodenal atresia is limited to the newborn nursery and presents within 24 hours of life. Malrotation with midgut volvulus typically presents with bilious vomiting within the first month of life. The modified double-bubble sign seen with HPS represents a dilated body of the stomach and pylorus and is associated with nonbilious emesis.

Figure 170-3 Upright abdom inal radiograph of an infant with bilious vom iting illustrates dilated loops of sm all bowel and a paucity of bowel gas distally consistent with proxim al obstruction secondary to m alrotation with m idgut volvulus. ((Courtesy of Mark A. Hostetler, MD))

The diagnostic procedure of choice to determine midgut volvulus is the upper GI series, which reveals abnormal position of the duodenal C-loop ( Figure 170-4 ) and small bowel with a characteristic corkscrew appearance ( Figure 170-5 ).[12] An ultrasound scan may be obtained because of abdominal pain and may

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reveal abnormal positioning of the duodenal C-loop and superior mesenteric artery. The place of ultrasound in the evaluation of children with midgut volvulus has yet to be determined, however.[]

Figure 170-4 This is the infant from Figure 170-2. The upper gastrointestinal film reveals abnorm al positioning of the duodenal C-loop to the right of the spinal colum n consistent with m alrotation. ((Courtesy of Mark A. Hostetler, MD))

Figure 170-5 Another spot film from the upper gastrointestinal series of the infant in Figure 170-2. This radiograph shows the characteristic corkscrew appearance seen on sm all bowel follow-through in patients with m alrotation. ((Courtesy of Mark A. Hostetler, MD))

Differential Considerations Vomiting in childhood is common and occurs across a wide spectrum of illnesses (see Table 170-3 ). Causes vary depending on the age of the child and whether the course of vomiting has been sudden in onset, gradually progressive, or chronic. GER classically begins early in life, usually shortly after birth, and remains relatively constant. Pyloric stenosis does not begin until 2 to 3 weeks of age, then becomes increasingly severe and projectile. Acute obstruction causes sudden-onset vomiting, which may be bilious. In a neonate, bilious vomiting requires careful consideration to rule out the possibility of malrotation with volvulus.[] Necrotizing enterocolitis (NEC) is another consideration because this life-threatening disease also presents with obstructive symptoms, including bilious emesis and abdominal distention. Although malrotation usually exhibits a paucity of small bowel air, NEC has diffusely dilated loops of small bowel. In addition, the presence of pneumatosis intestinalis is diagnostic of NEC and not present in cases of malrotation.

Management Infants with sudden onset of bilious emesis who appear ill or have a distended abdomen require emergency consultation with a pediatric surgeon.[16] Intravenous access should be obtained and laboratory studies sent for CBC, electrolytes, and liver function tests. Repeated fluid boluses of normal saline, 20 mL/kg, are necessary until adequate circulation has been obtained. A finger-stick blood glucose and cultures of blood and urine should be obtained. A nasogastric or orogastric tube should be placed to decompress the abdomen. After consultation with a pediatric surgeon, an upper GI series may be needed emergently. Ill-appearing infants require broad-spectrum, triple-antibiotic coverage with ampicillin, gentamicin, and either clindamycin or metronidazole. Time is of the essence in the evaluation and operative management of these patients. Rapid pediatric surgical consultation should be obtained in any neonate or infant with bilious vomiting, especially infants who are ill appearing. In contrast with HPS, in which surgery does not need to be immediate, operative management must occur quickly to save the bowel from necrosis.

Disposition Patients suspected to have malrotation require definitive imaging and an immediate surgical evaluation. If the diagnosis is confirmed or equivocal, surgical management and admission are required.

NECROTIZING ENTEROCOLITIS Perspective

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NEC is the most common GI emergency occurring in neonates, affecting 2000 to 4000 infants in the United States every year.[17] NEC is also the most common cause of intestinal perforation occurring during the newborn period.[17] Considering that most of the infants are premature and develop NEC in the neonatal intensive care unit, NEC is usually not considered an emergency department disease. Many of these infants may be discharged relatively early, however, because they are “feeding and growing” and present in the first month of life. Ten percent of infants with NEC are full-term births.[18] Development of NEC is related closely to gestational age. Infants of 24 to 28 weeks' gestation develop NEC within 2 to 4 weeks of life.[19] Infants of 29 to 32 weeks' gestation develop NEC within 1 to 3 weeks of life. More mature, or full-term, infants tend to develop NEC in the first week of life.[17] Children who survive NEC may develop complications, including strictures (10% to 20%), fistulae, and short gut syndrome.

Principles of Disease The exact mechanism is unclear, but seems to be multifactorial. Proposed risk factors include prematurity, aggressive enteral feedings, birth-related hypoxic-ischemic insults, and infectious causes. Prematurity is the most common and universally accepted risk factor and occurs in 90% of all affected infants.[] Rapid advancement of feedings also has been associated with increased rates of NEC.[20] Infection has been implicated as an important causative mechanism.[21] Evidence suggests that hypoxic-ischemic insults are not an independent risk factor for the development of NEC.[18] The primary pathologic event may be inflammation or injury to the intestinal wall, which begins in the mucosa, then extends transmurally. The distal ileum and proximal colon are more commonly affected, and the involvement may be continuous or patchy.[22]

Clinical Features Infants with NEC present with feeding intolerance and emesis. Emesis may be either nonbilious or bilious. Occasionally, individual loops of bowel become distended with air and are palpable on abdominal examination. In the more severe stages of the disease, infants may be extremely ill-appearing and have hematemesis, hematochezia, and shock. NEC commonly is placed into one of three clinical stages based on criteria developed by Bell.[23] Stage I represents early or suspected NEC based on feeding intolerance, vomiting, or ileus. Stage II represents definite NEC as proved by abdominal radiographs showing intestinal dilation and pneumatosis intestinalis. Stage III represents advanced disease and is associated with perforation. Infants in this stage are acutely ill with marked abdominal distention, metabolic acidosis, disseminated intravascular coagulation, and shock.

Diagnostic Strategies Dilated loops of bowel are a common but nonspecific finding in stage I. Another early and more specific radiographic sign is the loss of a normal symmetric gas pattern and replacement with an asymmetric pattern of bowel gas that has varying degrees of dilation. Intramural air (pneumatosis intestinalis) is specific for NEC and is present in stage II ( Figure 170-6 ).[23] Pneumatosis is present in 75% of patients with NEC.[18 ] Air also may be seen within the biliary tract (portal venous gas) or occasionally in the gastric wall (pneumatosis gastralis) (see Figure 170-5 ). Portal venous gas is present in 10% to 30% of cases.[18] Ultrasonography and barium enema, which have been described as an adjunct to diagnostic imaging of patients suspected to have NEC, are rarely helpful in the emergency department. No individual laboratory features are diagnostic or specific for NEC.

Figure 170-6 Plain radiograph of an infant with necrotizing enterocolitis. Shorter arrows indicate air within the wall of the sm all bowel and gastric m ucosa (pneum atosis intestinalis and gastralis). Curved arrows indicate air in the biliary tree (portal venous gas). ((Courtesy of Mark A. Hostetler, MD))

Differential Considerations

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Etiologic possibilities vary depending on whether the emesis is bilious and whether the course of vomiting has been sudden in onset, gradually progressive, or chronic (see Table 170-3 ). GER classically begins early in life, usually shortly after birth, and remains relatively constant. Pyloric stenosis does not begin until 2 to 3 weeks of age, then becomes increasingly severe and projectile. In neonates, bilious vomiting requires careful consideration to rule out the possibility of malrotation with volvulus. Malrotation usually has a paucity of small bowel air, whereas NEC usually has diffusely dilated loops of small bowel. In addition, the presence of pneumatosis is diagnostic of NEC and not present in cases of malrotation.

Management Patients suspected to have NEC should be kept nothing by mouth (NPO) and have their stomach and small bowel decompressed with either an orogastric or a nasogastric tube. These patients frequently appear quite ill and may have periods of apnea or significant respiratory distress. The airway should be secured as indicated. Intravenous access should be obtained and routine laboratory studies sent for CBC, electrolytes, type and screen, and coagulation studies (prothrombin time/partial thromboplastin time [PT/PTT]). A bedside blood glucose value should be obtained. Cultures of the blood and urine should be obtained. Careful attention should be given to managing fluids and electrolytes because considerable third spacing of fluids may occur. Repeated fluid boluses at 20 mL/kg of normal saline should be administered until adequate circulation is obtained. These boluses may be augmented with dopamine or epinephrine drips as necessary for patients in refractory shock when euvolemia has been achieved. Fluids should be continued with 5% dextrose in water and half-normal saline at a minimum of 1.5 to 2 times maintenance. Ill-appearing infants require broad-spectrum, triple-antibiotic coverage with ampicillin, gentamicin, and either clindamycin or metronidazole. Emergent consultation should be obtained from a pediatric surgeon. Patients with evidence of perforation, peritonitis, or gangrenous bowel require surgical intervention. Only one half to three quarters of patients with perforation have free air detectable on x-ray.[23]

Disposition Ill-appearing children suspected to have NEC require admission to the hospital and pediatric surgical consultation.

GASTROESOPHAGEAL REFLUX Perspective GER is one of the most common causes of vomiting during infancy and refers to the regurgitation of stomach contents into the esophagus.

Principles of Disease GER occurs as a result of an incompetent lower esophageal sphincter. Chronic reflux of gastric contents into the esophagus may result in esophagitis, aspiration, and, if severe, failure to thrive.

Clinical Features Symptoms occur along a wide spectrum of disease, from occasional episodes of spitting up to severe, persistent vomiting and failure to thrive. GER generally responds to conservative measures and resolves with age. GER may be associated with stereotyped opisthotonic movements (Sandifer's syndrome). In Sandifer's syndrome, children exhibit extension and stiffening of the arms and legs, extension of the head, and often a shrill or guttural cry. It may be associated with a brief period of apnea and pallor as formula is refluxed into the esophagus. Sandifer's syndrome occurs most commonly shortly after feeding and usually is not associated with cyanosis.

Diagnostic Strategies In the emergency department, the diagnosis of GER is made based on a careful history and physical examination. There are a variety of ways in which to diagnose GER, including esophageal pH probes checking for reflux of acid, barium swallow, and direct visualization via endoscopy.

Differential Considerations Children with GER exhibit nonbilious emesis that begins shortly after birth and is relatively constant over time. There is usually not a sudden starting or ending point as would be suggested by an acute obstruction. Vomiting is usually neither gradually progressive nor projectile as seen with pyloric stenosis. Most children with milder severities of GER continue to gain weight.

Management Most infants respond to conservative measures, such as smaller feedings, frequent burpings, thickening of

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formula with cereal, and maintaining a semiupright position for 45 minutes to 1 hour after feeding. Pharmacologic regimens are reserved for more severe cases. Weight loss is an important historical feature and necessitates referral for evaluation. Children exhibiting failure to thrive or esophagitis are often placed on medical management with ranitidine and metoclopramide. Ranitidine, a histamine blocker, reduces gastric acid secretion. Metoclopramide increases lower esophageal tone, reduces pyloric sphincter tone, and increases gastric motility. Patients not responding to medical management occasionally require surgical intervention with a Nissen fundoplication, which involves wrapping a portion of the stomach around the esophagus.

Disposition Most children can be discharged home safely with conservative measures. Children with failure to thrive should be referred to a pediatrician or pediatric gastroenterologist for consideration of pharmacologic management. Children with dehydration and children with questionable diagnoses yet to be excluded may benefit from admission and further evaluation.

INTUSSUSCEPTION Perspective Intussusception is the most common cause of intestinal obstruction in children younger than 2 years old and occurs most commonly in infants 5 to 12 months old.[] There is an estimated incidence of 1 per 2000 children younger than age 15 years with a male predominance.[23] Siblings of affected children have a relative risk 15 to 20 times higher than the general population. Mortality for untreated intussusception is high.

Principles of Disease The exact etiology of intussusception is unclear, but the most prevalent theory relates to a lead point that causes telescoping of one segment of intestine into another.[23] As the process continues and intensifies, edema develops and obstructs venous return, resulting in ischemia of the bowel wall. As ischemia of the bowel wall continues, peritoneal irritation ensues, and perforation may occur. In younger children, lead points are most often the result of enlarged Peyer's patches secondary to a recent viral infection. In children older than 5 years, an underlying lesion is found in more than 75% of cases; lesions include Henoch-Schönlein purpura (HSP) vasculitis, Meckel's diverticulum, lymphoma, polyps, postsurgical scars, celiac disease, and cystic fibrosis.[] Intussusceptions may occur at any point along the GI tract. Ileocolic intussusceptions are most common. Ileoileal intussusceptions may occur in children with HSP.

Clinical Features The classic triad of symptoms in intussusception is abdominal pain, vomiting, and bloody stools. All three symptoms occur in less than one third of patients, however. Three quarters of patients with intussusception have two findings, and 13% have either none or only one.[28] In a typical presentation, the child presents with cyclical episodes of severe abdominal pain. The pain typically lasts 10 to 15 minutes and has a periodicity of 15 to 30 minutes. During the painful episodes, the child is inconsolable, often described as drawing the legs up to the abdomen and screaming in pain. Children occasionally present without a history of pain and instead present with profound lethargy. Children may have vomiting or diarrhea associated with their presentation. Blood may be present in either the stool or the emesis. Diarrhea containing mucus and blood constitutes the classic “currant jelly” stool most often associated with intussusception, although in actuality it occurs relatively infrequently. Children often have had a viral illness recently. Palpation of the abdomen may reveal a sausage-like mass in the right upper quadrant representing the actual intussusception and an empty space in the right lower quadrant representing the movement of the cecum out of its normal position. This is called Dance's sign and is considered pathognomonic for intussusception. Its occurrence is relatively uncommon, however. Intussusception usually is not associated with a high fever; however, low-grade fevers may occur.

Diagnostic Strategies Initial screening films should be obtained with a minimum of two views of the abdomen. Attention should be focused on visualizing the entire colon and in particular the cecum. Films also should be examined for evidence of a soft tissue mass or mass effect, obstruction, and free air ( Figure 170-7 ). Normal radiographs of the abdomen revealing complete visualization of the entire colon, including the cecum, essentially exclude the possibility of intussusception. Indeterminate or nonspecific films in which the entire colon cannot be visualized do not rule out intussusception and require additional imaging. Ultrasound is the least invasive and most commonly used modality for visualizing intussusceptions.[29] Ileocolic intussusceptions are most

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common and easily detected by ultrasound, even in inexperienced hands.[30] The exception may be in patients with HSP and severe abdominal pain. In HSP, ileoileal intussusceptions may occur, and the imaging modality of choice should be a CT scan. Barium enemas historically have been the gold standard and can be diagnostic and therapeutic. Contrast enemas reveal a sharp cutoff at the point where the intussusceptum meets the contrast material ( Figure 170-8 ). Air contrast enemas are equally efficacious, have success rates averaging greater than 60%, and are preferred by some physicians over barium contrast studies.[] Both enemas require readily available backup by a pediatric surgeon in the event of failure to reduce or perforation. Before sending the patient to radiology, the patient should have intravenous access obtained, at least one 20 mL/kg bolus of normal saline, and parenteral pain relief.

Figure 170-7 Plain radiograph of a child with cram py abdom inal pain and vom iting later confirm ed to have intussusception. Findings include a poorly defined soft tissue density in the right upper quadrant, obscuration of the liver edge, and focally dilated loops of sm all bowel consistent with an acute obstructive process (intussusception).

Figure 170-8 Contrast enem a of a child with intussusception shows a sharp cutoff where the contrast m aterial m eets the intussusceptum and the acute obstruction.

Differential Considerations Differential considerations for abdominal pain in children by age are listed in Table 170-4 . Slow, progressive onset of pain is more likely associated with appendicitis, constipation, or pancreatitis. Children with peritoneal irritation invariably lie still, often on their sides with their knees bent, and refrain from all extraneous movement. Sudden onset of severe pain is associated most often with acute obstruction or vascular occlusion as seen with intussusception, volvulus, or torsion. Children with intussusception have severe colicky pain and often rock back and forth, frequently moaning or crying with pain. Children with ischemic pain exhibit symptoms out of proportion to their examination. They may appear diaphoretic, clammy, or pale and complain of excruciating abdominal pain, although having only mild tenderness to palpation and no localizing findings. Table 170-4 -- Differential Considerations for Abdominal Pain by Age Infancy Mechanical

Inflammatory/infectious

Malrotation with midgut volvulus Intussusception Incarcerated hernia Meckel's diverticulum Hirschsprung's disease Necrotizing enterocolitis

Childhood

Adolescence

Constipation

Constipation

Incarcerated hernia Meckel's diverticulum Bowel obstruction

Incarcerated hernia Meckel's diverticulum Bowel obstruction

Gastroenteritis Appendicitis Henoch-Schönlein purpura Pancreatitis

Gastroenteritis Appendicitis Henoch-Schönlein purpura Pancreatitis

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Infancy

Genitourinary

Urinary tract infection

Other/atypical

Colic Occult trauma (abuse) Toxic ingestions Munchausen by proxy

Childhood Gastritis Biliary tract disease Urinary tract infection

Pneumonia Diabetic ketoacidosis Sickle cell Toxic ingestions Occult trauma (abuse) Munchausen by proxy

Adolescence Gastritis Biliary tract disease Urinary tract infection Nephroureterolithiasis Pregnancy, ectopic Pelvic inflammatory disease Testicular/ovarian torsion Pneumonia Diabetic ketoacidosis Sickle cell Toxic ingestions Occult trauma (abuse) Munchausen/Munchause n by proxy

Management Patients require intravenous access and screening CBC and electrolytes. Intravenous fluids are given in boluses of 20 mL/kg of normal saline until adequate vascular volume is achieved. Children should be maintained NPO. Nasogastric tube decompression may be necessary if there is evidence of significant gaseous distention. Prompt surgical consultation is required. Ill-appearing or febrile children require broad-spectrum, triple-antibiotic coverage with ampicillin, gentamicin, and either clindamycin or metronidazole. Diagnostic and therapeutic interventions depend on location and resources available. Patients may undergo an initial ultrasound or go straight to either air or hydrostatic barium enema. Surgical intervention is required if the reduction is unsuccessful or if perforation occurs. Intussusception may recur in 7% to 10% of radiologic reductions and 2% to 5% of surgical reductions, usually within 24 hours. Admission for observation usually is recommended for all patients after reduction.[31]

Disposition Children with suspected intussusception require definitive imaging with ultrasound. Children with documented intussusception require reduction with either enema or surgery. Admission is recommended for all patients after reduction.

HIRSCHSPRUNG'S DISEASE Perspective Hirschsprung's disease accounts for approximately 20% of cases of partial intestinal obstruction in early infancy. Hirschsprung's disease occurs at a rate of 1 in 5000 live births and is four to five times more common in boys. It is usually sporadic, but may be associated with Down syndrome or a variety of other anomalies of the GI, genitourinary, or nervous systems.[34]

Principles of Disease Hirschsprung's disease represents congenital aganglionosis of the colon and is characterized by an absence of ganglion cells in the myenteric plexus of the distal colon.[34] The anus is invariably involved with the disease, usually extending proximally 4 to 25 cm. Absence of colonic ganglion cells interferes with that segment's ability to relax, creating a functional obstruction. Stool accumulates proximal to the level of obstruction and produces dilation of the colon, the so-called megacolon.

Clinical Features Neonates with Hirschsprung's disease often present in the nursery with failure to pass meconium. Infants may present with a history of constipation and obstipation. Vomiting, irritability, and abdominal distention may occur. Symptoms may be subtle and involve a history of chronic constipation and poor weight gain or failure to thrive. Hirschsprung's disease usually is diagnosed in infancy; however, there is a spectrum of disease, and presentations may occur later in life. Children who are ill appearing with fever should be evaluated for

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enterocolitis and toxic megacolon. Enterocolitis is characterized by abdominal distention, bloody stools, fever, and an elevated white blood cell count.

Diagnostic Strategies Plain films of the abdomen may reveal evidence of fecal impaction with proximal obstruction, air and fluid levels, and dilated colon. A barium enema revealing a narrowed aganglionic segment with proximal dilation is highly suggestive of Hirschsprung's disease.[] The diagnosis is confirmed by biopsy or manometry.

Differential Considerations Constipation is one of the most common causes of abdominal pain and vomiting in children.[] Children in the process of potty training occasionally become pathologic in their ability to delay defecation. Pathologic causes of constipation are uncommon. In addition to Hirschsprung's disease, considerations include cystic fibrosis, infantile botulism, and hypothyroidism. An acquired variant of the disease also may occur in which other factors produce similar dilated colonic findings, resulting in acquired megacolon. Risk factors include anal fissures; fecal impaction; toilet training issues; and neuromuscular dysfunction secondary to neurologic disease, drugs, or metabolic causes. The exact definition of constipation is elusive because it varies with age and diet. Infants during the first few months of life may have stool frequencies that vary from one per feeding to one every other day, with breast-fed infants having more frequent stools than formula-fed infants. Frequency continues to decrease with age such that during the first year of life infants may average two to three stools per day, and from 1 to 5 years of age, one or two per day. Defecation occurs as a combination of physiologic, behavioral, and psychological factors. Relaxation of the external sphincter required for defecation is under voluntary control, whereas relaxation of the internal sphincter is involuntary. Children with a history of unpleasant or painful experiences associated with defecation may contract the external sphincter voluntarily in an effort to delay defecation for as long as possible. Accumulation of stool over time causes the rectum to dilate and decrease its propulsive activity, resulting in an increasing capacity for stool and chronic constipation. Acute episodes may occur as a result of dietary changes, travel, lack of normal exercise, or stress.

Management Initial management is focused on ensuring adequate fluid and electrolyte status. Abdominal films should be obtained. If there is acute obstruction as evidenced by marked dilation, decompression may be necessary. Decompression usually can be accomplished easily with a rectal tube. Children who are ill appearing with fever should be evaluated for enterocolitis and toxic megacolon. Enterocolitis is characterized by abdominal distention, bloody stools, fever, and an elevated white blood cell count. Patients with enterocolitis require broad-spectrum, triple-antibiotic coverage with ampicillin, gentamicin, and either clindamycin or metronidazole. Urgent consultation should be made with a pediatric surgeon. Definitive therapy is surgical with resection of the aganglionic segments. Acquired megacolon is managed by decompressing the colon and addressing the underlying problems. Management of constipation requires three considerations: cleanout, maintenance, and behavior modification. Acute constipation is easier to manage because there are fewer functional problems. The acute management of constipation is usually relatively easy and requires primarily the cleaning out of stool. Most recommend an approach that includes stool softeners or laxatives from above and suppositories or enemas from below. In milder cases, only the administration of enemas is necessary to soften feces and stimulate defecation. Tap water, Castile soap, and oil enemas all are generally equally efficacious. Maintenance includes keeping the stool soft for as long as necessary using stool softeners or laxatives. Dietary modifications include increasing fiber and water in the diet and avoiding foods that may be constipating. Management of chronic constipation is more difficult and usually requires a multidisciplinary approach with attention to behavior modification. Children with underlying pathology, such as cystic fibrosis, may benefit from more intense measures, such as large volumes of polyethylene glycol (GoLYTELY).

Disposition Unless children are ill appearing, most can be managed safely as outpatients.

MECKEL'S DIVERTICULUM Perspective Meckel's diverticulum is the most common congenital malformation of the small intestine and follows the rule of 2s. It occurs in 2% of the population, and only 2% of affected patients ever become symptomatic.[37] Approximately half of all patients with the condition become symptomatic by age 2 years, and most present by age 20.[37] The diverticulum is 2 cm wide, 2 cm long, and usually located within 2 feet of the ileocecal

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valve.

Principles of Disease Diverticula are remnants of the omphalomesenteric duct and contain bowel wall with 60% containing heterotopic tissue.[38] This tissue most commonly involves gastric mucosa, but other types include pancreatic, duodenal, and endometrial tissue.[] Bleeding occurs when acid secretion from ectopic gastric mucosa causes ulceration and erosion.

Clinical Features Patients are classically boys younger than age 5 who present with an acute onset of massive, painless rectal bleeding. Some children may have some complaints of abdominal cramping. The bleeding often is described as brick red in color. Complications may include intussusception, obstruction, perforation, and peritonitis.

Diagnostic Strategies A technetium scan, also known as a Meckel's scan, is the diagnostic modality of choice and has an accuracy of 90% when ectopic gastric mucosa is present.[39] Administering pentagastrin, cimetidine, or glucagon may increase the sensitivity of the test.[39] Definitive diagnosis is confirmed by laparoscopy or laparotomy.

Differential Considerations GI bleeding is uncommon in childhood. The first step in evaluating a child with suspected GI bleeding is to determine whether the substance is actually blood. Children commonly eat or drink substances containing dyes that lead to factitious changes in the stool's color. A simple Hemoccult test of the stool or Gastroccult test of the emesis can document the presence of hemoglobin. False-positive results may occur with red meat and iodine. Patients consuming products with bismuth (Pepto-Bismol), iron, and spinach may have black stools falsely appearing as melanotic; they test Hemoccult negative. After it has been determined that the substance is blood, the second step is to determine its origin. The location of bleeding is often difficult to determine, but may be theorized based on the appearance of the blood. Hematemesis implies bleeding proximal to the ligament of Treitz. Blood exposed to gastric acids for any period of time develops the classic coffee-ground appearance. Bright red upper GI bleeding implies either more proximal bleeding, such as varices or esophagitis, or brisk gastric or duodenal bleeding. Bleeding that originates beyond the ligament of Treitz but proximal to the ileocecal valve results in melena. Hematochezia, visibly red to maroon in appearance, implies bleeding from the descending colon. Distal lesions, such as fissures or hemorrhoids, result in bright red blood. Endoscopic examination has the highest rate of determining the location of bleeding. Barium contrast studies of the upper and lower GI tract sometimes are helpful; however, nuclear scans (Meckel's scan) are the procedure of choice in detecting Meckel's diverticulum. In neonates, the most common cause of bleeding is idiopathic. Careful examination of the rectum should be performed because the most identifiable cause for bleeding is a fissure or excoriation of the perirectal area. In young neonates, an Apt test may be performed to determine if the blood is maternal or fetal. One percent sodium hydroxide is added to the bloody stool. Fetal hemoglo-bin resists oxidation and remains pinkish red, whereas maternal hemoglobin changes to a dark brown color. Another common cause for GI bleeding in infancy is milk protein allergy. Affected children typically are younger than 6 months old with a history of sudden-onset mucoid, blood-streaked stools. Children otherwise appear well. Although the most well-described occurrence is with milk protein, GI bleeding may occur with any protein and has been described in relation to soybean-based products. Children with persistent perianal excoriations and fissures refractory to standard emollients may be infected with group A streptococci and may benefit by treatment with an oral penicillin. Table 170-5 lists the differential considerations for GI bleeding in children by age. Table 170-5 -- Differential Considerations for Gastrointestinal Bleeding by Age Infancy Childhood Adolescence Factitious

Swallowed maternal blood Dyes in foods/beverages Dyes in foods/beverages Swallowed nasopharyngeal blood Vaginal origin Vaginal origin

Dyes in foods/beverages Swallowed nasopharyngeal blood Vaginal origin

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Infancy Upper GI

Lower GI

Urinary origin Necrotizing enterocolitis Intussusception Gastroenteritis Gastritis Esophagitis/varices (rare) Necrotizing enterocolitis Intussusception Gastroenteritis Milk allergy Vascular malformation

Childhood Urinary origin Esophagitis Gastroenteritis Gastritis Peptic ulcer disease Esophageal varices Gastroenteritis Intussusception Meckel's diverticulum Inflammatory bowel disease Vascular malformation Henoch-Schönlein purpura Hemolytic uremic syndrome Colitis

Rectal

Rectal fissure

Rectal fissure

Other/atypical

Bleeding dyscrasia Occult trauma (abuse) Toxic ingestions Munchausen by proxy

Bleeding dyscrasia Toxic ingestions Occult trauma (abuse) Munchausen by proxy

Adolescence Urinary origin Esophagitis Gastroenteritis Gastritis Peptic ulcer disease Esophageal varices Gastroenteritis Intussusception Meckel's diverticulum Inflammatory bowel disease Vascular malformation Henoch-Schönlein purpura Hemolytic uremic syndrome Polyps Colitis Rectal fissure Hemorrhoids Trauma Bleeding dyscrasia Toxic ingestions Occult trauma (abuse) Munchausen/Munchause n by proxy

GI, gastrointestinal.

Management Management of GI bleeding begins with assessing and ensuring adequate circulatory status. Screening laboratory studies should include a CBC, coagulation studies (PT/PTT), and a type and screen. Two views of the abdomen should be obtained to rule out obstruction or perforation. A technetium scan is the imaging modality of choice to evaluate for Meckel's diverticulum. Consultation with a pediatric surgeon should be obtained.

Disposition Children with suspected Meckel's diverticulum should undergo a Meckel's scan. Children with minor bleeding and normal screening laboratory studies may be followed closely as outpatients. Children with more active bleeding should be admitted and followed by either a pediatric surgeon or a pediatric gastroenterologist.

HENOCH-SCHÖNLEIN PURPURA Perspective HSP, also known as anaphylactoid purpura, is a systemic vasculitis commonly associated with abdominal pain and rash. It is most common in children age 4 to 11 years, but also may occur in adults. HSP occurs most commonly in the spring after a viral upper respiratory infection. It also has been associated with insect stings and drugs.[41]

Principles of Disease HSP is a hypersensitivity vasculitis with immune complex deposition with immunoglobulin A mainly affecting

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the arterioles and capillaries. Although it is most well known for its characteristic petechial-to-purpuric rash, HSP is a systemic vasculitis and may affect any blood vessel. Less common manifestations occur when the disease is more severe or widespread.

Clinical Features Symptoms include abdominal pain, nausea, vomiting, and diarrhea. Patients most often are diagnosed clinically based on the appearance of a classic rash, abdominal pain, microscopic hematuria, and mild arthralgias. The classic rash is palpable purpura located on the buttocks and lower extremities ( Figure 170-9 ). Seventy percent of patients with HSP have GI complaints. Microscopic hematuria occurs in 50%.[42] Intussusception may occur and may be atypical in that ileoileal intussusception is more common than the ileocolic intussusception that normally occurs. The syndrome is often relapsing and remitting over several weeks and may be associated with arthralgias. HSP may have associated nervous system involvement, although it is uncommon in children.[43]

Figure 170-9 Henoch-Schönlein purpura in a 7-year-old child. Note typical red-purple rash in the lower extrem ities. ((Courtesy of Marianne Gausche-Hill, MD.))

Diagnostic Strategies Patients most often are diagnosed clinically based on the appearance of a classic rash, abdominal pain, microscopic hematuria, and mild arthralgias. Screening studies should include a CBC with differential and platelets, urinalysis, blood culture, and sedimentation rate. Children with severe abdominal pain require CT to rule out ileoileal intussusception.

Differential Considerations The most important entity in the differential diagnosis for this type of a rash is meningococcemia, in which the patient has a fever and is toxic appearing often with an abnormally elevated white blood cell count and leftward shift. The clinician must ensure that meningococcemia is excluded from the differential diagnosis because the condition is life-threatening and requires an entirely different management with intravenous antibiotics. The classic triad of palpable purpura, abdominal pain, and hematuria in an otherwise well-appearing child virtually ensures the diagnosis. Erythema nodosum occasionally is confused with the rash of HSP; however, in erythema nodosum the rash is described most often as subcutaneous purplish red nodules with the appearance of a bruise located on the extensor surfaces of the distal extremities. Erythema nodosum usually involves only the shins, but in more severe cases also may involve the forearms, hands, and feet.

Management Most children with HSP can be managed with close follow-up and require no treatment other than symptomatic. Patients with severe abdominal pain should be suspected of having intussusception and have imaging done with a CT scan because ileoileal intussusception may occur and is not detected easily by ultrasound. Management with steroids is controversial. Steroids, 1 mg/kg/day (maximum 60 mg), are reserved for patients on the more severe end of the spectrum with abdominal pain, hematuria, or arthralgias.

Disposition Indications for admission include uncertain diagnosis to exclude the possibility of meningococcemia, severe abdominal pain, or vomiting. Most patients can be managed safely with close outpatient follow-up.

INFLAMMATORY BOWEL DISEASE Perspective The two major entities included within inflammatory bowel disease (IBD) are Crohn's disease and ulcerative colitis. Approximately 20% of patients present before age 20.[44] Most patients do not present until

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adolescence, although childhood presentations occur. IBD is rare in children younger than age 1 year.[45]

Principles of Disease Ulcerative colitis is an inflammatory disease primarily involving the mucosa and submucosa of the rectum and distal colon. Crohn's disease is a transmural inflammatory disease that may involve any portion of the intestinal tract. The singularly most common area of involvement is distal ileum; however, multiple segments in different areas may be involved. Chronic inflammation may result in the formation of abscess, fistula, and stricture.

Clinical Features Although patients experiencing complications frequently present to the emergency department, the diagnosis is rarely made there. More commonly, children with known disease present in the midst of a flare, usually with bloody diarrhea and abdominal pain. Extraintestinal manifestations also occur and include fever, anemia, oral ulcerations, erythema nodosum, pyoderma gangrenosum, uveitis, liver dysfunction, and failure to thrive.[45] Some of these manifestations may even occur before the child has had any GI symptoms. The most feared complication is toxic megacolon, which classically presents with abdominal pain, fever, and bloody diarrhea.

Diagnostic Strategies Flares are diagnosed by the presence of increased frequency of diarrheal or bloody stools and abdominal pain. Patients who are ill appearing require plain films of the abdomen to rule out toxic megacolon. Patients with toxic megacolon usually have a fever, appear volume depleted, and have significant abdominal tenderness. X-rays reveal dilation of the trans-verse colon greater than 6 to 7 cm in diameter. Free air also should be looked for because perforation may occur. Screening laboratory studies should be obtained to evaluate for hematologic, fluid, and electrolyte abnormalities and include a CBC with differential and platelets, type and screen, coagulation studies (PT/PTT), and electrolytes.

Differential Considerations There are a wide number of differential considerations for abdominal pain and GI bleeding (see Tables 170-4 and 170-5 ). Gastroenteritis is the most common consideration. Children with their first episode are much more likely to be misdiagnosed as having an acute gastroenteritis. Children outside of the usual age of presentation also are more likely to be misdiagnosed as having gastroenteritis. Children with recurrent symptoms or a family history of IBD should be referred to a pediatric gastroenterologist for further evaluation.

Management Steroids are the mainstay of treatment for acute exacerbations. Prednisone at a dose of 1 mg/kg/day (maximum 60 mg/day) usually is recommended and should be provided in consultation with a pediatric GI specialist. Other agents commonly used include sulfasalazine, azathioprine, and a host of other immunosuppres-sive agents. Management begins with attention to volume status and resuscitation with boluses of 20 mL/kg of normal saline until the volume status is adequate. Patients with suspected toxic megacolon require intravenous broad-spectrum triple antibiotics (ampicillin, gentamicin, metronidazole) and surgical consultation.

Disposition Indications for admission include children who are dehydrated, febrile, or ill appearing. Children with ongoing bloody diarrheal stools usually benefit from intravenous fluids until the flare has been controlled. Children with evidence of toxic megacolon require surgical consultation and admission.

GASTROINTESTINAL FOREIGN BODIES Perspective Most GI foreign bodies occur in toddlers, as they experience life by first putting it in their mouths. Children younger than 3 years are particularly at risk because of inappropriate mouthing of objects and a general lack of coordination in swallowing. Although food is the most common esophageal foreign body in adults, coins are most common in children.[] Children with mental retardation swallow a variety of objects. Adolescents occasionally swallow objects in an attempt at suicide. Rectal foreign bodies are uncommon in the pediatric age group.

Principles of Disease Most swallowed foreign bodies pass without difficulty. Foreign bodies may become lodged in any of three areas of normal physiologic narrowing: upper esophageal sphincter (cricopharyngeus muscle)/thoracic inlet

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(C6-T1), the aortic arch/tracheal bifurcation (T4-6), and the lower esophageal sphincter/diaphragmatic hiatus (T10-11). In general, 80% to 90% of objects that have made it into the stomach are passed without difficulty.[ 48]

Clinical Features The classic example is a child who is seen from across the room putting coins in his or her mouth. Children frequently gag and sputter as they attempt to swallow the object. Aspirated objects generally produce persistent coughing, wheezing, or increased work of breathing. Objects that have been swallowed may result in the child remaining asymptomatic or produce symptoms ranging from persistent gagging to drooling and continuous dry heaves. Larger foreign bodies may compress the airway and cause significant respiratory distress. Rapidly progressive symptoms of dysphagia, pain, respiratory distress, or fever raise the possibility of a perforation. Perforation is uncommon, even with sharp objects such as straight pins. The ileocecal valve is the most common site for perforation, and this occurs in less than 1% of patients.[48] Button batteries warrant special mention. Button batteries in the esophagus should be removed in as rapid a manner as possible because erosions and mediastinitis ultimately may occur. Button batteries in the stomach usually pass without difficulty and do not require removal unless they fail to pass the pylorus within 24 to 48 hours of ingestion.[49] Occasionally, objects pass into the stomach that are too large to pass through the pylorus; this is uncommon and heralded by persistent vomiting. Long-standing unrecognized foreign bodies may result in erosion, perforation, infection, stricture, or fistula formation.[50]

Diagnostic Strategies Plain films are the most common method of visualizing location and are used to verify positioning past the lower esophageal sphincter into the stomach. Patients who are symptomatic after foreign body ingestion require imaging to determine location. Occasionally patients who are asymptomatic also have objects remaining in the esophagus.[51] Radiographs should include anteroposterior and lateral films of the chest and neck ( Figure 170-10 ). The lateral film helps to delineate soft tissues in the hypopharynx and evaluate for swelling, particularly if the foreign body is either unknown or of a nonradiopaque material. Often a single view of the neck, chest, and upper abdomen can be performed easily on the pediatric patient in one film. Unless the patient becomes symptomatic, repeat films are otherwise never necessary. Patients presenting with button batteries are the exception in that they require repeat films to document passage beyond the pylorus. Rather than using standard radiography, some institutions have noted success with in-department fluoroscopy or hand-held metal detectors.[] Contrast studies may be helpful to delineate nonradiopaque foreign bodies or to evaluate for perforations.

Figure 170-10 Plain radiographs of a child with an esophageal coin foreign body. Posteroanterior (A) and lateral (B) radiographs show the expected orientation for coins lodged in the esophagus. ((Courtesy of Mark A. Hostetler, MD))

Differential Considerations Not all foreign bodies are radiopaque and visible with standard radiography. Patients who remain symptomatic require further contrast-enhanced imaging or direct visualization.

Management If the object has made it into the stomach, usually no further symptoms occur, and no further treatment is necessary. If the foreign body is in the esophagus, most authors recommend removal within 24 hours to decrease the risk of aspiration and esophageal erosion. The preferred method by which to remove esophageal foreign bodies is controversial and varies by institution. Options include fluoroscopic Foley catheter removal, bougienage advancement into the stomach, endoscopic removal in the emergency department, and removal by rigid bronchoscopy under general anesthesia in the operating room. Foley catheter removal and bougienage do not require sedation in cooperative patients, but young children invariably require sedation in the operating room. The latter two methods actually hold onto the foreign body

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and—at least theoretically—decrease the chance of inadvertent aspiration. They also have the additional benefit of directly visualizing the integrity of the mucosa and evaluating for perforation. Gastric foreign bodies generally do not require removal. Indications for surgical removal of gastric foreign bodies include objects that are greater than 2 cm in width, objects that are greater than 5 cm in length, and objects that are sharp.

Disposition Esophageal foreign bodies require removal as described previously. After foreign bodies have made it into the stomach, most pass without difficulty and require no further follow-up. Button batteries are the exception and require follow-up films to document passage beyond the pylorus.

PANCREATITIS Perspective Pancreatitis is uncommon in childhood, especially in children younger than age 10. Pancreatitis has an incidence of approximately 1 in 50,000 in children and a mortality of 14%.[] In adults, pancreatitis is associated most commonly with alcohol and biliary tract disease. In children, there is a fairly equal association of approximately 10% to 20% each for trauma, infection, structural disease, systemic disease, and drugs or toxins.[55] Mumps is the most common viral cause of pancreatitis and accounts for 10% to 15% of all cases.[55] Idiopathic causes account for 30% of cases.

Principles of Disease Whether the result of trauma, obstruction, or inflammation, a series of events occurs resulting in inflammation, edema, and autodigestion of pancreatic tissue by pancreatic enzymes. In severe cases, this situation may progress to necrosis and hemorrhage, resulting in necrotizing or hemorrhagic pancreatitis. Further complications include the formation of abscesses, pseudocysts, and fistulae.

Clinical Features Patients classically present with complaints of severe epigastric pain that radiates to the back. Pain is gradually progressive and constant and often is associated with nausea and vomiting. Pain classically is described as being worse with eating. There is usually significant abdominal tenderness in the epigastric area with voluntary guarding and hypoactive bowel sounds. The abdomen may be slightly distended.

Diagnostic Strategies Screening laboratory studies reveal elevations in serum amylase or lipase. Plain films of the abdomen may be indicated to consider the possibility of free air or obstruction. An ileus pattern is common, often with a sentinel loop of dilated small bowel noted in the left upper quadrant. An ultrasound or CT scan may be helpful to evaluate anatomy for congenital malformations or biliary tract disease and to evaluate for pseudocyst formation. Patients with pseudocysts may develop hemorrhagic pancreatitis that may become life-threatening. For patients with respiratory distress, a chest x-ray can be helpful to evaluate for a coexistent pleural effusion caused by the pancreatitis.

Differential Considerations Slow, progressive onset of pain is more likely associated with appendicitis, constipation, or pancreatitis. Children with peritoneal irritation invariably lie still, often on their sides with their knees bent, and refrain from all extraneous movement. Sudden onset of severe pain is associated most often with acute obstruction or vascular occlusion as seen with intussusception, volvulus, or torsion. Differential considerations for abdominal pain in children by age are listed in Table 170-4 ; differential considerations for the causes of pancreatitis are listed in Table 170-6 . Table 170-6 -- Differential Considerations for Pancreatitis in Children Trauma Handle-bar injury Infectious Viral: mumps, influenza A, EBV, CMV, hepatitis A and B, rubella, rubeola Bacterial: salmonellosis, leptospirosis Structural Choledochal cyst, duplication cyst, anomalous bile duct, duodenal stenosis Pancreas divisum Tumor Cholelithiasis

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Systemic/genetic

Systemic/acquired

Drugs/toxins

Idiopathic

Cystic fibrosis Glycogen storage disease Familial hyperlipidemias p 1-antitrypsin deficiency Sickle cell disease Systemic lupus erythematosus Kawasaki disease Hemolytic uremic syndrome Henoch-Schönlein purpura Crohn's disease Reye syndrome Diabetes mellitus Steroids, oral contraceptives Valproic acid Sulfasalazine, azathioprine Rifampin, pentamidine, metronidazole, tetracycline Thiazides, ethacrynic acid, furosemide Alcohol, L-asparaginase No definitive cause found

CMV, cytomegalovirus; EBV, Epstein-Barr virus.

Management Management begins with attention to volume status and correction of electrolyte abnormalities if present. A bedside finger-stick blood glucose value should be obtained. Patients should be given adequate pain relief with parenteral narcotics. Patients should be maintained NPO and given adequate fluids. Intravenous fluids are given in boluses of 20 mL/kg of normal saline until adequate vascular volume is achieved, then followed by 5% dextrose in water and half-normal saline at 1.5 times maintenance. Antiemetics are indicated to help control nausea and vomiting. A nasogastric tube is usually not necessary or helpful, unless an ileus or persistent vomiting is present. Steroids and antibiotics are not indicated.

Disposition Most children with pancreatitis require admission, unless they have known or recurrent disease with an adequate outpatient regimen for providing adequate analgesia and hydration.

APPENDICITIS Perspective Appendicitis is the most common surgical condition involving the abdomen, and the most common nontraumatic surgical emergency in children.[12] Approximately 200,000 appendectomies are performed every year, and approximately 1 of every 15 individuals develops appendicitis sometime during their lifetime.[] The peak age of incidence of appendicitis is between 9 and 12 years old, and it is uncommon in children younger than age 5 years.[] Acute appendicitis has an overall mortality rate of less than 1%. For unruptured appendicitis, the mortality rate is 0.1%; the mortality rate increases to about 3% for ruptured appendicitis. In children, the rate of appendiceal perforation before surgery varies from 17% to 40% and is inversely related to age, with higher rates of perforation occurring in younger age groups. In children younger than age 2 years, 90% will have perforated by the time of surgery.

Principles of Disease The appendix is a blind pouch that may become obstructed. After it is obstructed, a vicious cycle occurs with increasing edema, vasocongestion, inflammation, ischemia, infarction, necrosis, and perforation. In

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adults, a thicker appendiceal wall protects against perforation, and a well-developed omentum aids in walling off the infection to prevent its diffuse spread. Children have neither and tend to rupture earlier and develop diffuse peritonitis more readily.

Clinical Features Patients classically present with a constellation of symptoms that includes abdominal pain, nausea, vomiting, fever, and anorexia. All of these symptoms are gradually progressive over 4 to 24 hours. Abdominal pain usually is described as vague, crampy, and periumbilical on origination, which then becomes more severe, constant, and localized to the right lower quadrant. Fever usually occurs later, sometimes not until after the patient already has presented to the emergency department. Nausea and vomiting are progressive and most often associated with anorexia. Patients occasionally may have a multiphasic course to their illness in which they begin with the classic abdominal pain; experience sudden resolution; and several days later develop fever, chills, and abdominal pain. This course represents acute appendicitis with spontaneous rupture and formation of abscess. Physical examination may reveal several classic findings. Patients with inflammation surrounding the appendix usually develop peritoneal findings that localize to the right lower quadrant. Pain occurs with movement, so patients prefer to lie still. Patients are unable to jump up and down and complain that even rocking the bed or tapping their heels causes pain. The abdomen is usually quiet with an absence of bowel sounds. Rebound tenderness is present in the right lower quadrant. Rovsing's sign also may be present and occurs when the examiner presses in the left lower quadrant and rapidly releases the examining hand, causing severe pain in the right lower quadrant. Other findings associated with appendicitis include the psoas and obturator signs. The psoas sign is elicited by having the patient lie on his or her side and hyperextending the right thigh at the hip stretching the psoas muscle, which overlies the inflamed appendix and causes pain. The obturator sign is similarly elicited by internally rotating the flexed right thigh against resistance to elicit pain.

Diagnostic Strategies Appendicitis may be diagnosed on the basis of history and physical findings alone. Patients with the appropriate constellation of findings consistent with appendicitis may not require any testing and proceed directly to the operating room for either laparoscopic or open exploration. Patients in whom the diagnosis is suspected usually require some diagnostic workup. Screening studies should include a CBC with differential, urinalysis, and pregnancy test. An estimated 96% of patients with appendicitis have either an elevated white blood cell count greater than 10,000/mm[3] or a left-shifted differential with more than 75% neutrophils.[57] Although an elevated white blood cell count supports the diagnosis, it is not specific for appendicitis. The appendix is in close proximity to the ureters and may induce some degree of sterile pyuria. Inflammatory changes related to appendicitis generally result in fewer than 5 to 10 white and red blood cells per high-power field and an absence of bacteria. Findings in excess of these amounts suggest a urinary tract etiology (infection, stone, mass, trauma). Consideration also may be given to adding a rapid streptococcal test in patients with red or sore throats. Diagnostic imaging options include plain films of the abdomen, limited CT scan of the appendix, and ultrasound. Plain films help to rule out free air or obstruction and occasionally show an appendiceal fecalith, also called an appendicolith ( Figure 170-11 ). Although the presence of an appendicolith is essentially pathognomonic for acute appendicitis, it is present in only 10% of cases.[56] Ultrasound findings consistent with appendicitis include an enlarged, noncompressible appendix that is painful during scanning. Ultrasound may show a fecalith inside an enlarged and inflamed appendix, the so-called target sign.[58] Appendiceal ultrasound studies have a sensitivity, specificity, and overall accuracy of 90% to 95%.[] Ultrasound is particularly useful for evaluating for abscesses and fluid collections; however, there is a great deal of operator and reader variability.

Figure 170-11 Fecalith in a child with appendicitis. ((Courtesy of Marianne Gausche-Hill, MD.))

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CT of the appendix is the latest technology and seems to be the imaging modality of choice based on current evidence.[] Limited CT scans of the appendix have sensitivities and specificities of 95% to 100%.[] For patients with relatively low probability of appendicitis, CT offers a cost-effective screening tool, particularly compared with inpatient admission and observation.[62] In addition, the availability of appendiceal CT has been shown to reduce the negative laparotomy rate from 20% to 7%.[66] The highest accuracy has been reported using new focused appendiceal CT with rectal contrast. Imaging the pelvis and specifically the right lower quadrant with this technique effectively not only establishes the diagnosis of appendicitis, but also aids in identifying the two most common differential diagnoses: IBD and mesenteric adenitis.[]

Differential Considerations Mesenteric adenitis is the most common condition associated with the signs and symptoms of appendicitis. It often has significant diffuse tenderness and may localize in the right middle to lower quadrant. Children often lack fever, however, and do not have true peritoneal signs. Mesenteric adenitis usually follows a viral illness and results from nonspecific inflammation of mesenteric lymph nodes. It is even perhaps more common than appendicitis. Differential considerations for abdominal pain by age are listed in Table 170-4 . Other considerations include nonaccidental trauma (abuse), malingering, and Münchausen syndrome.[67] Girls of reproductive age require a consideration of gynecologic origin and require a pregnancy test, pelvic examination, and consideration of ovarian torsion, particularly if the pain seems to be severe and out of proportion to physical examination. Boys require an external genital examination to rule out the possibility of testicular torsion. Cryptorchidism in the face of acute abdominal pain should raise the suspicion of testicular torsion.

Management Patients with suspected appendicitis should be maintained NPO and have an intravenous line established. Most patients have vomiting and anorexia and benefit from at least one fluid bolus of 20 mL/kg of normal saline, then 1.5 to 2 times maintenance fluids with dextrose 5% in water and half-normal saline. Screening studies should be initiated, and appropriate consultation should be made with a surgeon. Ongoing pain should be addressed adequately. Intravenous narcotics are safe and effective and should not alter the diagnostic accuracy of the physical examination. It is best to consult with a surgeon first, however, in the event that the surgeon would like to examine the abdomen before any narcotics are given. Pain relief should not be withheld indefinitely, however, pending a surgeon's examination. Patients with high fever, suspected perforation, or unusual delay to surgery require coverage with intravenous broad-spectrum antibiotics, which should be initiated in the emergency department after consulting with the surgeon.[68] Reasonable choices for antibiotics include ampicillin, gentamicin, and either metronidazole or clindamycin. Nasogastric tubes are reserved for patients with persistent nausea or vomiting related to abdominal distention or ileus.

Disposition In the past, patients with suspected but not obvious appendicitis would be admitted and observed. The accuracy of CT is rapidly replacing this practice and may prove to be a more cost-effective alternative.

BILIARY TRACT DISEASE Perspective Biliary tract disease is uncommon in childhood and has causes distinct from disease in adults. In children, gallstones are associated with hemolytic disease, cystic fibrosis, total parenteral nutrition, sepsis, and dehydration.[] Ceftriaxone also has been associated with sludging and biliary disease, particularly in neonates. Acute acalculous cholecystitis has been associated with Rocky Mountain spotted fever and a variety of bacterial infections ranging from Salmonella and Shigella organisms. Hydrops of the gallbladder is associated with viral upper respiratory or GI infections, Kawasaki disease, streptococcal pharyngitis, mesenteric adenitis, nephrotic syndrome, and leptospirosis.

Principles of Disease Gallstones are classified as either cholesterol or pigment stones. Pigment stones occur in childhood, whereas cholesterol stones do not usually begin appearing until adolescence. Pigment stones result from the excess breakdown of red blood cells and are seen most commonly in hemolytic anemias, such as sickle cell disease and spherocytosis. Gallstones occurring in infants usually are associated with abdominal surgery, sepsis, necrotizing enterocolitis, or administration of total parenteral nutrition.[71] Young children most commonly develop gallstones as a result of their hemolytic disease. Adolescents form gallstones in association with oral contraceptives, pregnancy, obesity, or underlying hemolytic disease. In acute acalculous cholecystitis, the sonogram reveals evidence of gallbladder inflammation in the absence of

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calculi. Hydrops of the gallbladder is an acute noninflammatory, noninfectious process that results in a markedly enlarged gallbladder without evidence of calculi.

Clinical Features Similar to adults, patients usually present with right upper quadrant pain that radiates through to the back and may be associated with fever, nausea, and vomiting. Jaundice occurs in one third of patients.[]

Diagnostic Strategies Biliary tract disease usually is associated with elevations in liver enzymes and bilirubin. Elevations in alkaline phosphatase suggest cholestasis. Elevated white blood cell counts are nonspecific, but if associated with fever may represent an acute infectious process (i.e., ascending cholangitis). Ultrasound is the imaging modality of choice. It can determine the presence of gallstones, reproduction of pain on scanning (sonographic Murphy's sign), the amount of dilation of the gallbladder and bile ducts, gallbladder wall thickness, and the anatomic configuration of the biliary and pancreatic collecting system. When ultrasound is equivocal or negative in the face of strong clinical suspicion, the gold standard for biliary tract imaging is still considered to be cholescintigraphy scanning.[71] Although only 15% of gallstones in adults are calcified and visible on plain radiographs of the abdomen, 50% of stones are visible in children.[]

Differential Considerations Biliary tract disease is uncommon in children and requires consideration of underlying or coexistent disease. Differential considerations for abdominal pain by age are listed in Table 170-4 .

Management Management of biliary tract disease begins with attention to fluid and electrolyte status. Adequate pain control should be provided, usually with a parenteral opioid. Asymptomatic patients with incidental findings of gallstones require no further emergent therapy and may be referred to a surgeon as an outpatient. Patients who are afebrile usually can be managed safely as an outpatient with adequate pain control. Febrile patients require admission and intravenous antibiotics. Reasonable choices for empiric antibiotic coverage include ampicillin and gentamicin, plus either clindamycin or metronidazole.

Disposition Indications for admission include pain control, hydration, fever, and need for operation.

KEY CONCEPTS {,

Phys iologi c and brea st milk jaun dice are the most com mon caus es of jaun dice in the neon atal perio d.

{,

Eval

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{,

{,

{,

uatio n of jaun dice requi res fracti onat ed level s of total and direc t biliru bin. Dire ct hype rbilir ubin emia in infan ts is alwa ys path ologi c and requi res a detai led work up. HPS pres ents with grad ually prog ressi ve nonb ilious eme sis that beco mes proje ctile. Infan ts with HPS appe ar

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{,

{,

{,

vigor ous and hung ry. Hypo chlor emic , hypo kale mic meta bolic alkal osis is the clas sic elect rolyt e abno rmali ty. Bilio us vomi ting in the neon ate shou ld imm ediat ely raise the susp icion of malr otati on and volvu lus. Infan ts with biliou s eme sis who are ill-ap peari ng,

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{,

{,

have a diste nded abdo men, or sho w an acut e obstr ucte d patte rn on abdo mina l radio grap hs repr esen ta true surgi cal eme rgen cy. NEC occu rs mor e com monl y in pre matu re infan ts, but 10% of affec ted infan ts are full-t erm. Pne umat osis intes tinali s is path ogno

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{,

{,

{,

moni c for NEC . GER begi ns early after birth and rem ains relati vely cons tant over time. GER usua lly resp onds to cons ervat ive mea sure s (posi tioni ng, thick enin g of form ula, smal ler and mor e frequ ent feedi ngs). The clas sic triad for intus susc eptio n is abdo mina l pain, vomi

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{,

{,

ting, and hem e-po sitive stool s; how ever, the triad occu rs in fewe r than one third of patie nts. Child ren with intus susc eptio n may pres ent with out pain and with letha rgy alon e. Hirs chsp rung' s dise ase is a com mon caus e of cons tipati on in the neon ate and is usua lly mani

Page 4143

{,

{,

feste d by dela yed pass age of mec oniu m. Hirs chsp rung' s dise ase may be com plica ted by toxic meg acol on, whic h is a true eme rgen cy. Altho ugh Hirs chsp rung' s dise ase is a cons idera tion in case s of cons tipati on, funct ional or acqu ired caus es are muc h mor

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{,

{,

{,

e com mon. Mec kel's diver ticul um follo ws the rule of 2s . Mec kel's diver ticul um clas sicall y pres ents in child ren youn ger than 5 year s old with painl ess, brick red recta l blee ding. The clas sic pres entat ion for HSP is a pete chial or purp uric rash on the butto cks and

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{,

{,

legs asso ciate d with GI com plain ts and arthr algia s in an other wise wellappe aring child . GI com plain ts in HSP most often inclu de abdo mina l pain, naus ea, vomi ting, and micr osco pic hem aturi a. IBD is rare in infan ts youn ger than 1 year old and unco mm on in child

Page 4146

{,

{,

{,

{,

ren and mor e com monl y begi ns in adol esce nce. Ster oids are the main stay of thera py for IBD. Toxi c meg acol on may occu r as a com plica tion and is a true eme rgen cy. More than 90% of forei gn bodi es pass with out diffic ulty. Butt on batte ries requi re repe at

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{,

{,

{,

films to docu ment pass age past the pylor us. Pan creat itis is unco mm on in child hood . Cau ses of panc reatit is inclu de virus es, trau ma, drug s, and toxin s. The clas sic cons tellati on of sym ptom s of panc reatit is inclu des abdo mina l pain, naus ea, vomi ting, anor exia, and fever

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{,

{,

{,

. The imag ing mod ality of choi ce for older child ren and adol esce nts who do not requi re surg ery on clinic al grou nds alon e is limit ed CT of the appe ndix. In child ren, pigm ent ston es are most com mon seco ndar y to hem olytic dise ase. Fifty perc ent of galls tone

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s in child ren may be calci fied and seen on plain radio grap hs.

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REFERENCES 1. Perlman M, Frank JW: Bilirubin beyond the blood-brain barrier. Pediatrics1988;81:304. 2. Hostetler MA: Hypoketotic hypoglycemic coma in a 21-month-old child. Ann Emerg Med1999;34:394. 3. American Academy of Pediatrics Clinical Practice Guidelines : Management of hyperbilirubinemia in the newborn of 35 or more weeks gestation. Pediatrics2004;114:297. 4. Zenn MR, Redo SF: Hypertrophic pyloric stenosis in the newborn. J Pediatr Surg1993;28:1577. 5. Vasavada P: Ultrasound evaluation of acute abdominal emergencies in infant and children. Radiol Clin North Am2004;42:445. 6. Kao H: Bilious vomiting during the first week of life. Acta Paediatr Sin1994;35:202. 7. Stringer MD, Brereton RJ: Current management of infantile hypertrophic pyloric stenosis. Br J Hosp Med 1990;43:266. 8. Najmaldin A, Tan HL: Early experience with laparoscopic pyloromyotomy for infantile hypertrophic pyloric stenosis. J Pediatr Surg1995;30:37. 9. Torres AM, Ziegler MM: Malrotation of the intestine. World J Surg1993;17:326. 10. Leonidas JC: Midgut volvulus in infants: Diagnosis with ultrasound. Radiology1991;179:491. 11. Shatzkes D: Malrotation of the bowel: Malalignment of the superior mesenteric artery-vein complex shown by CT and MR. J Comput Assist Tomogr1990;14:93. 12. Felter RA: Nontraumatic surgical emergencies in children. Emerg Med Clin North Am1991;9:589. 13. Bonadio WA, Clarkson T, Naus J: The clinical features of children with malrotation of the intestine. Pediatr Emerg Care1991;7:348. 14. Seashore JH, Touloukian RJ: Midgut volvulus: An ever-present threat. Arch Pediatr Adolesc Med 1994;148:43. 15. Messineo A: Clinical factors affecting mortality in children with malrotation of the intestine. J Pediatr Surg 1992;27:1343. 16. Spigland N, Brandt ML, Yarbeck S: Malrotation presenting beyond the neonatal period. J Pediatr Surg 1990;25:1139. 17. Neu J: Pediatric gastroenterology: II. Necrotizing enterocolitis: The search for a unifying pathogenic theory leading to prevention. Pediatr Clin North Am1996;43:409. 18. Kliegman RM, Fanaroff AA: Necrotizing enterocolitis. N Engl J Med1984;310:1093. 19. Neu J, Weiss MD: Necrotizing enterocolitis: Pathophysiology and prevention. J Parenter Enteral Nutr 1999;23:S13. 20. Anderson DM, Kliegman RM: The relationship of neonatal alimentation practices to the occurrence of endemic necrotizing enterocolitis. Am J Perinatol1991;8:62. 21. Larson HE: Neonatal necrotizing enterocolitis: A neonatal infection. J Hosp Infect1988;1:334. 22. Balance WA: Pathology of neonatal necrotizing enterocolitis: A 10 year experience. Pediatrics 1990;117:806. 23. Buchert GS: Abdominal pain in children: An emergency practitioner's guide. Emerg Med Clin North Am 1989;7:497. 24. Friman S, Svanvik J, Radberg G: Intussusception at four separate locations in the small intestine: Case report. Acta Chir Scand1988;154:485. 25. Ravikumar K, Khope S, Rao P: Idiopathic colo-colic intussusception. J Postgrad Med1988;34:246. 26. McCombe AW, Orr JD: Gastric lipoma and intussusception in a child. Scott Med J1988;33:310. 27. Mir E: Surgical complications in Henoch-Schönlein purpura in childhood. Z Kinderchir1988;43:391. 28. Kim YS, Ruh JH: Intussusception in infancy and childhood: Analysis of 385 cases. Int Surg1989;74:114. 29. Bhisitkul DM: Clinical application of ultrasonography in the diagnosis of intussusception. J Pediatr 1992;121:182. 30. Del-Pozo G, Albillos J, Tejedor D: Intussusception: US findings with pathologic correlation—the crescent in doughnut sign. Radiology1996;121:182. 31. Hadidi AT, El Shal N: Childhood intussusception: A comparative study of nonsurgical management. J Pediatr Surg1999;34:304. 32. Meyer JS, Dangman BC, Buonomo C, Berlin JA: Air and liquid contrast agents in the management of intussusception: A controlled, randomized trial. Radiology1993;188:507.

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33. Lui KW: Air enema for diagnosis and reduction of intussusception in children: Clinical experience and fluoroscopy time correlation. J Pediatr Surg2001;36:479. 34. Qualman SJ, Murray R: Aganglionosis and related disorders. Hum Pathol1994;25:1141. 35. Franken EA: Intestinal motility disorders of infants and children: Classification, clinical manifestations and roentgenology. Crit Rev Diagn Imaging1987;27:203. 36. Loening-Baucke V: Constipation in early childhood: Patient characteristics, treatment, and long-term follow up. Gut1993;34:400. 37. Ludtk F: Incidence and frequency of complications and management of Meckel's diverticulum. Surg Gynecol Obstet1989;169:537. 38. Brown CK, Olshaker JS: Meckel's diverticulum. Am J Emerg Med1988;6:157. 39. Cooney DR: The abdominal technetium scan (a decade of experience). J Pediatr Surg1982;17:611. 40. Rerksuppaphol S, Hutson JM, Oliver MR: Ranitidine-enhanced 99mtechnetium pertechnetate imaging in children improves the sensitivity of identifying heterotopic gastric mucosa in Meckel's diverticulum. Pediatr Surg Int2004;20:323. 41. Conn DL, Hunder GG, O'Duffy JD: Vasculitis and related disorders. In: Kelly UN, ed.Textbook of Rheumatology, 4th ed. Philadelphia: WB Saunders; 1993: 42. Koskimies O: Renal involvement in Schonlein-Henoch purpura. Acta Paediatr1974;63:357. 43. Tervaert JWC, Kallenberg C: Neurologic manifestations of systemic vasculitides. Rheum Dis Clin North Am1993;19:913. 44. Grand RJ, Homer DR: Approaches to inflammatory bowel disease in childhood and adolescence. Pediatr Clin North Am1975;22:835. 45. Mamula P: Inflammatory bowel disease in children 5 years of age or younger. Am J Gastroenterol 2002;97:2005. 46. Friedman E: Caustic ingestions and foreign bodies in the aerodigestive tract of children. Pediatr Clin North Am1989;36:1403. 47. Stanley P, Law BS, Young LW: Down's syndrome, duodenal stenosis/annular pancreas, and a stack of coins. Am J Dis Child1988;142:459. 48. Binder L, Anderson WA: Pediatric gastrointestinal foreign body ingestions. Ann Emerg Med1984;13:112. 49. Sheikh A: Button battery ingestions in children. Pediatr Emerg Care1993;9:224. 50. Hernanz-Schulman M, Naimark A: Avoiding disaster with esophageal foreign bodies. Emerg Med Rep 1983;4:133. 51. Sacchetti A, Carraccio C, Lichenstein R: Hand-held metal detector identification of ingested foreign bodies. Pediatr Emerg Care1994;10:204. 52. Biehler JL, Tuggle D, Stacy T: Use of the transmitter-receiver metal detector in the evaluation of pediatric coin ingestions. Pediatr Emerg Care1993;9:208. 53. Ros SP, Cetta F: Detection of ingested foreign bodies with a metal detector. J Pediatr1992;121:837. 54. Mader TJ, McHugh TP: Acute pancreatitis in children. Pediatr Emerg Care1992;8:157. 55. Haddock G: Acute pancreatitis in children: A 15-year review. J Pediatr Surg1994;29:719. 56. Doherty GM, Lewis FR: Appendicitis: Continuing diagnostic challenge. Emerg Med Clin North Am 1989;7:3537. 57. Dueholm S, Bagl P, Bud M: Laboratory aid in the diagnosis of acute appendicitis. Dis Colon Rectum 1989;32:855. 58. Kao SCS: Acute appendicitis in children: Sonographic findings. AJR Am J Roentgenol1989;153:375. 59. Sim KT: Ultrasound with graded compression in the evaluation of acute appendicitis. J Natl Med Assoc 1988;81:984. 60. Takada T, Yasuda H, Uchiyama K: Ultrasonic diagnosis of acute appendicitis complicated by paralytic ileus and generalized peritonitis. J Clin Ultrasound1988;16:123. 61. Amland PF: Ultrasonography and parameters of inflammation in acute appendicitis. Acta Chir Scand 1989;155:185. 62. Garcia-Pena BM: Effect of computed tomography on patient management and costs in children with suspected appendicitis. Pediatrics1999;104:440. 63. Rao PM, Rhea JT, Novelline RA: CT diagnosis of mesenteric adenitis. Radiology1997;202:145. 64. Rao PM: Effect of computed tomography of the appendix on the treatment of patients and use of hospital resources. N Engl J Med1998;338:141. 65. Rao PM: The computed tomography appearance of recurrent and chronic appendicitis. Am J Emerg Med1998;16:26. 66. Rao PM: Introduction of appendiceal CT: Impact on negative appendectomy and appendiceal perforation rates. Ann Surg1999;229:344. 67. Purcell TB: Nonsurgical and extraperitoneal causes of abdominal pain. Emerg Med Clin North Am 1989;7:721. 68. Elmore JR, Dibbins AW, Curci MR: The treatment of complicated appendicitis in children. Arch Surg 1987;122:424. 69. Debray D: Cholelithiasis in infancy: A study of 40 cases. J Pediatr1993;122:385.

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70. Friesen CA, Robert CC: Cholelithiasis: Clinical characteristics in children. Clin Pediatr (Phila) 1989;28:294. 71. Holcomb GW, O'Neill J, Holcomb GW: Cholecystitis, cholelithiasis and common duct stenosis in children and adolescents. Ann Surg1980;191:626. 72. Takiff H, Fonkalsrud EW: Gallbladder disease in childhood. Am J Dis Child1984;138:565.

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Chapter 171 – Infectious Diarrheal Disease and Dehydration Roger M. Barkin David G. Ward[*] * Material new to this chapter in this edition was prepared by David Burbulys, MD, Department of Em ergency Medicine, Harbor-UCLA Medical Center, Torrance, CA, and is indicated in bracketed italic type.

ACUTE INFECTIOUS DIARRHEA Perspective Worldwide, diarrhea is one of the most significant causes of morbidity and mortality and is responsible for 4 to 5 million deaths per year in children younger than 5 years of age. Variability among regions reflects resource availability, epidemiology, underlying general health status of the population, availability of safe food and water, among other factors. In the United States, acute gastroenteritis (AGE) historically accounts for 10.6% of U.S. hospital admissions of children younger than 5 years of age, estimated at 220,000 admissions per year; 300 to 400 deaths per year are caused by diarrhea, most occurring in the first year of life.[] Children remain at a higher risk than adults for complications of diarrhea, fluid loss, and electrolyte abnormalities because of their physical size, physiology, an immune system that is still developing, and a dependency on adults for fluid and nutrients. Contaminated municipal water supplies and nationally distributed food sources, as well as the possibility of increasing antibiotic resistance in routine microbial agents, may affect the prevalence of diarrheal disease in the future.[3] The recognition of the role of fluids and electrolytes in the management of AGE has resulted in the widespread use of intravenous (IV) therapy for treating volume disorders in this country. In some situations, diarrhea-related volume depletion can be managed by oral replacement.

Epidemiology In general, viruses are responsible for 60% of cases; bacteria, 20%; parasites, 5%; parenteral illnesses, 10%; and only 5% are in an unknown category.[4] A study of 147 children ages 2 to 11 years who were treated as outpatients documented an etiology in 60.5% of the children, 10% of whom had multiple agents identified. Rotavirus was found in 29.3% of the cases with a spring and winter peak whereas Giardia was noted in 15% of children, primarily in the spring. Hep-2 cell ad-herent Escherichia coli was isolated in 10.2% and less common etiologies identified were enteric adenoviruses, salmonella, E. coli, Entamoeba histolytica, and Campylobacter jejuni.[5] Infectious diarrhea in children is most often contracted by poor hygiene, contamination through the fecal-oral route, and poor food-handling practices. Handling diapers, fecal-oral transmission, and cleaning toys remain sources of concern in daycare centers. Causative agents may be endemic, epidemic with food- and waterborne outbreaks, or sporadic. For most agents, a large inoculum is required to transmit the disease. Individuals who have recently been hospitalized, treated with antibiotics, traveled to developing countries, are immunosuppressed, malnourished, or chronically ill are at risk of diarrheal illness and potential complications.[6]

Principles of Disease Pathophysiology Up to 9 L of fluid from diet and endogenous secretions enter the proximal bowel each day in the adult. In children, less total fluid enters the gut but a proportionately larger volume/weight ratio of fluid is required (e.g., 125 ml/kg/24 hr in adults versus 220 ml/kg/24 hr in a newborn). Ninety percent of the fluid is absorbed in the small bowel and the remainder in the large bowel. Water passively follows osmotic gradients created by transport of electrolytes, sugars, and amino acids. Transport includes active and passive transport-facilitated mechanisms. Glucose and certain amino acids are absorbed by active, carrier-mediated transport and coupled to the sodium exchange. Diarrhea occurs through a variety of mechanisms: osmotic diarrhea is a response to the presence of poorly absorbed solutes in the colon as a result of altered bacterial gut flora, damage of the mucosal absorptive

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surface, or ingestion of substances.[7] These osmotically active substances alter the normal mechanisms of fluid transport by creating an osmotic gradient across the bowel lumen. This results in movement of water and electrolytes into the lumen and a hypertonic luminal fluid. Acute gastroenteritis in children produces injury to the gut epithelium, decreasing absorptive area and preventing normal fluid, electrolyte, and nutrient absorption. Diagnostic clues to an osmotic etiology are diarrhea that decreases or stops if the patient fasts, the stool pH is less than 5, and reducing substances are present in the stool. Secretory diarrhea is the result of the presence of an enterotoxin that causes an increase in cyclic adenosine monophosphatase (cAMP) in the endothelial cell, resulting in increased chloride secretion. Enterotoxin-producing bacteria include Salmonella and Shigella organisms, Vibrio cholera, E. coli, and Clostridium difficile. Noninfectious causes are rare and include malabsorbed bile acids, fatty acids, prostaglandins, and gastrointestinal hormones. Secretory diarrhea is notable for no reduction in stool volume with fasting, a stool pH greater than 6, and no reducing substances present in the stool. Infectious agents attach directly to the gut mucosa, causing cell damage, bleeding, and mucus production. The agent may enter the systemic circulation or body tissues.[8] Diarrhea caused by altered motility, increased or decreased transit time (diabetes, scleroderma, neuromuscular disease), reduced surface area (short gut, celiac disease), or inhibited active ion transport is uncommon in children. Dysentery is important to recognize because of the implication that the infection has compromised the bowel wall and therefore, the risk of systemic infection is increased. Although blood loss may be clinically appreciable, it is less significant than the fluid and electrolyte losses. Systemic infection may be suspected if the total white blood count is increased or if clinical signs of prostration, chills and fever, or dysentery are present. During childhood, children's body makeup changes with respect to the surface area to volume ratio and the fluid compartment distribution of body water. The extracellular fluid compartment begins in life as 80% of the total body water content but by adulthood makes up 50% to 55%.[9] Children have limited stores of substrate and may not tolerate fluctuations or losses of fluid, electrolytes, or nutrients that are often encountered in acute diarrheal illness. Abnormalities of acid-base homeostasis associated with acute diarrheal illness and volume disorders may lead to metabolic acidosis with varying degrees of respiratory compensation. The metabolic acidosis usually results from the loss of HCO3− and Cl− in diarrheal fluid but may also involve renal tubular acidosis, excessive acid production from poor tissue perfusion, starvation, infection, and therapeutic interventions (salicylates). The effects of metabolic acidosis may result in an increase in tidal volume and respiratory rate to correct the decreased pH by lowering the Paco2. In this manner, excess acids can be eliminated by transporting the acids to the lungs by hemoglobin and other buffer systems. The maximum respiratory compensation of metabolic acidosis is a decrease in Paco2 to 12 to 15 mm Hg and may occur within minutes to hours of the onset of the abnormality. Nonvolatile acids (especially sulfur and phosphoric acids) must be excreted by the kidneys and can be expected to take several hours to days to occur. Children with intravascular volume depletion resulting in metabolic acidosis require restoration of their volume status to deliver nutrient substrate and to eliminate byproducts of cellular metabolism rather than correction of the acid-base disorder with buffer alone. Because the patient depends on the respiratory system to help eliminate acid excess in a state of poor tissue perfusion (respiratory compensation), correction of volume depletion often corrects what appears as respiratory distress in the severely volume-depleted child.

Etiology Virus The virus responsible for most acute viral gastro-enteritis and a disproportionate amount of morbidity caused by diarrheal illness in the United States is rotavirus. It peaks in the winter and spring and can usually be managed on an outpatient basis. This virus is endemic and accounts for nearly one third of children with diarrhea.[] Less commonly found are Norwalk agent, adenovirus, and hepatitis A virus. Rotavirus invades the epithelium of the small intestinal mucosa and involves the villus more than the crypt. A proliferative response occurs, producing an abundance of incompletely differentiated cells on the gut mucosa. In the healthy host, repair of the epithelium and differentiation of the immature brush border take approximately 3 to 5 days and should occur without specific intervention.[10] In the chronically ill or

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nutritionally compromised child, this leads to high risk for malabsorption and severe complications beyond the usual brush border injury. Failure to repair the epithelium leads to progressive epithelial injury, complications, and a vicious circle of events. Rotavirus causes acute febrile illness with vomiting and diarrhea. Severity may vary, but the diarrhea is usually watery in consistency, and the volume is large enough to cause significant and rapid intravascular volume compromise. Rotavirus may also involve symptoms of an upper respiratory tract infection. Most infections are transmitted person to person, probably through the fecal-oral route and possibly through respiratory secretions. The incubation period is 1 to 3 days. Postinfection excretion may be prolonged, ranging from 4 to 57 days. Diagnosis is made by demonstration of the presence of antigens in stool specimens by enzyme immunoassay, many having 97% sensitivity and 97% specificity for rotavirus antigens in human stool. The test can be performed on undiluted stool without special preparation.[12] An effective vaccine was available for a short time until it was noted to be associated with increased risk of intussusception.[13] Hepatitis A virus (HAV) infections are seen as an acute febrile illness with anorexia, nausea, vomiting, and malaise. HAV invades the hepatocytes causing immunologically mediated hepatocellular damage. In children, it may be asymptomatic, present as an anicteric illness and be misdiagnosed as a nonspecific viral gastroenteritis. HAV is not seasonal and is spread by a common food or water source with fecal-oral contamination. The incubation period is 2 to 6 weeks, and individuals shed virus for 1 to 3 weeks beginning 1 to 2 weeks before symptoms develop. Lifelong immunity is expected. Household contacts should be offered immunoglobulin prophylaxis. A vaccine for HAV has recently become available.[14]

Bacteria The most common bacterial organisms causing acute diarrhea in the United States are, in order of fre-quency, Shigella species, Salmonella species, C. jejuni, and Yersinia enterocolitica. Clostridium perfringens, Staphylococcus aureus, Vibrio cholerae, and Vibrio parahaemolyticus each make up less than 1% of cases. Enterotoxigenic, enteroinvasive, and enterohemorrhagic E. coli are also found in the United States. Shigella species consists of four antigenic groups of 40 serotypes. S. sonnei is the most common cause of dysentery (diarrhea with significant blood, pus, and mucus) in the United States. Shigellosis usually begins as an enterotoxin-like diarrhea with watery stools and fever that may progress to bacillary dysentery with or without systemic manifestations. Illnesses vary from mild to severe. Shigella species can invade the intestinal mucosa. It rarely infects infants younger than 3 months of age and is most common between 6 months and 10 years of age.[15] Because of antibiotic resistance to ampicillin, trimethoprim-sulfamethoxazole (4 to 5 mg/kg/dose TMP, 20 to 25 mg/kg/dose SMX bid orally for 7 to 10 days) is recommended for more severe illnesses.[16] (Reviewer suggests Because of approximately 50% resistance to ampicillin and trimethoprim/sulfamethoxazole, a fluoroquinolone [such as ciprofloxacin or ofloxacin] in adults or azithromycin in children given orally for 5 days is recommended for more severe illness.) The 1700 serotypes of Salmonella species are grouped as Salmonella enteritidis. Clinical syndromes include a carrier state, acute gastroenteritis (AGE), bacteremia, and a disseminated abscess syndrome. It is presumed that Salmonella species invade the mucosa and produce a cholera-like enterotoxin and a cytotoxin. Salmonella species gastroenteritis is a febrile illness marked by nausea and fever, although it may vary from dysentery to a cholera-like illness. AGE occurs at any age but is most common in the first year of life. Antibiotic treatment is indicated in complicated illness, whereas AGE is treated symptomatically. Complications requiring therapy may include failure to improve within 5 to 7 days when not treated with antibiotics or focal infection in the central nervous system (CNS), bone, joint, kidney, or pericardium. Increased bacteriology and symptomatic relapse is associated with ampicillin and amoxicillin therapy. Campylobacter species account for much of the diarrheal disease in the world. The organism is found in the gastrointestinal tract and feces of wild and domestic fowl, farm animals, and pets. Of the five types, C. jejuni and E. coli (Reviewer suggests C. coli) are the most prominent. Illness consists of abdominal cramps, diarrhea, chills, fever, a Shigella-like dysentery, or a presentation similar to acute appendicitis. Invasion of the mucosa with toxin production has been described. A 1- to 7-day incubation period is normal, and the illness usually lasts less than a week. Campylobacter species is transmitted by ingestion of contaminated food or water. Diagnosis is made by dark-field microscopy, and although erythromycin (40 mg/kg/24 hr qid orally for 7 to 10 days) (Reviewer suggests Azithromycin [12 mg/kg daily PO for 5 days].) may shorten the course of the illness, most children do not need antibiotic therapy.[17]

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Y. enterocolitica is a relatively uncommon cause of simple self-limited AGE with diarrhea and vomiting. Diarrhea may be watery, mucoid, or bloody. Older children and adults have more nonenteric symptoms, presenting an appendicitis-like illness as a result of mesenteric adenitis. Enterotoxin production may play a role. Duration of the gastroenteritis is often 14 days or more, but antibiotics are seldom indicated. Pseudomembranous colitis presents with diarrhea, abdominal cramps, and fever. Caused by C. difficile, systemic toxicity, abdominal tenderness, and dysenteric stools are often present, although asymptomatic infections and mild AGE have also been reported. It most often occurs in hospitalized patients with onset during or after antibiotic therapy. The organism is ubiquitous and transmitted by fecal-oral contamination. Incubation time is unknown. The presence of pseudomembranes, friable rectal mucosa, and C. difficile toxin in the stool is diagnostic. Stopping the offending agent and therapy with vancomycin, 40 mg/kg/24 hr orally, (Reviewer suggests Metronidazole, 30 mg/kg/day, divided qid, PO for 7 days.) is indicated. Ingested C. perfringens produces an enterotoxin during sporulation in the gut that causes fluid collection in ileal loops and diarrhea. This short-lived illness is characterized by watery diarrhea, moderate to severe abdominal cramps, midepigastric pain, and an absence of fever. Vomiting is uncommon. Food source contamination, often from catered food services, is the usual source of outbreaks. The incubation time is 6 to 24 hours. Diagnosis is made by high spore counts in the stool; no specific treatment is required. S. aureus produces the archetypal food poisoning from ingesting preformed enterotoxin, usually from contaminated food. It is short-lived and self-limited. Nausea, vomiting, abdominal cramps, and diarrhea with a notable absence of fever is the typical pattern often occurring within hours of exposure. V. cholerae 01 (responsible for epidemic cholera) and non-01 (all other strains) is an Asian-African organism of which a uniquely subtypable strain is endemic to the Gulf Coast of the United States. Diarrhea is caused by a heat-labile enterotoxin that increases cAMP through adenyl cyclase, resulting in inhibition of sodium reabsorption with chloride and fluid secretion into the gut. This cholera toxin is mostly absent in U.S. strains. Vibrio parahaemolyticus is commonly found in water, shellfish, and fish. It is most commonly associated with ingestion of contaminated raw foods. Diarrhea, abdominal cramps, and nausea are common, whereas vomiting, headache, fever, and chills are less common. Invasion of the mucosa is a possible mechanism of infection. E. coli consists of several recognized categories. The enterotoxigenic form produces heat-stable and heat-labile toxins and colonization factor, which are important in the mechanism of disease. It affects travelers of all ages. The enteroinvasive form is closely related antigenically and biochemically to Shigella species and causes a similar dysenteric illness. E. coli is identified by distinct groups of either somatic or flagellar antigens that determine virulence properties. Plasmid infection usually is associated with invasive qualities. This form affects mostly adults and is often food borne. The enteropathogenic form is responsible for sporadic and endemic diarrhea in infants. It is defined by serotypes and the absence of virulent qualities, such as toxins. The enterohemorrhagic form produces bloody diarrhea without fever and is associated with a cytotoxin. Last, the enteroadherent form is related to acute and chronic diarrhea of travelers to Mexico and India. Prophylaxis with several agents is effective but difficult to achieve and not recommended. Treatment with antibiotics is helpful to shorten the course in only selected cases.[18] The specific cause of acute diarrheal illnesses in chronically ill and immunosuppressed patients requires attention to the previously discussed agents, normal flora, and several unusual organisms. In patients with acquired immunodeficiency syndrome, clinical presentations may be acute, chronic, or recurrent and difficult to treat.[19] Unusual organisms may include Mycobacterium avium, Cryptosporidium, cytomegalovirus, and adenovirus. Treatment-related complications caused by C. difficile, Candida albicans, and Pseudomonas aeruginosa are more common in immune-suppressed patients because of frequent antibiotic exposure.

Clinical Features Diagnostic Findings Fluid and electrolyte disorders in children require meticulous diagnostic skills because serious illness may be overlooked with cursory examination or treatment. The principal concern in diarrheal illness relates to the fluid, electrolyte, acid-base, or nutrient defects that may result from vomiting, diarrhea, or decreased oral intake. Diarrhea can be defined as an increase in liquidity, frequency, or volume of stools. It is often difficult to quantitate these characteristics from the history provided by the parents. Helping the parent describe the stool relative to usual bowel habits will provide valuable information for comparison.

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History should include specific information regarding the order of presentation, duration, severity, and quantity of each symptom. It should reveal the presence or absence of fever, nausea, vomiting, hematemesis, abdominal pain, diarrhea, hematochezia, and emesis. The consistency and content of stools is important. Inquire about the relationship of symptoms to eating and drinking. It is helpful to know whether others in the household have a similar illness and whether previous episodes have occurred. A history of travel to endemic or epidemic areas may provide important information. Quantity and time of recent oral intake and information about recent preillness weight can be helpful. If the patient is old enough, information about orthostasis and the patient's activity level is desirable. The physical examination should address the vital signs. Older children and adults may manifest symptoms at a lesser degree of volume disorder because of relatively smaller total body water and extracellular fluid volume. Important areas to emphasize are addressed in Table 171-1 . Table 171-1 -- Clinical Assessment of Degree of Dehydration Mild (2 sec

+ + − Lethargic + + + + >2 sec

Volume

Small

Oliguria

Oliguria/anu ria

Specific gravity[*]

≥1.020[†]

>1.030

>1.035

Urine

Blood BUN WNL[†] Elevated pH (arterial) 7.40–7.30 7.30–7.00 From Barkin RM, Rosen P: Emergency pediatrics, ed 5, St Louis, 1999, Mosby.

Very high 6 mm) indicates a deficit. Vascular assessment should include evaluation of the pulse at the wrist and capillary refill of the hand. Patients should have ongoing assessment for the development of compartment syndrome of the forearm. If there is pain on flexion or extension of the fingers, forearm tenderness, or pain that is disproportionate to the injury, compartment pressures should be measured immediately. Unrecognized ischemic injury can result in Volkmann's ischemic contracture. Table 174-3 -- Neurologic Examination of the Distal Upper Extremity Nerve

Motor Findings

Sensory Findings

Radial

Wrist extension

Thumb and first finger web space

Ulnar

Wrist flexion and adduction

Little finger

Finger spread

Ulnar aspect of palm of hand

Wrist flexion and abduction

Thumb, index, and middle fingers

Thumb opposition

Radial aspect of palm of hand

Distal phalanx flexion (thumb/first finger)

None

Median Anterior interosseous

Radiographic evaluation of any elbow injury should include an AP view of the extended elbow and a lateral view of the flexed elbow. If these views do not show a fracture but clinical suspicion is high, oblique views are helpful. Even with proper radiographs, diagnosis of a pediatric elbow fracture can be difficult. The elbow is largely cartilaginous during early childhood, and the six secondary centers of ossification around the elbow can camouflage or be mistaken for fractures ( Figure 174-12 ). These ossification centers can be remembered by the mnemonic CRITOE—capitellum, radius, internal (medial) epicondyle, trochlea, o lecranon, and external (lateral) epicondyle. The approximate age at which these sites ossify may be estimated at 1, 3, 5, 7, 9, and 11 years, respectively ( Table 174-4 ).

Figure 174-12 Ossification centers of the elbow. 1, Capitellum; 2, radial head; 3, m edial epicondyle; 4, trochlea; 5, lateral epicondyle. ((From Connolly JF: DePalm a's Managem ent of Fractures and Dislocations. Philadelphia, WB Saunders,

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1981.)Elsevier Inc.)

Table 174-4 -- Sequence of Ossification around the Elbow (CRITOE) Ossification Center

Age of Appearance

Capitellum

6–12 months

Radial head

4–5 years

Medial (Internal) epicondyle

5–7 years

Trochlea

8–10 years

Olecranon

8–9 years

Lateral (External) epicondyle

9–13 years

Bony relationships are helpful when evaluating a radiograph for the presence of a supracondylar fracture ( Figure 174-13 ). In a true lateral view, the anterior humeral line should bisect the capitellum. If the capitellum falls posterior to this line, an extension-type supracondylar fracture is likely. In all views, the proximal end of the radius and radial neck should point to the capitellum. Baumann's angle is also helpful in diagnosing subtle supracondylar fractures ( Figure 174-14 ). This angle is formed by drawing a line that follows the growth plate of the capitellum and transecting it with a line that runs perpendicular to the axis of the humerus. The angle should be approximately 75 degrees. Baumann's angle should be the same in both elbows, and differences between elbows can be used to detect subtle supracondylar fractures. Postreduction alterations in Baumann's angle reliably predict the final carrying angle.[9]

Figure 174-13 Lateral radiograph dem onstrating the bony relationships in a norm al elbow. The anterior hum eral line (solid) and proxim al radial line (dashed) bisect the capitellum. ((From Weissm an BN, Sledge CB: Orthopedic Radiology. Philadelphia, WB Saunders, 1986.)Elsevier Inc.)

Figure 174-14 Baum ann's angle in a norm al elbow on an anteroposterior radiograph. ((From Worlock P: Supracondylar fractures of the hum erus: Assessm ent of cub itus varus b y the Baum ann angle. J Bone Joint Surg Br 68:755, 1986.))

Fat pads also provide a means for detecting occult supracondylar fractures. A lateral radiograph with the elbow flexed at 90 degrees may show an anterior fat pad protruding from the coronoid fossa. This finding is normal unless the pad is bulging or in the shape of a ship's sail. This “sail sign” may indicate fluid in the joint, although alone it may not be a reliable predictor of a fracture. The posterior fat pad, however, sits snugly within the olecranon fossa and should never be seen unless there is a fracture around the elbow. In this

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case, blood pushes the fat pad laterally and thus makes it visible on a lateral radiograph of the elbow. Therefore, visualization of a posterior fat pad suggests the presence of an occult fracture around the elbow and, if the fracture is not seen, warrants oblique views of the elbow ( Figure 174-15 ), splinting, and follow-up.

Figure 174-15 Lateral radiograph of a supracondylar fracture with an anterior fat pad “sail sign” and a posterior fat pad.

Plain radiographs are usually sufficient for diagnosing supracondylar fractures; however, if the diagnosis remains in question after AP, lateral, and oblique radiographs are obtained, ultrasound may be useful in infants,[10] and magnetic resonance imaging (MRI) may be useful in older children.[11] With strong clinical suspicion, some orthopedic surgeons bypass MRI in favor of an intraoperative arthrogram.[12] Emergency department treatment of supracondylar humeral fractures is determined by displacement and neurovascular status. A pale, pulseless cold hand mandates emergency consultation with an orthopedic surgeon. If an orthopedic surgeon is unavailable and the vascular supply has not been restored, reduction should be attempted ( Figure 174-16 ). If necessary, reduction can be performed by a single operator: with the patient supine, the shoulder held in 90 degrees of forward flexion, and the elbow slightly flexed, both hands are placed on the arm proximal to the fracture and both thumbs are placed on the posterior aspect of the fracture fragment. Then, while directing the thumbs distally, the fragment is lifted onto the distal metaphysis. The return of blood supply is marked by the hand becoming warm and pink. If perfusion does not improve, another reduction may be attempted, with care taken to not entrap the brachial artery and median nerve. Multiple attempts at reduction increase the likelihood of neurovascular injury and swelling; therefore, no more than two reductions should be attempted. A supracondylar fracture with a pulseless hand that is warm and pink does not need to be reduced and should be splinted as it lies so that vascular status is not further compromised. The elbow should be splinted in relative extension because too much flexion in conjunction with swelling may obstruct the brachial artery and contribute to limb ischemia.

Figure 174-16 Steps in reduction of (A) a displaced supracondylar fracture. B, The assistant fixes the arm of the patient while the physician grasps the patient's wrist and applies steady traction in line with the long axis of the arm while keeping the forearm in the neutral, thum b-up position. C, If the distal fragm ent is displaced laterally, it is pushed inward with the physician's other hand. If it is displaced m edially, it is pushed outward. Throughout manipulation, traction is m aintained. D, After length is restored and the m edial and lateral displacem ent corrected, the physician's thum b is placed over the anterior surface of the proxim al fragm ent with the fingers behind the olecranon, and the elbow is gently flexed. The arm is then im m obilized with the forearm pronated, and laterally displaced fractures are imm obilized with the forearm supinated. ((From Geiderm an JM, Magnusson AR: In Rosen P, Barkin R [eds]: Hum erus and Elb ow in Em ergency Medicine: Concepts and Clinical Practice, 4th ed. St Louis, CV Mosb y, 1998.)CV Mosb y)

Gartland type I fractures can be splinted in the emergency department with the arm maintained in flexion and neutral rotation. Hospital admission is not required, but referral to an orthopedic surgeon the next day is recommended. These fractures are generally treated with 3 to 4 weeks of immobilization. Gartland type III fractures require immediate orthopedic consultation and should be treated by either closed reduction and percutaneous pinning or open reduction and internal fixation in the operating room. Treatment of a partly displaced type II fracture is controversial. Some surgeons reduce and pin it in the operating room, whereas others perform closed reduction and keep it immobilized in a cast. However, treatment of displaced supracondylar fractures by closed reduction and casting is associated with higher complication rates than

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treatment by closed reduction and pinning is[13]; therefore, most are treated with pins and casting for 3 to 4 weeks. The primary complications of supracondylar fractures are related to neurovascular injury. Type III fractures are at greatest risk, with neurovascular compromise occurring in as many as 49% of patients.[9] The median nerve is involved in half the cases and is associated with posterolateral displacement, and the radial nerve is involved in almost a third of patients and is associated with posteromedial displacement. Brachial artery injuries occur in approximately 40% of patients and are found with either type of displacement. Fortunately, the brachial artery has many branches around the elbow, and flow to the forearm and hand can be maintained even when the brachial artery is injured. Despite the frequency of neurovascular deficits immediately after the accident, most nerve palsies are caused by stretching or contusion and resolve spontaneously. The typical course for nerve injuries is complete resolution. Although motor function usually returns within 12 weeks, sensory function may not return for 6 months or longer.[14] If there is no clinical or electromyographic evidence of nerve recovery after 5 months, exploration and neurolysis are indicated.[15] Volkmann's ischemic contracture and permanent limb disability are the end result of untreated vascular injury. It is extremely rare and easily prevented by close observation and evaluation for the development of compartment syndrome. A few supracondylar fractures heal with a “gunstock” deformity; however, the combination of varus, hyperextension, and medial rotation of the limb is not a functional problem and, except in severe cases, requires no treatment. Severe cases can be corrected by humeral osteotomy.

Monteggia Fracture-Dislocation Monteggia fracture-dislocation are characterized by a fracture of the proximal third of the ulna plus dislocation of the radial head. They can be very subtle, with only a minor greenstick fracture or bowing of the ulna. Isolated ulna fractures are rare in children; therefore, in all such fractures, AP and lateral radiographs of the elbow should be taken to rule out dislocation of the radial head. Monteggia fracture-dislocations require urgent referral to an orthopedic surgeon for closed reduction of the radial head dislocation and repair of the ulna fracture. Complications include permanent radial head dislocation, valgus deformity of the arm, loss of pronation, and late radial nerve palsy.

Nursemaid's Elbow Radial head subluxation, or nursemaid's elbow, is the most common upper extremity injury in children younger than 6 years who are taken to a pediatric emergency department.[16] It typically occurs when axial traction is placed on an extended and pronated arm, as when a child is pulled up or swung by the arms. It may also occur when a child falls onto an outstretched arm, sustains minor direct trauma to the elbow, or simply twists the arm. In infants, radial head subluxation can occur when an extended arm is caught beneath the infant's body while being rolled over. Pathologically, subluxation occurs when the annular ligament becomes loosened from the head of the radius and slips into the radiocapitellar joint, where it becomes entrapped ( Figure 174-17 ).

Figure 174-17 Nursem aid's elbow. In a nursem aid's elbow injury, as an axial force is applied, the annular ligam ent around the radial head is dislodged. The ligament is then partially dislocated into the radiocapitellar joint when the arm is released. ((From Sim on R, Kownigsknecht S: Em ergency Orthopaedics: The Extrem ities, 2nd ed. E Norwalk, Conn, Appleton & Lange, 1987.)Appleton & Lange)

Nursemaid's elbow is an injury that occurs in children a few months old to 5 years of age and has a peak incidence between 2 and 3 years of age.[17] It has been reported in children younger than 6 months[17] and has been seen in children as old as 9 years. It has a slight predilection for girls. Children often have a consistent history followed by an acute onset of arm pain that may or may not be localized to the elbow. The affected arm is held still against the body, with the elbow slightly flexed and the arm pronated. Physical examination is significant for a lack of swelling, erythema, ecchymosis, or deformity.

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There may be mild tenderness on palpation of the radial head. Pain is elicited with supination, pronation, and elbow flexion. The diagnosis of nursemaid's elbow is made clinically, and radiographs are not necessary. If, however, significant point tenderness, swelling, or ecchymosis is present or if the history suggests another injury, such as a supracondylar fracture, radiographs should be obtained. Though not commonly used as a diagnostic procedure, ultrasound may demonstrate a widened space between the radial head and capitulum.[18] Radial head subluxation is an orthopedic injury that is easily reduced without sequelae. Classically, the affected elbow is gripped with the practitioner's thumb over the radial head, and with the other hand, the practitioner flexes and supinates the patient's arm. As the radial head relocates, the practitioner feels it click or clunk under the thumb. Hyperpronation of the forearm is also effective in reducing radial head subluxation. As is done in the flexion-supination maneuver, the practitioner holds the affected elbow with the thumb over the radial head, but then flexion-supination is replaced with hyperpronation of the forearm. Success rates range from 80%[17] to 92%[19] with supination and 93%[20] to 98%[21] with pronation. Pronation may also be less painful to the patient and is the reduction method of choice.[21] After successful reduction, the child typically uses the arm normally within 10 minutes. This may be delayed in younger children and when the injury occurred more than 4 to 6 hours before reduction. Inability to reduce a nursemaid's elbow may result from improper reduction technique, swelling of the annular ligament as a result of edema, hemorrhage, or hematoma, or disruption of the annular ligament. Failure to reduce a nursemaid' elbow is also more likely if it is attempted 12 or more hours after the injury. If two attempts at reduction fail to result in normal use of the arm, alternative diagnoses should be entertained. Because of the similarity in clinical findings, children should be assessed for fractures of the clavicle and elbow. If no other pathology is found and the child is still not using the arm, a posterior splint should be applied with the elbow kept at 90 degrees and the forearm in supination. Follow-up evaluation with an orthopedic surgeon should be arranged for the next day. Recurrence rates of radial head subluxation range from 5% to 39%, depending on the referral population studied.[] With recurrent subluxations, immobilization in a posterior splint with the elbow maintained at 90 degrees and the forearm supinated may be warranted. The need for open reduction or repair of the annular ligament is exceedingly rare.

Toddler's Fracture Toddler's fractures are oblique nondisplaced fractures caused by low-energy torsional forces applied to the very porous bone of infants and young children. Previously, it referred only to tibial fractures in children between 9 and 36 months of age, but the term is now applied more loosely. The mechanism of injury can be as mild as a child twisting on the leg while walking or a fall from an insignificant height. In some instances, there may be an unknown mechanism of injury. The child will have a limp or refuse to walk on the affected leg. Some children will revert to crawling and can crawl without pain. Examination may show mild swelling of the leg and point tenderness. Gentle twisting of the lower part of the leg may elicit pain. AP and lateral radiographs may reveal a spiral or oblique fracture extending downward and medially through the distal third of the tibia ( Figure 174-18 ). An internal oblique radiograph is helpful if there is no evidence of fracture on the AP or lateral views. If all views are negative, consideration should be given to fractures elsewhere in the limb. If no fracture is apparent, the child should be splinted for comfort and radiographs repeated in 10 days, at which time periosteal new bone or sclerosis of the fracture edges will make the fracture visible. If these radiographs are negative and the child is still limping, further evaluation should be undertaken to rule out osteomyelitis and malignancy. Bone scans are often helpful in assessing a limping toddler and are more sensitive for fractures than plain radiographs are. Treatment of a toddler's fracture consists of a below-knee walking cast for approximately 3 weeks.

Figure 174-18 Toddler's fracture.

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The presence of a spiral fracture without an appropriate history may raise concern of child abuse. Midshaft fractures, which are more common in abused children, tibial fractures in nonambulating children, or other unexplained or frequent injuries should prompt further evaluation.

Skeletal Aspects of Child Abuse Perspective Fractures are the second most common manifestation of child abuse, second only to soft tissue injury, and are present in up to 70% of physically abused children. Fractures associated with child abuse occur in the very young: 50% in children younger than 12 months[22] and 94% in children younger than 3 years.[23] With child abuse, a timely and accurate diagnosis is imperative because children who are returned to an abusive home face a 35% chance of repeated abuse and a 10% chance of death. No fracture is pathognomonic for abuse, but certain fracture patterns are more worrisome than others. Any fracture in a child younger than 1 year, fractures of different ages, and bilateral or multiple fractures indicate a need for thorough assessment for intentional injury. Injuries that are especially concerning include complex skull fractures, rib fractures, metaphyseal fractures, and vertebral fractures or subluxations. Midshaft humeral and scapular fractures are nearly always associated with abuse, as are approximately 70% of femoral fractures in children younger than 1 year.

Specific Disorders/Injuries Diaphyseal Fractures Although multiple fractures of different ages are strongly suggestive of child abuse, the most common manifestation of child abuse is an isolated diaphyseal fracture, which occurs four times as often as classic metaphyseal fractures. The humerus, femur, and tibia are the most frequently fractured long bones; the radius and ulna are the most infrequently fractured. With the exception of supracondylar fractures, all fractures of the humerus in children younger than 3 years are strongly suggestive of abuse.[24]

Metaphyseal Fractures Though less common than diaphyseal fractures, metaphyseal fractures are more specific for child abuse. Metaphyseal fractures most commonly affect the tibia, femur, and proximal end of the humerus. Corner fractures and bucket handle fractures, which may be the same fracture viewed in two different projections, result from violent shaking or forceful pulling or twisting of an infant's limb. The diagnosis is made by careful evaluation of high-quality plain radiographs. However, the tight adherence of the periosteum at the metaphysis precludes an active periosteal response, thus making these fractures difficult to diagnose even in the healing stages. Bone scans, though sometimes helpful, are difficult to interpret because of the normally increased radionuclide uptake in the metaphyseal area.

Rib Fractures Rib fractures are present in 5% to 27% of cases of child abuse, with 90% occurring in children younger than 2 years. The young pediatric rib cage is very compliant, and it takes considerable force to break a rib. Because of the force involved, rib fractures are seldom seen in unintentional injury and are never seen after cardiopulmonary resuscitation.[25] In a child younger than 3 years, the positive predictive value of a rib fracture as an indicator of intentional trauma approaches 100%.[26] Posterior rib fractures are most common and result from maximal mechanical stress as the rib is levered over the transverse process of the vertebral body when infants are grasped and shaken. The ribs fail mechanically at the head or neck. Abuse-related rib fractures tend to be multiple and symmetrical and may be difficult to diagnose acutely by standard radiographs. Radiographs repeated at 7 to 10 days after the injury are advised if the initial films are negative but suspicion is high. Radiographic findings include callus formation or widening of the rib neck as a result of apposition of new bone subperiosteally. Bone scans can be helpful in detecting fractures in the acute setting.

Skull Fractures Skull fractures are the second most frequent orthopedic injury in abuse and occur more commonly in abuse than in unintentional trauma.[22] Eighty percent occur in infants younger than 1 year, and although complex skull fractures are more suspicious for abuse, linear skull fractures are the most common type. Standard skull radiographs may not be adequate for diagnosis and are reported to miss more than 25% of head injuries. Children who meet high-risk criteria (the presence of rib fractures, multiple fractures or facial injury, or age younger than 6 months) should undergo CT or MRI to assess for occult head injury.[27]

Periosteal New Bone Formation

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Periosteal new bone formation, which is one of the most common findings in cases of abuse, reflects separation of the periosteum from the bone and may be the only finding of orthopedic trauma related to child abuse. It may be present with or without a fracture. It results from shaking, from acceleration-deceleration forces applied to an unsupported limb, or from forceful gripping.

Diagnostic Strategies Radiography Conventional skeletal radiography is the screening examination of choice in cases of suspected physical abuse. Unsuspected fractures are found in 22% of physically abused children and are more common in the very young. A complete skeletal survey is recommended for all physically abused children younger than 2 years and for all infants younger than 1 year with evidence of abuse or neglect. Complete skeletal surveys are rarely indicated in children older than 5 years, and in children between 2 and 5 years old, the need for a skeletal survey is determined on a case-by-case basis. A skeletal survey consists of an AP view of the extremities (including the hands and feet), frontal and lateral views of the thoracolumbar spine, including the ribs, and an AP and lateral skull series. In cases in which abuse is strongly suspected but radiographs are negative, bone scanning serves as an adjunct and is complementary to the skeletal survey in detecting injury. It is sensitive for subtle rib, spine, and diaphyseal trauma, especially in the acute setting, but because findings can persist for years, it is not reliable in determining the age of the fracture.

Differential Considerations Although most cases of intentional injury are easily diagnosed with a thorough history and physical examination, certain conditions can be confused with child abuse. Metaphyseal cupping and spurring and periosteal new bone formation are two normal variants that radiographically are almost identical to what is seen in cases of child abuse. These findings occur in more than 40% of normal infants. They appear between 2 and 3 months of age and may persist until 8 months of age. These findings can be differentiated from child abuse by subtle radiographic clues: normal-variant infantile metaphyseal spurs are in continuity with normal bone and cortex, and physiologic periostitis is bilateral, confined to the diaphysis, and smooth and lamellar in appearance. Physiologic periostitis also tends to be more obvious on the medial aspect of the bone and most commonly involves the femur, although it also is seen in the humerus and tibia. Radiographic differentiation between normal variants and trauma-related injury is extremely difficult, and the clinical findings must be taken into account. Osteogenesis imperfecta (OI), a heritable disorder of connective tissue, is an alternative cause of multiple fractures with minimal trauma. In the United States, the estimated incidence is 1 in 20,000 persons. This estimate includes children in whom the condition is diagnosed within 1 year of birth but does not include milder forms of the disease that are not diagnosed until later in life. As such, the incidence of OI could be significantly higher. Most types of OI have been linked to mutations in type I collagen genes that interfere with either the synthesis or the construction of collagen subunits. Clinical features include bone fragility, ligament laxity, defective dentinogenesis, short stature, scoliosis, middle ear deafness, blue sclera and tympanic membranes, and misshapen skulls. On radiographs, the bones are diffusely osteopenic with thin cortices and attenuated trabecular patterns. The long bones have narrow diaphyses, and bowing and fractures are common ( Figure 174-19 ).

Figure 174-19 Radiograph of a child with osteogenesis im perfecta. Note the narrow diaphyses, osteopenia, and m ultiple fractures.

There are four types of OI, and depending on the type, the severity of disease ranges from intrauterine demise to an infant with multiple fractures to an almost symptom-free adult ( Table 174-5 ). The diagnosis of OI is made on the basis of the history, physical examination, and radiographic findings. Confirmation is by skin biopsy and culture of dermal fibroblasts for evaluation of type I collagen. However, because the molecular basis for the entire spectrum of disease has not been established, up to 10% of cases of OI would be missed with skin biopsy alone.[28] Emergency department management of children with OI

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includes appropriate orthopedic referral for fractures and primary care referral for hearing evaluation. Table 174-5 -- Classification of Osteogenesis Imperfecta Type I

Inheritance

Sclerae[*]

Bone Fragility

Autosomal dominant Mild to moderate

Blue

Other Most common form of OI

Onset of fractures after birth

Presenile hearing loss

Most fractures in preschool years

Type A: normal teeth Type B: dentinogenesis imperfecta

II

Autosomal dominant Very severe —new mutation; autosomal recessive

Dark blue

Subtypes A, B, and C based on radiographic findings

Normal

Occasional deafness

Lethal in perinatal period III

Autosomal dominant Moderate to severe —new mutation; autosomal Severe recessive osteoporosis Fractures at birth with progressive deformity

IV

Autosomal dominant Mild to moderately severe More severe than type I

Normal, gray or blue Occasional in infancy deafness Normal by adolescence

Type A: normal teeth Type B: dentinogenesis imperfecta

*

Blue sclerae are norm al in infants up to 4 m onths old.

In addition to musculoskeletal complaints, children with OI are predisposed to abdominal pain and neurologic abnormalities. The abdominal pain is thought to be related to the trefoil-shaped pelvis and acetabular protrusion associated with OI. These structural abnormalities narrow the pelvic outlet and result in partial rectosigmoid obstruction and subsequent constipation or obstipation. Patients with this problem respond to an aggressive bowel program and disimpaction. Referral to a gastrointestinal specialist may be warranted. Neurologic abnormalities associated with OI result from basilar impression. Basilar impression, or elevation of the floor of the posterior cranial fossa, is reported to occur in 25% of patients with OI.[29] It is seen most frequently in children with OI type IVB (71%), and 50% of patients with this type of OI will have neurologic signs or symptoms of compression of the posterior fossa structures.[29] The signs (nystagmus, facial spasm, nerve paresis, pyramidal signs, and papilledema) may predate the symptoms (headache, neuralgia, imbalance, weakness, and incontinence). The most serious outcomes of basilar impression include brainstem compression, respiratory arrest, and sudden death. Any neurologic changes in a patient with OI mandate neurosurgical evaluation. Several metabolic abnormalities can be associated with frequent fractures and radiographic abnormalities. Rickets, which results from vitamin D or calcium deficiency or hyperparathyroidism, can be manifested by diffuse osteopenia, fraying of the metaphysis, fractures, periosteal new bone formation, widening of the physis, and well-defined transverse stress fractures in the shafts of long bones. The diagnosis can be

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confirmed with laboratory testing. Menkes' kinky-hair syndrome, a rare X-linked recessive disorder involving inadequate copper absorption, is characterized by wormian skull bones, osteopenia, and metaphyseal fractures and spurring. These children have sparse, kinky hair, abnormal dentition, and developmental delay. Serum levels of copper and ceruloplasmin are low and confirm the diagnosis. Hypervitaminosis A, though a rare cause of fractures, does result in a thick periosteal reaction of tubular bones, most frequently the ulna and metatarsals, and widening of the cranial sutures. The epiphyses and metaphyses are normal. The diagnosis is based on the history and vitamin A levels. Congenital syphilis can also mimic nonaccidental injury. Skeletal findings of congenital syphilis are frequently diffuse and symmetrical and involve the long bones, skull, and small bones of the hands and feet. Radiographic findings include osteolytic defects, periosteal reaction, and metaphyseal lucencies parallel to the physis. The diagnosis is confirmed by serologic testing.

Developmental Dysplasia of the Hip Perspective Developmental dysplasia of the hip (DDH), formerly known as congenital dislocation of the hip, is abnormal formation of the hip joint that occurs between organogenesis and fetal maturity.[30] It encompasses a spectrum of disease ranging from subluxatable, or loose, hips to frankly dislocated hips. In white neonates, the incidence of dysplasia is 1%, and the incidence of dislocated hips is 0.1%. It is more common in Native American populations and less common in African American, Korean, and Chinese populations. There appears to be a familial predilection for the development of DDH; one British study noted that more than 20% of children who required treatment of DDH had a positive family history.[30] DDH is more common in girls and most frequently unilateral (80%). With unilateral involvement, there is a slight predilection for the left side. Associated birth factors include oligohydramnios, breech presentation, torticollis, talipes equinovarus, metatarsus adductus, and being first born.[31] DDH has also been associated with congenital muscular torticollis.[32] Postnatally, swaddling infants with their hips and knees in extension predisposes to dislocation.

Principles of Disease The etiology of DDH is not entirely clear. Three theories have been postulated: mechanical issues related to fetal position and environment, primary acetabular dysplasia, and ligamentous laxity that is enhanced by maternal relaxin hormone. Each theory has merit, and it is most likely a combination of factors that contribute to the development of DDH.

Clinical Features DDH may be diagnosed at birth, or despite frequent and appropriate physical examinations, it may not be discovered until later in life. In one study, 6% of children with documented DDH had normal physical examinations at birth.[30] Conversely, in more than 50% of infants found to have unstable hips at birth, the hips become spontaneously stable within 3.5 days.[33] The manifestations and physical findings of DDH are as diverse as the disease itself. This variability is due to differences in the severity of the dysplasia and the progressive changes that occur over time. Up to 4 to 6 months of age, the diagnosis of DDH is based on physical examination findings of leg length, skinfold, and range-of-motion asymmetry and abnormal findings on the Barlow provocative test and the Ortolani reduction maneuver. Skinfold asymmetry can be noted in the groin, below the buttock, and along the thighs. Although skinfold asymmetry is not specific for DDH, being present in approximately 30% of infants with normal hips, it is sensitive, and the diagnosis of DDH is very unlikely in infants with normal skinfold symmetry. Range of hip motion is also helpful in diagnosing DDH; any asymmetries in hip flexion, abduction, and external rotation should prompt further investigation. Although the general physical examination can be helpful in assessing hip stability, the physical diagnostic cornerstones for diagnosing DDH in young infants are the Ortolani reduction maneuver and the Barlow provocative test. The Ortolani reduction maneuver is performed in an attempt to reduce a dislocated hip back into normal position, and the Barlow provocative test detects a subluxatable or dislocatable hip ( Box 174-1 ). Abnormal findings include the presence of a “clunk” with the Ortolani test and any abnormal movement between the femoral head and the acetabulum with the Barlow maneuver. BOX 174-1 Ortolani and Barlow Maneuvers Ortolani (Reduction) Maneuver

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1.

2.

3.

Stabi lize the pelvi s with one hand . With the other hand , sligh tly abdu ct the infan t's hip. With the inde x and long finge rs over the great er troch anter , pull up the thigh to gentl y redu ce the hip.

Barlow (Provocative) Test

1.

Stabi lize the pelvi s with one

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2.

3.

4.

hand . Plac e the thum b on the inner aspe ct of the thigh near the less er troch anter . Addu ct the hip. Exer t dow nwar d pres sure on the thigh with the thum b and push it into the table .

After about 4 to 6 months of age, soft tissue contractures develop, the Ortolani and Barlow tests yield less information in detecting unstable hips, and range-of-motion abnormalities become more apparent. Parents may notice limited or asymmetric leg movements or difficulty with diapering. On examination there is limited abduction, relative shortening of the femoral segment (Galeazzi's sign) ( Figure 174-20 ), and skinfold asymmetry. In children with bilateral DDH, the diagnosis is even more difficult beyond the first few months of life because of the absence of asymmetry. After the development of contractures, physical findings in bilateral DDH include widening of the perineum, abduction less than 45 degrees, and the appearance of abnormally short thigh segments.

Figure 174-20 Galleazzi's sign. A positive Galeazzi test reveals asym m etry in the level of the patient's knees. ((From Tolo VT, Wood B: Pediatric Orthopedics in Prim ary Care. Baltim ore, William s & Wilkins, 1983.)William s & Wilkins)

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With the onset of walking, gait asymmetry or asymmetric in-toeing or out-toeing is a clue to the presence of DDH. Adduction and flexion contractures, a positive Galeazzi sign, hyperlordosis, and a waddling gait are common findings. Clinical observation reveals a Trendelenburg sign: while standing, the patient lifts one leg up at a time, and because the gluteal muscles are weakened on the affected side, the pelvis drops to the opposite side. With bilateral DDH, children have a wide-based waddling gait.

Diagnostic Strategies Radiographs of infant hips are extremely difficult to interpret and may provide a false sense of security if they seem normal. Before the child is 3 to 6 months old, at which time the femoral head ossifies, an abnormal relationship between the upper end of the femur and the acetabulum may not be apparent. Additionally, in infants with unstable, but nondislocated hips, radiographs show the hip in position and its instability is not detected. Before femoral head ossification, a better diagnostic test is ultrasonography.[34] Because a large percentage of infants will have abnormal ultrasound findings in the first week of life, with many of these abnormalities resolving within a few weeks,[30] it is best to delay ultrasound in children with nondislocated, but possibly unstable hips until 4 to 6 weeks of age. Children with dislocated hips require immediate ultrasound. After approximately 6 weeks the ossific nucleus of the femoral head is detectable, and radiographs are more likely to reveal abnormalities and asymmetry. A standard AP pelvis radiograph with both legs extended in neutral abduction is then sufficient for diagnosis. Radiographic findings may include lateral displacement of Shenton's line and a widened acetabular angle; angles greater than 30 degrees are abnormal, and those greater than 40 degrees indicate dislocation.

Management Treatment of DDH is most successful when begun early, and delay in detection may lead to a significantly worse prognosis. Patients with untreated abnormal hips that persist beyond the newborn period are at risk for osteoarthritis, pain, abnormal gait, leg length discrepancy, and decreased agility. For this reason, all children who are seen in the emergency department should have their hips examined until they are able to walk. Neonates who have a dislocated hip at birth should be referred to a pediatric orthopedist immediately. When a newborn has a loose, but nondislocated hip, referral can be made within 2 weeks. Children who are seen after the newborn period should be immediately referred to a pediatric orthopedic surgeon. The essential, basic goals of treatment are concentric reduction of the hip. After concentric reduction, stability must be obtained so that when the leg is allowed to move, it does not sublux or dislocate. This position is maintained until all the dysplastic features of the bone and cartilage have resolved. The two most important complications are failure to achieve these goals and aseptic necrosis of the femoral head. In the first 6 months of life, the Pavlik harness is the mainstay of treatment. It is a dynamic splint that allows movement while preventing hip extension or adduction. Other treatment options include the Craig and vonRosen splints.[35] If these modalities are unsuccessful, a hip spica cast is usually the next choice. Beyond 6 months of age, a hip spica cast or fixed orthosis is required. Surgical release of contracted muscles may be necessary in older infants and children, and open surgical reduction is required if complete closed reduction is not achieved. Femoral or pelvic osteotomy (or both) may be necessary to reduce and stabilize dislocated hips in children older than 2 or 3 years.[36] Beyond 4 years of age in bilateral cases and 8 years of age in unilateral cases, reduction should not be attempted. The risk of aseptic necrosis and the potential for a poor result are too high.[31]

Hip Pain in Children Perspective Hip pain in children is an extensive topic with myriad causes ( Box 174-2 ). The extensive differential diagnosis precludes an in-depth review of the topic in this chapter, but an overview of some of the more common causes of hip pain in children is presented. BOX 174-2 Causes of Hip Pain in Children

Trauma Hip or

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pelvi s fract ures Over use injuri es

Infection Septi c arthri tis Oste omy elitis

Inflammation Tran sient syno vitis Juve nile rheu mato id arthri tis Rhe umat ic fever

Neoplasm Leuk emia Oste ogen ic or Ewin g's sarc oma Meta stati c dise ase

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Hematologic Disorders Hem ophili a Sickl e cell ane mia

Miscellaneous Legg -Cal vé-P erthe s dise ase Slipp ed capit al femo ral epip hysi s

Specific Disorders/Injuries Transient Synovitis Transient synovitis is the most common cause of hip pain in childhood.[37] It is a self-limited inflammatory condition caused by a nonpyogenic inflammatory response of the synovium. Although it has been reported in children as young as 3 months and occasionally occurs in adults,[38] its peak incidence is between 3 and 6 years of age. Transient synovitis of the hip affects boys more commonly than girls and has a slight predilection for the right side. Less than 5% of cases are bilateral. Approximately half the patients are initially seen acutely, usually within the first 3 days of the onset of symptoms, whereas the other half have a more insidious course, with symptoms occurring for weeks to months before medical evaluation.[39] Though most commonly affecting the hip, transient synovitis can also affect the knee. The etiology of transient synovitis is unknown. Current theories imply an association with active or recent infection, trauma, or allergic hypersensitivity. At least half the children with transient synovitis have or recently have had an upper respiratory illness.[40] One study demonstrated a fourfold rise in viral titer in 45% of patients and elevated serum interferon levels, consistent with a concurrent viral infection, in 43% of patients with transient synovitis.[41] Trauma is commonly associated with transient synovitis, but no clear relationship has been demonstrated. Similarly, a causal association with an allergic reaction to an infectious agent has been suggested but not proved. It is estimated that transient synovitis of the hip may occur in up to 3% of children. Hip or groin pain is the most common initial finding, but referred pain to the medial aspect of the thigh or knee is found in 10% to 30% of patients. Affected patients either walk with a limp or, with severe pain, refuse to walk at all. The leg is held in flexion with slight abduction and external rotation. On examination, passive movement is usually pain free; however, there may be pain and a slightly decreased range of motion with extreme internal rotation or abduction. Although most children with transient synovitis tend to otherwise be well, some will have a

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low-grade fever and malaise. The diagnosis of transient synovitis is one of exclusion and relies on the history and physical examination in combination with limited laboratory testing and AP and “frog-leg” lateral radiographs of the pelvis. Laboratory tests are used to help differentiate children with transient synovitis from those with septic arthritis. In transient synovitis, laboratory values may be normal or may reveal mild elevations in the white blood cell count and erythrocyte sedimentation rate (ESR), both consistent with a nonspecific inflammatory process. One study showed that children with septic arthritis had a significantly higher mean ESR (44 mm/hr versus 19 mm/hr) and a higher mean white blood cell count (13.2 × 109/L versus 11.2 × 109/L) than children with transient synovitis did. The temperature of children with septic arthritis was also significantly higher (38.1° C versus 37.2° C). An ESR greater than 20 mm/hr, a temperature higher than 37.5° C, or both, identified 97% of all cases of septic arthritis of the hip. However, there was a wide overlap of values between the two groups, and with the same criteria, 50% of patients with transient synovitis would have unnecessarily undergone hip aspiration.[42] Another study that combined clinical and laboratory evaluation found four criteria to be more indicative of septic arthritis than transient synovitis: severe hip pain and spasm (present in 62% of patients with septic arthritis versus 12% of patients with transient synovitis), tenderness on palpation (present in 86% of patients with septic arthritis versus 17% of those with transient synovitis), a temperature of 38° C or higher (present in 81% of patients with septic arthritis versus 8% of those with transient synovitis), and an ESR of 20 mm/hr or greater (present in 90% of patients with septic arthritis versus 10.9% of those with transient synovitis). The same study found that the duration of symptoms, history of antecedent viral infection, and elevations in white blood cell count were not helpful in distinguishing between transient synovitis and septic arthritis.[43] An ESR higher than 50 mm/hr has been shown to herald serious disease and should be monitored closely.[44] Although radiographs of the hip and pelvis tend to be normal in transient synovitis, they are helpful in excluding other diseases. Radiographic findings consistent with transient synovitis include medial joint space widening, an accentuated pericapsular shadow, and Waldenström's sign, which is lateral displacement of the femoral epiphysis with surface flattening secondary to effusion. However, these findings are also apparent in Legg-Calvé-Perthes (LCP) disease and, if present, mandate close follow-up or further investigation with MRI. In unclear or atypical cases, ultrasonography, which is as accurate as CT or MRI in detecting effusions,[] can be used to look for an intracapsular effusion or guide hip joint aspiration. Effusions are present in 60% to 70% of cases of transient synovitis; however, they are also present in septic arthritis, osteomyelitis, acute slipped capital femoral epiphysis (SCFE), LCP disease, rheumatoid and infectious arthritis, malignancy, and osteoid osteoma. As such, an effusion is neither sensitive nor specific for transient synovitis, and its presence should not, in and of itself, determine treatment. Nuclear scintigraphy in patients with transient synovitis is helpful in differentiating transient synovitis from osteomyelitis (with or without septic arthritis), LCP disease, and SCFE. Scintigraphy may demonstrate asymmetry in uptake in the capital femoral epiphysis, with decreased uptake early in the course of the disease and increased uptake later on. The early changes are also seen with very early LCP disease and suggest that some children with transient synovitis experience ischemia of the capital femoral epiphyses. This ischemia may be caused by an intracapsular effusion that tamponades vessels along the femoral neck. These ischemic findings have not yet been shown to have clinical significance. Most cases of transient synovitis can be managed at home with close follow-up by the child's primary care provider. Generally, these children have a mild limp and, if treated with nonsteroidal anti-inflammatory drugs, often show improvement in symptoms. A complete blood count, ESR, and radiographs should be obtained. Patients with severe symptoms, fever, and an elevated ESR should be evaluated for septic arthritis. If there is any doubt about the diagnosis, immediate orthopedic consultation is necessary. Treatment of transient synovitis is twofold: (1) rest via non–weight bearing or, in cases of extreme pain, bed rest and (2) reduction of synovitis with anti-inflammatory medications. Temperatures should be monitored closely, and any fever should be reported to the physician. Children are allowed a gradual return to activity as the pain subsides, and full, unrestricted activity is permitted when the hip is completely pain free with no evidence of a limp. Although many children with transient synovitis have an effusion, aspiration of the joint is not routinely performed, and there is no strong evidence that aspiration shortens the clinical course or prevents osteonecrosis. Repeat examination is recommended for all children within 12 to 24 hours and then again after 10 to 14 days if the symptoms have not resolved. The prognosis for children with transient synovitis is excellent. Up to 75% of patients have complete resolution of pain within 2 weeks and 88% within 4 weeks. The remainder may have less intense, but persistent pain for up to 8 weeks. Relapse is possible, though infrequent, and usually occurs within 6 months. In general, there are infrequent long-term sequelae of transient synovitis, including asymptomatic coxa magna (enlargement and deformity of the femoral head and neck caused by hypertrophy of cartilage secondary to inflammation) and mild degenerative cystic changes of the femoral neck. These changes persist for years and may be accompanied by radiographic degenerative change, but they do not tend to

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cause long-term functional disability. Additionally, a small number (2%) of cases of transient synovitis follow a clinical and radiographic course consistent with LCP disease. Whether this is due to ischemia of the capital femoral epiphyses during the early stages of synovitis or reflects an initial misdiagnosis is unclear. It is recommended that children with persistent symptoms undergo ultrasonography to evaluate for the presence of an effusion. Persistent joint effusion beyond 4 to 6 weeks is concerning for the subsequent development of LCP disease.[48] Some authors recommend routine 6-month follow-up radiographs for all children with transient synovitis,[39] whereas others reserve radiographs for children who remain symptomatic.[49]

Acute Septic Arthritis Septic arthritis refers to microbial invasion and infection of the joint space. Bacterial pathogens are common in patients with acute septic arthritis, whereas fungal and mycobacterial pathogens tend to be associated with chronic septic arthritis. Acute septic arthritis occurs in all age groups but is more common in children: 70% of cases occur in children younger than 4 years, and the peak incidence is between 6 and 24 months. Boys are affected twice as frequently as girls. Predisposing factors include preceding viral infection, trauma, im-munodeficiency, hemoglobinopathy, hemophilia with recurrent hemarthroses, diabetes, intravenous drug abuse, rheumatoid arthritis, and intra-articular injections or operations. Seventy-five percent of septic arthritis cases involve the joints of the lower extremity, with the knee being most commonly and the hip second most commonly involved. Other affected joints, in order of involvement, include the ankle, elbow, shoulder, and wrist. More than 90% of cases are monarticular. Hematogenous seeding, local spread, or traumatic or surgical infection may cause septic arthritis. In children, it most commonly results from hematogenous spread as bacteria pass into the synovial space through the highly vascular synovial membrane. The synovial membrane lacks a limiting basement membrane, which facilitates bacterial translocation. The bacteria then bind to bone and cartilage and initiate an inflammatory response that breaks down the joint by two mechanisms: directly through the effects of proteolytic enzymes and indirectly through pressure necrosis caused by accumulation of purulent synovial fluid. Contiguous spread of infection from osteomyelitis to the joint space occurs in approximately 10% of cases and is more common in newborns and young infants. In these children, blood vessels cross the physis and thereby connect the metaphysis and epiphysis and allow bacteria direct access into the joint space. Additionally, the joint capsules of the hip and shoulder overlie the bony metaphyses of the femur and humerus, thus facilitating direct extension of osteomyelitis into these joint spaces. The most common bacterial causes of septic arthritis are listed in Table 174-6 . Additional causative organisms include Neisseria gonorrhoeae in neonates and sexually active adolescents, Pseudomonas aeruginosa and Candida species in intravenous drug abusers, Salmonella species in children with sickle cell disease, and gram-negative bacteria in immunosuppressed children. Table 174-6 -- Septic Arthritis Pathogens and Treatment Age

Organism

Birth to 2 months

Group B Streptococcus

2 months to 3 years

Staphylococcus aureus Gram-negative rods Staphylococcus aureus

3 years to 12 years

Haemophilus influenzae Streptococcus pneumoniae Staphylococcus aureus

>12 years

Streptococcus pneumoniae Streptococcus pyogenes Staphylococcus aureus

Treatment Nafcillin, 50 mg/kg, and gentamicin, 2.5 mg/kg

Nafcillin, 50 mg/kg, and ceftriaxone, 50 mg/kg (consider vancomycin, 10 mg/kg)

Nafcillin, 50 mg/kg, and ceftriaxone, 50 mg/kg (consider vancomycin, 10 mg/kg)

Nafcillin, 50 mg/kg, and ceftriaxone, 50 mg/kg (consider

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Age

Organism

Treatment vancomycin, 10 mg/kg)

Streptococcus pneumoniae Neisseria gonorrhoeae

The clinical picture of septic arthritis varies with age. Clinically, infants tend to have fever, failure to feed, lethargy, pseudoparalysis of the extremity, and pain with diaper changes. In a recent study, however, neonates (younger than 1 month) were found to have less fever and fewer systemic signs of illness than older infants, thus making the diagnosis even more difficult.[49] Most older children have systemic symptoms of fever, malaise, poor appetite, and irritability, as well as localized symptoms of pain and limp or refusal to walk. With septic arthritis, the onset of symptoms is more acute than with osteomyelitis. Physical examination reveals local erythema, warmth, and swelling. If the hip is affected, it is often held in flexion, abduction, and external rotation. Range of motion is decreased because of pain and muscle spasm, and passive joint movement is painful. In infants, joint dislocation may be observed. Laboratory studies helpful in diagnosing septic arthritis include a white blood cell count, ESR, C-reactive protein, blood cultures, and evaluation of joint fluid. Use of the white blood cell count and ESR is discussed in the section on transient synovitis. It should be noted that the ESR rises 24 hours or more after the onset of signs and symptoms of infection, so it may not be helpful during the first day of illness. C-reactive protein may be a better monitor of septic arthritis than the ESR is. It is a simpler test that requires only a finger stick sample of blood. It rises more quickly than the ESR does, is typically elevated at initial evaluation, and with appropriate therapy, will normalize within a week; in contrast, the ESR will not normalize for more than a month.[50] Blood cultures should be included in the evaluation of a child with suspected septic arthritis. They are positive in 20% to 50% of cases[51] and, when positive, not only help direct antibiotic treatment but provide an organism for serum bactericidal testing as the children progress to oral antibiotics. Evaluation of synovial fluid is the mainstay for diagnosing septic arthritis. If septic arthritis is being considered, joint aspiration should be performed without delay and the sample sent for Gram stain, aerobic and anaerobic cultures, cell count with differential, glucose determination, and a mucin clot test. The mucin clot test is a test of the integrity of hyaluronic acid, which tends to be degraded when bacteria are present. It is performed by placing two drops of 5% acetic acid into a mixture of 4 mL of water and 1 mL of synovial fluid while stirring with a glass rod. A normal result is a tight rope of mucin. The test is considered positive if the fluid's consistency changes to that of curdled milk as the clot flakes and shreds. Abnormal mucin clot test results are found with septic arthritis and rheumatic fever; however, with rheumatic fever, a fibrous band resembling a tethered rope forms on the glass stir rod. The synovial fluid in patients with septic arthritis tends to be turbid or grossly purulent with a white cell count greater than 40,000 cells/mm[3] and a predominance of polymorphonuclear cells. Synovial glucose may be low (synovial fluid/blood glucose less than 0.5) and protein and lactate elevated ( Table 174-7 ). Because of the intrinsic immunoglobulins in the synovial fluid, culture of the fluid will be positive in only half the children with a clinical picture consistent with septic arthritis. Synovial fluid can be cultured on agar plates or blood culture media. Either way, the specimen requires immediate inoculation. Table 174-7 -- Synovial Fluid Findings in Different Types of Arthritis Character WBC Count PMNs (%) Mucin Clot (/mL) Normal Clear; yellow Juvenile Turbid rheumatoid arthritis Reactive arthritis Cloudy to turbid; may be clear Lyme arthritis Turbid Septic arthritis Turbid; white-gray

75

Poor Poor

Other

50% with decreased complement Increased complement Low glucose High lactate

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Character

WBC Count (/mL)

PMNs (%)

Mucin Clot

Other

PMN, polymorphonucle ar leukocytes; WBC, white blood cell count.

In septic arthritis, plain radiographs of the hip may be normal or, in the presence of a large joint effusion, may show periarticular soft tissue swelling, widening of the joint space, obliteration or displacement of the gluteal lines, and asymmetric fullness of the iliopsoas and obturator soft tissue planes. Late in the course of infection, subchondral bone erosions and narrowing of the joint space are seen. Ultrasonography is much more sensitive than plain radiography in detecting hip effusion and provides direct visualization of the fluid and needle during joint aspiration. Scintigraphy may also be useful in diagnosing septic arthritis; during the “blood pool” or delayed images of the joint, symmetrical uptake in periarticular tissue on both sides of the joint is seen. Scintigraphy is diagnostic of septic arthritis earlier than other imaging techniques are and is also a useful adjunct in identifying associated osteomyelitis or avascular necrosis of the femoral head. CT and MRI can confirm the presence of an effusion but do not differentiate septic from nonseptic arthritis; however, they may be useful in complicated or atypical cases.[52] Septic arthritis requires immediate admission, antibiotics, and surgical intervention. Surgical options range from needle aspiration to open surgical drainage, but no randomized controlled trials have compared these two treatment approaches. Some authors recommend surgical drainage in all infants and young children with septic arthritis because needle aspiration has been shown to be inferior in this population.[53] Indications for surgical drainage in children with septic arthritis include involvement of the hip joint, the presence of large amounts of pus or debris in the joint, loculated fluid, recurrence of joint fluid after four or five aspirations, and lack of clinical improvement within 3 days of the initiation of appropriate therapy.[] In joints other than the hip, the need for surgical drainage is determined on a case-by-case basis. Empirical antibiotic therapy for septic arthritis is directed against the most likely organisms based on patient age and comorbid conditions (see Table 174-6 ). Treatment may then be changed after culture and sensitivity results are known. To maximize culture results, antibiotics should not be given until a specimen of joint fluid is obtained. Initial treatment is parenteral to ensure adequate serum antibiotic concentrations. After the patient's clinical condition is stabilized, oral antibiotic therapy can be instituted. In general, doses two to three times those used for mild infections are sufficient. Response to therapy is measured by clinical improvement and acute phase reactants, including ESR and C-reactive protein. The mortality rate associated with septic arthritis has fallen to less than 1%, but the morbidity remains significant. Sequelae include leg length discrepancy, persistent pain, limited range of motion and ambulation, and aseptic necrosis of the femoral head. Predictors of a poor outcome include infection of the hip and shoulder, adjacent osteomyelitis, a delay of 4 days or more before antibiotic and surgical intervention, and prolonged time to sterilization of synovial fluid.

Legg-Calvé-Perthes Disease Idiopathic avascular necrosis of the proximal femoral epiphysis, also known as Legg-Calvé-Perthes disease, is named after the men who independently described it in the early 1900s. It usually occurs between the ages of 3 and 12 years, with the peak incidence between 5 and 7 years of age. LCP disease has been reported in teenagers as well as children as young as 2 years. Boys are affected three to five times more frequently than girls, and the disease is familial approximately 10% of the time. The disorder is bilateral in up to 20% of cases. LCP disease is associated with breech presentation, later-born children (particularly the third to sixth child), lower socioeconomic group,[58] higher parental age,[59] lower birth weight, attention-deficit/hyperactivity disorder,[60] delayed bone age,[61] short stature, smoking,[62] infection with human immunodeficiency virus,[63] and chronic renal disease.[] The increased incidence of LCP disease in Japanese, Asians, Eskimos, and central Europeans and the decreased incidence in Native Australians, Native Americans, Polynesians, and African Americans suggest that racial factors may also play a role. Trauma is often related to the onset of symptoms of LCP disease, but a direct relationship between the two

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has not been clearly established. Despite extensive research, the etiology of LCP disease remains unclear. Ponseti and colleagues[66] suggested that LCP disease is a local manifestation of a transient, generalized disorder of epiphyseal cartilage. Their histologic studies showed thickening and disorganization of the growth plate, which could block penetration of the blood vessels and render the femoral epiphysis avascular. Other etiologic theories involve abnormalities in the vascular anastomotic network around the femoral epiphysis, increased blood viscosity leading to infarction, and abnormalities in growth hormone. Clinically, children with LCP disease initially have an insidious and stuttering onset of a limp. Associated pain, when present, is usually related to activity and relieved by rest. The pain tends to be localized to the groin or referred to the anteromedial aspect of the thigh or knee region. On examination, children have limited hip motion, particularly abduction and medial rotation. Early in the course of disease, the limited abduction is secondary to synovitis and muscle spasm. As the disease progresses, limitation of motion of the hip is due to deformity of the femoral head, and with time, the limited abduction may become permanent. Children with LCP disease have a positive Trendelenburg test (see the section “Developmental Dysplasia”) accompanied by thigh, calf, and buttock atrophy related to disuse. With advanced disease and femoral head collapse, there may be limb length discrepancy. The role of laboratory evaluation in the diagnosis of LCP disease is limited to ruling out other causes of hip pain (e.g., septic arthritis) when the diagnosis is in question or evaluating for hormonal, metabolic, or genetic causes in patients with bilateral hip involvement. LCP disease is diagnosed and staged by plain radiographs taken in the AP and frog-leg lateral position. These radiographs show both the extent of epiphyseal involvement and the stage of the disease. Plain radiographs also supply prognostic information such as “head at risk” signs, lateral subluxation, and metaphyseal changes. These prognostic signs help guide treatment. In early LCP disease, radionuclide bone scanning may be diagnostic before the development of abnormalities on plain film. Bone scintigraphy has also been shown to provide accurate information concerning the extent of the necrotic process, as well as the degree of vascularization and therefore the stage of the disease. Scintigraphy, however, was not able to predict disease outcome.[67] When compared with plain radiographs and bone scan, MRI gives earlier and more reliable information about the extent of necrosis of the femoral head. MRI is also better than scintigraphy at showing revascularization. Despite the use of MRI in early LCP disease, its role in healed LCP disease is limited because it provides no further information regarding the configuration and structure of the femoral head than plain radiography does.[67] Arthrography is useful in delineating flattening of the femoral head, demonstrating the hinge abduction phenomenon with abduction of the leg, and in conjunction with plain films or CT, diagnosing osteochondritis dissecans after LCP disease. There are four radiographic classification stages of LCP disease: initial, fragmentation, reossification, and healed. Radiographic findings in the initial stage include a femoral head that appears smaller than the opposite unaffected femoral head, widening of the medial joint space, a subchondral lucent zone (subchondral collapse—“crescent sign”), an irregular physeal plate, and a blurry and radiolucent metaphysis ( Figure 174-21 ). In the fragmentation phase, the repair aspects of the disease become more prominent. The epiphysis begins to fragment, and there are areas of increased radiolucency as new bone forms, as well as areas of increased radiodensity. During the reossification stage, the repair process continues as normal bone density returns, radiodensities replace radiolucencies, and alterations in the shape of the femoral head and neck become apparent. The healed stage is the final radiographic stage of LCP disease, and radiographs of the proximal third of the femur taken during this stage of the illness will demonstrate any residual deformities.

Figure 174-21 Crescent sign (subchondral lucent zone) in early Legg-Calvé-Perthes disease. ((Courtesy Marianne Gausche-Hill, MD.))

Multiple prognostic classification systems of LCP disease have been devised. In general, a poor prognosis is associated with a greater degree of deformity of the femoral head and acetabulum at maturity, disease onset

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in children 6 to 8 years or older, female sex, and prolonged duration of disease. When the diagnosis of LCP is suspected, orthopedic consultation is recommended. Goals in the treatment of LCP disease are to improve range of motion, prevent deformity, limit growth disturbance, and prevent degenerative joint disease. Treatment is not indicated in all children with LCP disease, but when indicated, it must be started in the initial or fragmentation phase of the disease. Treatment is recommended for patients who have a poor prognosis based on clinical and radiographic findings. The cornerstone for treatment of LCP is referred to as “containment”: the femoral head is contained within the acetabulum to equalize pressure on the head and subject it to the molding action of the acetabulum to maintain the spherical nature of the femoral head. Containment can be achieved through nonoperative or operative methods, and optimal treatment is determined on a case-by-case basis. Residual deformities resulting from LCP disease follow four patterns: coxa magna, premature physeal arrest, irregular head formation, and osteochondritis dissecans. Despite these deformities, most patients with childhood hip disease are capable of bony remodeling with subsequent improvement in femoral head deformities. During their early years, regardless of radiographic appearance, patients with LCP disease tend to do well.[68] The majority (70% to 90%) of patients with LCP disease are active and pain free and have good range of motion 20 to 40 years after the onset of symptoms. Only patients with flattened irregular femoral heads at the time of primary healing or premature physeal closure had clinical deterioration and increasing pain.[69] Later in life there is a marked reduction of function, with degenerative joint disease developing in the majority of patients by their 50s and 60s.[68] With noncontainment treatment, however, the outcome is not as good. Yrjonen found that at an average of 35 years of follow-up, 48% of patients had evidence of degenerative joint disease and 17% had either undergone total hip arthroplasty or had clinical symptoms that warranted total hip arthroplasty.[70]

Slipped Capital Femoral Epiphysis SCFE refers to posterior and inferior slippage of the proximal femoral epiphysis on the metaphysis. The femoral head sits securely in the acetabulum, whereas the epiphysis separates from the femoral neck through the growth plate. The average annual incidence of SCFE is 2 per 100,000, with boys being affected more than twice as frequently as girls. The peak incidence occurs during the adolescent growth spurt: boys between 12 and 16 years of age (mean age, 13.5 years) and girls between 10 and 14 years of age (mean age, 11.5 years). The age at diagnosis decreases with increasing obesity. The majority of children with SCFE have delayed skeletal maturation, with bone age being as much as 20 months behind chronologic age. African American children are affected more frequently than white children. The literature reports SCFE to be bilateral in up to 80% of cases, although 30% to 40% of these cases are asymptomatic and discovered only on screening radiographs. In unilateral cases, the left hip is affected twice as often as the right. SCFE is associated with endocrine disorders (hypothyroidism, panhypopituitarism, hypogonadism, and growth hormone administration), renal osteodystrophy, and radiation therapy. Most cases of SCFE, however, are idiopathic and associated with obesity. The etiology of idiopathic SCFE is unknown. It is likely to be multifactorial and related to biomechanical factors such as obesity and physeal architecture, as well as hormonal factors that weaken physeal strength. Obesity results in increased shear forces across a more vertically and posteriorly oriented growth plate that has been weakened by architectural irregularities and hormonal changes of puberty. The consequence is slippage of the epiphysis inferiorly and posteriorly in the direction of the weight-bearing force. The traditional classification of SCFE was based on the duration of symptoms, with acute slippage defined as symptom duration of less than 3 weeks, chronic slippage defined as symptoms for 3 weeks or more, and acute-on-chronic slippage defined as symptoms for more than 3 weeks' duration with a recent, sudden exacerbation. Of late, this classification has been replaced by one based on stability: in stable SCFE, ambulation is possible (with or without crutches), whereas in unstable SCFE, ambulation is not possible (with or without crutches).[71] This classification system is preferred over the traditional classification because it does not rely on patient or parent recall for duration of symptoms and provides information regarding prognosis. The signs and symptoms of SCFE vary with its stability. Children with stable SCFE have symptoms of intermittent limp and pain of several weeks' to months' duration. Stable SCFE is found in approximately 90% of all cases. The pain of SCFE may be localized to the hip but more commonly is poorly localized to the thigh, groin, or knee. Atypical manifestations of SCFE include weakness and easy fatigability of the affected limb and limping on exertion. With continued slippage, internal rotation, flexion, and abduction are lost, and parents and children may note progressive external rotation and shortening of the involved lower extremity with subsequent difficulty in daily activities such as tying shoes. On examination, children initially have a

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slight loss of internal rotation and experience pain only at the extremes of motion. Their gait is antalgic and muscle atrophy is minimal. As the slip becomes more severe, the gait becomes more antalgic, internal rotation is lost, abduction and flexion of the hip increase, thigh and gluteal muscle atrophy is more pronounced, and leg length discrepancy develops. A frequently seen sign associated with SCFE can be demonstrated during passive flexion of the affected hip: as flexion is increased from an extended position, the thigh abducts and externally rotates. Unstable SCFE in children tends to initially come to attention after a sport-related injury or a fall with a twisting injury. They have an acute onset of extreme pain and, on examination, hold the hip in flexion, external rotation, and abduction. These children resist any type of movement of the affected leg, and if unstable SCFE is suspected, no passive movement should be attempted for fear of further displacing the epiphysis. The diagnosis of SCFE is made with AP and lateral radiographs of both hips ( Figure 174-22 ) With stable slippage, AP and frog-leg lateral pelvic radiographs should be obtained. When an unstable slip or a minimal slip is suspected, a cross-table radiograph replaces the frog-leg lateral view. Early in the course of SCFE the initial slippage is posterior; therefore, the AP view is normal or shows widening of the physis, and the slip is better seen on the lateral projection. Early findings on lateral radiographs include a minimal posterior step-off at the anterior physeal plate or widening of the growth plate. On AP radiographs, signs of slippage include Klein's line and the blanch sign of Steele. Klein's line is a line drawn along the superior margin of the femoral neck. With a normal hip, the line intersects or falls within the epiphysis, whereas in a hip with a slipped epiphysis, the line does not come in contact with the epiphysis. The blanch sign of Steele is a crescent-shaped area of increased density in the proximal portion of the femoral neck that is created by superimposition of the posteriorly displaced epiphysis on the femoral neck. The femoral metaphysis of the affected hip also appears to be more laterally displaced from the medial wall of the acetabulum. As the slip continues, the epiphysis continues to be displaced inferiorly and posteriorly relative to the metaphysis. Over time, remodeling smoothes away the superior and anterior portion of the femoral neck, and in an attempt to buttress the slippage, callus is formed at the inferior and posterior portions of the femoral neck. Unstable slips in children without previous symptoms will not have evidence of bone healing or remodeling.

Figure 174-22 Anteroposterior radiograph of the pelvis with a unilateral slipped capital fem oral epiphysis.

Ultrasonography has been used in the diagnosis of SCFE but offers little, if any information over conventional radiography. CT and MRI can be used to confirm and quantitate epiphyseal displacement in patients who have symptoms but no radiographic findings suggestive of SCFE. Slip severity is described in one of two ways. The simplest classification describes the amount of displacement of the femoral head on the femoral neck. In mild SCFE, the amount of displacement is less than a third, moderate SCFE has displacement between a third and a half, and severe SCFE is marked by the femoral head being displaced more than half the width of the femoral neck. A more accurate description of the magnitude of slippage is obtained by measuring the epiphyseal-shaft angle of Southwick. On a frog-leg lateral radiograph of the pelvis, a line is drawn between the anterior and posterior tips of the epiphysis at the physeal plate level. A second line is then drawn perpendicular to the epiphyseal line. Next, a line is drawn along the midshaft of the femur. The epiphyseal-shaft angle is formed by the intersection of the perpendicular and the femoral shaft lines. The magnitude of slip displacement is the angle of the involved hip minus the angle of the normal hip. If involvement is bilateral, 12 degrees is used as the control angle. Mild SCFE is less than 30 degrees, a moderate slip is between 30 and 50 degrees, and severe displacement is greater than 50 degrees. When SCFE is diagnosed in the emergency department, the child should be made non–weight bearing, either with crutches or a wheelchair, and an immediate orthopedic consultation should be obtained. For a stable slip, definitive treatment is best if performed within a few days; however, hospital admission is prudent. With an unstable slip, some orthopedic surgeons recommend immediate fixation. The goals of treatment are to prevent further slippage and achieve physeal stability. A stable slip can be fixed

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with internal fixation (pinning), bone graft epiphyseodesis, corrective osteotomy, or spica cast immobilization. Most orthopedic surgeons recommend internal fixation with a single central screw. Failure of this repair is very rare, and with new techniques that avoid opening the hip joint, it has become a procedure associated with minimal blood loss and wound complications and minimal need for hospitalization and rehabilitation. Postoperatively, non–weight bearing or touch-toe weight bearing for 4 to 6 weeks is followed by a gradual return to normal activity. Running and contact sports may be resumed once the physis is closed. With unstable SCFE, there is controversy regarding the timing of the surgery, the optimum number of fixative devices that should be used, whether reduction should be performed, and whether preliminary traction and bed rest should be used before surgery. Treatment is dependent on the degree of slippage and the preference and experience of the orthopedic surgeon. The two most worrisome short-term complications of SCFE are avascular necrosis and chondrolysis; the risk for either process increases with the severity of the initial slippage.[] Avascular necrosis has been reported to occur in 10% to 15% of children with SCFE. The risk is higher with unstable SCFE, greater degrees of slippage, attempts at reduction, and treatment with a spica cast. In children with stable slips treated by single-screw internal fixation without reduction, the rate of avascular necrosis is as low as 0% to 5%.[74] Chondrolysis occurs in approximately 5% of SCFE patients, with an increased incidence in children with greater degrees of slippage. Chondrolysis can occur before and as a result of treatment. It should be suspected when pain and loss of motion are disproportionate to the severity of the slip. On radiographs, loss of articular cartilage may be seen. When SCFE is treated by spica cast immobilization, the rate of chondrolysis is reported to range from 19% to 67%.[] Approximately 50% of cases of chondrolysis will resolve; however, it may progress to such severe pain and contractures that hip arthrodesis is needed. Other complications of SCFE include nonunion, premature closure of the epiphyseal plate, and degenerative changes. Degenerative hip arthritis develops gradually over decades and has an earlier onset with more severe degrees of slippage.

Apophyseal Injuries Perspective and Principles of Disease The apophysis is a cartilaginous structure that serves as a site for insertion of tendons on the growing bone. It has its own growth plate, but it has a slower rate of growth than the nearby epiphyseal plate. Apophysitis is unique to patients with skeletal immaturity and involves inflammation of this actively growing bony prominence that is under great tensile stress. Common apophyseal injuries include medial epicondylitis, Osgood-Schlatter disease, and Sever's disease. Apophysitis develops from a single episode of macrotrauma or from repetitive microtrauma to the secondary center of ossification, which causes multiple tiny avulsion fractures. This scenario sets up an inflammatory cycle that is perpetuated by continued activity and trauma to the apophysis. Growth also contributes to the development of apophysitis. As the musculoskeletal system goes through a growth spurt, muscle development lags behind bony development. This difference in development leads to a muscle-tendon imbalance manifested as tight and inflexible muscle groups in which excessive stress is placed on the apophyseal centers where these muscles insert. The true incidence of apophysitis is unknown. One study found an incidence of 18% in a population of 1000 patients seen at an urban general pediatric clinic over a 4.5-month period.[76] Another series, which looked at patient visits to a sports medicine clinic, found an incidence of 31%.[77] Children between 8 and 15 years of age are most frequently affected, with different apophyses being affected at different ages.

Specific Disorders/Injuries Osgood-Schlatter Syndrome In 1903 Osgood and Schlatter independently reported traumatically induced apophyseal injury to the tibial tubercle in adolescents.[78] This entity, Osgood-Schlatter syndrome, is the most common of the apophyseal disorders.[79] It is found most commonly in boys between 10 and 15 years old and in girls between 8 and 13 years old and is frequently bilateral. Boys are affected more often than girls, although this trend is changing as more girls are becoming increasingly involved in competitive sports. Bilateral involvement is found in 20% to 30% of patients. Clinically, patients with Osgood-Schlatter syndrome have tenderness, pain, and swelling at the site of

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insertion of the patellar tendon on the tibial tubercle. The tibial tubercle may be prominent and the quadriceps tight. Pain is worsened with activities such as running or jumping by causing the quadriceps to contract and thereby stressing the tubercle. Extension of the knee against resistance causes pain, but resisted straight leg raises are painless. Osgood-Schlatter syndrome is a clinical diagnosis and radiographs are not generally indicated. However, if taken, lateral radiographs of the tibial tubercle may be normal or may show an enlarged, fragmented, and irregular tibial tuberosity with or without an overlying bony ossicle. Ultrasound, which has been proposed as a diagnostic tool by some authors, may reveal pretibial swelling, fragmentation of the ossification center, insertional thickening of the patellar tendon, or excessive fluid collection in the infrapatellar bursa.[80] Treatment of Osgood-Schlatter syndrome is conservative and symptomatic. Initially, the pain can be effectively managed with ice, modification of activity, with or without nonsteroidal anti-inflammatory medications. After the acute inflammatory process has resolved, treatment focuses on strengthening and stretching of the quadriceps muscle. Mild pain during activity is not an absolute contraindication to participation; however, with more severe symptoms, the risk of avulsion of the tibial tubercle should be weighed against the benefits of competing. In rare instances, conservative therapy is insufficient and a 2- to 3-week trial of crutches is required. Steroid injections have been used in the past but are not currently recommended. Complete recovery without residual pain or weakness is the rule. Recovery usually occurs within weeks but, in some cases, may not be complete until the underlying growth plate is closed. However, if the patient reaches skeletal maturity and is still symptomatic, consideration should be given to surgical removal of the tibial tubercle or the bony ossicle overlying the tibial tubercle (or both).

Sever's Disease Sever's disease, which was initially described in 1912,[81] is commonly manifested as posterior heel pain in an 8- to 13-year-old athlete. It is bilateral in 60% of cases. As with other apophyseal injuries, pain is exacerbated by activity. Sever's disease can be associated with growth, tight heel cords, or other biomechanical abnormalities. Frequently implicated sports are soccer and running. Patients have pain at the insertion site of the Achilles tendon and plantar fascia on the calcaneus. Tenderness is elicited when the calcaneus is squeezed bilaterally. Dorsiflexion of the ankle is restricted. Radiographs may be normal or may show partial fragmentation and increased density of the calcaneal apophysis, although this finding can also be seen in normal feet. As in Osgood-Schlatter syndrome, treatment of Sever's disease is conservative and symptomatic. Treatment consists of ice, massage, stretching of the plantar fascia and involved muscles (gastrocnemius-soleus complex and ankle invertors or evertors), nonsteroidal anti-inflammatory drugs, and shock-absorbing shoe inserts. Heel cups have also been found to be helpful, but they must be accompanied by stretching to avoid exacerbating the calf muscle contracture. Modification of activity may be necessary, and infrequently, a trial of crutches for 1 to 2 weeks is helpful. Plantar fasciitis can cause heel pain as well, but patients will experience tenderness along the plantar fascia, especially at the attachment of the fascia to the calcaneus. Treatment involves the use of anti-inflammatory agents, rest, and relaxation of the plantar fascia with heel support pads.

Elbow Apophysitis Little Leaguer's elbow (medial epicondylitis), most commonly affecting the medial epicondyle, is an overuse phenomenon that results in inflammation at the site where the forearm flexor muscles originate. As its name suggests, it commonly affects baseball pitchers and is associated with overhead arm motion. It is also seen in other skeletally immature overhand athletes, including tennis players. Medial epicondylitis is caused by the excessive forces placed on the medial side of the elbow during the late cocking and acceleration phases of throwing. Patients tend to be preadolescents with pain on the medial aspect of the elbow, diminished throwing effectiveness, and decreased throwing distance. Examination reveals localized tenderness and swelling over the medial epicondyle and pain with resisted flexion of the wrist. There may be a slight flexion contracture. Radiographs may be normal or may show fragmentation, sclerosis, and widening of the medial epicondylar apophysis. Treatment includes ice, nonsteroidal anti-inflammatory drugs, and modification of activity. Throwing is restricted until the symptoms have resolved. After resolution, the patient can begin a program of muscle stretching and strengthening and make a slow return to throwing. During recovery, alteration of the throwing style to reduce the degree of sidearm delivery is advisable. Recovery usually takes 4 to 6 weeks. If pain returns during resumption of pitching, rest should be reinstituted.

Apophysitis of the Hip

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Apophyseal injuries of the hip involve sites around the hip where major abdominal and hip muscles either originate or insert: the anterior superior iliac spine, the anterior inferior iliac spine, the iliac crests, and the ischial tuberosities. Dancers and distance runners are most commonly affected. Patients with apophysitis of the hip have a dull pain located near the hip that is related to activity. Treatment includes strengthening and stretching of the abdominal and hip muscles and restriction of activity.

Avulsion Fractures Apophysitis tends to have an insidious onset; therefore, any patient with a sudden onset of apophyseal pain after an acute traumatic event should be evaluated for an avulsion fracture. Such fractures occur when the muscular attachments to the apophyses are pulled off during strong active contractions against resistance. Examination will reveal localized tenderness and swelling. The diagnosis is usually readily apparent on plain films ( Figure 174-23 ); however, bone scan and ultrasonography may play a role when the diagnosis is in question. Ultrasonography has the advantages of no radiation exposure, the ability to detect a fracture before the development of an ossification center, and the ability to provide a dynamic examination. Findings consistent with an avulsion fracture include a hypoechogenic zone, increased distance to the apophysis, dislocation of the apophysis, and mobility of the apophysis on dynamic examination.[82] Treatment of an avulsion fracture is based on the degree of separation. If the displacement is minimal (less than 2 cm with a hip avulsion and less than 5 mm with avulsion of the medial epicondyle[83]), immobilization for 4 to 6 weeks with subsequent slow resumption of activities is usually sufficient. With widely separated avulsion fractures, some authors recommend open reduction and fixation.[83]

Figure 174-23 Avulsion injury of the elbow. This degree of displacem ent required surgical treatm ent.

KEY CONCEPTS {,

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skel etally imm ature . Child abus e must be susp ecte d in child ren youn ger than 3 year s with nons upra cond ylar hum erus fract ures, femu r fract ures, rib fract ures, and com plex skull fract ures. Child ren with displ aced supr acon dylar fract ures are at signi fican t risk for neur ovas cular

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injur y and shou ld have frequ ent eval uatio ns to asse ss for com part ment synd rom e. All child ren who are not yet walki ng shou ld have a thoro ugh hip eval uatio n with each visit to the eme rgen cy depa rtme nt. All patie nts with a gait distu rban ce need a thoro

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ugh phys ical exa mina tion and direc ted labor atory and radio graphic eval uatio n. Septi c arthri tis is a medi cal and surgi cal eme rgen cy that man date s imm ediat e ortho pedi c cons ultati on. Exa mine the hip of all patie nts with knee pain.

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Marx: Rosen's Emergency Medicine: Concepts and Clinical Practice, 6th ed., Copyright © 2006 Mosby, Inc.

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Arch Dis Child1988;63:1408. 65. Boechat MI: Avascular necrosis of the femoral head in children with chronic renal disease. Radiology 2001;8:411. 66. Ponseti IV: Legg-Calvé-Perthes disease: Histochemical and ultrastructural observations of the epiphyseal cartilage and physis. J Bone Joint Surg Am1983;65:797. 67. Kaniklides C: Diagnostic radiology in Legg-Calvé-Perthes disease. Acta Radiol1996;406:1. 68. Weinstein SL: Legg-Calvé-Perthes syndrome. In: Morrisey RT, Weinstein SL, ed.Lovell & Winter's Pediatric Orthopedics, 4th ed. Philadelphia: Lippincott-Raven; 1996: 69. Weinstein SL: Legg-Calvé-Perthes disease: Results of long-term follow up. In: Fitzgerald Jr RH, ed.The Hip: Proceedings of the Thirteenth Open Scientific Meetings of the Hip Society, St Louis: CV Mosby; 1985: 70. Yrjonen T: Prognosis in Perthes' disease after non-containment treatment: 106 hips followed for 28-47 years. Acta Orthop Scand1992;63:523. 71. 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of avascular necrosis. J Bone Joint Surg Am1996;78:398. 73. Carney BT, Weinstein SL, Noble J: Long term follow up of slipped capital femoral epiphysis. J Bone Joint Surg Am1991;73:667. 74. Ward WT: Fixation with a single screw for slipped capital femoral epiphysis. J Bone Joint Surg Am 1992;74:799. 75. Meier MC, Meyer LC, Ferguson RL: Treatment of slipped capital femoral epiphysis with a spica cast. J Bone Joint Surg Am1992;74:1522. 76. de Inocencio J: Musculoskeletal pain in primary care pediatric care: Analysis of 1000 consecutive general pediatric clinic visits. Pediatrics1998;102:e63. 77. Micheli LJ, Fehlandt Jr JrAF: Overuse injuries to tendons and apophyses in children and adolescents. Clin Sports Med1992;11:713. 78. Osgood RB: Lesions of the tibial tubercle occurring during adolescence. Boston Med J1903;148:114. 79. Peck DM: Apophyseal injuries in the young athlete. Am Fam Physician1995;51:1891. 80. Blankstein A: Ultrasonography as a diagnostic modality in Osgood-Schlatter disease. A clinical study and review of the literature. Arch Orthop Trauma Surg2001;121:536. 81. Sever JW: Apophysitis of the os calcis. N Y Med J1912;95:1025. 82. Lazovic D: Ultrasound for the diagnosis of apophyseal injuries. Knee Surg Sports Traumatol Arthrosc 1996;3:234. 83. Bennet JB, Tullos HS: Ligamentous and articular injuries in the athlete. In: Morrey BF, ed.The Elbow and Its Disorders, Philadelphia: WB Saunders; 1985:

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Marx: Rosen's Emergency Medicine: Concepts and Clinical Practice, 6th ed., Copyright © 2006 Mosby, Inc.

REFERENCES 1. Fletcher K, Forch W: Acute symptom assessment: Determining the seriousness of the presentation. Prim Care Pract1999;3:216. 2. Ailani RK: Dyspnea differential index: A new method for rapid separation of cardiac versus pulmonary dyspnea. Chest1999;119:1100. 3. Sivak ED, Shefner JM, Sexton J: Neuromuscular disease and hypoventilation. Curr Opin Pulm Med 1999;5:335. 4. Kline JA, Wells PS: Methodology for a rapid protocol to rule out pulmonary embolism in the emergency department. Ann Emerg Med2003;42:266. 5. Michelson E, Hollrah S: Evaluation of the patient with shortness of breath: Evidence based approach. Emerg Clin North Am1999;17:221. 6. Murray S: Bi-level positive airway pressure (BiPAP) and acute cardiogenic pulmonary oedema (ACPO) in the emergency department. Aust Crit Care2002;15:51. 7. Rodrigo GJ: Inhaled therapy for acute adult asthma. Curr Opin Allergy Clin Immunol2003;3:169. 8. Peigang Y, Marini JJ: Ventilation of patients with asthma and chronic obstructive pulmonary disease. Curr Opin Crit Care2002;8:70.

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Chapter 175 – Sudden Infant Death Syndrome and Apparent Life-Threatening Events Marianne Gausche-Hill

PERSPECTIVE The National Institute of Child Health and Human Development defined the sudden infant death syndrome (SIDS) as the “sudden death of an infant less than 1 year of age which remains unexplained after a thorough case investigation, including performance of a complete autopsy, examination of the death scene, and review of the clinical history.” Passed in 1974, the Sudden Infant Death Syndrome Act provided a needed focus on research and public information. It was not until 1992, however, that the American Academy of Pediatrics recommended that infants be placed to sleep in a nonprone position to reduce the risk of SIDS, and a Back to Sleep (BTS) campaign was initiated in 1994 by a joint effort of the U.S. Public Health Service, the American Academy of Pediatrics, the SIDS Alliance, and the Association of SIDS and Infant Mortality Programs. Since then, the frequency of prone sleeping has decreased from 70% to 20% and the SIDS rate has concomitantly decreased by greater than 40%.[1]

Epidemiology of Sudden Infant Death Syndrome In 1994, SIDS declined from the second leading cause to the third leading cause of infant mortality. The 1995 data indicate that the SIDS rate declined 18.3% from 1994, demonstrating a continuing declining trend.[2] The overall incidence of SIDS in the United States was approximately 0.72 per 1000 live births in 1998, down from 1.5 per 1000 live births reported in the 1980s. Despite the dramatic decline in the incidence of SIDS, approximately 3000 infants still die each year of SIDS in the United States. SIDS remains the leading cause of postneonatal mortality in the United States, accounting for one third of all such deaths, and it is the third most common cause of infant deaths.[] SIDS may occur at any time during the first 2 years of life, but it is rare (1%) in children younger than 1 month of age and in those older than 1 year (2%). Ninety-five percent of SIDS infants die before 6 to 8 months with a peak between 2 and 4 months of age.[4] There is also epidemiologic variation among different racial and ethnic groups. In 1997, the rate was 1.53 per 1000 live births in the black population, 0.64 per 1000 in whites, 0.48 per 1000 in Hispanic Americans, 0.51 per 1000 among Asian Americans, and 5.93 per 1000 among Native Americans. The smaller proportionate decline in the postnatal SIDS mortality rate among black infants over the last decade has exacerbated the racial disparity.[5] In contrast, between 1985 and 1996, the decline in infant mortality rate and SIDS among Northwest American Indians and Alaskan Natives was of greater magnitude than the national decline in SIDS.[6] Other epidemiologic risk factors include male sex and multiple births. Whereas triplets have an incidence as high as 8.3 per 1000, there does not appear to be an increased incidence among twin gestations. There also appears to be an increased incidence in the winter months, and 62% of SIDS cases occur during the colder season in California.[7]

Definitions Because of the confusion that exists with the myriad of terms describing infants who present with cardiopulmonary distress, the 1986 National Institutes of Health Consensus Development Conference on Infantile Apnea and Home Monitoring delineated the following terms[8]: Apnea is a cessation of airflow. The respiratory pause may be central or diaphragmatic (i.e., no respiratory effort), obstructive (usually caused by upper airway obstruction), or mixed. Short (20 seconds) or is associated with cyanosis, marked pallor, hypotonia, or bradycardia. Apnea of prematurity is periodic breathing with pathologic apnea in a premature infant. Apnea of prematurity usually ceases by 37 weeks' gestation (menstrual dating) but occasionally persists past term. Apnea of infancy is an unexplained episode of cessation of breathing for 20 seconds or longer or a shorter respiratory pause associated with bradycardia, cyanosis, pallor, or marked hypotonia. It generally refers to infants who are more than 37 weeks' gestational age at the onset of pathologic apnea. The term apnea of infancy should be reserved for those infants in whom no specific cause of an apparent life-threatening event (ALTE) can be defined. Periodic breathing is a breathing pattern in which there are three or more respiratory pauses of greater than 3 seconds' duration with less than 20 seconds of respiration between the pauses. Periodic breathing may be a normal event. Symptomatic premature infants are preterm infants who continue to have pathologic apnea at the time when they otherwise would be ready for discharge from the hospital. An apparent life-threatening event is “an episode that is frightening to the observer and is characterized by some combination of apnea (central or occasionally obstructive), color change (usually cyanotic or pallid but occasionally erythematous or plethoric), marked change in muscle tone (usually limpness), choking, or gagging.” Often the observer fears that the infant has died.[9] ALTE is a term used until a precise causative diagnosis can be established, but more than 50% of ALTEs never receive a definitive diagnosis despite an extensive workup. Previously used terms such as near-miss SIDS or aborted crib death should not be used because they imply an unproven, misleading association between an ALTE and SIDS. Sudden infant death syndrome is “the sudden death of an infant under 1 year of age, which remains unexplained after a thorough case investigation, including performance of a complete autopsy, examination of the death scene, and review of the clinical history.” Breath-holding spells occur when infants perform a Valsalva maneuver in response to pain, fright, crying, coughing, or defecation. During the spell, minute ventilation decreases without any adverse effects. Breath-holding spells, however, if severe and prolonged, may result in cyanosis, unconsciousness, and seizures. Severe breath-holding spells are reported to occur in 5% of normal children before 6 years of age. Pallid breath-holding spells have been distinguished from cyanotic breath-holding spells. It is thought that pallid spells result from a primary central parasympathetic disturbance, leading to vagally mediated cardiac inhibition.[10] In contrast, cyanotic spells are hypothesized to have a more complex pathogenesis, involving the interaction of hyperventilation, Valsalva maneuvers, expiratory apnea, and intrinsic pulmonary mechanisms.[11]

PRINCIPLES OF DISEASE Risk Factors for Sudden Infant Death Syndrome In the 1980s, several risk factors were identified, such as low birth weight, preterm gestational age, cardiac dysrhythmias, young maternal age, maternal education, high parity, race, and poor socioeconomic status. Since then, many other predisposing factors have been proposed. Risk factors for SIDS may be divided into maternal, neonatal, and postnatal factors, and further differentiation may be made between modifiable and nonmodifiable risk factors ( Box 175-1 ). Maternal smoking during pregnancy, age younger than 20 at the time of first pregnancy, short interpregnancy intervals, lack of prenatal care, illicit drug use (cocaine and narcotics), illness during pregnancy, being unmarried, and having a low socioeconomic status are characteristics that are prevalent in mothers of SIDS infants.[12] BOX 175-1 Maternal Risk Factors for Sudden Infant Death Syndrome

Modifiable Maternal smoking during pregnancy Illicit drug use Low socioeconomic status

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Nonmodifiable Maternal age 300 mg/24 hours) and eclampsia is the occurrence of seizures in the patient with signs of preeclampsia. Progression of preeclampsia to eclampsia is unpredictable and can occur rapidly. Pregnancy-aggravated hypertension is chronic hypertension with superimposed preeclampsia or eclampsia. Chronic or coincidental hypertension is present before pregnancy or persists more than 6 weeks postpartum.[] Approximately 2% to 7% of pregnancies are complicated by pregnancy-induced hypertension. The incidence of actual eclampsia has progressively declined but is still one of the top three causes of maternal mortality.[ 16] The risk of pregnancy-induced hypertension is greatest in women younger than 20 years old; primigravidas; those with twin or molar pregnancies; those with hypercholesterolemia, pregestational diabetes, or obesity; and those with a family history of pregnancy-induced hypertension.[48]

Principles of Disease Gestational hypertension/preeclampsia is a vasospastic disease of unknown cause unique to pregnant women. Vasospasm, ischemia, and thrombosis associated with preeclamptic changes cause injury to maternal organs, placental infarction and abruption, and fetal death from hypoxia and prematurity. The cause of eclampsia is not known, but recent research has centered on vascular responsiveness to endogenous vasopressors in the preeclamptic woman. Vascular responsiveness is normally depressed during pregnancy, which is a high-output, low-resistance state. Gestational hypertension is characterized by an even greater elevation in cardiac output, followed by an abnormally high peripheral resistance as the disease develops clinical manifestations. In patients with preeclampsia, the cardiac output eventually drops as peripheral resistance rises.[49] The causes of these changes is not known, but they are associated with a relative increase in various substances, including those prostaglandins associated with vasoconstriction, and a generalized intravascular inflammatory reaction that results in vascular injury.[50] One study found that women with preeclampsia have significantly decreased prostacyclin production many months before the clinical onset of preeclampsia.[51] The vasospastic effects of gestational hypertension/preeclampsia are protean. Intravascular volume is lower than in normal pregnancy; central venous pressures are normal, and capillary wedge pressures are variable. Liver effects are believed to be due to hepatocellular necrosis and edema resulting from vasospasm. Renal injury causes proteinuria and may result in decreased glomerular filtration. Microangiopathic hemolysis may result from vasospasm, causing thrombocytopenia. Central nervous system effects include microvascular thrombosis and hemorrhage, as well as focal edema and hyperemia.[48]

Clinical Features Signs and Symptoms The patient with gestational hypertension has mild systolic or diastolic blood pressure elevation, no proteinuria, and no evidence of organ damage. Mental status assessment, testing of reflexes, abdominal examination, liver function studies, and coagulation studies should all yield normal results. Preeclampsia is associated with kidney changes, and, in severe cases, other end-organ symptoms. Edema is often difficult

Page 4422

to assess, because pregnancy is normally associated with excess extracellular fluid and dependent edema, and is no longer used as a criterion for recognizing preeclampsia. Proteinuria (>300 mg/24 hours) is variable at any given time and may not be detectable in a random urine specimen.[47] In cases of severe preeclampsia, diastolic blood pressure can exceed 110 mm Hg, proteinuria is more severe, and there is evidence of vasospastic effects in various end organs. Central nervous system effects commonly include headache or visual disturbances. Thrombocytopenia may be present, liver function test findings may be elevated, and the liver is often tender. Renal dysfunction may be indicated by oliguria and elevated creatinine levels in addition to proteinuria.

Complications The HELLP syndrome is a particularly severe form of preeclampsia that develops in 5% to 10% of women who have preeclamptic symptoms and is characterized by h emolysis, e levated l iver enzymes, and l ow p latelet count (fewer than 100,000/mm3). Prothrombin time, partial thromboplastin time, and fibrinogen level are all normal, and blood studies reveal microangiopathic hemolytic anemia. Other complications of preeclampsia include spontaneous hepatic and splenic hemorrhage and abruptio placentae. The most dangerous complication is eclampsia, which is the occurrence of seizures or coma in the setting of signs and symptoms of preeclampsia. Warning signs for development of frank eclampsia include headache, nausea and vomiting, visual disturbances, and mean arterial pressure greater than 160 mm Hg.[ 52] Elevated lactate dehydrogenase, aspartate aminotransferase, and uric acid concentrations are also predictive of increased morbidity for the patient with severe preeclampsia.[53] Particularly in early eclampsia before 32 weeks' gestation, seizures may develop abruptly and hypertension may not be associated with edema or proteinuria.[54] One third of eclamptic seizures occur after delivery, usually during the first 48 hours but occasionally as long as 28 days after delivery.[55] After 48 hours postpartum and without predelivery signs of preeclampsia, other diagnoses such as intracranial hemorrhage should be considered. Maternal complications of eclampsia include permanent central nervous system damage from recurrent seizures or intracranial bleeding, renal insufficiency, and death. The maternal mortality rate from eclampsia has been reduced with modern management and is currently less than 1%. Perinatal mortality has also decreased, although it remains 4% to 8%.[48] Causes of neonatal death include placental infarcts, intrauterine growth retardation, and abruptio placenta. In addition, fetal hypoxia from maternal seizures and the complications of premature delivery mandated by the maternal condition contribute significantly to fetal mortality and morbidity.

Diagnostic Strategies The patient who has severe preeclampsia should have an intravenous line and fetal monitoring initiated in a quiet but closely observed area. Blood testing should include complete blood cell count, renal function studies, liver function tests, platelet count, and coagulation profile. A baseline magnesium level should also be obtained. In the patient with actual seizures, serum glucose should be tested. If a history of preeclampsia is not obtained or the symptoms are refractory to magnesium sulfate therapy, a computed tomography (CT) scan of the head should be performed to exclude cerebral venous thrombosis or an intracranial bleed, either of which can occur in pregnancy (with or without pregnancy-induced hypertension) and may require specific treatment. CT scan abnormalities can be seen in half of patients with eclampsia. Patchy hemorrhage and microinfarcts of the cortex are characteristic, and may be due to loss of cerebral autoregulation in patients with severe pregnancy-related hypertension. Diffuse cerebral edema and increased intracranial pressure can also be seen.[56]

Differential Considerations Peripheral edema is common in normal pregnancy, and it may be difficult to differentiate normal edema from that of early preeclampsia. Differentiation of gestational hypertension from preexistent hypertension is often impossible in an emergency department population if no record of normal blood pressure is available. Seizures during pregnancy may be due to epilepsy, as well as to other intracranial catastrophes such as thrombosis or hemorrhage.

Management Prehospital Eclampsia should always be considered in the patient with a seizure who is visibly pregnant (i.e., >20 weeks). Likewise, the pregnant patient who has trauma (e.g., in a single-vehicle motor vehicle crash) without obvious cause should be suspected of eclampsia. Moderate or severe preeclampsia associated with edema

Page 4423

and hyperactive reflexes requires no prehospital treatment other than prophylactic venous access. If the patient has seizures, routine seizure management and protection of the patient's airway should be initiated. In some regions, magnesium sulfate is available to prehospital providers and can be given according to preset protocols, as described later. Diazepam can be administered as an anticonvulsant, although studies have suggested that it is not as effective as magnesium.[]

Emergency Department In the patient who has mild preeclampsia, appropriate management includes documentation of blood pressure and reflexes, weight, and testing to ensure normal end-organ function. Accurate determination of gestational age by ultrasonography is needed to allow optimal management if symptoms progress. Limitation of physical activities (including bed rest) is the only demonstrated means of reducing blood pressure and allowing the pregnancy to be sustained longer. Definitive treatment is delivery of the fetus. Arrangement for close follow-up is mandatory. Hospitalization is usually required for patients with sustained hypertension above 140/90 mm Hg and signs of severe preeclampsia. Baseline laboratory studies to identify end-organ effects in the liver, kidney, and hematologic systems should be obtained. Both diuresis and antihypertensive therapy have been remarkably unsuccessful in improving fetal outcome or prolonging pregnancy. Admission does, however, allow the obstetrician to accurately assess fetal age and well-being, maternal organ function, and the effect of bed rest on blood pressure before deciding the optimal timing of delivery.[47] Fulminant or severe preeclampsia, with marked blood pressure elevation (>160/110 mm Hg), associ-ated with epigastric or liver tenderness, visual disturbance, or severe headache, is managed in the same way as eclampsia ( Box 177-4 ). The goal is prevention of seizures and permanent damage to maternal organs. Magnesium sulfate is given for seizure prophylaxis. BOX 177-4 Management of Eclampsia and Severe Preeclampsia

{,

{,

{,

Control seizures with magnesium sulfate. Control hypertension after seizure control if diastolic blood pressure > 105 mm Hg. Draw initial laboratory studies to assess organ injury: Com plete bloo d coun t and plate let coun t Liver funct ion tests BUN ,

Page 4424

{,

{,

{,

{,

{,

creat inine Monitor urine output: maintain at 105 mg/dL. Fetal—PTD, low birth weight, fetal thyroid Management of thyroid storm is the same dysfunction, fetal loss as for the nonpregnant patient and includes a search for the underlying precipitant. Maternal—preeclampsia, heart failure Therapy for hyperthyroidism in the absence of thyroid storm: Reversal of sympathetic effects: propanolol in standard doses is useful until thyroid hormone synthesis has been blocked by thioamides Thioamides: both propylthiouracil and methimazole at the lowest effective dose are acceptable Surgical therapy: thyroidectomy useful in refractory cases Other: avoid iodide if possible; hydrocortisone decreases peripheral conversion of T4 to the more active T3 and can be used during pregnancy. Radioactive iodine is absolutely contraindicated. Fetal—congenital malformations, low Maintenance therapy includes birth weight, fetal loss, fetal thyroid levothyroxine 0.15 mg/day. dysfunction and goiter

Page 4448

Medical Illness

Gestational Concerns Maternal—preeclampsia, abruption, postpartum hemorrhage, need for cesarean section

Tuberculosis

Fetal—fetal loss, low birth weight, PTD; fetal and neonatal tuberculosis

Maternal—preeclampsia; potential for delayed diagnosis and treatment out of concern for the fetus

HIV/AIDS

Syphilis

Fetal—HIV infection, PTD, fetal loss; neonatal drug withdrawal if the mother uses intravenous drugs Maternal—postpartum endometritis, uterine bleeding (in the setting of thrombocytopenia)

Fetal—congenital syphilis, fetal loss, PTD, IUGR, nonimmune hydrops

Treatment Appropriate treatment prevents adverse obstetric and fetal outcomes. Myxedema coma is rare but when present treatment is the same as for the nonpregnant patient. PPD positive/chest radiograph negative: 6- to 9-month course of isoniazid (starting after the first trimester) for patients with recent conversion (2 years may defer treatment until after delivery but should still be offered a course of isoniazid since it is safe in pregnancy Active tuberculosis: 9-month course (starting immediately) of isoniazid plus rifampin or ethambutol Multidrug-resistant tuberculosis: warrants aggressive therapy without regard to potential teratogenicity Pyridoxine is mandatory for all patients receiving isoniazid. Antiretroviral therapy:

1. Highly active retroviral therapy (HAART) should be offered to all pregnant patients with HIV and viral load > 1000. The HAART regimen should include zidovudine (AZT) to prevent vertical transmission of the virus. 2. There are specific HAART drug-related concerns during pregnancy—decisions regarding therapy are best made by appropriate specialists. 3. ART monotherapy is not recommended except in those patients with a low viral load who do not wish to take HAART. In these cases, AZT is appropriate reduce disease transmission. Cesarean section is recommended with viral load > 100. Opportunistic infections require standard therapies despite the potential fetal effects. Primary, secondary, early latent (1 year or unknown duration): BPG, 2.4 million units IM weekly × three doses Neurosyphilis: aqueous penicillin G, 2–4 million units IV q 4 hours × 10–14 days or procaine penicillin G, 2.4 million units IM and probenecid 500 mg PO q 6 hours × 10 –14 days

Page 4449

Medical Illness

Gestational Concerns

Treatment

ACE I, angi oten sinconv ertin g enzy me inhib itor; AEM , antie pilep tic med icine ; AID S, acq uire d imm uno defic ienc y synd rom e; ARB , angi oten sin II rece ptor bloc ker; DKA , diab etic keto acid osis; GD M, gest ation al diab etes melli tus; HIV, hum

Page 4450

Medical Illness

Gestational Concerns

Treatment

an imm uno defic ienc y virus ; IDD M, insul in-d epe nde nt diab etes melli tus; IUG R, intra uteri ne gro wth retar datio n; NID DM, non – insul in-d epe nde nt diab etes ; PCI, perc utan eou s coro nary inter venti on; PTD , pret erm deliv ery.

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Table 178-2 -- Drugs Used in the Treatment of Asthma During Pregnancy Pharmacologic class Inhaled b-agonists

Examples Albuterol

Comments First-line therapy

Metaproterenol Injectable b-agonists

Inhaled corticosteroids

Dosages Continuous nebulization or 2 puffs q4–6 hours 2 puffs q4–6 hours

Epinephrine

Decreases 0.3 mL SC of uteroplacental blood 1:1000 conc. flow

Terbutaline

May inhibit labor

0.25 mL SC

Beclomethasone

Not for use in mild asthma

2–4 puffs qid

Preferred steroid for maintenance therapy Systemic corticosteroids

Indications for use in acute exacerbations: inadequate response to b-agonists, steroid dependence

Maintenance therapy variable; consider alternate-day regimens

Oral

Prednisone

60 mg PO q6h for exacerbations

Intravenous

Prednisolone

125 mg IV q6h

Anticholinergics

Ipratropium bromide Limited efficacy, ↓ clearance in third trimester; follow serum levels

2 puffs q6h

Methylxanthines

Theophylline

Use only in refractory disease

400–1200 mg/day

Aminophylline

Not for routine use in 4–5 mg/kg IV, then the emergency 0.5 mg/kg/hr IV department; ↓ aminophylline clearance in pregnancy may result in maternal toxicity

Montelukast

Limited data on their 10 mg PO qhs efficacy in acute asthma exacerbations or pregnancy

Leukotriene modifiers

Zafirlukast Smooth muscle relaxants

Magnesium sulfate

20 mg PO BID Limited data on its efficacy in pregnancy

2–3 g IV; may repeat q4h

Corticosteroids remain a core component of treatment for asthma in the pregnant patient. In fact, current data support the chronic use of inhaled corticosteroids in most asthmatic patients whose disease is of at least moderate severity.[8] Other agents including the methylxanthines and newer agents including nedocromil, salmeterol, montelukast, or zafirlukast are acceptable and can be continued throughout

Page 4452

pregnancy if a high level of control has been achieved. Conversely, zileuton has been shown to be teratogenic in animals and should be avoided during pregnancy.[9] Magnesium sulfate recently has received a great deal of attention in the acute treatment of refractory asthma exacerbations because it has a wide safety profile and potent bronchodilator properties. Very little literature exists concerning its use in the pregnant asthmatic patient, although large doses have been used for the treatment of eclampsia for many years and it appears to be safe and may be effective for treating asthma.[10] Caution should be exercised when using magnesium during labor because it relaxes uterine smooth muscle. Perhaps the most important tenet of treatment to recognize is that if the mother is hypoxic, the fetus is hypoxic as well. The fetus is more sensitive to hypoxia than the mother, and normal maternal oxygen saturation does not preclude fetal distress. Supplemental oxygen should be administered to all pregnant patients with an acute asthma exacerbation.

Hypertension Chronic Hypertension and Hypertensive Emergencies Chronic hypertension is defined as elevated blood pressure that is present before the onset of pregnancy or that begins prior to the 20th week of gestation. It affects 1% to 5% of pregnancies and represents a significant source of maternal and fetal mortality and morbidity (see Table 178-1 ).[] The emergency physician might be required to provide therapy for hypertensive emergencies in patients with chronic hypertension and to differentiate between the various hypertensive disorders of pregnancy ( Table 178-3 ). Although treatment of mild disease during pregnancy is not indicated,[12] patients with more severe blood pressure elevations probably need maintenance medical therapy (see Table 178-1 ). This is best done by the patient's primary care practitioner in conjunction with her obstetrician. Table 178-3 -- Hypertensive Disorders of Pregnancy Chronic Hypertension

Definition Findings Time of onset

Gestational Hypertension

Preeclampsia

1. Hypertension[*] that antedates pregnancy 2. Hypertension diagnosed prior to 20 weeks of gestation

Hypertension diagnosed after 20 weeks gestation in the absence of preeclampsia; considered transient if hypertension resolves by 12 weeks postpartum or chronic if it persists beyond that period

Hypertension+ that begins after 20 weeks of gestation occurring in association with other clinical findings (see below)

< 20 weeks gestation Mild to severe Absent Rare Absent

Usually third trimester Mild Absent Absent Absent

≥ 20 weeks gestation Severity Mild to severe Proteinuria Usually present Hyperuricemia Usually present Thrombocytopenia Present in severe disease Liver dysfunction Absent Absent Present in severe disease Adapted with permission from Sibai BM: Drug therapy: Treatment of hypertension in pregnant women. N Engl J Med 335:257–265, 1996. +

Defined as blood pressure > 140 mm Hg systolic or > 90 mm Hg diastolic in a previously normotensive female or increases in systolic and diastolic pressures of 30 mm Hg and 15 mm Hg respectively. *

Defined as blood pressure > 140 m m Hg systolic or > 90 m m

Page 4453

Hg diastolic.

In the treatment of hypertension in pregnancy, the emergency physician must balance the goal of reducing maternal blood pressure with the requirements to maintain cardiac output and minimize adverse effects for both mother and fetus. Precipitous and marked decreases in blood pressure may significantly diminish uteroplacental blood flow. Nearly all of the major classes of antihypertensive agents are acceptable in the pregnant patient, with the exception of angiotensin enzyme inhibitors and angiotensin II receptor blockers. p -Blockers may have adverse fetal effects when given early in pregnancy but are considered safe later in gestation.[13] Hydralazine, labetalol, and sodium nitroprusside ( Table 178-4 ) are the agents most commonly used for hypertensive emergencies associated with eclampsia and are also appropriate for such emergencies in the patient with chronic hypertension. Table 178-4 -- Antihypertensive Agents for Hypertensive Emergencies Antihypertensive Agents Hydralazine

Dose 5 to 10 mg IV

Comment Consider another agent if inadequate response despite administration of 20 mg

Repeat every 20 minutes until target blood pressure is achieved Labetalol

20 mg IV

Consider another agent if inadequate response despite administration of 220 mg

Can double the dose every 10 Standard contraindications apply minutes until target blood pressure is achieved Sodium nitroprusside

Infusion rates vary—start at 0.1 mg/kg/min

Avoid prolonged infusions—fetal cyanide toxicity is possible after several hours

Diagnosis of preeclampsia in the pregnant patient with chronic hypertension is challenging but necessary. Patients with chronic hypertension are more likely to develop preeclampsia, a situation that results in increased morbidity and mortality as compared with either process in isolation. Coexistence of the two disorders should be suspected in the following settings: (1) new onset of proteinuria prior to 20 weeks' gestation in a patient with known hypertension, and (2) pregnant patients with hypertension and proteinuria prior to 20 weeks' gestation who develop an acute increase in proteinuria or blood pressure, thrombocytopenia, or increased transaminases.[11]

Pulmonary Hypertension Primary (idiopathic) pulmonary hypertension, Eisenmenger's syndrome (pulmonary hypertension associated with intracardiac left-to-right shunts), and secondary vascular pulmonary hypertension (i.e., secondary to connective tissue disease) have extremely high mortality in association with pregnancy, ranging from 30% to 52%. The majority of deaths are a result of heart failure.[14] Unfortunately, mortality is unaffected by peripartum management in most cases, although some patients benefit from selective pulmonary artery vasodilators such as prostacyclin and inhaled nitric oxide.[14] The primary goals of the emergency physician are to ensure high right ventricular filling pressures by diligently maintaining adequate volume status and to obtain early consultation with obstetrics and cardiology specialists. Patients with early gestations should be referred for elective pregnancy termination.

Cardiac Disorders Acute Coronary Syndromes Coronary artery disease is rare in pregnant women, and acute myocardial infarction (MI) is reported to occur in fewer than 1 in 10,000 pregnant patients; however, MI in this setting requires special considerations in management and carries a worse prognosis with a maternal mortality rate of 21% overall and 35% during the peripartum period.[15] Normal physiologic changes of pregnancy such as increased cardiac output and

Page 4454

reduced oxygen-carrying capacity secondary to physiologic anemia have the potential to exceed the threshold for angina if a fixed coronary artery stenosis is present. Pregnancy-specific abnormalities such as hypercoagulability and preeclampsia might contribute to acute coronary thrombosis as well. The risk of MI in a patient with significant coronary atherosclerosis increases with the duration of the gestation and peaks during labor, which is associated with further increases in cardiac output as well as increased systolic and diastolic blood pressures. A significant percentage of pregnant women with MI have normal coronary arteries—29% overall and 75% of those with postpartum MI. Other pathophysiologic mechanisms besides atherosclerosis that cause MI in the pregnant patient include coronary artery dissection, coronary artery aneurysm, and vasospasm; the relative significance of these lesions varies according to the gestational period. Atherosclerotic disease causes the majority of MIs in the antepartum period and coronary artery dissection is responsible for most postpartum events.[15] Pulmonary embolus, reflux esophagitis, biliary colic, chest pain from mitral valve prolapse, and aortic dissection are all more common than myocardial ischemia during pregnancy and need to be considered in the differential diagnosis. It is also important to consider cocaine use in the pregnant patient presenting with chest pain. Unfortunately, some women continue to use illicit drugs during their pregnancy, and it is possible that pregnancy enhances cocaine-induced cardiovascular toxicity.[16] The diagnosis of angina is primarily clinical. Because normal pregnancy is often associated with electrocardiographic changes such as left axis deviation, minor ST wave depression, and T wave inversion,[ 17] treadmill evaluation may be necessary. Echocardiography is useful in correlating suspicious electrocardiographic findings with wall motion abnormalities. The enzymatic diagnosis of MI is unchanged except during and after delivery, when troponin is preferred over creatinine kinase and myoglobin, which are both elevated above baseline during this time period.[18] Angiography is generally avoided because the large dose of radiation poses a risk to the fetus, but it can be used in certain clinical situations. Treatment of acute MI during pregnancy is similar in most respects to treatment of the nonpregnant patient. Survival of the mother is the primary concern, and therapy to improve maternal outcome should not be withheld. Standard treatment includes aspirin, nitroglycerin, p -blockers, and antithrombotic agents. However, there are potential adverse effects of such therapy on the mother and fetus (see Table 178-1 ). Heparin has long been considered the antithrombotic agent of choice in pregnant patients, but newer lower molecular weight agents, specifically dalteparin and enoxaparin, appear to be efficacious and safe.[] Heparin might be preferable for patients in the late third trimester, since there is a more predictable response to protamine sulfate should labor begin. The use of magnesium sulfate has not been studied in pregnant patients with MI but would presumably be safe, considering its long history of use in eclampsia, and it may improve survival in patients with acute MI complicated by hypomagnesemia. Experience with thrombolytic therapy in pregnancy is limited and is more extensive with disorders other than MI (i.e., pulmonary embolus). Although such therapy may reduce maternal and fetal mortality, pregnancy is considered a relative contraindication to its use. A comprehensive review of cases in which thrombolytic agents were used during pregnancy reveals significant hemorrhagic complications in 8.1% of cases.[21] Reported effects have included maternal hemorrhage, maternal death, placental abruption, preterm delivery, fetal death, and fetal intracranial hemorrhage, although the causal relationship in many of these cases is unclear. The majority of patients had favorable maternal and fetal outcomes, but most were being treated for indications other than MI.[] Because thrombolytic therapy precludes major surgery in the days immediately after administration, the emergency physician must carefully consider whether to use these agents in pregnant women who are close to term, especially if the need for cesarean delivery is anticipated. Cardiac surgery, including coronary artery bypass grafting, during pregnancy is associated with a maternal mortality rate of 2.2% and fetal mortality rate of 9.5%.[22] Emergency angioplasty with stent placement has been reported with good maternal and fetal outcomes.[23] In the setting of peripartum MI, labor should be conducted with continuous monitoring of both the mother's hemodynamic status and fetal well-being. There are benefits and risks of both vaginal and operative delivery. Cesarean section avoids prolonged exertion by the mother but subjects the patient to general anesthesia and other typical postoperative complications. Therefore, assisted vaginal delivery (i.e., vacuum) is preferred unless there is an obstetric reason for cesarean section.[15] Resolution of angina may occur during the postpartum period as physiologic demands lessen, but its occurrence during pregnancy merits a complete investigation.

Valvular Heart Disease

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Maternal valvular heart disease can be congenital or acquired and is one of the leading causes of nonobstetric death.[24] Acquired valvular disease is mainly the result of rheumatic fever and endocarditis. In the United States, most cases of significant congenital heart disease are identified and corrected surgically before puberty. Still, in many patients valvular heart disease remains undiagnosed until cardiac decompensation occurs. Asymptomatic or mildly symptomatic valvular disease is generally considered low risk, and most of these patients tolerate pregnancy without any ill effects. On the other hand, advanced aortic stenosis, aortic and mitral lesions associated with moderate to severe ventricular dysfunction or pulmonary hypertension, and prosthetic valves can result in significant maternal mortality and require directed therapy.[25] All patients with suspected valvular disease should undergo echocardiography.

Mitral Stenosis Mitral stenosis is the most important lesion to detect in early pregnancy because maternal mortality is appreciable. The increased resting heart rate seen in normal pregnancy shortens left ventricular diastolic filling time and consequently results in reduced stroke volume. The demand for increased cardiac output during pregnancy creates a vicious cycle in which further acceleration of heart rate occurs. This tachycardia, combined with the expanded plasma volume of pregnancy, ultimately produces high left atrial pressures, pulmonary vascular congestion, and the symptoms and physical findings typical of left ventricular failure. Atrial fibrillation is common and is associated with a maternal mortality rate of 15% during pregnancy.[24] Treatment is aimed at reducing plasma volume and slowing the heart rate (see Table 178-1 ). Emergency commissurotomy can be performed at any time during the pregnancy if the mother's status deteriorates, and this procedure is tolerated relatively well by the fetus.[24] Treadmill testing is useful in predicting how well the patient will tolerate pregnancy and labor. Delivery should be conducted under epidural anesthesia with the use of forceps to decrease straining.

Aortic and Mitral Regurgitation In most cases, regurgitant valvular lesions are well tolerated during pregnancy and may even improve as the reduced systemic vascular resistance of pregnancy allows more forward and less regurgitant flow. Consequently, if the mother is relatively asymptomatic before becoming pregnant, it is likely that she will do well during pregnancy. However, in the setting of ventricular dilation or atrial fibrillation, it is recommended that the mother terminate the pregnancy because of the high risk of congestive heart failure or systemic embolization. Acute aortic insufficiency resulting from acute bacterial endocarditis is an indication for immediate surgical repair at any stage of pregnancy.[24]

Aortic Stenosis Symptomatic aortic stenosis during pregnancy usually occurs in the setting of a congenital bicuspid valve and is uncommon.[25] Older reports note a high rate of maternal mortality with severe aortic stenosis (up to 17%); however, more recent series have reported uniformly successful outcome of pregnancy with aortic stenosis.[26] It is particularly important to avoid the supine hypotensive syndrome with aortic stenosis, because sudden death can occur. Invasive hemodynamic monitoring and vigorous replacement of fluids are indicated during delivery.

Hematologic Disorders Anemia By far the most common medical complication of pregnancy is anemia. Up to 50% of all pregnancies manifest some type of anemia.[27] The physiologic adaptations to pregnancy include expansion of plasma volume in excess of the increase in red blood cell (RBC) mass, resulting in the dilutional, physiologic anemia of pregnancy. Any type of anemia can complicate pregnancy, but the three types most commonly involved are iron deficiency, macrocytic, and sickle cell anemia.

Iron Deficiency Anemia Iron deficiency anemia is common, occurring in approximately 20% of pregnancies in industrialized countries.[28] Without iron supplementation, this number doubles.[29] Apart from chronically low or marginal iron stores in many women, diversion of maternal iron to the fetus for development of its own RBCs and iron stores and increased maternal demand for iron exacerbate the deficiency during pregnancy. Any episodes of blood loss during pregnancy tax an already stressed hematopoietic system and need to be taken very seriously. Maternal anemia has relatively little impact on perinatal mortality until a hemoglobin level of 6.0 g/mL is reached.[24] Less severe anemia (hemoglobin < 11.0 g/mL) is associated with an increase in preterm

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delivery and low birth weight. Iron supplementation (see Table 178-1 ) is indicated to improve maternal iron stores but has not been proven to improve either of these fetal outcome measures, and pregnant women with mild, dilutional anemia generally have uncomplicated pregnancies.[] Iron deficiency anemia secondary to malnutrition or disease is more worrisome.[28] Pregnant patients are subject to other causes of iron deficiency anemia, such as chronic blood loss from the gastrointestinal or genitourinary tracts, and these possibilities need to be considered. The diagnosis of iron deficiency anemia is most accurately made by analysis of bone marrow, because all other methods have limitations. Serum ferritin levels less than 10 g/L, transferrin saturation less than 16%, and reticulocyte counts less than 1% are characteristic of iron deficiency anemia. Serum ferritin is the preferred test, but values can be affected by inflammation and by the dilutional effect of increased plasma volume characteristic of pregnancy. It is recommended that serum ferritin levels be determined during the first trimester if possible to minimize the dilutional effect.[28] Although RBC indices classically reveal a microcytic and hypochromic anemia, these indices are found in only 11% of pregnant patients with iron deficiency anemia and are not a reliable screening tool.[24]

Megaloblastic Anemia Megaloblastic anemia is most commonly caused by dietary deficiency of vitamin B12 or folate, although in pregnancy folate deficiency is responsible for almost all cases. It is estimated that 1% to 4% of pregnancies in the United States are complicated by megaloblastic anemia, although 9% to 30% of pregnant women show depletion of folate stores and the megaloblastic bone marrow changes that precede anemia.[24] Patients with multiple gestations have an eightfold increased risk of developing folate deficiency and megaloblastic anemia. Other patients at higher risk include those with malnutrition, hyperemesis gravidarum, malabsorption syndromes, anticonvulsant therapy, alcoholism, and chronic hemolysis. Iron deficiency and megaloblastic anemias often coexist, making the peripheral blood smear difficult to interpret. Effects on the fetus depend on the degree of anemia and include neural tube defects, preterm delivery and intrauterine growth retardation.[30] Consequently, oral folate supplementation with 1 mg/day is routinely prescribed. Treatment response is usually brisk and transfusion is rarely required.

Sickle Cell Anemia Sickle cell disease (SCD) is one of the major sources of maternal and fetal complications in the United States. The sickle cell trait has a prevalence of 8% in African Americans.[31] The details of the pathophysiology and genetics of SCD are discussed in Chapter 119 , but it is useful to review the most common phenotypes that affect pregnancy. The sickle gene can be homozygous (hemoglobin SS or SCD), and this form of the disease is responsible for most pregnancy complications. The sickle gene can also be heterozygous with normal hemoglobin A (sickle cell trait or hemoglobin SA), in which case symptoms are rare except under extreme environmental conditions. The hemoglobin S can also be heterozygous with a large number of abnormal hemoglobins such as hemoglobin C, several variants of thalassemia, and other rare hemoglobin variants, and each variant has its own complication profile. Of these, the most relevant in terms of pregnancy complications is hemoglobin SC. Patients with SCD are subject to many chronic medical problems secondary to a variety of pathophysiologic mechanisms, including sickling of RBCs, anemia, immunosuppression caused by autosplenectomy, and the need for repeated transfusion. The mortality rate is 20% in the first decade of life, but many patients now live longer than 40 years and fertility is generally unaffected, so it is likely that the emergency physician will encounter pregnant patients with the disease. The incidence of serious medical complications of pregnancy in patients with SCD ranges from 50% to 80% and includes preeclampsia, antepartum and postpartum infections, more frequent pain crises, heart failure, and pulmonary infarction.[] Despite these complications, the maternal mortality rate is less than 1% with current treatment. Sickle cell disease also results in adverse effects on the fetus (see Table 178-1 ). Placental infarction is common, with small-for-gestational-age and low-birth-weight infants resulting from placental insufficiency. In addition, the need for emergency cesarean section for fetal distress is increased.[33] A high rate of fetal loss has been noted in the past, although a recent study found no increase in the rate of perinatal death.[32] An incidental complication is that the Apt test and Kleihauer-Betke test to distinguish fetal from maternal blood will yield false-positive results because of the compensatory persistence of hemoglobin F in the mother. Treatment of SCD in pregnant patients is similar to treatment in nonpregnant patients (see Table 178-1 ). Folate supplementation is standard even in the nonpregnant state because of the increased turnover of RBCs. Supplemental iron is controversial because of the fear of iron overload. Because iron stores tend to

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be low in pregnant patients, even those with SCD, most specialists provide iron supplements. Transfusion is reserved for patients with symptomatic anemia, cardiovascular instability, or acute chest syndrome, preoperatively for anticipated blood loss, and for a hematocrit less than 18%.[31] Hydroxyurea has not been used extensively in pregnancy because of fears of fetal toxicity, but there have not been any adverse effects among the few cases reported.

Neurologic Disorders Epilepsy Epilepsy is the most common neurologic complication of pregnancy, occurring in 0.8% of all gestations.[34] Epilepsy refers to a broad spectrum of seizure disorders that range from relatively benign and infrequent seizures to a disabling condition with daily, poorly controlled generalized convulsions; therefore, care must be individualized. Management of epilepsy during pregnancy must balance the risk of increased frequency and duration of seizures to both the mother and the fetus against the teratogenic risks of antiepileptic medications (AEMs). The effect of pregnancy on epilepsy is variable. Most (50-83%) epileptic patients experience no change in their seizure frequency, whereas 20% to 33% experience more frequent seizures, and 7% to 25% experience improvement in their seizure disorders.[35] Deterioration may be due to alterations in the volume of distribution or metabolism of AEMs, resulting in subtherapeutic levels or a voluntary noncompliance with medications to avoid teratogenic effects on the fetus. In addition, pregnancy-associated increased levels of estrogen, decreased levels of p~-aminobutyric acid, respiratory alkalosis, and fatigue have all been implicated as potential causes of increasing seizure frequency.[36] All of the older, commonly used AEMs have measurable teratogenic effects. A twofold to threefold increase exists in the incidence of serious congenital malformations in offspring of epileptic mothers taking AEMs.[37] The “fetal anticonvulsant syndrome” has been described and consists of neural tube defects, cleft palate, major limb defects, microcephaly, mental deficiency, and cardiac anomalies. Controversy exists as to whether infants of epileptic patients not taking AEMs have an increased incidence of congenital malformations compared with the general population. A recent study comparing these infants with infants born to mothers without epilepsy found a similar incidence of malformations.[37] Care should be provided by specialists in high-risk obstetrics and neurology disciplines; however, emergency physicians may be forced to confront this problem in several clinical scenarios—the pregnant patient with a first-time seizure or status epilepticus and the patient with epilepsy who is found to be pregnant.

New-Onset Seizure Pregnant patients may seek treatment for idiopathic new-onset seizures; however, drug toxicity or withdrawal, head injury, meningitis, stroke, and eclampsia should be considered as possible causes. The most important of these is eclampsia. Eclampsia generally occurs in the setting of progressive preeclampsia, although the diagnosis may be difficult. Preeclampsia consists of the triad of hypertension, peripheral edema, and proteinuria. Patients in the immediate postictal phase often manifest hypertension resulting from massive sympathetic discharge, and even those with normal pregnancies may have mild edema of the lower extremities. Consequently, urinalysis should be performed to search for proteinuria, which may be the only differentiating factor in the initial assessment of these patients. After a period of observation, blood pressure in the noneclamptic patient will revert to normal or low. If the patient remains hypertensive or manifests other signs of eclampsia, magnesium sulfate and other agents are indicated to prevent further seizures and to control blood pressure. In patients who do not manifest signs of eclampsia, investigation of the cause of the seizure should proceed as with the nonpregnant patient (see Chapter 100 ).

Status Epilepticus Pregnant patients with known epilepsy may arrive in the emergency department in status epilepticus. Any of the causes of seizures, including eclampsia, may result in status epilepticus. Despite this, status epilepticus in pregnancy is relatively rare and only anecdotal reports are available to guide therapy.[38] The risk of status epilepticus to both the mother and the fetus clearly outweighs the potential for adverse teratogenic effects, and standard resuscitative measures as well as drug therapy are indicated. Continuous fetal monitoring should be instituted as soon as possible and the mother positioned to avoid the supine hypotensive syndrome.

Pregnant Epileptic Patient

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Patients with epilepsy coming to the emergency department for unrelated reasons may be found to be pregnant. Although no immediate change in their therapeutic regimen needs to be made, these patients should be advised of the potential risk of AEMs in pregnancy and be referred to appropriate specialists. Unintentional pregnancy is seen even in patients taking oral contraceptives, because AEMs can cause increased clearance of these medications, thereby reducing their efficacy.[39] There are many obstetric complications related to prolonged seizure activity and long-term treatment with an AEM for patients with such ictal events is indicated (see Table 178-1 ). Many patients who have nonconvulsive seizure disorders or who have been free of seizures for a sufficient period can be taken off AEMs, but this decision should be deferred to the patient's primary physician or neurologist. Because diphenylhydantoin, carbamazepine, valproate, and possibly other AEMs interfere with folate metabolism, oral supplementation with at least 0.4 mg/day is recommended for all women of child-bearing age taking AEMs.[ 35] Higher doses are recommended for women using AEMs known to cause neural tube defects. Many AEMs, including carbamazepine, diphenylhydantoin, and phenobarbital, cause neonatal vitamin K deficiency, resulting in a high rate of infant mortality (>30%) as well as coagulopathy in up to 50% of neonates, with serious bleeding episodes in 7%.[] Consequently, the mother should receive oral vitamin K (10 mg) during the last month of gestation, and vitamin K 1 mg intramuscularly or intravenously should be given to the newborn.[35] Experience with the newer AEMs, such as gabapentin, felbamate, lamotrigine, topiramate, and tiagabine, in pregnant patients is limited, but these agents are likely to have a more desirable side effect profile and have less interference with folate metabolism.[41]

Multiple Sclerosis Multiple sclerosis (MS) affects 250,000 Americans and is twice as common in women as men. The peak age of onset is from 20 to 35 years of age, which overlaps peak childbearing years. The disease is characterized by intermittent episodes of central nervous system demyelination with consequent neurologic impairment that follows a relapsing-remitting course. Progressive neurologic deficits and permanent disability develop in certain patients. The impact of pregnancy on the course of MS has been closely studied in various cohorts of women, and a pattern has emerged. Like other autoimmune diseases, the frequency and severity of exacerbations of MS improve because of the immunosuppressant effects of pregnancy. During the 3 months after delivery, the rate of relapse increases and then returns to the prepregnancy baseline.[42] The long-term effects of pregnancy on the disease course may be beneficial. Several studies have found that patients who had at least one pregnancy after the onset of MS had a significantly longer interval until wheelchair dependence than patients who did not have a pregnancy (18.6 years versus 12.5 years)[43] and were less likely to develop progressive disease.[44] Studies involving a shorter period of follow-up do not reveal such a benefit. Children of parents with MS have an increased susceptibility to develop MS themselves, reflecting at least a partial genetic component to the disease. Labor may be complicated by uncoordinated voluntary motor activity in pushing, but generally pregnancies in these patients progress without undue complications.

Spinal Cord Injury Because spinal cord injury (SCI) occurs mainly in young persons and usually does not impair fertility, there is a relatively large population of paraplegic and quadriplegic patients who become pregnant. Although many of these pregnancies are uneventful, these patients are at risk for certain complications. The incidence of urinary tract infection is relatively high, and these infections often progress to pyelonephritis during pregnancy with the resultant increased risk of fetal loss, prematurity, and maternal sepsis. The increased coagulability of pregnancy combined with chronic immobilization results in an increased incidence of venous thrombosis and pulmonary embolus.[45] A unique problem in the patient with SCI is the detection of the onset of labor, which may be painless and precipitous. Patients with spinal cord lesions below T12 have an intact uterine nerve supply and will experience labor pains; however, with lesions above T10, labor may be imperceptible or experienced as only mild abdominal discomfort. In 85% of patients with lesions above T5 to T6, labor is heralded by an explosive autonomic dysreflexia.[] This manifests as severe paroxysmal hypertension, pulsatile headache, tachycardia, blotching of the skin, diaphoresis, piloerection, mydriasis, and nasal congestion. Because the response is not specific to labor and may be precipitated by distention of bowel or bladder, other causes must be pursued as well. Pregnant patients with SCI who have these symptoms should be assessed for cervical dilation and have uterine contractions monitored. Emergency department treatment is directed at

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restoring normal blood pressure with nitroprusside, nitroglycerin, or hydralazine. Definitive therapy is with regional anesthesia. Both spinal and epidural anesthesia obliterate and prevent this response and should be used as soon as possible during labor for all women with SCI.[47] Because of the difficulty in detecting labor, pregnant patients with SCI are often admitted for observation at 35 weeks' gestation.

Myasthenia Gravis Myasthenia gravis is a rare disorder in which autoimmune destruction of the postsynaptic cholinergic receptor results in profound muscle fatigability. Treatment with cholinesterase inhibitors can supply additional acetylcholine to achieve virtually normal muscle contractility but must be titrated to avoid precipitating a cholinergic crisis. Adjustments in medication dosing are frequently required to preserve this balance. The effect of pregnancy on myasthenia gravis is unpredictable in the individual patient, but overall approximately one fifth to one third experience exacerbation of disease with the remainder having improvement or no change in disease severity.[] Improvement during the last two trimesters of pregnancy is likely due to the relative immunosuppressant effect seen during that time.[49] Several important pregnancy complications are associated with myasthenia gravis. Because of weight gain, anemia, and other physiologic adjustments of pregnancy that may result in fatigue, the distinction between normal pregnancy symptoms and myasthenia may be difficult. Although uterine contractile force is unaffected by myasthenia gravis, labor may be prolonged because of fatigue of abdominal muscles during active pushing. Arrest of labor can occur, requiring the use of high forceps or other extraction methods.[50] Ten to 20% of neonates born to mothers with myasthenia develop a transient neonatal myasthenic syndrome that may be life-threatening.[] The onset of neonatal myasthenia may be delayed as much as 1 week and consists of poor feeding and suck, diminished reflexes, hypotonia, and respiratory failure. As with adults, the symptoms respond to cholinesterase inhibitors, but treatment should be done in an intensive care unit setting, and these neonates should be observed for at least 1 week. The duration of the syndrome depends on the clearance of maternal antibodies, and medication must be continually adjusted. Finally, maternal myasthenia gravis can exacerbate precipitously during the postpartum period as the protective immunosuppressant effect of pregnancy dissipates. Treatment in the emergency setting is no different than treatment for nonpregnant patients and might include ventilatory support, pyridostigmine, corticosteroids, and plasmapheresis (see Table 178-1 ). Continuous pulse oximetry and arterial blood gas determination will guide respiratory therapy. For patients presenting with weakness, a “Tensilon challenge test” or its equivalent can distinguish myasthenic from cholinergic crisis but should only be attempted after appropriate ventilatory assistance is provided. Use of immunosuppressive medications may be associated with a higher incidence of congenital malformations, although azathioprine appears to be safe. Epidural anesthesia is recommended for labor and delivery; sedatives and other agents that increase fatigue should be avoided during this time.[49]

Renal Disorders Several alterations in renal hemodynamics occur during pregnancy. Both the glomerular filtration rate and effective renal plasma flow increase by 30% to 50% compared with the nonpregnant state.[51] Because no substantial alterations are present in the production of creatinine or urea nitrogen, levels of these solutes decrease from average nonpregnant values of 0.7 and 12.0 mg/dL to 0.5 and 9.0 mg/dL, respectively. Thus, blood urea nitrogen and creatinine levels considered normal in nonpregnant women (creatinine > 0.8 mg/dL and blood urea nitrogen > 13 mg/dL) indicate underlying renal impairment and warrant further investigation. In the past, chronic renal parenchymal disease of any severity was considered a virtual contraindication to pregnancy, but this view has changed with recent studies that show good pregnancy outcomes and preserved renal function in the majority of patients with mild to moderate insufficiency. On the other hand, patients with severe renal dysfunction have a much higher risk of further decline in renal function as well as poor fetal outcome.[] Other variables that have been shown to adversely affect pregnancy outcome are prepregnancy hypertension and a history of long-term hemodialysis. Conception is uncommon in women on long-term dialysis and is extremely risky for both the mother and the fetus. Pregnancy termination is usually advised. Typically, less than 50% of these pregnancies result in a viable infant, although recent advances in maternal and neonatal care may improve the success rate.[53] Pregnant women with preexisting renal disease or hypertension are more susceptible to preeclampsia. Because worsening of the underlying renal disease is manifested by hypertension and proteinuria, differentiation from preeclampsia can be difficult. It is always best to treat the patient for presumed

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preeclampsia, but measurement of serum magnesium levels is indicated prior to use of magnesium sulfate. Pregnant women with chronic renal failure require aggressive and timely management to optimize their chances for a successful gestation without causing further deterioration in renal function. Baseline renal function studies are done early in pregnancy and then reassessed every 4 to 6 weeks. Evidence of renal function deterioration or the development or exacerbation of hypertension warrants admission for specialized inpatient care. Failure to reverse these parameters is usually an indication to terminate the pregnancy.

Metabolic and Endocrine Disorders Diabetes Diabetes is one of the most common chronic disorders that complicate pregnancy, affecting 3% to 5% of all pregnancies.[54] Three types of diabetes are involved in pregnancy: type I or insulin-dependent diabetes mellitus (IDDM), type II or non–insulin-dependent diabetes mellitus (NIDDM), and gestational diabetes mellitus (GDM) in which glucose tolerance becomes abnormal during pregnancy but returns to normal after delivery. Although pregnant patients with NIDDM tend to have less severe disease than those with IDDM, maternal and fetal complications relate more to the duration of diabetes as well as the presence of vascular complications or severe renal insufficiency rather than to the type of diabetes. All pregnant patients with diabetes are considered “brittle” and demand close follow-up by appropriate specialists.

Maternal Complications The physiology of glucose regulation during pregnancy is complex. During the first trimester, under the influence of elevated progesterone and estrogen levels, the sensitivity to insulin increases. When combined with emesis, increased use of glucose by the placenta and fetus, and a decrease in hepatic glucose production, hypoglycemia occurs more easily. Consequently, patients with IDDM are at risk for hypoglycemic coma during early pregnancy and insulin dosage should be decreased. During later gestation, however, there is progressive insulin resistance that peaks during the third trimester.[] Pregnancy also predisposes to ketosis and this effect is exacerbated in the setting of emesis. The effects of pregnancy on underlying diabetes vary depending on the organ system. The data are limited, but pregnancy termination is generally advised for diabetic patients with coronary artery disease because of the cardiovascular demands of pregnancy and the high mortality of acute MI during pregnancy.[] Patients with diabetic nephropathy are at increased risk for severe preeclampsia and often experience a transient increase in proteinuria with resolution after delivery. Those patients with severe renal dysfunction are more likely to experience permanent effects. Retinopathy does not appear to be permanently affected by pregnancy, but it may worsen during pregnancy, especially in patients with hypertension and in the setting of overaggressive correction of hyperglycemia.[] Autonomic neuropathy does not accelerate during pregnancy, but the combination of hyperemesis gravidarum and gastroparesis often causes problems. Frequent vomiting results in dehydration and inadequate intake of food that can result in hypogly-cemic episodes if the insulin dosage is not adjusted accordingly. Diabetic ketoacidosis occurs in 1% to 3% of insulin-requiring diabetic patients during pregnancy and may represent the initial presentation of diabetes. Diabetic ketoacidosis is most commonly seen in those patients with IDDM but also complicates pregnancies in women with NIDDM and GDM.[55] Common precipitating events include hyperemesis, use of p -mimetic medications for tocolysis, use of corticosteroids, infection, and noncompliance or errors in insulin dosage.[55] The serum pH may be deceptively normal in a pregnant patient with diabetic ketoacidosis, because the initial pH tends to be higher in pregnancy due to physiologic hyperventilation. Loss of gastric acid through vomiting will also counteract the metabolic acidosis of diabetic ketoacidosis. Serum glucose may be only moderately elevated because the fetus continues to secrete insulin and use glucose.[24] Maternal mortality is rare in appropriately treated diabetic ketoacidosis. Fetal mortality rates are decreasing with advances in diabetic and obstetric care but still remain relatively high, ranging from 9% to 50%.[]

Fetal Complications Diabetes has many deleterious effects on the fetus (see Table 178-1 ). Both hyperglycemia and hypoglycemia appear to be teratogenic during early pregnancy. The rate of congenital malformations in patients with prepregnancy diabetes is increased threefold to fourfold over the nondiabetic population.[58] The poorly controlled diabetic patient is also more likely to have either macrosomic or low-birth-weight infants. Glucose crosses the placenta and prolonged fetal exposure to maternal hyperglycemia induces fetal pancreatic hyperplasia and high insulin production. Elevated insulin levels in turn promote fetal growth, resulting in macrosomia. Consequently, the incidence of fetopelvic disproportion, shoulder dystocia, and

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asphyxia during delivery is high in diabetic pregnancies.[] Conversely, preeclampsia and placental infarction secondary to vascular disease may result in impaired fetal development. After delivery, continued high insulin secretion in the absence of a maternal glucose supply results in neonatal hypoglycemia in 25% of cases.[59] The incidence of respiratory distress syndrome is increased in infants of diabetic mothers with inadequate glycemic control because surfactant production is decreased. Macrosomic infants have an increased risk of intrauterine fetal demise during the last weeks of gestation but lack of fetal lung maturity may prevent early elective delivery.[54]

Management Treatment of NIDDM and IDDM requires individualized and carefully adjusted insulin administration (see Table 178-1 ). Treatment of diabetic ketoacidosis does not differ from treatment given in the nonpregnant state except that fetal viability and well-being should be assessed. The timing of delivery is a balance between the delayed fetal lung maturity and the condition of the fetus or mother. Generally, elective delivery for poorly controlled diabetic patients is timed to occur about 2 weeks early to avoid fetal growth into the macrosomic range. Patients undergoing elective delivery prior to 39 weeks' gestation require amniocentesis to assess fetal lung maturity. For patients with term gestations, fetal size is estimated by ultrasonography and a nonstress test is performed to determine the fetus's ability to tolerate labor.[54]

Gestational Diabetes Gestational diabetes is more common than IDDM or NIDDM and has little impact on the fetus if detected and treated early in the pregnancy; however, untreated GDM carries a fourfold increase in fetal mortality.[59] The implication of GDM is greater for the mother in that 17% to 63% will develop diabetes within the following decade.[] Patients at increased risk include those with obesity, poor insulin secretion, and onset early in pregnancy.[60] The issue of screening for GDM is controversial. Some sources recommend universal screening while the American Diabetes Association advocates selective screening of patients at increased risk for GDM. This group includes patients older than 25 years of age; certain high-risk ethnic groups; and patients with obesity, known first-degree relatives with diabetes, a personal history of diabetes or glucose intolerance, and a personal history of poor pregnancy outcome.[54] A positive screening test is an indication for a formal 3-hour glucose tolerance test. Treatment is initially aimed at dietary control, followed by insulin administration if dietary control is unsuccessful (see Table 178-1 ). Practitioners have avoided oral medications in the past but studies show that glyburide is safe and effective for GDM.[]

Thyroid Disorders Thyroid function remains essentially unchanged during pregnancy despite an increase in thyroglobulin levels. Human chorionic gonadotropin stimulates the thyroid gland and is structurally similar to thyroid-stimulating hormone; high circulating levels of human chorionic gonadotropin during the first trimester may cause a temporary and clinically insignificant increase in free thyroxine (T4). However, free triiodothyronine (T3), T4, and thyroid-stimulating hormone levels usually remain within normal range.[] Negligible amounts of maternal thyroid hormone, thyroid-stimulating hormone, or exogenous thyroxine cross the placenta; however, thyroid-releasing hormone from the hypothalamus and thyroid-stimulating immunoglobulin G do cross the placenta and can also cause fetal hyperthyroidism.[63]

Hyperthyroidism The peak incidence of autoimmune disease and thyroid disease is in women of childbearing age, and 0.2% of pregnancies are complicated by hyperthyroidism.[63] Because the symptoms of hyperthyroidism resemble the physiologic changes expected during pregnancy in many respects, the diagnosis may not be immediately evident. Symptoms such as dyspnea, heat intolerance, hyperemesis, tachycardia, palpitations, systolic flow murmurs, increased appetite, and fatigue are common to both conditions, making clinical diagnosis difficult. In cases of suspected hyperthyroidism, thyroid function studies are indicated and will confirm the presence of disease. The most common cause of hyperthyroidism is Graves' disease, in which autoimmune thyroid-stimulating immunoglobulin G results in increased production and release of thyroid hormone. Patients with Graves' disease have other characteristic findings in addition to the more nonspecific signs and symptoms of sympathetic stimulation. These include a diffusely enlarged, soft, mildly tender thyroid gland; exophthalmos; and dermopathy. Thyroid storm is the most serious manifestation of disease. It may be precipitated by stressors such as infection and delivery and manifests with fever, dysrhythmias, congestive heart failure, psychosis, and circulatory collapse. As with other autoimmune conditions, transient improvement during

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pregnancy is common, with rebound and clinical deterioration occurring after delivery.[64] There are several obstetric concerns for both mother and fetus in the setting of untreated hyperthyroidism (see Table 178-1 ).[63] In addition, Graves' disease places the fetus at risk for autoimmune-mediated thyroid dysfunction. One to 2% of neonates of mothers with Graves' disease have transient hyperthyroidism lasting 3 to 12 weeks because of the transfer of maternal thyroid-stimulating immunoglobulin G across the placenta. The condition gradually clears as maternal antibodies are metabolized. These infants may have goiter, congestive heart failure, premature craniosynostosis, frontal bossing, low birth weight, pulmonary hypertension, and hypertrophic cardiomyopathy. The mortality rate from severe neonatal hyperthyroidism approaches 25%, so the condition must be recognized promptly and treated aggressively.[65] Treatment of hyperthyroidism (see Table 178-1 ) occurs in two stages. The first priority is the reversal and stabilization of the end-organ and hemodynamic effects of sympathetic stimulation, followed by reduction in the production of thyroid hormone. Most patients respond to pharmacologic manipulation, although thyroidectomy may be considered in severe cases. Use of 131I radionuclide to ablate the maternal thyroid is absolutely contraindicated because it will also destroy the fetal thyroid gland. Propylthiouracil is typically preferred over methimazole because of a more rapid onset of effect, although either drug can be used. Both drugs cross the placenta and can cause fetal hypothyroidism.[63] Consequently, neonatal thyroid function must be assessed periodically. Both drugs also enter breast milk, but they are still considered safe for breast-feeding.[63] Iodides transiently block the release of stored T4 from the thyroid gland and inhibit organification of iodide. However, the fetal thyroid is extremely sensitive to iodide, which may result in neonatal goiter and hypothyroidism. Therefore, iodide use should be reserved for severe cases and should not be continued beyond 7 to 10 days during pregnancy.

Postpartum Thyroiditis Postpartum thyroiditis is a common but relatively benign condition that develops in 5% to 9% of parturients within 9 months of delivery. Patients typically experience transient hyperthyroidism followed by transient hypothyroidism.[64] Pharmacologic treatment may be required; however, the need for medication seems to be confined to those patients with hypothyroidism.[] Up to 30% of patients with postpartum hypothyroidism may have permanent thyroid failure several years later, and this percentage may be even higher in subsequent years.[64]

Hypothyroidism Overt hypothyroidism is often associated with infertility, so most cases seen during pregnancy are less severe or subclinical forms. Subclinical hypothyroidism may become overt during pregnancy, because physiologic adjustments result in a greater requirement for thyroid hormone production. In addition, iodine deficiency may be exacerbated by pregnancy, because renal losses of iodine increase as the glomerular filtration rate increases and as the fetus diverts iodine for its own thyroid hormone synthesis. The resulting lack of thyroid hormone results in increased thyroid-stimulating hormone level and goiter formation. Symptoms are identical to those in the nonpregnant state and include coarse hair, dry skin, fatigue, weight gain, cold intolerance, constipation, irritability, and paresthesias. Myxedema coma is extremely rare but must be considered with other causes of coma in a pregnant patient. As with hyperthyroidism, there is an increased incidence of adverse maternal and fetal effects (see Table 178-1 ).[] Treatment consists of the replacement of thyroid hormone at a dosage of 0.15 mg/day orally, which is slightly higher than the recommended dosage in nonpregnant patients.[63] The fetus produces its own thyroid hormone after 12 weeks' gestation and is consequently euthyroid at birth. Congenital hypothyroidism, associated with cretinism and severe mental retardation, occurs in 1 in 4000 births. It is most often the result of sporadic thyroid dysgenesis or various genetic disorders rather than maternal thyroid dysfunction.[68] Diagnosis is often difficult, since clinical signs and symptoms may be masked by maternal thyroid hormone.[63] Congenital hypothyroidism is amenable to in utero diagnosis and treatment, and screening for congenital hypothyroidism is mandated in most developed countries.

Systemic Infections Tuberculosis The effect of tuberculosis on pregnancy is unclear. Some studies reveal a significant increase in gestational complications (see Table 178-1 ), but these outcomes are likely significantly influenced by the site of disease

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and specifics of treatment. Complications are more likely in patients with inadequate or delayed treatment, delayed diagnosis, and extrapulmonary (extranodal) tuberculosis.[] A recent study found no significant increase in gestational complications in 111 pregnant patients with properly treated tuberculosis.[72] On the other hand, exposure to undiagnosed and untreated active disease places the infant at significant risk for acquiring tuberculosis during the first year of life, with significant mortality. In addition, the fetus can become infected via the placenta or aspiration of infected amniotic fluid, but congenital tuberculosis is rare if the mother has received appropriate therapy.[71] Current recommendations are to administer a tuberculin skin test early in pregnancy to all patients at high risk for disease and to obtain a chest radiograph if the purified protein derivative (PPD) skin test is positive or if the patient's signs and symptoms suggest tuberculosis. Definitive treatment varies depending upon the duration of PPD positivity and whether the patient has active disease (see Table 178-1 ).[73] Isoniazid, ethambutol, and rifampin in their usual doses have not been shown to be teratogenic to human fetuses and are acceptable during pregnancy. On the other hand, streptomycin causes fetal ototoxicity when given at any time during gestation, and little is known about the safety of pyrazinamide during pregnancy.[71] These agents as well as the other less commonly used medications should be avoided in pregnancy except in the case of multidrug-resistant disease. Bacille Calmette-Guérin vaccine is recommended for infants with a negative tuberculin skin test who are at high risk for infection by virtue of prolonged exposure to individuals who are untreated or noncompliant with treatment.[71]

Human Immunodeficiency Virus and Acquired Immunodeficiency Syndrome The human immunodeficiency virus (HIV) is one of the leading health problems in pregnancy. In 2002, 26% of cases of acquired immunodeficiency syndrome (AIDS) in the United States were in women, with the vast majority (80%) in their childbearing years.[74] Estimates of the seroprevalence of HIV in pregnant women vary on a regional basis. In some African countries, these figures range from less than 1% to 24%.[] In the United States, the nationwide prevalence ranges from 1.5 to 1.7 per 1000 women but is as high as 2% in some inner city populations.[] Vertical transmission of HIV in the United States declined by 67% from 1992 through 1997, a decline that coincides with the implementation of routine voluntary testing and zidovudine (AZT) prophylaxis for HIV-positive pregnant women.[79] However, vertical transmission remains a global concern; it is estimated that perinatal infection occurs in 10% to 60% of deliveries if the mother is untreated.[80] The mechanism of vertical transmission is unknown, but the majority of cases are thought to occur during delivery through exposure to maternal blood and secretions; other infants are likely infected in utero or via breast-feeding. Various factors influence the rate of transmission, the most important of which is maternal viral load; others include vaginal delivery, intravenous drug use, and prolonged rupture of membranes.[80] In countries in which alternative nutritional sources are available, breast-feeding should be avoided because it doubles the risk of fetal infection. Antepartum AZT therapy that is continued through delivery decreased the rate of vertical transmission from 25.5% to 8.3% in one study and decreased the rate to 4.25% in a smaller, more recent investigation.[] Because of this beneficial effect, voluntary screening should be offered to all pregnant women, and all pregnant patients presenting to the emergency department should be referred to anonymous testing centers or specialty clinics if their HIV status is unknown. Although long-term data are not available, AZT has not been found to cause any specific congenital abnormalities; however, it is associated with reversible neonatal anemia.[83] Other infections, such as with cytomegalovirus, syphilis, and hepatitis B and C, can also be vertically transmitted concurrently with HIV. The incidence of prematurity, stillbirth, and low birth weight is higher with symptomatic maternal HIV infection. Seropositive mothers have an increased risk of postpartum endometritis, but asymptomatic patients generally have good pregnancy outcomes.[] Commonly used serologic tests for HIV yield positive results in virtually all of these neonates because of transfer of maternal antibodies. These findings may remain positive for up to 18 months and are not an accurate indicator of neonatal infection; in fact, the vast majority of infants are seronegative after these antibodies clear. In addition, some children in whom HIV has been directly isolated using culture or detection of viral RNA have been clear of the virus in subsequent testing.[87] Only a fraction of exposed infants develop HIV infection, but of these, approximately 20% develop AIDS during the first year of life.[88] Common initial symptoms are generalized lymphadenopathy, hepatosplenomegaly, and thrush. Infants with AIDS typically present with recurrent bacterial infections, Pneumocystis pneumonia, encephalopathy, and lymphoid interstitial pneumonia.[] Isolation of virus within the first week of life is associated with the onset of early,

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severe disease.[89] The rapidity of disease progression in the infant is also directly proportional to the severity of the mother's HIV illness as manifested by the viral load and CD4 count. Early antiretroviral treatment during infancy has been shown to reduce the likelihood of death as well as the development of AIDS.[90] The effect of pregnancy on the course of HIV in the mother is unclear. CD4 lymphocyte counts transiently decrease in normal pregnancy but then normalize postpartum. Counts remain depressed in the HIV-infected patient.[91] It seems intuitive that the incidence of opportunistic infections would increase, but this does not occur, at least in women with mild to moderate HIV disease.[] Treatment of the pregnant patient with HIV includes appropriate antiretroviral treatment (see Table 178-1 )[80] as well as standard therapy for opportunistic infections when they occur. Use of highly active antiretroviral treatment (HAART) has become commonplace in nonpregnant patients and limits the emergence of resistant organisms within an individual. There is limited experience using HAART during pregnancy, but recent studies suggest that there is no increase in serious adverse effects. Protease inhibitors have been linked to an increase in prematurity and low birth weight, but there is disagreement about this association.[] The risk of perinatal HIV transmission increases with the degree of maternal viral load, even in the setting of prophylactic AZT therapy.[] Consequently, pregnant patients with HIV infection should be offered the more effective HAART regimen, particularly if the viral load is greater than 1000 copies.[80]

Syphilis Fortunately, the incidence of syphilis in the United States in 2000 was the lowest it has been since 1941.[96] Likewise, the incidence of congenital syphilis has been declining but the disease remains a concern among those patients without access to prenatal care.[97] Syphilis causes numerous gestational complications (see Table 178-1 ), but its most significant sequela is congenital syphilis. This syndrome is characterized by clinical abnormalities such as hepatosplenomegaly, osteochondritis, jaundice, lymphadenopathy, rhinitis, Hutchinson's teeth, and anemia. Perinatal mortality for cases occurring from 1992 to 1998 was 6.4%.[98] If untreated, vertical transmission rates are high at approximately 50% but can be reduced to negligible levels (2%) with appropriate penicillin therapy.[99] Screening for all pregnant patients is indicated at the first prenatal visit and at 32 to 36 weeks for high-risk patients.[99] Either Venereal Disease Research Laboratory or rapid plasma reagin testing can be used to detect nontreponemal antibody. Pregnancy may cause false-positive results for nontreponemal studies, so confirmation using specific treponemal tests is indicated for a positive Venereal Disease Research Laboratory test or rapid plasma reagin finding. Patients with latent syphilis and those whose titers fail to respond to therapy should undergo cerebrospinal fluid analysis to screen for tertiary syphilis.[100] Treatment is identical to that given to nonpregnant patients using benzathine penicillin G (see Table 178-1 ).[ 100] Penicillin-allergic patients should undergo skin testing and desensitization if the skin test result is positive because erythromycin, although adequate for the mother, is not reliably effective in preventing congenital syphilis.

Hepatitis Hepatitis B The prevalence of hepatitis B virus infection among pregnant women varies depending on the population studied. In U.S. urban areas, 0.14% to 5.79% of pregnant women are positive for HbsAg, with Asians having the highest seroprevalence.[101] The rate of vertical transmission depends on the acuity of maternal infection and when during the gestation it occurs. Perinatal transmission approaches 90% in mothers who are seropositive for HBsAg and HBeAg and is more likely if the mother has acute infection during the third trimester or first few months postpartum, or if she is a chronic carrier.[] Infection earlier in pregnancy does not result in high rates of perinatal transmission because maternal antibody to HBsAg has time to clear the virus from both mother and fetus. Of babies who develop hepatitis B virus infection, 60% to 90% become chronic carriers as adults and are at risk for complications such as cirrhosis and hepatocellular carcinoma.[ 102]

Routine screening for hepatitis B virus during early pregnancy is recommended because treatment with hepatitis B immunoglobulin and hepatitis B vaccine is very effective in reducing the rate of vertical transmission.[103] Infant immunization and treatment with hepatitis B immunoglobulin is 85% to 95% effective in preventing perinatal disease transmission, and vaccination is recommended for all infants in the United States. The treatment schedule varies depending on maternal seropositivity. Infants of HBsAg-positive

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mothers should receive hepatitis B immunoglobulin and the first dose of vaccine within 12 hours of birth. Pregnancy is not a contraindication to either therapy, and all pregnant patients who are exposed to hepatitis B virus should also receive hepatitis B immunoglobulin and vaccine.[103]

Hepatitis C As with hepatitis B virus, the prevalence of hepatitis C infection among pregnant women varies depending on the population; overall, 1% of pregnant women has hepatitis C but the prevalence is as high as 4.3% in some urban areas.[] Vertical transmission of hepatitis C is much less common than hepatitis B virus but can occur. The rate of perinatal transmission is increased by the presence of viremia, coinfection with HIV, and a history of intravenous drug use. Overall, vertical transmission occurs in 1.7% of mothers with antihepatitis C antibodies, but this increases to 4% to 7% in viremic mothers and is greater than 8% in intravenous drug use patients. The rate increases sixfold for those with HIV.[105] No available vaccine exists to prevent hepatitis C, although testing of potentially infected neonates is advised to identify those at risk for chronic hepatitis.

Inflammatory Disorders Rheumatic diseases or collagen vascular diseases are characterized by sterile inflammation in multiple anatomic sites. The most common rheumatic diseases encountered in pregnancy are systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), scleroderma, and juvenile rheumatoid arthritis. Patients with collagen vascular disease may have preexisting cardiovascular or renal compromise and may not tolerate the increased intravascular volume that occurs during pregnancy. The following discussion focuses on SLE, which is the rheumatic disease responsible for the majority of gestational complications. Most of the treatment guidelines for SLE are relevant to other rheumatologic disorders as well.

Systemic Lupus Erythematosus Systemic lupus erythematosus primarily affects women of reproductive age, and fertility is usually unaffected. The disease course during pregnancy is a matter of controversy but it seems that flare-ups are common.[106] The gestational effects of SLE are variable, depending on the severity of underlying disease. Although many patients do well, lupus pregnancies are associated with an increased rate of complications, including preeclampsia, preterm delivery, intrauterine growth retardation, and fetal loss.[] The risk of preeclampsia is increased in patients with preexisting renal disease and antiphospholipid antibodies.[106] Increasing proteinuria warrants a careful evaluation to distinguish between lupus glomerulonephritis and preeclampsia. The presence of RBC casts in the urine sediment, increasing titers of anti-DNA antibody, decreasing levels of C3 and C4, disease activity in other organs, and a positive response to prednisone point to lupus nephritis.[106] Numerous other organ systems in addition to the kidneys are involved in SLE, and differentiation from pregnancy-related changes may be difficult. Thrombocytopenia occurs in normal pregnancies and is also common in patients with SLE, although the clinical significance varies from patient to patient. Anemia is a frequent complication of lupus and magnifies the normal dilutional anemia of pregnancy; this anemia can compromise the fetus even if the mother is relatively asymptomatic. Various musculoskeletal and cutaneous symptoms associated with pregnancy, such as arthralgias and facial and palmar erythema can also resemble active SLE. In addition, preexisting lupus rashes become more erythematous because of the increased cutaneous blood flow during pregnancy. Arthritis occurs in approximately 90% of SLE patients, and many develop inflammatory effusions late in pregnancy. Neurologic disease in SLE may manifest as psychosis, seizures, chorea, or peripheral neuropathy. The incidence of these complications is low during pregnancy, although the occurrence of seizures in late pregnancy in patients with coexistent hypertension and renal insufficiency poses a diagnostic dilemma between the neurologic effects of SLE and eclampsia.

Other Rheumatologic Diseases Rheumatoid arthritis is characterized by chronic, destructive, symmetric joint inflammation. Less common manifestations include the development of subcutaneous nodules, neuropathy, pleuropericarditis, and vasculitis. Systemic symptoms, including weight loss, lymphadenopathy, and fatigue, are common. Approximately two thirds of patients with RA experience an amelioration of symptoms during pregnancy, although often an exacerbation follows delivery.[108] RA appears to have little effect on pregnancy outcome. Patients with other rheumatologic diseases including Sjögren's syndrome, scleroderma, CREST syndrome (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia), and polymyositis may have symptomatic improvement during pregnancy.

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Treatment The rheumatologic diseases are very similar with respect to the therapeutic approach. Corticosteroids form the basis of treatment for most disease complications and exacerbations. Prednisone and methylprednisolone do not readily cross the placenta and are considered relatively safe to use during pregnancy, even at high dosages. Although animal studies suggest an increased incidence of cleft palate, no teratogenic effects have been documented in humans. Steroid use during pregnancy predisposes the patient to GDM and hypertension, and these patients require close follow-up.[] Aspirin can be effective in treating thrombocytopenia in pregnant SLE patients and is often used as the mainstay of therapy in nonpregnant RA patients. Nonsteroidal anti-inflammatory drugs are also a mainstay of therapy in many patients with rheumatic diseases. There are numerous potential adverse effects of aspirin and nonsteroidal anti-inflammatory drugs on gestation, including premature closure of the fetal ductus arteriosus, increased maternal bleeding secondary to platelet dysfunction, and prolongation of gestation and labor. On the other hand, aspirin has gestational benefits as well, since it reduces the incidence of perinatal death and preeclampsia in high-risk patients, including those with renal disease.[110] Use of these agents during the last weeks of pregnancy should be avoided to minimize the risks of maternal and fetal hemorrhage and premature ductus closure.[106] Acute flares often require institution of cytotoxic drugs. Cyclophosphamide and methotrexate are contraindicated during the first trimester and should be used only in extreme circumstances because of their teratogenicity and abortifacient properties. Azathioprine has a better documented safety profile because of its use in renal transplant patients and is the cytotoxic agent of choice during pregnancy. Although the drug and its metabolites cross the placenta, there is not a significant increase in congenital malformations. Cyclosporin A is an acceptable alternative to azathioprine.[106] Other agents used in the treatment of SLE or RA include chloroquine, injectable gold complexes, D-penicillamine, and sulfasalazine. These drugs cross the placenta, and reports of congenital malformations have been associated with their use. On the other hand, hydroxychloroquine appears safe, and its use may allow for a decrease in corticosteroid dosage.[]

KEY CONCEPTS {,

{,

The phys iologi c dem ands of preg nanc y may caus e previ ousl y occu lt medi cal cond ition s to beco me appa rent. The phys

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iologi c adju stme nts of preg nanc y alter the nor mal rang es for certa in labor atory valu es. The adju sted valu es need to be cons idere d in inter preti ng resul ts. {,

The poss ibility of preg nanc y must be cons idere d in the differ entia l diag nosi s of certa in cond ition s, inclu

Page 4468

ding new onse t seiz ures or statu s epile pticu s (ecla mpsi a), gluc ose intol eran ce (GD M), persi stent vomi ting (hyp ere mesi s gravi daru m), and thyro id disor ders. {,

The imm unos uppr essi ve effec ts of preg nanc y may caus e temp orary impr ove ment in infla mm atory and

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autoi mm une cond ition s. This bene ficial effec t is lost in the post partu m perio d, resul ting in exac erbat ions of asth ma, thyro id disor ders, and mya sthe nia gravi s. Medi catio n requi rem ents can chan ge drast ically durin g preg nanc y and the post partu m perio d. {,

Cert

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ain medi cal cond ition s in the moth er resul t in neon atal com plica tions requi ring spec ial resu scita tive mea sure s.

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29. Scholl TO, Reilly T: Anemia, iron, and pregnancy outcome. J Nutr2000;130:S443. 30. Scholl TO, Johnson WG: Folic acid: Influence on the outcome of pregnancy. Am J Clin Nutr 2000;71(Suppl):S1295. 31. Hassan M: HCV in sickle cell disease. J National Med Assoc2004;95:864-867.872-874 32. Sun PM: Sickle cell disease in pregnancy: Twenty years of experience at Grady Memorial Hospital, Atlanta, Georgia. Am J Obstet Gynecol2001;184:1127. 33. Seoud MA: Outcomes of pregnancies complicated by sickle cell and sickle-C hemoglobinopathies. Am J Perinatol1994;11:187. 34. Schupf N, Ottman R: Likelihood of pregnancy in individuals with idiopathic/cryptogenic epilepsy: Social and biologic influences. Epilepsia1994;35:750. 35. Pennell PB: Pregnancy in the woman with epilepsy: Maternal and fetal outcomes. Semin Neurol 2002;22:299. 36. Devinsky O, Yerby MS: Women with epilepsy. Neurol Clin North Am1994;12:479. 37. Holmes LB: The teratogenicity of anticonvulsant drugs. N Engl J Med2001;344:1132. 38. Mendez-Quijada J: Status epilepticus in pregnancy: A case report. J Reprod Med1990;35:289. 39. Mattson RH, Cramer JA: Epilepsy, sex hormones, and antiepileptic drugs. Epilepsia1985;26:40S. 40. Krumholz A: Epilepsy in pregnancy. In: Goldstein PJ, Stern BJ, ed.Neurologic Disorders in Pregnancy, 2nd ed. Mount Kisco, NY: Futura; 1992: 25-51. 41. Palmieri C, Canger R: Teratogenic potential of the newer antiepileptic drugs: What is known and how should this influence prescribing?. CNS Drugs2002;16:755. 42. Confavreux C: Rate of pregnancy-related relapse in multiple sclerosis. N Engl J Med1998;339:285. 43. Damek DM, Shuster EA: Pregnancy and multiple sclerosis. Mayo Clin Proc1997;72:977. 44. Runmarker B, Anderson O: Pregnancy is associated with a lower risk of onset and a better prognosis in multiple sclerosis. Brain1995;118:253. 45. Westgren N, Levi R: Motherhood after traumatic spinal cord injury. Paraplegia1994;32:517. 46. Hughes SJ: Management of the pregnant woman with spinal cord injuries. Br J Obstet Gynaecol 1991;98:513. 47. American College of Obstetricians and Gynecologists : ACOG Committee Opinion: Number 275, September 2002. Obstetric management of patients with spinal cord injuries. Obstet Gynecol2002;100:625. 48. Batocchi AP: Course and treatment of myasthenia gravis during pregnancy. Neurology1999;52:447. 49. Djelmis J: Myasthenia gravis in pregnancy: Report on 69 cases. Eur J Obstet Gynecol2002;104:21. 50. Fox MW: Selected neurologic complications of pregnancy. Mayo Clin Proc1990;65:1595. 51. Sanders CL, Lucas MJ: Renal disease in pregnancy. Obstet Gynecol Clin North Am2001;28:593. 52. Abe S: An overview of pregnancy in women with underlying renal disease. Am J Kidney Dis1991;17:116. 53. Chao A-S: Pregnancy in women who undergo long-term dialysis. Am J Obstet Gynecol2002;187:152. 54. Gabbe SG, Graves CR: Management of diabetes mellitus complicating pregnancy. Obstet Gynecol 2003;102:857. 55. Kamalakannan D: Diabetic ketoacidosis in pregnancy. Postgrad Med J2003;79:454. 56. Lucas MJ: Diabetes complicating pregnancy. Obstet Gynecol Clin North Am2001;28:513. 57. ACOG technical bulletin, Diabetes and pregnancy. Number 200—December 1994. Committee on Technical Bulletins of the American College of Obstetricians and Gynecologists. Int J Gynaecol Obstet 1995;48:33. 58. Sheffield JS: Maternal diabetes mellitus and infant malformations. Obstet Gynecol2002;100:925. 59. Reece EA, Homko C: Diabetes-related complications of pregnancy. J Natl Med Assoc1993;85:537. 60. Kjos SL, Buchanan TA: Current concepts: Gestational diabetes mellitus. N Engl J Med1999;341:1749. 61. Damm P: Predictive factors for the development of diabetes in women with previous gestational diabetes mellitus. Am J Obstet Gynecol1992;167:607. 62. Langer O: Oral hypoglycemic agents in pregnancy: Their time has come. J Matern Fetal Neonat Med 2002;12:376. 63. American College of Obstetricians and Gynecologists : ACOG Practice Bulletin. Clinical management guidelines for obstetrician-gynecologists. Number 37, August 2002. Thyroid disease in pregnancy. Obstet Gynecol2002;100:387. 64. Lazarus JH: Thyroid dysfunction: Reproduction and postpartum thyroiditis. Semin Reprod Med 2002;20:381. 65. Mestman J: Hyperthyroidism in pregnancy. Clin Obstet Gynecol1997;40:45. 66. Leung AS: Perinatal outcome in hypothyroid pregnancies. Obstet Gynecol1993;81:349. 67. Wasserstrum N, Anania CA: Perinatal consequences of maternal hypothyroidism in early pregnancy and inadequate replacement. Clin Endocrinol (Oxf)1995;42:353. 68. Smallridge RC, Ladenson PW: Hypothyroidism in pregnancy: Consequences to neonatal health. J Clin Endocrinol Metab2001;86:2349. 69. Jana N: Perinatal outcome in pregnancies complicated by pulmonary tuberculosis. Int J Gynaecol Obstet1994;44:119. 70. Jana N: Obstetrical outcomes among women with extrapulmonary tuberculosis. N Engl J Med

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1999;341:645. 71. Ormerod P: Tuberculosis in pregnancy and the puerperium. Thorax2001;56:494. 72. Tripathy SN, Tripathy SN: Tuberculosis and pregnancy. Int J Obstet Gynecol2003;80:247. 73. ACOG technical bulletin. Pulmonary disease in pregnancy. Number 224—June 1996. American College of Obstetricians and Gynecologists. Int J Obstet Gynaecol1996;54:187. 74. Centers for Disease Control. HIV/AIDS Surveillance Report, No. 14, 2002. 75. Kigadye RM: Sentinel surveillance for HIV-1 among pregnant women in a developing country: 3 years' experience and a comparison with a population serosurvey. AIDS1993;7:849. 76. Hinderaker SG: Low HIV-seroprevalence in pregnant women in a rural area in Tanzania. Acta Obstet Gynecol Scand2001;80:1152. 77. Landesman S: Serosurvey of human immunodeficiency virus infection in parturients. JAMA 1987;258:2701. 78. Davis SF: Trends in HIV prevalence among childbearing women in the United States, 1989-1994. J Acquir Immune Defic Syndr Hum Retrovirol1998;19:158. 79. Lindegren ML: Trends in perinatal transmission of HIV/AIDS in the United States. JAMA1999;282:531. 80. Minkoff H: Human immunodeficiency virus infection in pregnancy. Obstet Gynecol2003;101:797. 81. Connor EM: Reduction of maternal-infant transmission of human immunodeficiency virus type-1 with zidovudine treatment. N Engl J Med1994;331:1173. 82. Carneiro M: Vertical HIV-1 transmission: Prophylaxis and paediatric follow-up. Placenta2001;22(Suppl A):S13. 83. European Cooperative Study. Exposure to antiretroviral therapy in utero or early life: The health of uninfected children born to HIV-infected women. J Acquir Immune Defic Syndr2003;32:380. 84. Kumar RM: Impact of maternal HIV-1 infection on perinatal outcome. Int J Gynaecol Obstet1995;49:137. 85. Temmerman M: Maternal human immunodeficiency virus-1 infection and pregnancy outcome. Obstet Gynecol1994;83:495. 86. De Santis M: Drug addiction in pregnancy: The HIV infection. Fetal Diagn Ther1994;9:125. 87. Jehuda-Cohen C: A new look at HIV transmission from seropositive mothers to their infants: The facts beyond serology. Isr J Med Sci1994;30:364. 88. Natural history of vertically-acquired human immunodeficiency virus-1 infection. The European Collaborative Study. Pediatrics1994;94:815. 89. Mayaux M-J: Neonatal characteristics in rapidly progressive perinatally acquired HIV-1 disease. JAMA 1996;275:606. 90. Abrams EJ: Maternal health factors and early pediatric antiretroviral therapy influence the rate of perinatal HIV-1 disease progression in children. AIDS2003;17:867. 91. Biggar RJ: Immunosuppression in pregnant women infected with human immunodeficiency virus. Am J Obstet Gynecol1989;161:1239. 92. Melvin AJ: Effect of pregnancy and zidovudine therapy on viral load in HIV-infected women. J Acquir Immun Defic Syndr Hum Retrovirol1997;14:232. 93. Hocke C: Prospective cohort study of the effect of pregnancy on the progression of human immunodeficiency virus infection. The Group d'Epidemiologie Clinique du SIDA en Aquitaine. Obstet Gynecol1995;86:886. 94. Tuomala RE: Antiretroviral therapy during pregnancy and the risk of an adverse outcome. N Engl J Med 2002;346:1863. 95. Mofenson LM: Risk factors for perinatal transmission of human immunodeficiency virus type 1 in women treated with zidovudine. Pediatric AIDS Clinical Trials Group Study 185 Team. N Engl J Med1999;341:385. 96. Centers for Disease Control and Prevention : Primary and secondary syphilis—United States 2000-2001. MMWR2002;51:971. 97. Centers for Disease Control and Prevention : Congenital syphilis—United States, 2000. MMWR 2001;50:573. 98. Gust DA: Mortality associated with congenital syphilis in the United States, 1992-1998. Pediatrics 2002;109:E79. 99. Wendel GD: Treatment of syphilis in pregnancy and prevention of congenital syphilis. CID2002;35(Suppl 2):S200. 100. Genç M, Ledger WJ: Syphilis in pregnancy. Sex Transm Infect2000;76:73. 101. Euler GL: Hepatitis B surface antigen prevalence among pregnant women in urban areas: Implications for testing, reporting, and preventing perinatal transmission. Pediatrics2003;111:1192. 102. Levy M, Koren G: Hepatitis B vaccine in pregnancy: Maternal and fetal safety. Am J Perinatol 1991;8:227. 103. Hepatitis in pregnancy. ACOG Technical Bulletin Number 174—November 1992. Int J Obstet Gynaecol 1993;42:189. 104. Silverman NS: Hepatitis C virus in pregnancy: Seroprevalence and risk factors for infection. Am J Obstet Gynecol1993;169:583. 105. Roberts EA, Yeung L: Maternal-infant transmission of hepatitis C virus infection. Hepatology

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2002;36(Suppl 1):S106. 106. Mok CC, Wong RWS: Pregnancy in systemic lupus erythematosus. Postgrad Med J2001;77:157. 107. Yasmeen S: Pregnancy outcomes in women with systemic lupus erythematosus. J Matern Fetal Med 2001;10:91. 108. Nelson JL: Maternal-fetal disparity in HLA class II alloantigens and the pregnancy-induced amelioration of rheumatoid arthritis. N Engl J Med1995;329:466. 109. Rayburn WF: Glucocorticoid therapy for rheumatic diseases: Maternal, fetal and breast-feeding considerations. Am J Reprod Immunol1992;28:138. 110. Coomarasamy A: Aspirin for prevention of preeclampsia in women with historical risk factors: A systematic review. Obstet Gynecol2003;101:1319. 111. Levy RA: Hydroxychloroquine (HCQ) in lupus pregnancy: Double-blind and placebo-controlled study. Lupus2001;10:401.

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Marx: Rosen's Emergency Medicine: Concepts and Clinical Practice, 6th ed., Copyright © 2006 Mosby, Inc.

Chapter 179 – Drug Therapy and Substance Abuse Rania Habal Diane Sauter

PERSPECTIVE The placenta previously was believed to act as a barrier, excluding toxins from the fetal circulation and protecting the fetus from environmental and pharmacologic exposures. In 1961, when an epidemic of amelia, a rare malformation characterized by an absence of limbs, was linked to the use of thalidomide during pregnancy, the vulnerability of the fetus to medications came into focus. Thalidomide was a sedative-hypnotic agent introduced in 1956. It immediately became popular in the treatment of nausea and vomiting during the first trimester of pregnancy, but in the years that followed, it was established that thalidomide was the agent responsible for the amelia/phocomelia epidemic. By the time thalidomide was withdrawn from the market, an estimated 5850 children were affected worldwide.[1] Similarly, it took an epidemic of debilitating congenital anomalies and deaths in the children of fishermen in Minimata, Japan, to recognize the teratogenicity of environmental pollutants.[] Minimata disease was due to the ingestion of fish contaminated by methylmercury, an industrial byproduct that was dumped into Minimata Harbor early in the 20th century. These two events sparked the development of numerous control agencies to oversee the safety of drugs in pregnancy and numerous environmental protection laws. Thalidomide's legacy continues to haunt physicians worldwide. Many physicians are reluctant to prescribe medications to pregnant women or to nursing mothers. The fact is, however, only a few medications have been identified as teratogens, and medication use during pregnancy is extremely common. In a worldwide survey of more than 14,000 patients, the World Health Organization reported that more than 86% of women used at least one prescription drug while pregnant. In a similar survey in the United States, more than 80% of pregnant women reported using medications during pregnancy, with 30% using more than four drugs.[] The contribution of these substances to the incidence of birth defects is thought to be low, accounting for 1% to 3% of all live birth defects.[] The emergency physician (1) must be able to discuss the risks and benefits of drug prescribing with a pregnant patient so that an informed decision may be made; (2) must be familiar with the acute and chronic untoward effects of drugs of abuse on the mother, the pregnancy, and the fetus; and (3) must understand the psychology of addiction and provide help in a nonjudgmental manner. Early intervention and referral to a maternal drug rehabilitation program and other social programs may hold the key to a successful and healthy pregnancy and delivery.

PRINCIPLES OF DISEASE Major birth defects affect 3% to 5% of all live births. Most are of unknown etiology, but 1% to 3% of these are thought to be due to pharmaceutical substances.[] Defects include major anatomic and physiologic abnormalities. A teratogen is any chemical, pharmacologic, environmental, or mechanical agent that can cause deviant or disruptive development of the conceptus. Included in this definition are physical malformations, growth retardation, fetal demise, and functional impairment.[7] Although serious effects on the mother are identified immediately, a drug's teratogenic effect may not be apparent for years.[8] Typically, there is variability in the expression of teratogenicity among animal species and among humans.[8] Malformations may range from subtle neurobehavioral effects to devastating physical deformities and physiologic effects, including death. Why one pregnancy would be affected and not another remains to be elucidated. Highly teratogenic medications seem to be few in number, estimated at less than 30 drugs ( Box 179-1 ).[] BOX 179-1 Drugs and Agents Considered Human Teratogens

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Angiotensin-converting enzyme inhibitors Methotrexate, aminopterin Androgens Busulfan Chlorobiphenyls Cocaine Coumarin derivatives Diethylstilbestrol Ethanol (in large doses) Isotretinoin Lithium Methyl mercury Paramethadione, trimethadione Phenytoin Tetracycline Thalidomide Valproic acid Modified from Shepard TH: Catalog of Teratogenic Agents, 10th ed. Baltimore, Johns Hopkins University Press, 2001.

When examining the effects of substances on the outcome of pregnancy, it is important to keep in mind that the process of establishing the risk and safety of drugs in pregnancy is tedious and often flawed. For ethical reasons, few controlled prospective human studies analyzing the risk-benefit relationship for any given exposure are available. As a result, much current knowledge has been derived from case reports, case-controlled studies, or cohort studies, which are inherently weak in establishing a causal relationship.[] Knowledge extrapolated from animal models, although valuable in determining risk initially, is not always applicable to humans.[] During the 9 months of gestation, the mother and fetus are exposed to a variety of chemicals. In evaluating data on the relationship between an exposure during pregnancy and a particular outcome, a multitude of confounding factors make the determination of a causal link difficult. The genetic background of the fetus, timing and duration of the exposure, environmental factors, occurrence of multiple exposures, presence of nutritional deficits, and illicit drug use all contribute to the outcome of pregnancy.[] Additionally, in the presence of disease, the outcome of pregnancy may be related to the medical condition and not the medication itself, and separating the risks of an anomaly from the expected background risk may be difficult. []

The study of teratogenicity is hindered further by several additional factors. First, the history of drug or environmental exposure is often obtained in retrospect, after 9 months of pregnancy and the delivery of an abnormal infant. By that time, significant recall bias may have been introduced, which may depend on the outcome of the birth.[10] Second, because many pregnancies are spontaneously aborted before maternal knowledge that conception has occurred, the cited prevalence of drug-induced birth defects may not be accurate.[] Finally, as in the case of diethylstilbestrol, teratogenicity may not be apparent for years after birth. Large population studies are needed to understand the connection between the outcome of a pregnancy and an associated in utero exposure.[12]

Classification of Teratogenic Risk To aid physicians in determining the teratogenic potential of a particular medication, the U.S. Food and Drug Administration has published a classification system that assigns risk based on currently available human and animal studies and case reports. Drugs are assigned one of five letters—A, B, C, D, and X—depending on the strength of evidence for their safety or teratogenicity ( Box 179-2 ). This classification system has been criticized as oversimplistic and perhaps inaccurate because it relies on data that are generally of poor quality. Some clinicians believe that the classification system conveys the incorrect impression that there is

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a gradation of reproductive risk from exposure across categories (i.e., that risk increases from A to B to C to D to X) and that the drugs within a given category present similar reproductive risks.[13] The Food and Drug Administration has acknowledged these problems and is working to change the present regulations. BOX 179-2 Food and Drug Administration Classification: Teratogenic Risk of Drugs

Class A: Controlled studies have shown no risk. Adequate, well-controlled studies in pregnant women have failed to show risk to fetus. Class B: No evidence exists of risk for humans. Animal studies show risk or are negative, but no human studies have been done. Class C: Use may engender risk for fetus. Human studies are lacking, and animal studies may be positive or lacking. Potential for benefit may outweigh potential for harm. Class D: Positive evidence of risk is based on studies or postmarketing data. Potential for benefit may outweigh potential for harm. Class X: Drugs are contraindicated in pregnancy based on human or animal studies or postmarketing reports that indicate benefit is clearly outweighed by risk.

Drug Transfer Across the Placenta The degree to which the fetus is affected by a given pharmaceutical agent and the nature of that effect depend on multiple factors. The transport of maternal substrates to the fetus and of waste products from the fetus to the mother is established during week 5 of gestation.[] Drug transfer across the placenta occurs most commonly by simple passive diffusion or by protein transport. A thin layer of trophoblastic cells is all that separates maternal from fetal circulation. The degree to which a drug gains access to fetal circulation depends on molecular size, ionic state, lipid solubility, and extent of protein binding. Drugs with a molecular weight of less than 5000 D readily diffuse. Anionic forms diffuse through the lipid layer more readily than ionized forms. Free drug diffuses more readily than a drug that is bound to plasma proteins. Because fetal pH is slightly more alkalotic than maternal pH, weak organic acids (e.g., salicylate) may become ion trapped in the fetal circulation, increasing fetal exposure.[14] Drugs may affect the fetus through a variety of mechanisms. Some drugs may alter the availability of substrates, such as vitamins, glucose, oxygen, and amino acids, needed for normal nutrition and growth.[14] Others may directly affect cellular growth and differentiation. The age of the fetus is crucial in determining the impact of any given exposure. During the time of organogenesis (days 21 to 56 of fetal life), the fetus is much more vulnerable to toxic insults. The major body organs are formed during this period, and exposure to a teratogen at this time may result in major anatomic defects. The central nervous system (CNS) develops over a longer period (10 to 17 weeks) so that later exposures may affect neurologic development and subsequent function. Exposure after the period of organogenesis may affect the growth and development of the fetus but does not have an impact on organogenesis.[]

Drug Transfer During Lactation For the most part, drugs and substances that are ingested or injected by the mother diffuse passively into milk, then back into the maternal circulation for excretion. The amount of drug diffusing into milk depends on many factors. Lipid-soluble and nonionic substances diffuse more readily, and highly protein-bound substances diffuse less readily. Whether a substance is concentrated in maternal milk or not, the neonate generally is able to detoxify it with no adverse effects, and only a few drugs pose a danger to a breast-feeding infant. The interruption of breast-feeding should not be advocated except in the rare situations of known drug toxicity to the infant.[] Table 179-1 summarizes medications and their effects in pregnancy and lactation. Table 179-1 -- Summary of Medication Safety in Pregnancy and Laction Medication Class Pregnancy Analgesic agents Acetaminophen or paracetamol Nonsteroidal anti-inflammatory drugs Salicylate (NSAIDs) Other NSAIDs

Lactation

Safe

Safe

Not recommended Not recommended

Safe for short-term use Safe

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Medication Class Opiates/opioids Morphine

Pregnancy

Lactation

Safe Safe Caution at time of delivery due to respiratory depression in newborn

Meperidine Oxycodone Antibiotics Penicillin

Safe

Safe May interfere with culture results in neonates

Cephalosporins

Safe

Chloramphenicol

Safe May interfere with culture results in neonates Unknown safety

Safe until term. Do not use at term, as it can cause “gray baby syndrome” Safe. Do not use estolate Safe salt of erythromycin, as it can cause hepatotoxicity in pregnant patient Azithromycin preferred over erythromycin

Dicloxacillin Ampicillin Penicillin derivatives

Macrolides

Erythromycin Azithromycin Clarithromycin Clindamycin Sulfonamides

Aminoglycosides Tetracycline Fluoroquinolones Metronidazole Antifungals Nystatin Clotrimazole and ketoconazole Fluconazole Antituberculous agents INH Rifampin Ethambutol Antiviral agents Acyclovir Anticoagulants Warfarin

Not recommended near term, as can cause kernicterus

Safe

Not recommended Not recommended Not recommended Not recommended

Except in premature infants or infants with G6PD deficiency or hyperbilirubinemia Safe Not recommended Safe Not recommended

Safe Safe Not recommended

Safe Safe Not recommended

Safe Safe Safe

Safe Safe Safe

Safe

Safe

Not recommended Causes fetal warfarin

Safe

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Medication Class Heparin Low-molecular-weight heparin Anticonvulsants Phenytoin

Carbamazepine Valproic acid Phenobarbital Ethosuximide Primidone Trimethadione

Benzodiazepines

Pregnancy syndrome Safe Safe

Lactation Safe Safe

Not recommended Causes fetal hydantoin syndrome in 5–10%, but may be used in selected cases Not recommended Not recommended Class D Not recommended Class D Not recommended Class C Not recommended Class D Not recommended Class D Fetal loss 85% Safe Class C

Safe

Safe Safe Safe Not recommended

Unknown Unknown Unknown Unknown

Safe Safe Safe Safe Safe, except with high doses Not recommended Class D, may use with refractory cases. Safe

Safe Safe Safe Unknown Safe

Not recommended

Safe (captopril and enalapril only)

Safe Safe Not recommended Safe Not recommended Not recommended

Not recommended May cause apnea in newborn

Newer drugs Felbamate Levetiracetam Gabapentin Lamotrigine Antidysrhythmics Digoxin Disopyramide Quinidine Procainamide Lidocaine Amiodarone

Adenosine Antihypertensives Angiotensin-converting enzyme inhibitors

Angiotensin II receptor antagonists p -Blockers Labetalol Atenolol

Class D Not recommended Safe

Not recommended

Safe

Unknown Safe Monitor neonate for adverse events

Caution in first trimester with atenolol

Metoprolol

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Medication Class

Pregnancy

Lactation

Propranolol Calcium channel blockers Diltiazem Verapamil

Safe Safe Caution for dehydration and electrolyte abnormalities

Safe Safe

Safe Caution: can cause hypotension Labetolol preferred

Safe

Nifedipine Diuretics Bendroflumethiazide Chlorthalidone Hydrochlorothiazide Hydralazine

Methyldopa

Safe (first-line therapy for Safe hypertension) Class C Safe Unknown Class C Unknown Second-line agent to labetalol

Clonidine Nitroprusside Medications used in the treatment of asthma, allergies, and upper respiratory infection p -Adrenergics Safe Safe Albuterol Metaproterenol Terbutaline Ipratropium Safe Safe Cromolyn sodium Safe Unknown Little data available Corticosteroids Safe Safe Prednisone Theophylline Safe Safe Aminophylline Leukotriene antagonists Safe Safe Zileutron Not recommended Not recommended Caution: may cause mutagenic effects Antihistamines Safe Not recommended Chlorpheniramine Safe Not recommended Diphenhydramine Safe Not recommended Dimenhydramine Safe Not recommended Doxylamine Safe Not recommended Hydroxyzine Safe Not recommended Meclizine Not recommended in first Not recommended trimester Loratadine Not recommended Decongestants Safe Pseudoephedrine Not recommended Not recommended Phenylpropanolamine Not recommended Drugs used for nausea and vomiting of pregnancy Dopamine antagonists Safe Unknown

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Medication Class

Pregnancy

Lactation

Phenothiazines Promethazine Chlorpromazine Perphenazine Metoclopramide 5-HT3 Antagonists

Safe

Safe

Ondansetron Medications used in the treatment of diabetes Insulin Sulfonylurea Glyburide

Safe Not recommended Not recommended

Glipizide

Not recommended

Metformin Acarbose

Not recommended Safe

Rosiglitazone Pioglitazone Antacids Ranitidine

Not recommended Not recommended

Safe Not recommended Caution: nursing infants should be monitored Caution: nursing infants should be monitored Not recommended Safe No studies have been done Not recommended Not recommended

Safe

Safe

G6PD, glucose-6-phosphate dehydrogenase.

DRUG THERAPY DURING PREGNANCY Analgesic Agents Acetaminophen Acetaminophen or paracetamol is widely used during pregnancy, and no significant increase in the incidence of congenital malformations has been identified. As a result, acetaminophen currently is considered safe for short-term use and at therapeutic doses at any time during pregnancy.[] Acute and chronic overdoses of acetaminophen have been associated, however, with a fatal outcome.[20] Acetaminophen is safe during lactation because only a little is excreted into breast milk, and the small amount that does get through is tolerated by the neonate's sulfhydration pathway.[18]

Nonsteroidal Anti-Inflammatory Drugs and Salicylate Nonsteroidal anti-inflammatory drugs (NSAIDs) interfere with the enzyme cyclooxygenase, which converts arachidonic acid to cyclic endoperoxides, prostacyclin, and thromboxane. In addition to its role in inflammation, thromboxane A2 regulates platelet adhesiveness. The progress of normal labor and delivery depends to some extent on prostaglandin. Interference with prostaglandin delays the onset of labor and increases its duration. The normal maintenance of a patent ductus arteriosus in utero is also a prostaglandin-dependent phenomenon. Increased pulmonary pressures that follow the premature closure of the ductus provoke hypertrophy of the small pulmonary vessels, which may interfere with the rapid reduction of pulmonary vascular resistance necessary for the fetus to establish normal pulmonary circulation after birth.[] Salicylate is the most thoroughly studied of the class of NSAIDs and is generally not recommended as an analgesic for use in pregnancy. Salicylate is readily absorbed, and although the extent of protein binding limits the free fraction available for diffusion across the placenta, salicylate that is unbound readily diffuses.

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Salicylate levels peak in the fetus within 60 to 90 minutes of maternal administration. Because early in pregnancy the fetus has a higher pH than the mother, the fetus may ion trap salicylate, perhaps resulting in a greater fetal risk for salicylate toxicity or congenital anomalies. Although salicylates were shown to be teratogenic in animal models, two meta-analyses in humans failed to show a teratogenic effect to salicylates, although there was a trend toward a slightly increased incidence of gastroschisis when used in the first trimester.[] Low-dose aspirin had no effect on perinatal mortality and was not associated with an increased risk for miscarriage.[22] Low-dose aspirin therapy (60 to 90 mg/day) late in pregnancy also has been found to be effective in treating certain inflammatory conditions associated with pregnancy (antiphospholipid antibody syndrome and lupus) without the production of adverse effects in either the mother or the neonate.[23] Chronic use of low-dose aspirin in patients with pregnancy-induced hypertension may increase the risk of abruption, however.[24] Aspirin has been associated with an increased risk of perinatal bleeding, increased of postmaturity, significant prolongation of labor, and a decrease in birth weight.[15] The increased risk of bleeding may extend to the neonate because platelet dysfunction and reduced factor XII activity have been noted.[] Additional effects of salicylates on neonates include derangements of intracellular glucose metabolism through effects on the Krebs cycle, resulting in an increased risk of hypoglycemia and in some reports fetal death.[] For all these reasons, salicylates are not recommended for analgesia in pregnant women. Aspirin is poorly excreted in breast milk and is safe for short-term use during lactation.[15] High-dose salicylate schedules may result in severe metabolic acidosis in newborns.[27] With the exception of indomethacin, the nonsalicylate NSAIDs have been less well studied during pregnancy and lactation, but they seem to be safe in breast-feeding.[15] Indomethacin is commonly used as a tocolytic agent but has been associated with premature closure of the ductus arteriosus, neonatal pulmonary hypertension, periventricular hemorrhages, and oligohydramnios and fetal nephrotoxicity.[] In a cohort study, the use of NSAIDs during pregnancy was associated with an increased risk of miscarriage, but not of congenital anomaly, preterm birth, or low birth weight.[28]

Opiates Morphine, meperidine, and oxycodone are considered safe analgesic agents for use at any time during pregnancy.[15] The use of codeine has been associated with the development of certain congenital defects, but it is unclear whether this association is statistically significant.[15] The use of opiates during labor may result in respiratory and CNS depression in the newborn. Chronic use of opiates during pregnancy may result in neonatal addiction and withdrawal.[15] Because opiates are poorly concentrated in milk, opiate analgesia may be used safely during breast-feeding.[15] Meperidine is associated with an increased incidence of neurobehavioral abnormalities in nursing infants compared with morphine.[]

Antibiotics Penicillin and Derivatives Penicillin, dicloxacillin, ampicillin, and other penicillin derivatives (including procaine and benzathine penicillin) are considered safe for use in pregnancy. They have been used extensively since the 1940s and are thought to be the safest antibiotics available for pregnant patients.[] Oral probenecid also is considered safe.[31] Penicillins are considered safe during breast-feeding, but their use may interfere with culture results if a neonatal fever workup is required.[15] Other side effects include allergic responses and the occurrence of loose stools in the infant.

Cephalosporins Most cephalosporins are considered safe during pregnancy and breast-feeding, although there are no controlled studies examining their safety.[] Some cephalosporins are excreted into breast milk and may have the same implications for the infant as described for penicillin.[15]

Chloramphenicol No relationship has been found between the use of chloramphenicol and congenital anomalies. Although it is considered safe throughout most of pregnancy, chloramphenicol should be used with caution at term. It has been associated with the development of cardiovascular collapse (the “gray baby” syndrome) in a neonate.[] The safety of chloramphenicol during breast-feeding is unknown.

Macrolides

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Erythromycin, azithromycin, clarithromycin, and clindamycin are considered to be safe for use in pregnancy and compatible with breast-feeding, although there are no well-controlled studies examining their effects on the fetus. The estolate salt of erythromycin has been associated with the development of hepatotoxicity in pregnant women[] and should be avoided. Erythromycin seems to be safe in breast-feeding despite the fact that it is highly concentrated in breast milk. Occasional reports have linked it to pyloric stenosis.[16] Azithromycin is poorly concentrated in breast milk and may be the preferred agent in lactating mothers.[]

Sulfonamides The primary use of sulfonamides during pregnancy is in the treatment of uncomplicated urinary tract infection. The sulfonamides readily cross the placenta to the fetus during all stages of gestation. Fetal levels may reach 90% of maternal plasma concentrations. Sulfonamides are contraindicated in pregnancy near term because they compete with bilirubin for protein-binding sites, leaving large amounts of free bilirubin to diffuse, be deposited in the infant's brain, and cause kernicterus.[] Sulfonamides are excreted into breast milk in low concentrations and are generally tolerated by a healthy neonate. They should be avoided, however, in ill or premature infants and in infants with hyperbilirubinemia or glucose-6-phosphate dehydrogenase deficiency.[]

Aminoglycosides Aminoglycosides readily cross the placenta. Their use in pregnancy has been linked to fetal ototoxicity, especially when high doses are used. The pattern of abnormalities is not consistent, however. Gentamicin is selectively taken up by the fetal kidney and may cause nephrotoxicity in the fetus.[] Gentamicin is secreted in small amounts in breast milk and is poorly absorbed from the gastrointestinal tract. It seems to be compatible with lactation.[]

Tetracycline Tetracycline should be avoided during pregnancy. It is associated with the development of fatty liver in pregnant women[] and readily crosses the placenta and reaches the fetus, where it chelates calcium, causing abnormalities in bone growth and staining of decidual teeth. Tetracycline also has been associated with fetal genitourinary anomalies, inguinal hernias, and limb abnormalities.[] Because tetracycline binds to breast milk calcium, only a little reaches the nursing infant, and it may be used for short periods (≤10 days) during breast-feeding.[16] Prolonged use of tetracycline is associated with stained teeth.[16] Doxycycline does not bind to calcium and is associated less with stained teeth than tetracycline. Doxycycline is present in greater quantities in breast milk. Although doxycycline is not contraindicated when prescribed for short periods, its long-term use is not advocated.[]

Fluoroquinolones Fluoroquinolones have been linked to numerous toxic effects on bone and cartilage growth in infants and should be avoided during pregnancy, particularly the first trimester.[] Because of these effects, some clinicians avoid prescribing them during lactation. The American Academy of Pediatrics considers fluoroquinolones compatible with breast-feeding, however, because breast-fed infant plasma levels are low.[ 16]

Metronidazole Human data on the use of metronidazole during pregnancy are mixed,[] and it is best avoided during the entire pregnancy. Metronidazole possesses a mutagenic effect and was found to be carcinogenic in mice.[] In view of its mutagenic effects and because it is highly concentrated in breast milk and poorly metabolized by infants 6 months old and younger, it is not recommended during breast-feeding.[16]

Antifungals Nystatin has a long safety profile during pregnancy and lactation. It is poorly absorbed from skin, mucous membranes, and gastrointestinal tract.[] Clotrimazole, miconazole, and ketoconazole seem to be safe during pregnancy and lactation, although ketoconazole is teratogenic in rats. As a result of the long-standing safety record of nystatin, the other agents are considered second-line treatment of fungal infections in pregnancy.[] Fluconazole is associated with a slight increase in craniofacial, bone, and joint abnormalities when high doses are used.[] These anomalies were not noted when lower doses were used or with single-dose therapy. No data are available concerning use of fluconazole during lactation,[] and it should be used with

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caution.

Antituberculous Agents Untreated tuberculosis places the mother and fetus at greater risk than the use of antituberculous medications. Isoniazid crosses the placenta, but it does not seem to affect the fetus and is considered safe in pregnancy.[] It also is considered safe during breast-feeding.[16] Rifampin crosses the placenta and occasionally has been implicated in case reports of congenital anomalies. There are, however, no controlled studies documenting these effects, and it is recommended as first-line therapy along with isoniazid in pregnant women with tuberculosis.[] Rifampin is considered compatible with breast-feeding.[16] Ethambutol crosses the placenta, but has not been associated with any congenital defect.[] It is considered safe for use in pregnancy and during breast-feeding.[16]

Antiviral Agents Acyclovir is a purine analogue, commonly used in the treatment of herpesvirus infections. During pregnancy, acyclovir is indicated for life-threatening maternal herpes simplex virus infections, such as disseminated disease and herpes encephalitis, and varicella pneumonia, which carries a maternal mortality of 44% if untreated.[32] The Centers for Disease Control and Prevention also recommend treatment of the first episode of genital herpes during pregnancy with oral acyclovir.[33] In humans, acyclovir seems to cross the placenta readily and reach higher concentrations in fetal circulation than in maternal circulation. There are no reports of teratogenicity or adverse effects in the fetuses or newborns of mothers using acyclovir.[] Acyclovir is concentrated in milk, where levels may be higher than in plasma. Because there are no reported adverse outcomes in infants of mothers taking acyclovir or infants treated with acyclovir for disseminated herpes, it is considered safe in breast-feeding.[]

Anticoagulants During the normal course of pregnancy, plasma concentrations of several procoagulants are increased, whereas fibrinolysis and the inhibition of coagulation are suppressed.[] These changes result in hypercoagulability and an increased risk for thromboembolic phenomena during pregnancy. Pulmonary embolism has emerged as the leading cause of maternal mortality during pregnancy.[35] The management of venous thrombosis and pulmonary embolism during pregnancy is problematic. The use of warfarin (Coumadin) derivatives is contraindicated because of a known risk of congenital anomalies with its use in pregnancy. As a result, when anticoagulation is indicated during pregnancy, heparin is considered the agent of choice.[15] Whenever possible, the diagnosis of venous thrombosis should be confirmed with a ventilation-perfusion lung scan, venography, or less invasive venous Doppler flow studies before the initiation of therapy.[35] Warfarin is a known human teratogen and affects 4% to 5% of exposed fetuses. The risk from exposure is greatest during 6 to 9 weeks of gestation and seems to be dose dependent.[] The fetal warfarin syndrome is associated with multiple abnormalities, such as hypoplasia of the nasal bones, midline dysplasia including agenesis of the corpus callosum, optic atrophy and blindness, mental retardation, seizures, and stippling of the bones with scoliosis and shortening of limbs.[] Additionally, exposed infants are at an increased risk of prematurity, abortion, and stillbirths.[] The type of anomaly seen depends on the timing and duration of warfarin ingestion. Warfarin-induced CNS malformations may occur at any time during pregnancy.[] Abnormalities in the axial skeleton are more prominent when warfarin is ingested during the early stages of pregnancy. Because warfarin is so highly protein bound, only a little is secreted into milk, and use by breast-feeding mothers is acceptable.[16] Caution should be used in breast-feeding premature infants because they may be at increased risk for intraventricular hemorrhage.[] Unfractionated heparin is a highly charged heterogeneous molecule with a molecular weight between 5000 and 35,000 D. It does not cross the placenta and does not present a direct risk to the fetus. Early reports on the use of heparin for the prevention or treatment of venous thromboembolism during pregnancy concluded that the risks to the fetus from prematurity, stillbirth, and hemorrhage might affect one third of infants. More recently, the increased risks previously associated with heparin were determined to be related to underlying maternal medical problems rather than heparin.[] When anticoagulation during pregnancy is required, heparin is considered the agent of choice.[15] Its use sometimes is associated with maternal osteopenia and immune-mediated thrombocytopenia. Patients need careful monitoring for these adverse effects. The risk of maternal hemorrhage at delivery is significant. Because of its high molecular weight, heparin is not excreted

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in breast milk and is compatible with breast-feeding.[] Additionally, it is quickly destroyed in the stomach when ingested. Low-molecular-weight heparin may be used during pregnancy and in the postnatal period for therapeutic or prophylactic anticoagulation.[37] All currently available low-molecular-weight heparin products have been used safely during pregnancy. Data are limited, however, because of their relatively recent introduction.[] Although pregnancy remains a contraindication for the use of thrombolytic therapy, these agents have been used successfully in pregnant women in cases of life-threatening pulmonary embolus or myocardial infarction. Alteplase, which has a high molecular weight, most likely does not cross the placenta. To date, no teratogenic effects have been reported in humans. Maternal hemorrhagic complications have been noted when alteplase was used during the intrapartum period but not at any other time.[] Although no specific recommendations exist, alteplase most likely would be safe for use in nursing mothers because it has a short half-life.[16]

Anticonvulsants The occurrence of generalized seizures during pregnancy has been associated with an increased risk of spontaneous abortion, hypoxic injury to the fetus, and impaired neuropsychologic functioning.[39] Anticonvulsants are known teratogens, however, and 30% of neonates exposed to commonly used anticonvulsants exhibit congenital anomalies. The risks for birth defects increase with the duration of exposure and with the number of agents used.[] Despite the risks, most practitioners believe that it is important to control seizures during pregnancy. Monotherapy seems to be the most appropriate option and is recommended at the lowest effective anticonvulsant dose. Dividing the daily dose to decrease peak plasma levels should be considered. The physiologic changes that accompany pregnancy result in lower maternal serum levels of most anticonvulsant medications. Adjustment of the dosage upward often is required to maintain adequate seizure control.[15]

Phenytoin Phenytoin is a human teratogen and readily crosses the placenta. The parent compound and all metabolites have been identified in fetal tissues. Of chronically exposed fetuses, 5% to 10% develop the fetal hydantoin syndrome.[15] This syndrome is characterized by various degrees of ossification abnormalities of the extremities and digits, craniofacial abnormalities including cleft lip and palate, impaired growth, delayed neurologic development, and cardiovascular anomalies.[] The last-mentioned include atrial septal defects, ventricular septal defects, coarctation of the aorta, and endocardial cushion defects.[] Phenytoin also has been associated with hemorrhagic disease of the newborn, presumably because it competitively inhibits placental transport of vitamin K. This inhibition results in a decrease in fetal levels of the vitamin K– dependent clotting factors, resulting in severe and potentially lethal hemorrhage during the first day of life.[] To avoid this rare complication, some clinicians have advocated the use of vitamin K during the last month of pregnancy. Evidence does not support its use, however.[39] Phenytoin also has been linked to a variety of tumors in infants. Phenytoin use is considered safe in breast-feeding.[16]

Carbamazepine Carbamazepine use during pregnancy is associated with a syndrome similar to fetal hydantoin syndrome, which is thought to be secondary to a toxic, teratogenic metabolite and not the parent compound itself.[] In one study, carbamazepine was associated with a twofold increase in major congenital abnormalities compared with nonexposed fetuses.[40] These abnormalities include craniofacial defects, fingernail hypoplasia, and developmental delay.[] In addition, in utero exposure to carbamazepine is associated with low birth weights and a 1% to 2% risk of neural tube defects.[40] Carbamazepine also has been reported to induce hemorrhagic disease of the newborn.[39] The use of carbamazepine is considered compatible with breast-feeding.[16]

Valproic Acid Valproic acid, a class D medication that should not be used in pregnancy, is an eight-carbon, branched-chain carboxyl acid that has been approved since 1978 for the treatment of absence seizures.[43] It is teratogenic in laboratory animals and in humans. It readily crosses the placenta and concentrates in the fetus. The concentration of valproic acid in the fetus is related to decreased albumin levels and increased levels of free fatty acids in the mother that occupy binding sites on maternal albumin; this increases the fraction of valproic acid available to equilibrate across placental membranes. Many authors have described a

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syndrome of defects associated with the use of valproic acid. The characteristics of the syndrome include multiple minor facial anomalies, low birth weight, delayed neurologic development, congenital heart defects, neural tube defects, hypospadias, strabismus, nystagmus, tracheomalacia, afibrinogenemia, and hyperglycemia.[] Several mechanisms have been proposed to explain the teratogenic effects of valproic acid, including inhibition of intestinal folic acid absorption; inhibition of liver microsomal epoxide hydrolase, resulting in fetal exposure to reactive epoxides; and interference with glutathione, lipid metabolism, or embryonic pH.[] Valproic acid is present in breast milk in low levels and is considered safe during breast-feeding.[16]

Phenobarbital Phenobarbital is considered a class D medication in pregnancy. It is associated with a slightly increased risk of congenital abnormalities, including congenital heart disease and cleft lip or palate and some minor malformations associated with the fetal hydantoin syndrome.[] It is occasionally associated with hemorrhagic disease in the newborn and may result in neonatal withdrawal.[15] Breast-fed infants of mothers taking phenobarbital have developed toxicity characterized primarily by sedation. These infants must be monitored closely for sedation while breast-fed and after breast-feeding for symptoms of withdrawal.[16]

Ethosuximide Ethosuximide is indicated primarily for the treatment of petit mal or absence seizures. It is considered a class C agent in pregnancy. Its use has been loosely associated with congenital cardiac abnormalities, orofacial clefting, and hydrocephalus.[15] Ethosuximide also may induce hemorrhagic disease of the newborn resulting from interference with the vitamin K–dependent clotting factors. The use of ethosuximide is considered compatible with breast-feeding.[16]

Primidone Primidone is considered a class D agent in pregnancy and lactation. It is used in the treatment of partial and generalized tonic-clonic seizures. It is metabolized to phenobarbital, and its use in pregnancy has been associated with the same problems associated with phenobarbital. Dysmorphic features similar to the features seen with hydantoin, congenital cardiac disease, orofacial clefting, and microcephaly have been described with the use of primidone.[15] This drug also may interfere with the vitamin K–dependent clotting factors and induce hemorrhagic disease of the newborn. Neonatal withdrawal may occur after birth. Similar to phenobarbital, primidone should be used with caution during breast-feeding, with attention given to the development of sedation and withdrawal after breast-feeding is stopped.[]

Trimethadione Trimethadione is used primarily in the treatment of petit mal and absence seizures. It is considered a class D medication in pregnancy and lactation. Fetal loss is reported to be 85%,[15] and in fetuses that survive, a congenital syndrome, including epicanthal folds, V-shaped eyebrows, low-set ears, irregular teeth, microcephaly, mental retardation, and orofacial clefting, may be seen in 70%. Trimethadione is contraindicated in pregnancy.[15]

Benzodiazepines Data on the fetal effects of benzodiazepines have been inconsistent. Some case reports and case-controlled studies have shown a significantly increased risk of oral clefts, whereas others have failed to show any increased risk for fetal anomalies.[] Different benzodiazepines may have different effects and risks. Whatever the risks, they seem to be small.[44] Neonates exposed to benzodiazepines may exhibit signs of toxicity, including apnea, cyanosis, unresponsiveness, hypotonia, poor feeding, and withdrawal symptoms characterized by irritability and tremulousness.[15] Clonazepam is a benzodiazepine used largely for refractory myoclonic seizures. It is considered a class C medication for use in pregnancy and lactation. There is no conclusive evidence of human teratogenicity associated with its use, although there is an increased risk of congenital cardiac effects.[15] Because of the reported risk of apnea, it is recommended that neonates exposed to benzodiazepines through breast-feeding be monitored closely.[]

Newer Drugs No adequate studies of human teratogenicity have been published regarding felbamate, levetiracetam, gabapentin, and lamotrigine, but all except lamotrigine seem to be safe during pregnancy. Lamotrigine

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seems to have an increased incidence of birth defects.[15] Safety in lactation is unknown.[15]

Cardiovascular Preparations Antidysrhythmics Digoxin, disopyramide, and quinidine all are considered safe for use during pregnancy and lactation.[45] Of the three agents, digoxin and quinidine have the longest records of safe use during pregnancy and are first-line agents for the treatment of significant maternal dysrhythmias.[38] Procainamide also is well tolerated and should be considered a first-line treatment of wide-complex tachydysrhythmias during pregnancy.[46] The use of procainamide in nursing mothers is controversial because procainamide and its metabolite N-acetyl-procainamide have been found in breast milk.[] Lidocaine is a weak base. It crosses the placenta rapidly and becomes ion trapped in the fetus. There is no evidence of a link between lidocaine and any fetal malformations.[] High doses used near term are associated with neonatal CNS depression, apnea, hypotonia, seizures, and bradycardia.[] For this reason, the lowest effective dose should be used in the mother.[31] Care also should be taken not to inject lidocaine into a major blood vessel.[31] Lidocaine is considered compatible with breast-feeding.[16] Few studies have addressed the use of the newer class IC agents. Encainide and flecainide have been used safely to terminate maternal and fetal tachycardia.[] Flecainide also is considered compatible with breast-feeding.[] Amiodarone, a class D agent, is used for refractory ventricular and supraventricular arrhythmias and is now recommended as first-line therapy for ventricular tachycardias. It contains large amounts of iodine and may result in congenital goiter. Neonatal hyperthyroidism and hypothyroidism have been reported.[15] Additionally, amiodarone use during pregnancy has been linked to many congenital abnormalities, including growth retardation, structural cardiac abnormalities, corneal deposits, and developmental delay.[] Its use during pregnancy should be limited to cases of refractory disease. The effects of maternal use of amiodarone on breast-fed infants are unknown. Because of its high iodine content, its excretion into milk, and its long elimination half-life, amiodarone should not be used in nursing mothers.[15]

Adenosine Adenosine is a naturally occurring compound that is metabolized quickly in the body. It has been used safely throughout pregnancy and is the drug of choice in terminating maternal supraventricular tachycardia despite the absence of large-scale studies.[]

Antihypertensives Angiotensin-Converting Enzyme Inhibitors The angiotensin-converting enzyme (ACE) inhibitors are categorized as category D drugs for use in pregnancy. ACE inhibitors are embryocidal in animals and increase the rate of stillbirths in some species. Although they seem to be safe in humans during the first trimester of pregnancy, many adverse fetal effects have been noted with their use during the second and third trimesters, precluding their use.[48] In the fetus, renal perfusion is generally low and depends on high levels of angiotensin. Because ACE inhibitors decrease levels of angiotensin II, they interfere with glomerular flow and renal perfusion, interfering with normal renal development.[15] Reported adverse neonatal effects include oligohydramnios, anuria, renal agenesis resulting in death, increased risk of stillbirth, intrauterine growth retardation (IUGR), fetal skull abnormalities, pulmonary hypoplasia, respiratory distress syndrome, and fetal and neonatal hypotension.[] Captopril and enalapril are considered compatible with breast-feeding.[]

Angiotensin II Receptor Antagonists Angiotensin II receptor antagonists have been reported to result in fetal abnormalities similar to the abnormalities seen with ACE inhibitors, including renal agenesis, neonatal anuria, oligohydramnios, IUGR, persistent patent ductus arteriosus, abnormal ossification, and death.[15] Angiotensin II receptor antagonists should be avoided during pregnancy.[15] Their safety in lactation is unknown.

p -Blockers All p -adrenergic blocking agents cross the placenta. The steady-state maternal-to-fetal ratio depends on the relative lipid solubility of the individual agent. The greatest experience with p -blockers has been with

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women requiring treatment during the last trimester of pregnancy, at which time they seem to be safe. Long-term in utero exposure and first-trimester exposure have not been studied.[] Labetalol, atenolol, and metoprolol are considered safe for use in pregnancy and lactation.[50] Atenolol seems to cause fetal harm when used in the first trimester, however, and IUGR and persistent p blockade in the newborn when used for prolonged periods in the third trimester. It seems to be safe in the third trimester when prescribed for short periods. Similarly, propranolol is associated with fetal and neonatal adverse effects, especially when dosages exceeding 160 mg/day are used. These adverse effects include IUGR, hypoglycemia, bradycardia, respiratory depression at birth, and hyperbilirubinemia.[] p -Blockers are reportedly safe in breast-feeding, but close monitoring of the infant for adverse effects is recommended.[]

Calcium Channel Blockers The calcium channel blockers are considered safe for use during pregnancy. Diltiazem, verapamil, and nifedipine have been used frequently during the first trimester of pregnancy without any increase in the risk of congenital anomalies.[] Fetal distress secondary to maternal hypotension has been reported with the use of sublingual nifedipine. These agents also are considered safe for use during breast-feeding.[]

Diuretics Thiazide diuretics have been used successfully for the treatment of hypertension in pregnancy but may result in electrolyte abnormalities in neonates when given near term.[31] An increase in perinatal mortality and congenital defects possibly caused by volume depletion has been reported.[31] First-trimester use has been associated with an increase in congenital anomalies.[15] Bendroflumethiazide, chlorthalidone, and hydro-chlorothiazide are considered safe during breast-feeding.[16]

Hydralazine Hydralazine previously was considered the drug of choice for the parenteral treatment of acute severe hypertension during pregnancy. Hydralazine is associated with higher rates of maternal hypotension, however, which may affect perinatal outcome.[] It also is associated with a lupus-like syndrome.[] Because other agents, in particular labetalol, are safer and just as effective, hydralazine is no longer recommended as a first-line agent in the treatment of hypertensive emergencies in pregnant women.[] Hydralazine is safe in lactation.[]

Methyldopa Methyldopa is considered safe in pregnancy. Many clinicians use it as first-line therapy to treat hypertension during pregnancy.[50] Methyldopa is compatible with breast-feeding.[31]

Clonidine Clonidine is categorized as a class C medication for use during pregnancy. It has been used during all three trimesters with few adverse effects on the pregnancy. Transient neonatal hypertension has been reported in neonates with in utero exposure to clonidine.[] Its effects on breast-feeding neonates are unknown.

Nitroprusside The use of nitroprusside for the treatment of hypertensive emergencies in pregnancy has all of the advantages and disadvantages seen in nonpregnant patients. Advantages include its rapid onset, rapid metabolism, and rapid excretion. Disadvantages of nitroprusside include the need for constant monitoring and cumbersome administration. During prolonged administration of high doses, nitroprusside may result in cyanide toxicity. It readily crosses the placenta and reaches fetal levels of cyanide that are twice maternal levels. Standard doses do not seem to subject the fetus to major risk of toxicity, but with the availability of safer alternatives, notably labetalol, nitroprusside is considered a second-line agent.[] When used, monitoring plasma and red blood cell cyanide and maternal pH are recommended. Nitroprusside is considered a category C medication. No data are available on its use during breast-feeding.[]

Asthma, Allergy, and Upper Respiratory Infection Medications p -Adrenergics Pregnant women with asthma are at risk of neonatal death, preterm birth, low-birth-weight infants, preeclampsia, and small-for-gestational-age infants. Asthmatic mothers also may have a higher rate of chorioamnionitis, hypertensive disorders of pregnancy, cesarean section, and prolonged hospital stay than control mothers.[] Better asthma control has been associated with an improved outcome.[53] Albuterol,

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metaproterenol, and terbutaline seem to be safe in pregnancy; none have been linked to congenital anomalies.[15] p -Adrenergic agents have been used during the last trimester to treat premature labor. Adverse reactions are related to the drugs' cardiovascular and metabolic effects, which are transient and generally well tolerated by the fetus. Transient hyperglycemia followed by insulin secretion may occur, resulting in neonatal hypoglycemia.[15] The concentration of albuterol in breast milk has not been studied, but similar to other p -mimetics, it seems compatible with breast-feeding. [16]

Ipratropium Ipratropium has not been found to be teratogenic in numerous animal models. Although human data are few, ipratropium seems to be safe for use during pregnancy and lactation.[]

Cromolyn Sodium Cromolyn sodium is considered safe for use in pregnancy, but adequate data are not available.[]

Corticosteroids Corticosteroids are commonly used during pregnancy for the treatment of various disorders, including autoimmune diseases, hyperemesis gravidarum, and asthma. Inhaled corticosteroids are mainstay therapy for the prevention of asthma exacerbations during pregnancy. They are not considered human teratogens, although in a meta-analysis, pooled data from case-control studies showed a small but significant increase in oral clefts associated with first-trimester use.[] Additionally, there seems to be an increased risk for IUGR and preeclampsia when corticosteroids are used during the third trimester.[15] Other authors also have raised concerns about the development of congenital adrenal hyperplasia in newborns. Prednisone is considered safe during breast-feeding.[]

Theophylline Theophylline is considered a useful bronchodilator in the management of asthma and chronic obstructive pulmonary disease during pregnancy. There are no reports of congenital abnormalities in the offspring of mothers taking theophylline. Aminophylline may reduce the frequency of respiratory distress syndrome in premature newborns.[15]

Leukotriene Antagonists There are no reports of teratogenicity for montelukast and zafirlukast, and they may be continued during pregnancy.[53] Zileuton seems to be mutagenic in ani-mal studies and should be avoided in pregnancy and lactation.[53]

Antihistamines Antihistamines have been used in different capacities during pregnancy—as antihistamines in the treatment of allergic reactions and as antiemetics in the treatment of nausea and vomiting of pregnancy. Antihistamines have been linked to the development of retrolental fibroplasia in premature infants when given during the last 2 weeks of pregnancy.[15] A meta-analysis reviewing 24 studies and involving more than 200,000 patients confirmed the safety of antihistamines, including chlorpheniramine, diphenhydramine, dimenhydramine, doxylamine, hydroxyzine, and meclizine, during pregnancy.[57] An interaction between diphenhydramine and temazepam has been reported in animal experiments, and at least one human pregnancy resulted in stillbirth.[15] The mechanism of this adverse interaction is unknown. Because little information on the use of newer generation antihistamines, such as cetirizine and loratadine, during pregnancy is available, their use in the first trimester is not recommended. They may be acceptable alternatives in severe allergies if the first-generation antihistamines are not tolerated.[15] First-generation antihistamines are not recommended during breast-feed-ing because they may inhibit lactation. Additionally, neonates receiving antihistamines appear to develop serious adverse CNS effects, including seizures, especially when premature.[]

Decongestants Pseudoephedrine is a known animal teratogen; however, no human teratogenicity has been reported.[15] The American Academy of Pediatrics considers pseudoephedrine compatible with breast-feeding.[31] Two cases of amelia have been associated with the use of oxymetazoline, a topical sympathomimetic vasoconstrictor and decongestant.[58] Phenylpropanolamine use may be associated with placental vasoconstriction and in utero hypoxemia.[15] A statistically significant association between first-trimester use of this medication and

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eye and ear abnormalities has been reported.[15] Use of most decongestants is not recommended during pregnancy or lactation.[16]

Drugs Used for Nausea and Vomiting of Pregnancy Dopamine Antagonists Phenothiazines, such as promethazine, chlorpromazine, perphenazine, and metoclopramide, are commonly used in the treatment of nausea and vomiting of pregnancy. Although some investigators have reported a teratogenic effect from these substances, most studies show no association between phenothiazine use and congenital malformations.[]

5-HT3 Antagonists Ondansetron, a serotonin 5-HT3 receptor antagonist, has been shown to be safe in pregnant rats and in a small randomized study in humans.[] It is not clear, however, whether ondansetron offers any additional antiemetic activity compared with promethazine.[57]

Diabetes Medications Insulin has been used safely during pregnancy and lactation for many years and is the drug of choice for glucose control in pregnancy. Sulfonylurea drugs traditionally have not been used during pregnancy. They are regarded as possibly teratogenic and less effective than insulin in the control of gestational diabetes. Sulfonylurea drugs also have been associated with neonatal hypoglycemia when used at term.[15] In reality, there is little information about their use in pregnant women. In a randomized study, glyburide proved to be as effective and safe during pregnancy as insulin.[59] Glyburide and glipizide are highly protein-bound, second-generation sulfonylureas. Although glyburide and glipizide are not likely to pass into breast milk, nursing infants should be monitored. Metformin has not been associated with fetal malformations in animals, but there are no controlled studies analyzing its effect in humans.[15] Metformin has been associated with serious adverse effects in adults, including severe life-threatening metabolic acidosis and hepatotoxicity. Because of its potential for serious effects in adults, metformin is not recommended for use in lactating mothers.[60] Human experience with acarbose, an oral p -glucosidase inhibitor that decreases the rate of digestion of carbohydrates, is limited, but it was not associated with birth anomalies in animals.[15] Acarbose is a large molecule and is not likely to be excreted into breast milk and is probably safe in lactation, although no controlled studies have been done.[60] Similarly, experience with rosiglitazone and pioglitazone, or insulin sensitizers, is limited in humans, and these agents are not recommended for use in pregnant or lactating women.[15]

Antacids Ranitidine has not been shown to be teratogenic and seems to be safe for long-term use during pregnancy and lactation.[]

SUBSTANCE ABUSE IN PREGNANCY Perspective Substance abuse during pregnancy is common. In a nationwide survey conducted in 2002, the National Household Survey on Drug Abuse (NHSDA) found that among pregnant women aged 15 to 44 years, more than 3% reported using illicit drugs in the month before their interview, and 9% used alcohol.[61] Alcohol and cigarettes are the most commonly abused substances during pregnancy, and marijuana is the most commonly used illicit drug.[61] Although the rates of drug use during pregnancy were significantly lower than the rates for nonpregnant women of the same age,[61] the true prevalence is likely to be higher because pregnant women consistently underreport drug use. Other methods to establish prevalence also have limitations. Urine toxicologic screening can test only for recent drug use, and meconium and hair analysis are tedious and time-consuming.[62]

Principles of Disease The effects of drugs and alcohol on a pregnant woman may be classified into three categories, each characterized by a special set of problems and complications: effects on the mother ( Box 179-3 ); effects on the course of pregnancy and delivery; and effects on the fetus, newborn, and developing child ( Box 179-4 ). Reports on drug use in pregnancy often have limitations that must be considered. Many studies do not

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control for confounding variables, such as inadequate nutrition, housing, and lack of prenatal care, all of which can affect the pregnancy. Additionally, many drug users use multiple substances simultaneously, making it difficult to differentiate each drug's contribution to the outcome of pregnancy.[63] In the NHSDA survey, 20% of women who reported using marijuana also used another illicit substance. A large proportion also smoked cigarettes and drank alcohol.[61] Concomitant use of multiple drugs has been shown to increase the risk of adverse effects on the fetus. Infants exposed to multiple drugs have the highest prenatal morbidity of all groups, the highest incidence of cesarean section, the highest incidence of prematurity, the highest incidence of poor growth, and an increased incidence of IUGR and fetal distress.[64] BOX 179-3 Maternal Complications of Drug and Alcohol Use

Res pirat ory com plica tions : infec tions , nonc ardio geni c pulm onar y ede ma, acut e respi rator y distr ess synd rom e, pneu moth orax, pneu mo medi astin um, hype racti ve airw ay dise ase, pulm onar y gran

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ulom atosi s, pulm onar y infar ction , ventil atory failur e Card iova scul ar com plica tions : hype rtens ion, hypo tensi on, ventr icula r dysr hyth mias , myo cardi al infar ction , endo cardi tis, cong estiv e heart failur e, cardi ogen ic pulm onar y ede ma, myo cardi tis, aorti c

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diss ectio n, deep vein thro mbo sis, vasc ulitis Neur ologi c com plica tions : seiz ures, hem orrh agic and isch emic cere brov ascu lar acci dent s, suba rach noid hem orrh age, septi c emb oli to the brain , cere bral absc esse s, isch emic spin al cord injur y, neur opat hies, psyc hosi

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s, com a Infec tious com plica tions : hum an imm unod efici ency virus and all of its com plica tions , hepa titis, endo cardi tis, pneu moni a, skin absc esse s, sexu ally trans mitte d dise ase, septi c emb oli Ren al and gastr ointe stina l com plica tions : acut e tubul ar

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necr osis, isch emia , pigm ent neph ropat hy, gastr itis, pepti c ulcer dise ase, bow el isch emia , bow el perfo ratio n, panc reatit is, hepa titis, cirrh osis Meta bolic com plica tions : anor exia, maln utriti on, vita min defic ienci es, rhab dom yolys is BOX 179-4 Obstetric and Fetal Complications of Drug and Alcohol Abuse

Plac enta

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previ a Abru ptio plac enta e Pre matu re ruptu re of me mbr anes Spo ntan eous abort ion Intra uteri ne grow th retar datio n Fetal demi se Pre matu re deliv ery Neo natal and deve lopm ental effec ts Birth defe cts

Specific Disorders Alcohol Alcohol is the oldest and the most common recreational substance used during pregnancy. Its effects on the mother and newborn evolve in a dose-dependent fashion. Social drinking (2 oz of absolute alcohol per day) may result in an increased risk of spontaneous abortion[67] and other, less clearly defined links, such as low birth weights and preterm labor. The most notable effects of chronic alcohol use affect the development of the fetus, especially the CNS, the face, and the cranium.

Fetal Alcohol Syndrome The spectrum of anomalies related to alcohol use ranges from minor behavioral abnormalities to a

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syndrome of structural, cognitive, and behavioral deficits termed the fetal alcohol syndrome ( Box 179-5 ). Fetal alcohol syndrome affects 2 out of 1000 live births and is the most common cause of preventable mental retardation in the United States. In its full expression, fetal alcohol syndrome is characterized by IUGR, craniofacial anomalies, and CNS defects. Craniofacial abnormalities include midface hypoplasia, flat or absent philtrum, low nasal bridge, short palpebral fissures, low-set ears, and a thin upper lip. CNS defects include microcephaly, agenesis of the corpus callosum, seizure disorder, and abnormal myelination.[] These abnormalities may be manifested by various neurodevel-opmental disorders, including mental retardation, cognitive impairment, sensory impairment, language impairment, poor coordination, and attention deficit disorder with hyperactivity.[70] BOX 179-5 Alcohol-Related Birth Defects

Central Nervous System Cog nitive impa irme nt Sen sory impa irme nt Lang uage impa irme nt Dela yed moto r deve lopm ent and poor coor dinat ion Seiz ure disor der Hype racti vity, atten tion defic it disor der Abno rmal myel inati on

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Micr ocep haly Corp us callo sum agen esis

Craniofacial Abnormalities Midf ace hypo plasi a Flat philtr um Low nasa l bridg e Thin uppe r lip Micr opht halm ia, strab ismu s, ptosi s Shor t palp ebral fissu res

Cardiovascular Vent ricul ar and atrial sept al defe cts Tetr

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alog y of Fallo t Grea t vess el abno rmali ties

Urogenital Hydr onep hrosi s, renal dysp lasia , hypo spad ias

Gastrointestinal Abse nt abdo mina l wall The mechanisms underlying the wide range of adverse cellular and biochemical effects of gestational alcohol use are multifactorial. Ethanol, which readily crosses the placenta and dissolves in the amniotic fluid, induces oxidative stress on fetal tissues, causing mitochondrial and cell membrane damage.[71] Ethanol and its metabolite, acetaldehyde, disrupt cellular differentiation and growth, limit DNA and protein synthesis, and inhibit cell migration. Ethanol and acetaldehyde also decrease the transfer of amino acids, glucose, folic acid, zinc, and other nutrients across the placental barrier, indirectly affecting fetal growth through intrauterine nutrient deprivation. Other mechanisms implicated in the development of fetal abnormalities relate to alcohol's effects on the activity of prostacyclin and thromboxane, which result in placental vessel constriction.[72] Elevated levels of erythropoietin, often seen in cord blood of alcohol-exposed newborns, is evidence of a state of chronic fetal hypoxia.[72]

Marijuana Marijuana, or cannabis, which contains tetrahydrocannabinol, is the most commonly used illicit drug during pregnancy.[] Tetrahydrocannabinol diffuses slowly across the placenta, despite its high lipid solubility. Cord blood concentrations are 2.5 to 6 times lower than in the maternal blood. The mechanism of this concentration gradient is not well understood given the highly lipophilic nature of the compound. It may be due to high maternal plasma protein binding or a placental filtering mechanism.[15] Tetrahydrocannabinol and its metabolites can be detected in neonatal urine and meconium.[] Other noted side effects of tetrahydrocannabinol include the inhibition of DNA, RNA, and protein synthesis, and a transitory impairment of cellular immunity and macrophage function.[75] Despite its widespread use during pregnancy, it is not clear that marijuana is associated with long-term

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consequences for the neonate. Data regarding the effects of marijuana are inconsistent. Some studies report an increased incidence of meconium staining, dysfunctional labor, placental abruption, preterm delivery, low birth weight, IUGR, and postnatal growth retardation.[] Other studies failed to find a clear link between marijuana use and any of the reported complications. A meta-analysis did not find that cannabis, in the amounts typically consumed by pregnant women, causes low birth weight.[77] Heavier use (greater than four marijuana cigarettes per week) may affect the birth weight in a dose-dependent fashion.[77] Studies on the long-term neurologic development of neonates and infants prenatally exposed to marijuana also have shown conflicting results. Neonates may exhibit tremors, exaggerated startle reflexes, abnormalities in sleep patterns, and a decrease in habituation to visual stimuli.[] Long-term follow-up of these children shows no significant effects on cognitive function or language development.[78]

Phencyclidine Phencyclidine (PCP) was introduced in 1957 as a dissociative anesthetic similar to ketamine. Its medical use soon fell out of favor because patients became agitated and delusional during the postoperative recovery period. It is now manufactured and used illegally as a hallucinogen and sold under various street names, such as angel dust, peace pill, and superweed, among others. PCP usually is smoked in combination with marijuana, but may be snorted, taken orally, or injected intravenously.[79] Little is known regarding the effects of gestational PCP use on the outcome of pregnancy and offspring. PCP has been shown to cross the placenta readily and accumulate at higher concentrations in fetal tissue than maternal blood.[] PCP also has been noted to inhibit N-methyl-D -aspartate receptor function in the brain. [81] Because N-methyl-D -aspartate may be critical in the differentiation and the survival of neuronal cells during fetal growth, PCP theoretically may have devastating effects on fetal CNS development. To date, however, no significant long-term consequences to the fetus have been established. Studies on the effects of PCP on birth weight, length, and head circumference have had inconsistent results. Neonates born to mothers intoxicated with PCP at delivery may exhibit behaviors and physical signs similar to those of adults acutely intoxicated with it. The most characteristic of these features are sudden outbursts of agitation with rapid changes in levels of alertness, increased lability and poor consolability, poor attention span, hypertonia, depressed neonatal reflexes, and jitteriness. These signs are self-limited and may be controlled easily with supportive care.[]

Cocaine Cocaine is an alkaloid derived from the leaves of Erythroxylon coca, a shrub that is indigenous to South and Central America. Its mind-altering properties and local anesthetic properties have been known for centuries, but it was not until modern times that its potential for abuse and its devastating effects have been recognized.[84] Cocaine blocks the reuptake of catecholamines, most notably dopamine, norepinephrine, and serotonin. This results in the perpetuation of adrenergic stimulation. It may be snorted, injected, or smoked in its freebase form (crack).[84] After an intravenous injection, 80% of the cocaine dose is rapidly metabolized and inactivated by liver and plasma cholinesterases. The remainder is demethylated in the liver, producing norcocaine, which is even more vasoactive than the parent compound. Factors that decrease the activity of pseudocholinesterases and factors that increase hepatic N-demethylation result in increased toxicity of cocaine.[84] Pregnancy stimulates hepatic N-demethylation and increases the toxicity of cocaine.[] The toxicity and lethality of cocaine, which are largely due to its vasoconstrictive effects, may be increased by repeated use and by the concomitant use of ethanol; this results in the formation of cocaethylene, which has been implicated in the occurrence of sudden death in cocaine users.[84] Cocaine and its metabolites readily pass through the placenta; achieve variable concentrations in the fetus; and have been detected in the urine, meconium, and hair of neonates.[] A dose-dependent inverse relationship seems to exist between maternal plasma cocaine levels and placental blood flow, paralleling uterine artery vasoconstriction and uterine vascular resistance.[] These changes are accompanied by a simultaneous increase in the maternal and fetal blood pressure and heart rate and a decrease in fetal blood oxygen content and other nutrient substances. Chronic decreases in placental blood flow result in chronic fetal hypoxemia, which is associated with adverse effects on fetal growth.[] The earliest reports on the complications of cocaine use during pregnancy greatly exaggerated and dramatized its effects on the mother, the pregnancy, and the neonate. The original cocaine literature was replete with reports linking its use to an increased risk of spontaneous abortion, premature labor and delivery, low birth weight, IUGR, precipitous delivery, placental abruption, embryonic and fetal demise,

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meconium staining of amniotic fluid, low Apgar scores, and stillbirths. In addition, many reports linked prenatal cocaine use to numerous structural anomalies in the neonate. These early reports did not control for confounding variables, however, such as polysubstance abuse and socioeconomic variables. More recent, rigorously designed studies have failed to reproduce many of the previously reported complications, such as an increase in the risk for spontaneous abortion, premature labor, or premature delivery.[] Similarly, newer studies did not find an increase in the incidence of sudden infant death syndrome, unless the infants weighed less than 2500 g.[89] The only consistently observed obstetric effect of cocaine use during pregnancy is a slightly increased incidence of placental abruption,[] and the only consistent fetal effect is a slightly reduced birth weight.[] More recent studies have failed to show any reproducible or specific teratogenic effects of cocaine. During the crack epidemic, a “crack baby” syndrome was described. Increased irritability, nervousness, tremors, hyperactivity, abnormal muscle tone and movements, and an aggressive suck characterized these neonates, and the symptoms persisted for a few days to weeks after birth.[92] More recent data, albeit incomplete, are showing a trend toward a self-limited nature of these symptoms within a supportive environment.

Amphetamines Amphetamines enhance the release and block the reuptake of catecholamines from the CNS, resulting in many adrenergic effects similar to those caused by cocaine.[93] Methamphetamine is one of the most potent amphetamines sold on the streets. Other amphetamines, such as 3,4-methylenedioxyamphetamine (MDMA), have a predominantly serotoninergic effect. In low doses, MDMA has mild sympathetic effects but heightens pleasure and sexuality. At high doses, it has side effects similar to its parent compound.[93] Little is known about the effect of amphetamines on the course and outcome of pregnancy. Clinical studies are limited by sample size and several confounding factors, such as polysubstance use and lack of prenatal care. Experience with designer amphetamines, such as MDMA, is even more limited. The most frequently reported effects of amphetamines on pregnancy are an increased risk of placental abruption, prematurity, preterm delivery, and sudden infant death syndrome.[] Data from different studies present conflicting results, however. Amphetamine use is associated with an increased risk of congenital malformations compared with cocaine use.[] Cleft lip and palate have been described in children of amphetamine-using women with some regularity, and similar effects have been reproduced in animal studies, confirming the teratogenicity of amphetamines. Prenatal exposure also has been implicated in the development of cardiac and CNS anomalies.[96] In addition, amphetamine use during pregnancy results in low-birth-weight infants, a finding most probably the result of vasoconstrictive effects on the fetomaternal circulation.[94] Amphetamine-exposed infants exhibit a high incidence of irritability, hypertonia, tremors, abnormal sleep patterns, abnormal feeding, vomiting, tachycardia, and tachypnea. These symptoms are self-limited and usually resolve without specific therapy when the drug has been eliminated.[94]

Opiates and Opioids Opiates and opioids are highly addictive substances; opiates are derived from the poppy plant, Papaver somniferum, and opioids are synthesized in the laboratory. They readily diffuse across the placenta. Peak fetal levels are noted within 1 hour of the intravenous injection of morphine. Heroin, morphine, methadone, and their metabolites may be detected in amniotic fluid, meconium, and neonatal urine. These drugs may be detectable in amniotic fluid long after cord blood levels fall to zero, suggesting that fetal exposure to a dose of opiates or opioids is prolonged.[] The emergency department presentations of acute heroin use are attributable to CNS depression and range from drowsiness to frank coma with respiratory and cardiovascular collapse. In addition, the intravenous use of drugs is associated with cellulitis, bacteremia, endocarditis, sepsis, hepatitis, acquired immunodeficiency syndrome (AIDS), and other sexually transmitted diseases,[64] which may greatly affect the pregnancy and its outcome. When interpreting research data, it is important to keep in mind these confounding medical factors. In addition, social factors, such as lack of prenatal care, poor nutrition, and polydrug use, are amplified in this patient population.[63] Pregnancy-related complications of opioid and opiate use include premature labor, premature rupture of membranes, chorioamnionitis, meconium staining, preeclampsia, placental abruption, fetal wastage, and fetal death. Whether these complications are due to a direct effect of the drug or to a combination of confounding factors remains to be determined.[] Fetal effects include IUGR, low birth weight, and premature birth. These effects have been observed in illicit heroin use and, to a lesser extent, in methadone-maintained

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pregnancies.[] The effects of opioid and opiate intoxication on the neonate do not differ from the effects seen in adults. At birth, an acutely intoxicated neonate may be unresponsive, bradypneic, apneic, or cyanotic. Severe hypoxia also may lead to cardiorespiratory arrest requiring resuscitation. The chronic exposure of the fetus to these substances leads to dependence. Neonates born to opioid- or opiate-addicted mothers are themselves addicted to the same substances. At birth, the neonate's withdrawal from narcotics leads to one of the most dramatic complications of opioid or opiate dependence, termed the neonatal abstinence syndrome. This syndrome, which occurs in 60% to 80% of infants born to narcotic-dependent mothers, develops within 48 to 72 hours after birth, but may be delayed 2 weeks. The neonatal abstinence syndrome is characterized by signs of CNS hyperactivity, autonomic instability, and respiratory and gastrointestinal abnormalities. Affected neonates develop irritability, tremulousness, hypertonia, mottling of the skin, diaphoresis, piloerection, tachycardia, tachypnea, respiratory distress, wheezing, vomiting and diarrhea, volume depletion, and aspiration.[] Myoclonic jerks are common, and in 7% of neonates these progress to generalized convulsions. [] Infants born at term are more susceptible to the neonatal abstinence syndrome than premature infants, owing to differences in the maturation level of the CNS and differences in total amount of drug exposure.[101] Methadone-dependent neonates have more frequent and more severe symptoms than heroin-exposed neonates.[98] Despite these complications, methadone continues to be recommended during pregnancy because it offers an opportunity for providing comprehensive medical care and stabilization of the nutritional and social environment.[98]

Summary The assessment and management of drug-dependent pregnant women pose additional challenges to the emergency physician. It is important to obtain an understanding of the psychology and physiology of addiction, and remain objective and nonjudgmental toward these patients. Acutely intoxicated and critically ill patients should be managed in a conventional manner. When medically stable, the most important part of the therapeutic management of drug-dependent pregnant patients is the referral to a drug maintenance program. Drug maintenance programs, such as methadone maintenance, provide a stable nutritional and social environment; decrease the risk of infectious complications in the mother and the fetus; and reduce the problems of cyclic intrauterine fetal withdrawal, chronic fetal hypoxia, and intrauterine death.[102]

KEY CONCEPTS {,

{,

{,

{,

Chemically induced birth defects are believed to be responsible for approximately 1% to 3% of anomalous births. The age of the fetus is crucial in determining the impact of any given exposure; during the time of organogenesis (days 21 to 56 of fetal life), when major body organs are formed, exposure to a teratogen may result in major anatomic defects. Certain medications, such as anticonvulsants, warfarin derivatives, NSAIDs, sulfonamides, fluoroquinolones, ACE inhibitors, and oral hypoglycemic agents, are known teratogens or cause potential toxic effects in the newborn and should be avoided, if possible, during pregnancy. Fetal alcohol syndrome affects 2 out of every 1000 live births in the United States and results in a wide variety of anatomic abnormalities (craniofacial and CNS defects) and neurodevelopmental disorders

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{,

{,

(mental retardation, poor coordination, and attention deficit disorder with hyperactivity). Neonatal abstinence syndrome occurs in 60% to 80% of infants born to narcotic-dependent mothers and is characterized by signs of CNS hyperactivity, autonomic instability, and respiratory and gastrointestinal abnormalities. The most important part of the therapeutic management of drug-dependent pregnant patients is the referral to a drug maintenance program.

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1992;118:933. 102. Joseph H: Methadone maintenance treatment (MMT): A review of historical and clinical issues. Mt Sinai J Med2000;67:347.

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Chapter 19 – Chest Pain James E. Brown Glenn C. Hamilton

PERSPECTIVE More than 5 million patients present to the emergency department each year with complaints of chest pain; this represents nearly 5% of all patients seen in emergency departments in the United States.[1] Chest pain is a symptom caused by several life-threatening diseases and has a broad differential diagnosis. It is complicated by a frequent disassociation between intensity of signs and symptoms and seriousness of underlying pathology. Accurately discerning the correct diagnosis and treatment of a patient with chest pain is one of the most difficult tasks for the emergency physician.

Epidemiology The epidemiology of the critical diagnoses causing chest pain varies widely. Acute coronary syndromes (ACS), aortic dissection, pulmonary embolus, pneumothorax, pericarditis with tamponade, and esophageal rupture are potentially catastrophic causes of chest pain. Because of its high incidence and high potential lethality, ACS is the most significant potential diagnosis in the emergency department. Of all deaths in the United States, 35% are attributed to atherosclerosis; this accounts for nearly 1 million deaths per year.[2] Historically, emergency physicians reportedly have missed approximately 3% to 5% of myocardial infarctions (MIs), accounting for 25% of malpractice losses in emergency medicine.[] Thoracic aortic dissection has an incidence of 0.5 to 1 per 100,000 population with a mortality rate exceeding 90% if misdiagnosed. Because of difficulties in making the diagnosis, the true incidence of pulmonary embolus is unclear. Estimates of 70 per 100,000 are published; this would equate to approximately 100,000 pulmonary embolism cases per year in the United States.[5] Although the incidence of tension pneumothorax is unclear, the incidence of spontaneous pneumothorax ranges from 2.5 to 18 per 100,000 total patients, depending on the study. The total incidence of esophageal rupture is 12.5 cases per 100,000 persons. The true incidence of pericarditis is unknown, but the diagnosis is made in 1 in every 1000 hospital admissions.[6] Most patients with chest pain presenting to the emergency department have a benign origin of their pain; the challenge is in separating out and appropriately treating patients with serious causes.

Pathophysiology Afferent fibers from the heart, lungs, great vessels, and esophagus enter the same thoracic dorsal ganglia. Through these visceral fibers, each organ produces the same indistinct quality and location of pain. The quality of visceral chest pain varies widely and has been described as “burning,” “aching,” “stabbing,” or “pressure.” Because dorsal segments overlap three segments above and below a level, disease of a thoracic origin can produce pain anywhere from the jaw to the epigastrium. Radiation of pain is explained by somatic afferent fibers synapsing in the same dorsal root ganglia as the thoracic viscera. This stimulation can “confuse” the patient's central nervous system into thinking the pain originates in the arms or shoulders.

DIAGNOSTIC APPROACH Differential Considerations Owing to the indistinct nature of visceral pain, the differential diagnosis of chest pain covers many organ systems and disease entities within those systems. The differential diagnosis of chest pain includes many of the most critical diagnoses in medicine and many nonemergent conditions ( Table 19-1 ). Table 19-1 -- Differential Diagnosis of Chest Pain Organ Critical Diagnoses System

Emergent Diagnoses

Nonemergent Diagnoses

Cardiov

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ascular

Pulmon ary

Acute myocardial infarction Acute coronary ischemia Aortic dissection Cardiac tamponade

Unstable angina Coronary spasm Prinzmetal's angina Cocaine induced Pericarditis Myocarditis

Valvular heart disease Aortic stenosis Mitral valve prolapse Hypertrophic cardiomyopathy

Pulmonary embolus Tension pneumothorax

Pneumothorax Mediastinitis

Pneumonia Pleuritis Tumor Pneumomediastinum

Esophageal tear (Mallory-Weiss) Cholecystitis Pancreatitis

Esophageal spasm Esophageal reflux Peptic ulcer Biliary colic

Gastroi Esophageal rupture ntestina (Boerhaave) l

Muscul oskelet al

Neurolo gic

Muscle strain Rib fracture Arthritis Tumor Costochondritis Nonspecific chest wall pain Spinal root compression Thoracic outlet Herpes zoster Postherpetic neuralgia

Other Psychologic Hyperventilation

Rapid Assessment and Stabilization The first questions the physician must ask are, “What are the life-threatening possibilities in this patient, and must I intervene immediately?” These questions usually can be answered within the first few minutes of the patient encounter. By assessing the patient's appearance and vital signs, the physician knows whether immediate intervention is needed. The one critical diagnosis that needs to be treated at this stage is tension pneumothorax. If a patient presents with chest pain, respiratory distress, shock, and unilateral reduction or absence of breath sounds, immediate intervention with needle/tube thoracostomy is re-quired. Additionally, patients with severe derangements in vital signs require stabilizing treatment while a search for the precipitating cause is begun. Patients who present with respiratory distress require immediate intervention and lead the physician to suspect a more serious cause of the pain ( Figure 19-1 ).

Figure 19-1 Initial assessm ent of critical diagnoses. ECG, electrocardiogram ; CXR, chest x-ray; RV, right ventricular.

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All patients except those with obvious benign causes of chest pain are transported as promptly as possible to the treatment area. The patient is placed on the cardiac monitor, oxygen therapy is initiated, and an intravenous line is placed. If the patient shows signs and symptoms of tension pneumothorax, immediate needle/tube thoracostomy is performed. If there are symptomatic derangements in vital signs, these are treated as appropriate. If vital signs are stable, a brief history and physical examination are performed. If the patient is older than age 30 years, an electrocardiogram (ECG) should be ordered and interpreted by the responsible physician promptly. Most patients also require a chest radiograph to evaluate the chest pain. If a cardiac cause is suspected, and vital signs are stable, pain relief with nitroglycerin (0.4 mg sublingual every 3 to 5 minutes) may be appropriate. Aspirin (81 to 325 mg) is given to patients without bleeding disorders or known allergies. Clopidrogrel (loading dose 300 mg) is given to patients with a contraindication to aspirin. Patients with low voltage on the ECG, diffuse ST segment elevation, elevated jugular venous pressure on examination,[7] and signs of shock should undergo prompt cardiac ultrasound or pericardiocentesis or both. The evaluation then proceeds. When a diagnosis is established, appropriate treatment is rendered.

Pivotal Findings The broad and complex nature of chest pain defies application of a simple algorithmic approach. An organized approach to a patient with chest pain is essential, however, to ensure that all causes are evaluated appropriately. The history and physical examination are key to diagnosis. In all, 80% to 90% of information pertinent to the differential diagnosis is obtained by the history, physical examination, and ECG.

History 1.

2.

3.

4.

5.

The patient is asked to describe the character of the pain or discomfort. Descriptions such as “squeezing,” “crushing,” or “pressure” lead the physician to suspect a cardiac ischemic syndrome, although cardiac ischemia can be characterized by nonspecific discomfort, such as “bloating” or “indigestion.” “Tearing” pain that may migrate from the front to back or back to front classically is described in aortic dissection. “Sharp” or “stabbing” pain is seen more in pulmonary and musculoskeletal diagnoses. Patients complaining of a “burning” or “indigestion” type of pain lead the physician to think of gastrointestinal etiologies. Because of the visceral nature of chest pain, however, any cause of pain may present with any of the preceding descriptions. Additional history about the patient's activity at the onset of pain may be helpful. Pain occurring during exertion would cause the physician to suspect an ischemic coronary syndrome, whereas progressive onset of pain at rest suggests acute MI. Pain of sudden onset would make the physician more suspicious of aortic dissection, pulmonary embolus, or pneumothorax. Pain after meals is more indicative of a gastrointestinal cause. The severity of pain is quantified. A 1-to-10 pain scale is commonly used. Alterations in pain severity are documented at times of onset, peak, present, and after intervention. The location of the discomfort is described. Pain that is localized to a small area is more likely to be somatic versus visceral in origin. Pain localized at the periphery of the chest makes a cardiac cause less likely and a pulmonary cause more likely. Lower chest/upper abdominal pain may be of cardiac or gastrointestinal origin. Any description of radiation of pain is noted. Pain that goes through to the back makes the diagnoses of aortic dissection and gastrointestinal causes, especially pancreatitis or posterior ulcer, more likely. Inferior/posterior myocardial ischemia also may present primarily as thoracic back pain. Radiation to the arms, neck, or jaw increases the physician's

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suspicion of cardiac ischemia as a cause.[] Pain located primarily in the back, especially interscapular back pain that migrates to the base of the neck, suggests aortic dissection.[ 10]

6.

7.

8.

Duration of pain is an important historical factor. Pain that lasts a few seconds is rarely of cardiac origin.[11] Pain that is exertional but lasts for only a few minutes after rest may be a manifestation of cardiac ischemia.[8] Pain that is maximal at onset may be due to aortic dissection.[10] Pain that is not severe and constantly persists over the course of days is less likely to be of serious origin. Pain that is severe or has a stuttering or fluctuating course is more likely to be serious, and this includes a cardiac origin. Aggravating or alleviating factors need be considered. Pain that worsens with exertion and is better with rest is more likely related to coronary ischemia.[8] Pain related to meals makes the physician more suspicious of a gastrointestinal cause. Pain that worsens with respiration is seen more often with pulmonary, pericardial, and musculoskeletal causes. Other associated symptoms may give a key to the visceral nature of the pain ( Table 19-2 ). The symptoms may appear as the initial chief complaint. Diaphoresis should lead to an increased clinical suspicion for a serious or visceral cause. Hemoptysis, a classic, although rarely seen symptom, would lead the physician to consider pulmonary embolus.[12] Syncope and near-syncope lead to higher suspicion for a cardiovascular cause or pulmonary embolus. Dyspnea is seen in cardiovascular and pulmonary disease. Nausea and vomiting may be seen in cardiovascular and gastrointestinal complaints. Table 19-2 -- Significant Symptoms of Chest Pain Symptom Finding Diagnosis Pain

Severe, crushing, pressure, substernal, exertional, radiation to jaw, neck, shoulder, arm

Tearing, severe, radiating to or located in back, maximum at onset, may migrate to upper back or neck

Acut e MI Coro nary isch emia Unst able angi na Coro nary spas m Aortic dissection

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Symptom

Finding

Diagnosis

Pleuritic Eso phag eal ruptu re Pne umot hora x Chol ecys titis Peri cardi tis Myo cardi tis Indigestion or burning

Associated syncope/nearsyncope

Acut e MI Coro nary isch emia Eso phag eal ruptu re Unst able angi na Coro nary spas m Eso phag eal tear Chol ecys titis Aorti c diss ectio n Pul mon ary emb olus

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Symptom

Finding

Diagnosis Acut e MI Peri cardi tis Myo cardi tis

Associated dyspnea (SOB, DOE, PND, orthopnea)

Associated hemoptysis Associated nausea/vomitin g

Acut e MI Coro nary isch emia Pul mon ary emb olus Tens ion pneu moth orax Pne umot hora x Unst able angi na Peri cardi tis Pulmonary embolus

Eso phag eal ruptu re Acut e MI Coro nary isch emia Unst able angi na Coro nary

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Symptom

Finding

Diagnosis spas m Eso phag eal tear Chol ecys titis

DOE, dyspnea on exertion; MI, myocardial infarction; PND, paroxysmal nocturnal dyspnea; SOB, shortness of breath.

9.

10.

A history of prior pain and the diagnosis of that episode can facilitate the diagnostic process, but the physician must be wary of prior presumptive diagnoses that may be misleading. A prior history of cardiac testing, such as stress testing, echocardiography, or angiography, may be useful in determining if the current episode is suspicious for cardiac disease. Similarly, patients with previous spontaneous pneumothorax or pulmonary embolus[13] are at increased risk of recurrence. The presence of risk factors for a particular disease is primarily of value as an epidemiologic marker for large population studies ( Box 19-1 ). Still, positive risk factors in a patient without established disease may increase or decrease the clinical likelihood (pretest probability) of a specific disease process. BOX 19-1 Risk Factors Associated with Potentially Catastrophic Causes of Chest Pain

Acute coronary syndromes Past history of coronary artery disease Family history of coronary artery disease Age Men >33 year s Wo

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men >40 year s Diabetes mellitus Hypertension Cigarette use/possible passive exposure Elevated cholesterol (LDL)/triglyceride s Sedentary lifestyle Obesity Postmenopausal Left ventricular hypertrophy Cocaine abuse Pulmonary embolism Prol onge d imm obiliz ation Surg ery > 30 days 3 mo Prior deep vein thro mbo sis or pulm onar y emb olus Preg nanc y or rece nt preg nanc y Pelvi c or lowe r extre

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mity trau ma Oral contr acep tives with cigar ette smo king Con gesti ve heart failur e Chro nic obstr uctiv e pulm onar y dise ase Obe sity Past medi cal or famil y histo ry of hype rcoa gula bility Aortic dissection Hype rtens ion Con genit al dise ase of the aorta or aorti c valve Infla

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mm atory aorti c dise ase Con necti ve tissu e dise ase Preg nanc y Arter ioscl erosi s Ciga rette use Pericarditis/myocarditis Infec tion Autoi mm une dise ase (e.g., syst emic lupu s eryth emat osus ) Acut e rheu mati c fever Rec ent myo cardi al infar ction or cardi ac surg ery Malig

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nanc y Radi ation thera py to medi astin um Ure mia Drug s Prior peric arditi s Pneumothorax Prior pneu moth orax Vals alva' s man euve r Chro nic lung dise ase Ciga rette use

Physical Examination Specific findings may be found in a variety of causes ( Table 19-3 ). Table 19-3 -- Pivotal Findings in Physical Examination Sign Finding Appearance

Diagnoses

Acute respiratory distress Pul mon ary emb olus Tens ion pneu moth orax Acut e MI Pne

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Sign

Finding

Diagnoses umot hora x

Diaphoresis Acut e MI Aorti c diss ectio n Coro nary isch emia Pul mon ary emb olus Eso phag eal ruptu re Unst able angi na Chol ecys titis Perf orate d pepti c ulcer Vital signs

Hypotension Tens ion pneu moth orax Pul mon ary emb olus Acut e MI Aorti c diss ectio n (late)

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Sign

Finding

Diagnoses Coro nary isch emia Eso phag eal ruptu re Peri cardi tis Myo cardi tis

Tachycardia Acut e MI Pul mon ary emb olus Aorti c diss ectio n Coro nary isch emia Tens ion pneu moth orax Eso phag eal ruptu re Coro nary spas m Peri cardi tis Myo cardi tis Medi astin itis Chol ecys titis

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Sign

Finding

Diagnoses Eso phag eal tear (Mall oryWei ss)

Bradycardia Acut e MI Coro nary isch emia Unst able angi na Hypertension Acut e MI Coro nary isch emia Aorti c diss ectio n (earl y) Fever Pul mon ary emb olus Eso phag eal ruptu re Peri cardi tis Myo cardi tis Medi astin itis Chol ecys titis Hypoxemia

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Sign

Finding

Diagnoses Pul mon ary emb olus Tens ion pneu moth orax Pne umot hora x

Cardiovascular examination

Significant difference in upper extremity blood pressures Narrow pulse pressure New murmur

Aortic dissection Pericarditis (with effusion) Acut e MI Aorti c diss ectio n Coro nary isch emia

S3/S4 gallop Acut e MI Coro nary isch emia Pericardial rub Audible systolic “crunch” on cardiac auscultation (Hamman's sign)

Pericarditis Eso phag eal ruptu re Medi astin itis

JVD Acut e MI Coro nary isch emia Tens ion pneu

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Sign

Finding

Diagnoses moth orax Pul mon ary emb olus Peri cardi tis

Pulmonary examination

Unilateral diminished/absent breath sounds

Pleural rub Subcutaneous emphysema

Tens ion pneu moth orax Pne umot hora x Pulmonary embolus Tens ion pneu moth orax Eso phag eal ruptu re Pne umot hora x Medi astin itis

Rales Acut e MI Coro nary isch emia Unst able angi na Abdominal examination

Epigastric tenderness Eso phag eal ruptu re

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Sign

Finding

Diagnoses Eso phag eal tear Chol ecys titis Pan creat itis

Extremity examination Neurologic examination

Left upper quadrant tenderness Right upper quadrant tenderness Unilateral leg swelling, warmth, pain, tenderness, or erythema Focal findings Stroke

Pancreatitis Cholecystitis Pulmonary embolus Aortic dissection Acut e MI Coro nary isch emia Aorti c diss ectio n Coro nary spas m

JVD, jugular venous distention; MI, myocardial infarction.

Ancillary Studies The two most commonly performed studies in patients with chest pain are chest radiograph and 12-lead ECG ( Table 19-4 ). ECG should be performed as soon as possible in all patients with chest pain in whom myocardial ischemia is suspected; this generally includes all patients 30 years old and older who complain of chest pain unless the cause is obviously noncardiac. Rapid acquisition of the ECG facilitates the diagnosis of acute MI and expedites the National Heart, Lung, and Blood Institute's recommended “door to drug” time of less than 30 minutes from arrival to administration of thrombolytic therapy or percutaneous coronary intervention in acute MI. Patients with a new injury pattern on ECG ( Table 19-5 ), with the appropriate history, should have therapy instituted for acute MI. New ischemic ECG changes indicate acute coronary ischemia or spasm, and appropriate therapy is instituted at this point ( Figure 19-2 ). An ECG showing right ventricular strain pattern, in the appropriate setting, should raise the clinical suspicion for pulmonary embolus. Diffuse ST segment elevation helps make the diagnosis of pericarditis. Table 19-4 -- Ancillary Testing of Patients with Chest Pain Test Finding

Diagnosis

ECG

Acute MI

New injury

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Test

Finding New ischemia

CXR

RV strain Diffuse ST segment elevation Pneumothorax with mediastinal shift Wide mediastinum Pneumothorax Effusion Increased cardiac silhouette Pneumomediastinum

ABG V/Q scan or spiral CT

Hypoxemia, A-a gradient High probability or any positive in patient with high clinical suspicion

Diagnosis Aortic dissection Coronary ischemia Coronary spasm Pulmonary embolus Pericarditis Tension pneumothorax Aortic dissection Esophageal rupture Pneumothorax Esophageal rupture Pericarditis Esophageal rupture Mediastinitis Pulmonary embolus Pulmonary embolus

ABG, arterial blood gas; CT, computed tomography; ECG, electrocardiogram; MI, myocardial infarction; RV, right ventricular.

Table 19-5 -- Electrocardiogram Findings in Ischemic Chest Pain Classic myocardial infarction ST segment elevation (>1 mm) in contiguous leads; new LBBB; Q waves ≥0.04 sec duration Subendocardial infarction T wave inversion or ST segment depression in concordant leads Unstable angina Most often normal or nonspecific changes; may see T wave inversion Pericarditis Diffuse ST segment elevation; PR segment depression LBBB, left bundle-branch block.

Figure 19-2 Clinical guidelines for em ergency departm ent m anagem ent of m yocardial ischem ic origin chest pain. SL, sublingual; IV, intravenous; ECG, electrocardiogram; MI, m yocardial infarction; LBBB, left bundle-branch block; LMWH, low-m olecular-weight heparin; CCU, critical care unit; OBS, observation; LV, left ventricular.

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A portable chest radiograph is performed for patients with suspected serious cause of chest pain. Pneumothorax is definitively diagnosed at this point. A wide mediastinum or ill-defined aortic knob increases the clinical suspicion for acute aortic dissection. Pleural effusion, subcutaneous air, or mediastinal air-fluid level may be seen in esophageal rupture. Increased cardiac silhouette may indicate pericarditis or cardiomyopathy. Pneumomediastinum is seen with esophageal rupture and mediastinitis. Serum D-dimer assay may help discriminate patients with pulmonary embolus. A low serum D-dimer in a patient believed to be at low pretest probability of pulmonary embolus effectively excludes the diagnosis.[] Patients at moderate or high pretest probability should undergo diagnostic imaging (multidetector computed tomography scan, pulmonary angiography, or ventilation-perfusion lung scan). High pretest probability warrants initiation of anticoagulation (heparin or low-molecular-weight heparin) therapy in the emergency department before the imaging study, in the absence of a contraindication. Laboratory testing may be useful in the evaluation of ACS. Creatine kinase (CK) has been used for many years. Although it is 95% sensitive for all MIs, it is less than 40% sensitive at 4 hours. CK also is associated with multiple false-positive results and has no use in the evaluation of unstable angina. CK-MB, an isoform of CK, is more specific for cardiac ischemia. There are fewer false-positive results, and peak sensitivity approaches 98%. Sensitivity at 4 hours is only about 60%, however. CK-MB isoforms improve sensitivity at 4 hours to 80%, approaching 93% at 6 hours. Myoglobin is an enzyme released in all muscle damage. Although its measurement is sensitive (90% at 4 hours), its false-positive rate is estimated at 50%. These markers and their corresponding sensitivities and specificities are used only for the diagnosis of MI, and none are useful in diagnosing other acute ischemic coronary syndromes, including unstable angina. Troponins (I and T), when elevated, identify patients with ACS who have the highest risk for adverse outcome. Sensitivity for ACS is 35%, but most of these patients are at high risk for complications.[15] Sensitivity for acute MI at 4 hours is 60% (similar to CK-MB). Studies have shown an advantage to serial enzyme testing over the course of 2 to 4 hours. A significant increase (two to three times the baseline value) has been shown to be more sensitive than isolated measurements of any enzyme. Single values of any enzyme cannot be used to exclude coronary ischemia as a cause of pain.[]

DIAGNOSTIC TABLE After the patient is stabilized and assessment has been completed, the findings are matched to the classic and atypical patterns of the seven potentially critical diseases causing chest pain. This matching process is continual while evaluating the patient and monitoring the response to therapy. Any inconsistency in findings with the primary working diagnoses requires a rapid review of the pivotal findings and the potential diagnoses ( Table 19-6 ). Table 19-6 -- Causes and Differentiation of Potentially Catastrophic Illness Presenting with Central Chest Pain or Discomfort Pa Associated Supporting History Prevalence in Ph Useful Tests Atypical or in Symptoms Emergency ysi Additional Hi Department cal Aspects st Ex or am y in ati on My oc ar dia l Inf ar cti on

Di sc o mf ort is us ual ly m od er ate

Diaphoresis, nausea, vomiting, dyspnea

May be precipitated by Common emotional stress or exertion. Often comes on at rest. May come on in early awakening period. Prodromal pain pattern often elicited. Previous history of MI or angina. >40 years old, positive risk factors, and male sex increase possibility

Pa tie nts ar e an xio us an d un co mf

ECG changes (new Q waves or ST segment–T wave changes) occur in 80% of patients. CK-MB and troponins are helpful if elevated, but may be normal

Pain may present as “indigestion” or “unable to describe.” Other atypical presentations include altered mental status, stroke, angina pattern without extended pain, severe fatigue,

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Pa Associated in Symptoms Hi st or y

ly se ver e to se ver e an d ra pid in on set . Ma y be m or e “pr es su re” tha n pai n. Us ual ly ret ro ste rn al, m ay ra dia te to ne ck, ja w, bot h ar m s, up

Supporting History

Prevalence in Emergency Department

Ph Useful Tests ysi cal Ex am in ati on

Atypical or Additional Aspects

ort abl e. Bl oo d pr es su re us ual ly is ele vat ed, but no rm ote nsi on an d hy pot en sio n ar e se en. Th e he art rat e is us ual ly mil dly inc re as ed, but br ad yc

syncope. Elderly may present with weakness, congestive heart failure, or chest tightness. 25% of nonfatal MIs are unrecognized by patient. The pain may have resolved by the time of evaluation

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Pa Associated in Symptoms Hi st or y

pe r ba ck, epi ga stri u m, an d sid es of ch est (lef t m or e tha n rig ht) . La sts m or e tha n 15 – 30 mi n an d is un reli ev ed by NT G

Supporting History

Prevalence in Emergency Department

Ph Useful Tests ysi cal Ex am in ati on

Atypical or Additional Aspects

ar dia ca n be se en. Pa tie nts m ay be dia ph or eti c an d sh ow pe rip he ral po or pe rfu sio n. Th er e ar e no dia gn ost ic ex a mi nat ion fin din gs for MI, alt ho

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Pa Associated in Symptoms Hi st or y

Un sta ble An gin a

Ch an ge s in pat ter n of pr ee xis tin g an gin a wit h m or e se ver e, pr olo ng

Often minimal. May have mild diaphoresis, nausea, dyspnea with pain. Increasing pattern of dyspnea on exertion

Supporting History

Prevalence in Emergency Department

Not clearly related to Common precipitating factors. May be a decrease in amount of physical activity that initiates pain. Previous history of MI or angina. Over 40 years old, presence of risk factors, and male sex increase probability

Ph Useful Tests ysi cal Ex am in ati on ug h S3 an d S4 he art so un ds an d ne w m ur m ur ar e su pp orti ve No ns pe cifi c fin din gs of a tra nsi ent nat ur e, m ay ha ve si mil ar ca rdi ac fin din

Ofte n no ECG or enzy me chan ges. Varia nt angi na (Prin zmet al's) has epis odic pain, at rest, often seve re, with pro mine

Atypical or Additional Aspects

May be pain-free at presentation. Full history is essential. Fewer than 15% of patients hospitalized for unstable angina go on to acute MI. May respond to nitroglycerin. May manifest similarly to non– Q wave infarction

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Pa Associated in Symptoms Hi st or y

ed, or fre qu ent pai n (cr es ce nd o an gin a). Pa in us ual ly las ts >1 0 mi n. An gin a at re st las tin g 15 – 20 mi n or ne won set an gin a (d ur ati on 1200 g who require special attention short of circulatory or ventilator support and major surgical procedures. Because they address the greatest diversity of neonatal disorders, these nurseries present perhaps the greatest challenge to health care providers. A high percentage of the problems in such nurseries relates to obstetric complications (e.g., birth trauma, fetal distress, obstetric anesthesia).

Level 3 Nurseries These nurseries are staffed and equipped to care for all newborn infants who are critically ill, regardless of the level of support required. They are regional institutions serving as referral centers for other nurseries and for this reason are often linked with transport services.

Perinatal Centers A perinatal center provides services to high-risk mothers and to infants requiring level 3 nursery care. Ample data show a higher neonatal survival rate for high-risk pregnancies cared for in such centers.

NORMAL DELIVERY Normal labor and delivery proceed to a good outcome without physician intervention in most cases. The mother and fetus are extremely vulnerable during labor and delivery, however, and medical attendance decreases morbidity and mortality. Although the epidemiology and high complication rate associated with emergency department births demand caution, most are normal deliveries. Knowledge of normal labor and

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delivery mechanics aids safe vaginal delivery and facilitates the identification of complications. Whenever a woman in the third trimester of pregnancy seeks treatment in the emergency department, the possibility that she is in labor must be considered. A wide array of nonspecific symptoms may herald the onset of stage 1 labor. Abdominal pain, back pain, cramping, nausea, vomiting, urinary urgency, stress incontinence, and anxiety all can be symptoms of labor. After 24 weeks' gestation, any medical assessment should include the mother and the fetus because fetal viability becomes established near that time. In addition, given the generally high-risk nature of this patient population and the abundance of bodily fluids that the health care provider and newborn are exposed to during delivery, serologic testing for infectious disease may be warranted. With the development of rapid bedside testing technology, human immunodeficiency virus (HIV) and hepatitis screening before delivery is indicated in a significant group of patients presenting with active labor.

False Labor Braxton Hicks contractions, or false labor, must be differentiated from true labor. During the third trimester, the uterus develops into a contractile organ. After 30 weeks' gestation, the previously small and uncoordinated contractions of the uterus become more synchronous and may be perceived by the mother. Although usually painless, the patient may indicate that her uterus or lower abdomen has become firm. By definition, this muscular activity is not associated with cervical dilation. Examination should reveal a minimally dilated cervix and intact membranes. Care not to rupture the membranes is important to avoid inducing labor prematurely. Braxton Hicks contractions do not increase in frequency or duration the way the contractions of true labor do. If the diagnosis remains in doubt, external electrical monitoring of uterine activity excludes true labor. Any discomfort associated with false labor usually is relieved with mild sedation and analgesia.

True Labor True labor is characterized by cyclic uterine contractions of increasing frequency, duration, and strength, culminating in delivery of the fetus and placenta. In contrast to Braxton Hicks contractions, true labor causes cervical dilation to begin, marking the first stage of labor.

Bloody Show Early in pregnancy, the cervix becomes increasingly vascular and develops edema, giving the cervix a boggy texture. The vascularity of the cervix also increases, giving rise to Chadwick's sign (a blue-violet coloration). At the onset of labor, the cervical mucous plug is expelled, resulting in what is called a bloody show. The bleeding associated with the process is slight, and usually only a few dark red spots are noticed. The dark color is due to its venous origin, and it is admixed with the mucous components of the cervical plug. The significance of a bloody show is that it is a fairly reliable indicator of the onset of labor (stage 1). Bloody show is not a contraindication to vaginal examination for determination of cervical effacement and dilation. If bleeding continues or is of a larger volume, more serious causes should be suspected, such as placenta previa and placental abruption, which are contraindications for a vaginal examination.

Stages of Labor First Stage of Labor The first stage of labor is the cervical stage and ends when the cervix is fully dilated and paper thin (fully effaced). Stage 1 is divided into a latent phase, with slow cervical dilation, and an active phase, with more rapid dilation. In multiparous women, the active phase can progress rapidly into stage 2 of labor (delivery of the fetus). Most women who deliver in the emergency department arrive while in the active phase of stage 1 or in early stage 2 labor ( Figure 180-1 ).[6]

Figure 180-1 Stages of labor and delivery. Stage 1, cervical stage; stage 2, fetal expulsion; stage 3, placental expulsion (20 m inutes); stage 4, uterine contraction (1 hour postpartum ).

The duration of the first stage of labor averages 8 hours in nulliparous women and 5 hours in multiparous women. During this time, frequent assess-ment of fetal well-being is important. For low-risk pregnancies,

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fetal heart tones should be auscultated approximately every 30 minutes. For higher risk pregnancies, continuous external electrical monitoring may help identify fetal distress, allowing appropriate intervention. The accurate determination of the stage of labor depends on examination of the cervix. A sterile approach using sterile gloves, a sterile speculum, and povidone-iodine (Betadine) solution is indicated to prevent ascending infection, such as chorioamnionitis. The cervix should be evaluated for the following: 1.

2.

3.

4.

Effacement refers to the thickness of the thinning cervical canal relative to the uneffaced cervix. A paper-thin cervix is 100% effaced. Dilation indicates the width of the cervical opening in centimeters. Complete, or maximum, dilation is 10 cm. Position describes the relationship of the fetal presenting part to the birth canal. The most common position of the head is occiput anterior. Station indicates the relationship of the presenting fetal part to the ischial spines ( Figure 180-2 ).

Figure 180-2 Fetal stations. The level of the ischial spines is considered “0” station. The silhouette of the infant's head is shown approaching station +1. ((Courtesy of Ross Lab oratories, Colum b us, Ohio.))

5.

Presentation specifies the anatomic part of the fetus leading through the birth canal.

In 95% of all labors, the presenting part is the occiput or vertex. On palpation, both are smooth surfaces with 360 degrees of firm bony contours and palpable suture lines. Palpation of the suture lines and the fontanelles where they join allows the examiner to determine in which direction the fetus is facing. Three sutures radiate from the posterior fontanelle, and four radiate from the anterior fontanelle ( Figure 180-3 ). The lateral margins should be examined carefully for fingers or facial parts that indicate compound or brow presentations.

Figure 180-3 Bony landm arks of the fetal skull. ((Modified from Willson JR, et al: Ob stetrics and Gynecology, 9th ed. St. Louis, Mosb y, 1991.)Elsevier Inc.)

Leopold's maneuvers may confirm the lie of the fetus ( Figure 180-4 ). After labor has begun, particularly

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during the active phase of stage 1, Leopold's maneuvers are difficult to use. The firm contractions of the uterus prevent the identification of fetal “small parts.” The third and fourth maneuvers are “negative” because of engagement of the head within the birth canal. Other modalities of assessing the lie may be necessary, such as emergency department ultrasonography, if presentation remains in question.[15]

Figure 180-4 Leopold's m aneuvers. A, The first Leopold m aneuver reveals what fetal part occupies the fundus. B, The second Leopold m aneuver reveals the position of the fetal back. C, The third Leopold maneuver reveals what fetal part lies over the pelvic inlet. D, The fourth Leopold maneuver reveals the position of the cephalic prom inence. ((Modified from Willson JR, et al: Ob stetrics and Gynecology, 9th ed. St. Louis, Mosb y, 1991.)Elsevier Inc.)

Maternal examination also provides a rough guide to gestational age. At 20 weeks' gestation, the uterine fundus reaches the umbilicus. Approximately 1 cm of fundal height is added per week of gestation until 36 weeks. At that time, the fundal height decreases as the fetus “drops” into the pelvis ( Figure 180-5 ). These estimates help to establish prematurity rapidly.

Figure 180-5 Height of fundus by weeks of norm al gestation with a single fetus. Dotted line indicates height after lightening. ((Modified from Barkaukas V, et al: Health and Physical Assessment. St. Louis, Mosb y, 1994.)Elsevier Inc.)

Second Stage of Labor The second stage of labor is characterized by full dilation of the cervix, accompanied by the urge to bear down and push with each uterine contraction. The fetal station advances to +3, with crowning of the presenting part as expulsion begins. Stage 2 uterine contractions may last 1 to 2 minutes and recur after a resting phase of less than 1 minute. The median duration of this stage is 50 minutes in nulliparous women and 20 minutes in multiparous women. More rapid progression through stage 2 should be anticipated for low-birth-weight premature infants.

Antenatal Fetal Assessment As indicated earlier, the assessment of any woman in the third trimester includes an assessment of fetal well-being. After 24 weeks' gestation, the fetal condition begins to affect clinical decision making. During labor and delivery, the identification of fetal distress and appropriate intervention can reduce fetal morbidity and mortality in genetically normal infants who develop intrapartum complications. The diagnosis of fetal distress has become more sophisticated because of technical advances in the 1980s and 1990s. At present, three major methods of assessing a fetus in utero exist. Clinical monitoring, electrical monitoring, and ultrasonography all have a role in the assessment of the fetus.[] External electrical monitoring and ultrasonography merit consideration for use in the care of women laboring in the emergency department. The machinery for both these technologies is portable and easy to use, making them attractive to the emergency physician.[] Both modalities can provide real-time information helpful for diagnosing fetal distress and assisting with intrapartum decision making.

Electronic Fetal Monitoring.

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Intrapartum fetal assessment by electronic fetal monitoring is most useful during stage 1 of labor. Electronic fetal monitoring confirms labor and may help diagnose fetal distress. Tracings of fetal heart rate and uterine activity provide information that, when combined with clinical data, can presage fetal damage and provide a window for intervention.

Uterine Activity. Uterine activity is measured transabdominally via a pressure transducer and creates a recording of the contraction frequency. Because the measurements are indirect, the strength of the contractions correlates poorly with the tracing. The tracings are position and placement sensitive. Documentation of organized cyclic uterine contractions confirms the onset of labor and rules out Braxton Hicks contractions that are too disorganized to register in this fashion. Premature onset of labor also can be diagnosed, and the efficacy of tocolysis can be documented using external electrical monitoring.

Fetal Cardiac Activity. Fetal heart rate tracings have several components that can be assessed: baseline heart rate, variability, accelerations, decelerations, and diagnostic patterns. Baseline heart rate, by definition, is maintained for 15 minutes in the absence of a uterine contraction (i.e., between contractions) and is the most important aspect of fetal heart rate monitoring. Variability can be instantaneous (beat-to-beat) or long-term over intervals of 1 minute or more. Both types of variability are indicators of fetal well-being. Accelerations of heart rate are an important component of long-term variability. Accelerations occur during fetal movement and reflect an alert, mobile fetus. Brief periods of umbilical cord compression also can cause accelerations by decreasing the venous return and reflexively generating fetal tachycardia. Decreased variability corresponds to an inactive, unresponsive fetus. Fetal acidemia, hypoxemia, and a wide array of drugs can cause decreased variability. Analgesics, sedative-hypnotics, phenothiazines, and alcohol all have been reported to cause decreased variability. Decelerations in the fetal heart rate are more complicated, and their interpretation must be integrated with the clinical situation. There are three types of deceleration: variable, early, and late ( Figure 180-6 ). These terms refer to the timing of the deceleration relative to the uterine contraction.

Figure 180-6 Deceleration patterns of the fetal heart rate (FHR). A, Early deceleration caused by head com pression. B, Late deceleration caused by uteroplacental insufficiency. C, Variable deceleration caused by cord com pression. ((Modified from Lowderm ilk DL, et al: Maternity and Wom en's Health Care, 6th ed. St. Louis, Mosb y, 1997.)Elsevier Inc.)

Variable and early decelerations are common. Present on more than 50% of all tracings, these heart rate changes can represent physiologic reflexes associated with head compression in the birth canal or intermittent cord compression. Variable decelerations that are persistent and repetitive usually indicate repeated episodes of umbilical cord compression. The resultant hypoxia and acidosis may cause fetal distress. Attempts to shift maternal and fetal weight off the umbilical cord by changing position are indicated. If these variable decelerations continue, the situation calls for efforts to hasten the delivery or, if obstetric backup becomes available, to perform an emergency cesarean section. Late decelerations are more serious and most often indicate uteroplacental insufficiency. The tracing contours are generally smooth, with the heart rate nadir occurring well after maximal uterine contraction. The lag, slope, and magnitude of late decelerations correlate with increasing fetal hypoxia. Late decelerations are particularly ominous in association with poor variability, nonreactivity, and baseline bradycardia. Immediate delivery to prevent further hypoxia is indicated when these findings are present. The need for newborn resuscitation should be anticipated and preparation for critical care established for these deliveries. Overall, 30% of infants with late decelerations have good outcomes. The remaining 70% have suboptimal outcomes related to either the underlying pathologic condition or hypoxia.

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Finally, some diagnostic fetal heart rate tracings are important. For the emergency physician, the most important of these is the sinusoidal tracing. Tracings of this type have low baseline heart rates and little beat-to-beat variability. The sinusoidal tracing is an ominous finding that is often premorbid. The differential diagnosis includes erythroblastosis fetalis, placental abruption, fetal hemorrhage (trauma), and amnionitis.

Ultrasonography. Ultrasonographic techniques have wide application to obstetric care. In the third trimester or during labor, ultrasonography can provide crucial information pertaining to the impending delivery.[18] Of immediate interest are fetal viability, lie, and presentation. Ultrasonography also reveals multiple gestations, allowing time for preparation and early communication with other specialists (from obstetrics, neonatology, and anesthesia).[15] When a technician and radiologist are available, gestational age can be established, a biophysical profile can be generated, the amniotic fluid index can be measured, and a survey of fetal and placental anatomy can be done ( Table 180-1 ).[] In 1991, the American College of Obstetricians and Gynecologists made recommendations regarding the indications for ultrasonography in the third trimester ( Box 180-2 ). Table 180-1 -- Biophysical Profile: 30 Minutes of Ultrasonographic Observation Element Assessed

Normal Score = 2

Abnormal = 0

Fetal heart rate reactivity

2 accelerations > 15 beats/min for 15 sec

Amniotic fluid index

1 pocket > 1 cm in orthogonal planes

No large pockets

Fetal muscle tone

1 episode of active flexion-extension with full

40 yr, teen ager s) Low

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er soci oeco nomi c statu s Toba cco use Coc aine abus e Prol onge d stan ding (occ upati on) Psyc hoso cial stres sors

Reproductive and Gynecologic Prior prete rm deliv ery Diet hylsti lbest rol expo sure Multi ple gest ation s Anat omic endo metri al cavit y ano mali es Cerv ical

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inco mpet ence Low preg nanc y weig ht gain First -trim ester vagi nal blee ding Plac ental abru ption or previ a

Surgical Prior repr oduc tive orga n surg ery Prior para endo metri al surg ery other than genit ourin ary (app ende ctom y)

Infections Urin ary tract

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infec tions Non uteri ne infec tions Geni tal tract infec tions (bact erial vagi nosi s)

Clinical Features The diagnosis of preterm labor requires the identification of uterine activity and cervical changes before 37 weeks' gestation. Early maternal signs and symptoms include an increase or change in vaginal discharge, pain resulting from uterine contractions (sometimes perceived as low back pain), pelvic pressure, vaginal bleeding (usually bloody show), and fluid leak.

Diagnostic Strategies If uterine contractions and cervical changes are present and the estimated fetal weight on ultrasonography is less than 2500 g, the diagnosis of premature labor is likely. The differentiation of false labor (Braxton Hicks contractions) from true labor is best done by electrical monitoring. Ultrasonography also may aid in the diagnosis because fetal breathing movements make the diagnosis of false labor unlikely. The initial evaluation of a woman with possible preterm labor should include urinalysis, complete blood count, and pelvic ultrasonography. If delivery is not imminent, these studies can be performed in the emergency department or obstetrics area, whichever would provide the best monitoring. When possible, these patients should be transferred to a perinatal center with an associated intensive care unit. If fetal assessment reveals intrauterine demise or major congenital anomalies, or if the mother is critically ill because of eclampsia or another diagnosis that mandates the termination of pregnancy, preterm labor should not be treated. When pregnancy is contraindicated or the fetus nonviable, termination of preterm labor by fetal expulsion is beneficial.[27]

Management A viable fetus and healthy mother are indications for medical management directed toward the prolongation of gestation. An important exception is the combination of preterm labor and PROM. When patients with PROM, fetal disorders, and maternal contraindications are excluded, only one fourth of all women in premature labor are candidates for medical management.[28] The treatment of preterm labor includes multiple modalities. Tocolytics to interrupt labor and fetal maturation therapy combined with bed rest and hydration are used in hopes of prolonging pregnancy ( Box 180-4 ). These patients optimally should be transferred to an appropriate center before delivery whenever possible because medical management fails in more than 25% of preterm patients in whom it is attempted.[29] Attempts to transfer these women to perinatal centers should occur when transfer without delivery en route is possible. BOX 180-4 Commonly Used Tocolytic Agents

Magnesium sulfate 4-6 g bolus over 30 min

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2-4 g/hr infus ion Terbutaline 2.5 mg PO q2-4 h 0.250.50 mg SC 0.01 0-0.0 80 mg/ min IV Ritodrine 10-20 mg PO q4h 0.05 0-0.3 50 mg/ min IV Isoxsuprine 20 mg PO q4h

PO, orally; SC, subcutaneously; IV, intravenously.

Tocolysis. The two classically used tocolytics were intravenous magnesium sulfate and the p -mimetic drugs. Other medications that have been shown to be as or more effective include prostaglandin synthetase inhibitors (nonsteroidal anti-inflammatory drugs) and calcium channel blockers.[] When indicated and in coordination with an obstetric consultant, tocolytics initiated in the emergency department may arrest premature labor and prevent imminent delivery. Allowing labor to continue may result in precipitous delivery of an immature, critically ill neonate.[32]

Magnesium Sulfate. Magnesium sulfate competitively inhibits calcium uptake into smooth muscle and allows relaxation. Magnesium also may produce respiratory and neurologic depression in the dosages used, and women treated with magnesium require monitoring. Cardiac dysrhythmias also have been reported.[33] These effects can be reversed rapidly by the administration of calcium-containing solutions (i.e., 1 g of 10% calcium gluconate solution). Because women with premature labor are at risk for ascending infections, early treatment with antibiotics often is indicated during magnesium therapy.[34]

p -Mimetics. p -Mimetics (ritodrine and terbutaline) cause smooth muscle relaxation by activating enzymes that bind calcium to the sarcoplasmic reticulum. This effect is mediated by p 2-receptors that increase cyclic adenosine monophosphate concentrations in the myometrium. The dosage of the p -mimetic is titrated to biologic effect. Only treatment success or side effects limit their administration. The dosage needed to eliminate uterine activity is unpredictable and varies. p -Mimetics freely cross the placenta and cause fetal tachycardia. Pulmonary edema is the main adverse effect of high-dose p -mimetics. This complication is more likely to occur in mothers with preexisting cardiac disease, multiple gestations, and maternal infection. This form of pulmonary edema is high-output failure and tends to occur when there is sustained maternal tachycardia greater than 120 beats/min. p -Mimetics should be gradually titrated according to uterine activity and

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maternal heart rate. Eventually, tachyphylaxis and receptor downregulation decrease the effectiveness of these drugs over 24 to 48 hours.[29] p 1-Related side effects can be problematic in diabetic mothers. p 1 Stimulation can lead to diabetic ketoacidosis and the usual cascade of metabolic and electrolyte abnormalities.[35] Surveillance of the urine for glucose and ketones is recommended. Fetal heart stimulation can result in increased cerebral perfusion pressures. A premature infant's central nervous system vasculature is frail and may not tolerate these changes. p -Mimetics are associated with an increased incidence of fetal intraventricular hemorrhage. [36] The prostaglandin synthetase inhibitors, specifically indomethacin and sulindac, have been shown to be superior to magnesium and the p -mimetics in multiple trials. Maternal side effects include a prolonged bleeding time. In the fetus, pulmonary hypertension, patent ductus arteriosus constriction, necrotizing enterocololitis, and intraventricular hemorrhage all have been reported.[] Calcium channel blockers also have been used as tocolytics with success. Nifedipine or nicardipine may be given. Onset is more rapid than magnesium, and the maternal and fetal side effect profiles are good.[] Aggressive titratable tocolytics are best for the initial 24 to 48 hours. After uterine contractions have been stopped, the patient usually can be maintained on oral agents, although the benefits of maintenance tocolysis, studied to date primarily with p -mimetics and magnesium, have yet to be shown. [31] The contraindications to tocolytics are important to review before initiating these therapies ( Box 180-5 ). Any patient receiving tocolytics should be externally monitored (electrically) for signs of fetal distress. BOX 180-5 Contraindications to Tocolysis

Absolute Acut e vagi nal blee ding Fetal distr ess (not tach ycar dia alon e) Leth al fetal ano maly Chor ioam nioni tis Pree clam psia or ecla mpsi a Sep

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sis Diss emin ated intra vasc ular coag ulop athy

Relative Chro nic hype rtens ion Card iopul mon ary dise ase Stabl e plac enta previ a Cerv ical dilati on > 5 cm Plac ental abru ption

Premature Rupture of Membranes Clinical Features PROM, also known as amniorrhexis, is defined as rupture of the amniotic and chorionic membranes before the onset of labor. Three percent of all gestations are affected by PROM.[38] During pregnancy, the chorionic and amniotic membranes protect the fetus from infection and provide an environment that allows fetal growth and movement. The amniotic fluid is constantly exchanged by fetal swallowing and urination and umbilical cord transfer. The fetal airway also contains a secreted fluid that allows for fetal breathing movements, promoting fetal respiratory development. This fluid is produced at 5 mL/kg/hr at term gestation and is resorbed rapidly by the pulmonary lymphatics, blood vessels, and upper airway at birth. The word premature in PROM refers to rupture before labor, not to fetal prematurity. In 10% to 15% of PROM cases, the fetus is at or near term, and PROM may result in normal labor. When PROM is associated with fetal prematurity, there is significant fetal morbidity and mortality. PROM is the inciting event in one third of all preterm deliveries. After the membranes rupture, the period from latency to the onset of labor varies. Longer latent periods are common earlier in pregnancy, and the latency shortens as gestational age increases. At term, labor is a desirable result of PROM, but with fetal immaturity labor is problematic because delivery would result in fetal

Page 4561

complications, such as hyaline membrane disease.

Diagnostic Strategies The diagnosis of PROM usually can be established by history, physical examination, and rapid bedside testing.[39] The patient usually describes a spontaneous gush of watery fluid followed by a low-level persistent seepage. In most cases, the patient suggests the diagnosis and usually is correct. Urinary incontinence or excess vaginal or cervical secretions occasionally are confused with PROM. Examination of women with potential PROM should be performed under sterile conditions to prevent ascending infection. Direct digital examination of the cervix should be avoided. The incidence of infection has been shown to be proportional to the number of examinations. A moist perineum and watery fluid pooling in the vaginal vault, with the characteristic odor of amniotic fluid, confirm the diagnosis. Nitrazine paper testing reveals a pH of 7.1 to 7.3 typical of amniotic fluid (normal vaginal pH in pregnancy is 3.5 to 6.0). Table 180-3 summarizes the bedside testing modalities available to confirm the diagnosis of PROM. Visualization of the cervix for prolapsed cord or abnormal fetal presentation (prolapse of a small part) should be done during the uterine evaluation for effacement and dilation. Cultures for group B streptococci, Chlamydia, and gonorrhea should be obtained. Table 180-3 -- Bedside Testing for Premature Rupture of Membranes Method

Result

Nitrazine

Amniotic fluid pH 7.1 to 7.3 turns nitrazine paper yellow; >7.3 is blue

Ferning

Amniotic fluid crystallizes

Smear combustion

Amniotic fluid, when flamed, turns white and crystallizes Vaginal secretions caramelize and turn brown

Management When the diagnosis of PROM is established, management depends on several factors: gestational age and maturity of fetus, presence of active labor, presence or absence of infection, and degree of fetal well-being or distress.[40] Obstetric consultation and admission are indicated. Further emergency department management may be for clarification of these factors or for delivery, if imminent. Gestational age may be well known by menstrual history and previous ultrasonographic scans. In the absence of such data, immediate ultrasonography provides an estimated gestational age quickly. Fetal maturity is a more complex determination. Beyond 36 weeks' gestation, fetal pulmonary maturity is likely. If the gestational age is less than 36 weeks, testing the amniotic fluid for the lecithin-to-sphingomyelin ratio or for phosphatidylglycerol can establish maturity. Fluid pooling in the posterior vaginal vault can be used for this purpose. In the immature fetus, administration of corticosteroids can accelerate pulmonary maturation. The benefit of this strategy has been shown with preterm labor; however, this therapy is less well documented for PROM. In PROM, treatment with steroids seems to decrease the incidence and severity of hyaline membrane disease, but it may increase the risk of maternal infectious complications. Rupture of the membranes also stimulates fetal lung maturation, making it more difficult to establish a treatment benefit in PROM compared with preterm labor. When gestational age is less than 26 weeks, the latent interval to delivery is often 1 week. Tocolytics are an obvious choice, but to date their use is controversial. When tocolytics are used, the goal is to temporize, allowing time for therapy to take effect. These treatment decisions should be coordinated with the receiving obstetrician. All patients with PROM should be assessed for intra-amniotic infection. Infectious complications should be diagnosed and treated before the mother develops overt clinical signs of infection.[41] The signs and symptoms of chorioamnionitis are late manifestations of advanced infection and include fever, tachycardia, leukocytosis, uterine tenderness, and purulent vaginal discharge for the mother and tachycardia with or without loss of variability for the fetus.[42]

Chorioamnionitis

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Box 180-6 summarizes the findings and evaluation of chorioamnionitis. Prophylactic antibiotic treatment has been controversial. It seems that early treatment, however, even before evidence of infection occurs, decreases neonatal morbidity and delays delivery, allowing fetal maturation.[] BOX 180-6 Chorioamnionitis Evaluation

Fluid in Vaginal Vault Pho spha tidylg lycer ol

Cervical Cultures Esc heric hia coli and other gra m-n egati ve bact eria Neis seria gono rrho eae

Vaginal Cultures Chla mydi a spp. Myc opla sma homi nis Grou pB strep toco cci

Amniocentesis Studies

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Gra m stain (gro up B strep toco cci) Cult ure Gluc ose Lecit hin-t o-sp hing omy elin ratio

Maternal Signs and Symptoms Pre matu re ruptu re of me mbr anes Uteri ne tend erne ss Feve r Tach ycar dia Malo doro us vagi nal disc harg e Leuk ocyt osis

Fetal Signs and Symptoms Decr ease

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d activi ty Abno rmal biop hysi cal profil e (ultra sono grap hic exa mina tion) Fetal tach ycar dia Decr ease d varia bility of fetal heart rate

Third-Trimester Bleeding Two entities, placenta previa and abruptio placentae, merit special consideration when they occur in the context of active labor.

Placenta Previa Clinical Features. The classic symptom of placenta previa is painless, bright red vaginal bleeding in the third trimester. The uterus remains soft, and fetal lie is often abnormal; breech, oblique, or transverse lie is common. The initial bleeding is often self-limited and not lethal. This bleeding usually occurs as cervical effacement exposes the placenta. The earlier in the effacement process the bleeding begins, the lower the placenta lies. Although labor and cervical effacement usually provoke the bleeding, other precipitants, such as sexual intercourse or minor trauma, may be identified. Instrumentation, digital examination of the cervix, and speculum examination can provoke severe, exsanguinating hemorrhage.[44] If obstetric evaluation cannot be obtained, a partial speculum insertion to identify blood loss at the os may be done. Transvaginal ultrasonography also can be used with care to diagnose placenta previa. Ideally a “double setup,” in which preparations for immediate cesarean section are made before the examination, protects the patient if any hemorrhage occurs. If possible, the vaginal examination should be performed in the delivery suite with the obstetrician in attendance. For the fetus, the greatest risk is due to preterm delivery. Placenta previa can occur at 20 weeks' gestation. One third of cases of placenta previa occur at less than 30 weeks' gestation. In addition to prematurity, the fetus is at risk because of an increased incidence of congenital abnormalities and intrauterine growth retardation that are associated with placenta previa.

Diagnostic Strategies. A vaginal examination is contraindicated. The diagnosis is best pursued by ultrasonography, which usually yields the diagnosis quickly; however, the emergency physician must keep the limitations of ultrasonography in mind. Obesity, a posteriorly located placenta, and ultrasonographic shadows of the fetal head all can result in false-negative scans. A distended bladder pushing the lower uterine segment into a horizontal plane

Page 4565

also can result in false-positive results. Transvaginal probes also have been used when transabdominal ultrasonography is unsuccessful. Although described as relatively safe, some potential to provoke hemorrhage is present owing to placement of the ultrasonographic probe.[45]

Management. In all cases of placenta previa, admission and obstetric consultation are indicated. Cesarean section is the preferred method of delivery. The decision to perform cesarean section depends on fetal maturity, the presence or absence of labor, and placental position. When placenta previa is diagnosed early in pregnancy, the condition may resolve. Placental migration away from a low uterine insertion is well described during the second trimester. Because prematurity is the main determinant of fetal outcome, conservative expectant management is indicated.[46] If delivery by cesarean section is anticipated, steroids can be administered to accelerate fetal lung development. Tocolysis is controversial. If tocolytics are used, magnesium sulfate is superior to p -mimetics because it does not produce increases in heart rate or decreases in maternal blood pressure. These vital sign changes are particularly problematic in a patient who also may be hemorrhaging because they mimic volume loss.[47] Vaginal delivery should be considered only with a dead or nonviable fetus in cases of placenta previa. A previable fetus (24 hours), prolonged stage 2 of labor (>12 hours), and frequent or excessive pelvic examinations all have been linked to these ascending gynecologic infections. Of all puerperal deaths, 8% have infection and sepsis as a direct or

Page 4585

contributing factor.[96] Causative organisms for these infections include gram-negative coliforms, Bacteroides, and streptococci. More rarely, Chlamydia and Mycoplasma species have been implicated. Infection occurs when these bacteria proliferate and invade the uterus or other tissues along the birth canal.

Clinical Features Endometritis is the most common puerperal infection, usually developing on the second or third day postpartum. Typically the lochia has a foul odor, and the white blood cell count is elevated. Fever and abdominal pain indicate greater severity, often warranting inpatient care and intravenous antibiotics. A search for retained products of conception is indicated, particularly if bleeding is ongoing.

Management Treatment in the emergency department is empiric and directed at the most likely organisms. Clindamycin in conjunction with an aminoglycoside is usually used, although second-generation and third-generation cephalosporins are acceptable alternatives.[97] Most patients require admission.

Postpartum Cardiomyopathy Perspective For unclear reasons, the postpartum period is associated with the relatively sudden onset of cardiomyopathy in healthy women without evidence of prior cardiac disease. Estimates indicate that postpartum cardiomyopathy (PPCM) occurs in 1 of 4000 pregnancies and is more common in African American women and multiparous women. Proposed etiologies include viral, immunologic, toxic, and genetic factors, but in most cases no specific cause is found.[98] Mortality rates for PPCM range from 18% to 56%.

Clinical Features Symptom onset varies, as does the severity of the cardiomyopathy. Onset is usually days to weeks after delivery, and symptoms range from mild fatigue to acute pulmonary edema. PPCM is often unrecognized in its milder form, leading to the consensus that the condition may be more prevalent than reported. Dyspnea on exertion, orthopnea, and fatigue may be easily misinterpreted as normal in a mildly anemic woman who is breast-feeding a new infant at home. The emergency physician must not dismiss these symptoms because congestive heart failure and dysrhythmias may ensue.

Management Treatment with diuretics, vasodilators, and oxygen relieves the symptoms in many cases. Angiotensin-converting enzyme inhibitors are contraindicated if PPCM occurs during the last month of pregnancy (owing to teratogenicity), but should be considered a mainstay of treatment postpartum. Amlodipine (a dihydropyridine calcium channel blocker) also may have a role in the treatment of PPCM.[] Cardiac function returns to normal in half of patients with PPCM during the following 6 months. Others have residual left ventricular dysfunction and a cardiac mortality of 85% over the next 5 years. The presence of cardiomyopathy after one pregnancy does not predict recurrence during subsequent pregnancies.[101] Most physicians recommend against future pregnancies, however, believing that there is some residual cardiac function impairment. If such a pregnancy cannot be avoided, it should be considered high risk and followed closely.

Postpartum Depression Perspective Postpartum depression affects 10% to 15% of mothers and is likely underdiagnosed. Although in many cases it is self-limiting and considered minor, the suicide of a young woman with a new infant is an enormous and possibly preventable tragedy. The condition has been recognized as having important consequences for the mother, infant, and family, even when self-limited.[102] Risk factors for postpartum depression include maternal attributes, such as low self-esteem, anxiety, and neuroticism; poor marital adjustment; adverse socio-economic factors; and recent life stressors.

Clinical Features Women with delivery problems and fetal complications may develop maternal despair. The method of delivery also may play a role in the development of postpartum depression. Studies reveal that women anticipating normal delivery who subsequently go on to emergent cesarean section are at increased risk.[103] Maternal self-blame for failure of labor to progress, fetal distress, or cephalopelvic disproportion may result in clinical depression. The loss of the “natural” birthing experience is a significant injury to the psyche of these

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women.[104] When unrecognized, these women are at high risk for suicide and may come to the emergency department with overdoses or other manifestations of an attempt. Most women with postpartum depression do not have vegetative signs or symptoms. Early discharge from childbirth hospitalization does not seem to be a factor in postpartum depression.[]

Management Early identification and referral are the key components of therapy. Dismissal of postpartum fatigue as normal, without considering the diagnosis of postpartum depression, can be disastrous. As with other depressed patients in the emergency department, depression is rarely the chief complaint. Many of these women also fear that they will harm their infants and are ashamed of these emotions. Sensitivity to the possibility of depression is crucial to successful treatment. Suicide in a new mother is a real possibility that must be addressed in these patients.[107] Occasionally the patient requires inpatient psychiatric care with suicide precautions.

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Use of this content is subject to the Term s and Conditions of the MD Consult web site.

Marx: Rosen's Emergency Medicine: Concepts and Clinical Practice, 6th ed., Copyright © 2006 Mosby, Inc.

KEY CONCEPTS {,

{,

{,

{,

{,

Emergency department deliveries should be considered high risk. A perinatal mortality rate of 8% to 10% for deliveries in the emergency department has been reported. To a large extent, the emergency department is selected by an obstetric population with unexpected complications. Antepartum hemorrhage, PROM, eclampsia, premature labor, abruptio placentae, precipitous delivery, malpresentation, and umbilical cord emergencies all are overrepresented in emergency department deliveries. Women with the urge to push or with the head of the infant crowning are at imminent risk of delivery, and their infants should be delivered in the emergency department. Otherwise, transfer of a woman with an impending high-risk delivery to a perinatal center must be tempered by clinical and medicolegal judgment. Most deliveries require only basic equipment to cut and clamp the umbilical cord and to dry and suction the infant. Given that most emergency department deliveries are high risk, however, the emergency physician must have the equipment and staff available to care for a newborn requiring further resuscitation. Maternal complications of labor and delivery include obstetric trauma, postpartum hemorrhage, uterine inversion and rupture, amniotic fluid embolism, coagulation disorders, and infections. Many of these problems can be managed nonsurgically in the emergency department. Deliveries complicated by dystocia, malpresentation, or multiple gestations are life-threatening emergencies. The emergency physician must develop strategies to treat each of these potential complications of delivery.

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Page 4588

Use of this content is subject to the Term s and Conditions of the MD Consult web site.

Marx: Rosen's Emergency Medicine: Concepts and Clinical Practice, 6th ed., Copyright © 2006 Mosby, Inc.

REFERENCES 1. Higgins SD: Emergency delivery: Prehospital care, emergency department delivery, perimortem salvage. Emerg Med Clin North Am1987;5:529. 2. Pons PT: Prehospital considerations in the pregnant patient. Emerg Med Clin North Am1994;12:1. 3. Moscovitz HC: Care and outcome of out-of-hospital deliveries. Acad Emerg Med2000;7:757. 4. Anderson Jr JrGV, Anderson Sr SrGV: Umbilical cord pro-lapse in the emergency department. J Emerg Med1989;7:207. 5. Harper RG: Unexpected, unattended deliveries. N Y State J Med1990;90:330. 6. Brunette DD: Prehospital and emergency department delivery: A review of eight years experience. Ann Emerg Med1989;18:1116. 7. Chasnoff JJ: Cocaine use in pregnancy. N Engl J Med1985;313:666. 8. Amara H: Violence during pregnancy and drug abuse. Am J Public Health1990;80:575. 9. Verenson A: Perinatal morbidity associated with violence experienced by pregnant women. Am J Obstet Gynecol1994;170:1760. 10. Abbott J: Domestic violence against women: Incidence and prevalence in an emergency department population. JAMA1995;273:1763. 11. Katz VL, Hansen AR: Complications in the emergency transport of pregnant women. South Med J 1990;83:7. 12. Ayres Jr JrRJ: Legal considerations in prehospital care. Emerg Med Clin North Am1993;11:853. 13. Strobos J: Tightening the screw: Statutory and legal supervision of interhospital patient transfers. Ann Emerg Med1991;20:302. 14. Low RB: Emergency transport of pregnant patients: The national experience. J Emerg Med1988;6:41. 15. Trott A: Diagnostic modalities in gynecologic and obstetric emergencies. Emerg Med Clin North Am 1987;5:405. 16. Paul RH: Clinical fetal monitoring: The evaluation and significance of intrapartum baseline fetal heart rate variability. Am J Obstet Gynecol1975;123:206. 17. Chang TS, Lepanto L: Ultrasound in the emergency setting. Emerg Med Clin North Am1982;10:1. 18. Howe RS: Embryonic heart rate in human pregnancy. J Ultrasound Med1991;10:367. 19. Jehle D: Emergency department sonography by emergency physician. Am J Emerg Med1989;7:605. 20. Eden RD: A modified biophysical profile for antenatal fetal surveillance. Obstet Gynecol1988;71:365. 21. Phelan JP: Amniotic fluid volume assessment with the four-quadrant technique at 36-42 weeks gestation. J Reprod Med1987;32:540. 22. Shiono P: Midline episiotomies: More harm than good?. Obstet Gynecol1990;75:765. 23. Borgatta L: Association of episiotomy and delivery position with deep perineal laceration during spontaneous delivery in nulliparous woman. Am J Obstet Gynecol1989;160:294. 24. Webb DA, Culhane J: Hospital variation in episiotomy use and the risk of perineal trauma during childbirth. Birth2002;29:132. 25. Macpherson T: Fact and fancy: What can we really tell from the placenta?. Arch Pathol Lab Med 1991;115:672. 26. Salatia CM, Vintzilcos AM: Why all placentas should be examined by a pathologist in 1990. Am J Obstet Gynecol1990;163:1282. 27. Gonik B, Creasy K: Preterm labor: Its diagnosis and management. Am J Obstet Gynecol1986;154:3. 28. Travis BE, McCullough M: Pharmacotherapy of preterm labor. Pharmacotherapy1993;13:28. 29. Canadian Preterm Labor Investigators Group : Treatment of preterm labor with the p -adrenergic agonist ritodrine. N Engl J Med1992;327:308. 30. Berkman ND: Tocolytic treatment for the management of preterm labor: A review of the evidence. Am J Obstet Gynecol2003;188:1648. 31. Rodts-Palenik S, Morrison JC: Tocolysis: An update for the practitioner. Obstet Gynecol Surv 2002;57:S9. 32. Beall MH: A comparison of ritodrine, terbutaline, and magnesium sulfate for the suppression of preterm labor. Am J Obstet Gynecol1985;153:854. 33. Elliott JP: Magnesium sulfate as a tocolytic agent. Am J Obstet Gynecol1983;147:277.

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34. Parsons MT: Thermic effects of tocolytic agents: Decreased temperature with magnesium sulfate. Obstet Gynecol1987;69:88. 35. Spellacy WN: The acute effects of ritodrine infusion on maternal metabolism measures of glucose, insulin, glucagon, triglycerides, cholesterol, placental lactogen, and chorionic gonadotropin. Am J Obstet Gynecol1978;131:637. 36. Groome LF: Neonatal periventricular-intraventricular hemorrhage after maternal p -sympathomimetic tocolysis. Am J Obstet Gynecol1992;167:873. 37. Sawdy RJ, Lye S, Fisk NM, Bennett PR: A double-blind randomized study of fetal side effects during and after the short-term maternal administration of indomethacin, sulindac, and nimesulide for the treatment of preterm labor. Am J Obstet Gynecol2003;188:1046. 38. Wenstrom KD: Premature rupture of membranes. Obstet Gynecol Clin North Am1992;19:241. 39. Janetta O: A new simple test for detecting rupture of the fetal membranes. Obstet Gynecol1984;63:575. 40. Capeless EL, Mead PB: Management of preterm premature rupture of membranes: Lack of a national consensus. Am J Obstet Gynecol1987;157:11. 41. Johnston MM: Antibiotic therapy in preterm, premature rupture of membranes: A randomized prospec-tive double blind trial. Am J Obstet Gynecol1990;163:743. 42. Amon L: Ampicillin prophylaxis in preterm premature rupture of the membranes: A prospective randomized study. Am J Obstet Gynecol1988;159:539. 43. Kenyon S, Boulvain M, Neilson J: Antibiotics for preterm rupture of membranes. Cochrane Database Syst Rev2003;2:CD001058. 44. Iyasu S: The epidemiology of placenta previa in the United States. Am J Obstet Gynecol1987;168:1424. 45. Haines CJ, Stock A: The diagnosis of marginal placental abruption in placenta previa using transvaginal sonography. Aust N Z J Obstet Gynaecol1992;32:174. 46. Droste S, Keil K: Expectant management of placenta previa: Cost-benefit analysis of outpatient treatment. Am J Obstet Gynecol1994;170:1254. 47. Mover JR: Placenta previa: Antepartum conservative management, inpatient versus outpatient. Am J Obstet Gynecol1994;170:1683. 48. Fleming AD: Abruptio placentae. Crit Care Clin1991;7:865. 49. Lowe TW, Cunningham FG: Placental abruption. Clin Obstet Gynecol1990;33:406. 50. Nyberg DA: Sonographic spectrum of placental abruption. AJR Am J Roentgenol1987;148:161. 51. Neiger R: Plasma fibrin D-dimer in pregnancies complicated by partial placental abruption. Tenn Med 1997;90:403. 52. Gilabert J: Abruptio placentae and disseminated intravascular coagulation. Acta Obstet Gynecol Scand 1985;64:35. 53. Bey M: The sonographic diagnosis of circumvallate placenta. Obstet Gynecol1991;78:515. 54. Hata K: An accurate diagnosis of vasa previa with transvaginal color Doppler ultrasonography. Am J Obstet Gynecol1994;171:265. 55. Approval of a new rapid test for HIV antibody. MMWR Morb Mortal Wkly Rep2002;51:1051. 56. Centers for Disease Control and Prevention (CDC) : Rapid point-of-care testing for HIV-1 during labor and delivery—Chicago, Illinois, 2002. MMWR Morb Mortal Wkly Rep2003;52:866. 57. Conner EM, Sperling RS, Gelber R: Reduction of maternal-infant transmission of HIV-1 with zidovudine treatment. N Engl J Med1994;331:1173. 58. Mofenson LM, Centers for Disease Control and Prevention, U.S. Public Health Service Task Force : U.S. Public Health Service Task Force recommendations for use of antiretroviral drugs in pregnant HIV-1 infected women for maternal health and interventions to reduce perinatal HIV-1 transmission in the United States. MMWR Recomm Rep2002;51(RR-18):1.quiz CE1 59. The mode of delivery and the risk of vertical transmission of HIV-1—a meta-analysis of 15 prospective cohort studies. The International Perinatal HIV Group. N Engl J Med1999;340:977. 60. Landesman SH: Obstetrical factors and the transmission of HIV-1 from mother to child. N Engl J Med 1996;334:1617. 61. Moodley D: A multicenter randomized controlled trial of nevaripine versus a combination of zidovudine and lamuvidine to reduce intrapartum transmission of HIV-1. J Infect Dis2003;187:725. 62. Simonds RJ: Impact of zidovudine use on risk and risk factors for perinatal transmission of HIV. AIDS 1998;12:301. 63. Collea JV: The randomized management of term frank breech presentation: Vaginal delivery versus caesarean section. Am J Obstet Gynecol1978;129:186. 64. Seffah JD, Armah JO: Antenatal ultrasonography for breech delivery. Int J Gynaecol Obstet2000;68:7. 65. Carlan SJ: Shoulder dystocia. Am Fam Physician1991;43:1307. 66. Nocon JJ: Shoulder dystocia: An analysis of risks and obstetric maneuvers. Am J Obstet Gynecol 1993;168:1732. 67. Morrison JC: The diagnosis and management of dystocia of the shoulder. Surg Gynecol Obstet 1992;175:515. 68. Veciana M: Labor and delivery management of the multiple gestation. Obstet Gynecol Clin North Am

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1995;22:235. 69. Malloy D: Multiple-sited (heterotopic) pregnancy after in vitro fertilization and gamete intra-fallopian transfer. Fertil Steril1990;53:1068. 70. Adams DM, Chervenak FA: Intrapartum management of twin gestation. Clin Obstet Gynecol1990;33:52. 71. Greig PC: The effect of presentation and mode of delivery on neonatal outcome in the second twin. Am J Obstet Gynecol1992;167:901. 72. Gocke SE: Management of the nonvertex second twin: Primary caesarean section, external version, or primary breech extraction. Am J Obstet Gynecol1989;161:111. 73. Koonings PP: Umbilical cord prolapse: A contemporary look. J Reprod Med1990;35:690. 74. Barnett WM: Umbilical cord prolapse: A true obstetrical emergency. J Emerg Med1989;7:149. 75. Critchlow CW: Risk factors and infant outcomes associated with umbilical cord prolapse: A population based case-control study among births in Washington state. Am J Obstet Gynecol1994;170:613. 76. Johnson RL: Duplex ultrasound diagnosis of umbilical cord prolapse. J Clin Ultrasound1987;15:282. 77. Katz Z: Management of labor with umbilical cord prolapse: A five year study. Obstet Gynecol 1988;72:278. 78. Migliorini GD, Pepperell RJ: Prolapse of the umbilical cord: A study of 69 cases. Med J Aust1977;2:522. 79. Barrett JM: Funic reduction for the management of umbilical cord prolapse. Am J Obstet Gynecol 1991;165:654. 80. Druelinger L: Postpartum emergencies. Emerg Med Clin North Am1994;12:219. 81. Zahn CM, Yoemans ER: Postpartum hemorrhage, placenta accreta, uterine inversion, and puerperal hematomas. Clin Obstet Gynecol1990;33:422. 82. Shapiro JL: Postpartum ultrasonographic findings associated with placenta accreta. Am J Obstet Gynecol1992;167:601. 83. Petrovic O: Placenta accreta: Postpartum diagnosis and a potentially new mode of management using real time ultrasonography. J Clin Ultrasound1994;22:204. 84. Reed BD: Postpartum hemorrhage. Am Fam Physician1988;37:111. 85. Goldrath MH: Uterine tamponade for the control of acute uterine bleeding. Am J Obstet Gynecol 1983;147:869. 86. Gilbert WM: Angiographic embolization in the management of hemorrhagic complications of pregnancy. Am J Obstet Gynecol1992;166:493. 87. Mitty HA: Obstetric hemorrhage: Prophylactic and emergency arterial catheterization and embolotherapy. Radiology1993;188:183. 88. Rilep DP, Burgess RW: External abdominal aortic compression: A study of a resuscitation maneuver for postpartum hemorrhage. Anaesth Intensive Care1994;22:571. 89. Stanco LM: Emergency peripartum hysterectomy and associated risk factors. Am J Obstet Gynecol 1993;168:879. 90. Gerbasi FR: Increased intravascular coagulation associated with pregnancy. Obstet Gynecol 1990;75:385. 91. Lago JD: Presentation of acute uterine inversion in the emergency department. Am J Emerg Med 1991;9:239. 92. Leung AS: Uterine rupture after previous caesarean delivery: Maternal and fetal consequences. Am J Obstet Gynecol1993;169:945. 93. American College of Obstetricians and Gynecologists : Vaginal birth after previous cesarean. ACOG Practice Bulletin 5, Washington DC, ACOG, 1999. 94. Davies S: Amniotic fluid embolism and isolated DIC. Can J Anaesth2000;47:481. 95. Green BT, Umana E: Amniotic fluid embolism. South Med J2000;93:721. 96. Hillier SL: A case-control study of chorioamnionitis in prematurity. N Engl J Med1988;319:972. 97. Rusnik E: Early postpartum endometritis: Randomized comparison of ampicillin/sulbactam versus ampicillin, gentamicin and clindamycin. J Reprod Med1994;39:467. 98. Rizeq MN: Incidence of myocarditis in peripartum cardiomyopathy. Am J Cardiol1994;74:474. 99. Pearson GD: Peripartum cardiomyopathy: NHLBI and the Office of Rare Disease (NIH) workshop recommendations and review. JAMA2000;283:1183. 100. Packer M: For the PRAISE study group: Effect of amlodipine on morbidity and mortality in severe chronic heart failure. N Engl J Med1996;335:1107. 101. Witlin AG: Peripartum cardiomyopathy: An ominous diagnosis. Am J Obstet Gynecol1997;176:182. 102. Jermain DM: Treatment of postpartum depression. Am Pharm1995;NS35:33. 103. Boyce PM, Todd AI: Increased risk of postnatal depression after emergency caesarean section. Med J Aust1992;157:172. 104. Wolman W: Postpartum depression and companionship in the clinical birth environment: A randomized, controlled study. Am J Obstet Gynecol1993;168:1388. 105. Atkinson LS, Baxley EG: Postpartum fatigue. Am Fam Physician1994;50:113. 106. Thompson JF: Early discharge and postnatal depression: A prospective cohort study. Med J Aust 2000;172:532.

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107. O'Hara MW: Prospective study of postpartum depression: Prevalence, course, and predictive factors. J Abnorm Psychol1984;93:158.

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Marx: Rosen's Emergency Medicine: Concepts and Clinical Practice, 6th ed., Copyright © 2006 Mosby, Inc.

Section III - The Geriatric Patient Chapter 181 – The Elder Patient Diane M. Birnbaumer There are no diseases of the aged, but simply diseases among the aged. Leonard Larson, 1960

PERSPECTIVE The population of the United States is becoming proportionately more elderly, with the proportion of people older than age 65 increasing at twice the rate of younger people. In 2000, 12.4% of the population were older than age 65, and by 2030, one in five people may be older than age 65.[1] The fastest growing subset of the U.S. population is people age 85 and older. This group is also the fastest growing population seen in the emergency department. About 35% of total health care dollars are spent on patients older than age 65.[2] These changing demographics have affected the practice of emergency medicine. Currently, elders account for 15% to 19% of emergency department visits, and 46% of these patients are admitted. This group accounts for nearly 43% of all emergency department admissions and 47% of all critical care admissions.[3] In general, elderly patients presenting to the emergency department are more likely to have an emergent condition than younger patients and spend a longer time being evaluated in the emergency department.[4] As this patient population increases, their presence will continue to have a direct clinical impact on the emergency department.

PRINCIPLES OF DISEASE Physiologic Changes of Aging Physiologic changes of aging affect virtually every organ system and can have many effects on the health and functional status of elders ( Table 181-1 ). Heart disease is the leading cause of hospitalization and death in elders.[2] Increased peripheral vascular resistance with aging leads to an increased risk of hypertension. Decreased inotropic and chronotropic functioning of the heart compromises the patient's ability to respond to physiologic stressors. Atherosclerosis is common and contributes not only to the rate of heart disease, but also to the risk of vascular conditions (e.g., stroke, mesenteric ischemia, peripheral vascular disease, aortic dissection, abdominal aortic aneurysms). Table 181-1 -- Physiologic Changes of Aging and Potential Effects Physiologic Change

Potential Effect

Nervous System Decreased efficiency of blood-brain barrier Decreased response to changes in temperature Alteration of autonomic system function

Increased risk of meningitis Potential for exaggerated medication responses Impaired thermoregulation Variations in blood pressure; risk of orthostatic hypotension Reduced erectile function Urinary incontinence

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Physiologic Change

Potential Effect

Alterations in neurotransmitters Skin/Mucosa

Slowing of complex mental functioning

Atrophy of all skin layers

Decreased insulation Increased risk of skin injury Increased risk of infection Potential for hyperthermia

Sweat glands decreased in number or activity Musculoskeletal System Progressive bone loss Atrophy of fibrocartilaginous and synovial tissues Decrease in lean body mass Increase in proportion of adipose tissue Immune System Decrease in cell-mediated immunity Decreased antibody titers Cardiovascular System Decreased inotropic response Decreased chronotropic response Increased peripheral vascular resistance Decreased ventricular filling Pulmonary System Decreased vital capacity Decreased lung/airway compliance Decreased chemoreceptor response to hypercapnia/hypoxemia Decreased ventilatory drive Decreased diffusion capacity

Increased risk of fractures Joint instability and pain Impaired balance and mobility Alteration in pharmacokinetics Alteration in pharmacokinetics Increased susceptibility to neoplasms Tendency to reactivate latent diseases Increased risk of infection Less efficient response to myocardial wall stress Decreased maximal heart rate Increased blood pressure Changes in organ perfusion

Increased airway resistance Potential for rapid decompensation Decreased PaO2 and increased PaCO2 Decreased PaO2

Hepatic Function Decrease in hepatic cell mass Decrease in hepatic blood flow Alterations in microsomal enzyme activity Renal System

Reduced ability to regenerate Alteration in pharmacokinetics Alteration in pharmacokinetics

Decrease in renal cell mass Thickening of basement membrane Reduced hydroxylation of vitamin D Decrease in total body water Decreased thirst response Decreased renal vasopressin response Gastrointestinal System

Decreased drug elimination Decreased drug elimination Risk of hypocalcemia, osteoporosis Alteration in pharmacokinetics Risk of dehydration/electrolyte abnormalities Risk of dehydration/electrolyte abnormalities

Decrease in gastric mucosa Decrease in bicarbonate secretion Decrease in blood flow to gastrointestinal system Decreased epithelial cell regeneration

Increased risk of gastric ulcer Increased risk of gastric ulcer Increased risk of perforation Longer healing times

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Elders are at higher risk for infections. Decreases in antibody titers make this population more prone to infection in general. Immunosenescence of cell-mediated immunity predisposes patients to reactivation of latent diseases (particularly tuberculosis) and may be associated with increased susceptibility to neoplasms. Cancer is the second most common cause of hospitalization and death in older patients.[2] Fractures are the fifth leading cause of hospitalization, reflecting the high rate of osteoporosis among elders, particularly women. Arthritis is the most prevalent outpatient disease in elders because of the wear on the cartilaginous joints, particularly of the knees, hips, and hands.[2] Arthritis greatly affects quality of life, with patients reporting fair or poor health approximately three times more often than patients without arthritis.[5] Although the physiology of aging often affects a patient's functional status, laboratory values usually are within the normal range. Abnormal laboratory values in elders should be evaluated as abnormal findings and should not be attributed to “normal effects of aging.”

Pharmacologic Considerations Polypharmacy, drug interactions, and misuse and abuse of medications in elders are crucial health care issues. Elders currently consume more than 30% of the prescription drugs in the United States, and this figure is projected to increase to 50% by 2020. More than 40% of elders use 5 or more drugs weekly, and 12% use 10 or more.[6] Although multiple medications may be necessary to treat the medical problems that occur with aging, significant adverse health effects may result. Underlying medical problems, multiple physicians, changing pharmacokinetics of aging, and treating side effects of one medication with another drug all contribute to this problem. Studies have shown that 12% to 30% of admitted elders have adverse drug reactions or interactions as a primary or major contributing factor to their admission,[7] and 25% of these drug reactions or interactions are serious or life-threatening.[8] Pharmacokinetics may change with age. Altered gastrointestinal motility and blood flow, decreased lean body mass, increased proportion of adipose tissue, decreased creatinine clearance, and decreased hepatic blood flow all may alter the absorption, distribution, and clearance of medications. Despite these changes, the bioavailability of most medications is not significantly altered in elders. Medication interactions and side effects pose significant problems, however, particularly because so many elders take multiple medications. Emergency physicians unwittingly may contribute to this problem by adding a new medication at discharge that may have an adverse drug interaction with a patient's preexisting medications. In addition, the altered pharmacokinetics in elders necessitates caution when medications are administered in the emergency department, particularly sedative-hypnotics and narcotics. A good rule of thumb is “start low and go slow.” The medications most often implicated in adverse reactions in elders in the ambulatory setting are cardiovascular medications, followed by diuretics, nonopioid analgesics, hypoglycemics, and anticoagulants. [9] Caution should be used when prescribing any of these classes of drugs because they can contribute to morbidity and mortality in this group. If possible, some drugs should be avoided completely. Narcotics and sedative-hypnotic drugs lead to decreased cognition and an increased risk of falls and accidents. Diuretics may cause dehydration or electrolyte imbalance and should be prescribed with caution. Nonsteroidal anti-inflammatory drugs (NSAIDs) may have serious and potentially lethal side effects, particularly in elders. The toxicity of NSAIDs includes azotemia, worsened hypertension, and congestive heart failure as a result of sodium retention; gastrointestinal toxicity ranges from bleeding to perforation.[] The data support using extreme caution when prescribing NSAIDs. These complications can be seen in patients taking widely available over-the-counter formulations of these drugs. Recent evidence shows a significant increase in cardiovascular risk with the use of COX-2 inhibitors, which must be taken into consideration when prescribing these agents. With these concerns about medications in elders, the issue of pain management is difficult. Although a “first, do no harm” philosophy is laudable, treatment of pain is one of the most important remedies physicians have to offer their patients. Three major considerations influence the choice of medication for elderly patients. First, chronic pain (e.g., arthritis pain) may need to be treated differently from an acute painful condition (e.g., wrist fracture). Second, the patient's underlying medical problems, social situation, and baseline functional status need to be considered. Third, starting with low doses and titrating upward to effect is the safest way to use these medications. Overall, acetaminophen has the highest safety profile in elders and often is the drug of choice for chronic painful conditions (e.g., degenerative joint disease). Care must be taken to avoid inadvertent excessive

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dosing, but acetaminophen is safe and should be considered first-line management for chronic pain and acute conditions causing mild to moderate pain. NSAIDs effectively ease pain, but these agents have a ceiling analgesic effect; increasing the dose increases the risk of side effects without increasing the analgesic benefit. These agents should be used as second-line agents after acetaminophen in chronic or acute painful conditions, and low doses should be used. Narcotics may be necessary for acutely painful conditions and chronic conditions refractory to acetaminophen or NSAIDs. The common side effect of constipation from these agents can be problematic, and older patients need to be instructed to exercise regularly, eat high-fiber foods or supplements, and keep well hydrated. Because these agents may decrease cognition in elders, starting with low doses and titrating upward as needed is particularly important.

Psychosocial Issues The problems of drug dependence and alcohol abuse should be considered when treating elders. Alcohol dependence is a factor in 14% of elders who come to the emergency department and is more prevalent than suspected.[] These patients often present with gastrointestinal complaints or after falls or other trauma. Iatrogenic dependence on prescription drugs, particularly sedative-hypnotics, also is more prevalent than suspected. The routine use of sedative-hypnotics in elders should be avoided, and duration of their use when necessary should be limited. Dependence on these drugs may cause decreased cognition, and withdrawal from these agents can be life-threatening. Psychiatric disease in elders often manifests in atypical fashion. Depression, a common problem, may manifest as agitation, anxiety, and somatic complaints, in addition to the typical depressive symptoms.[] Depression often follows chronic illness, loss of physical mobility, diminished cognitive function, bereavement from the death of a spouse or long-time friend, and financial pressures, all of which are common features of old age.[] Social isolation and loss of independence produce a sense of helplessness and hopelessness that may result in suicidal ideation or action. Certain types of depression, such as “late-life delusional depression” and involutional depression, occur exclusively in old age. In addition, depression may be caused by medication side effects or rever-sible physiologic conditions (e.g., thyroid disease, malnutrition). Elders often respond to pharmacologic treatment of depression but are prone to develop adverse effects from tricyclic antidepressants; selective serotonin reuptake inhibitors seem to be safer.[17] A phenomenon known as sundown syndrome occurs in elderly demented patients, who become highly agitated and disoriented after dark when visual sensory input is diminished and the environment becomes unfamiliar.[18]

EVALUATION AND CLINICAL FEATURES The evaluation of elders can be frustrating and difficult. Elders living independently have an average of 3 medical problems, which increases to 10 for elders living in care facilities. Underlying illnesses complicate the evaluation. Studies have shown that many emergency physicians are uncomfortable evaluating elders because managing an elderly patient with a specific complaint is significantly more difficult than managing the same problem in a younger patient. Use of ancillary services can be increased 50% in elders, most likely because of vague or atypical presentations and complicated medical backgrounds.

History Obtaining a medical history from an elderly patient requires meticulous and painstaking work. Cognitive and physical deficits must be recognized, and the emergency physician often needs to be creative and thorough. Cognitive deficits may compromise an elder's recall and result in an inaccurate medical history. Enlisting family members, consulting with the patient's primary care physician, and reviewing past medical records may be necessary. Particular attention should be paid to past medical and surgical problems and to the patient's current medications, including over-the-counter and herbal preparations. Physical deficits also may impede the history taking process. Sequelae from previous strokes (e.g., aphasia) are usually obvious. In addition, elders often have difficulty hearing, which impairs communication and can lead to dangerous misunderstandings. Because elders tend to lose the ability to hear high-pitched sound earlier than other ranges, physicians should lower the pitch of their voice and speak loudly to ensure that the patient can hear questions, always bearing in mind the patient's privacy. Because hearing loss can be embarrassing for the patient, the physician should address the issue with sensitivity to allow for adequate communication while maintaining the patient's dignity.

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Physical Examination Because of the physiologic changes that occur with aging, elders may have vague complaints that could be the only indication of a life-threatening medical or surgical problem. The physical examination of an elder should be more thorough than that of a younger patient with a similar complaint. The physician also must be aware that the physical examination may be misleadingly benign in an elder, despite the presence of a potentially lethal illness. In addition to physiologic changes that may affect the physical examination, medications may alter the response of elders to physiologic stressors. Antihypertensives in particular may alter the patient's ability to mount tachycardia in response to hypovolemia or sepsis (p -blockers) or may predispose the patient to hypotension. Fever or lack of fever in elders is significant. Of elders with a serious infection, 30% present with a blunted or absent fever response.[19] The temperature measurement must be accurate; oral temperatures may be spuriously low in elders, so rectal temperatures should be taken when fever is uncertain in a patient with a possible infectious disease. When fever is present, elders are much more likely to have a serious (nonviral) infection than younger patients.[20] Of febrile elders presenting to an emergency department, 89% prove to have an infectious disease. About one third are respiratory tract infections; one fifth, urinary tract infections; and nearly 20%, bacteremia or sepsis.[20] Fever in an elder must be taken seriously, with appropriate ancillary testing and a low threshold for admission. A lack of fever does not exclude infection, and emergency physicians should consider radiographic and laboratory tests in elders with vague complaints.

DIAGNOSTIC STRATEGIES More diagnostic tests tend to be performed in elders presenting to the emergency department than in their younger counterparts.[4] Increased use of resources is often necessary because the accuracy of diagnosis needs to be higher in elders because they have less reserve. Because elders may present with only vague complaints despite having significant medical or surgical problems, this increased use of resources seems warranted.

SPECIFIC DISORDERS Myocardial Infarction The incidence of atypical presentation of myocardial infarction increases with increasing age.[] In patients older than age 85, atypical presentation of myocardial infarction may be typical, and a lack of chest pain may be the rule. Studies show, however, that only 2% to 6% of elders with myocardial infarction have an asymptomatic presentation.[22] A painless myocardial infarction is more common with increasing age and occurs in women more often than men. Sudden onset of dyspnea may be the presenting complaint in 35% to 59% of elders with myocardial infarction. Other presenting complaints include syncope, flulike symptoms, nausea, vomiting, confusion, and weakness. The prognosis for myocardial infarction in elders who present atypically is the same as for elders who present typically; atypical presentations are not more benign.

Infections Elderly patients are more prone to infectious diseases than younger patients, with greater morbidity and higher mortality from these diseases. Common infections occur regularly, but aging causes this patient population to be more susceptible to unusual organisms. Although immunosenescence is a contributing factor, predisposing illnesses and institutionalization are more significant causes of this increased risk of infection. Hospitalization carries the risk of acquiring nosocomial infections. Instrumentation and catheterization, also significant risk factors for acquiring infectious diseases, should be kept to a minimum, and early ambulation and discharge should be a goal. Evaluating infections may be difficult because 48% of elders with proven bacterial infections do not have a fever.[20] In addition, the sensitivity of an elevated white blood cell count and elevated band count is poor, about 44% and 32%, respectively.[19] The absence of these findings does not eliminate the presence of sepsis. Several infections, particularly pneumonia, urinary tract infections, and sepsis, occur more often in elders.[] Pneumonia is one of the 10 leading causes of hospitalization and death in elders.[2] With decreased vital capacity, lung and airway compliance, ventilatory drive, and ciliary function, the infection takes hold more easily in these patients. Pneumonia likely results from decreased cough response, decreased ciliary function, and increased esophageal reflux with microaspiration. Pneumococcus is still a common cause of pneumonia, but gram-negative organisms also are common, as are mixed infections. Reactivation of tuberculosis also must be considered in this age group.

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Urinary tract infections have a high incidence in the elderly. The incidence of bacteriuria is 20% in men older than age 70 and 20% in women ages 65 to 70, increasing to 23% to 50% in women older than age 80. Laxity of the pelvic floor and urinary incontinence are significant risk factors in women; prostate enlargement is the most common cause in men. The incidence of urinary tract infections increases dramatically in patients with chronic indwelling catheters.

Abdominal Pain Abdominal pain may be the most difficult presenting complaint to evaluate in elderly patients. Despite this difficulty, most patients have a specific diagnosis made in the emergency department. Two thirds of elders with abdominal pain are admitted, and nearly one fifth go directly to the operating room from the emergency department. The differential diagnoses ( Table 181-2 ) of abdominal pain in elders differ significantly from those in younger patients, particularly in regard to the number of serious and potentially life-threatening causes. More than 60% of the causes of abdominal pain in elders are surgical in nature, a rate nearly double that of younger patients. In addition, these surgical causes have a 10-fold higher risk of mortality compared with younger patients.[25] Table 181-2 -- Differential Diagnoses of Abdominal Pain in Elderly Patients Disorder

Incidence (%)

Cholecystitis/biliary colic

12–41

Nonspecific abdominal pain

9.6–23

Appendicitis

2.5–15.2

Obstruction

7.3–14

Hernia

4–9.6

Perforation

2.3–7

Pancreatitis

2–7.3

Diverticular disease

3.4–7

Because of the physiologic changes of aging, even life-threatening causes of abdominal pain may present with few or no alarming findings, and elders may complain of vague abdominal pain despite the occurrence of a catastrophic process. The complication rates of typically benign processes in younger patients are dramatically higher in older patients. With aging, the abdominal musculature decreases, and patients are less able to manifest guarding and rebound. In addition, the omentum shrinks and is less able to contain intra-abdominal processes. Atherosclerotic disease, with its resultant decrease in blood flow, causes increased perforation rates in diseases such as cholecystitis and appendicitis. This increased rate of vascular disease also contributes to higher rates of vascular causes of abdominal pain, such as mesenteric ischemia and leaking or ruptured abdominal aortic aneurysms. The high prevalence of gallstones in elders leads to an increased risk of cholecystitis. Because of vague presentation and high rate of serious disease, evaluating an elderly patient with abdominal pain often requires an extensive battery of laboratory and radiographic tests. Elderly patients with potentially catastrophic intra-abdominal processes may not present with a fever or an elevated white blood cell count,[] so adjunctive tests, such as ultrasonography, computed tomography, radionuclide studies, and occasionally angiography, may be important. Because many elderly patients with abdominal pain have a serious disease, the patient should be considered for admission and close observation if the diagnosis is still unclear after a workup. If the patient is not admitted, a prolonged period of emergency department observation or re-evaluation within 12 hours is prudent.

Major Trauma Major trauma in elders (see also Chapter 37 ) is relatively uncommon, constituting 8% to 15% of cases in major trauma databases; however, elder trauma patients experience higher mortality and poorer functional recovery for a given trauma score compared with younger patients.[] In any elderly trauma patient, the circumstances leading to the injury need to be determined. Motor vehicle crashes, particularly crashes involving a single vehicle, may result from transient loss of consciousness from dysrhythmias, syncope, medication side effects, transient ischemic attacks, strokes, or myocardial infarctions. These serious

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medical problems require simultaneous diagnosis and treatment in the setting of trauma and at times may take priority over the trauma assessment. The presence of comorbid illness and the limited physiologic reserve in the cardiopulmonary and renal systems often complicate the trauma resuscitation in this age group. More aggressive ventilatory support and early use of invasive hemodynamic monitoring are indicated to guide volume resuscitation.[31] Shock is poorly tolerated in elders because hemodynamic compensation is limited, and end-organ failure occurs earlier. Certain injuries are more common and more severe in elders.[32] A subdural hematoma may occur after relatively trivial head trauma, and chronic subdural hematoma may present as progressive dementia with only subtle “hard” neurologic findings. Increasing ankylosis of the spine, osteoarthritis, and decreased bone density as a result of osteoporosis make the geriatric cervical spine more susceptible to fracture. Preexisting pulmonary pathology and a brittle thoracic wall account for the greater severity of pulmonary contusions and the higher incidence of rib fractures and resultant complications (e.g., atelectasis, pneumonia). Skeletal fractures are more common and lacerations of atrophic skin are more difficult to repair and more prone to infection. This thin skin also is prone to decubitus breakdown in patients who are immobile, even for short periods (e.g., spinal immobilization on a backboard).

PREVENTIVE CARE Immunizations Pneumonia, influenza, accidents, and adverse events are among the top seven causes of death in elders.[2] These conditions account for 15% of admissions and are potentially preventable. Annually, 36,000 adults die of complications from influenza and pneumococcal infections, and most of these deaths occur in elders. Immunization could reduce the incidence of clinical and serologic influenza by half in this patient population. The Centers for Disease Control and Prevention (CDC) has set a goal of an 80% immunization rate for patients in high-risk groups, including elders. Studies have shown that the actual vaccination rate falls significantly below this goal; in patients 65 years old, 66% and 62% were vaccinated for influenza and pneumococcus, with the lowest rates among nonwhite ethnic groups and people of lower socioeconomic means.[33] To combat this problem, the CDC has recommended that potential vaccination sites be extended to include walk-in clinics and emergency departments. Data suggest that half of elders who had not been hospitalized or seen their primary care physician in the previous 3 years had made at least one visit to an emergency department, and many are willing to be vaccinated in the emergency department.[34] Despite this information, controversy exists regarding vaccination of elders in the emergency department. In one study, half of all emergency physicians surveyed were reluctant to give vaccinations in the emergency department, citing time constraints and their concern over delivering primary care in the emergency department. In this same study, 89% of emergency physicians rarely or never administer influenza vaccine, and 94% rarely or never give pneumococcal vaccine.[34] In addressing the feasibility of vaccinating elders in the emergency department, another study found that 50% to 60% of eligible elders want to be and are able to be vaccinated during an emergency department visit.[35] Considering the low threshold we have in the emergency department for administering another vaccine, the tetanus vaccine, it seems feasible that influenza and pneumococcal vaccination programs could be set up relatively easily in the emergency department and could save lives.

Falls In combination with vaccinations, education about accident prevention in the home could have a considerable impact on the overall morbidity and mortality in elders; falls and adverse events are the seventh leading cause of death in elders.[2] A primary care or social service provider more appropriately supplies this instruction; however, the emergency department may be an additional resource for providing educational services to elders on a case-by-case basis, particularly in reference to any specific incident that led to the need for emergency care. Studies suggest that the leading cause of falls in elders is related to the use of pharmacologic agents, often prescription drugs.[36] Reviewing the patient's medications, looking for agents that might cause decreased cognition or dehydration, and addressing the need for these agents with the patient and the primary care provider could decrease significantly the risk for falls and resultant morbidity and mortality. In addition, informing the patient's primary care provider that the patient has fallen may facilitate education by the primary physician.

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KEY CONCEPTS • • •

• • • •

Evaluation of elders often requires patience and diligence, including accessing other resources. Polypharmacy and side effects of prescription and nonprescription drugs often occur in elderly patients and should be considered in their evaluation. Physiologic changes that occur with aging may make evaluation of elders difficult and must be taken into account. A more in-depth evaluation, including ancillary testing, than one would perform for a younger patient with the same complaint is often indicated. Elderly patients may have a blunted fever response to infection and a less elevated white blood cell count. Myocardial infarction frequently presents atypically in elderly patients. Abdominal pain in an elderly patient often is caused by a surgical condition and may require an extensive workup in the emergency department, including radiographic studies. Elderly trauma patients have a higher morbidity and mortality than their younger counterparts because of exacerbation of underlying medical problems.

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REFERENCES 1. U.S. Bureau of the Census : The 65 Years and Over Population: 2000. Census 2000 Brief, Washington, DC, U.S. Government Printing Office, 2000. 2. Desai MM, Zhang P: Surveillance for morbidity and mortality among older adults—United States, 1995-1996. MMWR Morb Mortal Wkly Rep1999;48:7. 3. Strange GR, Chen EH: Use of emergency department by elder patients: A five-year follow-up study. Acad Emerg Med1998;5:1157. 4. Aminzadeh F, Dalziel WB: Older adults in the emergency department: A systematic review of patterns of use, adverse outcomes, and effectiveness of interventions. Ann Emerg Med2002;39:238. 5. Health-related quality of life among adults with arthritis—behavioral risk factor surveillance system, 11 states, 1996-1998. MMWR Morb Mortal Wkly Rep2000;29:366. 6. Kaufman DW: Recent patterns of medication use in the ambulatory adult population of the United States: The Slone Survey. JAMA2002;287:337. 7. Willcox SM, Himmelstein DU, Woolhandler S: Inappropriate drug prescribing for the community dwelling elderly. JAMA1994;272:292. 8. McDonnell PJ, Jacobs MR: Hospital admissions resulting from preventable adverse drug reactions. Ann Pharmacother2002;36:1331. 9. Gurwitz JH: Incidence and preventability of adverse drug events among older persons in the ambulatory setting. JAMA2003;239:1107. 10. Jones RH, Tail CL: Gastrointestinal side effects of NSAIDs in the community. Br J Clin Pract1995;49:67. 11. Buffum M, Buffum C: Nonsteroidal anti-inflammatory drugs in the elderly. Pain Manag Nurs2000;1:40. 12. Ganry O: Prevalence of alcohol problems among elderly patients in a university hospital. Addiction 2000;95:107. 13. Friedmann PD: The effect of alcohol abuse on the health status of older adults seen in the emergency department. Am J Drug Alcohol Abuse1999;25:529. 14. Casey DA: Depression in the elderly. South Med J1994;87:559. 15. Muller-Spahn F, Kock C: Clinical presentation of depression in the elderly. Gerontology1994;40:10. 16. Jorm AF: The epidemiology of depressive states in the elderly: Implications for recognition, intervention, and prevention. Social Psychiatry Psychiatr Epidemiol1995;30:53. 17. Naranjo CA: Recent advances in geriatric psychopharmacology. Drugs Aging1995;7:184. 18. Little JT: Sundown syndrome in severely demented patients with probable Alzheimer's disease. J Geriatr Psychiatry Neurol1995;8:103. 19. Norman DC: Fever in the elderly. Clin Infect Dis2000;31:148. 20. Marco CA: Fever in geriatric emergency patients: Clinical features associated with serious illness. Ann Emerg Med1995;26:18. 21. Tresch DD: Comparison of elderly and younger patients with out-of-hospital chest pain: Clinical characteristics, acute myocardial infarction, therapy, and outcomes. Arch Intern Med1996;156:1089. 22. Gregoratos G: Clinical manifestations of acute myocardial infarction in older patients. Am J Geriatr Cardiol2001;10:345. 23. Beck-Sague C, Benerjee S, Jarvis WR: Infectious diseases and mortality among US nursing home residents. Am J Public Health1993;83:1739. 24. Michielsen W: Bacterial surveillance cultures in a geriatric ward. Age Ageing1993;22:221. 25. Marco CA: Abdominal pain in geriatric emergency patients: Variable associated with adverse outcomes. Acad Emerg Med1998;5:1163. 26. Potts FE IV, Vukov LF: Utility of fever and leukocytosis in acute surgical abdomens in octogenarians and beyond. J Gerontol A Biol Sci Med Sci1999;54:M55. 27. Parker JS, Vukov LF, Wollan PC: Abdominal pain in the elderly: Use of temperature and laboratory testing to screen for surgical disease. Fam Med1996;28:193. 28. Knudson MM: Mortality factors in geriatric blunt trauma patients. Arch Surg1994;129:448. 29. Schiller WR, Knox R, Chleborad W: A five-year experience with severe injuries in elderly patients. Accid Anal Prev1995;27:167. 30. Zietlow SP: Multisystem geriatric trauma. J Trauma1994;37:985.

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31. DeMaria EJ: Evaluation and treatment of the elderly trauma victim. Clin Geriatr Med1993;9:461. 32. Lonner JH, Koval KJ: Polytrauma in the elderly. Clin Orthop1995;318:136. 33. Centers for Disease Control and Prevention (CDC) : Public health and aging: Influenza vaccination coverage among adults aged > or =50 years and pneumonococcal vaccination coverage among adults aged > or =65 years—United States, 2002. MMWR Morb Mortal Wkly Rep2003;52:987. 34. Wrenn K, Zeldin M, Miller O: Influenza and pneumococcal vaccination in the emergency department: Is it feasible?. J Gen Intern Med1994;9:245. 35. Rodriguez RM, Baraff L: Emergency department immunization of the elderly with pneumococcal and influenza vaccines. Ann Emerg Med1993;22:1729. 36. Ensrud KE: Central nervous system-active medications and risk for falls in older women. J Am Geriatr Soc2002;10:1629.

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Section IV - The Patient with Compromised Immune Function Chapter 182 – The Immunocompromised Patient Michael J. Burns Mark I. Langdorf

PERSPECTIVE Infections in immunocompromised patients are more common and severe, progress more rapidly, are more often fatal, and are caused by a wider variety of organisms than in individuals with intact immunity.[] This chapter presents an approach to the immunocompromised patient that focuses on presentation, diagnosis, and emergency therapy ( Table 182-1 ). Table 182-1 -- Incidence of Compromised Immune Function in Groups of Emergency Department Patients Condition Incidence (%) Old age Diabetes Alcoholism Drug abuse Cancer Transplantation Malnutrition HIV/AIDS Immunosuppressive drugs Burns Renal or hepatic failure Autoimmune disorders

10–20 5 10–20 5–10 5 38°C), shortness of breath, hypoxia, hypotension, poorly controlled hypertension, or new dysrhythmia should be admitted. Chest pain is rarely related to cardiac ischemia because the denervated heart is incapable of producing angina.[27] Accelerated atherosclerosis of the graft vessels is the hallmark of chronic rejection, but the ischemia is manifest as CHF, ventricular dysrhythmias, hypotension, syncope, or sudden death.[] A CMV infection appears to be a risk factor for accelerated atherosclerosis.[]

Drug Toxicity Lifelong immunosuppression is required in these patients. Most centers use a three-drug regimen of cyclosporine, prednisone, and azathioprine. Each drug has a potential for toxicity, and the combination of cyclosporine and prednisone worsens the hyperlipidemias common in many of these patients.[] Rarely, cyclosporine toxicity can result in a neurotoxic syndrome of seizures, confusion, cortical blindness, and quadriplegia, even progressing to coma. Seizure management is with standard anticonvulsants.[]

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Rejection Acute rejection occurs in 75% to 85% of patients within the first 3 months. Its manifestations may be subtle with cyclosporine included in the immunosuppressive regimen. Previously, rejection was obvious, with decreased QRS voltage, a new S3 heart sound, new-onset CHF, or atrial dysrhythmias. Currently, these features are present only during episodes of severe rejection, and the diagnosis of rejection is made by endomyocardial biopsy showing lymphocyte infiltration or myocyte necrosis.[] Because most episodes of early or mild rejection are asymptomatic, frequent biopsies are performed to monitor the success of the immunosuppressive regimen.[] Acute rejection is treated with increased doses of corticosteroids (methylprednisolone, 500 to 1000 mg/day) and cyclosporine or with OKT3 or antithymocyte globulin. Immunosuppression is continued lifelong, with endocardial biopsies at least every 3 months.[] The transplanted heart maintains a rate of 100 to 110 beats/min without vagal parasympathetic tone. The electrocardiogram typically demonstrates two P waves ( Figure 183-5 ). One wave is from the native sinus node in the posterior right atrium, which is left in place with its vena caval connections during surgery. The second P wave is from the donor sinoatrial node, which should conduct to the ventricles as usual with a normal PR interval. The heart rate can increase with exercise or stress through the effects of endogenous catecholamines, up to 70% of maximum for age. Exogenous pressor drugs work well in the transplanted heart. Upregulation of p -adrenergic receptors appears to occur in the graft, with a slightly enhanced response to norepinephrine and isoproterenol.[] Antihypertensive agents can be used to treat hypertension, even of crisis proportions, as in the nontransplant patient. Atropine is ineffective at increasing the sinus node rate or relieving atrioventricular block.

Figure 183-5 A 68-year-old m ale status postheterotopic heart transplant; native heart rate of 55 and donor heart rate of 75 beats per m inute.

Infection Infection in heart transplant patients has many causes. One fourth of deaths after transplantation result from infection. The most vulnerable period is the first 3 months, when immunosuppression is maximal. Although one third of patients have a major infection develop in the first year, life-threatening infection after 1 year is rare.[] In the first month, nosocomial infection predominates, with the usual gram-positive and gram-negative bacteria. After the first 3 months, patients experience an overall 20% per year rate of infection. The most common skin infection is herpes zoster; high-dose acyclovir limits cutaneous and visceral dissemination, even when begun more than 3 days after the onset of rash. Nausea, vomiting, or diarrhea should prompt a search for CMV by culture and serologic testing.[] All heart transplant patients with fever should be presumed to have a new infection. An aggressive diagnostic workup, including blood and urine cultures, computed tomography (CT) scan, lumbar puncture, and bronchoscopy, should begin in the emergency department. In addition, complete blood count, glucose, serum chemistries, blood urea nitrogen and creatinine, chest radiograph, and electrocardiogram are recommended. In one series of 131 emergency department visits by such patients, 23 patients were admitted with a diagnosis of “rule out sepsis” and 12 (52%) had an infecting organism identified.[15] Any new headache with or without visual changes may be the first symptom of meningitis or brain abscess, and a CT scan of the head and a lumbar puncture should be obtained. Fever, lethargy, headache, altered mental status, or seizures are presenting signs of Listeria, cryptococcal meningitis, Toxoplasma gondii, or brain abscesses from Nocardia or Aspergillus. A more definitive diagnosis can often be made through biopsy of a mass lesion or drainage of an abscess. This often obviates the need for lumbar puncture. Aseptic meningitis occurs in 10% to 14% of patients treated with OKT3 approximately 6 to 10 days after therapy.[]

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Because of the attendant risk of endocarditis, antibiotic prophylaxis should be provided for invasive procedures likely to cause bacteremia, such as abscess drainage and urethral catheterization. Endotracheal intubation requires no such prophylaxis. VZV immune globulin is recommended as soon as possible when seronegative patients are exposed to chickenpox or herpes zoster.[]

Liver Transplant Liver transplants have 1- and 3-year survival rates of 86% and 76%, respectively.[26] They represent the second most frequently performed solid-organ transplant procedure. Complications are common, and loss of function of the graft organ is rapidly life threatening. Postoperative complications include intra-abdominal hemorrhage, vascular thrombosis, and biliary leaks or obstructions.[18]

Anatomic Considerations The typical liver transplant is connected to its host by five anastomoses ( Figure 183-6 ). The vessels are connected first, allowing organ reperfusion. The biliary system is then reconstructed and often stented with a T tube to prevent stenosis. In the early posttransplantation period, T tubes may be replaced if restenosis develops.

Figure 183-6 Typical anastom oses of an orthotopic liver transplant. ((From Powelson JA, Cosim is AB, Liver transplantation. In Ginnes LG, Cosim i AB, Morris PJ [eds]: Transplantation. Malden, Mass, Blackwell Science, 1999, p 352.)Blackwell Science)

Rejection Liver transplant rejection is common despite immunosuppressive therapy, occurring in up to one third of patients. Rejection often begins 1 to 2 weeks after surgery, with fever, right upper quadrant pain, and elevated bilirubin and transaminases. Leukocytosis may occur but is nonspecific. Related conditions that simulate graft rejection are mechanical biliary obstruction, primary nonfunctioning graft, ischemia from clotting of vascular anastomoses, viral hepatitis, CMV infection, drug hepatotoxicity, and recurrent primary disease.[] As soon as transplant rejection is suspected, treatment with high-dose methylprednisolone should begin. Hospitalization is routine. If this treatment fails to diminish the rejection episode, OKT3 monoclonal antibodies are again used in addition to polyclonal antilymphocyte globulin.[40]

Infection The risk of infection is highest in the postoperative recovery period. After the first postoperative month, opportunistic infections replace the common postsurgical complications. Viral (CMV, HSV), fungal ( Aspergillus, Candida, Cryptococcus), protozoan (Pneumocystis, Toxoplasma), and unusual bacterial ( Nocardia, Legionella, Listeria) infections occur. In addition, liver transplant patients are at risk for cholangitis because a biliary stent is left in place for many weeks and colonization by staphylococcal species, enterococci, and gram-negative organisms is common. Subsequent injury to the graft during diagnostic biopsy or cholangiography can cause clinical cholangitis or liver abscess. Because immunosuppressive therapy must be continued indefinitely, these patients remain at risk for opportunistic infection for the rest of their lives.[]

Kidney (Renal) Transplant With survival rates of 96% at 1 year and 91% at 3 years, renal transplants have proved highly successful. They are the most common solid-organ transplants in the United States.[26] Injury of the transplanted kidney is rare, despite its location in the retroperitoneal area of the anterior pelvis, where it may be at risk from direct blows as well as seatbelt injuries.[25]

Infection The classic example of bacterial infection in transplanted organs is pyelonephritis in renal allografts. It often

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occurs in the first month after surgery during high-dose immunosuppression. This timing presents an increased risk of sepsis. Responsible organisms are the usual gram-positive organisms associated with wound infections and gram-negative organisms from the gut. Pyelonephritis occurs in 35% of patients during the first 4 months but can be prevented with prophylactic antibiotics. All patients with a transplant who have pyelonephritis are admitted to the hospital for aggressive antibacterial therapy.[] Hepatitis C virus infection is the most common cause of hepatitis in renal transplant patients. It may be transferred to the recipient by blood transfusion or through the donor organ because pretransplantation antibody testing is a poor predictor of latent hepatitis C virus infection. Liver disease develops in approximately 50% of seropositive patients, occurring approximately 4 months after transplantation. Most patients develop chronic hepatitis, with accompanying immune defects and susceptibility to sepsis and spontaneous bacterial peritonitis. No specific effective treatment is available for hepatitis C virus infection. Pretransplantation screening with newer techniques is the only current avenue of prevention.[]

Rejection Early kidney transplant rejection is mediated through attack by T lymphocytes against antigenic donor tissues, including cytotoxic CD8 and CD4 cells, but B lymphocytes, natural killer cells, and macrophages also infiltrate the foreign tissues. The B lymphocytes manufacture specific antibodies, which results in microvascular lesions impairing perfusion. Chronic transplant rejection occurs after several years of adequate function and is a result of nephrosclerosis. This process involves proliferation of the vascular intima of renal vessels with a marked decrease in the lumen size. Systemic hypertension ensues as the graft fails from ischemia and tubular and glomerular atrophy.[46] With cadaveric kidney transplants, histocompatibility differences are almost universal and routinely require long-term immunosuppressive therapy. Immunosuppression is accomplished with a combination of azathioprine, prednisone, and cyclosporine. Azathioprine inhibits both DNA and RNA synthesis, which inhibits lymphoid cell proliferation by halting mitosis while making existing cells unable to respond to antigen exposure with messenger RNA production. Prednisone is begun at a high dose immediately after transplantation but tapered rapidly to minimize interference with wound healing and reduce wound infection. On diagnosis of acute rejection, high-dose methylprednisolone (500 to 1000 mg) is begun daily and continued for 3 days. After 6 to 12 months, many patients only need lower doses (10 to 20 mg/day).[] Clinically, renal graft rejection arises as fever, swelling and tenderness over the allograft, and decreased urine output. Early therapy can save the graft. A subtle rise in serum creatinine should prompt great concern. Renal ultrasonography should be performed to rule out obstruction, abscess, and perirenal collections of blood, pus, or lymph. Early consultation with the nephrologist is prudent.

Lung Transplant The lung may be transplanted alone or in combination with the heart, with 1-year survival rates of 76% and 56%, respectively.[26] Lung transplants are usually done unilaterally, except for cystic fibrosis. Inequity of lung sounds is to be expected. There is no published experience with lung injury after transplantation. Comparison of chest radiography with preinjury studies is critical in the evaluation of trauma. Chest tube placement on the transplanted side may be difficult because of adhesions and loculations.[25]

Rejection Although still rare, lung transplantation is increasing in frequency; more than 800 are performed annually in the United States. Most patients develop early rejection, and 25% to 40% have chronic rejection. An episode of acute rejection can occur as early as a few days after transplantation or as late as several years. Clinically, the patient presents with cough, dyspnea, and fever. Rales and rhonchi are heard on lung examination, with deterioration in oxygenation and pulmonary function. Early rejection is often accompanied by infiltrates on the chest radiograph. When rejection occurs more than a month after transplantation, 75% of radiographs are normal or unchanged. The diagnosis of rejection is made by transbronchial biopsy showing lymphocytic infiltration.[] Suspected episodes of acute rejection are treated with high-dose methylprednisolone (500 to 1000 mg/day). This is successful in reversing most episodes, but OKT3 can be used in refractory cases.[49] Chronic lung transplant rejection is a leading cause of late morbidity and mortality. Antecedent acute rejection and CMV pneumonia are risk factors. Pathologically, vascular sclerosis and progressive limitation

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to airflow result from obliterative bronchiolitis. Rejection can occur several years after transplantation, but the mean time to onset is 8 to 12 months. Clinically, this rejection mimics an upper respiratory infection or bronchitis. If dyspnea is a component of the presenting complaint, a search for transplant rejection should be initiated.[] Chronic rejection is treated with high-dose methylprednisolone (500 to 1000 mg/day), with the first dose begun in the emergency department. Antilymphocyte antibodies are used as well, but relapse of the rejection episode is common.

Infection Transplanted lungs are highly susceptible to pneumonia because they are colonized by bacteria during the ventilator stage of the brain-dead donor. After transplantation, diminished mucociliary clearance, decreased cough reflex (because the transplanted lung is denervated), and defective function of alveolar macrophages are present. The most common infections are caused by gram-negative bacteria, especially Pseudomonas and Staphylococcus aureus. Antibiotic therapy should be aggressively directed toward any pathogenic bacteria cultured from the tracheobronchial tree. On long-term follow-up, most pneumonias are gram negative, but community-acquired infections occur as well. Pneumocystis pneumonia is uncommon because of routine prophylaxis with TMP-SMX.[] CMV pneumonia is the most common opportunistic pulmonary infection after lung transplantation. Patients are at highest risk between 3 weeks and 4 months. Clinically, CMV infection closely resembles transplant rejection; tissue biopsy and viral culture are required to differentiate the two entities. Treatment with ganciclovir is effective. Colonization by Candida is common, but not invasive disease. Aspergillus provides the most significant fungal threat to the transplanted lung. Reactivation of tuberculosis is rare.[]

Pancreas Transplant The pancreas may be transplanted singly or in combination with a kidney, typically secondary to diabetes. Pancreatic transplants have a high complication rate, with 1-year graft survival rates as low as 72%.[26] Because the exocrine functions of the allograft pancreas are usually drained into the bladder, genitourinary complaints are also common. Duodenocystostomy fistula may form in the early posttransplantation period. The clinical findings are abdominal pain, tenderness, hyperamylasemia, leukocytosis, and elevated serum creatinine. Other types of pancreatic transplant complications include urinary tract infections, hematuria, reflux pancreatitis, rejection, and pancreatic graft thrombosis.[] Anatomic considerations are important when these patients suffer major trauma because pancreas transplants are placed in the pelvis overlying the iliac vessels. Because exocrine secretions are drained into the bladder for excretion, patients have a chronic non–anion gap acidosis through loss of bicarbonate into the bladder. This condition should not be confused with lactic acidosis. These trauma patients should not require exogenous insulin unless the graft is injured. Positive amylase on peritoneal lavage (CT is recommended if the patient is stable) can result from either native organ or graft trauma or from a ruptured bladder. CT scanning should be done with rectal contrast in addition to IV and oral contrast to better define the native and transplanted pelvic organs.[25] Islet cell transplantation is under investigation as a means to treat diabetes mellitus.[55] This procedure is in its infancy, but, if successful, it may negate the need for future pancreas transplants and the resultant complications.

DISPOSITION Patients with solid-organ transplants presenting to the emergency department have a much higher than average rate of hospitalization.[] Because of the insidious nature of the diseases affecting this immunosuppressed population, a thorough approach to evaluation is warranted in all patients. If organ rejection, infection, or drug toxicity is evident, local transplantation specialists should be consulted. Physicians without significant transplant experience should notify the patient's transplant center to obtain consultation and coordinate follow-up care. Patients who are discharged require careful instructions and close follow-up.

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REFERENCES 1. McCaig LF, Burt CW: National Hospital Ambulatory Medical Care Survey: 2001 emergency department summary. Adv Data2003;335:1. 2. Kochanek KD, Smith BL: Deaths: Preliminary data for 2002. Natl Vital Stat Rep2004;52:1. 3. Karcz A: Malpractice claims against emergency physicians in Massachusetts: 1975-1993. Am J Emerg Med1996;14:341. 4. Pope JH: Missed diagnoses of acute cardiac ischemia in the emergency department. N Engl J Med 2000;342:1163. 5. Silverstein MD: Trends in the incidence of deep vein thrombosis and pulmonary embolism: A 25-year population-based study. Arch Intern Med1998;158:585. 6. Lorell BH: Pericardial disease. In: Brunwald E, ed.Heart Disease: A Textbook of Cardiovascular Medicine, 5th ed. Philadelphia: WB Saunders; 1997: 1478-1534. 7. McGhee S: Evidence-Based Physical Diagnosis, Philadelphia, WB Saunders, 2001. 8. Goodacre S, Locker T, Morris F, Campbell S: How useful are clinical features in the diagnosis of acute, undifferentiated chest pain?. Acad Emerg Med2002;9:203. 9. Panju AA, Hemmelgarn BR, Guyatt GH, Simel DL: Is this patient having a myocardial infarction?. JAMA 1998;280:1256. 10. Klompas M: Does this patient have an acute thoracic aortic dissection?. JAMA2002;287:2262. 11. Lee TH: Acute chest pain in the emergency room: Identification and examination of low-risk patients. Arch Intern Med1985;145:65. 12. Kline J, Wells P: Methodology for a rapid protocol to rule out pulmonary embolism in the emergency department. Ann Emerg Med2003;42:266. 13. Eichinger S: Symptomatic pulmonary embolism and the risk of recurrent venous thromboembolism. Arch Intern Med2004;164:92. 14. Clinical policy: Critical issues in the evaluation and management of adult patients presenting with suspected pulmonary embolism. Ann Emerg Med2003;41:257. 15. Ohman EM: Cardiac troponin T levels for risk stratification in acute myocardial ischemia. N Engl J Med 1996;335:1333. 16. Clinical policy: Critical issues in the evaluation and management of adult patients presenting with suspected acute myocardial infarction or unstable angina. American College of Emergency Physicians. Ann Emerg Med2000;35:521. 17. Karras DJ, Kane DL: Serum markers in the emergency department diagnosis of acute myocardial infarction. Emerg Med Clin North Am2001;19:321.

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KEY CONCEPTS {, {, {, {, {,

The possibility of organ rejection, infection, or drug toxicity should be considered in all organ transplant patients who present to the emergency department. The symptoms and signs of significant medical problems are often subtle in transplant patients. A patient's inability to take oral immunosuppressants for even a single day should be considered an emergency condition. When infectious disease is evident, every effort should be made to administer the appropriate antibiotics as soon as possible. Unusual infectious etiologies should be considered. When prescribing care in the emergency department, the physician must be careful to avoid drug interactions and toxicity.

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REFERENCES 1. Dummer JS, Ho M: Infections in solid organ transplant recipients. In: Mandell GL, Bennett JE, Dolin R, ed. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Disease, 5th ed. Philadelphia: Churchill Livingstone; 2000: 3148-3156. 2. Rubin RH, Fishman JA: Infection in the organ transplant recipient. In: Ginns LC, Cosimi AB, Morris PJ, ed. Transplantation, Malden, Mass: Blackwell Science; 1999: 747-769. 3. Sweny P: Infection in solid organ transplantation. Curr Opin Infect Dis1993;6:412. 4. Sweny P, Burroughs AK: Infections in solid organ transplantation. Curr Opin Infect Dis1994;7:436. 5. Richardson WP: Glomerulopathy associated with cytomegalovirus viremia in renal allografts. N Engl J Med1981;305:57. 6. O'Grady JG: Cytomegalovirus infection and donor/recipient HLA antigens: Interdependent cofactors in pathogenesis of vanishing bile duct syndrome after liver transplantation. Lancet1988;2:302. 7. Rubin RH: The indirect effects of cytomegalovirus infection on the outcome of organ transplantation. JAMA1989;261:3561. 8. Grattan MT: Cytomegalovirus infection is associated with cardiac allograft rejection and atherosclerosis. JAMA1989;262:3561. 9. Benkerron M, Durandy A, Fischer A: Therapy for transplant-related lymphoproliferative disease. Hematol Oncol Clin North Am1993;7:467. 10. Pettersson E: Prophylactic oral acyclovir after renal transplantation. Transplantation1985;39:279. 11. Dallman MJ: Immunobiology of graft rejection. In: Ginns LC, Cosimi AB, Morris PJ, ed.Transplantation, Malden, Mass: Blackwell Science; 1999: 23-36. 12. Keown PA: Molecular and clinical therapeutics of cyclosporine in transplantation. In: Ginns LC, Cosimi AB, Morris PJ, ed.Transplantation, Malden, Mass: Blackwell Science; 1999: 101-112. 13. Harlan DM, Kirk AD: The future of organ and tissue transplantation: Can T-cell costimulatory pathway modifiers revolutionize the prevention of graft rejection?. JAMA1999;282:1076. 14. Halloran PF: Immunosuppressive agents in clinical trails in transplantation. Am J Med Sci1997;313:283. 15. Sternbach GL: Emergency department presentation and care of heart and heart/lung transplant recipients. Ann Emerg Med1992;21:1140. 16. Pratt PW, Ball GV: Gout: Clinical and laboratory features. In: Klippel JH, ed.Primer on the Rheumatic Diseases, Atlanta: Arthritis Foundation; 1997: 209-218. 17. Petri WA: Infections in heart transplant recipients. Clin Infect Dis1994;18:141. 18. Freeman L, Awad SH: Evaluation and management of solid organ transplant patients in the emergency department. Emerg Med Rep2004;25(2):11. 19. Walker RG: Steroids and transplantation. In: Ginns LC, Cosimi AB, Morris PJ, ed.Transplantation, Malden, Mass: Blackwell Science; 1999: 115-123. 20. Bungardner GL, Roberts JP: New immunosuppressive agents. Gastroenterol Clin North Am 1993;22:421. 21. Rayhill SC, Sollinger HW: Mycophenolate mofetil: Experimental and clinical experience. In: Ginns LC, Cosimi AB, Morris PH, ed.Transplantation, Malden, Mass: Blackwell Science; 1999: 147-162. 22. Parlevliet KJ, Schellekens PT: Monoclonal antibodies in renal transplantation: A review. Transplant Int 1992;5:234.pp 127-136. 23. Klintmalm GB: Tacrolimus. In: Ginns LC, Cosimi AB, Morris PJ, ed.Transplantation, Malden, Mass: Blackwell Science; 1999: 24. Gerber D, Bonham C, Thomson A: Immunosuppressive agents: Recent developments in molecular action and clinical application. Transplant Proc1998;30:1573. 25. Barone GW: Trauma management in solid organ transplant recipients. J Emerg Med1997;15:169. 26. Scientific Registry of Transplant Recipients website. Accessed at www.ustransplant.org April 17, 2004 27. Gao SZ: Acute myocardial infarction in cardiac-transplant recipients. Am J Cardiol1989;664:1092. 28. Hosenpud JD: Coronary artery disease after heart transplantation and its relation to cytomegalovirus. Am Heart J1999;138:S469. 29. Weis M, von Scheidt W: Cardiac allograft vasculopathy: A review. Circulation1997;96:2069.

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30. Wagoner LE: Management of the cardiac transplant recipient: Roles of the transplant cardiologist and primary care physician. Am J Med Sci1997;314:173. 31. Hunt SA, Schroeder JS: Managing patients after cardiac transplantation. Hosp Pract1989;24:83. 32. Cooper DK: Does central nervous system toxicity occur in transplant patients with hypocholesterolemia receiving cyclosporine?. J Heart Transplant1989;8:221. 33. Rubin AM: Transient cortical blindness and occipital seizures with cyclosporine toxicity. Transplantation 1989;47:572. 34. Velu T, Debusscher L, Stryckmans PA: Cyclosporine-associated fatal convulsions. Lancet1985;1:219. 35. Cainelli F, Vento S: Infections and solid organ transplantation rejection: A cause and effect relationship?. Lancet Infect Dis2002;2:543. 36. Taylor AJ, Bergin JD: Cardiac transplantation for the cardiologist not trained in transplantation. Am Heart J1995;129:578. 37. Miniati DN, Robbins RC, Reitz BA: Heart and heart-lung transplantation. In: Braunwald E, ed.Heart Disease: A Textbook of Cardiovascular Medicine, 6th ed. Philadelphia: WB Saunders; 2001: 615-630. 38. Borow KM: Cardiac and peripheral vascular responses to adrenoceptor stimulation and blockage after cardiac transplantation. J Am Coll Cardiol1989;14:1229. 39. Yusuf S: Increased sensitivity of the denervated transplanted human heart to isoprenaline both before and after beta-adrenergic blockade. Circulation1987;75:696. 40. Powelson JA, Cosimi AB: Liver transplantation. In: Ginns LC, Cosimi AB, Morris PJ, ed.Transplantation, Malden, Mass: Blackwell Science; 1999: 324-366. 41. Jain A: Immunosuppressive therapy. Surg Clin North Am1999;79:59. 42. Munoz SJ: Long-term care of the liver transplant recipient. Clin Liver Dis2000;4:691. 43. Savitsky EA, Uner AB, Votey SR: Evaluation of orthotopic liver transplant recipients presenting to the emergency department. Ann Emerg Med1998;31:507. 44. Patel R: Infections in recipients of kidney transplants. Infect Dis Clin North Am2001;15:901. 45. Rubin RH: Infectious disease complications of renal transplantation. Kidney Int1991;44:221. 46. Ponticelli C: Renal transplantation strengths and shortcomings. J Nephrol2001;14(Suppl 14):S1. 47. Lo A, Alloway RR: Strategies to reduce toxicities and improve outcomes in renal transplant recipients. Pharmacotherapy2002;22:316. 48. Glover FL: The past, present, and future of lung transplantation. Am J Surg1997;173:523. 49. Ginns LC, Wain JC: Lung transplantation. In: Ginns LC, Cosimi AB, Morris PJ, ed.Transplantation, Malden, Mass: Blackwell Science; 1999: 490-550. 50. Midthun DE: Medical management and complications in the lung transplant recipient. Mayo Clin Proc 1997;72:175. 51. Scott JP: Posttransplantation physiologic features of the lung and obliterative bronchiolitis. Mayo Clin Proc1997;72:170. 52. Hickey DP: Urological complications of pancreatic transplantation. J Urol1997;157:2042. 53. Stegall MD: Pancreas transplantation for the prevention of diabetic nephropathy. Mayo Clin Proc 2000;75:49. 54. Allen RM: Pancreas transplantation. In: Forsythe JLR, ed.Transplantation Surgery, London: WB Saunders; 1997: 55. Markmann JF: Insulin dependence following isolated islet transplantation and single infusions. Ann Surg 2003;237:741.pp 741-749.

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Section VI - The Alcoholic or Substance Abuse Patient Chapter 184 – Alcohol-Related Disease David B. McMicken John T. Finnell

PERSPECTIVE Epidemiology The disastrous effects and widespread incidence of alcoholism are well known to the emergency physician. Motor vehicle accidents, drowning, suicides, homicides, divorce, violent crime, child abuse, unemployment, and disruption of the family are often either directly or indirectly associated with excessive alcohol consumption. The tragic effects of alcohol not only affect the individual drinker but also have far-reaching implications for the family, community, and workplace. The prevalence of alcoholism or inappropriate drinking among emergency department patients ranges from 8% to 40%. The 5-year mortality rate among alcohol-intoxicated emergency department patients was 2.4 times that of a comparison group in one study.[1 ]

A simple, rapid, and respectful screening test for alcoholism is the four CAGE questions. Have you ever felt: the need to Cut down on your drinking? Annoyed by criticism of your drinking? Guilty about your drinking? the need to drink an Eye opener in the morning?

Positive answers to two or more of these questions are sufficient to identify individuals who require more intensive evaluation.[2] Also, a positive answer to the question “Have you ever had a drinking problem?” plus evidence of alcohol consumption in the previous 24 hours provides greater than 90% sensitivity and specificity as a screening tool for identifying alcoholism. Alcohol is the most common recreational drug taken by Americans, and per capita consumption is increasing. Alcoholism permeates all levels of society and is the leading cause of mortality and morbidity in the United States, with a cost to the nation estimated to be greater than $130 billion annually. An estimated 18 million alcoholics reside in the United States. More than 100,000 alcohol-related deaths occur each year, and alcohol is the third leading cause of preventable death in the United States.[3]

Definition and Natural History A precise definition of alcoholism is difficult. A proposed definition encompassing the features of alcoholism is “a primary chronic disease with genetic, psychosocial, and environmental factors influencing its development and manifestations.” The disease is often progressive and fatal. It is characterized by impaired control over drinking, preoccupation with and use of alcohol despite adverse consequences, and distortions in thinking, most notably denial. Each of these symptoms may be periodic or continuous.[4] When drinking adversely affects an individual's physical health, ability to function in society, or interpersonal relationships, alcoholism is present. Certainly, the patient who has a dependence on ethanol can be labeled “alcoholic.” The cause of alcoholism is not completely understood but appears to be a complex interaction between biologic and environmental factors. Data show that a genetic variability of enzymes for alcohol metabolism

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may be a risk factor. The validity of genetic factors is supported by family, twin, and adoption studies.[5] The natural history of alcoholism is variable, and it may appear in any patient despite age or social status. The age of onset of alcoholism continues to decrease. Up to 6% of high school seniors drink daily, and it is not unusual to see children younger than 16 years of age who have already graduated from an alcohol detoxification program.[6] Many individuals also begin drinking heavily after age 60. The fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) has two categories for substance disorders, which include alcohol abuse. It lists criteria for substance abuse and substance dependence.[7] The chronic substance abuse of alcohol eventually leads to acquired tolerance, a condition in which larger and larger doses of alcohol are required for the same effect. An inborn tolerance also exists. A wide variance in the behavioral abnormalities is manifested, independent of the patient's drinking experience. Continued alcohol abuse progresses to substance dependence, defined in DSM-IV as a maladaptive pattern of substance use leading to clinically significant impairment, as manifested by three or more of the following occurring in the same 12-month period: 1. 2. 3. 4. 5. 6.

Physiologic dependence, as evidenced by tolerance or withdrawal Alcohol taken in larger amounts or over a longer period than was intended Persistent desire or unsuccessful efforts to control alcohol consumption Great amount of time spent in activities necessary to obtain alcohol or recover from its effects Important social, occupational, or recreational activities forsaken for sustained alcohol use Continued alcohol use despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by alcohol

PRINCIPLES OF DISEASE: METABOLISM OF ALCOHOL Ethanol is rapidly absorbed from the stomach and small intestine. It is distributed uniformly to all organ systems, including the placenta if present. Most alcohol is metabolized in the liver. The oxidation of alcohol is a complex process involving three enzyme systems, all contained in the hepatocyte. The pharmacokinetic properties of alcohol metabolism are well known. The class I alcohol dehydrogenase (ADH) isoenzymes, ADH1, ADH2, and ADH3, oxidize ethanol. ADH2 and ADH3 have polymorphic properties with distinct kinetic properties. At the ADH3 locus, two alleles account for pharmacokinetic differences of 2.5-fold in maximum velocity of ethanol oxidation.[8]

An alternative pathway, the microsomal ethanoloxidizing system (MEOS), can be induced by chronic alcohol exposure. Many effects of alcoholism are produced by the toxic byproducts (hydrogen, acetaldehyde), the acceleration of metabolism of other drugs, and activation of hepatotoxic compounds by these metabolic pathways. Although the liver is the major site of ethanol metabolism, other tissues contribute to its metabolism. ADH is found in the gastric mucosa, but the gastric metabolism of alcohol is decreased in women. This increased bioavailability of ethanol or decreased first-pass metabolism may explain the enhanced vulnerability of women to acute and chronic complications of alcoholism. Studies have shown two alcohol elimination curves. The alcohol elimination rate approximates zero-order kinetics (constant rate) for lower ethanol levels and first-order kinetics (amount of drug removed over time is

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proportional to the concentration of the drug) for higher levels, especially in chronic alcoholics. The MEOS pathway may account for the increased elimination rate of ethanol. The absorption and elimination rates of alcohol vary by individual and depend on many factors: diet, gender, body weight and habitus, speed of consumption, gastric motility, presence of food in the stomach, smoking history, age, whether the person is a chronic alcohol consumer with enzyme induction and high-activity MEOS, advanced cirrhosis, presence of ascites, and the state of nourishment.[9] There is enormous variation among patients in the rate of disappearance of ethanol from the blood, ranging from 9 to 36 mg/dL/hr in published data. Although the clearance rate may be as high as 36 mg/dL/hr in some chronic drinkers, 20 mg/dL/hr is a reasonable rate to assume in any intoxicated emergency department patient. This holds true for adults, adolescents, and children. In the unusual circumstance that an accurate prediction of the rate of clearance is required, a second measurement should be obtained several hours after the initial value.[10] Physiologic effects vary directly with the blood alcohol ( Table 184-1 ). Diminished fine motor control and impaired judgment appear with alcohol concentrations as low as 20 mg/dL (0.02 mg%), but wide individual variability exists. Chronic alcoholics can exhibit impressive tolerance. The blood alcohol concentration (BAC) of a person cannot be accurately determined without quantitative testing. More than 50% of the adult population are obviously intoxicated with a level of 150 mg/dL (0.15 mg%). As the ethanol level rises, the patient's level of consciousness declines, eventually ending in coma. Death is caused by aspiration or respiratory depression. Table 184-1 -- Physiologic Effects and Blood Alcohol Levels Blood Alcohol Concentration (mg/dL)

Effects[*]

20–50

Diminished fine motor control

50–100

Impaired judgment; impaired coordination

100–150

Difficulty with gait and balance

150–250

Lethargy; difficulty sitting upright without assistance

300

Coma in the novice drinker

400

Respiratory depression

*

These effects are for the occasional drinker. Chronic drinkers can function at m uch higher alcohol concentrations because of tolerance. On the other hand, patients m ay becom e com atose with low levels of alcohol in mixed alcohol-drug overdose.

In most states, the legal level of intoxication is 80 to 100 mg/dL (0.08 to 0.1 mg%). Many states now allow administrative driver's license revocation at BACs as low as 20 mg/dL (0.02 mg%). Expired breath alcohol or saliva testing can be used to obtain a reliable approximation of BAC in a cooperative patient. This value can be used as a rapid screen for alcohol intoxication.[11]

DIFFERENTIAL CONSIDERATIONS Acute alcohol intoxication is a diagnosis of exclusion. Before assuming that a patient's behavior is caused only by alcohol, other conditions must be considered. Hypoglycemia, hypoxia, carbon dioxide narcosis, mixed alcohol-drug overdose, ethylene glycol or methanol poisoning, hepatic encephalopathy, psychosis, severe vertigo, and psychomotor seizures can manifest in a manner similar to ethanol intoxication. The possibility of occult head trauma and the presence of associated metabolic disorders need to be recognized after alcohol intoxication has been established. Adequate history from paramedics and family, repeated physical examinations by the same physician, and diagnostic adjuncts can help resolve this dilemma.

MANAGEMENT Ethanol is similar to general anesthetics that act on the lipid moiety of cell membranes. Because there are no specialized receptors for alcohol, a specific antagonist does not exist. Comatose or stuporous patients need to have their airway and breathing evaluated. The airway is protected as necessary, including endotracheal intubation. Gastric lavage and activated charcoal are of little value in

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ethanol overdose because of the rapid absorption of alcohol but may be appropriate in a suspected mixed drug-alcohol overdose. Thiamine (100 mg intravenously [IV]) to prevent or treat Wernicke's syndrome, glucose (dextrose, 25 to 50 g IV) for hypoglycemia, and naloxone (0.8 mg IV) for possible opioid ingestion are considered in comatose patients. Whenever possible, hypoglycemia should be documented before the administration of empirical glucose. With the airway maintained and respirations supported, the patient's liver eventually metabolizes the alcohol, and the patient should recover. Glucose (dextrose, 25 g IV) produces a dramatic response in alcohol-induced hypoglycemic patients. Unlike hypoglycemia of other causes, alcohol-induced hypoglycemia may be unresponsive to glucagon because of depleted liver glycogen stores. The possibility of precipitating Wernicke's encephalopathy by administering glucose before thiamine has little scientific merit. Although Wernicke's encephalopathy is a medical emergency, alcohol-induced hypoglycemia is a much more common condition with serious and permanent morbidity if left untreated. Therefore, thiamine can be given in a timely fashion, but glucose therapy should never be delayed.[12] Intoxicated patients require evaluation and treatment in the emergency department regardless of their obstreperousness. Inappropriate discharge and failure to diagnose are two common areas of liability when treating the alcohol-dependent patient. The theoretical liability for detention by reasonable restraint is less than the potential liability for injury sustained by the alcohol-dependent patient or an innocent bystander after premature discharge. Discharge (after excluding significant abnormal laboratory values or suspected head injury) can be considered if a concerned, sober adult is willing to take responsibility for and remain with the patient for the next 24 to 48 hours.

ALCOHOL WITHDRAWAL SYNDROME Principles of Disease The neurophysiology of alcohol withdrawal is complex and not fully understood. Chronic alcohol consumption has a depressant effect on the central nervous system (CNS). The hallmark of alcohol withdrawal is CNS excitation with increased cerebrospinal fluid (CSF), plasma, and urinary catecholamine levels. Chronic alcohol consumption affects central adrenergic p -receptors, glutamate, central adrenergic p -receptors, the inhibitory neurotransmitter p~-aminobutyric acid (GABA), and dopamine turnover. The effectiveness of lofexidine and clonidine (p 2-adrenergic agonists), propranolol and atenolol (p -blockers), haloperidol (dopamine blocker), and benzodiazepines and propofol (GABA transmission blockers) in suppressing the signs and symptoms of alcohol withdrawal supports this concept.[]

Differential Considerations Alcohol withdrawal syndrome can initially be confused with acute schizophrenia, encephalitis, drug-induced psychosis, thyrotoxicosis, anticholinergic poisoning, and withdrawal from other sedative-hypnotic-type drugs. It may be difficult to differentiate between alcohol withdrawal and alcohol-induced hypoglycemia. Acute schizophrenia usually has its onset in adolescence or early adulthood. Manifestations include multiple bizarre delusions and a flat affect with the patient otherwise oriented. The patient in alcohol withdrawal is usually older (20s or 30s), hyperactive, and often disoriented. Encephalitis can produce headache, confusion, fever, and seizures. Thyrotoxicosis is more common in women, and its features include irritability, insomnia, tremor, weight loss despite a good appetite, palpitations, and frequent stools. Physical examination may reveal lid lag, tachycardia, and a bruit over the thyroid. No relationship exists between the onset of encephalitis or thyrotoxicosis and alcohol consumption. Anticholinergic poisoning can occur with several different drugs or plant ingestion. The classic clinical picture is a patient with dry mouth, dry eyes, dry skin, hypoactive bowel sounds, urinary retention, and delirium. Amphetamine and cocaine intoxications produce anorexia, insomnia, and physical signs of CNS sympathetic overactivity. In opioid withdrawal, patients complain of abdominal pain and diarrhea, the mental status is usually normal, the patient is afebrile, and seizures are uncommon (with the exception of meperidine). In contrast, patients with major alcohol withdrawal are usually disoriented and febrile and may have seizures. Signs of alcohol withdrawal usually begin 6 to 24 hours after a decrease in the patient's usual intake of

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alcohol. If patients manifest withdrawal 3 days or more after their last drink, drugs with a longer half-life should be considered. The barbiturate and benzodiazepine withdrawal syndromes usually progress more slowly, with a higher frequency of seizures later (7 days versus 2 days), and status epilepticus is more common than with alcohol withdrawal.

Clinical Features Isbell's classic study in 1955 confirmed the relationship between alcohol and the withdrawal syndrome.[15] He documented that the severity of signs and symptoms depends on both the dose and the duration of ethanol consumption. The withdrawal syndrome may occur any time after the blood alcohol level starts to fall. Therefore, only a reduction, not the abrupt cessation, of ethanol intake may result in withdrawal. The withdrawal syndrome usually develops 6 to 24 hours after the reduction of ethanol intake and lasts from 2 to 7 days. The alcohol withdrawal state ranges from mild withdrawal with insomnia and irritability to major withdrawal with diaphoresis, fever, disorientation, and hallucinations. Minor alcohol withdrawal occurs as early as 6 hours and usually peaks at 24 to 36 hours after cessation of or significant decrease in alcohol intake. It is characterized by mild autonomic hyperactivity: nausea, anorexia, coarse tremor, tachycardia, hypertension, hyperreflexia, sleep disturbances (e.g., insomnia, vivid dreams), and anxiety.[16] Major alcohol withdrawal occurs after more than 24 hours and usually peaks at 50 hours but occasionally takes up to 5 days to manifest after the decline or termination of drinking. The syndrome is characterized by pronounced anxiety, insomnia, irritability, tremor, anorexia, tachycardia, hyperreflexia, hypertension, fever, decreased seizure threshold, auditory and visual hallucinations, and finally delirium.[17] Delirium tremens is the extreme end of the spectrum and consists of gross tremor, profound confusion, fever, incontinence, frightening visual hallucinations, and mydriasis. It seldom appears before the third postabstinence day. Only 5% of patients hospitalized for alcohol withdrawal develop delirium tremens. Other causes of delirium to be considered in the alcoholic patient include sepsis, meningitis, hypoxia, hypoglycemia, hepatic failure, and intracranial bleeding. True delirium tremens is rare and is not synonymous with alcohol withdrawal. Seizures can occur in major withdrawal or delirium tremens.

Management Prehospital Care The alcohol-dependent patient in withdrawal may also have a mixed alcohol-drug ingestion, occult head trauma, or cervical spine injury. Patients who are unable to sit without assistance or have an altered mental status require IV access. Thiamine (100 mg), naloxone (0.8 mg), and glucose (dextrose, 25 g) may be given in an IV bolus. Although rapid blood glucose testing is preferable, it is acceptable to give glucose for altered mental status if this testing is not readily available. The airway must be maintained and respirations supported. Emergency medical service personnel should monitor the patient's vital signs and neurologic status. The cervical spine should be immobilized if trauma is suspected. It is usually best to withhold additional treatment until the patient can be evaluated in the emergency department. Emergency medical service personnel should be alert for other medical disorders that accompany alcoholism, such as pneumonia, sepsis, gastrointestinal bleeding, pancreatitis, hepatic failure, hypoglycemia, and intracranial hemorrhage.

Hospital Care Initial Assessment Family, friends, bystanders, or paramedics may give more reliable historical data than the patient. Accurate vital signs are essential. This may require a rectal temperature. Hyperthermia, hypothermia, tachypnea, or tachycardia may suggest serious disorders that often accompany the alcohol-dependent patient. These disorders should be considered during this first assessment. A rapid, thorough examination should be done with attention to the level of consciousness, signs of hepatic failure, or coagulopathy. Signs of trauma are sought, such as subcutaneous emphysema, ecchymosis, subconjunctival hemorrhage, Battle's sign, or fractures. The neurologic examination should search for focal findings, including central facial nerve palsy, hemiparesis, asymmetry of reflexes, or asymmetry of pupillary response.

Treatment Plan The alcohol withdrawal syndrome must be promptly recognized and treated. Treatment is necessary (1) to

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provide relief from anxiety and hallucinations, (2) to halt progression to major withdrawal and withdrawal seizures, (3) to allow detection of a treatable primary psychiatric illness, (4) to prepare the patient for long-term alcohol abstinence with the lowest risk of new drug dependence, and (5) to calm the patient and allow adequate examination for the detection of medical illnesses that typically accompany alcoholism, such as gastritis, dehydration, pancreatitis, pneumonia, electrolyte disorders, and hepatitis. Detention by reasonable restraint is an option to prevent potential injury patients may inflict on themselves or the hospital staff. Appropriate restraints are preferable to allowing decision-incapacitated patients to sign an “against medical advice” (AMA) form and be discharged.

Pharmacologic Intervention Patients suffering from alcohol withdrawal should receive pharmacologic intervention along with supportive care. More than 150 different drugs and drug combinations have been reported in the literature for the treatment of alcohol withdrawal. The ideal drug for alcohol withdrawal would have a rapid onset, a wide margin of safety, a metabolism not dependent on liver function, and limited abuse potential. Although no one drug class fits all these requirements, benzodiazepines are clearly the mainstay of treatment.

Benzodiazepines. The benzodiazepines have superior anticonvulsant activity, have the least respiratory and cardiac depressive effect of all the CNS depressants, and can be given parenterally in the uncooperative patient. By interacting with receptors linked to the GABA-associated chloride ion channel, benzodiazepines substitute for the withdrawal of the GABA-potentiating effect of alcohol and abate withdrawal signs and symptoms.[18] Numerous benzodiazepines, including alprazolam (Xanax), chlordiazepoxide (Librium), clorazepate (Tranxene), diazepam (Valium), lorazepam (Ativan), midazolam (Versed), and oxazepam (Serax), have been studied. No evidence of clear superiority of any one benzodiazepine exists. Lorazepam has good bioavailability with oral, intramuscular (IM), and IV routes. It is rapidly and completely absorbed from IM sites in agitated patients with no IV access. Lorazepam's half-life is intermediate (7 to 14 hours), and it reaches a steady state in 36 to 48 hours without active metabolites. Excessive sedation, confusion, and ataxia are potential complications of all benzodiazepines with prolonged half-lives. Lorazepam is metabolized (conjugated) in the liver, yielding inactive products. Although lorazepam's half-life increases in patients with cirrhosis or liver failure, it is much less than the increase with chlordiazepoxide. Lorazepam's elimination is only minimally altered in patients with renal failure and in elderly persons. Lorazepam may be given IV in a dose of 2 to 4 mg, depending on the severity of the withdrawal. Dosing can be repeated at 10- to 30-minute intervals for patients in severe withdrawal. An IM dose of 0.07 mg/kg can be used. The oral schedule for moderate withdrawal is 6 mg/day in three divided doses, tapering the amount by 1 to 2 mg/day over 4 to 6 days. If lorazepam is unavailable, diazepam can be given, with 5 mg IV every 5 to 10 minutes in major withdrawal until the patient is calm. When patients are admitted to the hospital, symptom-triggered dosing of benzodiazepines has been shown to be superior to a fixed dose schedule.[19] The dosage of benzodiazepines required for alcohol withdrawal is highly variable. Practically, the dose is titrated to the patient's agitation. Massive IV drug doses have been required in patients with delirium tremens, including a recorded 2640 mg of diazepam and 35 mg of haloperidol over 48 hours, 75 mg of midazolam in 1 hour, and 2850 mg of midazolam over 5 days.[20]

Butyrophenones. Haloperidol, a dopamine antagonist, can be considered in patients with major alcohol withdrawal or delirium tremens not responding to IV benzodiazepines. Haloperidol is more potent than chlorpromazine, has lower anticholinergic properties, and has less propensity to cause cardiovascular side effects or lower the seizure threshold. Haloperidol has little effect on myocardial function or respiratory drive, and its safety and efficacy by the IV, IM, or oral route in the emergency department have been established. Haloperidol has no anticonvulsant properties. Haloperidol and lorazepam in combination are safe and may be synergistic. Safe use in extremely high doses in patients with serious underlying medical illness has been documented in several studies: 240 mg of haloperidol and 480 mg of lorazepam given over 24 hours in a patient and 485 mg of haloperidol over 8 hours in another patient without significant adverse effects. Some advocate an aggressive protocol with escalating doses of the combination of haloperidol and lorazepam.[21]

p -Blockers. Alcohol withdrawal has been associated with increased noradrenergic activity. Benzodiazepines do not

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possess any direct antiadrenergic effects. Propranolol and atenolol have been studied in alcohol withdrawal. In one study, vital signs and clinical (tremor) and behavioral (agitation, anxiety) signs in patients taking atenolol and oxazepam resolved more rapidly than in patients taking placebo and oxazepam. Over 4 to 5 days of treatment the atenolol group required substantially smaller doses of oxazepam on each treatment day. p -Blockers can be considered as an adjunctive therapy in mild to moderate alcohol withdrawal. Relative contraindications include insulin-dependent diabetes, hypotension, lung disease with bronchospasm, congestive heart failure, and second-degree or third-degree heart block.

p -Agonists. The p -adrenergic agonist clonidine has proved effective in opiate withdrawal. Clonidine is not a controlled substance and has little or no addictive or abuse potential. It improves vital signs and the subjective complaints of alcohol withdrawal. Clonidine appears to be most effective in attenuating blood pressure changes versus other withdrawal symptoms. Theoretically, clonidine avoids the potential for oversedation and the dependence on benzodiazepines and may be helpful with mixed alcohol-apioid withdrawal. It is ineffective in preventing seizures. Clonidine may be considered in patients with mild alcohol withdrawal with no history of alcohol-related seizures who are candidates for an outpatient program or who have coincident opiate addiction.

Anticonvulsants. Carbamazepine, gabapentin, and valproate have been tried in outpatient treatment of mild to moderate alcohol withdrawal with some success.[]

Emergency Department and Outpatient Approaches Rapid, aggressive control of alcohol withdrawal is crucial. The cornerstone of treatment is a benzodiazepine. Lorazepam may be preferable because of its previously discussed qualities. An initial test dose of 1 to 2 mg of lorazepam or 5 mg of diazepam IV can be given to the patient in the emergency department. The doses can be repeated with observation of the patient for 2 to 6 hours guiding the emergency physician concerning the dose required for outpatient treatment. Patients remain under observation or are admitted until the manifestations of withdrawal do not progress after the effects of the benzodiazepine have dissipated.[18] Outpatient treatment consists of lorazepam, 1 to 2 mg three times a day in a tapering dose for 3 to 6 days; chlordiazepoxide, 25 to 100 mg three times a day, in a tapering dose for 3 to 6 days; or diazepam, 30 mg once a day tapered over 5 days depending on the severity of symptoms. Adequate diet, abstinence, and participation in a rehabilitation program in the community are also desirable. Any patient requiring 300 mg of chlordiazepoxide or 60 mg of diazepam per day to control withdrawal should be considered for admission. Patients with major alcohol withdrawal (disorientation, hallucinations, diaphoresis, or fever) are admitted. Doses approximately equivalent to 100 mg of chlordiazepoxide are 20 mg of diazepam and 5 mg of lorazepam.[18] Haloperidol (5 mg IV) or propofol (100 mg IV) can be considered in major withdrawal or delirium tremens not responding adequately to benzodiazepines. In stable admitted patients, p -blockers may be considered as an adjunct to benzodiazepine therapy if no contraindications are present. Combination therapy is reasonable in alcohol withdrawal; benefits include reduction of the risks associated with prolonged and heavy sedation, faster symptom resolution, and quicker recovery. Benzodiazepines should be used only for the minimum time required to avoid their abuse, addiction, and withdrawal in the alcoholic. The previous suggestions are only guidelines, and therapy must be individualized.

Adjunctive Therapy Patients being treated for major alcohol withdrawal should receive thiamine (100 mg IV) and magnesium (2 g IV). Although magnesium sulfate does not decrease the severity of withdrawal symptoms, the incidence of delirium, or seizures, it carries no significant risk or cost. In the nonacute setting, oral magnesium supplementation in chronic alcoholics improves liver function tests, electrolyte balance, and muscle strength.[24] Multivitamin preparations may be considered for chronic malnutrition. Although their clinical benefit is not proved, they carry no significant risk or cost.[14] If present, volume depletion can be corrected with normal saline. Reversal of electrolyte and metabolic

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disorders (hypomagnesemia, hypophosphatemia, hypokalemia, and acidosis) is discussed in the following section. Although treatment of electrolyte disorders and acidosis benefits the patient, it does little to abate the withdrawal syndrome. Phenothiazines are contraindicated because they can produce hypotension, lower seizure threshold, disturb central temperature regulation, and cause extrapyramidal effects in the dosages required to calm patients in alcohol withdrawal.

ALCOHOL-RELATED SEIZURES With the various medical problems related to alcohol abuse, the differential diagnosis and management of seizures remain among the most challenging and controversial ( Box 184-1 ). A patient arriving at the emergency department with seizures should be questioned about alcohol intake. From 20% to 40% of seizure patients presenting to an emergency department have their seizures related to alcohol abuse.[25] Alcohol is a causative factor in 15% to 24% of patients with status epilepticus.[26] BOX 184-1 Differential Diagnosis of Alcohol Related Seizures

With draw al (alco hol or drug s) Exac erbat ion of idiop athic or postt rau mati c seiz ures Acut e intoxi catio n (am phet amin es, antic holin ergic s, coca ine, isoni azid, orga noph osph ates,

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phen othia zine s, tricy clic antid epre ssan ts, salic ylate s, lithiu m) Meta bolic (hyp ogly cemi a, hypo natre mia, hype rnatr emia , hypo calc emia , hepa tic failur e) Infec tious (me ningi tis, ence phali tis, brain absc ess) Trau ma (intra crani al hem orrh age) Cere brov ascu lar acci dent

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Slee p depri vatio n Non com plian ce with antic onvu lsant s The primary consideration in the initial care of these patients is the recognition and treatment of life-threatening causes of seizures, such as CNS infection, hypoglycemia, or intracranial hematoma. Alcohol may act in one of several ways to produce seizures in patients with or without underlying foci: (1) by its partial or absolute withdrawal after a period of chronic inebriation, (2) by an acute alcohol-related metabolic brain disorder (e.g., hypoglycemia, hyponatremia), (3) by creating a situation leading to cerebral trauma, or (4) by precipitating seizures in patients with idiopathic or posttraumatic epilepsy. Moreover, alcoholics are more susceptible to other causes of seizures, including cerebral infarction, subarachnoid hemorrhage, neurosyphilis, acquired immunodeficiency syndrome (AIDS), brain abscess, and meningitis.[27]

Alcohol Withdrawal Seizures Alcohol withdrawal is one of the most common causes of adult-onset seizures. Descriptions of alcohol withdrawal seizures (AWSs) were based on data collected on 241 alcohol abusers with seizures or alcohol-related illness complicated by seizures initially described by Victor and Brausch.[28] These patients with AWSs were confirmed alcoholics of many years with the onset of seizures in adulthood. The seizures occurred 6 to 48 hours after the cessation of drinking. Ninety percent had one to six generalized tonic-clonic seizures, which occurred abruptly without warning. Sixty percent experienced multiple seizures, usually two to four within a 6-hour period. However, more recent data suggest a much lower repeat seizure rate of 13% to 24%.[29] The incidence of partial (focal) seizures, common with posttraumatic epilepsy, is increased by alcohol withdrawal. However, partial seizures still should be considered indicative of a mass lesion until proved otherwise. The term alcohol withdrawal seizure is reserved for seizures with the characteristics described by Victor and Brausch.[28] The term alcohol-related seizure (ARS) is used to refer to all seizures in the aggregate associated with alcohol use, including this subset of AWSs.

Management Historically, up to one third of patients with AWSs progressed to delirium tremens because of inadequate treatment. Currently, this proportion has decreased to less than 5% with early, aggressive benzodiazepine therapy. An IV line of normal saline with magnesium, similar to the alcohol withdrawal regimen, should be established. If the patient has an altered mental status, thiamine, dextrose, and naloxone should be considered. Again, empirical glucose bolus dosing should not be used if a prompt, accurate determination of blood glucose is possible. Although fever may suggest meningitis, it may be found in intracranial hemorrhage, brain abscess, alcohol withdrawal, toxic ingestions, and infections outside the CNS. Temperature can rise as a result of tonic-clonic seizure. If meningitis is suspected but a possibility of increased intracranial pressure exists, the patient can have specimens drawn for blood cultures and be started empirically on antibiotics. A lumbar puncture (LP) may be delayed until a space-occupying lesion is ruled out with computed tomography (CT) scanning, but antibiotics cannot be delayed if meningitis is a possibility. Contraindications of LP include intracranial mass, papilledema, localizing neurologic findings, coagulopathy,

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and local infection in the area of the LP. If an LP is performed relatively soon after a single IV dose of antibiotics (1 to 2 hours), subsequent CSF cultures are likely to remain positive in most adult patients. In addition, the CSF leukocyte count, protein level, and glucose concentration are not significantly affected. Delay in administering antibiotics in meningitis adversely affects patients' morbidity and mortality. LP should be considered in febrile alcoholics with delirium, with the previous precautions. Interestingly, occult CNS infections in febrile alcoholics with an altered mental status are uncommon.[30]

Patients Presenting with a Normal Neurologic Examination New-Onset Alcohol-Related Seizures Patients with new-onset ARSs must be thoroughly evaluated. This includes alcoholics who claim to have had seizures in the past but for whom no documentation of previous seizures or of an appropriate workup is available. Metabolic disorders, toxic ingestion, infection, and structural abnormalities are ruled out by history, repeated physical examinations, laboratory testing including electrolytes and glucose, and CT scan, as necessary. An electroencephalogram scheduled during follow-up may be considered (but its value is limited) in the patient whose seizures have not been explained.[31] If the initial assessment is normal, patients who remain seizure free and symptom free with no sign of withdrawal after 4 to 6 hours of observation may be discharged. Optimal outpatient treatment includes clear guidelines for follow-up and re-evaluation and the help of a concerned family member or friend (who is not a drinking partner). Ideally, this individual should remain with the patient for 1 to 2 days. These criteria may be difficult to meet, and the physician must use discretion in deciding to admit for observation when the patient is at risk for serious injury. The ideal disposition is participation in a detoxification-rehabilitation program. It may be unclear whether the patient has had a pure AWS or the new onset of epilepsy in the setting of alcohol ingestion. At this point, such a patient probably does not require further treatment. The literature provides little useful information about the natural history, including the risk of subsequent seizures, in patients presenting with an unprovoked seizure.[32] Beginning anticonvulsants in a patient after a new-onset single seizure is controversial, and the final decision about treatment should be individualized and made after consultation with a neurologist or the patient's primary care provider. The patient with a first-time ARS who has a history consistent with AWS and a negative workup can be treated as presented in the next section.

Seizures in the Alert Patient with a History of Seizures during Prior Withdrawal Alcoholic patients with the manifestations of alcohol withdrawal who have not had a recent seizure but relate a history of AWSs are seen frequently in the emergency department. The risk of seizure increases 10-fold in this subset of patients. Benzodiazepines alone are sufficient to prevent AWSs.[29] Many of these patients are sporadically taking one or more anticonvulsants. It is difficult, if not impossible, to decide in the emergency department whether these anticonvulsants were given for idiopathic epilepsy, posttraumatic epilepsy, or AWSs. To prevent AWSs effectively, detoxification with benzodiazepines should be initiated early because most AWSs occur within the first 24 hours after alcohol withdrawal. Treatment should be started with the understanding the patient will be observed for 4 to 6 hours and referred to a detoxification-rehabilitation program (if available). An initial dose of 2 mg of lorazepam or 10 mg of diazepam can be given orally or 1 to 2 mg of lorazepam or 5 mg of diazepam given IV to the patient in the emergency department. This dose may be repeated depending on the patient's response. The patient is observed for 4 to 6 hours, which guides the dose required for outpatient treatment. Prescribing anticonvulsants, such as benzodiazepines (other than a short 3- to 6-day course for alcohol withdrawal) and phenytoin, to the outpatient alcoholic may increase the potential for addiction and paradoxically may increase the number of acute seizures. The poorly compliant alcoholic patient may do better without outpatient anticonvulsants for a concurrent seizure disorder. Therefore, the ideal disposition is admission to a detoxification-rehabilitation unit.

Alert Patient with a Seizure before or after Presentation The alcoholic patient with a documented history of ARSs who experiences a single seizure or a short burst of seizures should be treated with lorazepam, 2 mg IV. These patients usually require observation with careful monitoring of neurologic status for at least 6 hours before discharge.

Patients with an Abnormal Neurologic Presentation

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New-Onset Partial Seizures Partial (focal) seizures are reported to account for up to 24% of ARSs. Conversely, studies have shown that 17% to 21% of patients with partial ARSs have structural lesions (hematomas, tumors, or vascular abnormalities).[33] These primary causes of partial ARS, such as prior head trauma, may be missed in the history taking. As a result, an urgent CT scan is indicated to evaluate new-onset partial seizures. The patient with a documented history of a focal ARS who has been previously evaluated does not require an emergency CT scan provided a return to baseline occurs promptly. A patient with a focal ARS associated with normal neuroimaging can be managed with supportive care, observation for 4 to 6 hours, and benzodiazepines for withdrawal signs or symptoms. Appropriate follow-up should be arranged.

Status Epilepticus When multiple seizures are interrupted only by brief periods of incomplete recovery or major motor convulsions are continuous for more than 30 minutes, status epilepticus is present. Although fewer than 8% of ARS patients go into status epilepticus, alcohol is implicated in 15% to 24% of status epilepticus cases.[34] Status epilepticus may also be the first presentation of ARSs. The most common cause of status epilepticus is discontinuation or erratic compliance with an anticonvulsant drug regimen, followed by ARS. However, status epilepticus may arise for a variety of reasons and is often multifactorial. Thus, it is essential to screen for all possible factors underlying repeated or prolonged seizures, even when a probable cause is thought to be readily apparent. After airway management and the initiation of two IV lines, IV lorazepam is given, along with thiamine, dextrose, and naloxone. Although lorazepam and diazepam are both effective in terminating seizures in status epilepticus, lorazepam is preferable because its anticonvulsant effect lasts several hours, whereas diazepam's anticonvulsant effects last only 20 to 30 minutes. Because of this, lorazepam is associated with fewer recurrent seizures and fewer repeated doses are required compared with diazepam.[] Lorazepam 4 mg can be given at 2 mg/min diluted in an equal volume of solution and repeated in 10 minutes if seizures persist. Diazepam is given at a rate of 5 mg/min, up to 20 mg. Intravenous benzodiazepines are associated with the complications of respiratory depression and hypotension. If seizures persist after lorazepam or diazepam, a loading dose of phenytoin (Dilantin), 18 mg/kg, or fosphenytoin (Cerebyx), 15 to 20 phenytoin equivalents mg/kg, is administered in the second IV line. Additional doses of 5 mg/kg of phenytoin, to a maximum of 30 mg/kg or 1500 mg/24 hours, can be given if status is not terminated. Most of the cardiac abnormalities associated with phenytoin infusion are caused by its solvent, propylene glycol. Caution is advised in patients who have preexisting heart disease. Using a 20-gauge line proximal to the forearm to avoid purple glove syndrome and keeping the phenytoin rate less than 50 mg/min helps to minimize the problem of hypotension and bradycardia. Fosphenytoin does not contain propylene glycol and is safe and well tolerated at IV rates of 100 to 150 mg/min. Rapid achievement of therapeutic free phenytoin levels without significant side effects has been documented using fosphenytoin in patients with status epilepticus.[37] The cost of fosphenytoin is approximately 20 times greater than that of phenytoin. Interestingly, emergency department studies comparing phenytoin and fosphenytoin (not involving status epilepticus) found no advantage of fosphenytoin over phenytoin.[] Phenobarbital at a maximum rate of 50 mg/min to 100 mg/min IV, with a loading dose of 20 mg/kg, was recommended in the past for a patient who does not respond to phenytoin and lorazepam or diazepam. (By this time, the admitting physician should be involved with the patient's care). Phenobarbital can be used in patients with cardiac disease or phenytoin allergy. The cardiorespiratory depressant effects of phenobarbital and lorazepam are additive. Experts have suggested skipping phenobarbital and considering pentobarbital, propofol, midazolam, or valproic acid instead at this stage.[] It is often difficult to rule out a CNS infection in alcoholics with status epilepticus because of concomitant hyperthermia, serum leukocytosis, and CSF pleocytosis. If CSF infection is a possibility, an LP should be considered.

Obtundation The obtunded or stuporous patient with a history of seizure activity poses a diagnostic challenge. The patient's decreased level of consciousness (LOC) may be the result of a postictal state, occult head trauma, unrecognized metabolic disorder, or poisoning. The first task is to determine the possibility of hypoglycemia

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(diagnosed and reversed at the bedside in seconds to minutes) or a neurosurgical lesion—intracranial mass (with morbidity and mortality directly related to the time of surgical intervention). Patients with focal neurologic findings on physical examination, new-onset seizures, partial (focal) seizures, or evidence of acute head trauma should be considered for an urgent CT scan. If the LOC is consistently improving, the patient is unlikely to have an immediate life-threatening problem. An unimproved or deteriorating LOC requires a CT scan.

No History of Seizures, No Current Seizure In the alcoholic patient in withdrawal who lacks a history of seizures, benzodiazepines generally have sufficient anticonvulsant activity to prevent withdrawal seizures.

Phenytoin-Anticonvulsant Conundrum Phenytoin has no significant benefit over placebo in preventing recurrence of AWSs.[] Considering the risks of phenytoin and no demonstrated benefit in the setting of AWS, it is not indicated for the treatment of an AWS. The sudden withdrawal of phenytoin may potentiate the convulsive effects of alcohol withdrawal. Withdrawal seizures may occur in epileptic patients withdrawn from phenytoin. In patients with status epilepticus, alcohol and noncompliance with anticonvulsant regimens may be synergistic. Alcoholic patients with preexisting seizure disorders pose a dilemma when they are supposed to be taking antiepileptic drugs but their blood levels suggest noncompliance. This is especially problematic when their epileptic attacks are uncommon and appear to occur exclusively in the context of alcohol withdrawal. Some of these patients may have AWSs and may have been misdiagnosed. Others may have a seizure disorder that appears to be confined to the setting of alcohol withdrawal. Such patients have demonstrated that they cannot maintain compliance with their treatment. A patient currently taking phenytoin for an antecedent seizure disorder who presents with a seizure while intoxicated falls into a different category. Such an episode could be an isolated event in a usually compliant patient without a history of chronic alcohol abuse. In this patient a seizure in the setting of a subtherapeutic phenytoin level may represent the consequences of noncompliance with phenytoin versus AWS.

OTHER CLINICAL FEATURES AND MANAGEMENT Cardiovascular Effects Acute and chronic ethanol consumption can affect the mechanical function of the heart, produce dysrhythmias, and exacerbate coronary artery disease (CAD). It may alter myocardial function by direct toxic effects, associated hypertension, or indirectly by altering specific electrolytes. Acute intoxication has minimal effects on patients who are not chronic alcoholics and do not have preexisting CAD. Acute intoxication can decrease cardiac output in both alcoholic and nonalcoholic patients with preexisting cardiac disease.[45] Several studies have linked moderate alcohol consumption (up to two drinks per day in men and one in women) to a protective effect from CAD. As much as 50% of the relative risk reduction of CAD can be explained by increased levels of high-density lipoprotein (HDL) and its subfractions HDL-2 and HDL-3. Genetic variations in the ADH allele may account for these changes. Low to moderate alcohol consumption is found to decrease platelet aggregation, raise plasma levels of endogenous tissue plasminogen activator,[ 46] and lower insulin resistance. Experimental data suggest that alcohol may have antioxidant properties, produce effects on smooth muscles through interactions with nitric oxide, and alter plasma total homocysteine levels.[] Studies suggest that moderate alcohol consumption, through a reduced risk of CAD, may also protect individuals from congestive heart failure ( Box 184-2 ).[49] All of these beneficial effects are lost in heavy drinkers, in whom chronic alcoholism is associated with hypertension and congestive cardiomyopathy. BOX 184-2 Risks and Benefits of Light, Moderate, and Heavy Drinking

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Light/Modera te Drinking Ri sk s Es tab lis he d

Be ne fit s He av y dri nki ng

Pr ob abl e

De cr ea se d ris k of co ro na ry he art dis ea se De cr ea se d ris k of isc he mi c str ok e De cr ea se d ris k of gal lst on es Un Br Po De re ea ssi cr sol st ble ea ve ca se d nc d er ris k of dia bet

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Light/Modera te Drinking Ri sk s

Be ne fit s es De cr ea se d ris k of pe rip he ral va sc ula r dis ea se

Fe tal da m ag e

Un Bo lik we ely l ca nc er He m orr ha gic str ok e Hi gh blo od pr es su re He av y Dr in ki ng Ri sk s

Be ne fit s

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Light/Modera te Drinking Ri sk s

Be ne fit s

No nc ar dio va sc ula r

Liv No er ne cir rh osi s Pa nc re atit is Ce rtai n ca nc er s Ac cid ent s Ho mi cid es Su ici de s Fe tal da m ag e De ge ne rati ve ce ntr al ne rvo us sy ste m dis or de

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Light/Modera te Drinking Ri sk s

Ca rdi ov as cul ar

Be ne fit s rs Hi gh blo od pr es su re Arr hyt h mi a He m orr ha gic str ok e Ca rdi o my op ath y

From Klatsky A: Drink to your health. Sci Am February, 2003. Copyright © Scientific American, Inc.

The typical patient with alcoholic cardiomyopathy is a man older than 30 with a greater than 10-year history of chronic alcohol intake. The signs and symptoms are no different from those of low-output congestive heart failure of other causes: dyspnea, palpitations, weakness and fatigue, jugular venous distention, poor R wave progression, nonspecific electrocardiographic abnormalities, and biventricular enlargement on a chest radiograph. Echocardiography shows four-chamber enlargement with decreased left and right ventricular contractile function. Up to one third of chronic alcoholic patients have left ventricular dysfunction demonstrated by a radionuclide ventriculogram, usually coexisting with skeletal muscle disease. Women appear to be more sensitive to the toxic effects of alcohol on striated muscle and are at greater risk for cardiomyopathy and myopathy. The diagnosis is made by obtaining a history of prolonged alcohol use and excluding hypertensive, coronary, valvular, and congenital disease. Heavy alcohol consumption (more than 2 ounces a day) has a detrimental effect on those with preexisting CAD. It can reduce exercise tolerance, induce coronary vasoconstriction, and raise heart rate and blood pressure.[50] Additive cardiovascular effects of ethanol and nicotine contribute to dysrhythmias and sudden death in patients with CAD. In one study, nearly half the patients with alcohol withdrawal had prolongation of the QT interval. Prolonged QT can precipitate a dysrhythmia, resulting in sudden death.[51] There is an increased incidence of sudden death among heavy drinkers regardless of concomitant CAD or smoking. Supraventricular (usually atrial fibrillation) and ventricular (usually transitory ventricular tachycardia)

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dysrhythmias, the “holiday heart,” have been documented in alcoholic patients who have been drinking heavily. One study reported that alcohol contributes to or causes new-onset atrial fibrillation in approximately two thirds of patients younger than 65. Alcohol also affects cardiac function indirectly by lowering potassium and magnesium levels. Data from the Framingham Heart Study indicate that patients with lower levels of potassium and magnesium have higher rates of dysrhythmias.[52] Left ventricular ejection fractions improve with either abstinence or sustained decrease of alcohol consumption starting at 1 year and continue to improve over at least 4 years. Tachydysrhythmias as a result of episodic drinking commonly revert to sinus rhythm with abstinence and do not require immediate intervention if the patient is hemodynamically stable. Nevertheless, correction of electrolyte abnormalities is prudent.

Pulmonary Effects Alcohol reduces the mobilization of alveolar macrophages and their bactericidal capacity. Their impairment is greatest in alcoholics with hepatic cirrhosis. These effects, along with aspiration, decreased airway sensitivity, concomitant smoking, and malnutrition, probably account for the increased incidence of pneumonia, particularly lobar pneumonia, among alcoholic patients.[53] At least 80% of alcoholics are smokers, making it difficult to distinguish between alcohol-induced and tobacco-induced injury to the lungs. Most studies have failed to show an independent effect of alcohol on pulmonary function. The high prevalence of respiratory disease in alcoholics is largely caused by smoking. Chronic alcohol abuse has been shown to increase the risk of developing adult respiratory distress syndrome in the intensive care unit setting.[54] Alcohol ingestion has been shown to induce bronchospasm in some asthmatics and to increase ventricular ectopy and sleep apnea in patients with chronic obstructive pulmonary disease. Alcoholic patients with hepatic cirrhosis can have hypoxemia develop as a result of precapillary shunting in their lungs. Hyperventilation and a respiratory alkalosis are also seen with hepatic cirrhosis. Low to moderate alcohol consumption (one or two drinks per day) has been shown to decrease the risk of pulmonary embolus and deep venous thrombosis in elderly patients.[55]

Gastrointestinal and Hepatic Effects Esophagus and Stomach Alcoholic patients have a higher incidence of esophagitis, gastric cancer, and esophageal carcinoma than the general population. Acute alcohol ingestion also decreases lower esophageal sphincter pressure, delays gastric emptying, and disrupts the normal gastric mucosal barrier. Vomiting is common among drinkers. Forceful or persistent emesis can lead to a Mallory-Weiss tear or Boerhaave's syndrome.

Gastrointestinal Bleeding Alcohol has a close association with gastrointestinal bleeding. Causes include Mallory-Weiss tears, esophagitis, esophageal varices, acute and chronic gastritis, thrombocytopenia, portal hypertensive gastropathy, qualitative and quantitative platelet disorders, and prolonged clotting times. Alcohol may exacerbate gastric mucosal damage when combined with nonsteroidal anti-inflammatory drugs (NSAIDs), but ethanol itself is not a risk factor for peptic ulcer disease. An inverse relationship exists between consumption of alcohol, particularly wine, and active Helicobacter pylori infection. Peptic ulcer disease is the most common cause of bleeding in alcoholic patients with upper gastrointestinal hemorrhage as well as those who do not drink.[56]

Liver The liver is the primary site of ethanol metabolism. Hepatic damage has been recognized for centuries as the hallmark of chronic alcohol abuse. The production of cytokines such as tumor necrosis factor p is one of the earliest events in many types of liver injury. This cascade may trigger the production of other cytokines that together enlist inflammatory cells, kill hepatocytes, and initiate healing through fibrogenesis. There is no one test that can be used to diagnose alcoholic liver disease (ALD) reliably. However, the ratio of aspartate transaminase (AST) to alanine transaminase (ALT) may provide a hint that alcohol is likely the cause of liver injury.[57] ALD is the most common liver disorder in the western world and, along with hepatitis C, is a leading cause of liver transplantation.

Fatty Infiltration The earliest, mildest, and most common liver change seen in alcoholism is the accumulation of

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macrovesicular fat in the hepatocytes, predominantly involving triglycerides. Alcoholic fatty liver is usually asymptomatic, associated with mild elevations of AST and ALT, and subsides with abstinence. It is usually detected by the finding of hepatomegaly on physical examination or abnormalities on ultrasonography or CT but is confirmed only by liver biopsy. Fatty liver is usually a reversible disorder if the patient can refrain from drinking.[58]

Alcoholic Hepatitis Alcoholic hepatitis is a more serious complication than fatty infiltration and develops in up to 35% of heavy drinkers.[59] These individuals usually have right upper quadrant pain, a tender enlarged liver, fever, jaundice, leukocytosis, and altered liver function tests. AST levels are usually less than 300 IU/L, and ALT levels are typically less than one half the AST level. Alcoholic hepatitis can have a range of clinical manifestations, from mildly symptomatic hepatomegaly to fulminant hepatic failure. The severity of the disease can be estimated in the emergency department by a prolonged prothrombin time/international normalized ratio (INR).[60] Symptomatic patients with alcoholic hepatitis require admission. Emergency department evaluation includes complete blood count, electrolytes, blood urea nitrogen, glucose, prothrombin time/INR, liver function tests, and urinalysis. If the patient has an abnormal prothrombin time/INR and is actively bleeding, fresh frozen plasma should be started in the emergency department. Steroids are indicated in severe cases (encephalopathy, coagulopathy).[61] Steroids are not indicated in patients with gastrointestinal bleeding or concurrent infection. Up to 80% of patients who continue to drink after having alcoholic hepatitis eventually develop cirrhosis.

Alcoholic Cirrhosis Cirrhosis is the disruption of the normal architecture of the liver by scarring and regenerating nodules of parenchyma. Alcoholism is the most common cause of cirrhosis in the United States and is responsible for approximately 50% of all cirrhotic deaths. Alcoholic cirrhosis usually requires 10 to 15 years of chronic drinking, often punctuated by one or more episodes of acute hepatic decompensation. The clinical outcome is determined by the development of complications of portal hypertension and by hepatic dysfunction. We are just beginning to understand the pathogenesis of alcoholic cirrhosis in animal models. Why hepatic damage develops in some alcoholic patients and not in others exposed to identical amounts of alcohol remains a mystery. The disorder was originally described as “nutritional cirrhosis,” but it has been shown that alcohol, independent of malnutrition, produces liver damage. Alteration of the normal hepatic architecture by fibrosis and nodule formation may eventually lead to portal hypertension. Portal hypertension may in turn be complicated by ascites and esophageal varices. Alcoholic cirrhosis is the most common cause of hepatic encephalopathy.[58] Hepatitis C antibodies are found in one third to one half of alcoholics with ALD. Patients with ALD and hepatitis C have histologically more severe disease, shorter survival, and increased rates (by a factor of 10) of cirrhosis and liver cancer.[62] No specific therapy of proven benefit exists for ALD other than abstinence, proper diet, and management of the subsequent hepatic decompensation (i.e., ascites and encephalopathy). A 60% decrease in mortality has been associated with decreasing the amount of alcohol consumed over 1 year.[63] Liver biopsy is the only way to identify precisely which type of ALD is present. Biopsy is contraindicated in patients with coagulopathy that has not been corrected. Although cirrhosis is irreversible, its progression may be halted with abstinence.

Pancreas and Intestines The association of ethanol with pancreatitis is well established, but the exact pathogenesis still eludes investigators. Hypotheses include reflux of duodenal contents and bile into the pancreatic duct, obstruction by a plug of pancreatic juice rich in proteins, and a direct toxic effect of ethanol. Ethanol abuse is associated with both acute and chronic pancreatitis. The diagnosis of alcoholic pancreatitis can be difficult because asymptomatic alcoholics may have an elevated amylase level. In addition, up to 30% of patients with acute alcoholic pancreatitis have an amylase value within normal limits. Serum lipase rises after amylase and remains elevated longer. It appears to be a more reliable indicator of alcoholic pancreatitis, especially when more than three times normal.[64] Alcohol is only one of several causes of acute pancreatitis; other causes include biliary tract disease, hypercalcemia, hypertriglyceridemia, penetrating peptic ulcer, abdominal trauma, and reactions to various drugs. Alcohol is the leading cause of chronic pancreatitis.

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Diarrhea and impaired intestinal absorption are common problems of the chronic alcoholic. Alcohol increases small intestine transit time and decreases brush border enzyme activity. Thiamine, vitamin B12, amino acids, folic acid, and glucose have all been shown to have impaired absorption in alcoholics. Dietary deficiencies in folic acid and protein, pancreatic insufficiency, abnormal biliary secretion, and direct toxic effects of ethanol on the gastrointestinal tract all contribute to malabsorption. Abstinence and adequate nutrition reverse the diarrhea and much of the malabsorption.[58]

Neurologic Effects Altered Mental Status and Coma Alcohol is often associated with an altered level of consciousness. Coma or an altered mental state may be caused by acute intoxication, mixed alcohol-drug overdose, postictal states, head trauma, hypoglycemia, shock from gastrointestinal bleeding or sepsis, hypothermia, hyperthermia, hepatic encephalopathy, methanol–isopropyl alcohol–ethylene glycol poisoning, or Wernicke-Korsakoff syndrome. A potential pitfall for the clinician is ascribing the cause of the patient's altered mental state to acute intoxication without considering the aforementioned conditions. These potentially catastrophic diagnoses are usually revealed by a thorough history and physical examination, a blood alcohol level (coma is rare in patients with blood alcohol levels less than 200 mg/dL), and close observation (an intoxicated patient's LOC should constantly improve over time). Patients with a less than classical presentation or course should receive appropriate laboratory analysis and a head CT scan.

Neuropathy A symmetrical sensorimotor polyneuropathy is common after chronic alcohol abuse. It usually manifests itself in the lower extremities. Its causes are thought to be a combination of nutritional deficiency with thiamine or B12 deficit and a direct neurotoxic effect of alcohol. Burning pain and paresthesia are common presenting complaints. Findings on physical examination include loss of light touch, decreased pinprick, and reduced lower extremity deep tendon reflexes. Distal muscle weakness is a late finding. The neuropathy may lead to nonhealing ulcers on the feet. “Saturday night palsy” or “honeymooner's syndrome,” an entity caused by radial nerve compression, consists of wristdrop. The patient usually has spent the night with the arm drooped over the back of a chair, bench, or a companion, compressing the radial nerve against the humerus and producing a neurapraxia. Treatment of alcoholic neuropathy is abstinence, adequate diet, and thiamine. Complete recovery is rare. With radial nerve neurapraxia, function usually returns after a few weeks to months.

Wernicke-Korsakoff Syndrome The classical description of Wernicke's encephalopathy includes (1) oculomotor disturbances (usually nystagmus and ocular palsies), (2) abnormal mentation (usually confusion), and (3) ataxia resulting in part from thiamine deficiency. Currently, Wernicke's encephalopathy, a medical emergency with a mortality rate of 10% to 20%, remains a clinical diagnosis and is poorly recognized because the complete triad is found in as few as 12% of patients.[14] Alternatively, contemporary criteria require two of these signs: (1) dietary deficiencies, (2) oculomotor abnormalities, (3) cerebellar dysfunction, and (4) either an altered mental state or mild memory impairment.[65] The diagnosis should be entertained in any alcoholic or malnourished patient presenting with ocular abnormalities, ataxia, altered mental status, hypothermia, or coma. Genetic and environmental factors may also play a part in the pathogenesis in this disorder. An inborn enzymatic error, a thiamine-dependent enzyme, transketolase, is deficient or less responsive in some patients with the Wernicke-Korsakoff syndrome. This may explain why the disorder develops in only a few alcoholics. Persons with transketolase deficiency are asymptomatic until they are stressed by thiamine deficiency. Protracted vomiting, inadequate diet, and malabsorption all contribute to thiamine deficiency in the alcoholic.[66] Korsakoff's psychosis or amnesic state, also called alcohol-induced persisting amnestic disorder, is a disorder with primarily recent memory impairment, inability to learn new information or recall previously learned information, apathy, and confabulation. Although common, confabulation is not essential for the diagnosis. Age older than 40 years and many years of heavy alcohol use are risk factors. The onset may be abrupt or insidious. In addition to chronic alcoholism, thiamine deficiency should be considered in other chronically ill patients (e.g., AIDS, hyperemesis gravidarum, thyrotoxicosis) and those undergoing dialysis or long-term furosemide

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therapy for congestive heart failure and disseminated cancer.[] Alcoholics with altered mental status should receive thiamine (100 mg IV) and either a rapid blood glucose determination or empirical dextrose (25 g IV). Naloxone (0.08 mg IV) should be considered if warranted by the clinical picture. Treatment for Wernicke-Korsakoff syndrome consists of abstinence, adequate diet, and thiamine. The ophthalmoplegia and nystagmus usually have a good response to thiamine (hours to days). The ataxia and mental changes may take days to weeks to improve and usually have a poorer prognosis. Less than 25% of patients show any real recovery, 50% show some recovery, and the remainder show no response despite adequate thiamine replacement. Because magnesium is a cofactor for this enzyme system, serum levels should be corrected. Patients with Wernicke's syndrome require admission and aggressive thiamine and magnesium repletion. Recovery is variable in the Korsakoff or alcohol amnesic state.

Cerebrovascular Accident As with CAD, many studies have shown that drinking light to moderate amounts of alcohol may decrease the risk of ischemic stroke. Conversely, several studies have linked heavy drinking to an increased risk of intracranial hemorrhage and ischemic brain injury. Chronic alcohol consumption is believed to increase the risk of hemorrhage through alcohol-induced hypertension, impaired hemostasis, decreased circulating levels of clotting factors, excessive fibrinolysis, and disseminated intravascular coagulation. In addition, cardiac dysrhythmias or cardiomyopathy may precipitate thromboembolic phenomena.[68] Fifty percent of middle-aged patients (45 to 55 years) with no apparent cause for their cerebrovascular accidents suffer from alcoholism.[7]

Myopathy Several studies have reported elevated creatine kinase values in patients who had been on drinking sprees. Although these patients were asymptomatic, many had muscular tenderness on examination. In these patients, cardiomyopathy often coexists. Both acute and chronic forms of this myopathy are recognized. Many chronic alcoholics have mild proximal muscle weakness and muscle atrophy on examination. Type II muscle fiber atrophy is found in chronic alcoholic myopathy. The role of ethanol, toxic metabolites, hypokalemia, hypocalcemia, hypomagnesemia, hyponatremia, malnutrition, unrecognized compression or crush injury, and other factors in the pathogenesis of atrophy remains to be determined.[69]

Movement Disorders Alcohol withdrawal is associated with tremor, ataxia, and myoclonus. Acute alcohol consumption ameliorates essential tremor and myoclonus. Persistent tremor is occasionally seen in chronic alcoholism. This alcoholic tremor may persist up to 1 year after abstinence. Although the pathophysiology is poorly understood, studies have confirmed that essential tremor and alcoholic tremor are distinct entities.[70]

Alcoholic Cerebellar Degeneration Characterized by ataxia of the extremities, cerebellar ataxia of alcoholism results in a wide-based stance and uncoordinated gait. Lower extremity involvement predominates, although the arms may rarely be involved. Pathologic changes consist of degeneration of elements in the cerebellum, especially the Purkinje cells. The diagnosis is based on history, physical examination, and magnetic resonance imaging or CT (which show severe cerebellar atrophy). Treatment consists of abstinence, adequate nutrition, and thiamine. [71]

Infections Alcohol is an immunosuppressive drug. Animal and human studies have implicated acute and chronic ethanol ingestion in causing decreased serum bactericidal activity, impaired mononuclear phagocyte function, diminished cell-mediated immune functions, reduced delayed hypersensitivity reaction, and defective polymorphonuclear neutrophils. Neutropenia may be found in up to 8% of hospitalized alcoholics.[72 ]

Alcohol ingestion prevents the normal delivery (chemotaxis) of polymorphonuclear neutrophils to sites of bacterial infection. Chronic alcohol exposure depresses the development and expression of cell-mediated immunity. This depression may contribute to the high incidence of tuberculosis and head, neck, and upper gastrointestinal cancers in alcoholics. Alcohol's suppression of macrophage function reduces the reticuloendothelial system's ability to clear particles. This may contribute to spontaneous bacteremia, spontaneous peritonitis, and pneumonia. Primary antibody response to new antigens is also depressed.

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Malnutrition and liver failure also contribute to an immunocompromised state in the alcoholic. The most common infection seen in alcoholism is pneumonia. Associated risk factors for pneumonia in alcoholics include smoking, decreased ciliary function, decreased surfactant production, depressed cough reflex, malnutrition, and poor oral hygiene. Although alcoholic patients may contract a variety of bacterial pneumonias, Streptococcus pneumoniae is still the most common organism. Periods of alcoholic stupor with incomplete glottic closure and subsequent aspiration can lead to aspiration pneumonia. Klebsiella pneumoniae, classically associated with alcoholism, is currently more common in patients with cytotoxic chemotherapy, hematologic malignancy, and transplantation than the chronic alcoholic. In addition, these infections now tend to be nosocomial rather than community acquired.[72] Alcoholism is also associated with a higher incidence of tuberculosis—55 times higher than that of the general population in one study. Alcoholism itself does not seem to influence the long-term relapse rates in tuberculous patients if they have closely supervised therapy of adequate duration. Homeless alcoholic patients are believed to constitute an important reservoir of tuberculosis in the United States. Spontaneous bacterial peritonitis occurs in cirrhotic patients with ascites and has a high mortality rate (50% to 90%). A common presentation consists of fever, abdominal pain, and peritonitis. Escherichia coli, K. pneumoniae, and S. pneumoniae are the most common bacteria cultured from the ascitic fluid. Patients with ascites and fever should have a diagnostic paracentesis as part of their evaluation. Hepatitis C appears to be related to concomitant IV drug use rather than the direct effect of alcohol abuse. Alcoholism is associated with a high prevalence of unsafe sexual behavior and human immunodeficiency virus (HIV) seropositivity.[73] New evidence suggests a potential for greater immunologic changes in HIV-1– positive patients who also consume alcohol.[74] The most serious impairment of the various host defenses occurs in patients with alcoholic cirrhosis and liver failure. Chronic alcoholics with cirrhosis have been reported to develop spontaneous bacteremia and to have a higher incidence of bacterial endocarditis. Alcoholism and cirrhosis increase the mortality rate in pneumococcal meningitis. Fever in the chronic alcoholic may result from a vast array of causes. The most common infection remains pneumonia. Occult urinary tract infections are more common than expected. The most common noninfectious causes of fever are alcohol withdrawal and alcoholic hepatitis. A leukocytosis is associated with both, often making the differentiation from infection difficult. Both infectious and noninfectious causes may coexist, as well as multiple sources of infection. Most febrile alcoholics without an identifiable source are best served by hospitalization. After the appropriate cultures and Gram stain, treatment for spontaneous bacterial peritonitis consists of a third-generation cephalosporin such as cefotaxime. Inoculating 10 mL of ascitic fluid into blood culture bottles at the bedside increases the percentage of positive cultures.[75]

Endocrine Effects Male hypogonadism and feminism have long been recognized in chronic alcoholics. Alcohol's effects on both the testes and the hypothalamus decrease testosterone production in men.[76] Alcohol may cause impotence by CNS sedation, secondary depression, or decreased testosterone production. Decreased testosterone, increased estrogen (in patients with liver disease), and increased prolactin can lead to decreased libido, feminization, and gynecomastia in male alcoholics and to abnormalities in lactation and menstruation in women. In female alcoholics, increased levels of testosterone and estrogen are found. Estrogen replacement therapy may increase hormonal levels threefold and thus increase the risk of cholelithiasis and breast cancer.[77] It is difficult to distinguish between obesity, alcoholism, and Cushing's syndrome because facial fullness, weakness, fatigue, and easy bruising related to thinning of the skin can be present in all three conditions. An alcohol-induced pseudo-Cushing's syndrome has also been described that resolves with abstention.[76]

Metabolic Effects Carbohydrates Alcohol-induced hypoglycemia is relatively uncommon, occurring in 1% to 4% of intoxicated emergency department patients. It is more frequently seen in chronic alcoholics.[78] Coma, seizures, hemiparesis, and a variety of other neurologic signs have been described in patients presenting with alcohol-induced hypoglycemia. Starvation, depletion of liver glycogen stores, decreased plasma cortisol levels, impaired

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release of growth hormone, and inhibition of gluconeogenesis may contribute to this phenomenon. Hyperglycemia and diabetes may be found in chronic alcoholism. However, studies in men exploring the association between light to moderate alcohol use and risk for type 2 diabetes suggest that an inverse relationship may exist.[79] Alcohol abuse can lead to chronic pancreatitis, resulting in underproduction of insulin by the damaged pancreatic cells. Alcohol also impairs peripheral glucose utilization, causing a relative insulin resistance (similar to type 2 diabetes). In diabetic patients, alcohol can induce hypoglycemia and may also mask the signs of hypoglycemia. This effect has been found to be more prominent in the fasting state.[80] Ethanol can be found as an active ingredient in hundreds of prescription and nonprescription drugs. Concentrations of 60% or greater can be found in some oral preparations, which pose a potential threat to the pediatric patient by producing profound intoxication or alcohol-induced hypoglycemia. Children seem particularly susceptible because of relatively decreased glycogen stores and delayed diagnosis. Hypoglycemia can also be seen with aspirin intoxication, prior gastric bypass surgery, hypothermia, or overwhelming sepsis.

Lipids A reversible hypertriglyceridemia occurs in many chronic alcoholics. Ethanol increases hepatic synthesis of triglycerides. Abstention is necessary to reduce elevated triglyceride levels. Except for its relationship to fatty infiltration of the liver, the clinical significance of this hyperlipidemia is unknown.[81]

Uric Acid Hyperuricemia is common with heavy drinkers. Alcohol increases urate levels by inhibiting renal clearance of urate and increasing urate synthesis by enhancing the turnover of adenine nucleotides. Although alcohol use can exacerbate primary gout, it is unlikely that alcohol itself can induce secondary gout.

Electrolytes Ethanol has numerous effects on electrolytes and mineral metabolism as summarized in Table 184-2 . Hyponatremia and hypokalemia are common findings in active drinkers. Vomiting, diarrhea, magnesium depletion, malnutrition, and metabolic alkalosis contribute to these abnormalities. Table 184-2 -- Effect of Ethanol on Mineral Metabolism Mineral Cause of Depletion Additional Effect of Compartment Shifts Magnesium

Phosphorus

Calcium

Alcohol

↓ Hyperventilation

Diarrhea Poor intake Phosphate depletion Hyperaldosteronism

↓ Free fatty acids

Poor intake Diarrhea Metabolic alkalosis Hypomagnesemia

↓ Metabolic alkalosis ↓ Respiratory alkalosis ↓ Glucose (refeeding) ↑ Hypoparathyroidism (secondary to hypomagnesemia) ↑ Rhabdomyolysis

Poor intake

Steatorrhea Hypovitaminosis K

↓ Hypoparathyroidism (secondary to hypomagnesemia) ↓ Rhabdomyolysis ↓ Hypovitaminosis D ↓ Hyperphosphatemia ↓ Pancreatitis

Consequences Pseudohypoparathyroidis m Myopathy Potassium depletion Phosphate depletion ECG abnormalities Seizures Rhabdomyolysis Platelet dysfunction WBC dysfunction CNS dysfunction

Cardiac failure Renal tubular acidosis Tetany

Seizures

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Mineral

Cause of Depletion

Potassium

Additional Effect of Compartment Shifts

Consequences

↓ Hypoalbuminemia ↑ Recovery from rhabdomyolysis ↓ Glucose (refeeding) ↓ Hyperventilation ↑ Rhabdomyolysis

Poor intake Weakness Metabolic alkalosis Paralysis Hyperaldosteronism Myopathy Diarrhea Sudden death From Kaysen G, Noth R: The effects of alcohol on blood pressure and electrolytes. Med Clin North Am 68:239, 1984. ↓, out of plasma; ↑, into plasma. CNS, central nervous system; ECG, electrocardiographic; WBC, white blood cell.

Alcoholism may be the most common cause of severe magnesium deficiency in adult outpatients. Thirty percent of alcoholics are magnesium deficient as a result of malabsorption, malnutrition, diarrhea, vomiting, and increased urinary losses. Correcting the magnesium level has been shown to improve liver enzyme levels and to correct other electrolytes.[] Hypocalcemia is a common finding in alcoholic patients with magnesium depletion. The mechanism is related to diminished parathyroid hormone secretion, decreased tissue responsiveness to parathyroid hormone, decreased vitamin D metabolism, and decreased calcium release from bone independent of parathyroid hormone. Correction of magnesium depletion is necessary to restore calcium to normal levels. Hypoalbuminemia, pancreatitis, or vitamin D deficiency may also contribute to low serum calcium or low total body stores of calcium in the alcoholic patient.[82] Hypophosphatemia is found in 30% to 50% of admitted patients with alcoholism. Phosphorus depletion results from malnutrition, vomiting, respiratory alkalosis, diarrhea, enhanced release of calcitonin, phosphate-binding antacids, and urinary loss (related to vitamin D deficiency and secondary hyperparathyroidism). Hypophosphatemic patients are often found to have low magnesium levels.[83] Rehydration, carbohydrate repletion, and parenteral alimentation further exacerbate phosphorus depletion. Glucose bolus and infusion have been shown to produce a significant fall in serum inorganic phosphate levels. Severe hypophosphatemia (less than 1 mg/dL) has been associated with acute respiratory failure; myocardial depression; dysfunction of erythrocytes, leukocytes, and platelets; CNS irritability; and rhabdomyolysis. Although chronic alcoholics requiring admission often have potassium, magnesium, and phosphate depletion, empirical treatment with potassium and phosphate is discouraged. Serum levels and renal function should be determined. Unintended hyperkalemia and hyperphosphatemia can produce significant morbidity, and phosphate infusion exacerbates hypocalcemia if present. Because most magnesium is intracellular, a normal serum magnesium level does not necessarily mean that total body magnesium levels are normal. If the serum level is normal, total body levels may be either normal or low. As long as renal function is adequate, empirical magnesium treatment can be considered. Abstinence and a proper diet resolve electrolyte and nutritional deficiencies in the ambulatory alcoholic patient who is healthy enough to be treated as an outpatient. Correcting these problems is usually the responsibility of the admitting physician. Therapy may be initiated in the emergency department. In most cases, oral supplementation is sufficient. In more severe cases, to correct both hypokalemia and hypophosphatemia, 20 mEq of potassium phosphate per liter of IV solution can be given. Two grams (16.2 mEq) of magnesium sulfate (maximum 30 to 40 g/day) may be given IV at a rate not to exceed 150 mg/min (equivalent to 1.5 mL of 10% solution).

Alcoholic Ketoacidosis Alcoholic ketoacidosis most frequently occurs in severe chronic alcoholics who have had a recent binge followed 1 to 3 days later by protracted vomiting, decreased food intake, dehydration, and abstinence.

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Nausea, vomiting, and abdominal pain are common presenting complaints.[84] These patients have tachypnea, dehydration, ketonuria, and little or no glucosuria. Serum glucose levels are usually less than 200 mg/dL. Normal blood pH may be found despite ketonemia because of coexisting respiratory alkalosis and metabolic alkalosis. The exact mechanism responsible for this increase in ketone bodies is unclear. Acute starvation superimposed on chronic malnutrition, as well as release of an alcohol-induced block in ketogenesis allowing marked ketosis, may explain the disorder. An increased ratio of reduced (NADH) to unreduced nicotinamide adenine dinucleotide (NAD) in the alcoholic predisposes to the accumulation of p -hydroxybutyrate and the inhibition of gluconeogenesis. The common occurrence of hypoglycemia in alcoholic ketoacidosis adds further weight to this hypothesis. The alcoholic patient with metabolic acidosis presents an interesting challenge. Most of these patients have an increased anion gap acidosis. In addition, a very high osmolal gap (>25 mOsm/kg) has been found to be very specific (88%) for methanol or ethylene glycol ingestion.[85] Quick examination of a urine specimen in the emergency department can be helpful in determining the cause of the acidosis: glucosuria may suggest diabetes; crystalluria can be seen in ethylene glycol poisoning; low specific gravity, proteinuria, and casts can be seen in renal failure; leukocytes and bacteria are present with urosepsis; and significant ketones in an otherwise normal urine may indicate starvation or alcoholic ketosis. Treatment of alcoholic ketosis consists of volume replacement by normal saline, glucose, thiamine, and correction of hypokalemia. This can be accomplished with 5% dextrose in normal saline and either 30 mEq of potassium chloride or 30 mEq of oral potassium. Bicarbonate is seldom necessary for the uncomplicated case but may be considered in the rare patient who has a pH less than 7.1. If no serious complicating illness is present, the ketosis is reversed in 12 to 24 hours with this treatment. Clinical improvement may be detected within hours of therapy. Nevertheless, most patients with alcoholic ketoacidosis need 1 or 2 days of inpatient treatment to correct fluid, electrolyte, and nutritional balance.[3]

Hematologic Effects The alcoholic presents the clinician with a myriad of hematologic abnormalities. The direct toxic effect of ethanol and its metabolites, secondary nutritional deficiency, and hepatic disease, individually or in combination, affect red blood cells (RBCs), white blood cells (WBCs), platelets, hemostasis, and the immune system ( Table 184-3 ).[86] Table 184-3 -- Origins of Hematologic Disorders in Acute and Chronic Alcoholism Direct Effect of Nutritional Liver Involvement Alcohol Deficiency or Sequelae RBC disorders Hypervolemia Decreased production

Increased destruction

WBC disorders Morphologic changes

+

Vacuolization of precursors Megaloblastic anemia Sideroblastic anemia Iron deficiency anemia

+ + + +

RBC abnormalities Hypersplenism Hypophosphatemia

Hypersegmentation Megaloblastic

+ + +

+ +

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Direct Effect of Alcohol

Nutritional Deficiency

Liver Involvement or Sequelae

changes Decreased production

Granulocytopenia Lymphopenia

+ +

+

+

+

+

Altered function Granulocytes + Lymphocytes + Disorders of hemostasis Coagulation factors Vitamin K– dependent factors Other factors Platelets Quantitative Thrombocytopenia + Thrombocytosis Qualitative + From Hamilton GC, Jurisic MA: Top Emerg Med 6:75, 1984.

+

+

+

RBC, red blood cell; WBC, white blood cell.

Anemia A common effect of alcohol on the hematopoietic system is anemia. Several different mechanisms are responsible for anemia in the alcoholic. Megaloblastic anemia resulting from folate deficiency is the most common type of anemia in alcoholics. The mean corpuscular volume (MCV) is typically increased but may be normal when iron deficiency coexists. Malnutrition, inability of the cirrhotic liver to store folate, excessive urinary loss, and malabsorption decrease folate stores. Alcohol accelerates the development of megaloblastic anemia in individuals with depleted folate (MCV > 100 fL) stores by an unknown mechanism. Macrocytosis is the most common hematologic manifestation of the chronic alcoholic. It may be caused by folate deficiency, reticulocytosis (the younger reticulocytes are larger), liver disease (producing an abnormal lipid coating of RBC membrane), or vitamin B12 deficiency. The most common cause is the idiopathic macrocytosis of alcoholism. Iron deficiency anemia is common among alcoholic patients and usually is a result of blood loss from the gastrointestinal tract. Alcoholics are subject to chronic inflammatory diseases such as endocarditis, tuberculosis, empyema, lung abscess, malignancy, and hepatic disease. These chronic inflammatory illnesses can produce the anemia of chronic disease, a mild microcytic or normocytic anemia in which the serum iron is low, the total serum iron-binding capacity is low or low-normal, and serum ferritin is increased. With iron deficiency anemia the serum iron is decreased, the total serum iron-binding capacity is elevated, and serum ferritin is decreased. Ethanol also has a direct toxic effect on erythropoiesis. Bone marrow biopsies reveal vacuolization of erythroid precursors, resulting in decreased reticulocytosis and a reversible sideroblastic anemia. Sideroblastic anemia, usually in the presence of malnutrition with pyridoxine deficiency and folate deficiency, occurs in 25% to 30% of anemic alcoholics.

Hemolytic Syndromes and Erythrocyte Abnormalities A variety of hemolytic syndromes have been associated with alcoholism. Zieve's syndrome is a transient hemolytic anemia with hyperlipidemia and fatty infiltration of the liver. Acquired stomatocytosis, a condition characterized by abnormally shaped RBCs that are susceptible to hemolysis and acanthocytosis (spur cell

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anemia), has been associated with alcohol abuse. Zieve's syndrome and stomatocytosis may be reversed with abstinence. Spur cells are RBCs with spicules. Spur cell hemolytic anemia is frequently linked to alcoholics with cirrhosis. With jaundice and splenomegaly, spur cell hemolytic anemia is usually fatal. When severe hemolysis is present, remission is rare.[87] These syndromes are associated with liver disease, which alters the lipid composition of the RBC membrane, and congestive splenomegaly, which produces hemolysis. Severe hypophosphatemia (50 leukocytes per high-power field) or detection of combined leukocyte esterase and nitrite positivity on dipstick urinalysis.[] Urine culture and sensitivities are indicated for all patients who undergo treatment, but the decision to treat should be based on the patient's symptoms. Common pathogens in SCI patients include Escherichia coli, coagulase-negative Streptococcus, Klebsiella pneumoniae, and Pseudomonas aeruginosa . Initial treatment should consist of ciprofloxacin or norfloxacin for 7 to 10 days, with adjustments made on the basis of urine cultures and sensitivity.[] Symptomatic patients with indwelling catheters can be treated as outpatients with ciprofloxacin or norfloxacin. If sepsis is suspected or cannot be ruled out, the patient requires hospitalization.

Neurologic Problems Posttraumatic Syrinx Posttraumatic syrinx (cystic myelopathy) is defined as any fluid-filled cystic cavity in the spinal cord, other than enlargement of the central canal, occurring after trauma to the spinal cord. The cystic cavity does not communicate with the fourth ventricle, central canal, or subarachnoid space. The annual incidence is approximately 3% of all SCI patients and is more common in quadriplegics. It may occur up to 30 years after the original injury. Posttraumatic syrinx begins at the original site of cord injury and extends cephalad in 80% and caudad in 20% of patients. Extension is predominantly in larger cysts, which can range up to 35 cm long. The etiology of cystic myelopathy is unknown. One theory is that cavitation in the cord develops after hematomyelia or necrosis of a myelomalacic core that results from the original injury.[] Syrinx development is suggested by new onset of pain, numbness, sensory change, or weakness that may be exacerbated by laughing, coughing, sneezing, or straining. The pain can be dull, aching, and constant in the neck or behind the ear and at the same time burning and intermittent in the upper limbs. It is generally located at or above the site of the original spinal injury but may be referred to the abdomen or lower extremity. The diagnosis is made by magnetic resonance imaging (MRI) of the spinal cord. The treatment is neurosurgical removal of the syrinx fluid with instillation of a shunt to prevent its reaccumulation.

Orthopedic Problems Long bone fractures of the lower extremities occur in SCI patients, with an annual incidence from 0.3% to 2.5%. As SCI patients age, they experience an increased fracture rate, which may be the result of years of immobility-related bone loss. In any case of extremity swelling in an SCI patient, fracture should be considered in the differential diagnosis. Signs and symptoms may be minimal, even if the femur is involved.

Multiple Sclerosis Multiple sclerosis (MS) is an autoimmune disease of the CNS that reportedly affects 350,000 persons in the United States with an annual incidence of about 12,000.[77] MS typically arises between the ages of 18 and 45. MS occurs more commonly in individuals of western European ancestry and is uncommon in certain

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ethnic and racial groups, such as Eskimos, Native American Indians, and Africans.[2] Susceptibility is also associated with particular genetic factors, such as human leukocyte antigen HLA-DR2.[] The histopathologic lesion in MS is the plaque, which is a localized area of demyelination in the white matter tracts of the CNS. Myelin destruction is probably mediated by the combined actions of infiltrating T lymphocytes and macrophages. The inflammatory cells may also be the source of cytokines that lead to oligodendral death and axonal degeneration. These white matter plaques, visible by MRI, have a predilection for the periventricular areas of the cerebrum, brainstem, spinal cord, and optic nerves. The initial trigger for the disease process has yet to be identified but may be quite diverse. One hypothesis has considered the role of immune dysregulation in the development of an autoimmune response against CNS myelin antigens.[] Mechanistically, this may involve an infectious trigger (e.g., virus, bacteria) that generates antigen exposure followed by an initially appropriate neutralizing immune response.[] MS can be classified into a variety of subtypes. Most patients initially present with neurologic attacks followed by remissions. This type of MS is referred to as relapsing-remitting (RR) MS and affects 85% of patients. Primary progressive MS occurs in about 10% of the MS population and involves a steady, almost imperceptible myelopathy from the onset not associated with relapses. In this form of the disease there is a much lower level of inflammatory markers and an equal distribution in men and women. The secondary progressive (SP) subtype of MS is characterized by a steady, insidious progressive deterioration of neurologic function, with or without ongoing relapses. SP MS most commonly produces disability with myelopathy, including a decline in ambulation, spasticity, and bladder and bowel dysfunction.[] The spectrum of clinical signs and symptoms of MS is very diverse. The initial symptom of MS is often blurred or double vision, red-green color distortion, or even blindness in one eye. Optic neuritis is one of the most common findings. It occurs in up to 64% of MS patients at some time during their illness.[80] Patients typically complain of loss of central vision with pain on movement of the globe. Visual loss is usually unilateral, and other causes must be considered. Management of intraocular disease should include an ophthalmology consultation. No treatment has proved effective in optic neuritis, including steroids. Vertigo, vomiting, and nystagmus are present in 30% of patients and are due to lesions near the vestibular complex. Diplopia may stem from involvement of the third, fourth, or sixth cranial nerve or internuclear ophthalmoplegia. This lesion involves the medial longitudinal fasciculus running between the sixth and third nerve nucleus. Although common in MS, internuclear ophthalmoplegia can be seen in vascular disease, brainstem tumors, or Wernicke's encephalopathy. Lesions in the cerebellum produce ataxia, intention tremor, or affect fine movements of hands, feet, or speech.[79] Approximately half of all persons with MS experience cognitive impairments such as difficulties with concentration, attention, memory, and judgment, but such symptoms are usually mild and are frequently overlooked.[77] Abnormalities of the spinal cord may produce dysautonomias involving the vesicourethral and gastrointestinal tracts and sexual function. Bladder dysfunction is common and occurs in association with motor dysfunction of the lower extremities. Morbidity and mortality in more than half of patients with MS are secondary to hydronephrosis, pyelonephrosis, and septicemia from urologic dysfunction. Severe constipation and sexual dysfunction are present in patients with advanced MS. Fever, acute illness, and stress may acutely worsen symptoms in MS patients. Evaluation of the underlying cause of fever or illness is warranted. As the acute illness is treated, resolution of the underlying symptoms should occur. To diagnose MS, the patient must have either two or more discrete episodes at least 1 month apart or a slow or stepwise progression of symptoms over at least 6 months.[80] In addition, the patient should be between 10 and 50 years at onset with evidence of two or more lesions of the CNS demonstrated by clinical examination or MRI findings that should predominantly involve the white matter. Finally, CSF abnormalities (the presence of oligoclonal immunoglobulin G [IgG] bands, elevated IgG synthesis rate, and elevated IgG index) should be present. MRI scanning is abnormal in 85% to 95% of patients. Multiple discrete lesions are noted in the supratentorial white matter, especially the paraventricular area. With gadolinium enhancement, MRI distinguishes active from inactive lesions. CT scanning is useful to exclude structural lesions of the CNS.[] Magnetic resonance spectroscopy (MRS) is a new tool being used to investigate MS. Unlike MRI, which provides an anatomic picture of lesions, MRS yields information about the biochemistry of the brain in MS. Evoked potential tests, which measure the speed of the brain's response to visual, auditory, and sensory stimuli, can sometimes detect lesions the scanners miss. Like imaging technologies, evoked potentials are helpful but not conclusive because they cannot identify the cause of lesions.[79]

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Some patients may experience atypical symptoms. Spasticity and tonic muscle spasms are due to spinal cord lesions. Spasticity may be relieved by physical therapy or diazepam use. Painful spasms may respond to anticonvulsants such as phenytoin or carbamazepine. Patients confined to wheelchairs are at high risk for carpal tunnel syndrome, sciatic neuropathy, or peripheral neuropathy. The differential diagnosis of MS includes virtually any disease of the CNS that may cause focal deficits. These include stroke or transient ischemic attack, migraine headache, brain or spinal tumor, subdural hematoma, spinal degenerative disease, transverse myelitis, systemic lupus erythematosus and other vasculitides, Lyme disease, syphilis, human immunodeficiency virus infection, and adrenomyeloleukodystrophy. MS is a chronic disease characterized by periods of relapses and remission. The development of new symptoms does not change the prognosis or treatment. However, the emergency physician should not assume that each new neurologic symptom is due to MS. Careful history and examination of each symptom must be undertaken to avoid misdiagnosis. No treatment for MS has been found to be truly effective. Agents used in treatment have included corticosteroids, azathioprine, cyclophosphamide, cyclosporine, and interferon. Although corticosteroids have been the mainstay in treatment of MS, studies suggest they are not effective, and the effectiveness of high-dose parenteral methylprednisolone appears to be marginal.[] However, interferon-p 1a and 1b, glatiramer acetate, and intravenous immunoglobulin have been shown to decrease the rate of relapse.

KEY CONCEPTS {,

{,

Und ersta ndin g the spec ific medi cal disor ders that are asso ciate d with each type of disa bility can facilit ate the care of disa bled patie nts. Com plica tions in disa bled patie

Page 4790

nts may be asso ciate d with hightech nolo gy equi pme nt (e.g., gastr osto my tube s, CSF shun ts, trach eost omie s, Fole y cath eters ). {,

The care of a patie nt with ment al retar datio n can be enha nced by focu sing on rece nt chan ges in the patie nt's beha vior as

Page 4791

expl aine d by the care giver ; by obse rving nonv erbal com muni catio ns such as facia l expr essi on, gest uring , and post ure; by errin g on the side of perfo rmin g ancill ary tests or obse rving the patie nt in uncl ear case s; and by adeq uatel y pre medi catin g the patie nt for nece ssar

Page 4792

y proc edur es. {,

Patie nts with chro nic spin al cord injur y expe rienc e seve ral uniq ue probl ems inclu ding auto nomi c dysr eflexi a, ortho stati c hypo tensi on, supe rior mes enter ic arter y synd rom e, and postt rau mati c syrin x. An unde rstan ding of the pres entat ion

Page 4793

and treat ment of thes e disor ders impr oves the care thes e patie nts recei ve in the eme rgen cy depa rtme nt. The sign s and sym ptom s of intraabdo mina l cata strop hes and ortho pedi c fract ures can be subtl e in patie nts with chro nic SCI. {,

The new onse t of seiz ures in

Page 4794

patie nts with deve lopm ental disa bilitie s and new neur ologi c sym ptom s in patie nts with multi ple scler osis requi re eval uatio n and shou ld not be simp ly ascri bed to the unde rlyin g dise ase.

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Marx: Rosen's Emergency Medicine: Concepts and Clinical Practice, 6th ed., Copyright © 2006 Mosby, Inc.

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30. Strum PF: Femur fractures in institutionalized patients after hip spica immobilization. J Pediatr Orthop 1993;13:246. 31. Cumella S: Needs for oral care among people with intellectual disability not in contact with dental services. J Intellect Disabil Res2000;44:45. 32. Pschirrer ER, Yeomans ER: Does asphyxia cause cerebral palsy?. Semin Perinatol2000;3:215. 33. Murphy KP: Medical problems in adults with cerebral palsy: Case examples. Assist Technol1999;11:97. 34. Gertzen PC: Intrathecal baclofen infusion and subsequent orthopedic surgery in patients with spastic cerebral palsy. J Neurosurg1998;88:1009. 35. Wright FV: Evaluation of selective dorsal rhizotomy for the reduction of spasticity in cerebral palsy: A randomized controlled trial. Dev Med Child Neurol1998;40:239. 36. Graham HK: Botulinum toxin A in cerebral palsy: Functional outcomes. J Pediatr2000;137:300. 37. Ralston E: Physician's attitudes and beliefs about deaf patients. J Am Board Fam Pract1996;9:167. 38. Sneed S, Joss D: Deafness and hearing loss—A global health problem. Work1999;12:93. 39. Kurz RS: The effects of hearing impairment on health services utilization. Med Care1991;29:878. 40. Steinberg A: Deaf women: Experiences and perceptions of healthcare system access. J Womens Health2002;11:729. 41. Zazove P: The health status and health care utilization of deaf and hard-of-hearing persons. Arch Fam Med1993;2:745. 42. Ebert D, Heckerling P: Communication with deaf patients. Knowledge, beliefs and practices of physicians. JAMA1995;273:227. 43. Jackson J: Health care providers' responsibilities toward hearing-impaired patients. NJ Med2003;100:22. 44. Lotke M: She won't look at me. Ann Intern Med1995;123:54. 45. Moller MA: Working with visually impaired children and their families. Pediatr Clin North Am1993;40:881. 46. Thompson L, Kaufman L: The visually impaired child. Pediatr Clin North Am2003;50:225. 47. Alexander JT, Haid RW: Upper cervical trauma outcome assessment. Clin Neurosurg1997;44:305. 48. McKinley WO: Long term medical complications after traumatic spinal cord injury: A regional model systems analysis. Arch Phys Med Rehabil1999;80:1402. 49. Urdaneta F, Layon AJ: Respiratory complications in patients with traumatic cervical spine injuries: Case report and review of the literature. J Clin Anesth2003;15:398. 50. Chui WC: Ligamentous injuries of the cervical spine in unreliable blunt trauma patients: Incidence, evaluation and outcome. J Trauma2001;50:457. 51. Herr R, Speed J: The patient with spinal cord injury. In: Herr R, Cydulka R, ed.Emergency Care of the Compromised Patient, Philadelphia: JB Lippincott; 1994: 43-65. 52. Keely BR: Recognition and treatment of autonomic dysreflexia. Crit Care Nurs1998;17:170. 53. Blackmer J: Rehabilitation medicine 1. Autonomic dysreflexia. CMAJ2003;169:931. 54. Karlsson AK: Autonomic dysreflexia. Spinal Cord1991;37:383. 55. Kewalramani LS: Autonomic dysreflexia in traumatic myelopathy. Am J Phys Med1980;59:1. 56. McGuire TJ, Kumar VN: Autonomic dysreflexia in the spinal cord injured. What the physician should know about this medical emergency. Postgrad Med1986;80:81. 57. Blackmer J: Orthostatic hypotension in spinal cord injured patients. J Spinal Cord Med1997;20:212. 58. Schwartz JJ: Orthostatic hypotension II. Clinical diagnosis, testing and treatment. Arch Intern Med 1984;144:1037. 59. Waring WP, Karonas RS: Acute spinal cord injuries and the incidence of clinically occurring thromboembolic disease. Paraplegia1991;29:8. 60. Merli G: Etiology, incidence and prevention of deep venous thrombosis in acute spinal cord injury. Arch Phys Med Rehabil1993;74:199. 61. Sommer RM: Clinical physiologic considerations and anesthetic management of patients with spinal cord injury. In: Errico TJ, Bauer BA, Waugh T, ed.Spinal Trauma, Philadelphia: JB Lippincott; 1991: 435-453. 62. Powell M: Duplex ultrasound screening for deep vein thrombosis in spinal cord injured patients at rehabilitation admission. Arch Phys Med Rehabil1999;80:1044. 63. Tunaka M, Uchiyami M, Itano H: Gastroduodenal disease in chronic spinal cord injuries. Arch Surg 1979;114:185. 64. Ramos M: Recurrent superior mesenteric artery syndrome in a quadriplegic patient. Arch Phys Med Rehabil1975;56:86. 65. Strauther GR: Appendicitis in patients with previous spinal cord injury. Am J Surg1999;178:403. 66. Neumoyer LA: The acutely affected abdomen in paraplegic spinal cord injury patient. Ann Surg 1990;21:561. 67. Juler GL, Eltarai IM: The acute abdomen in spinal cord injury patients. Paraplegia1985;23:118. 68. Viroslav J, Rosenblatt R, Tomazevic S: Respiratory management, survival and quality of life for high level traumatic tetraplegias. Respir Care Clin North Am1996;2:313. 69. Montgomerie JZ: Infections in patients with spinal cord injuries. Clin Infect Dis1997;25:1285. 70. Sugarman B, Brown D, Musher D: Fever and infection in spinal cord patients. JAMA1982;278:66. 71. Siroky M: Pathogenesis of bacteriuria and infection in the spinal cord injured patient. Am J Med

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2002;113(Suppl 1A):67S. 72. Lightner DJ: Contemporary urologic management of patients with spinal cord injury. Mayo Clin Proc 1998;73:434. 73. Madersbacher HG: Neurologic bladder dysfunction. Curr Opin Urol1999;9:303. 74. Liptak GS: Screening for urinary tract infection in children with neurogenic bladders. Am J Phys Med Rehabil1993;72:122. 75. Pedersen SS: Peroral treatment with ciprofloxacin of patient with spinal cord lesion and bacteriuria caused by multiple resistant bacteria. Paraplegia1990;28:41. 76. Rossier AB: Posttraumatic cervical syringomyelia. Brain1985;108:439. 77. Frohman EM: Multiple sclerosis. Med Clin North Am2003;87:867. 78. O'Connor P: Key issues in the diagnosis and treatment of multiple sclerosis. Neurology2002;59(6 Suppl 3):S1. 79. Pellagrino T: The patient with multiple sclerosis. In: Herr R, Cydulka R, ed.Emergency Care of the Compromised Patient, Philadelphia: JB Lippincott; 1994: 91-99. 80. Rodriguez M: Multiple sclerosis: Basic concepts and hypothesis. Mayo Clin Proc1989;64:570. 81. Sharrack B: The effect of oral and intravenous methylprednisolone treatment on subsequent relapse rate in multiple sclerosis. J Neurol Sci2000;173:73. 82. Goodin DS: The use of immunosuppressive agents in the treatment of multiple sclerosis: A critical review. Neurology1991;41:980. 83. Palace J: New and old treatments for multiple sclerosis. Neurologia1998;13:162.

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Marx: Rosen's Emergency Medicine: Concepts and Clinical Practice, 6th ed., Copyright © 2006 Mosby, Inc.

Section VIII - The Patient in Pain Chapter 187 – Pain Management Paul M. Paris Donald M. Yealy

PERSPECTIVE The relief of acute pain is key in the modern practice of emergency medicine.[1] Why should pain relief assume such an importance to this specialty? 1. 2. 3. 4.

5.

Pain is the most common complaint of emergency department patients, seen in one half to three quarters of all patients.[] One essential mission of all health care providers is the relief or prevention of suffering, and we have the tools readily available for this mission. Patients judge physicians by how they treat pain. Satisfaction with emergency care often depends on the techniques and timeliness of analgesia as well as the discharge plans for pain relief.[4] Many of the diagnostic and therapeutic procedures in the practice of emergency medicine cause pain if appropriate analgesia is not used. Pain during subsequent procedures may actually be increased if successful analgesia was not provided during previous procedures.[5] Unrelieved pain is associated with a long list of potential negative physiologic outcomes, including, but not limited to, a. increased sympathetic outflow, b. increased peripheral vascular resistance, c. d. e. f. g.

6.

7.

increased myocardial oxygen consumption, increased production of carbon dioxide, hypercoagulability, decreased gastric motility, and decreased immune function.

The Joint Commission on Accreditation of Healthcare Organizations (JCAHO) now requires hospitals to develop comprehensive programs for the measurement, treatment, documentation, and institution of quality improvement efforts related to acute pain management.[6] Poorly treated acute pain can aid in the development of chronic pain syndromes.

Methods must be not only effective but also safe. Physicians often believe they practice safe analgesia because side effects seldom develop. In reality, physicians often prescribe a suboptimal drug in an inadequate dose at an excessive interval or via an inappropriate route.

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Pain relief is best addressed with a plan that incorporates administration, nurses, and clinicians. Triage algorithms should consider pain as a medical emergency. The degree of pain and the overall acuity should determine the rapidity of care. Pain scales should be used, with frequent charting of the patient's subjective report of degree of pain in a fashion analogous to the recording of vital signs. We provide an overview of the principles and practice of providing analgesia in emergency medicine. The definitions of important terms relating to analgesic practices are listed in Box 187-1 . BOX 187-1 Definitions of Terms Related to Analgesia

Analgesia—relief from pain Anesthesia—a state with five conditions as follows: 1. Analgesia 2. 3. 4. 5.

Amnesia Unconsciousness Muscle relaxation Physiologic stability

Local anesthesia—creating an area of insensibility to pain by the injection of a local anesthetic agent Hypnotic—an agent that promotes the onset of sleep Induction agent—a drug that promotes the quick, short-lived onset of unconsciousness, allowing endotracheal intubation to be performed (there should be unresponsiveness to command and loss of the ciliary reflex) Nociceptor—a receptor that is sensitive and responsible for transmitting a noxious stimulus Noxious stimulus—a stimulus that is damaging or potentially damaging and results in sensation of pain Pain—an unpleasant sensory and emotional experience arising from actual or potential tissue damage or described in terms of such damage Sedative—an agent that decreases activity, moderates excitability, and calms the patient Conscious sedation—pharmacologically producing a state of profound sedation while maintaining all protective reflexes Dissociative sedation—a chemically produced (e.g., ketamine) unique state with the following features: 1. Analgesia 2. 3. 4.

Amnesia Cooperation Maintenance of all protective reflexes

Unconscious sedation—sedation associated with loss of protective reflexes Rapid tranquilization—chemically sedating severely agitated or violent patients

ACUTE VERSUS CHRONIC PAIN Acute pain is a symptom of noxious or tissue-damaging stimulation produced by a tissue injury or illness ( Box 187-2 ). Acute pain usually is caused by an identifiable pathologic condition and serves the useful function of warning the individual that a potentially threatening illness or injury exists, thus motivating the patient to seek medical assistance. Acute pain also may force the patient to limit certain activities that could potentially exacerbate the underlying pathophysiology. Chronic pain is a complex disease that lasts for

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months to years and serves no useful function to the patient. It commonly has no readily identifiable or treatable cause. Patients with chronic pain commonly seek aid in the emergency department, presenting challenges to emergency physicians because there is no quick fix for their problems. They often have a multitude of problems that may include sleep and appetite disturbances, irritability, and somatic preoccupations. It is common for chronic pain patients to arouse animosity in the emergency department staff because of their demands and limited provider ability to “fix” things. BOX 187-2 Acute Versus Chronic Pain Acute Pain

Chronic Pain

Is a symptom of injury or illness

Is the problem

Serves a biologic purpose

Has no biologic function

Causes anxiety

Causes depression

Is associated with identifiable pathology May or may not be associated with identifiable pathology Is present for less than 6 months

Is present for more than 6 months

Adapted from Stewart CE, MacMurdo D: Chronic pain. In Paris PM, Stewart RD (eds): Pain Management in Emergency Medicine. Norwalk, Conn, Appleton & Lange, 1988.

Although acute pain often last days to weeks, and chronic pain for more than 3 months, this distinction does not define the emergency department approach to these two syndromes. For example, pain from bony metastases, while often long in duration, is best categorized as persistent acute pain (because of the underlying tissue distortion). Similarly, sickle-cell vaso-occlusive events are frequent but best considered recurrent or persistent acute pain syndromes rather than chronic. Another approach to categorization is to distinguish malignant “chronic” (applied solely because of duration) pain from other forms of chronic pain. Irrespective of the specific classification scheme used, acute pain (including malignant) therapy requires analgesia and removal of the cause (if possible), whereas chronic nonmalignant pain therapy seeks adaptation, return to functioning, and psychosocial improvements primarily. Patients with chronic pain syndromes visiting the emergency department can be classified into four categories ( Box 187-3 ). Therapy for groups 2 and 3 should involve referral to a multidisciplinary pain evaluation and treatment center where a team of professionals can attempt to treat the multiple manifestations of these diseases. Patients with a significant change in the pattern of their chronic pain caused by cancer or a terminal illness should be evaluated for a new process to account for the pain. Opioids should be used liberally to bring pain relief in patients with terminal illnesses.[7] The remainder of this chapter focuses on the treatment of acute pain. BOX 187-3 Categories of Chronic Pain Patients

1.

Patie nts with chro nic pain caus ed by canc er or a termi nal illnes

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2.

3.

4.

s (e.g., acqu ired imm unod efici ency synd rom e) Patie nts with wellkno wn synd rom es (e.g., tic doul oure ux) Patie nts with no obje ctivel y confi rme d caus e for the com plain ts Patie nts who are frank ly mali ngeri ng or feign ing pain

PATHOPHYSIOLOGY OF ACUTE PAIN Pain Conduction Pathways The pain experience can be divided into four separate processes, namely receptor activation, information transmission, signal modulation, and perception.

Receptor Activation The somatosensory system is responsible for sensation of pain as well as tactile, proprioceptive, and

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thermal sensations. Receptors responsible for transmitting information related to noxious stimuli are called nociceptors. These receptors are free nerve endings and are widespread throughout the skin and deeper tissues. They are capable of converting mechanical, thermal, or chemical stimulation into electrical activity. Strong mechanical pressure may result in a release of a variety of chemicals (potassium, prostaglandin, cyclic adenosine monophosphate, leukotrienes, bradykinins, serotonin, substance P, thromboxanes, platelet-activating factor) that sensitize receptors or actually result in conduction of nociceptive stimuli. Nociceptors in the viscera respond to different stimuli than those in the skin and soft tissues. Receptors are individually connected to a specific nerve fiber.

Information Transmission Peripheral Nerve Fibers All sensory neurons are composed of a cell body, which is located in the dorsal root ganglia, and a receptor located within a given dermatome. A variety of classification systems have been described to catalog nerve fibers, but the relatively simple system in Table 187-1 allows a basic understanding of the roles of different fibers. Table 187-1 -- Peripheral Nerve Fibers Fiber Sensation Dorsal Horn Termination A-p

Light touch

Ascending Tract

Conduction Mean Rate (M/sec) Diameter (mmol/L)

Myelin

Deep

Ipsilateral 100 15 Heavy dorsal column A-p 50 8 A-p3 Sharp pricking Superficial Contralateral 15 3 Thin spinothalamic tract C Long-lasting Superficial Contralateral 1 1 None burning spinothalamic tract Adapted from Paris PM, Uram M, Ginsburg MJ: Physiological mechanisms of pain. In Paris PM, Stewart RD (eds): Pain Management in Emergency Medicine. Norwalk, Conn, Appleton & Lange, 1988.

Dorsal Horn The dorsal horn is the gray matter in the posterior aspect of the spinal cord ( Figure 187-1 ). It is the anatomic area of the spinal cord where pain integration, modification, and relay occur. The dorsal horn is structured in six layers called laminae. Each lamina receives specific types of nerve fibers, and the various laminae are connected by multiple interneurons. Substantia gelatinosa is the term given to laminae II and III, and many of the A-p3 and C fibers synapse at this level of the spinal cord.

Figure 187-1 Diagram tracing the path of the m ajor tract that carries pain stim uli to the brain, the lateral spinothalam ic tract.

Ascending Tracts Associated with Pain and Tactile Stimuli Fibers carrying pain impulses exit the dorsal horn and ascend the spinal cord to the brain. The predominant pathways for pain conduction are the spinothalamic tract and the spinoreticular tract; both are located in the anterior lateral aspect of the spinal cord ( Figure 187-2 ).

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Figure 187-2 Cross-section of entire spinal cord with all m ajor tracts labeled. Spinothalam ic tract synapses in the thalam us, with third-order neurons ascending the som atosensory cortex.

The spinoreticular tract ends in synapses in the reticular formation, with subsequent neurons going to the thalamus and then to the cerebral cortex.

Signal Modulation It is now generally accepted that pain sensation can be modified—multiplied or divided—in the descending tracts that modulate sensory information that is transmitted from the periphery. The two primary pathways identified originate in the midbrain (periaqueductal gray matter and locus ceruleus) and medulla (nucleus raphe magnus and nucleus reticularis giganto-cellularis). The nociceptive modulation is transmitted to the spinal cord via the dorsolateral funiculus. Electrical stimulation of this pathway produces analgesia comparable to that produced with opioids. Several specific neurotransmitters are involved in these pathways, including serotonin and norepinephrine. It is believed that the activation of this system is responsible for the placebo effect.

Pain Perception and Reaction The threshold for the perception of a painful stimulus (that is, “Is pain present?”) is similar in everyone, whereas the threshold for pain tolerance varies widely. These thresholds can be lowered by certain chemicals (e.g., the mediators of inflammation). The discrete cognitive processes and pathways involved in the interpretation of painful stimuli remain a mystery, being affected by culture, personality, experiences, and the underlying emotional state. These reactions can be greatly influenced by both pharmacologic and nonpharmacologic interventions. For drugs such as nitrous oxide and low-dose opioids, much of the effect is on the cognitive interpretation and emotional reaction to pain rather than on the transmission of the pain stimulus. Noninvasive techniques (e.g., distraction and hypnosis) can limit pain perceptions and increase tolerance.

Sites of Analgesia At each level in the physiologic process of pain production or transmission, interventions are available to alter the process ( Table 187-2 ). Table 187-2 -- Sites and Mechanisms of Analgesia Modality Opioid analgesic agents

Nonsteroidal anti-inflammatory agents Local anesthetic agents Transcutaneous nerve stimulation Acupuncture Nitrous oxide Ketamine Hypnosis Biofeedback Music Placebo Distraction

Mechanisms of Action Bind to opiate receptors in the central nervous system and possibly periphery Block production of prostaglandins Block transmission of nerve impulses Closes “gate” in dorsal horn of spinal cord; may also be some endorphin component Same as transcutaneous nerve stimulation Blunts emotional reaction to pain; endogenous opioid system may play a role Dissociates thalamocortical and limbic systems Causes cognitive reinterpretation of pain stimulus Decreases muscle tension Decreases anxiety and allows cognitive focus on stimuli other than pain Activates descending pain inhibitory paths; also possibly endorphins Allows cognitive focus on stimuli other than pain

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Modality

Mechanisms of Action

MANAGEMENT PRINCIPLES Pain Evaluation and Documentation Pain is a complex experience—a composite of anatomic, chemical, and psychological factors that affect people differently. Unfortunately, no singular test or physiologic index exists to measure pain reliably.[8] Numerical rating scales, employing a verbal 0 to 10 “none to worst” report, have been validated in the emergency department setting.[9] Conversely, visual analogue scales, often consisting of a 10 cm straight line with anchors at either extreme (similar to verbal scales), are used in research because of beliefs regarding accuracy and reproducibility but offer little practical advantage over verbal reports in the daily practice of medicine ( Table 187-3 ).[10] Table 187-3 -- Techniques for Grading Pain Intensity Before and After Treatment[*] Techniqu How Pain Is Graded e

Five-point 0 = None global scale

Verbal quantitativ e scale

Visual analogue scale (10-cm line, slide-rule devices)

1 = A little 2 = Some 3 = A lot 4 = Worst possible 0 …5…10

Ap pli ca tio n Ro uti ne be dsi de ev alu ati on

Ro uti ne be dsi de ev alu ati on Ro uti ne be dsi de ev alu ati on W he n “h

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Techniqu How Pain Is Graded e

Ap pli ca tio n ar d co py” is de sir abl e Ca n be us ed wit h chi ldr en ag e6 ye ar s an d old er

Place a mark on the line to show how much pain you are having. Behavioral Restlessness, grimacing, vocalization, sweating, lacrimation, pupil dilation, tachycardia, and hypertension, and discoordinate mechanical ventilation may all be signs of pain. (These signs physiologi have not been validated so should be used with caution.) c parameter s

Observer- Can patient perform important functions associated with recovery (deep breathing, cough, generated spirometry, range of motion in joint, ambulation)? Yes/No assessme

Un co ns cio us ne ss, un re sp on siv e, co nfu se d, crit ica lly ill pat ien ts Adj un ct

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Techniqu How Pain Is Graded e

nt of function

Global satisfactio n question

Observergenerated pediatric pain

Ap pli ca tio n

to pat ien t-g en er ate d su bje cti ve pai n re po rts Sh oul d be us ed in all pat ien ts Are you satisfied with your pain relief? Cl arif Yes/No ica tio n of co nfu sin g re sp on se; for un so phi sti cat ed pat ien ts Observe facial expressions, crying, cardiorespiratory responses; compare with children who Ne are not in pain. on ate to

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Techniqu How Pain Is Graded e

Ap pli ca tio n

scales

ag e3 ye ar s an d so m e ag ed 36 ye ar s

Pa Over age 6 years and some aged 3-6 years tie a. nt- Pictori ge al ne rat ed pe Fa Point at (or circle, or color) the face that shows how you feel. dia ce tric s pai Dr Estimate location, character, intensity from drawing. n aw sc a ale pic s tur e of yo ur pai n b. Numer ic “Pi Poker chips represent pain that child can give to therapist. ec es of Hu rt” (p ok er chi ps ) Hu Similar to visual analogue scale for adults. rt

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Techniqu How Pain Is Graded e

Ap pli ca tio n

the rm o m ete r Modified from Ready BL, Edwards WT: Management of Acute Pain. Seattle, I.A.S.P. Publications, 1992. *

Many problem s can be m islabeled as pain. The reports of pain obtained using these techniques m ust be interpreted carefully. Pain should be assessed both at rest and during stim ulation (deep breathing, coughing, am bulation).

The only accurate barometer in treating pain is the patient's report. Pain behavior is unique to each individual and is a product of many influences, including past experiences with pain, cultural background, and the psychosocial makeup of the patient. Changes in facial expressions or vital signs do not correlate reliably with a patient's subjective sensation of pain. Patients may be experiencing severe pain despite smiles or even laughter. Simply stated, pain exists if the patient says it does. Including a pain scale as a routine part of vital signs is now mandated (by the JCAHO and other agencies) ( Box 187-4 ).[6] This encourages clinicians to initially and frequently communicate with patients to assess their pain. It also allows charts to be used for continuous quality improvement efforts to improve pain control practices on a departmental level. BOX 187-4 The Visual Analogue Pain Scale No pain 1

2

Unbearabl e pain 3

4

5

6

7

8

9

10

Oligoanalgesia Physicians in a variety of specialties tend to underestimate the degree of patient pain and, more importantly, undertreat it.[11] Numerous studies confirm inadequate treatment of pain by both physicians and nurses in a variety of medical and surgical settings involving adults and children. Studies in emergency departments have demonstrated the same insensitivity and lack of success in treating the acute pain state.[12] Data from the National Hospital Ambulatory Medical Survey evaluated all isolated closed fractures of extremities and clavicle and showed that only 64% of patients received an analgesic and only 42% received an opioid.[13] As in other studies, children and elderly patients were less likely to receive analgesics than patients in other age groups. Unfortunately, recent studies show only modest improvements in emergency medicine–based pain management. A recent review suggests that the oligoanalgesia phenomena may emanate from “(1) a lack of educational emphasis on pain management practices in nursing and medical school curricula and postgraduate training programs; (2) inadequate or nonexistent clinical quality management programs that evaluate pain management; (3) a paucity of rigorous studies of populations with special needs that improve pain management in the emergency department, particularly in geriatric and pediatric patients; (4) clinicians' attitudes toward opioid analgesics that result in inappropriate diagnosis of drug-seeking behavior and inappropriate concern about addiction, even in patients who have obvious acutely painful conditions and request pain relief; (5) inappropriate concerns about the safety of opioids compared with nonsteroidal anti-inflammatory drugs that result in their underuse (opiophobia); (6) unappreciated cultural and sex differences in pain reporting by patients and interpretation of pain reporting by providers; and (7) bias and disbelief of pain reporting according to racial and ethnic stereotyping.”[14] Even when analgesia is administered in the emergency department, there frequently is a long delay. When opioids are used, they frequently are given in subtherapeutic doses. One study of trauma centers showed

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that of the 38% of patients who did receive an analgesic, the average time of administration of the first dose of analgesic was 109 minutes after arrival.[15] One of the most common excuses for withholding analgesia in the emergency department is the fear of masking the diagnosis. This unproven historical belief, which originated before modern diagnostic approaches, including imaging, were developed, has no validity and has not been supported by any recent study. Patients can be made comfortable without impeding normal diagnostic approaches. Inadequate treatment of acute pain does not seem to be limited to the United States. A study in Costa Rica showed that analgesic agents were given to only 11% of adults and 4% of children.[16] The most striking finding was that opioids were not used for any patients, including those who had severe pain. A study from the United Kingdom looked at 172 children with limb trauma and discovered that only 49% received any analgesic, of which 70% received only paracetamol and 30% morphine. An Australian study of 176 patients with femoral neck fractures showed that only 49% received prehospital analgesia despite a protocol that would have encouraged analgesic use.

Priorities Correcting the problems of inadequate treatment of a patient's pain requires a major effort by educational institutions in all specialties of medicine, surgery, and emergency medicine. For emergency medicine, the approach to analgesia in acute care medicine must emphasize the following: 1.

2.

3.

Safety: Ongoing, untreated pain is harmful to the patient and must be mitigated. Conversely, analgesic agents can cause harm. Any analgesic procedure or agent must be administered with proper technique and monitoring to ensure safety. Speed of onset: Triage protocols can decrease time to administration of analgesics. Nebulized fentanyl can also provide rapid analgesia.[] Ease of administration: Techniques used must be suited to the emergency department environment and to staff resources. For most patients, oral agents given early are ideal, whereas intravenous medications are needed for severe pain or when oral use cannot occur.

Opioid Analgesic Agents In the emergency department, opioid analgesic agents are the mainstay of therapy for most of the conditions that cause moderate to severe acute pain.

Mechanism of Action The physiologic actions of opioids are primarily mediated through their binding to specific opiate receptors in the spinal cord and brain. Recently, peripheral opiate receptors have also been implicated in analgesia. Several different classes of opiate receptors exist, and the unique actions of various opioids are explained by the specific binding properties of the agent to the different receptors. The classification of opioid receptors is currently changing. The traditional classification system of using Greek letters, namely mu (p-), kappa (p&), delta (p3), and epsilon (ϵ) is changing ( Table 187-4 ). The Greek symbols have been replaced by their Arabic alphabet equivalents, followed by OP for “opioid peptide receptor.” Stimulation of opioid receptors inhibits pain conduction in nociceptive pathways by inhibiting the release of neurotransmitters. There is also inhibition of the postsynaptic membrane.

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Table 187-4 -- Opioid Receptors and Their Actions Receptor p- (MOP)

Action

p& (KOP)

Supraspinal analgesia Euphoria Miosis Urinary retention Low addiction potential Respiratory depression Gastrointestinal actions Cardiovascular effects Addiction risk Spinal analgesia

p3 (DOP) ϵ

Dysphoria* Psychotomimetic effects* Several subtypes proposed Low addiction potential Primarily spinal analgesia. Binds enkephalin Identified in animals

OP, opioid peptide receptor.

Common Therapeutic Mistakes Opioids are often poorly used.[12] Common mistakes seem to result from a lack of understanding of the basic pharmacologic principles of this class of analgesics ( Box 187-5 ). BOX 187-5 Common Errors in the Use of Opioid Analgesic Agents that Limit Their Efficacy

Relu ctan ce to use this clas s of agen ts Wro ng dose Wro ng route of admi nistr ation Wro ng frequ

Page 4812

ency Wro ng opioi d Inap prop riate use of adju nctiv e agen ts Exce ssiv e susp icion of drug -see king beha vior

Reluctance to Use Opioid Analgesic Agents In 1680, Sydenham wrote “among the remedies it has pleased Almighty God to give to man to relieve his sufferings, none is so universal and so efficacious as opium.”[19] Centuries later, this statement is still accurate, but a reluctance to use opioids continues to exist among clinicians. Physicians have an irrational fear of creating opioid addiction in patients or causing uncontrollable life-threatening side effects (e.g., respiratory depression). When comparing the occurrence and the severity of side effects, one can actually make a strong case that opioids are safer than nonsteroidal anti-inflammatory drugs (NSAIDs). The iatrogenic creation of opioid addiction, a new addiction where one did not previously exist, is a relatively rare phenomenon. The results of the Boston Drug Collaborative Study showed that only 4 in 11,892 inpatients treated with opioid analgesic agents developed new opioid abuse.[20] The authors concluded iatrogenic development of addiction is rare in medical patients treated with opioid analgesic agents unless they have a prior history of addiction. Even as lay press addiction stories abound (recently surrounding oxycodone preparations), many experts believe this most often represents a change in addiction rather than creation of a “new” addict.

Suspicion of Drug-Seeking Behavior Some patients feign pain to receive opioids. Suspected drug-seeking behavior should be well documented and the information relayed to other emergency physicians in a way that does not violate the Healthcare Insurance Portability and Accountability Act (HIPAA) or state or federal statutes. Patients should be given the benefit of the doubt until it is obvious the patient is trying to deceive the hospital staff. It is possible to maintain patient confidentiality and act in the best interest of the patient while maintaining files of suspected nontherapeutic drug seeking.[21] Such files must be stored in a secure fashion, such as a password-protected computerized system with limited access, and the process must be guided by the approval of a qualified individual or committee. If one is suspicious, but uncertain, of opioid-seeking behavior, use of parenteral opioids can be limited to those in the agonist-antagonist class (e.g., nalbuphine [Nubain] or butorphanol [Stadol]). These drugs work well as analgesic agents without creating much of the euphoria that opioid abusers may seek. Another approach is to tell patients they will be receiving a potent opioid analgesic agent that has very few side effects except in persons addicted to opioids, in which case it precipitates withdrawal symptoms. If the clinician is fooled and administers a parenteral opioid, it represents one consequence of having a humane approach to the treatment of acute pain. When writing prescriptions for oral opioids, caution must be taken if there is a suspicion of opioid abuse. In these cases, the number of pills should be limited and the drug that is

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most notorious for abuse, Oxycontin, should be avoided.

Wrong Dosage The most important factor in achieving adequate analgesia with a given opioid is titrating the dosage to achieve the desired degree of analgesia. A wide inter-patient variability exists in the effective analgesic concentration. The “one amp” approach of treating all patients with 10 mg of morphine is ineffective and potentially dangerous in many patients.[19] The proper way to achieve the effective dosage for moderate to severe pain is to use a deliberate intravenous titration.

Wrong Route of Administration The intramuscular route of administration of opioids—while common—has several disadvantages ( Box 187-6 ). The intramuscular route does not allow timely titration. When using the intramuscular route, one must estimate the proper dose and then wait 20 to 60 minutes to observe for peak effect. If too small a dose is used, the patient must experience another painful injection and wait another 20 to 60 minutes to determine whether effective analgesia is achieved. If too large a dose is given, the patient is at risk of side effects. In short, IM opioids have little role in acute pain management in the emergency department—most patients are best managed with oral agents if mild to moderate pain exists and intravenous agents if pain is moderate to severe. BOX 187-6 Disadvantages of Intramuscular Opioid Administration

Pain on injec tion Dela yed onse t of actio n Inabil ity to predi ct effec t Inabil ity to easil y titrat e dosa ge Diur nal varia tion in level achi eved Dise ase state may affec

Page 4814

t level achi eved Leve l depe nden t on mus cle used Hem atom as may occu r if coag ulop athy exist s Poor tech niqu e may dam age other struc tures If an intravenous line cannot be established, the subcutaneous route is preferable to the intramuscular route because it is less painful. The rate of absorption for a subcutaneous injection is almost identical to one given by the intramuscular route. Opioids can be delivered through the oral transmucosal or intranasal mucosal route.[] The potent opioid buprenorphine can be given by sublingual route. Fentanyl is available in an impregnated, sweetened matrix called a fentanyl oralet (oral transmucosal fentanyl citrate). Nasal butorphanol and sufentanil also produce rapid clinical effects.

Wrong Frequency Optimal use of opioids requires titrating the initial “loading” dose to desired relief of pain, then the administration of repeated doses at a frequent enough interval to prevent the return of significant discomfort. The best way to determine the need to administer another dose of opioid is to use the patient's subjective impression. The dose of opioid to prevent pain is less than the dose to treat well-established pain. Patient-controlled analgesia is a technique that uses a computerized delivery system that allows patients to self-administer a prescribed dose of opioid at a predetermined frequency based on their own determination of need. A recent study using patient-controlled analgesia for sickle cell pain crisis in a pediatric emergency department showed that this technique could be used safely and result in quicker care with high patient satisfaction.[24]

Wrong Opioid In general, most opioids are effective in achieving analgesia if given in the proper dose. The major exception to this rule is the use of oral codeine and propoxyphene. At any dose, codeine is a weak analgesic. Although it sometimes suffices for mild to moderate pain, it is rarely successful for moderate to severe pain. Codeine has a high incidence of inducing nausea, vomiting,

Page 4815

and constipation and can cause abdominal pain. Studies have not distinguished the analgesic superiority of acetaminophen plus codeine versus acetaminophen alone. Oxycodone and hydrocodone are excellent oral opioid analgesics. The long-acting oxycodone preparation Oxycontin has been abused so widely that its use in the practice of emergency medicine should be limited to management of patients with chronic pain of known cause (e.g., malignancy). Propoxyphene (Darvon, Darvocet) has limited indications for use. Many studies have shown its analgesic efficacy to be no better or only marginally better than placebo. In toxic doses, it can cause early refractory seizures, respiratory arrest, and significant risk of death. In those patients who have had success with the use of propoxyphene for past episodes of pain, it may be a reasonable choice for mild to moderate pain. Oral meperidine is similarly not recommended because of its unsatisfactory side effect profile, significant abuse potential, and lack of analgesic efficacy due to its significant hepatic first-pass metabolism. The most commonly used parenteral opioids are morphine, hydromorphone, and meperidine ( Table 187-5 ). Morphine has many advantages over meperidine, including a longer half-life, much less central nervous system (CNS) toxicity, a metabolism that is little affected by renal or hepatic disease, and no myocardial depression.[19] Hydromorphone has a longer half-life and effect than morphine, with similar actions otherwise. Table 187-5 -- Meperidine versus Morphine Meperidine

Morphine

Half-life

2½-3 hr

Parenteral potency Oral/parenteral potency Respiratory depression Abuse potential Metabolism Liver disease Renal disease Histamine release Biliary tract spasm Urinary tract spasm Side effects

2½-3 hr 1

/8 morphine

50% Moderate High Hepatic Half-life prolonged Increased CNS toxicity

15% Moderate High Hepatic Half-life unaffected Unaffected (active metabolite accumulation) Yes Significant Yes See text

Yes Significant Yes Similar to morphine but higher CNS toxicity Cardiovascular system Increased pulse, decreased No change or increased pulse, no contractility, decreased peripheral change in contractility, decreased vascular resistance peripheral vascular resistance Allergic reactions Extremely rare Extremely rare Constipation Minimal Moderate Cough suppression Minimal Marked Routes of administration PO, IM, IV, SQ PO, IM, IV, SQ Dose-response curve Very steep Steep Interaction with MAO inhibitors Potentially lethal Not reported Modified from Paris PM, Blenko JW: Narcotic agonist-antagonist analgesics. In Paris PM, Stewart RD (eds): Pain Management in Emergency Medicine. Norwalk, Conn, Appleton & Lange, 1988. CNS, central nervous system; IM, intramuscularly; IV, intravenously; MAO, monoamine oxidase; PO, orally; SQ, subcutaneously.

Meperidine is contraindicated in patients on monoamine oxidase inhibitors. Rare but potentially fatal

Page 4816

malignant hyperthermia may be induced by this combination. The historical rationale for using meperidine rather than morphine was based on a presumed lack of smooth muscle stimulation, notably biliary spasm. In reality, all opioid agonists have similar smooth muscle effect in equipotent doses. Because of the many advantages of morphine, it is the preferred agent for most situations in emergency medicine that require parenteral analgesia. Meperidine has been removed from pain treatment guidelines and many hospital formularies.

Incorrect Use of Adjuvant Agents Adjuvant analgesic agents have a primary indication other than pain relief but are often combined with analgesic agents to enhance pain relief. Some of the agents that have been used as adjuvant analgesics are antidepressants, neuroleptics, hydroxyzine, corticosteroids, benzodiazepines, anticonvulsants, and caffeine. A historical practice for clinicians was to use less than the full analgesic dose of an opioid and to combine it with another agent in an attempt to potentiate the given dose of opioid and decrease side effects (e.g., nausea, vomiting, and respiratory depression). In general, this practice could add to the potential toxicity of other agents. The most commonly used adjunctive agents for this purpose are phenothiazines and hydroxyzine (Vistaril, Atarax). Use of adequate and appropriate dosages of opioids provides at least equal efficacy at less cost than the use of a lower dosage of opioid with an adjuvant agent. Although many different phenothiazines have been used to potentiate the analgesic effect of opioids, most studies do not show any significant benefit of their use. Some authors believe that some phenothiazines (e.g., promethazine [Phenergan]) may be antianalgesic. Considering the side effects of phenothiazines and the absence of compelling evidence of efficacy, their use to potentiate opioids is not well founded. Hydroxyzine is commonly used as an adjunct to opioids. This drug has been shown to potentiate opioid analgesia. The major disadvantage of hydroxyzine is that it is not approved for intravenous use and therefore is most commonly given as a potentially painful intramuscular injection. Hydroxyzine can potentiate the sedation and respiratory depression associated with opioids. When titrating the dose of an opioid intravenously, there is little need for the routine use of hydroxyzine. In general, antinausea drugs are not used routinely when administering opioids, and nausea can be expected to abate when the pain is managed. Antinauseant medication should be reserved for cases of severe nausea and vomiting that persist after analgesia has been obtained.

Parenteral Opioids The terminology and classification system used to describe opioid analgesic agents can be confusing. The commonly used word narcotic has legal implications and is imprecise because it includes many classes of drugs that are not opioids. The term opiate defines a naturally occurring or semisynthetic derivative of opium alkaloid. The term opioid, as used in this chapter, is the most correct, because it refers to all natural opiates, plus all synthetic drugs that bind opiate receptors and produce effects similar to those of the natural opiates ( Table 187-6 ). Table 187-6 -- Opioid Classification Generic Proprietary Oral Dose Name Name

Parenteral Dose

Duration

Naturally Occurring Alkaloids and Semisynthetic Opiates Natural Morphine 30–60 mg 10 mg 3–4 hr sulfate

Codeine

30–100 mg

30–100 mg

4 hr

Comments

Precaution

Standard opioid for all comparisons. Duration may vary widely, especially in patients with severe pain, or elders. Excellent cough suppressant. Poor analgesic.

Respiratory depression, hypotension, histamine release, sedation.

Much constipation, nausea and vomiting. Decreased

Page 4817

Generic Name

Proprietary Name

Oral Dose

Parenteral Dose

Duration

Comments

Precaution with supine position. Abuse potential.

Semisynthetic Hydromorpho Dilaudid ne

2–6 mg

1–2 mg

2–4 hr

Hydrocodone Hycodan

5–10 mg

Not available

3–4 hr

5–10 mg

15 mg

3 hr

Parenteral Euphoria form not predisposes available in to abuse. United States. Very effective analgesic.

Percocet Tylox Meperidine and Related Phenylpiperidines Meperidine Demerol 250–300 mg 75–125 mg

2–3 hr

Fentanyl

Sublimaze

Not available

100–200 mg

1–2 hr

Alfentanil

Alfenta

Not available

1 mg/kg

1–1.5 hr

See Table 187-5 for comparison with morphine. No advantages and several disadvantages vs morphine. No histamine release. Good for short periods. Transcutaneo us and transmucosal absorption. Minimal cardiovascular side effects. Less potent, with shorter half-life than fentanyl. Shortest

Vicodan

Very soluble, allowing small volumes to be used for injection. Available as suppository. Excellent cough suppressant. Greater potency than codeine. Perhaps fewer side effects.

Much euphoria.

Greater abuse potential than codeine.

Lorcet Vicoprofen Oxycodone

Percodan

CNS tachycardia. Caution if renal or hepatic failure. Avoid with MAO inhibitors. May produce truncal rigidity in higher doses

Muscular rigidity in high dose or if administered too quickly. Expensive.

Page 4818

Generic Name

Sufentanil

Remifentanil

Proprietary Name

Sufenta

Ultiva

Oral Dose

Not available

Not available

Parenteral Dose

5–15 mg

Duration

1–1.5 hr

0.5–1 mg/kg

6 min

Methadone and Related Drugs Methadone Dolophine 10–20 mg

10 mg

4–6 hr

Propoxyphene Darvon-N

100 mg

Not available

3 hr

Nalorphine Type Pentazocine Talwin

50–100 mg

30–60 mg

2–3 hr

Nalbuphine

Nubain

40 mg

5–15 mg

3–4 hr

Butorphanol

Stadol

Not available

1–4 mg

4–7 hr

Dezocine

Dalgan

Not available

5–20 mg

Comments half-life of all opioids. Administered by intravenous infusion during general anesthesia. Minimal cardiovascular side effects. More potent, with shorter half-life than fentanyl.

Precaution

Muscular rigidity in high dose or if administered too quickly.

Expensive. Muscle rigidity and decreased blood pressure possible. Expensive. Analgesic half-life not the same as plasma half-life. Not much euphoria. Very weak analgesic.

Long plasma half-life may produce cumulative toxicity.

Overdoses are complicated and serious.

Suppositories Increased available. cardiac stroke work. High incidence of psychotomim etic effects. Minimal if any Can hemodynamic precipitate effects. withdrawal if Ceiling on dependence respiratory on opioid depression. agonist. Low abuse potential. Nasal Cardiovascula metered-dose r effects available. similar to pentazocine. Can precipitate withdrawal. More potent Mild

Page 4819

Generic Name

Proprietary Name

Oral Dose

Parenteral Dose

Duration

Comments

Precaution

analgesia than cardiovascula other r depression. agonists/antag onists. Buprenorphine Buprenex 0.3–0.6 mg 5–6 hr Partial Not agonist. Can completely be given antagonized sublingually. by naloxone. Long analgesic action. Adapted from Paris PM, Blenko JW: Opioid agonist-antagonist analgesics. In Paris PM, Stewart RD (eds): Pain Management in Emergency Medicine. Norwalk, Conn, Appleton & Lange, 1988. CNS, central nervous system; IV, intravenous; MAO, monoamine oxidase.

Morphine Morphine is the opioid analgesic agent to which all other opioids are compared. When administered intravenously, morphine reaches its peak of action in a few minutes and has a half-life of 1.5 to 2 hours in healthy young adults, and slightly longer in elderly patients. The clinical duration of action is variable but is in the range of 3 to 4 hours in most patients. It is common for repeat doses to be required earlier than the total duration interval, especially in patients with severe pain syndromes. Morphine is conjugated to an active and inactive metabolite in the liver, with renal excretion of the conjugate. The active metabolite is morphine-6-glucuronide; this substance has little analgesic activity but can cause profound sedation. The cardiovascular effects of analgesic doses of morphine are relatively minimal. Morphine does not decrease cardiac contractility, but it does cause the release of histamine, which results in peripheral venous and arteriolar dilation. The property of increasing venous capacitance is what makes morphine so helpful in the treatment of cardiogenic pulmonary edema. In patients who are relatively hypovolemic, this effect can lead to a decrease in blood pressure. If hypotension does occur, patients should first be treated with fluid administration and supine positioning. Naloxone is not effective at blocking the decreased peripheral vascular resistance. On occasion, morphine can increase vagal tone, leading to a decrease in heart rate. Like most other opioids, morphine releases histamine, which may result in urticaria and, rarely, an increase in bronchospasm in patients with reactive airways disease. True immunoglobulin-mediated allergies are rare for morphine and other opioids. Like other opioids, morphine has significant effects on the gastrointestinal tract. Morphine increases antral tone and decreases gastric motility, thereby delaying stomach emptying. Because colonic peristalsis is slowed significantly, constipation commonly results from opioid use. Morphine, like the other pure agonist opioids, causes a significant increase in biliary pressure.[19] The increased intrabiliary pressure usually is not associated with symptoms.

Meperidine Meperidine has several disadvantages compared with morphine (see Table 187-5 ). The duration of action of meperidine is only 2 to 3 hours, which is less than that of morphine. Perhaps the greatest disadvantage of meperidine is the CNS toxicity that is caused by a metabolite, normeperidine, which is a cerebral irritant. The adverse CNS actions that can be caused by normeperidine include anxiety, disorientation, tremors, seizures, hallucinations, and psychosis. Normeperidine is renally excreted and also has a longer half-life in elderly patients. Repeated doses of meperidine should be avoided when possible in patients with renal insufficiency and in elderly patients. Of particular concern is the potentially lethal interaction of meperidine with monoamine oxidase inhibitors. Meperidine can also cause a serotonin syndrome in patients who are taking a selective serotonin reuptake inhibitor.[25] The majority of studies have not definitively shown a marked advantage for the use of meperidine in patients with biliary tract disease or pancreatitis. Meperidine has been removed from formularies, or its

Page 4820

indication has been limited in many hospitals.

Fentanyl Fentanyl (Sublimaze) is a synthetic opioid of the phenylpiperidine group that has some unique properties that make it a useful agent in emergency medicine. The most prominent properties of fentanyl are its short half-life, lack of histamine release, and lack of decrease in cardiac contractility. Fentanyl is lipid soluble, which allows it to cross the blood-brain barrier rapidly and thus have a rapid onset of action (< 5 minutes). The half-life of fentanyl is 90 minutes, but the duration of action is often less because of redistribution, which makes it an ideal agent for brief procedures (e.g., dislocated joint relocation and incision and drainage of abscesses). Emergency department use of fentanyl is associated with a very low (1.1%) incidence of potentially serious complications.[26] Because fentanyl and its derivatives are the only opioid analgesic agents that do not release histamine, they are ideal for treating pain in patients with bronchospastic lung disease. High or repeated doses of fentanyl may produce muscle rigidity. This side effect usually occurs with anesthetic doses (>15 mg/kg) and may be so severe that it interferes with respiration but is exceedingly rare with analgesic use. This rigidity can be treated with naloxone or (if severe) neuromuscular blockade plus intubation. Fentanyl does not directly decrease cardiac output, but it may blunt central sympathetic output, which can potentially decrease cardiac output in selected patients who depend on sympathetic drive. Combining fentanyl with nitrous oxide or benzodiazepines can also cause mild cardiovascular compromise. Because fentanyl can be readily absorbed through the oral mucosa, it has been put into a candy matrix, oral transmucosal fentanyl citrate. This is particularly useful for treating children. The nebulized inhaled fentanyl has been described in the emergency department treatment of patients with abdominal pain.[18] Intranasal delivery of fentanyl in children with a variety of painful conditions also is an analgesic option.[17] Alfentanil (Alfenta) and sufentanil (Sufenta) are fentanyl derivatives with even shorter durations of action. These agents are commonly used for anesthesia and procedural analgesia/sedation, though not commonly in the emergency department. Sufentanil can also be given by the intranasal and transmucosal routes.[]

Remifentanil Remifentanil is the first opioid from a new class of ultrashort-acting 4-anilidopiperidines.[28] It is rapidly hydrolyzed by nonspecific plasma and tissue esterases with a duration of action of less than 6 minutes. Like fentanyl, it does not release histamine and seems to be safe for use in patients with renal failure and chronic liver disease. In large doses, it has also been associated with muscle rigidity, like fentanyl, and several cases of bradycardia have been described. Despite not increasing histamine concentrations, a mild decrease in blood pressure may occur. Because of its very short duration of action, this drug may play an increasing role in procedural analgesia/sedation. It is supplied as a lyophilized powder only available for intravenous use. There has been little emergency department experience with this drug.

Hydromorphone Hydromorphone (Dilaudid) has a few unique properties that make it useful for selected emergencies. It is a potent analgesic agent with excellent bioavailability when given orally. Since it lasts longer than morphine and many other opioids after an intravenous dose (4-6 hours), it is an excellent choice in many severe pain syndromes, especially sickle cell vaso-occlusive events. It is also one of the few opioids commercially available as a rectal suppository.[19] Because hydromorphone has high solubility, large doses of the drug can be given in small quantities of fluid for subcutaneous or intramuscular injection.

Opioid Agonist-Antagonist Analgesic Agents The agonist-antagonist group of opioids were synthesized in an attempt to provide analgesia with little or no respiratory depression and abuse. It is believed that the analgesia provided by these agents is caused by agonist action at the p& (KOP) receptors, whereas the ceiling on respiratory depression is caused by antagonism of the p- (MOP) receptors ( Box 187-7 , Table 187-6 ). BOX 187-7 Properties of the Agonist-Antagonists

Ceili ng on

Page 4821

respi rator y depr essi on Mod erate to pote nt anal gesi a in thera peuti c dose Less euph oria than agon ists Less abus e pote ntial than agon ists Slow er deve lopm ent of toler ance than agon ists Milde r with draw al than agon ists Prec ipitati on of with draw al in patie nts depe nden

Page 4822

t on agon ists Prob ably fewe r side effec ts than agon ists Exte nsiv e firstpass effec t with oral admi nistr ation (hep atic meta bolis m) Pos sible psyc hoto mim etic effec ts Sed ation most com mon side effec t Pent azoc ine only agon ist-a ntag onist subj ect to Cont rolle d Sub

Page 4823

stan ce Act Buto rpha nol avail able in nasa l spra y Adapted from Paris PM, Blenko JW: Opioid agonist-antagonist analgesic. In Paris PM, Stewart RD (eds). Pain Management in Emergency Medicine. Norwalk, Conn, Appleton & Lange, 1988.

The primary advantages of these drugs are the ceiling on respiratory depression (not absence) and diminished abuse potential. Some practitioners have also suggested that a ceiling may exist on analgesia, but whether this has clinical significance is unclear.

Pentazocine Pentazocine (Talwin) was first introduced in 1967. Today, because of its side effect profile, it has little use. The most significant side effect is a psychotomimetic reaction in up to 7% of patients taking this agent. This reaction may include visual or auditory hallucinations, disorientation, dysphoria, and feelings of depersonalization or panic. Another unique side effect of pentazocine is a fibrous myopathy that occurs after intramuscular injections. Abuse of pentazocine seems to occur less commonly than abuse of morphine or heroin but still is a problem. Winthrop Laboratories has now added 0.5 mg of naloxone to its tablets (Talwin Nx) to combat parenteral use of the oral form. Because naloxone is not absorbed through the gastrointestinal tract, the oral route for the drug remains effective. There are no emergency medicine indications for which pentazocine offers an advantage over other available opioids.

Nalbuphine Nalbuphine (Nubain) has many potential uses as a parenteral analgesic. Its major advantages are a ceiling on respiratory depression and no demonstrated cardiovascular side effects. The half-life of the drug is 3.5 hours, and the effects of renal or hepatic disease on metabolism are not completely known. Psychotomimetic reactions occur but in fewer than 1% of patients, which is much less often than with pentazocine.[29] Abuse potential of nalbuphine seems to be low. The usual therapeutic parenteral dose is 10 mg, but as with all other opioids, the dose must be individualized. Nalbuphine currently is not subject to regulation under the Controlled Substance Act. This fact may be a benefit in some emergency medical service systems[30] where opioids are currently not used because of the difficulties of maintaining distributions of controlled substances. When nalbuphine is used in a prehospital or hospital environment, patients subsequently may require higher doses of morphine or other pure p--agonist opioids.

Butorphanol Butorphanol (Stadol) is a synthetic opioid with properties similar to those of nalbuphine. One major difference, however, is that butorphanol increases systemic and pulmonary artery pressures. Because it increases cardiac afterload, butorphanol is not recommended in cases of myocardial infarction or states of decreased myocardial contractility. The major advantage of this drug is its transmucosal absorption, with a transnasal preparation commercially available.[31] The latter allows rapid, easily self-titrated analgesia to patients. Each nasal spray delivers 1 mg. The most common side effect of butorphanol is sedation. Psychotomimetic reactions have been described but are rare. The usual therapeutic dose is 2 to 4 mg. The half-life is 3 hours; hepatic metabolism and renal excretion both contribute to drug elimination.

Dezocine Dezocine is a newer agonist-antagonist opioid under investigation. Currently, it is not available in the united

Page 4824

states. It may provide more potent analgesia than other members of the agonist-antagonist class of drugs.[32 ] Dezocine does cause some respiratory depression, but it has a ceiling effect like the other agonist-antagonist opioids. It may cause mild cardiovascular depression in selected patients.

Buprenorphine Buprenorphine (Buprenex) is a semisynthetic opioid analgesic agent in the agonist-antagonist category, but it differs from the other drugs in that it acts as a partial agonist at the p- opiate receptor.[33] Opioid antagonists do not completely reverse the actions of buprenorphine. Buprenorphine is well absorbed orally and sublingually. Buprenorphine is gaining use in the treatment of opioid dependence. Little information has been published on analgesic uses of buprenorphine in emergency medicine.

Oral Opioids Many oral opioids suffer from the first-pass effect of hepatic metabolism, requiring the dosage to be adjusted accordingly. If the proper dosage is used, then the oral route is excellent for moderate pain and a good follow-up to intravenous analgesics for severe pain. Oral opioids are appropriate for moderate pain and are often safer and more effective than nonopioid analgesic agents. Most emergency medicine conditions for which oral opioid analgesics are prescribed are fairly short-lived and require no more than 10 to 20 doses, with cancer and sickle cell vaso-occlusive pain as notable exceptions. Codeine with acetaminophen or aspirin (Tylenol #4, Tylenol #3, Empirin with codeine, Bufferin with codeine) is a commonly used oral opioid. This group of preparations enjoyed great and undeserved popularity because of the relative lack of euphoria it produces and a belief that it has a lesser abuse potential. Codeine commonly produces nausea, often with vomiting. Even in higher doses, codeine is not a very effective analgesic agent, performing frequently no better than placebo. It has no legitimate role as an analgesic in modern emergency medicine practice. Patients under consideration for a codeine analgesic should simply be given acetaminophen or an NSAID. If the pain is believed to be too severe for an NSAID, a more potent opioid (e.g., oxycodone or hydrocodone) is indicated. Propoxyphene (Darvon, Darvocet-N) was once one of the most commonly prescribed drugs in the United States. This drug is a poor analgesic agent, only marginally if at all better than placebo. Overdoses with this opioid can be toxic, with refractory seizures and respiratory depression leading to death. For these reasons, the use of propoxyphene compounds in emergency medicine should be rare. Oxycodone (Percodan, Percocet, Tylox) is a potent, effective oral analgesic. The major drawback to this agent is that it causes significant euphoria in many patients, making it a popular drug of abuse. For moderate to severe acute pain, it is an excellent choice, but the quantity of pills prescribed should be limited to only a few days' supply for most emergency medicine indications. A long-acting oxycodone preparation (Oxycontin) has received much negative publicity because of its abuse potential. Although this agent has many indications for the treatment of chronic pain syndromes, it has few indications in the practice of emergency medicine. Hydrocodone (Anexsia, Zydone, Vicodin, Hycodan, Lorcet, Vicoprofen), a semisynthetic derivative of codeine, has gained great popularity in the last decade. Drug manufacturers have promoted it as more potent than codeine with fewer gastrointestinal side effects. The few controlled studies that have compared hydrocodone to codeine also suggest that it is a more effective analgesic with fewer side effects. Hydrocodone may cause some euphoria and has become one of the most commonly abused oral opioids.[ 34]

Oral morphine has one sixth the potency of parenteral morphine, but it is still an excellent analgesic agent if given in the proper dose. It is a mainstay of therapy in patients with cancer pain. In addition to short-acting oral preparations, a long-acting oral preparations (MS Contin) is available in 15, 30, 60, and 100 mg tablets. Oral meperidine has half the potency of the parenteral preparation, and it is generally not recommended because of the superiority of other oral agents. The risk of neurotoxicity may be higher when using meperidine orally. Methadone (Dolophine) is widely used as a treatment for opioid addiction. It is able to suppress opioid withdrawal and causes little or no euphoria. The long plasma half-life (24-36 hours) allows it to suppress opioid withdrawal with a single daily oral dose, but its duration of action as an analgesic is only 4 to 5 hours. When methadone is used to treat pain, care must be taken to avoid the increasing sedation that can occur with multiple daily doses.

Tramadol

Page 4825

Tramadol (Ultram, ultracet) is a unique centrally acting analgesic. The affinity of tramadol for the p- (MOP) receptor is 6000 times less than that of morphine; its analgesia persists in the presence of naloxone, leading to the conclusion that the opioid receptor binding activity accounts for only a fraction of its analgesic effect. Its other actions are caused by inhibition of reuptake of norepinephrine and serotonin. The major side effect to this agent is seizures, reported even in patients receiving therapeutic doses as well as occurring during sudden discontinuation of the drug. When administered with selective serotonin reuptake inhibitors, the risk of the serotonin syndrome is increased. This drug has a long history of widespread use in Europe; it is actually unrestricted in Germany and is the most popular analgesic agent in that country. Tramadol can be administered orally with 60% bioavailability and seems to have an excellent safety profile.[35] Respiratory depression has not been reported in recommended dosages. Tramadol has very little potential for abuse or addiction. Tramadol should be considered a mild analgesic and not a good choice for moderate to severe pain. In a dental model, tramadol was found to have similar effect to 60 mg of codeine but was less effective than a codeine/NSAID combination or a full-dose NSAID regimen.[36] An emergency department study of acute musculoskeletal pain showed tramadol to be less effective than any combination of hydrocodone plus acetaminophen.[37]

Opioid Use in Abdominal Pain In his treatise on abdominal pain, Cope stated, “Though it may appear cruel, it is really kind to withhold morphine until one is certain whether surgical interference is necessary, i.e., until a reasonable diagnosis has been made.” He added, “If morphine be administered, it is possible to die happy in the belief that he is on the road to recovery, and in some cases the medical attendant may for a time be induced to share the same delusive hope.” This outdated philosophy was written before modern diagnostic techniques were developed and before the ability to accurately titrate the intravenous use of opioids. Now, several studies have concluded that the titrated use of low doses of opioids does not interfere with the diagnostic timing and accuracy.[] Furthermore, many physicians have suggested that it actually improves the ability to make an accurate diagnosis by improving patient cooperation with examination. In the modern edition of the Cope text, the current author Silen stated that, “The cruel practice of withholding analgesics is to be condemned, but I suspect that it will take many generations to eliminate it because the rule has become so firmly ingrained in the minds of physicians.”[41] Several small studies have been conducted questioning the safety of administering opioid analgesics to children and adults with acute abdominal pain. Almost all of these studies have agreed that analgesic therapy provides relief of discomfort without compromising diagnosis or definitive therapy.[] When opioids are used in the treatment of abdominal pain, a few basic principles should be followed. The dosage of the opioid should be titrated to provide patient comfort but not to seek complete pain obliteration. While limiting the pain, the search for the cause and any change must be ongoing, often through repeat examinations, directed testing, surgical consultation, or close observation. Patients who have a resolution of pain should be observed for a few hours and be provided careful follow-up and discharge instructions if a nonemergency cause is found.

Nonopioid Analgesic Agents/Nonsteroidal Anti-Inflammatory Drugs Nonopioid analgesic agents are the most widely used analgesics in the practice of emergency medicine. The classification system for nonopioid analgesics is inexact. They have no anti-inflammatory activity, so they are not considered NSAIDs. The mechanism of action of NSAIDs is thought to be inhibition of the cyclooxygenase enzyme and thereby interference with prostaglandin production. NSAIDs also inhibit production of leukotrienes. The pharmacologic actions and therapeutic advantage of giving NSAIDs are dependent on the degree to which selected prostaglandins and leukotrienes are inhibited. Prostaglandin inhibition accounts for the antipyretic and anti-inflammatory properties. A newer class of NSAID agents, cyclooxygenase 2 (COX-2) inhibitors, are now available. These agents offer similar analgesic and anti-inflammatory effects to those of nonselective (and usually cheaper) traditional NSAIDs, with a lower degree of gastric and renal side effects. The magnitude of the latter benefits is debated and likely small and seen in high-risk patients or with prolonged use. In the emergency department, they offer no particular advantage over traditional NSAIDs in treating acute pain or inflammatory syndromes. The most commonly used of the nonopioid analgesic agents are aspirin, acetaminophen, and ibuprofen; however, more than 20 different NSAIDs are currently available in the United States. The most common emergency department indications for acetaminophen and NSAIDs include musculoskeletal pain,

Page 4826

dysmenorrhea, and headache. They are also effective for pain associated with inflammation such as pericarditis and pleuritis. The NSAIDs have become one of the mainstays of therapy in patients with renal colic. The inhibition of prostaglandin lessens renal capsule distention (through diminished renal blood flow) and ureteral peristalsis, causing less pain.[19] NSAIDs are also effective in providing some analgesia in patients with biliary colic.[44] Rather than decide between an NSAID and an opioid for colic syndromes, an optimal approach is to use both agents.

The Safety Myth The widespread use of acetaminophen and NSAIDs is largely the result of the perceived safety of these drugs, especially less respiratory depression and abuse potential. Although these drugs lack the selected side effects of opioids, they are not problem free and can cause significant morbidity and even mortality. Even the safest of the nonnarcotic analgesic agents, acetaminophen, has serious side effects. Because NSAIDs are associated with numerous potentially serious side effects, they should be used only when considered to be particularly effective for a given type of pain and not automatically prescribed for all pain conditions because of the misperception that they are “safer than opioids.”

Side Effects As a group, and because of their wide use, NSAIDs are responsible for more serious drug-related side effects than any other class of analgesic drugs. The majority of these side effects occur in patients who are taking NSAIDs for chronic conditions. It is estimated that there are more than 100,000 hospital admissions and approximately 16,500 deaths each year from gastrointestinal bleeding related to NSAID use for osteoarthritis and rheumatoid arthritis.[45] One survey estimated that for every 100,000 people taking NSAIDs each year, there are 300 gastrointestinal-related deaths, 5 liver-related deaths, 4 renal-related deaths, and some number of congestive heart failure–related deaths.[46] The major side effects of NSAID analgesic agents are gastrointestinal bleeding, renal failure, anaphylaxis, and platelet dysfunction. Aspirin is not recommended as an antipyretic for children with viral syndromes because of its association with Reye's syndrome. One of the little publicized theoretical concerns regarding NSAIDs is its potential inhibition of bone healing. Animal evidence suggests that prostaglandins promote bone formation and that NSAIDs might inhibit the process. Animal experiments have confirmed the inhibition of fracture healing, but human evidence is currently unconvincing.[47]

Routes of Administration The NSAIDs can be administered by the oral, rectal, topical ophthalmic, and parenteral routes. Indomethacin (Indocin) suppositories are useful in treating patients unable to tolerate oral medications because of vomiting. Ketorolac tromethamine (Toradol) is the first NSAID analgesic agent available for intravenous and intramuscular use in the United States. It is not more effective in relieving pain than other NSAIDs at equipotent doses. A study comparing 60 mg of intramuscular ketorolac to 800 mg of oral ibuprofen showed no difference in the efficacy of analgesia for the treatment of acute musculoskeletal pain.[48] In general, ketorolac is best used only in cases in which a parenteral NSAID is required, such as renal colic. Diclofenac ophthalmic solution has been shown to be effective in decreasing discomfort from corneal abrasions.[49]

Acetaminophen Acetaminophen has analgesic and antipyretic properties due to actions on the CNS. It has been postulated that acetaminophen may act on the recently identified COX-3 enzyme in the brain.[50] The analgesic actions of acetaminophen are comparable to those of NSAIDs, and it may be that the combination of acetaminophen with an NSAID actually improves analgesia. Acetaminophen's lack of peripheral activity accounts for its absence of anti-inflammatory properties. Acetaminophen is available in many formulations, including caplets, tablets, and liquid and rectal formulations. The recommended dose of acetaminophen for an adult is 325 to 1000 mg not to exceed 4000 mg/day. Acetaminophen is metabolized in the liver primarily through conjugation to sulfate or glucuronides. A minor pathway for the oxidative metabolism of acetaminophen produces the toxic metabolite N-acetyl-p -benzoquinoneimine (NAPQI). NABQI requires glutathione for detoxification and elimination. Hepatic toxicity can occur when glutathione pathways are overwhelmed by an increase in NAPQI or a decrease in glutathione. Hepatic toxicity is rare with ingestions less than 10 g in a 24-hour period unless underlying liver

Page 4827

disease exists or concomitant alcohol abuse is ongoing. In the latter cases, therapeutic doses can cause clinical hepatotoxicity.[51] Acetaminophen toxicity is discussed in Chapter 146 .

Ibuprofen Ibuprofen is the most widely used drug in the NSAID class. It is now available over the counter in a variety of preparations, including tablets, liquid suspension, and suppository. Ibuprofen is rapidly absorbed in the upper gastrointestinal tract. It is an excellent analgesic and there is little reason to think other NSAIDs offer any particular analgesic advantage. Ibuprofen has minimal interaction with other medications.

COX-2 Specific Inhibitors The NSAIDs produce analgesic, anti-inflammatory, and antipyretic effects primarily by altering production of leukotrienes ( Figure 187-3 ). This is accomplished via inhibition of cyclooxygenase, which is present in two isoforms in humans (COX-1 and COX-2). Most traditional (or nonselective) NSAIDs block both of these isoforms, although at low doses COX-1 effects are more prominent. Each isoform is found in specific areas ( Box 182-8 ). Another difference in these isoforms is in function and response to stimuli. COX-1 serves as a “clean up” or reparative agent in addition to anti-inflammatory and analgesic actions and is minimally increased after stimuli. COX-2 is normally present in lower levels but is inducible, and its levels are closely related to the response to stimuli, especially inflammation or injury.

Figure 187-3 Mechanism of action of nonsteroidal anti-inflam m atory drug.

BOX 187-8 Anatomic Distribution of COX-1 and COX-2

COX-1 Syno vium Sto mac h Plate lets End othel ial cells Kidn ey (arte ries, arteri oles, glom eruli, colle cting duct s) Man y other tissu

Page 4828

es

COX-2 Syno vium Cent ral nerv ous syst em Kidn ey (asc endi ng limb of Henl e, papill ae) Fem ale repr oduc tive tract Three agents, rofecoxib (Vioxx), celecoxib (Bextra), and valdecoxib (Celebrex), offer selective COX-2 inhibition and are approved for use in the United States. For practical purposes, these agents appear to share similar effect and side effect profiles, even though direct comparisons are lacking. In September 2004, merck announced a voluntary withdrawal of rofecoxib. Based on the APPROVe trial, there was a small but real increase for cardiovascular events, especially myocardial infarction and stroke in patients who had been taking rofecoxib for 18 months. The FDA is currently investigating closely this entire class of drugs. Nonetheless, these data have little impact on emergency department prescribing practice, where COX-2 agents offer no real advantage over nonselective agents, given the short duration of usual therapy. Celecoxib can be started at 100 mg bid or 200 mg once daily. The COX-2 inhibitors are eliminated primarily by the liver, with drug interactions similar to those seen with traditional NSAIDs (e.g., warfarin, lithium, angiotensin-converting enzyme inhibitors). Also, both agents (like traditional NSAIDs) can precipitate asthma, urticaria, and other allergic manifestations in patients with known aspirin hypersensitivity. Celecoxib is metabolized by the cytochrome P450 system and shares allergic potential with sulfonamides. The major advantage of the COX-2 inhibitors is the ability to provide anti-inflammatory effects and moderate analgesia with less risk of gastrointestinal side effects compared with nonselective NSAIDs, albeit at a much higher cost per dose.[52] Although the Food and Drug Administration–approved indications for the COX-2 inhibitors are not identical, each appears effective in persistent inflammatory pain syndromes (osteoarthritis and rheumatoid arthritis) and other leukotriene-mediated pain syndromes (e.g., dysmenorrhea and postsurgical pain). Their role in other pain syndromes that are often either short-lived (e.g., sprain, renal and biliary colic) or non-leukotriene-mediated (e.g., headache or sickle cell vaso-occlusive crisis) is not well studied, although COX-2 inhibitors will likely afford similar relief seen with equipotent doses of traditional NSAIDs. The COX-2 inhibitors are associated with fewer gastrointestinal effects compared with equipotent doses of traditional NSAIDs. Traditional NSAIDs used in anti-inflammatory doses on a regular basis produce a 10% to 20% rate of ulcer formation, although often asymptomatic and spontaneously healing after cessation of

Page 4829

therapy. When COX-2 inhibitors are used for similar periods, the rate of asymptomatic gastric irritation, erosion, and ulcer is much lower (approximately 3% to 10%) compared to nonselective NSAIDs. The rates of symptomatic gastrointestinal side effects, including perforation, obstruction, and gastrointestinal bleeding, are also lower, but the difference is much smaller (2%-4% with traditional NSAIDs vs 0.5-2% with COX-2 inhibitors, depending on doses used and concomitant use of low-dose aspirin).[53] The frequency of renal failure does not appear to be different between COX-2-inhibiting agents and traditional NSAIDs. COX-2 inhibitors also have limited effects on platelet function and bleeding time, although the benefit of this compared to traditional NSAID use in practice is not well defined. Patients prescribed a COX-2 inhibitor should be counseled about potential side effects, including the smaller but still present risk of upper gastrointestinal bleed, and drug/disease interactions rather than assuming that risk is eliminated. In particular, higher doses of either selective or nonselective agents increase the risk of symptomatic gastric complications, as does use together with other irritative agents (e.g., low-dose aspirin or corticosteroids). COX-2 inhibitors are many times more expensive than their nonselective siblings, and infrequently offer an advantage to offset the additional cost.

General Guidelines for Nonopioid Analgesic Agents Several general guidelines suggested by Kaplan may be useful when choosing a nonopioid analgesic agent[ 54] : {,

{,

{,

{,

{,

Elderly patients are more likely to suffer adverse effects from NSAIDs than are younger patients. For most indications, there is little clinical evidence that any one of these agents is consistently more effective than another, but in some cases, the patient may respond to one nonopioid analgesic and not another. There is a 50-fold cost differential between some of the newer NSAIDs such as ketorolac, diclofenac, etodolac, ketoprofen, celecoxib, and rofecoxib, and the older NSAIDs, such as aspirin, acetaminophen, ibuprofen, and naproxen. In patients to whom cost is of concern, prices should be considered in selecting an agent. A number of dosages or regimens are available for NSAIDs: Piroxicam, oxaprozin, nabumetone, Naprelan (naproxen sodium), and rofecoxib can be administered once daily; regular naproxen, etodolac, sulindac, diflunisal, ketoprofen (Oruvail) extended release, and other selected salicylate derivatives can be administered twice daily. Sustained-release indomethacin and celecoxib can be administered once or twice daily. Most NSAIDs have potent anti-inflammatory actions. Those possessing no or only minimal anti-inflammatory action include acetaminophen and mefenamic acid.

Page 4830

{,

{,

All NSAIDs have the potential for producing gastrointestinal distress. The least irritating NSAIDs appear to be nonacetylated salicylates, acetaminophen, ibuprofen, naproxen, and sulindac. The COX-2 NSAIDs offer little real safety benefit in short-term use (as is often prescribed in the emergency department). Hypersensitivity reactions can occur after initial administration or rechallenge with an NSAID. In aspirin-intolerant patients, it appears that acetaminophen has the lowest cross-reactivity. NSAIDs may interfere with the antihypertensive actions of numerous drugs.

Skeletal Muscle Relaxants Skeletal muscle relaxants have been marketed as an adjunct to analgesics in the management of musculoskeletal pain with a “spasm” component, principally back pain. This practice has been based on a number of small, poorly designed studies, and there is currently no clear evidence that the addition of a skeletal muscle relaxant to an analgesic offers any superiority over the analgesic (in adequate doses) alone. In one small trial, 10 mg of cyclobenzaprine three times a day was compared in a double-blind fashion with ibuprofen 800 mg three times a day in 77 patients with acute myofascial strain secondary to minor trauma.[ 55] There was no difference in pain scores or satisfaction, but there was an increased incidence of side effects in the group receiving the cyclobenzaprine. A meta-analysis of “muscle relaxants” for low back pain concluded that in the 30 trials that met inclusion criteria, there was insufficient evidence to demonstrate with statistical likelihood that these agents are more effective than placebo for short-term relief. Evidence is strong, however, that they are associated with an increase in CNS side effects, particularly sedation.[56] Skeletal muscle relaxants should not be used in the management of acute musculoskeletal pain as a substitute for proper doses of effective analgesics. A benzodiazepine, offering sedation and anxiolysis, may be a reasonable adjunct in cases of particularly disabling or difficult pain.

Nitrous Oxide/Oxygen Mixtures The analgesic and anesthetic properties of nitrous oxide were discovered more than 200 years ago. Combined with oxygen, a mixture of nitrous oxide and oxygen in a 50:50 ratio has been shown to be safe when self-administered by the patient. This technique is one of the original forms of patient-controlled analgesia. Nitrous oxide and oxygen administered by nasal mask have long been used by dentists. Experience in children would indicate that the nasal mask facilitates use in this group, but experience in emergency medicine with nitrous oxide has been greatest with self-administered hand-held masks in the ratio of 50:50.[57]

Basic Pharmacology and Physiology In its pure form, nitrous oxide is a colorless gas that is heavier than air. It is nonflammable but supports combustion when mixed with oxygen. The most notable physical property important for its use as a medical gas is its ability to diffuse through membranes, although it is poorly soluble in blood. The actual mechanism of analgesia and anxiolysis has not been fully delineated. In the two-tank, self-administered system, a fixed-ratio nitrous oxide/oxygen mixture is delivered to the patient through a demand valve activated when the patient inhales through a face mask or mouthpiece. A − 3 to − 5 cm H2O pressure must be produced within the mask or mouthpiece to activate the flow of gas. This element provides the fail-safe and patient-controlled aspects of the system. Physiologic effects of inhaling the gas mixture are slight with the low-dosage self-administered forms. No documented adverse hemodynamic effects have occurred with the self-administered forms of this agent. This safety has also been confirmed in the prehospital care setting.

Page 4831

The nitrous oxide-to-oxygen ratio must be adjusted for altitude because patients will not obtain adequate pain relief otherwise. At significant elevations (e.g., Denver, 5000ft), nitrous oxide may need to be increased to 70%. This would mean, however, that oxygen concentration is only 30%, which can be a problem in patients who need a greater degree of oxygen supplementation. In 10% to 15% of patients, nitrous oxide is ineffective.[57] It is much more potent as an anxiolytic than as an analgesic agent. As with all analgesic agents, its success should be determined by the patient's subjective feedback. When necessary, nitrous oxide should be supplemented with other analgesics.

Contraindications Nitrous oxide-oxygen mixtures are relatively or absolutely contraindicated in the following patients: {, {, {,

Those with altered consciousness or unable to follow instructions Patients with head injury Patients with decompression sickness

Patients with severe chronic obstructive pulmonary disease who retain CO2 should be given nitrous oxide-oxygen mixtures carefully because the mixture contains 50% oxygen. Because nitrous oxide does diffuse into body cavities, it can worsen a pneumothorax or bowel obstruction. However, one swine experiment failed to show any hemodynamic compromise as a result of nitrous oxide administration in an experimental pneumothorax model.[58]

Side Effects Minor side effects of the analgesic gas mixture have been reported in 5% to 50% of patients. Most common is light-headedness, with occasional patients complaining of paresthesias and nausea. Although the use of nitrous oxide for anesthesia has been associated for some years with nausea and vomiting, clinical experience and recent studies suggest that low-dosage forms do not cause a significant incidence of these complications. Side effects usually resolve within minutes of discontinuation.

Indications Nitrous oxide/oxygen mixtures can be used in the emergency department or prehospital care setting to reduce anxiety in patients and to manage mild to moderate pain states. The gas mixture is particularly useful in the prehospital environment to provide safe and effective sedation and analgesia to injured patients, particularly those who are trapped or facing a long extrication or transport time. Patients in labor and those suffering burns, fractures, and other trauma also respond favorably to nitrous oxide. Even minor procedures (e.g., venipuncture) may be an indication for nitrous oxide if the patient is extremely apprehensive and has a significant aversion to needles.

Precautions Nitrous oxide is a potent medication and should be dispensed with care and regard for patient and attendant safety. It should be used with a scavenging device to prevent trace concentrations in the environment being raised above National Institute of Occupational Safety and Health (NIOSH) standards. Roland and colleagues[59] showed a reduction in fertility among female dental assistants exposed to long periods of nitrous oxide at trace levels. Since that study, NIOSH has been very careful in recommending that scavenging devices be used routinely.[60] Scavenging devices are now available that collect exhaled air and remove it from the patient care areas. These devices can reduce nitrous oxide levels far below 1200 ppm, the level now considered standard for use with the agent in the emergency department. Nitrous oxide levels in ambulances vary with the airflow within the patient compartment of the vehicle. If air conditioning or fans are operating and the ambulance is moving, trace levels of nitrous oxide are reduced to safe levels even without scavenging devices. Chronic use or abuse of nitrous oxide has been associated with B12 antagonism and secondary hematologic effects as well as development of a myelopathy.[] Concern regarding abuse by medical personnel familiar with nitrous oxide use exists, although no cases of repeated abuse have been reported in ambulance or emergency department settings. A strict protocol of accountability for its use must be in place in both settings. Such a protocol should balance security with ready availability so that clinicians will not be dissuaded from using the agent for pain relief in patients. A

Page 4832

simple locking mechanism can be added to cylinders of the gas in the ambulance; in the emergency department, the delivery valve or mouthpiece can be locked in the drug box or opioid cupboard. After use of nitrous oxide, adults should not be allowed to drive a motor vehicle or operate machinery for at least 1 hour. Nitrous oxide can be used carefully in conjunction with intravenous opioids, but the dosage of opioids should be lowered and the patient watched carefully. The problems of oversedation with analgesic therapy are not so great when the self-administered form of nitrous oxide is used. Some myocardial depression has been described with the combined use of nitrous oxide and opioids.

Local Anesthesia Mechanism of Action Peripheral nerves are responsible for transmitting pain information from the pain receptors to the spinal cord. Nerve fibers themselves vary in their anatomy and function. Each fiber consists of an axon surrounded by a covering called the Schwann cell. The Schwann cell can cover the axon in numerous ways. If several axons are covered by a single-layer projection of one Schwann cell, the nerve fiber is said to be unmyelinated. A myelinated axon is one that is covered by the projection of a Schwann cell that wraps itself many times around the axon. Hence, the myelinated fiber has a many-layered phospholipid cover called the myelin sheath. Embedded in the phospholipid membrane are protein channels through which sodium and other ions can pass. An impulse is generated in the nerve fiber by a sudden influx of sodium ions through the protein channel, a process called depolarization. Repolarization follows, during which the resting transmembrane potential is reestablished through active transport mechanisms. Cutaneous pain receptors, when stimulated, cause sodium channels in the nerve endings to open, which depolarizes the nerve and causes the sensation of pain. Local anesthetics are much more effective at penetrating unmyelinated or lightly myelinated fibers than heavily myelinated ones. This differential explains the fact that ordinarily local anesthetic agents provide sensory block without a motor block. The effect of local anesthetic agents is the result of their ability to reversibly block the protein channel of the lipid membrane and therefore prevent the sudden influx of sodium ions into the axon (i.e., depolarization). Although other substances also can block the sodium channel, no substance does it as reliably, quickly, or effectively as local anesthetic agents, which do not have to be placed within the nerve because they penetrate the membrane on their own. The sequence of events after injection of a local anesthetic begins when tissue buffers increase the pH of the agent, thus releasing some of its lipid-soluble base form. Its lipid solubility allows this nonionized moiety to penetrate the lipid membrane of the axon where it then ionizes and enters the sodium channel, thus blocking it. A receptor is likely associated with this process. In simple terms, the ionized form of the agent plugs up the channel. Such a mechanism does not explain the action of benzocaine, for example, which does not ionize. It may be that benzocaine-like drugs cause the channel to swell, thus blocking the passage of sodium ions.

Classes of Local Anesthetic Agents Local anesthetic agents are chemical compounds that consist of an aromatic and an amine group separated by an intermediate chain. The class that has an ester link between the intermediate chain and aromatic portion are called amino esters; procaine, chloroprocaine, and tetracaine are the only ones in use today. Amides have an amide link and are more commonly used; lidocaine, mepivacaine, prilocaine, bupivacaine, and etidocaine are examples. Esters are unstable in solution and are metabolized in the body by the plasma enzyme cholinesterase. The amides, after absorption into the body, are destroyed by enzymes in the liver.[63]

Profiles Each local anesthetic has a predictable effect when used in appropriate doses and by the appropriate route. The main considerations in the clinical use of these agents are potency, duration of anesthesia, and speed of onset ( Table 187-7 ). Table 187-7 -- Characteristics of Common Local Anesthetic Agents

Page 4833

Agent

Trade Name(s) Potency (Lipid Soluble)

Procaine (ester) Novocaine

Tetracaine (ester)

Lidocaine (amide) Mepivacaine (amide)

Neocaine Pontocaine

Xylocaine Dilocaine Ultracaine Carbocaine

Duration (min)

Onset

Comments

1

60–90

Slow

Solutions of 0.5%-2%; infiltration, blocks

8

180–600

Slow

Topical eye Most commonly used; 1½ times as toxic as procaine infiltration, blocks

3

90–200

Rapid

2.4

120–240

Very rapid

Slightly less potent than lidocaine; 75% as toxic as procaine infiltration, blocks, epidurals Bupivacaine Marcaine 8 180–600 Intermediate Blocks; recent (amide) toxicity reported, now not used in emergency department for intravenous regional Etidocaine Duranest 6 180–600 Rapid Twice as toxic (amide) as lidocaine blocks; epidurals Modified from Paris PM, Weiss LD: Narcotic analgesics: The pure agonists. In Paris PM, Stewart RD (eds): Pain Management in Emergency Medicine. Norwalk, Conn, Appleton & Lange, 1988.

Potency The ability of a local anesthetic drug to penetrate the lipid membrane of the axon determines its potency. Agents that have a high lipid solubility (e.g., tetracaine, etidocaine) are more potent than those with a low lipid solubility (e.g., procaine, mepivacaine).

Duration of Anesthesia Agents that bind well to protein in the sodium channel are longer acting and provide anesthesia of long duration. Tetracaine and bupivacaine have a high affinity for protein and provide long-lasting anesthesia, whereas procaine, poorly bound, does not.

Onset of Action In most cases, it is helpful to have an anesthetic agent that acts quickly. The speed of onset of any local anesthetic agent is directly related to how quickly that agent, after injection, can diffuse through tissues to the nerve and through the nerve membrane to the axoplasm. After injection, the local anesthetic solution will be in two forms, ionized and nonionized. The percentage of the solution in the nonionized form is determined by the pKa of the agent (the pH at which 50% of the solution is nonionized and 50% is ionized). Because only the nonionized form of the agent will diffuse through membranes, solutions with a larger percentage of nonionized form at tissue pH have a more rapid onset of anesthesia. That is, local anesthetic agents with higher pKas take effect more slowly. At a tissue pH of 7.4, 5% of tetracaine (pKa 8.5) is in the nonionized form compared with 35% of lidocaine (pKa 7.9) solution. Low tissue pH (5 or 6) in surrounding infected tissue inhibits local anesthesia by direct infiltration in situations such as abscess incision and drainage,

Page 4834

because the anesthetic is primarily in an ionized state. Several other factors influence the clinical performance of local anesthetic agents. In the clinical dosages used, these agents (except cocaine) are vasodilators, which tend to shorten the duration of anesthesia. Injection of the solutions into vascular tissues not only shortens the duration of anesthesia but also increases systemic absorption and hence the chance of toxicity. For these reasons, a vasoconstrictor is sometimes added to local anesthetic solutions. Epinephrine, in a dose of 10 p-g/mL (1:200,000), is the usual additive. Less bleeding occurs when this preparation is used.

Allergy Patients sometimes provide a history of allergy to local anesthetic agents, but it is not an immunoglobulin-mediated true allergy. Allergy to ester agents has been reported and is most probably caused by the preservative methylparaben and its breakdown products. True allergy to the amide group is exceedingly rare. When allergy is reported, it is often caused by one of the preservatives used. Because the two groups do not cross-react, if a patient gives a history of allergy to an agent of one group, an agent from the other group can be used. A study of 236 patients with apparent adverse reactions to local anesthetics were tested using commercial preparations of unrelated local anesthetics. The study confirmed that no patient exhibited a systemic reaction.[64] In those patients who insist they are allergic to all “caine” anesthetic agents, and the allergy is believed to be legitimate (a very rare circumstance), diphenhydramine (Benadryl) can be used; 1 mL of a 50-mg/mL ampule can be diluted to 5 to 10 mL (1% to 0.5% solution) and can be used for local infiltration or nerve block. Diphenhydramine may cause direct tissue toxicity and should be avoided when possible in areas with poor collateral circulation (e.g., digits, penis, pinna, nose).[65]

Local and Systemic Toxicity Many reactions to local anesthetic infiltration are autonomically mediated (e.g., vasodepressor syncope) attacks from the injection or from the inadvertent intravascular injection of an anesthetic solution containing epinephrine; however, both local and systemic toxicity can occur, even when these agents are injected locally.

Local Toxicity Local anesthetic agents are directly toxic to tissue, depending on the concentration. The use of a vasoconstrictor in the anesthetic solution produces a reduction in blood flow that may theoretically increase the wound healing time and the vulnerability of the wound to infection, although this has never been demonstrated. Although the evidence of direct local toxicity and the role of vasoconstriction in the healing of wounds are controversial, it is perhaps wise clinical practice to restrict the use of vasoconstrictors to well-vascularized areas and to ensure that wounds are well irrigated. Nerve blocks are preferable to local infiltration for wounds that are contaminated or old. Epinephrine-containing solutions have traditionally been taught to be contraindicated on digits, the penis, ears, or the nose. Recent literature, however, suggests that dilute epinephrine can be used safely on digits and possibly these other areas as well.[] A comprehensive review of the use of epinephrine in digits has concluded that it was safe when diluted to 1:200,000 or less, but it should not be used in patients with vascular disease.[68]

Systemic Toxicity All local anesthetics can produce systemic toxicity in high blood or CNS concentrations. Table 187-8 provides a rough guideline to safe doses that can be administered for local anesthesia. It must be remembered that these “safe doses” depend on the location and rate of administration. As little as 1 mL of local anesthetic injected into the vertebral artery during a stellate ganglion block can cause seizures, while much larger doses are well tolerated when used in infiltration. The more lipophilic agents (e.g., etidocaine, bupivacaine) are more cardiotoxic. Cardiac toxicity is also increased by the use of epinephrine.[63] Special care should be exercised in children and in performing certain blocks known to produce high blood levels (e.g., intercostal). In pediatric patients, total dose guidelines are important and the maximum dose must be calculated before administration. Table 187-8 -- Guidelines for Maximum Doses of Commonly Used Agents[*] Agent Without Epinephrine With Epinephrine Lidocaine HCl[†]

3–5 mg/kg

7 mg/kg

Mepivacaine HCl

8 mg/kg

7 mg/kg[‡]

Page 4835

Agent

Without Epinephrine

With Epinephrine

[§]

Bupivacaine HCl 1.5 mg/kg 3 mg/kg Adapted from Stewart RD: Local anesthesia. In Paris PM, Stewart RD (eds): Pain Management in Emergency Medicine. Norwalk, Conn, Appleton & Lange, 1988. *

All m axim um doses should be reduced 20% to 25% in very young, old, and very sick patients.

†

A lidocaine level of 0.5 to 2.0 m g/m L m ay be reached for every 100 m g of lidocaine infiltrated for blocks.

‡

Epinephrine adds to the potential cardiac toxicity of this drug.

§

Not to be used for pudendal blocks or intravenous regional anesthesia. Not recom m ended for children younger than 12 years old.

Central Nervous System Toxicity. A wide variety of symptoms may be experienced by the patient with local anesthetic toxicity. These include light-headedness, headache, tingling of lips or tongue, drowsiness, ringing of ears, difficulty with concentration, abnormal body sensations, slurred speech, and twitches.[69] A very clear predicted relationship exists between the local anesthetic blood level and the CNS symptoms that are experienced. Increasing the intravenous dose of lidocaine from 1 mg/kg to 1.5 mg/kg increases the incidence of experiencing CNS subjective side effects from 10% to 80%. CNS toxicity may result in seizures. The clinical spectrum begins with drowsiness and progresses to confusion, convulsions, and coma. Direct intravascular injection of a large dose can provoke CNS symptoms, which usually begin with circumoral paresthesias, tinnitus, and light-headedness and progress to dysarthria, drowsiness, and tonic-clonic seizures. Longer-acting, more potent agents (e.g., bupivacaine and etidocaine) are more likely than lidocaine to cause CNS symptoms at lower blood levels.[69] Some classes of anticonvulsants (e.g., phenytoins [Dilantin]) are strikingly ineffective as prophylaxis or therapy for local anesthetic-induced seizures. The benzodiazepines work best for treating local anesthetic-induced seizures. Thiopental (pentothal), 50 to 100 mg IV, can also be used as an anticonvulsant.

Cardiovascular Effects. Local anesthetic agents have direct effects on cardiac automaticity, conductivity, contractility, and vascular tone. In animal experiments, the cardiac toxicity of bupivacaine is commonly seen before the CNS toxicity, and this toxicity is exacerbated by epinephrine. Management of cardiovascular collapse caused by toxic levels of local anesthetic agents should follow standard advanced cardiac life support guidelines. Unless the overdose is massive, the toxicity should be relatively short-lived because of the redistribution of the lipophilic agents. Hypotension can be treated with fluids and p -adrenergic agents. Dysrhythmias that occur should be treated by standard algorithms.

Reducing the Pain of Injection Counterirritation by scratching the skin or repetitive pinching of the skin during needle puncture or injection has been shown to reduce discomfort[70] ( Box 187-9 ). BOX 187-9 Techniques that Can Be Used to Reduce the Pain of Injection

Buff ering of local anes theti c agen ts Cou nterir ritati

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on Cha ngin g size of need le used Slow ing rate of injec tion Cha ngin g dept h of injec tion Cha ngin g site of injec tion Use of topic al anes theti cs War ming solut ion Distr actio n tech niqu es The addition of sodium bicarbonate to lidocaine immediately before injection significantly reduces patient discomfort.[] A standard preload syringe of sodium bicarbonate (8.4% in 50 mL) can be used as a multidose vial and the bicarbonate added to a syringe containing lidocaine in a ratio of 1:10 (e.g., 1 mL bicarbonate to 10 mL lidocaine, or 0.5 mL to 5 mL). Buffered lidocaine can be kept in the emergency department and has been shown to stay effective for up to 1 week.[73] Slow injection of this combination can produce painless anesthesia. Bupivacaine (Marcaine) can also be buffered, but the ratio should be 1:50 (i.e., 0.1 mL bicarbonate to 5 mL bupivacaine). One study concluded that slow injection attenuates pain of infiltration to a greater degree than buffering of the solution.[74] Injection of local anesthetic into the edges of the laceration has been shown to be less painful than injection through intact skin surrounding the wound.[75] On the other hand, subdermal injection requires more time to produce anesthesia, an effect not seen for at least 5 minutes. When time permits, warming the anesthetic or the application of a topical anesthetic agent can also greatly decrease the initial sensation associated with

Page 4837

needle injection.[]

Topical Anesthesia Several agents are useful when applied to mucosal surfaces. Caution must be used, as 1% equals 10 mg/mL of the anesthetic. Therefore, a 5% solution has 50 mg/mL. 1.

2.

3.

4.

5.

Cocaine: This agent is unique among local anesthetic agents because it is a potent vasoconstrictor and is therefore useful intranasally. A 4% (40 mg/mL) solution provides rapid and effective anesthesia for the treatment of epistaxis and other procedures on the nose. Higher concentrations are not necessary. Although the accurate dose is unknown, more than 200 mg should not be exceeded in adults. Cocaine should not be used in patients with known coronary artery disease because it may cause coronary artery vasoconstriction. It is also a component in TAC (tetracaine, epinephrine, and cocaine). Lidocaine: This drug, used in 2% or 4% solution in a viscous matrix, can be useful in endoscopic procedures, including passing nasogastric tubes and gastric lavage tubes. It can be helpful in the cleansing of open abrasions and “road rash.” Lidocaine jelly (2%) can be used for urethral anesthesia, but to be effective it must be injected into the urethra with a catheter-tip syringe and be in contact with the area for 5 to 20 minutes. Lidocaine spray (4%) has been demonstrated to decrease the discomfort of nasogastric tube insertion. Lidocaine spray (10%) is useful for upper airway anesthesia, including intranasal use. It is supplied in a metered-dose spray with a long delivery stem. Tetracaine: This potent ester is used for surface anesthesia of the cornea (Pontocaine) and is a component of TAC solution. Benzocaine: Almost insoluble in water, benzocaine is so poorly absorbed from mucous membranes that it is used commonly in intraoral preparations to dull the discomfort of needle puncture. It comes in various flavors. TAC: The combination of tetracaine, adrenaline (epinephrine), and cocaine (TAC)

Page 4838

6.

7.

was popular in the past, but has been largely replaced with LET and EMLA, which do not contain cocaine. Between 5 and 10 mL on sterile cotton is applied to the open wound, which is covered with gauze and held in place for 10 to 20 minutes. Complete anesthesia is evident in approximately 85% of cases of the scalp and face and a lower percentage of extremity wounds.[78] Application of the solution to the mucous membranes (eye, intranasal) can result in toxic blood levels of both tetracaine and cocaine; this complication has caused death.[79] LET: A solution of lidocaine, epinephrine, and tetracaine (LET) has been studied in an attempt to find an effective topical anesthetic solution that avoids the potential complications of cocaine. The solution has been called LET, TLE, and LAT. The combination of tetracaine, lidocaine, and epinephrine is as effective and less expensive than TAC.[] Since it requires 20 minutes for analgesia, one study showed success when the application was administered at the time of triage in children with a simple laceration.[84] EMLA: EMLA is a e utectic m ixture of l ocal a nesthetic agents— namely, lidocaine and prilocaine— along with some other chemicals to allow the mixture to be kept in oil phase.[85] Eutectic refers to a property whereby combining the agents results in a melting point that is higher than that of either agent alone. The mixture is thickened to a cream that should be applied on the desired area with an occlusive dressing 30 to 60 minutes before the desired procedure is performed. Heating the EMLA for 20 minutes improves analgesia over 20 minutes without heat but is far less effective than a routine 60 minute application with or without heat.[86] After such application, local anesthesia is achieved for 1 to 5 hours. Possible indications for use of EMLA would be venipuncture, arterial puncture, lumbar puncture, or arthrocentesis when a 30- to 60-minute delay in performing the procedure is not an impediment. It may be particularly

Page 4839

8.

useful in children. The most significant side effect is the development of methemoglobinemia. Currently, EMLA is not recommended for use on mucous membranes or for skin wounds. In open wounds, EMLA has a theoretical disadvantage of decreasing local tissue defenses.[ 87] It has limited depth of penetration; hence, for many procedures, it is advantageous to inject an additional anesthetic. Ethyl Chloride and Flori-Methane sprays: These sprays are occasionally used for limited skin incisions, e.g., small superficial abscess drainage. The agents evaporate quickly and supply a short-lived (less than 1 minute) but effective local anesthetic. Any injection or incision should be made immediately after or even during the application of the agent.

The major advantage to the use of topical anesthesia is that it is well tolerated and nonthreatening, especially to children. Although its use in wounds is questioned because of animal work showing increased wound infection and problem with healing times, recent clinical experience refutes this claim.[] It does demonstrate a benefit in starting intravenous lines, selected injection sites, and limited incisions.

Intravenous Regional Anesthesia (Bier Block) The intravenous regional anesthesia procedure is an effective and rapid technique to anesthetize extremities for fracture reduction or repair of extensive wounds. The method involves the intravenous injection of a local anesthetic agent (lidocaine, prilocaine) into a previously exsanguinated limb. This procedure has been adapted for use in the emergency department in the form of a minidose of 100 mg of lidocaine. A safe alternative is to use the relatively nontoxic local anesthetic agent prilocaine.

Nonpharmacologic Interventions Transcutaneous Electrical Nerve Stimulation Physicians have attempted to treat pain with electricity since 46 AD, when Scribonus Largus used the electric eel to provide analgesia for headache, arthritis, and gout. Modern use of electric stimulation was greatly accelerated with the publication of the gate control theory by Melzack and Wall in 1965.[89] This theory suggests that the selective stimulation of large myelinated A fibers closes a spinal cord gate, thereby inhibiting pain transmission of small unmyelinated C fibers. The basic components of a transcutaneous electric nerve stimulation system include a pulse generator, amplifier, and electrodes. Most transcutaneous electric nerve stimulation generators are capable of producing electric impulses with different waveforms, pulse widths, and frequencies. Some are also capable of modulating the patterns of stimulation. More simple and inexpensive disposable devices better suited to the practice of emergency medicine are also available.[90] While transcutaneous electric nerve stimulation has been successfully used in a variety of acute pain conditions such as fractured ribs and acute myofascial pain secondary to injury, it has not been well studied in emergency medicine.[91]

Hypnosis Trance can be accomplished quickly in the emergency department. The induction of trance allows the patient to refocus attention away from pain and anxiety-producing stimuli to other images and feelings. Hypnosis can be used as an adjunct to pharmacologic interventions or, in some cases, as a substitute. Trance can often be induced after the clinician utters just a few sentences.[92]

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When using nitrous oxide, patients are susceptible to suggestion. The clinician can enhance the efficacy of nitrous oxide administration by taking advantage of the trance and using the techniques of guided imagery and posthypnotic suggestion. Even when trance induction is not formally attempted, the verbal skills used in hypnosis can be valuable in most therapeutic encounters.

Psychological Techniques One of the most neglected aspects of the treatment of pain is the attention to the psychological factors involved in reaction to a given painful stimulus and the use of proper communication techniques to ameliorate pain and suffering. Patients who present to the emergency department in pain are focused on the painful stimuli and the threatening, unfamiliar environment of the hospital. They are frightened by the loss of control and fear of what the pain represents. By recognizing these patient concerns and establishing a trusting physician-patient relationship, the physician can mitigate reactions to a given painful stimulus and lessen the suffering. Attempts should be made to distract patients from the pain of their condition or procedures they must undergo. Providing patients with a portable stereo cassette player and their choice of music lessens their pain during laceration repair.[93]

Pain Management in Children Several studies have shown that children are less likely than adults to receive analgesic agents for their painful conditions. Although safety should be a primary concern with any therapeutic intervention, when used properly most of the techniques described in this chapter can be adapted to use in children. Overall, the same general principles that apply to providing analgesia to adults apply to children. The major difference in providing analgesia to children is the difficulty of accurately assessing subjective sensation of pain, particularly in the very young. The most common indication for providing analgesia in children in an emergency department is for procedural analgesia and sedation. The same drugs used for analgesia in adults are safe in children in size- and age-adjusted doses. The general approach to a child can be important in developing a trusting relationship with both child and parent. Techniques in communicating with children should take into account the unique developmental aspects of each age group. Words should be chosen carefully, with care taken to avoid threatening words. All equipment (e.g., syringes, scissors, and suture holders) should be kept out of sight of the child. Play therapy and a slow, friendly, nonthreatening manner can be invaluable. The decision to separate children from their parents must be individualized, but many authorities suggest avoiding the separation when possible. Parents can help distract the child and reinforce the suggestions of the medical team. Children deserve even more attention than adults with regard to safe and effective analgesia because their early experiences will affect their lifelong outlook and trust in the medical profession. Recently, there has been much interest in providing children analgesia and sedation by less threatening routes of administration. Transmucosal fentanyl in the form of lollipops and transnasal butorphanol and transnasal midazolam are examples.

Pediatric Pharmacology Most of the principles relating to the pharmacokinetics of drugs, including absorption, distribution, and elimination, are similar for children and adults.[94] In neonates and infants younger than 3 months old, clearance of opioids may be slow compared with older children. Opioids in this age group may also have a greater effect because of decreased protein binding, resulting in higher levels of free drug, and an immature blood-brain barrier that allows passage of a greater degree of opioid. These patients need to have lower dosages of local anesthetics because of decreased protein binding and decreased metabolism. For mild pain, acetaminophen can be very effective in doses of 15 mg/kg orally or 20 mg/kg rectally every 4 hours. Aspirin is also an excellent analgesic but should be avoided during febrile illnesses because of the possible relationship to Reye's syndrome. Tolectin, ibuprofen, and naproxen are officially approved for use in children and are probably equally efficacious for painful conditions.

Pain Management in the Elderly Approximately 80% of elderly patients have at least one chronic ailment commonly associated with pain.[95] Many studies have attempted to determine whether people lose pain sensitivity with increasing age, but results have varied with different experimental models. Extra caution must be taken to avoid side effects when using analgesic agents in elderly patients. This group needs lower dosages of opioid analgesic agents. In addition, opioids seem to produce sedation and constipation more often. NSAIDs must also be used cautiously in this group because of the many potentially serious side effects (e.g., worsening renal function

Page 4841

and gastrointestinal bleeding).

Prehospital Analgesia Because the prehospital environment is less controlled, safety becomes of paramount importance during analgesic administration. The basic tenets of establishing rapport with the patient, providing reassurance, using gentle movement and handling, using proper splinting, and controlling the temperature are the groundwork on which pharmacologic support can be added.[96] Unfortunately, despite protocols allowing for use of drugs such as nitrous oxide and opioids, moderate to severe pain is treated in only the minority of patients in the prehospital environment.[97] The study of lower extremity or hip fractures showed that only 18% of patients received an analgesic.[98] Another study of suspected extremity fractures showed that despite a protocol allowing the use of either morphine sulfate or nitrous oxide, among 1073 patients analgesia was administered to only 18 patients (1.8%). These studies have led the National Association of EMS Physicians to publish a position paper encouraging more liberal use of analgesics in the prehospital environment.[99] Self-administered 50% nitrous oxide offers many advantages for use in the field. Opioids also should be used when indicated. For the pain of myocardial ischemia, morphine should be titrated. Nalbuphine also has been described as safe and effective in the field treatment of trauma patients.[30] In disaster and war situations, ketamine has been described as a useful analgesic agent in the field. Fentanyl has been shown to be a safe analgesic agent in prehospital air medicine use.

KEY CONCEPTS {,

Pain is best treat ed early ; untre ated or unde rtrea ted pain bege ts mor e pain. A corol lary is not to allow previ ous relief to com plete ly vani sh befor

Page 4842

{,

{,

e redo sing (whe ther orall y or pare ntera lly). Anal gesi a and a sear ch for the caus e of pain shou ld happ en in tand em; with holdi ng pain relief until diag nosti c certa inty exist s is inhu man e and may impe de the eval uatio n. Pain scal es shou ld be used routi nely, and conti

Page 4843

{,

{,

nuou s quali ty impr ove ment prog ram s shou ld be base d on adeq uacy of pain thera py. Unre lieve d pain is asso ciate d with a long list of nega tive psyc holo gical and phys iologi c outc ome s. Titrat ed opioi d anal gesi cs shou ld be the main stay of eme rgen cy depa

Page 4844

{,

{,

rtme nt thera py of mod erate to seve re pain. For the majo rity of opioi d indic ation s in the eme rgen cy depa rtme nt, mor phin e is a suita ble agen t. The NSAI Ds are effec tive in a wide varie ty of acut e pain state s but also have a wide varie ty of signi fican t side effec ts

Page 4845

{,

{,

that need to be cons idere d whe n used for mor e than 1 or 2 days . COX -2 spec ific inhibi tors are muc h mor e expe nsiv e than NSAI Ds but do offer the adva ntag e of less risk of gastr ointe stina l side effec ts, parti cular ly in sele cted patie nts. Topi cal and local

Page 4846

anes theti cs can be used to prev ent or amel iorat e disc omfo rt asso ciate d with the majo rity of the eme rgen cy depa rtme nt proc edur es.

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Page 4847

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Marx: Rosen's Emergency Medicine: Concepts and Clinical Practice, 6th ed., Copyright © 2006 Mosby, Inc.

Chapter 20 – Syncope Robert A. De Lorenzo

PERSPECTIVE Syncope is the sudden transient loss of consciousness with a loss of postural tone. Syncope is a common presenting complaint among patients in the emergency department, yet consensus on diagnostic approach and disposition remains elusive. This lack of consensus is due in part to its varied etiology and a lack of definitive diagnostic studies. Diagnostic accuracy relies largely on the synthesis of patient risk factors and reported symptoms, with limited reliance on the physical examination and ancillary testing.

Epidemiology At some time in their lives, 12% to 48% of people may experience syncope.[1] Up to five percent of patients presenting to the emergency department complain of syncope, and 1% to 6% of hospitalized patients have syncope as a reason for admission.[] Institutionalized patients older than age 75 have a 6% annual incidence of syncope.[3] Of children, 15% to 50% experience at least one episode of syncope. Most causes of syncope are benign and are associated with favorable outcomes. Patients with preexisting cardiovascular disease and syncope from any cause are at the greatest risk of short-term and long-term mortality.[] Syncope from cardiovascular causes also has a high risk of death, with a 1-year mortality rate of 18% to 33%.[] Increasing age and other serious comorbidities are important cofactors in raising this rate.[2] In contrast, reported 1-year mortality for syncope of unknown etiology is 6%, and 1-year mortality from other, noncardiovascular causes is 12%.[] Recurrence of syncope, particularly among the elderly, is common, reported to be 30%.[6] Benign causes of syncope predominate in adolescents and young adults. Approximately 30% of athletes dying during exercise had syncope as a sentinel event, however.[7] Prospective outcome studies in children are lacking, but most reports suggest that mortality is low overall.[8] Significant trauma may result from syncope and can contribute to mortality and morbidity, particularly in the elderly.[]

Pathophysiology The final common pathway resulting in syncope is dysfunction of both cerebral hemispheres or the brainstem (reticular activating system), usually from acute hypoperfusion. Reduced blood flow may be regional (cerebral vasoconstriction) or systemic (hypotension). Loss of consciousness results in loss of postural tone, with the resulting syncopal episode. By definition, syncope is transient; the cause of central nervous system dysfunction likewise must be transient.[] Persistent causes of significant central nervous system dysfunction result in coma or altered mental status. These causes may overlap with causes of syncope. Hypoperfusion resulting in approximately 35% or more reduction in cerebral blood flow usually produces unconsciousness, and any mechanism that adversely affects the components of perfusion (cardiac output, systemic vascular resistance, blood volume, regional vascular resistance) can cause or contribute to syncope. Other mechanisms of central nervous system dysfunction resulting in syncope include hypoglycemia, toxins, metabolic abnormalities, failure of autoregulation, and primary neurologic derangements.

DIAGNOSTIC APPROACH Differential Considerations There are numerous potential causes of syncope ( Box 20-1 ). The chief differential consideration in syncope is to distinguish life-threatening causes, primarily cardiovascular in origin, from more benign forms.

Page 4848

Chief among the serious causes of syncope are dysrhythmias and myocardial ischemia.[3] Less frequently encountered but equally serious is cerebrovascular disease, toxic-metabolic abnormalities, and structural cardiac lesions, such as critical aortic stenosis.[11] Rarely encountered as a primary presentation of syncope, but potentially catastrophic if not diagnosed promptly, are thoracic dissection of the aorta, massive pulmonary embolus, and subarachnoid hemorrhage.[3] BOX 20-1 Causes of Syncope Cns, Central nervous system.

Focal Hypoperfusion of CNS Structures Cerebrovascular disease Hyperventilation Subclavian steal Subarachnoid hemorrhage Basilar artery migraine Cerebral syncope

Systemic Hypoperfusion Resulting in CNS Dysfunction Outflow obstruction Mitral, aortic, or pulmonic stenosis Hypertrophic cardiomyopathy Atrial myxoma Pulmonary embolism Pulmonary hypertension Cardiac tamponade Congenital heart disease Reduced cardiac output Tachycardias Supraventricular tachycardia Ventricular tachycardia Ventricular fibrillation Wolff-Parkinson-White syndrome Torsades de pointes Bradycardias Sinus node disease Second-degree and third-degree blocks Long Q-T syndrome Pacemaker malfunction Implanted cardioverter-defibrillator malfunction Other cardiovascular disease Aortic dissection Myocardial infarction Cardiomyopathy Vasomotor—neurally mediated (reflex vasodepressor) Neurocardiogenic (vasovagal) Emotion Pain

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Situational Carotid sinus sensitivity Necktie syncope Shaving syncope Miscellaneous reflex Cough, sneeze Exercise/postexercise Gastrointestinal—swallowing, vomiting, defecation Postmicturition Raised intrathoracic pressure (weightlifting) Other causes of hypoperfusion Orthostatic hypotension—volume depletion Anemia Drug-induced

CNS Dysfunction Not as a Result of Hypoperfusion Hypoglycemia Hypoxemia—asphyxiation Seizure Narcolepsy Psychogenic Anxiety disorder Conversion disorder Somatization disorder Panic disorder Breath-holding spells Toxic Drugs Carbon monoxide Other agents Undetermined causes

Pivotal Findings Because most cases of syncope arise from benign causes, the evaluation is focused largely on excluding serious pathology. Young, healthy patients with clearly benign causes of syncope may require no formal diagnostic evaluation other than a thorough history and physical examination.[12] The clinical examination alone can suggest the diagnosis in 45% of cases. Nevertheless, 50% of patients may not have a clear diagnosis for syncope after an initial evaluation in the emergency department.[13]

Symptoms The patient is asked to describe the character of the syncopal event.[11] Witnesses may be able to supplement and corroborate the patient's incomplete recall, and their history should be solicited. Key characteristics include the setting (e.g., postprandial), any possible prodrome, rate of onset (gradual or abrupt), position on symptom onset (e.g., standing, sitting, or supine), duration, and rate of recovery. Abrupt onset, occurrence while sitting or supine, and duration of more than a few seconds are usually ascribed to serious, often cardiac causes of syncope.[3] Similarly, incomplete syncope, or near-syncope, may be less serious, but definitive studies linking symptom characteristics and outcome have not been performed. The diagnostic approach to presyncope is the same as for syncope. Additional history on the events preceding the syncope is helpful.[11] Occurrence during significant exertion

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suggests outflow obstruction, whereas occurrence after exercise or a prolonged exposure to heat stress suggests orthostasis. The myriad mechanisms that may mediate a neurocardiogenic response (e.g., vagal stimulation) must be addressed, including significant emotional events, micturition, bowel movements, emesis, and movement or manipulation of the neck causing stimulation of the carotid sinus. Seizures may be preceded by an aura. Events during the syncopal episode may suggest a cause.[11] Tonic-clonic movements suggest seizure, although a few brief hypoxic-mediated myoclonic jerks are common in uncomplicated syncope. Trauma from a fall or other mechanism may mask the underlying syncope that caused the incident.[10] The patient should be queried about postsyncopal events. Symptoms consistent with a postictal state are characteristic of seizures. Initial vital signs and electrocardiogram (ECG) monitoring by prehospital providers may provide clues to primary cardiac dysrhythmias. Associated symptoms can offer potentially impor-tant clues.[3] Chest pain or shortness of breath can suggest myocardial ischemia or pulmonary embolus. Diaphoresis and light-headedness are nonspecific, but if prominent and accompanied by a graying of vision may suggest orthostasis or vasovagal causes. Tongue biting and incontinence of urine or stool suggest seizures. The past medical history is important in stratifying risk.[14] Among hospitalized patients, syncope was associated with orthostatic hypotension, complete heart block, chronic cerebral disease, migraine headache, aortic stenosis, and gastrointestinal bleeding. Prior coronary artery or cerebrovascular disease, diabetes, hypertension, or other significant disease increases the risk of mortality after syncope.[15] Certain medications are well established to be associated with syncope ( Box 20-2 ). Q-T interval– prolonging agents, p -blockers, insulin, and oral hypoglycemics, in particular, deserve attention because of the likelihood of repeated syncope without careful medication monitoring.[15] BOX 20-2 Drugs That May Induce Syncope

Cardiovascular p Bloc kers Vaso dilat ors (p bloc kers, calci um chan nel bloc kers, nitrat es, hydr alazi ne, angi oten sin-c onve rting enzy me inhibi

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tors, phen othia zine s, phos phod ieste rase inhibi tors) Diur etics Cent ral antih ypert ensi ves (clon idine , meth yldo pa) Othe r antih ypert ensi ves (gua nethi dine) Q-T prolo ngin g (ami odar one, diso pyra mide , fleca inide , proc aina mide , quini dine, sotal ol, enca inide ) Othe r

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antid ysrh ythm ics

Psychoactive Antic onvu lsant s (car bam azep ine, phen ytoin ) Antip arkin soni ans Cent ral nerv ous syst em depr essa nts (bar bitur ates, benz odia zepi nes) Mon oami ne oxid ase inhibi tors Tricy clic antid epre ssan ts Narc otic anal gesi cs Sed ating and

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nons edati ng antih ista mine s Choli nest eras e inhibi tors (don epez il, tacri ne)

Drugs with Other Mechanisms Drug s of abus e (can nabi s, coca ine, alco hol, heroi n) Digit alis Insuli n and oral hypo glyc emic s Neur opat hic drug s (vinc ristin e) Non stero idal anti-i nfla mm atory

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drug s Bro moc riptin e

Signs The physical examination focuses primarily on the elements affecting the cardiovascular and neurologic systems ( Table 20-1 ).[14] Signs of orthostasis should be sought in all cases in which this mechanism is suspected.[16] Rectal examination and testing stool for occult blood are recommended in all patients with syncope. Table 20-1 -- Directed Physical Examination in Syncope System Pivotal Finding Vital signs

Skin HEENT

Neck

Lungs

Heart

Abdomen Rectum Pelvis Extremities Neurologic

Significance

Pulse rate and rhythm

Tachycardia, bradycardia, other dysrhythmias Respiratory rate and depth Tachypnea suggests hypoxia, hyperventilation, or pulmonary embolus Blood pressure Shock may cause decreased cerebral perfusion, hypovolemia may lead to orthostasis. May contribute to cause of syncope in up to 15–30% of patients Temperature Fever from sepsis, may cause orthostasis Color, diaphoresis Signs of decreased organ perfusion Tenderness and deformity Signs of trauma Papilledema Increased intracranial pressure, head injury Breath Ketones from ketoacidosis Bruits Source of cerebral emboli Jugular venous distention Right heart failure from myocardial ischemia, tamponade or pulmonary embolus Breath sounds, crackles, wheezes Infection, left heart failure from myocardial ischemia; pulmonary embolus Systolic murmur Aortic stenosis, hypertrophic cardiomyopathy Rub Pericarditis, tamponade Pulsatile mass Abdominal aortic aneurysm Hematest stool Anemia, hypovolemia Uterine bleeding, adnexal Anemia, ectopic pregnancy, tenderness hypovolemia Pulse equality in upper extremities Subclavian steal, thoracic dissection of the aorta Mental status, focal neurologic Seizure, stroke, or other primary findings neurologic disease

HEENT, head, eyes, ears, nose, and throat.

Page 4855

Ancillary Studies The chief diagnostic adjunct in evaluating syncope is the 12-lead ECG ( Table 20-2 ). ECG is warranted in all cases of syncope except cases with a clear cause occurring in otherwise healthy, young adults or adolescents.[12] New ischemic ECG changes indicate acute coronary ischemia and warrant appropriate therapy at this point. Dysrhythmias, shortened P-R intervals, or prolonged Q-T intervals may be identified on the 12-lead ECG. Continuous limb-lead ECG monitoring in the emergency department also may identify transient dysrhythmias. An ECG showing a right ventricular strain pattern may suggest pulmonary embolus, whereas diffuse ST segment elevation or electrical alternans helps diagnose pericarditis associated with pericardial tamponade. Table 20-2 -- Ancillary Studies in Syncope Study

Indication

12-lead ECG Limb-lead ECG monitoring Tilt-table test, orthostatic vital signs Hemogram Electrolytes, serum Glucose, serum or blood p -hCG Drug screen, urine Ethanol, serum Arterial blood gas CXR Computed tomography, head Echocardiogram

Cardiac dysrhythmia, ischemia Dysrhythmia Orthostatic hypotension Anemia Metabolic abnormality Hypoglycemia Pregnancy Drug syncope Drug syncope Hypoxemia, hyperventilation Thoracic dissection New-onset or focal seizure, head trauma Cardiac outflow obstruction, tamponade, thoracic dissection Ventilation-perfusion scan Pulmonary embolus Abdominal ultrasound Abdominal aortic aneurysm Pelvic ultrasound Ectopic pregnancy Tests Usually Performed as Part of an Outpatient Evaluation Holter or loop ECG Exercise/thallium ECG Electrophysiologic study Carotid ultrasound Magnetic resonance imaging, head Tilt-table test Electroencephalogram

Dysrhythmia Myocardial ischemia Dysrhythmia Stroke, TIA Seizures, stroke Orthostatic hypotension Seizures

CXR, chest radiograph; ECG, electrocardiogram; hCG, human chorionic gonadotropin; TIA, transient ischemic attack.

Routine blood, serum, and urine studies have limited utility in the evaluation of syncope and are generally unrewarding.[17] When suggested by the history and physical examination, however, selective use of hemogram, serum electrolytes and glucose, urine drug screen, and pregnancy test may exclude some uncommon causes of syncope. As a general rule, radiographic studies offer limited yield in most cases of

Page 4856

syncope and unless specific pathology is suspected are not routinely indicated. In cases of syncope in which outpatient evaluation is warranted, several modalities are useful. Transient dysrhythmias can be detected with either Holter or loop ECG long-term monitoring. In selected patients, stress testing, electrophysiologic studies, or magnetic resonance imaging may be indicated. Electroencephalography has a low yield unless seizure is suspected. Tilt-table testing, although infrequently used, may have diagnostic value in elderly patients and children in whom chronic orthostatic hypotension is suspected. Although not technically an ancillary study, formal psychiatric evaluation deserves mention as an important diagnostic tool in syncope.[18] In patients with compatible signs and symptoms or negative medical evaluation and continued syncope, psychiatric evaluation may be revealing.

DIFFERENTIAL DIAGNOSIS Critical Diagnoses The critical diagnoses to consider are listed in Table 20-3 . Table 20-3 -- Critical Diagnoses to Consider in Syncope Myo cardi al infar ction Life-t hreat enin g dysr hyth mias Aorti c diss ectio n Criti cal aorti c sten osis Hype rtrop hic cardi omy opat hy Card iac tamp onad e Abdo mina l aorti c aneu

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rysm Pul mon ary emb olis m Sub arac hnoi d hem orrh age Stro ke Toxi c-m etab olic dera nge ment s Seve re hypo vole mia or hem orrh age

Emergent Diagnoses The emergent causes of syncope are protean (see Box 20-1 ). Many other causes, such as neurocardiogenic and reflex-mediated syncope, have benign mechanisms. Any cause of syncope may recur, however, and result in falls or accidents. A thorough evaluation for treatable causes is warranted.

Diagnostic Algorithm After stabilization and assessment, the findings are matched to the likely causes of syncope ( Table 20-4 ). In many cases of syncope, it is possible to use a stepwise approach to diagnose the cause and risk-stratify the patient ( Figure 20-1 ). Table 20-4 -- Clinical Features of Common and Serious Causes of Syncope Cause Onset and Recovery Features Dysrhythmia

Abrupt onset, rapid recovery

Cardiac outflow obstruction

Exertion causes rapid symptoms; rapid recovery

Myocardial infarction

Exertion or at rest; recovery often incomplete with chest pain persisting

Past cardiac history, risk factors for CAD more common in elderly; implanted pacemaker or cardioverter-defibrillator Murmurs not always audible; mechanical valves warrant close monitoring Past cardiac history, risk factors for CAD; chest pain and shortness of breath common but occasionally absent in diabetics and the elderly

Page 4858

Cause

Onset and Recovery

Pulmonary embolus

Abrupt onset; recovery often Chest pain, dyspnea, incomplete with dyspnea persisting hypercoagulable state, DVT, pregnancy Spontaneous; recovery often Tearing chest pain; associated incomplete with abdominal pain with hypertension, Marfan's persisting syndrome, cystic medial necrosis Spontaneous; recovery often Abdominal or back pain; incomplete with abdominal pain associated with peripheral vascular persisting disease Penetrating chest trauma or Beck's triad of hypotension, JVD, thoracic cancer muffled heart sounds Exercise Left coronary artery arises from right of Valsalva; usually detected in childhood Unpredictable; TIAs may resolve Focal neurologic findings; over hours vertebrobasilar ischemia may present with ataxia, vertigo, “drop attacks”; history of atherosclerosis Rapid onset; sentinel event may Focal neurologic findings; resolve “thunderclap” worst headache; nuchal rigidity Posture change or neck movement Vertigo, nausea, dysphagia, dysarthria, blurry vision common associated symptoms Bleeding, emesis, heat stress, Orthostatic hypotension dehydration; gradual onset Bleeding, often occult or gradual Orthostatic hypotension commonly from menses or gastrointestinal associated sources; iron deficiency or decreased red blood cell production Gradual onset; incomplete Diabetes, ingestion/injection of spontaneous recovery common hypoglycemics/insulin; diaphoresis, anxiety, jitteriness Usually gradual; spontaneous Carbon monoxide, natural gas, recovery if asphyxiating sewer gas, bleach/ammonia mix circumstance is reversed Onset with or after trauma (which Elderly, alcoholics at greater risk may be trivial) Diving Hyperbaric oxygen key treatment Associated with myocardial Risk factors for myocardial infarction or pulmonary embolus infarction or pulmonary embolus Medication associated with Consider illicit and alternative drug syncope use; elderly at risk for polypharmacy and drug interactions Patient often unaware of Abdominal pain, abnormal pregnancy tenderness; positive p -hCG test Abrupt or with aura postictal state Past history common common Carotid sinus sensitivity; rapid Shaving, necktie, sudden neck onset and recovery movement; carotid massage may provoke symptoms Gastrointestinal, genitourinary, or Urination, defecation, cough, thoracic stimulation eating, swallowing, weight lifting Emotion, pain are common Prodrome of light-headedness,

Aortic dissection

Abdominal aortic aneurysm

Pericardial tamponade Anomalous left coronary artery

Stroke

Subarachnoid hemorrhage

Vertebrobasilar insufficiency

Hypovolemia Anemia

Hypoglycemia

Hypoxemia

Subdural hematoma Air embolus Pulmonary hypertension Drug syncope

Ruptured ectopic pregnancy Seizure Carotid sinus sensitivity

Reflex syncope Neurocardiogenic (vasovagal)

Features

Page 4859

Cause

Hyperventilation

Narcolepsy Basilar artery migraine

Onset and Recovery

Features

triggers; upright posture; gradual onset; rapid recovery once supine Emotion, pain; gradual onset; patient often unaware of rapid respirations Often spontaneous Specific triggers often known to patient

graying or blurring of vision, nausea, sweats common Perioral tingling, carpopedal spasms, extremity numbness

Trigeminal or glossopharyngeal neuralgia Subclavian steal Psychogenic

Sudden onset; specific triggers often known to patient Moving affected arm Variable

Breath holding Drop attack

Deliberate breath holding Unpredictable

Known history Visual prodrome often absent. More common in young women; vertigo and nausea common Lancinating pain in characteristic location Thoracic outlet syndrome Anxiety or psychiatric history; diagnosis by examining symptom pattern and excluding organic cause Usually toddlers or young children Not true syncope—no loss of consciousness; usually elderly; loss of tone, ataxia, vertigo

CAD, Coronary artery disease; DVT, deep vein thrombosis; hCG, human chorionic gonadotropin; JVD, jugular venous distention; TIA, transient ischemic attack.

Figure 20-1 Managem ent approach for patients with syncope. ECG, electrocardiogram ; p -hCG, p -hum an chorionic gonadotropin; US, ultrasound; V/Q, ventilation-perfusion; CT, com puted tom ography; EEG, electroencephalogram ; TIA, transient ischem ic attack; SAH, subarachnoid hem orrhage; PE, pulm onary em bolus; HCM, hypertrophic cardiomyopathy.

EMPIRIC MANAGEMENT Rapid Assessment and Stabilization The patient's acute symptoms and status of vital signs dictate the need for immediate stabilization. Because syncope is by definition a transient event, most patients are asymptomatic on presentation. Most asymptomatic patients do not need immediate attention, but consideration should be given to bringing elderly patients and patients with preexisting cardiovascular disease directly into the treatment area of the emergency department. If these patients have normal or near-normal vital signs, they require no immediate stabilization, and a brief history and physical examination are performed. The subset of patients with repeated episodes of syncope or associated symptoms of a concerning nature (e.g., chest pain) should undergo a rapid search for the cause. Significantly abnormal vital signs (in particular, severe bradycardia or tachycardia and hypotension) demand immediate attention. Patients with repeated episodes of syncope, significant associated symptoms, or abnormal vital signs should be placed on pulse oximetry and ECG monitoring. Intravenous access, preferably with a large-bore catheter, should be accomplished. Most patients presenting with syncope require confirmatory bedside

Page 4860

diagnostic evaluation or testing to exclude life-threatening causes. The 12-lead ECG is the principal tool to evaluate cardiac causes of syncope, and the orthostatic vital signs may support a diagnosis of volume depletion.[17] Figure 20-2 shows an approach to the diagnosis and general management of syncope.

Figure 20-2 General approach to the m anagem ent of syncope. H&P, history and physical exam ination; p -hCG, p -hum an chorionic gonadotropin; ECG, electrocardiogram .

The treatment of syncope is directed toward the underlying cause, if known. Patients with critical diagnoses generally are admitted to the intensive care unit with appropriate consultation. Patients with emergent or unknown diagnoses typically are admitted to the hospital, most often on telemetry units. Patients with nonemergent diagnoses most frequently are managed as outpatients. Hospitalization is required in patients with associated chest pain, significant signs of congestive heart failure, or valvular disease.[] Patients with ECG evidence of ventricular dysrhythmias, ischemia, prolonged Q-T interval, or new bundle-branch block also are admitted.[] Admission to a monitored setting also should be considered in patients with any of the following characteristics: age older than 60 years, preexisting cardiovascular or congenital heart disease, family history of sudden death, or exertional syncope.[] Frequently, emergency department evaluation of patients complaining of syncope is inconclusive. After a history, physical examination, and 12-lead ECG, 50% of patients do not have a firm diagnosis.[] Patients younger than age 45 and without worrisome signs, symptoms, or ECG findings are generally at lower risk for an adverse outcome and often may be managed as an outpatient. Discharged patients should be warned of the hazards of recurrent syncope occurring during activities such as driving or working at heights.

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Emerg Med1996;28:385. 28. Vercauteren M: Intranasal sufentanil for preoperative sedation. Anaesthesia1988;43:270. 29. Schmidt WK: Nalbuphine. Drug Alcohol Depend1985;14:339. 30. Hyland-Mcguire P, Guly HR: Effects on patient care of introducing prehospital intravenous nalbuphine hydrochloride. J Accident Emerg Med1998;15:99. 31. Gillis JC, Benfield P, Goa KL: Transnasal butorphanol: A review of the pharmacodynamic and pharmacokinetic properties, and therapeutic potential in acute pain management. Drugs1989;38:225. 32. O'Briens JJ, Benfield P: Dezocine: A preliminary review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy. Drugs1989;38:225. 33. Kosten TR: Buprenorphine for cocaine and opiate dependence. Psychopharmacol Bull1992;28:15. 34. Mitka M: Abuse of prescription drugs: Is a patient ailing or addicted?. JAMA2000;283:1126. 35. Lehmann KA: Tramadol for the management of acute pain. Drugs1994;47:19. 36. Moore PA: Pain management in dental practice: Tramadol vs. codeine combinations. J Am Dent Assoc 1999;130:1075. 37. Turturro MA, Paris PM, Larkin GL: Tramadol versus hydrocodone-acetaminophen in acute musculoskeletal pain: A randomized, double blind clinical trial. Ann Emerg Med1998;32:139. 38. Mackway-Jones K: Analgesia and assessment of abdominal pain. J Accid Emerg Med2000;17:128. 39. Brewster GS, Herbert ME, Hoffman JR: Medical myth: Analgesia should not be given to patients with an acute abdomen because it obscures the diagnosis. West J Med2000;172:209. 40. Vermeulen B: Acute appendicitis: Influence of early pain relief on the accuracy of clinical and US findings in the decision to operate: a randomized trial. Radiology1999;210:639. 41. Silen W: Cope's Early Diagnosis of the Acute Abdomen, 21st ed. New York, Oxford University Press, 2004. 42. Kim MK, Straite RT, Sato TT, Hennes HM: A randomized clinical trial of analgesia of children with abdominal pain. Acad Emerg Med2002;9:281. 43. Thomas SH, Silen W: Effect on diagnostic efficiency of analgesia for undifferentiated abdominal pain. Br J Surg2003;90:5. 44. Henderson SO, Swadron S, Newton E: Comparison of intravenous ketolorac and meperidine in the treatment of biliary colic. J Emerg Med2003;23:237. 45. Singh G: Recent considerations in nonsteroidal anti-inflammatory drug gastropathy. Am J Med 1998;105:31S. 46. Hernadez-Diaz S: Epidemiologic assessment of the safety of conventional nonsteroidal anti-inflammatory drugs. Am J Med2001;110:20. 47. Do NSAIDs inhibit bone healing?. In: Moore A, Edwards J, Barden J, McQuay H, ed.Bandolier's Little Book of Pain, New York: Oxford University Press; 2003: 153-160. 48. Turturro MA: Intramuscular ketorolac versus oral ibuprofen in acute musculoskeletal pain. Ann Emerg Med1995;26:117. 49. Szucs PA: Safety and efficacy of diclofenac ophthalmic solution in the treatment of corneal abrasions. Ann Emerg Med2000;35:131. 50. Schwab JM, Schluesener HJ, Laufer S: COX-3: Just another COX or the solitary elusive target of paracetamol?. Lancet2003;361:981. 51. Matin A, Williams R: Paracetamol hepatotoxicity and alcohol consumption in deliberate and accidental overdose. Q J Med2000;93:341. 52. Wolfe M, Lichtenstein D, Singh G: Gastrointestinal toxicity of nonsteroidal anti-inflammatory drugs. N Engl J Med1999;340:1888. 53. Silverstein FE: Gastrointestinal toxicity with celecoxib vs. nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis. JAMA2000;284:1247. 54. Kaplan R: Non-narcotic analgesia. In Paris PM, Grass J (eds): Textbook of Acute Pain Management. Philadelphia, WB Saunders, private communication. 55. Turturro MA, Frater CR, D'Amico FJ: Cyclobenzaprine with ibuprofen versus ibuprofen alone in acute myofascial strain: A randomized, double-blind clinical trial. Ann Emerg Med2003;41:818. 56. van Tulder MW: Muscle relaxants for nonspecific low back pain: A systematic review within the framework of the Cochran collaboration. Spine2003;28:1978. 57. Annequin D: Fixed 50% nitrous oxide oxygen mixture for painful procedures: A French survey. Pediatrics 2000;105:850. 58. Seaberg DC, Yealy DM, Ilkhanipour K: Effective nitrous analgesia on a pneumothorax. Acad Emerg Med 1995;2:287. 59. Roland AS: Reduced fertility among the women employed as dental assistants exposed to high levels of nitrous oxide. N Engl J Med1992;327:993. 60. US Department of Health and Human Services : Controlling exposures to nitrous oxide during anesthetic administration. NIOSH Alert, Washington, D.C., US Department of Health and Human Services, 1994. 61. Butzkueven H, King JO: Nitrous oxide myelopathy in an abuser of whipped cream bulbs. J Clin Neurosci 2000;7:73.

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62. Ogundipe O: Sickle cell disease and nitrous oxide-induced neuropathy. Clin Lab Haematol1999;21:409. 63. Covino BG: Pharmacology of local anesthetic agents. Br J Anaesth1986;58:701. 64. Berkun Y: Evaluation of adverse reactions to local anesthetics: Experience with 236 patients. Ann Allergy Asthma Immunol2003;91:342. 65. Green SM, Rothrock SG, Gorchynski J: Validation of diphenhydramine as a dermal local anesthetic. Ann Emerg Med1994;23:1284. 66. Sylaidis P, Logan A: Digital blocks with adrenaline: An old dogma refuted. J Hand Surg [Br]1998;1:17. 67. Wilhelmi BJ: Epinephrine in digital blocks: Revisited. Ann Plast Surg1998;41:410. 68. Kenkler K: A comprehensive review of epinephrine in the finger: To do or not to do. Plast Reconstr Surg 2001;108:114. 69. de Jong RH: Local Anesthetics, St Louis, Mosby, 1994. 70. Fosko SW, Gibney MD, Harrison B: Repetitive pinching of the skin during lidocaine infiltration reduces patient discomfort. J Am Acad Dermatol1998;39:74. 71. Bartfield JM, Ford DT, Homer PJ: Buffered versus plain lidocaine for digital nerve blocks. Ann Emerg Med1993;22:216. 72. Ong EL, Lim NL, Koay CK: Towards a pain-free venipuncture. Anaesthesia2000;55:260. 73. Fatovich DM, Jacobs IG: A randomized controlled trial of buffered lidocaine for local anesthetic infiltration in children and adults with simple lacerations. J Emerg Med1999;17:223. 74. Scarfone RJ, Jasani M, Gracely EJ: Pain of local anesthetics: Rate of administration and buffering. Ann Emerg Med1998;31:36. 75. Bartfield JM, Sokaris SJ, Raccio-Robak N: Local anesthesia for lacerations: Pain of infiltration inside vs. outside the wound. Acad Emerg Med1998;5:100. 76. Mader TJ, Playe SJ, Garb JL: Reducing the pain of local anesthetic infiltration: Warming and buffering have a synergistic effect. Ann Emerg Med1994;23:550. 77. Pryor GJ, Kilpatrick WR, Opp DR: Local anesthesia in minor lacerations: Topical TAC vs lidocaine. Ann Emerg Med1980;9:568. 78. Hegenbarth MA: Comparison of topical tetracaine, adrenaline, and cocaine anesthesia with lidocaine infiltration for repair of lacerations in children. Ann Emerg Med1990;19:63. 79. Dailey RH: Fatality secondary to misuse of TAC solution. Ann Emerg Med1988;17:159. 80. Ernst AA: Topical lidocaine adrenaline tetracaine (LAT gel) versus injectable buffered lidocaine for local anesthesia in laceration repair. West J Med1997;167:79. 81. Blackburn PA: Comparison of tetracaine-adrenaline-cocaine (TAC) with topical lidocaine-epinephrine (TLE): Efficacy and cost. Am J Emerg Med1995;13:315. 82. Ernst AA: LAT (lidocaine-adrenaline-tetracaine) versus TAC (tetracaine-adrenaline-cocaine) for topical anesthesia in face and scalp lacerations. Am J Emerg Med1995;13:151. 83. Schilling CG: Tetracaine, epinephrine (adrenaline), and cocaine (TAC) versus lidocaine, epinephrine, and tetracaine (LET) for anesthesia of lacerations in children. Ann Emerg Med1995;25:203. 84. Priestley S: Application of topical local anesthetic at triage reduces treatment time for children with lacerations: A randomized controlled trial. Ann Emerg Med2003;42:34. 85. Gagrag NM, Pennant JH, Watcha MF: Eutectic mixture of local anesthetics (EMLA cream). Anesth Analg 1994;78:574. 86. Liu DR, Kirchner HL, Petrack EM: Does using heat with eutectic mixture of local anesthetic cream shorten analgesic onset time? A randomized, placebo-controlled trial. Ann Emerg Med2003;42:27. 87. Powell DM: Damage to tissue defenses by EMLA cream. J Emerg Med1991;9:205. 88. Martin JR: The effect of local anesthetics on bacterial proliferation: TAC versus lidocaine. Ann Emerg Med1990;19:987. 89. Melzack R, Wall PD: Pain mechanisms: A new theory. Science1965;150:971. 90. Merrill DC: Clinical evaluation of FasTENS, an inexpensive, disposable transcutaneous electrical nerve stimulator designed specifically for postoperative electroanalgesia. Urology1989;33:27. 91. Nash TP: Transcutaneous electrical nerve stimulation. In: Rice ASC, Warfield CA, Justins D, Eccleston C, ed.Clinical Pain Management: Practical Applications & Procedures, London: Arnold; 2003: 343-354. 92. Bierman SF: Hypnosis in the emergency department. Am J Emerg Med1989;7:238. 93. Menegazzi JJ: A randomized controlled trial of the use of music during laceration repair. Ann Emerg Med 1991;20:348. 94. Berde CB, Sethna N, Koka BV: Pediatric pain management. In: Warfield CA, ed.Principles and Practice of Pain Management, New York: McGraw-Hill; 1993: 325-346. 95. Nation EM, Warfield CA: Pain in the elderly. Hosp Pract1989;4:113. 96. Stewart RD: Pain control in prehospital care. In: Paris PM, Stewart RD, ed.Pain Management in Emergency Medicine, Norwalk, Conn: Appleton & Lange; 1988: 313-322. 97. Turturro M: Pain, priorities and prehospital care. Prehosp Emerg Care2002;6:486. 98. McEachin CC, McDermott JT, Swor R: Few emergency medical services patients with lower-extremity fractures receive prehospital analgesia. Prehosp Emerg Care2002;6:406.

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99. Alonso-Serra HM, Wesley K: National association of EMS physicians standards and clinical practices committee. Prehosp Emerg Care2003;7:482.

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Chapter 188 – Procedural Sedation and Analgesia Carl R. Chudnofsky Marie M. Lozon Performing painful diagnostic and therapeutic procedures has become a routine aspect of emergency department care. Accordingly, the ability to safely provide adequate sedation and analgesia for patients of all ages has become a necessary skill for emergency physicians.[] Procedural sedation and analgesia (PSA) is the use of analgesic, dissociative, or sedative agents to prevent the pain, anxiety, and unpleasant memories associated with painful diagnostic and therapeutic procedures. All of the agents used for PSA have the potential for serious adverse effects, including respiratory depression and cardiovascular compromise ( Table 188-1 ). This chapter presents an overview of sedation and analgesia for procedures. Recommendations are based on current medical evidence whenever possible. Where no evidence exists, practice guidelines and consensus opinions are provided. Table 188-1 -- Agents for Procedural Sedation and Analgesia (PSA) Agent

Class

Fentanyl (Sublimaze)

Opioid

Midazolam (Versed)

Benzodiazepine

Methohexital (Brevital)

Barbiturate

Ketamine (Ketalar) Phencyclidine derivative

Route IV TM IV

IM PO PR IN IV PR IV

IM PO PR IN Propofol (Diprivan) Alkylphenol derivative IV Infusion Etomidate Imidazole derivative IV PO PR Nitrous oxide Anesthetic gas Inhalation Advantages Serious Adverse Effects Respiratory depression

Rapid onset

Usual Total Dose[*]

Onset

Duration[†]

2–3 p-g/kg 10–15 p-g/kg 0.02–0.1 mg/kg (adult) 0.05–0.15 mg/kg (child) 0.05–0.15 mg/kg 0.5–0.75 mg/kg 0.5–0.75 mg/kg 0.2–0.5 mg/kg 0.75–1.0 mg/kg 20–30 mg/kg 1–2 mg/kg

1–2 min 20–30 min 15–30 min 60–120 min 1–2 min 30 min

10–15 min 15–30 min 10–30 min 10–15 min 55 years of age).[] At typical PSA doses (0.1-0.2 mg/kg), respiratory depression is rare. When it does occur, it is generally transient and mild, although some patients may require a brief period of assisted ventilation.[] No studies have reported the need to intubate a patient after the use of etomidate for emergency department PSA. Myoclonus associated with etomidate is typically described as benign muscle contractions of variable regularity and symmetry.[57] While the precise mechanisms have yet to be described, myoclonus is most likely related to hyperexcitability of the brain neurons affecting muscle movement and control. In emergency department studies evaluating the use of etomidate for PSA, the incidence of myoclonus has ranged from 0% to 21%.[] When myoclonus does occur, it is generally minor and short-lived, does not cause postsedation muscle discomfort, and rarely interferes with the procedure.[] However, myoclonus is

Page 4887

occasionally described as severe and, as such, could potentially lead to respiratory compromise.[57] Thus, even though myoclonus-induced respiratory depression has not been reported with emergency department use, it is important for clinicians using etomidate to be aware of this possibility. The risk of nausea and vomiting after administration of etomidate appears to be dose related and is generally not a problem with the typical doses used for emergency department PSA (0.1-0.2 mg/kg). In emergency department studies published to date, the incidence of nausea and vomiting ranges from 0% to 5%.[] More importantly, there have been no documented cases of aspiration. Pain on injection is also reported with etomidate and is most likely caused by the propylene glycol solvent. Using larger veins, flushing with saline, pretreating with fentanyl, or mixing 1 mL of lidocaine with each 10 mL of etomidate can reduce the discomfort.[54] Alternatively, a lipid-emulsion formulation is available that is associated with decreased injection pain.[53] Etomidate suppresses adrenal function by inhibiting 11-beta-hydroxylase activities. This seems to be clinically relevant only for patients on long-term infusions. One-time administration has not been reported to cause inadequate stress responses or significant electrolyte abnormalities.[54] In one study of emergency department patients requiring rapid sequence intubation, Schenarts and colleagues[58] found that patients who received etomidate (0.3 mg/kg) had a lower 4-hour serum cortisol response to cosyntropin stimulation than patients who were induced with midazolam. However, cortisol levels in both groups remained within normal limits, and the difference between the groups resolved within 12 hours.

Nitrous Oxide Nitrous oxide is a colorless, sweet-smelling gas that has been used since the 1950s for sedation and analgesia in a variety of inpatient and outpatient settings. It rapidly diffuses across biologic membranes, producing sedation and analgesia in as little as 1 to 2 minutes. Its duration of action is likewise very short, usually around 3 to 5 minutes. The drug is excreted unchanged by the lungs and it does not bind to hemoglobin. Consequently, it has little effect on organ systems other than the CNS.[59] Nitrous oxide is thought to exert its analgesic and sedative effects by binding opiate receptors in the CNS. Clinically, however, its sedative and anxiolytic effects are more evident than its analgesic properties. Therefore, for more painful procedures, some clinicians prefer to also administer a short-acting opioid such as fentanyl. The usual dose of nitrous oxide for PSA ranges from 30% to 50%. Lower concentrations (30%) may be less effective for emergency department use, particularly in children younger than 8 years of age.[60] Higher concentrations (i.e., 65%-70%) are required at high altitudes. Nitrous oxide must be administered with at least 30% oxygen to avoid hypoxia (i.e., the maximum concentration of nitrous oxide is 70%). However, the use of a 70/30 nitrous/oxygen mix can result in deep sedation with loss of protective airway reflexes. In addition, nitrous oxide can diffuse into any air-filled space, possibly worsening conditions where there is an abnormal collection of air, such as bowel obstruction and pneumothorax. Other adverse effects include nausea, dizziness, voice change, euphoria, and laughter. Nitrous oxide is a known teratogen and mutagen and should not be used in pregnant patients or around pregnant staff members. The use of nitrous oxide requires a well-ventilated room with a scavenger system to prevent inhalation by emergency department staff. A double-tank system is commonly used to deliver the nitrous oxide and O2 mixture. The system relies on a mixing valve preset to deliver a fixed ratio of nitrous oxide to oxygen and will deliver gas only when O2 is flowing. The double-tank system contains a fail-safe device that automatically stops the flow of nitrous oxide when the O2 supply is depleted. The safest method to administer nitrous oxide is via a self-administered demand-valve. The demand-valve requires that the patient generate a negative pressure of 3 to 5 cm H2O within a handheld mask or mouthpiece for gas to flow. If patients become too somnolent, they will not be able to generate sufficient negative pressure or the mask will fall from their face; in either case, delivery of nitrous oxide will cease. This feature significantly reduces the risk of oversedation. Unfortunately, uncooperative patients and those too small to generate sufficient negative pressure will be unable to utilize a demand-valve. For these patients, a continuous-flow technique utilizing a mask strapped over the nose or nose and mouth can be used.[61] This technique requires an additional physician dedicated to continuous gas titration to avoid oversedation and is associated with a higher rate of emesis.[] In addition, the mask may interfere with procedures involving the perioral and nasal areas of the face.

REVERSAL (“RESCUE”) AGENTS Naloxone

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Naloxone is a pure opioid antagonist with a high affinity for p--opiate receptors and less affinity for the p&and p)-receptors. It is the most commonly used agent for reversal of opioid-induced sedation and respiratory depression. It has a rapid onset of action and a mean half-life of 64 minutes. However, the clinical effects of opioid reversal may last only 15 to 30 minutes. Naloxone can also be administered via the intramuscular, subcutaneous, or endotracheal routes but should optimally be given intravenously when used for reversal of PSA. The dose of naloxone for adults is 0.1 to 2 mg IV; for complete reversal, at least 2 mg should be given. If the procedure has not been completed, but the patient becomes overly sedated or experiences respiratory depression, partial reversal can be achieved using incremental doses of 0.1 to 0.4 mg. Because large doses of naloxone are not associated with toxicity, dosing recommendations are similar for children. For partial reversal, smaller initial doses (e.g., 0.005-0.05 mg/kg) can be used. When administered for reversal of PSA, naloxone is associated with very few adverse effects. Potential problems include acute opioid withdrawal in patients addicted to opioids and resedation in patients who have received a long-acting opioid (e.g., meperidine, morphine). Therefore, these patients should be observed for 90 to 120 minutes after administration of naloxone. Alternatively, nalmefene, a long-acting opioid antagonist, can be used. Resedation is usually not a problem for patients who have been given fentanyl in doses recommended for PSA. Nevertheless, these patients should be observed for a minimum of 1 hour after administration of naloxone. This is especially important for patients who have received large doses of fentanyl to ensure that redistribution of fentanyl within the body does not result in recurrence of sedation.

Flumazenil Flumazenil is an imidazobenzodiazepine derivative that antagonizes the effects of benzodiazepines by competitively and reversibly binding to GABA-benzodiazepine receptors in the CNS. After an intravenous injection, the onset of reversal is usually evident within 1 to 2 minutes, with peak effect occurring after 6 to 10 minutes. The duration of action is dose related. A dose of 1.0 mg (maximum recommended dose for reversal of PSA) will sustain antagonism for approximately 48 minutes.[63] Data regarding the use of flumazenil to reverse PSA in the emergency department is sparse. One study has demonstrated that a dose of 1.0 mg of flumazenil is safe and effective in reversing the sedating and psychomotor effects of midazolam without interfering with its amnesic effect or diminishing the analgesic effect of coadministered fentanyl.[64] However, its use does not obviate the need for close monitoring of the patient's respiratory status and aggressive intervention to assist breathing when needed. Data regarding indications for flumazenil use in the context of PSA are lacking. Possible indications for its use may include hypoventilation unresponsive to stimulation or a brief period of bag/mask ventilation or deep sedation with loss of protective airway reflexes. Routine reversal is not recommended, and PSA should not be planned with reversal in mind. To reverse sedation in adults, flumazenil should be administered intravenously in increments of 0.2 mg until the desired level of consciousness is achieved, or a maximum of 1.0 mg has been given. Incremental doses should be given 60 seconds apart with each dose administered over 15 seconds. Serious potential adverse effects of flumazenil include seizures, benzodiazepine withdrawal, and resedation. Risk factors for seizures include (1) concurrent major sedative-hypnotic withdrawal, (2) recent therapy with repeated doses of parenteral benzodiazepines, (3) myoclonic jerking or seizure activity before administration of flumazenil, and (4) concurrent cyclic antidepressant poisoning. In addition, flumazenil may precipitate seizures in patients taking a benzodiazepine for control of an underlying seizure disorder. Flumazenil can cause benzodiazepine withdrawal in patients who chronically take benzodiazepines. This may occur after only 2 weeks of benzodiazepine use.[63] Withdrawal is more likely to occur with high doses of flumazenil (>1.0 mg); therefore, the lowest possible dose of flumazenil required for adequate reversal should be used. Resedation may be a problem if flumazenil is used to reverse a long-acting benzodiazepine, such as diazepam or lorazepam, or if it is administered to a patient who has received a large dose (>10 mg) of midazolam. In one recent study of emergency department patients requiring PSA for cardioversion, five of six patients (average weight 71 kg; range, 70-76 kg) who received midazolam (0.2 mg/kg) followed by flumazenil (0.5 mg bolus followed by 0.5 mg infusion over 1 hour) experienced resedation prior to discharge.[ 50] Hence, these patients should be observed for at least 2 hours after receiving flumazenil. Even when small doses of midazolam are used, it is advisable to observe patients for at least 60 minutes after administration

Page 4889

of flumazenil. If resedation occurs, repeat doses of flumazenil can be administered at 20-minute intervals as needed. Repeat doses should be given in increments of 0.2 mg with a maximum of 1.0 mg every 20 minutes and no more than 3.0 mg within any 1 hour.

Drug Selection and Administration When selecting a strategy for PSA, the clinician must consider the type of procedure being performed, specific procedural requirements, the length of the procedure and whether it may need to be repeated, and the ability to use topical, local, or regional anesthesia ( Table 188-2 ). One must also take into account the patient's age, comorbid conditions, and past medical history. When more than one PSA strategy may be appropriate, the clinician is encouraged to choose the agents that they are most familiar with, as there are few scientific data comparing one PSA regimen to another. Once the agent or agents have been chosen, proper drug administration is the key to safe and effective use. Table 188-2 -- Drug Selection Strategies Procedure Type Common Recommendation Emergency Department Examples

Alternatives

Noninvasive

Radiologic imaging Echocardiography

Methohexital (PR)

Methohexital (IV) Etomidate (IV) Midazolam (IV)

Low pain

Simple laceration repair Lumbar puncture Simple foreign body removal Eye irrigation Slit lamp examination Abscess irrigation and drainage Fracture/joint reduction Burn debridement

Midazolam

Ketamine (IM)

(IV, PO, IN, PR)

Nitrous oxide

Midazolam and

Propofol (IV) or

Fentanyl (IV)

Etomidate (IV) or

or

Chest tube placement Cardioversion Sexual assault examination

Ketamine (IM/IV)

Methohexital (IV) plus: Fentanyl (IV)

High anxiety

High pain High anxiety

Comments

IV access is often not required in these patients. Methohexital given rectally is likely safer than methohexital or etomidate given IV. Midazolam does not consistently render children motionless. These procedures generally do not require more than moderate sedation, and analgesia can usually be provided using local or topical anesthesia. Evidence now exists to support the use of any of these agents. However, there are far more data supporting the safety and efficacy of midazolam/fentanyl and ketamine for emergency department use than the other regimens. In children, administer ketamine IV or IM with atropine or glycopyrrolate. In adults, administer ketamine IV preceded by midazolam IV.

Page 4890

Procedure Type

Common Emergency Department Examples

Recommendation

Alternatives

Comments

IM, intramuscular; IN, intranasal; IV, intravenous; PO, oral; PR, rectal.

Procedures can be divided into three broad categories: (1) noninvasive, (2) low pain, high anxiety, and (3) high pain, high anxiety procedures (see Table 188-2 ). For noninvasive procedures in which complete immobilization is required (e.g., computed tomography), rectal methohexital is safe, effective, and easily administered. Alternatives include intravenous methohexital, intravenous etomidate, or intravenous midazolam. These agents will provide adequate sedation, but intravenous access is seldom required for these procedures, and intravenous administration may increase the risk of adverse events. In addition, midazolam does not consistently render children motionless. Low pain, high anxiety procedures such as laceration repair and lumbar puncture generally require only minimal to moderate sedation, whereas analgesia can usually be provided with topical or local anesthetics. For these procedures, midazolam provides safe and effective sedation and can be administered via multiple routes. Alternatives include intramuscular or intravenous ketamine or nitrous oxide (see Table 188-2 ). Ketamine may work well, but complete dissociation is generally not necessary for procedures in this category. If available, nitrous oxide can also provide adequate sedation and seems to work particularly well for laceration repair. In a recent study of children 2 to 6 years of age requiring facial suturing, Luhmann and associates[61] found that a 50:50 mixture of nitrous oxide and oxygen delivered via a continuous-flow system (rather than via a demand-valve) was more effective in reducing stress and had fewer adverse effects and shorter recovery times than oral midazolam. However, the continuous-flow system required the presence of two physicians (one to administer the nitrous oxide and the other to perform the procedure) and was associated with a higher incidence of emesis (10%). For procedures that cause high pain and high anxiety (e.g., fracture or joint reduction, abscess irrigation and drainage), the use of intravenous fentanyl/midazolam or intravenous ketamine (or intramuscular in children) are strongly supported by current literature. Alternatives include intravenous propofol, intravenous etomidate, or intravenous methohexital. While evidence to support the use of these agents is growing, there remain far more data substantiating the safety and efficacy of fentanyl/midazolam and ketamine for emergency department use (see Table 188-2 ). The combination of fentanyl and midazolam remains one of the most popular and most broadly recommended regimens to facilitate a wide variety of emergency department procedures. These agents have a rapid onset and short duration of action; they can be titrated to the desired level of sedation and analgesia ( Box 188-2 ); and they have a long safety record with emergency department use. They should be used with caution in elderly patients and in patients with chronic obstructive pulmonary disease who have a higher incidence of respiratory depression and prolonged sedation. BOX 188-2 Drug Administration Strategies

Methohexital {, Adult s: 1.0 mg/k g IV bolu s with

Page 4891

{,

{,

addit ional 0.5 mg/k g bolu ses as need ed. Child ren: 1.0 mg/k g IV bolu s with addit ional 0.5 mg/k g bolu ses as need ed up to a maxi mu m of 2.0 mg/k g or 25 mg/k g recta lly[*] Meth ohex ital shou ld be give n over 60 seco nds to avoi d apne a and respi rator y

Page 4892

depr essi on. Ketamine {,

Adult s: 1.5 to 2.0 mg/k g IV over 2 minu tes with addit ional 0.5 mg/k g bolu ses as need ed; admi niste r mida zola m 0.05 mg/k g appr oxim ately 1 minu te prior to keta mine to atten uate cardi ovas cular stim ulati on and redu ce or elimi nate eme rgen

Page 4893

ce phen ome na. {,

Child ren: 1.5 to 2.0 mg/k g IV over 2 minu tes with addit ional 0.5 mg/k g bolu ses as need ed, or 4 to 5 mg/k g IM; add atrop ine 0.01 mg/k g (mini mu m dose 0.1 mg; maxi mu m dose , 0.5 mg) or glyc opyrr olate (0.00 5 mg/k g to a maxi mu m dose

Page 4894

{,

of 0.25 mg) to the sam e syrin ge to prev ent exce ssiv e saliv ation . Keta mine shou ld be give n at a rate of 0.5 mg/k g/mi n or over 90 to 120 seco nds to avoi d respi rator y depr essi on.

Propofol[†] {, Adult s: 1.0 mg/k g IV bolu s with addit ional 0.5 mg/k g bolu ses as

Page 4895

{,

{,

need ed, or a cons tant infus ion at 25 to 125 p-g/k g/mi n titrat ed to effec t. Child ren: 1.0 mg/k g IV bolu s (max imu m 40 mg) with addit ional 0.5 mg/k g bolu ses (max imu m 20 mg per bolu s) as need ed, or a cons tant infus ion at 25 to 125 p-g/k g/mi n titrat ed to effec t. Bolu

Page 4896

s dose s of prop ofol shou ld be give n over 60 to 120 seco nds to avoi d apne a and respi rator y depr essi on. Etomidate {, Adult s: 0.1 mg/k g IV bolu s with addit ional 0.05 to 0.1 mg/k g bolu ses as need ed. {, Child ren: 0.1 mg/k g IV bolu s with addit ional 0.05 to 0.1 mg/k

Page 4897

g bolu ses as need ed. {, Eto mida te shou ld be give n over 90 to 120 seco nds to avoi d respi rator y depr essi on. Nitrous oxide {, Adult s: 50% nitro us oxid e (50 % oxyg en) via dem andvalve . {, Child ren: 30% to 50% nitro us oxid e (70 % to 50% oxyg en) via dem and-

Page 4898

valve or conti nuou s-flo w usin ga nasa l mas k (cont inuo us-fl ow tech niqu e requi res the pres ence of two phys ician s). Fentanyl and midazolam {, Gen eral Prin ciple s of Admi nistr ation : {, The dose of each drug ultim ately depe nds on the patie nt's age and pain thres hold, the proc edur

Page 4899

e bein g perfo rme d, the conc omit ant use of other drug s, and the pres ence of unde rlyin g medi cal probl ems. {,

Striv e to achi eve a “bala nced ” effec t of anal gesi a and seda tion. For exa mple , if the patie nt is very drow sy but expe rienc ing pain, addit ional anal

Page 4900

gesi a (fent anyl) is indic ated. On the other hand , if the patie nt is too alert, then mor e seda tion (mid azol am) shou ld be give n. {,

The drug s must be slowl y and caref ully titrat ed to the desir ed level of anal gesi a and seda tion. Admi niste r each dose over 1 minu te

Page 4901

and wait 2 to 3 minu tes betw een dose s to fully appr eciat e the effec ts of the previ ous dose and avoi d over dosi ng. {,

The endp oint of drug admi nistr ation is a patie nt who is very drow sy and frequ ently falls asle ep whe n not stim ulate d. Ther e is a varia ble amo unt of

Page 4902

ptosi s pres ent, nyst agm us occu rs, and the spee ch is slurr ed and often not unde rstan dabl e. How ever, airw ay refle xes are intac t; the abilit y to swall ow is pres erve d; and the patie nt is arou sabl e to verb al or painf ul stim uli, altho ugh the resp onse to pain is great

Page 4903

ly temp ered. At the heig ht of pain, patie nts may grim ace or expr ess obje ction s. This does not signi fy inad equa te anal gesi a or seda tion, but rathe ra lack of gene ral anes thesi a. {,

If respi rator y depr essi on occu rs, patie nts shou ld be enco urag ed to take seve ral

Page 4904

deep breat hs. In most case s, this is all that is requi red. Admi nistr ation of a painf ul stim ulus may also be helpf ul. If nece ssar y, nalo xone or flum azen il can be admi niste red. A brief perio d of assi sted ventil ation usin ga bag/ mas k devi ce may be perfo rme d until

Page 4905

the patie nt resu mes spon tane ous respi ratio n, elimi natin g the need for rever sal agen ts. {,

Adult s: An initial dose of 1 to 1.5 p-g/k g of fenta nyl is give n, and the effec t is obse rved. This is follo wed by an initial dose of 1 to 2 mg of mida zola m. All dose s are admi niste red over

Page 4906

1 minu te. Addit ional fenta nyl and mida zola m are give n in incre ment s (50 p-g per dose of fenta nyl, 1 mg per dose of mida zola m) at 2to 3-mi nute inter vals until the desir ed level of anal gesi a and seda tion is achi eved . In elder ly patie nts or thos e with signi

Page 4907

fican t unde rlyin g cardi ores pirat ory dise ase, initial and incre ment al dose s of both agen ts shou ld be halv ed. {,

Child ren: An initial dose of 1 p-g/k g of fenta nyl and 0.05 mg/k g of mida zola m is admi niste red as previ ousl y desc ribed . Sub sequ ent dose s of fenta nyl are give

Page 4908

n in incre ment s of 0.25 to 0.5 p-g/k g, and addit ional mida zola m is admi niste red in dose s of 0.02 to 0.03 mg/k g until the desir ed level of anal gesi a and seda tion is achi eved . The princ iples of slow caref ul titrati on, achi eve ment of a bala nced effec t, and endp oints

Page 4909

of drug admi nistr ation are ident ical in adult s and child ren. * For rectal use of m ethohexital, add 5 m L of sterile water or saline to a 500 m g vial of m ethohexital and m ix well; this provides a m ethohexital solution of 100 mg/m L. Adm inister the appropriate dose of m ethohexital using a sm all rubber feeding tube or plastic intravenous catheter with the needle removed; be sure to deliver m ethohexital into the rectum , not the colon, and squeeze or tape the buttocks together im m ediately after adm inistration to avoid expulsion. † To prevent injection pain with propofol, place a rubber tourniquet distal to the injection and adm inister 0.5 m g/kg of IV lidocaine 30 to 120 seconds before propofol. Be sure to remove the tourniquet prior to propofol administration.

Multiple studies have demonstrated the safety and efficacy of ketamine in pediatric patients.[] As a result, it has become one of the most widely used agents for emergency department PSA in children. While data regarding the use of ketamine in adult emergency department patients is limited, a recent study has demonstrated a high success rate with minimal complications.[37] Ketamine should be avoided in children younger than 3 months of age, and in patients with uncontrolled hypertension, ischemic heart disease, and upper respiratory infections and those at risk for elevated intraocular or intracranial pressure. Over the past several years, propofol has been gaining popularity and acceptance as a safe and effective agent for emergency department PSA in both children and adults. Propofol's popularity stems from its clinical properties, including an almost immediate onset of action after intravenous administration, uniformly successful sedation, extremely rapid recovery, and antiemetic effects. Propofol's acceptance as an appropriate agent for emergency department use has been driven by a number of recent studies demonstrating safe administration by emergency physicians.[] However, before using propofol for the first time, it is advisable to spend some time observing propofol sedation by an experienced clinician, as there is a “learning curve” with respect to dosing and titration. Based on current data, propofol appears best suited for brief intensely painful procedures (e.g., cardioversion, fracture reduction) or brief procedures that require complete immobilization (e.g., ocular examination). The safety of propofol for extended administration in the emergency department has not been documented.[65] Since propofol typically induces deep sedation, close patient monitoring is mandatory. In the majority of the emergency department studies to date, two physicians were present; one to administer propofol and observe the patient, and another to perform the procedure.[] However, there is no evidence that the presence of two physicians improves outcome. Tactics to decrease the risk of aspiration should also be employed, including avoidance of oversedation (and therefore the need for assisted ventilation) and adopting a more conservative approach to recent oral intake.[65] Although etomidate enjoys widespread acceptance as an induction agent for emergency department RSI, limited data are available to support its safety and efficacy for PSA. In a prospective study of 60 patients, Ruth and associates[56] found that 98% of patients were successfully sedated with etomidate. There was a low incidence of adverse effects, including oxygen desaturation below 90% (5 patients), myoclonus (4 patients), vomiting (1 patient), pain on injection (1 patient), and a brief episode of bradycardia (1 patient). Several other studies have demonstrated similar results.[] Intravenous methohexital is not easily titrated and may be associated with a slightly higher incidence of apnea and respiratory depression when compared with a combination of fentanyl and midazolam or ketamine.[30] The use of rectal methohexital has demonstrated use in sedating children for radiologic procedures.[31]

SPECIAL CONSIDERATIONS FOR PEDIATRIC PATIENTS Although it is clear that children may find even the most routine emergency department procedures terrifying,

Page 4910

they historically have received less pain control and anxiolysis than adult patients with similar conditions.[] Over the last several years, PSA agents previously restricted to use in the operating suite have been used with increasing frequency in pediatric ambulatory treatment settings. In response to reports of adverse outcomes (including deaths), the American Academy of Pediatrics Committee on Drugs has published guidelines for PSA.[] These documents provide a useful, pediatric-focused adjunct to the Practice Guidelines set forth by the American College of Emergency Physicians.[1]

Approach to Sedation in Children When planning a strategy for performing a painful procedure on a child in the emergency department, one must balance the desire to reduce pain and fear in the child with the level of safety and invasiveness inherent in some methods of PSA. In some cases, a calm and reassuring bedside manner combined with distraction techniques may be successful. For other procedures, the use of topical agents such as EMLA cream (eutectic mixture of local anesthetics), tetracaine/adrenaline/cocaine, and lidocaine/epinephrine/tetracaine solutions and gels, in conjunction with transmucosal anxiolytics, may provide adequate sedation and analgesia and obviate the need for placement of an intravenous line (see Table 188-2 ). Local anesthetics are potential cardiac depressants and can cause CNS depression or excitation, even if injected intradermally. Maximum recommended doses should be calculated in advance to avoid overdosing in small children.[5] Intravenous PSA is indicated when intravenous access is required for other reasons and when the clinician believes that the benefits of intravenous administration outweigh the potential problems (e.g., pain, technical difficulty) associated with intravenous line placement. In addition, intravenous administration should be considered when repeat doses of medications are likely to be needed (i.e., for prolonged procedures). Guidelines for patient preparation, personnel requirements, monitoring, drug administration, recovery care, and discharge criteria for children receiving PSA are similar to those outlined for adults, but some special concerns should be highlighted. Dosages must be calculated precisely using the child's current weight, not the parent's estimate. Equipment to manage the airway and resuscitation supplies must be size appropriate, and the treating physician must be skilled in airway management and pediatric resuscitation.

Pharmacology Agents used for PSA often have different pharmacokinetics in infants and children than in adults. The body's content of water, muscle, and fat vary significantly from birth to adulthood, and this, along with factors such as protein-binding capacity and the level of maturity of hepatic and renal function, can affect the half-life elimination of medications. While not universally true for all drugs, neonates have more prolonged clearance times than children older that 2 years, but after 2, the half-life is longer than in adults. As the child approaches the teen years, the pharmacokinetics approach adult patterns. Precise dosing according to weight and anticipation of age-dependent responses to these medications are essential for their safe use. The benefits of intravenous drug administration may be outweighed by the difficulty in obtaining intravenous access in some children. In this situation, alternative routes of administration (e.g., oral, nasal, rectal, intramuscular) can be used (see Table 188-1 ).

Opioids As in adults, fentanyl has become the opioid of choice for PSA in children. When administered intravenously, it should be titrated slowly, keeping in mind that the potential for respiratory depression is enhanced when fentanyl is used in concert with other sedatives.[] The metabolism of fentanyl in small infants (40 minutes), prolonged recovery time, and residual sedation (often lasting up to 24 hours) make it unsatisfactory for emergency department use. Likewise, the combination of meperidine (Demerol), promethazine (Phenergan), and chlorpromazine (Thorazine), also known as DPT or the “lytic” cocktail, is not recommended. Unacceptable rates of sedation failure, prolonged sedation times, the risk of respiratory depression, and the possibility of dystonic reactions (from the combination of phenothiazines) argue against its use.[]

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Marx: Rosen's Emergency Medicine: Concepts and Clinical Practice, 6th ed., Copyright © 2006 Mosby, Inc.

REFERENCES 1. American College of Emergency Physicians : Clinical policy: Procedural sedation and analgesia in the emergency department. Ann Emerg Med2005;45:177. 2. Innes G: Procedural sedation and analgesia in the emergency department. Canadian consensus guidelines. J Emerg Med1999;17:145. 3. Krauss B, Green SM: Sedation and analgesia for procedures in children. N Engl J Med2000;342:938. 4. American Academy of Pediatrics Committee on Drugs : Guidelines for the elective use of conscious sedation, deep sedation, and general anesthesia in pediatric patients. Pediatrics1985;76:317. 5. American Academy of Pediatrics Committee on Drugs : Guidelines for monitoring and management of pediatric patients during and after sedation for diagnostic and therapeutic procedures. Pediatrics 1992;89:1110. 6. Green SM, Krauss B: Procedural sedation terminology: Moving beyond “conscious sedation.”. Ann Emerg Med2002;39:433. 7. Joint Commission on Accreditation of Healthcare Organizations : Accreditation manual for hospitals, Oakbrook Terrace, Ill, Joint Commission on Accreditation of Healthcare Organizations, 2001. 8. American Society of Anesthesiology : Practice guidelines for sedation and analgesia by non-anesthesiologists. Anesthesiology2002;96:1004. 9. American Academy of Pediatrics Committee on Drugs : Guidelines for monitoring and management of pediatric patients during and after sedation for diagnostic and therapeutic procedures: Addendum. Pediatrics 2002;110:836. 10. Green SM, Krauss B: The semantics of ketamine. Ann Emerg Med2000;36:480. 11. Agrawal D: Preprocedural fasting state and adverse events in children undergoing procedural sedation and analgesia in a pediatric emergency department. Ann Emerg Med2003;42:636. 12. Cote CJ, Karl HW, Notterman DA: Adverse sedation events in pediatrics: A critical incident analysis of contributing factors. Pediatrics2000;105:805. 13. Gill M: A study of bispectral index monitor during procedural sedation and analgesia in the emergency department. Ann Emerg Med2003;41:234. 14. Agrawal D: Bispectral index monitoring quantifies depth of sedation during emergency department procedural sedation and analgesia in children. Ann Emerg Med2004;43:247. 15. Miner JR: Bispectral electroencephalographic analysis of patients undergoing procedural sedation in the emergency department. Acad Emerg Med2003;10:638. 16. Miner JR, Heegaard W, Plummer D: End-tidal carbon dioxide monitoring during procedural sedation. Acad Emerg Med2002;9:275. 17. Newman DH: When is a patient safe for discharge after procedural sedation? The timing of adverse effect events in 1,367 pediatric procedural sedations. Ann Emerg Med2003;42:627. 18. Chudnofsky CR: The safety of fentanyl use in the emergency department. Ann Emerg Med1989;18:6. 19. Schutzman SA: Oral transmucosal fentanyl citrate for premedication of children undergoing laceration repair. Ann Emerg Med1994;24:1059. 20. Wright SW: Comparison of midazolam and diazepam for conscious sedation in the emergency department. Ann Emerg Med1993;22:201. 21. Bailey PL: Frequent hypoxemia and apnea after sedation with midazolam and fentanyl. Anesthesiology 1990;73:826. 22. Hill AB: Prevention of rigidity during fentanyl-oxygen induction of anesthesia. Anesthesiology1981;55:452. 23. Mostert JW: Clinical comparison of fentanyl with meperidine muscle rigidity. J Clin Pharmacol J New Drugs1968;8:382. 24. Scott TC, Sarnquist FH: Seizure-like movements during a fentanyl infusion with absence of seizure activity in a simultaneous EEG recording. Anesthesiology1985;62:812. 25. Flacke JW: Histamine release by four narcotics: A double-blind study in humans. Anesth Analog 1987;66:723. 26. Ramoska EA, Linkenheimer R, Glasgow C: Midazolam use in the emergency department. J Emerg Med 1991;9:247. 27. Shane SA, Fuchs SM, Khine H: Efficacy of rectal midazolam for the sedation of preschool children

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undergoing laceration repair. Ann Emerg Med1994;24:1065. 28. Connors K, Terndrup TE: Nasal versus oral midazolam for sedation of anxious children undergoing laceration repair. Ann Emerg Med1994;24:1074. 29. Reves JG: Midazolam: Pharmacology and uses. Anesthesiology1985;62:310. 30. Austin T: Safety and effectiveness of methohexital for procedural sedation in the emergency department. J Emerg Med2003;24:315. 31. Pomeranz ES: Rectal methohexital sedation for CT imaging of pediatric patients in the ED. Pediatrics 2000;105:1110. 32. Miner JR: Randomized clinical trial of propofol versus methohexital for procedural sedation during fracture and dislocation reduction in the emergency department. Acad Emerg Med2003;10:931. 33. Green SM, Johnson NE: Ketamine sedation for pediatric procedures: Part 2, review and implications. Ann Emerg Med1990;19:1033. 34. Kim G: Ventilatory response during dissociative sedation in children: A pilot study. Acad Emerg Med 2003;10:140. 35. Hemmingsen C, Nielsen PK, Odorico J: Ketamine in the treatment of bronchospasm during mechanical ventilation. Am J Emerg Med1994;12:417. 36. Green SM: What is the optimal dose of intramuscular ketamine for pediatric sedation?. Acad Emerg Med 1999;6:21. 37. Chudnofsky CR: A combination of midazolam and ketamine for procedural sedation and analgesia in adult ED patients. Acad Emerg Med2000;7:228. 38. Green SM: Intramuscular ketamine for pediatric sedation in the emergency department: Safety profile in 1,022 cases. Ann Emerg Med1998;31:688. 39. Green SM, Nakamura R, Johnson NE: Ketamine sedation for pediatric procedures: Part 1, A prospective series. Ann Emerg Med1990;1:1024. 40. Wathen JE: Does midazolam alter the clinical effects on intravenous ketamine sedation in children? A double-blind, randomized, controlled, emergency department trial. Ann Emerg Med2000;36:579. 41. Sherwin TS: Does adjunctive midazolam reduce recovery agitation after ketamine sedation for pediatric procedures? A randomized, double blind, placebo-controlled, emergency department trial. Ann Emerg Med 2000;35:229. 42. Hostetler MA, Davis CO: Prospective age-based comparison of behavioral reactions occurring after ketamine sedation in the ED. Am J Emerg Med2002;20:463. 43. Luhmann JD: Sedation for peritonsilar abscess drainage in the pediatric emergency department. Pediatr Emerg Care2002;18:1. 44. Acworth JP, Purdie D, Clark RC: Intravenous ketamine plus midazolam is superior to intranasal midazolam for emergency paediatric procedural sedation. Emerg Med J2001;18:39. 45. Bassett KE: Propofol for procedural sedation in children in the emergency department. Ann Emerg Med 2003;42:773. 46. Godambe SA: Comparison of propofol/fentanyl versus ketamine/midazolam for brief orthopedic procedural sedation in a pediatric emergency department. Pediatrics2003;112:116. 47. Guenther E: Propofol for sedation by emergency physicians for elective pediatric outpatient procedures. Ann Emerg Med2003;42:783. 48. Skokan EG: Use of propofol sedation in a pediatric emergency department: A prospective study. Clinical Pediatrics2001;40:663. 49. Havel Jr JrCJ, Strait RT, Hennes H: A clinical trial of propofol vs. midazolam for procedural sedation in a pediatric emergency department. Acad Emerg Med1999;6:989. 50. Coll-Vincent B: Sedation for cardioversion in the emergency department: Analysis of effectiveness in four protocols. Ann Emerg Med2003;42:767. 51. Picard P, Tramer MR: Prevention of pain on injection with propofol: A quantitative systematic review. Anest Analg2000;90:963. 52. Dickinson R, Singer AJ, Carrion W: Etomidate for pediatric sedation prior to fracture reduction. Acad Emerg Med2001;8:74. 53. Vinson DR, Bradbury DR: Etomidate for procedural sedation in emergency medicine. Ann Emerg Med 2002;39:592. 54. Dursteler BB, Wightman JM: Etomidate-facilitated hip reduction in the emergency department. Am J Emerg Med2000;18:204. 55. Burton JH: Etomidate and midazolam for reduction of anterior shoulder dislocation: A randomized controlled trial. Ann Emerg Med2002;40:496. 56. Ruth WJ, Burton JH, Bock AJ: Intravenous etomidate for procedural sedation in emergency department patients. Acad Emerg Med2001;8:13. 57. Van Keulen SG, Burton JH: Myoclonus associated with etomidate for ED procedural sedation and analgesia. Am J Emerg Med2003;21:556. 58. Schenarts CL, Burton JH, Riker RR: Adrenocortical dysfunction following etomidate induction in emergency department patients. Acad Emerg Med2001;8:1.

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59. Stewart RD: Nitrous oxide sedation/analgesia in emergency medicine. Ann Emerg Med1985;14:2. 60. Gamis AS, Knapp JF, Glenski JA: Nitrous oxide analgesia in a pediatric emergency department. Ann Emerg Med1989;18:177. 61. Luhmann JD: A randomized clinical trial of continuous-flow nitrous oxide and midazolam for sedation of young children during laceration repair. Ann Emerg Med2001;37:20. 62. Krauss B: Continuous-flow nitrous oxide: Searching for the ideal procedural anxiolytic for toddlers. Ann Emerg Med2001;37:61. 63. Philip BK: Flumazenil: A Review of the Literature, New Jersey, Excerpta Medica, 1992. 64. Chudnofsky CR: The safety and efficacy of flumazenil in reversing conscious sedation in the emergency department. Acad Emerg Med1997;4:944. 65. Green SM, Krauss B: Propofol in emergency medicine: Pushing the sedation frontier. Ann Emerg Med 2003;42:792. 66. Hostetler MA, Szilagyi PG, Auinger P: Do children in the emergency department really receive less analgesia and sedation than adults [abstract]?. Acad Emerg Med2000;7:549. 67. Strauss SG, Lynn AM, Spear RM: Progress in pain control for very young infants. Contemp Pediatr 1995;12:80. 68. Cote CJ: Sedation for the pediatric patient. Pediatr Clin North Am1994;41:31. 69. Yaster M, Desphanpande KT: Management of pediatric pain with opioid analgesics. J Pediatr 1988;113:421. 70. Friesen RH, Lockhart CH: Oral transmucosal fentanyl citrate for preanesthetic medication of pediatric day surgery patients with or without droperidol as a prophylactic anti-emetic. Anesthesiology1992;76:46. 71. Clark RF: Delayed onset lorazepam poisoning successfully reversed by flumazenil in a child: Case report and review of the literature. Pediatr Emerg Care1995;1:32. 72. Sugarman JM, Paul RI: Flumazenil: A review. Pediatr Emerg Care1994;10:37. 73. Massanari M, Novitsky J, Reinstein LJ: Paradoxical reactions in children associated with midazolam during endoscopy. Clin Pediatr1997;36:681. 74. Proudfoot J: Analgesia, anesthesia and conscious sedation. Emerg Med Clin North Am1995;13:357. 75. Terndrup TE: A prospective analysis of intramuscular meperidine, promethazine, and chlorpromazine in pediatric emergency department patients. Ann Emerg Med1991;20:31.

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Marx: Rosen's Emergency Medicine: Concepts and Clinical Practice, 6th ed., Copyright © 2006 Mosby, Inc.

Section IX - The Problem Patient Chapter 189 – The Combative Patient Gregory P. Moore Louise Kao

PERSPECTIVE Background Dealing with combative patients is one of the most difficult challenges an emergency physician encounters. Often brought in against their will, such patients may be agitated, confrontational, and nearly impossible to examine. If not controlled, they may harm themselves or others, including the emergency department staff, other patients, and visitors. Although it is important to manage the combative patient, it is preferable to recognize signs of impending violence early in order to prevent its occurrence. The emergency physician should control the patient and the situation, diagnose and treat reversible causes of violence, and protect the patient and staff from harm. Emergency physicians are often called on to provide medical clearance before psychiatric admissions. The physician must recognize a medical etiology of an apparent psychiatric disorder to perform appropriate triage at disposition and avoid inadequate care. Medicolegal considerations include informed consent, battery, false imprisonment, and duty to warn. This chapter discusses these aspects of the management of the combative patient in the emergency department.

Epidemiology Violence has been called our nation's shameful epidemic. Injury is the leading cause of death in persons younger than 44 years, and homicide is the second leading cause of death in persons aged 15 to 24 years.[1] Homicide rates in the United States are the highest of any industrialized country,[2] and rates of death from firearms are eight times higher in the United States.[3] For each death there are an estimated 19 additional injuries requiring hospitalization.[4] The estimated lifetime medical cost for treating all gunshot injuries in the United States in 1994 was $2.3 billion; taxpayers covered an estimated $1.1 billion of this expense.[5] Because of its nature, the emergency department lends itself easily to becoming a setting for violent behavior. The emergency department is an environment of high stress owing to illness, prolonged waiting times, confusion, and frequent lack of communication. The 24-hour open door policy, availability of potential hostages, and widespread accessibility of drugs and weapons compound the problem.[6] In 1999, the Bureau of Labor Statistics estimated that there were 2637 nonfatal assaults on hospital workers, with the highest frequency of violent attacks occurring in the emergency department, psychiatric ward, waiting rooms, and geriatric units.[7] Up to 50% of human service providers become victims of violence sometime during their careers.[] In a survey of 461 emergency medicine residents in 1994, 62% were concerned about their personal safety while working in the emergency department and 50% thought that security measures in their hospitals were inadequate.[10] A 1999 survey of psychiatry residents revealed that 73% reported being threatened and 36% had been physically assaulted in residency. Two thirds of them had received either no or inadequate training in managing combative patients.[11] Unfortunately, despite the obvious risks, we as providers are typically not trained in the identification and management of combative patients. A 1988 survey of emergency department directors in 170 U.S. teaching hospitals with volumes of at least 40,000 visits per year showed that, of 127 responding hospitals, 32% reported at least one verbal threat daily, 18% reported at least one threat with a weapon daily, and 25% reported restraining at least one patient daily.[12] Within the previous 5 years, 7% of institutions had experienced a violent death in the emergency department, and 80% had a staff member injured by violence. The violent patient suffered as well, with 13%

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of hospitals reporting injuring patients while restraining them, including one strangulation death. Litigation was pending in 16% of surveyed emergency departments because of restraint of patients. However, only 40% of hospitals surveyed provided formal nursing education on this topic and only 62% had 24-hour security personnel in the emergency department. A 1994 survey of 44 pediatric emergency department directors revealed that more than half received one or more verbal threats a week, 77% reported one or more physical attacks on staff per year, and 25% reported actual injury to staff.[13] The survey found that 24-hour security was in place at only 54% of emergency departments. In addition, studies have shown that an emergency department census of 50,000 per year or more and an average waiting time of 2 hours or more were significantly associated with increased incidence of violence.[] Patients who are armed with lethal weapons pose a serious threat to emergency department staff. Weapons carriage in the emergency department population has been estimated at approximately 4% to 8%, [] with one large university-county hospital emergency department reporting confiscating an average of 5.4 weapons a day using a metal detector.[16] At this center, 26.7% of major trauma patients seen over a 14-year period were armed with lethal weapons (84% knives and 16% guns). A total of 115 incidents of violence involving weapons occurred over this period, resulting in four fatalities of patients and six minor injuries to the staff.[16] They also documented a disturbing trend of decreasing average age of major trauma patients carrying weapons from a mean of 24 in 1979 to a mean of 19 in 1992. This finding parallels national surveillance data on firearm-related fatalities from 1992 to 1995, which reveal that firearm deaths are on the rise among males aged 15 to 24 years.[17] Clearly, the prevalence of weapons carriage in the emergency department represents a potential for rapid escalation of violence. Unfortunately, predicting weapons carriage in any particular patient is not an easy task.[18] As a result, one should assume that all violent patients are armed until proved otherwise, especially those presenting with major trauma. Identification of potentially violent patients is difficult, with male gender, prior history of violence, and drug or alcohol abuse being the only positive predictors.[] Ethnicity, diagnosis, age, marital status, and education are not reliable identifiers. A study conducted in an outpatient psychiatric setting found that the incidence of violent behavior did not vary with the experience of the psychiatrist.[19] Actuarial prediction of patients' violence in a 6-month time period using criteria such as age, drug use, and prior history of violence was substantially more accurate than prediction by evaluating attending psychiatrists.[23] How are we, as emergency physicians, to predict, prevent, and control violent outbursts in the emergency department? Appreciation of the potential for violence, preparedness, and proper utilization of verbal techniques and physical or chemical restraints allow us to assist the patient while preventing injury.

PRINCIPLES OF DISEASE Pathophysiology The pathogenesis of violent behavior is not well understood, as evidenced by the multitude of theoretical explanations. Theories postulated have explored environmental, historical, interpersonal, biochemical, electrical, genetic, hormonal, neurotransmitter, and alcohol and substance abuse disorders as potential etiologies.[] Known psychiatric illness is also a risk factor, with schizophrenia (paranoid and nonparanoid), personality disorders, mania, and psychotic depres-sion being most often associated with violent behavior.[] Schizophrenics with delusions often become violent because they believe that others are attempting to harm them. They may also have auditory hallucinations commanding harm to others. Patients with antisocial and borderline personality disorder typically do not feel remorse for their violent actions. The manic patient is particularly dangerous because of emotional lability; pleasantness can quickly turn to aggression. However, the magnitude of the risk of violence associated with psychiatric illness is debatable.[] Alcohol and substance abuse disorders are consistently found to be associated with violent behavior in both psychiatric and nonpsychiatric populations. Biologically, the serotonin system has been postulated to control aggression and inhibition, with diminished serotonergic function thought to disinhibit aggression against the self and others.[] Low levels of cerebrospinal fluid 5-hydroxyindoleacetic acid, a metabolite of serotonin, have been correlated with violent suicides or crimes.[36] Whole-blood serotonin, when measured in a representative birth cohort of 781 individuals, was significantly related to violence in men but not in women.[37] Generalized brain dysfunction has also been hypothesized to predispose to violent behavior by disrupting the regulation of aggression. Research on animals and humans who have suffered brain insults has implicated specific areas of the brain, particularly the prefrontal cortex and the temporal cortex.[] Positron emission tomography of murderers in one study showed reduced glucose metabolism in the prefrontal cortex, superior parietal gyrus, left angular gyrus, and the corpus callosum as well as abnormal asymmetry between left and right hemispheres

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of the brain, providing further evidence for the existence of abnormal brain function in violent individuals.[41] The discovery of a disproportionately higher census of XYY males in institutionalized populations has led to genetic studies showing that XYY males have increased impulsiveness that may lead to increased aggression. Increased testosterone in males and hormonal fluctuation in females have also been implicated. [33]

MANAGEMENT Risk Assessment Evaluation of the combative patient begins with risk assessment and attention to safety measures. Violence usually erupts after a period of mounting tension. The astute practitioner may identify verbal and nonverbal cues and subsequently have the opportunity to defuse the situation.[28] Verbal cues include speech that is insistent, becoming progressively louder and ultimately threatening. Nonverbal cues include tense posture and motor restlessness. In a typical scenario, the patient first becomes angry, then resists authority, and finally becomes confrontational and may perform violent deeds. However, violent behavior may erupt without warning (especially with organic etiologies), and clinicians should not feel overly confident in their ability to sense impending danger. As a whole, practitioners tend to be poor predictors of impending violence. Despite this, one should respond and take appropriate precautions in response to a “gut feeling” that a dangerous situation may be developing.[6] An obviously angry patient should always be considered potentially violent. Provocative behavior, an angry demeanor, pacing, loud speech, tense posture, gripping arm rails intensely, frequently changing body position, pounding walls or throwing things, and clenched fists are all signs of impending violence.[] The patient should be removed from contact with other belligerent accomplices, as well as from other provocative patients, to prevent escalation. A quiet area with a window or direct observation is optimal. Because increased waiting times correlate positively with violent behavior,[] one should consider seeing the potentially violent patient expeditiously to prevent escalation of aggression. Often, the aura of preferential treatment defuses patients' anger. All patients should be disarmed before the interview. Metal detectors can be used for this purpose to remove weapons from all patients before emergency department entry. The practice of undressing all patients and placing them in a gown is useful both as a nonconfrontational search for weapons and for easy identification in the event that the patient escapes from the emergency department. Although searching patients for weapons may appear to be a violation of privacy, routine disarming of all patients presenting to the emergency department results in an increased feeling of safety for both patients and staff.[] The setting of the patient's interview should be one of privacy but not isolation.[] Some emergency departments have seclusion rooms specifically intended for the purpose of interviewing potentially dangerous patients. Security should be nearby and the door should be left open to allow both intervention and escape. The patient and interviewer may be seated roughly equidistant from the door, or the interviewer may sit between the patient and the door. Blocking the door, however, poses a risk of harm to the clinician if the patient feels the need to escape. A physician who is trapped in the room with a violent patient is at high risk for personal injury. Ideally, two exits should be available and doors should swing outward. This arrangement facilitates escape but could increase the chance of injury to those standing outside the door. The clinician should have unrestricted access to the door and therefore should never sit behind a desk. The room should not contain heavy objects that may be thrown, such as ashtrays, or other potential weapons such as electrical cords, scalpels, needles, or hot liquids. The clinician should have a mechanism for alerting others that he or she is in danger, such as a panic button or a code word or phrase that instructs others to call for security (e.g., “I need Dr. Armstrong in here”). For personal protection, glasses, earrings, and necklaces should be removed and neckties should be removed or tucked into shirts. Personal accessories that may be used against the emergency physician, such as a stethoscope, scissors, or pocket knives, should be removed. The physician should be aware of any objects within the room or on the patient's body, such as pens, watches, or belts, that may be used as weapons.[]

Verbal Management Techniques The patient should be made as comfortable as possible, and the interviewer should adopt an honest and straightforward manner.[44] In some cases, an agitated patient may be aware of his or her impulse control problem and may welcome limit-setting behavior by the clinician (e.g., “I can help you with your problem, but I cannot allow you to continue threatening me or the staff”).[6] The interviewer should act as an advocate for the patient. Offering a soft chair or something to eat or drink (not a hot liquid, which may be used as a weapon) may help to establish trust. A significant percentage of patients decompress at this point because

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offering food or drink appeals to their most basic human needs and attention to these needs builds trust. The interviewer should adopt a nonconfrontational demeanor and be an attentive and receptive listener without conveying weakness or vulnerability. The interviewer should respond verbally in a calm and soothing tone of voice. It is also important to avoid direct eye contact, avoid approaching the patient from behind, stand at least an arm's length away, and avoid sudden movements.[6] A key mistake when interviewing such a patient is failing to address violence directly.[] The patient should be asked relevant questions such as “Do you consider yourself a fighter?” or “Do you carry a gun?” Stating the obvious (e.g., “You look angry”) may help the patient to begin sharing emotions. If the patient becomes more agitated, it is important to speak in a conciliatory manner and offer supportive statements such as “You obviously have a lot of will power and are good at controlling yourself” to help defuse the situation. If this is not successful, a respectful offer of medication or restraints to the patient may prevent further escalation. Clinicians should be aware of their own reactions to potentially violent patients and avoid countertransference of anger toward them. Arguing, exhibiting machismo or condescension, commanding the patient to calm down, or threatening to call security may be seen as a challenge to such patients to “prove themselves” and have disastrous consequences. It is important not to lie to the patient (e.g., “I am sure you will be out of here in no time” when this is not the case) because violent consequences may follow when the lie is discovered. The innocent nurse or unsuspecting colleague who follows the interviewer may become the victim. It is especially important not to deny or downplay threatening behavior, which places the interviewer at increased risk for assault and injury. A chilling illustration of this principle involves a psychiatrist who was killed after entering the waiting room with a patient he knew was potentially violent and armed. He erroneously believed that the strength of the physician-patient relationship ensured his personal safety.[19] All threats should be taken seriously to prevent assault and injury. If verbal techniques are unsuccessful and escalation of violence occurs, the physician should excuse himor herself from the room and summon help using a predetermined code word or phrase or panic button.

Physical Restraints Physical restraints should be considered when, despite a professional and proper approach to the combative patient, verbal techniques have been unsuccessful. The use of restraints can be humane and effective while facilitating diagnosis and treatment of the patient and preventing injury to the patient or medical staff.[45] Overall, the liability one incurs for restraining a patient against the patient's will is negligible compared with the potential liability for allowing a patient to lose control and hurt him- or herself or others.[6] Indications for emergency seclusion and restraint are (1) to prevent imminent harm to others, (2) to prevent imminent harm to the patient, (3) to prevent serious disruption of the treatment program or significant damage to the environment, and (4) as part of an ongoing behavior treatment program. Seclusion may be used to decrease environmental stimulation and at the patient's request. The clinician may find it helpful to classify patients into three categories: those with an organic disorder in which restraints facilitate evaluation, those with functional psychosis in which verbal techniques are less effective and restraints facilitate administration of neuroleptics, and those with personality disorders in which verbal techniques are not useful.[6] Seclusion or restraint may be contraindicated because of a patient's clinical or medical condition. Seclusion should not be used in an unstable patient who requires close monitoring. Seclusion should also be avoided when the patient is suicidal, self-abusive, self-mutilating, or has had an ingestion or overdose.[] Restraints are not to be applied for convenience only or as a punitive response for disruptive behavior, as injury to the patient and litigious consequences may follow. Having a colleague document agreement with the application of restraints is useful, as is the documentation of specific rather than general indications (e.g., “I restrained Mr. Smith because he told me he was going to beat me up and then took a swing at me” is preferable to “I restrained Mr. Smith because he was violent”). The implementation of restraints should be systematic and performed in accordance with an institutional or departmental protocol. Typical protocols begin with the examiner leaving the room to summon a trained restraint team when verbal techniques have proved unsuccessful. It may be helpful to consider the application of restraints as a procedure analogous to running an advanced cardiac life support code. The restraint team consists of at least five people, including a team leader. The leader is the only person giving orders and should be the individual with the most experience in implementing restraints, whether a physician, nurse, or security officer. Before entering the room, the leader outlines the restraint protocol and warns of anticipated danger (e.g., the presence of objects that may be used as weapons). All team members should remove personal effects that the patient could use against them. If the patient to be

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restrained is female, at least one member of the restraint team should be female to diminish potential allegations of sexual assault. The team enters the room in force and displays a professional, rather than threatening, attitude.[6] Many violent individuals decompress at this point, as a large show of force protects their ego (i.e., “I would have fought back but there were too many against me”). The leader speaks to the patient in a calm and organized manner, explaining why restraints are needed and what the course of events will be (i.e., “You will receive a medical and psychiatric examination as well as treatment”). The patient is instructed to cooperate and lie down to have restraints applied. Some patients are relieved at the protection to self and others afforded by restraints when they feel themselves losing control. However, even if the patient suddenly appears less dangerous, when the decision to restrain has been made, it must be carried out. One should not negotiate with the patient at this point. If physical force becomes necessary, one team member restrains a preassigned extremity by controlling the major joint (knee or elbow). The team leader controls the head. If the patient is armed, two mattresses can be used to charge and immobilize or sandwich the patient. Restraints are applied securely to each extremity and tied to the solid frame of the bed (not side rails, as later repositioning of side rails also repositions the patient's extremity). Leather restraints are optimal because they are physically strong and thus more efficacious in preventing escape and less constricting than typical soft restraints. For this reason, gauze should not be used. Soft restraints are helpful in restricting extremity use in the semicooperative patient but are unwarranted in the truly violent patient who is continuing to struggle and attempt escape. If chest restraints are used, it is vital that adequate chest expansion for ventilation is ensured. Applying a soft Philadelphia collar to the patient's neck prevents head banging and biting. Whenever possible, the treating physician should not actively participate in applying restraints to preserve the physician-patient relationship and not be viewed as adversarial. Restraining patients on their side helps prevent aspiration, although supine with the head elevated is more comfortable for the patient and allows a more thorough medical examination while providing some protection against aspiration.[] When the patient is immobilized, announcing that “the crisis is over” has a calming effect on the restraint team and the patient. After restraints have been applied successfully, the patient should be monitored frequently and positions changed to prevent neurovascular sequelae such as circulatory obstruction, pressure sores, and paresthesias as well as to avoid rhabdomyolysis associated with continued combativeness. A standardized form is recommended for this monitoring and should be developed by every emergency department that physically restrains patients ( Figure 189-1 ). Documentation should include the specific indication for restraints and, if possible, a colleague's agreement that restraints were necessary. The restraint team should review their performance and discuss ways to improve efficiency in the future. Education and rehearsal by staff are imperative to maintain skills.

Figure 189-1 Leather/soft restraint record.

Sudden, unexpected deaths have been reported in patients who have been restrained.[] Restraints applied by prehospital personnel in the prone or hobble (arms and legs restrained behind the patient) position have resulted in deaths presumed by some to be due to positional asphyxia.[50] Research has cast some doubt on this theory.[52] Patients who are cocaine or stimulant intoxicated and restrained appear to be uniquely at risk for adverse outcomes.[] Increased sympathetic tone and altered pain sensation have been postulated to allow exertion beyond normal physiologic limits in these patients, whereas sympathetic induced vasoconstriction may impede clearance of metabolic waste products. Alteration of respiratory mechanics in an acidemic patient resulting from a restraint position could be a contributing factor by impairing respiratory compensation. It seems prudent to recommend avoiding the prone restraint position altogether and using aggressive chemical sedation in the patient continuing to struggle in physical restraints. The Joint Commission on Accreditation of Health Care Organizations (JCAHO) (PC.11.10 through PC 12.190, effective January 1, 2004) has written guidelines governing the use of restraint and seclusion for

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behavioral health patients, which must be reviewed by each hospital using these procedures. The reader is urged to review this publication. Educational materials regarding seclusion and restraint are available for purchase through their website: http://www.jcaho.org/index.html . To paraphrase, several essential elements must be provided for in a restraint situation including the following: 1.

2. 3. 4. 5.

6.

The implementation of restraint or seclusion is limited to emergencies where imminent risk of harm exists to patient or others. Staff is trained and competent to apply restraint safely. Staff is trained to minimize the use of restraint. Patients in restraints are regularly evaluated and monitored. Orders for restraint use are provided by licensed practitioners and are time limited. Medical records document that the use of restraint or seclusion is consistent with organizational policy.

Rapid Tranquilization Rapid tranquilization may be necessary to control an agitated patient and may be used in conjunction with physical restraints. The ideal pharmacologic agent for this purpose should be effective with multiple routes of administration, nonaddictive, immune to tolerance, and have a low side effect profile. In the 1900s, amobarbital was used but frequently was associated with respiratory depression. In the 1950s, chlorpromazine was found to have good efficacy; however, orthostatic hypotension, sedation, and tolerance to effects limited its usefulness. Rapid tranquilization with newer medications has been shown to be safe and effective in the management of psychotic and potentially assaultive patients.[] Antipsychotic medications, also called neuroleptics, are useful for rapid tranquilization because of their high therapeutic index, lack of tolerance to the desired effects, and lack of addictive potential.[] Classic antipsychotics block dopaminergic receptors and also have variable effects on cholinergic, adrenergic, histaminic, and serotonergic receptors. Antipsychotics can be divided into low potency (chlorpromazine, mesoridazine, thioridazine), midrange potency (loxapine, molindone), and high po-tency (haloperidol, fluphenazine, thiothixene, trifluoperazine). The incidence of sedation, hypotension, and seizures is highest in the low-potency group and the incidence of extrapyramidal symptoms (EPSs) is greatest in the high-potency group. Haloperidol (Haldol) is generally recommended as the drug of choice to sedate a violent patient, and rapid tranquilization is achieved using dosages of 2.5 to 10 mg intramuscularly (IM) at 30- to 60-minute intervals, with half doses used in elderly patients.[] After IM injection, effects are typically seen in 10 to 30 minutes, with most patients requiring less than three doses to achieve the desired effect.[53] Although no ceiling dose has been established, it has been recommended that patients not receive more than six doses in 24 hours. However, 300 mg intravenously (IV) has been used over 24 hours without adverse effects (although the question of medication efficacy is raised with such dosing).[6] Using the lowest effective dose minimizes the risk of side effects. Of note, haloperidol is not approved for IV administration by the U.S. Food and Drug Administration (FDA); however, it has been used safety and effectively by this route with such widespread acceptance that FDA approval is most likely to be deferred indefinitely. The company is not likely to spend money to gain approval for a route of administration already in widespread use. Droperidol (Inapsine), an analogue of haloperidol, has had a long history of success at doses of 5 to 20 mg IM with typically only one or two doses needed to control an agitated patient.[] Intravenous dosing of droperidol starts at 1.25 to 2.5 mg per dose. One study showed that droperidol IM resulted in more rapid control of an agitated patient than the same dose (5 mg) of haloperidol IM; however, both drugs were equivalent after IV administration.[56] Compared with haloperidol, droperidol has a shorter duration of effect, a lesser incidence of EPSs, and a greater incidence of sedation and orthostatic hypotension.[55] The most common side effects of haloperidol and droperidol include sedation, orthostatic hypotension, and EPSs. EPSs are not dose related, can occur after one dose, and may occur up to several days after

Page 4922

administration.[55] After acute administration, patients may develop akathisia (extreme restlessness) or acute dystonia, which may be manifest as involuntary turning or twisting movements in the neck (torticollis), back (opisthotonos), and eyes (oculogyric crisis). Rarely, the mouth and tongue can be affected, compromising the airway.[53] The treatment for each of these symptoms is benztropine (Cogentin), 1 to 2 mg, or diphenhydramine (Benadryl), 25 to 50 mg, either IM or IV. Relief generally occurs within minutes. Haloperidol and droperidol have negligible anticholinergic properties and are often coadministered with anticholinergic agents (benztropine or diphenhydramine) in order to attenuate dystonia.[59] Neuroleptic malignant syndrome is an idiosyncratic reaction that leads to autonomic instability. Symptoms include hyperthermia, hypertension, and lead-pipe rigidity of extremities. This reaction occurs in approximately 1% of patients receiving antipsychotic medications.[53] Clinicians should be familiar with this syndrome when administering antipsychotic medications. If neuroleptic malignant syndrome develops, supportive care should be administered and further neuroleptic medications withheld. Some neuroleptic medications (especially phenothiazines such as chlorpromazine) may lower the seizure threshold; therefore, the use of neuroleptics in sympathomimetic-intoxicated patients has been controversial. In clinical practice, seizure activity occurring after haloperidol or droperidol administration appears to be a rare event. One retrospective review of 2468 patients receiving droperidol in an emergency department setting showed 3 patients with seizure activity.[58] A retrospective review of patients receiving droperidol for combative behavior revealed that of 189 sympathomimetic-intoxicated patients (78 cocaine, 23 amphetamine) who received droperidol, none had an adverse outcome.[60] In addition, haloperidol has been found in an animal model to prevent seizures in cocaine and amphetamine intoxication.[61] Conduction disturbances, specifically prolongation of the QT interval and in some cases torsades de pointes, have been reported in patients sedated with haloperidol[] and droperidol.[] In December 2001, droperidol was given a “black box” warning by the FDA for cases of QT prolongation and torsades de pointes.[70] These cases originated from worldwide postmarketing surveillance and typically involved very high doses of droperidol (up to 100 mg IM). However, some cases were reported with low doses (60%) in helicopter and airplane transports. Other combinations—RN/RN, RN/emergency medical technician (EMT), RN/physician, RN/respiratory therapist, and EMT-paramedic/EMT-paramedic—account for less than 10% each.[2] Flight nurses generally have extensive experience in intensive care units or emergency departments. They may be specialized within the transport team to care for adult, pediatric, or neonatal patients. Paramedics often make their greatest contribution in the transport of critical patients from the scene of illness or injury. Respiratory therapists bring expertise in airway and ventilator management and oxygen delivery systems. Flight physicians may be residents, attending physicians, or medical directors of flight programs. Much research has focused on the specific benefit of the onboard physician.[] Although the answer to this question remains controversial, what is clear is that the crew used by an AMT program must be explicitly tailored to the needs of the community and the patients it serves. A poorly considered aspect of air medical staffing is the effect of the AMT environment on the ability of crew members to provide patient care. Human factors work has shown that most medical care procedures are rated more difficult to perform in an AMT vehicle than in other ground-based settings.[7] Auscultation of the lungs, palpation of pulses, performance of cardiopulmonary resuscitation, endotracheal intubation, and recognition of visual alarms all are impaired while aloft.[] In addition, fatigue, motion sickness, an erratic pattern of work activity, and the high risk involved in AMT operations may affect task performance significantly.[12]

Medical Direction All air medical services require the active involvement of a physician as air medical director, who is responsible for supervising, evaluating, and ensuring the quality of medical care provided by the AMT team. The air medical director must have the final authority over all clinical aspects of the air medical service. The medical director should ensure that the medical personnel have adequate training and qualifications to deliver appropriate medical care, that appropriate medical equipment and supplies are available, and that the correct vehicle is selected for transport. Medical care policies and procedures should be established, including specific provisions for on-line and off-line medical control. The Air Medical Physician Association and the National Association of EMS Physicians have established guidelines for the medical direction of an air medical service.[13]

Safety Safety is the predominant concern of air medical operations, and ensuring safe conduct is a fundamental part of every flight program. Continual training of aircraft pilots and mechanics is essential, and both participate in ensuring the airworthiness of the vehicle. Medical personnel must be proficient in the emergency operations of the aircraft and the routine procedures in and around their helicopter or airplane.

Page 5001

Crew fatigue and other self-imposed stresses that could affect safety, such as the use of prescription or over-the-counter medications, tobacco, and alcohol, must be scrupulously avoided. Weather requirements or “minimums” must be strictly enforced. On receipt of a flight request, the pilot must verify the weather conditions and the condition of the aircraft. To ensure impartiality, the pilot should not be told of the patient's condition or acuity. The pilot always has the right to decline a mission because of aircraft or weather considerations. These decisions must not be influenced or reversed by administrators, flight crew, or other parties.

Landing Zones Helicopter landing zones are inherently dangerous places. The most obvious risk of injury is from impact with rotor blades. This danger is heightened during ground operations, as the blades dip lowest to the ground at the slower rotor speeds associated with engine startup and shutdown. Injuries also may occur as a result of debris being propelled through the air by “rotor wash,” increased noise levels and an inability to hear warnings, and slippery surfaces found on exposed landing sites. Many hospitals have designated landing areas that are appropriately lit and secured ( Figure 192-2 ), with fixed coordinates and predesignated liftoff and approach patterns. Most primary responses occur at unmarked sites, however. Ground personnel must be trained to designate and secure a safe landing zone for helicopter operations ( Box 192-1 ). AMT programs have an obligation to help train ground staff on proper landing zone setup and conduct ( Box 192-2 ).

Figure 192-2 Landing zone safety is param ount to delivery of patients to hospitals. ((Photo courtesy of Dan Lem kin, MD.))

BOX 192-1 Helicopter Safety and Air Medical Transport

{,

Vehi cles and pers onne l shou ld be kept at least 100 ft from the landi ng zone .

{,

Spe ctato rs shou ld be kept

Page 5002

{,

{,

{,

{,

at least 200 ft from the landi ng zone . No smo king or runni ng is per mitte d withi n 50 ft of the helic opter . All item s (e.g., IV lines , pole s) shou ld be kept belo w shou lder heig ht. The flight crew open s and clos es aircr aft door s. The flight crew direc ts

Page 5003

{,

{,

{,

and supe rvise s the loadi ng and unlo adin g of the patie nt and equi pme nt. Grou nd pers onne l shou ld use eye and ear prote ction . Appr oach the helic opter only whe n sign aled to do so by the pilot or an on-b oard crew me mbe r. Appr oach and depa rt the helic opter only

Page 5004

{,

{,

{,

forw ard of the rear cabi n door and in a crou ched posit ion with your head dow n. Nev er appr oach or depa rt from the rear of the helic opter . Stay clear of the tail rotor ; it is virtu ally invisi ble and extre mely dang erou s. If the aircr aft is park ed on a slop e, appr oach

Page 5005

{,

{,

{,

and depa rt on the dow nhill side (gre atest clear ance unde r the blad es). Kee p the landi ng zone clear of (or hold on to) all loos e articl es (e.g., hats, scar ves, shee ts, pillo ws). Prot ect patie nt from the dust and debri s. Follo w the flight crew 's instr uctio ns at all time s.

Page 5006

{,

In disa ster situa tions and mas s casu alty incid ents, victi ms, witn esse s, and spec tator s may beco me hyst erica l or exhi bit sign s of an acut e situa tiona l react ion. Thes e indivi dual s must be kept clear of the landi ng zone and helic opter at all time s. Injur ed victi

Page 5007

{,

ms who exhi bit this beha vior shou ld not be triag ed for helic opter trans port, or they shou ld be trans porte d only with adeq uate phys ical or che mica l restr aints in use. If you do not know , ask.

Courtesy of University of Chicago Hospitals Aeromedical Network (UCAN) and Illinois Association of Air and Critical Care Transport (IAACCT), 2005. BOX 192-2 Landing Zone (LZ) Requirements for Air Medical Transport

Landing Area {,

LZ shou ld be as clos

Page 5008

{,

{,

{,

e as poss ible to the scen e or hosp ital entra nce, but not so clos e that it may interf ere with grou nd oper ation s or patie nt care. LZ shou ld be at least 100 × 100 ft. LZ shou ld be as flat and level as poss ible. LZ must be clear of debri s.

Hazards and Obstructions

Page 5009

{,

{,

{,

Ident ify all pote ntial haza rds that may be on the grou nd or near the appr oach /dep artur e path of LZ. LZ shou ld be clear of wire s, pole s, trees , buildi ngs, vehi cles, and spec tator s. Roa d cone s, rope s, tape, and barri cade s are not reco mm ende d for use near

Page 5010

{,

{,

LZ. Peri mete r of LZ shou ld be at least 50 ft awa y from pote ntial obstr uctio ns and haza rds. LZ shou ld be locat ed upwi nd from any haza rdou s mate rial incid ent.

Approach and Departure Path {,

Path shou ld point into the wind and be free of obstr uctio n to an altitu de of 500 ft

Page 5011

{,

abov e the surfa ce. Path shou ld not pass over com man d post s, treat ment area s, or oper ation ally cong este d area s on the grou nd.

Day Operations {,

{,

Use radio com muni catio ns and hand sign als. Stan d with your back to the wind .

Night Operations {,

Use radio

Page 5012

{,

{,

com muni catio ns and lighti ng to desi gnat e LZ. Spotl ights shou ld be direc ted at the top of poss ible haza rds, not towa rd the appr oach ing or depa rting aircr aft. Posit ion a porta ble light, vehi cle head light s, eme rgen cy vehi cle flash ing light s, flare, or che mica l stick

Page 5013

{,

at each corn er, with a fifth light upwi nd. Non esse ntial light s shou ld be turne d off.

Light Sources {,

{,

{,

Light s must be clear of LZ. If porta ble, light s must be well secu red. Nev er point light s towa rd an appr oach ing or depa rting helic opter .

Wind Indicator

Page 5014

{,

{,

{,

Indic ator may be a wind sock , flag, flare, or smo ke. Indic ator must be clear of LZ. If porta ble, indic ator must be well secu red.

Courtesy of University of Chicago Hospitals Aeromedical Network (UCAN) and Illinois Association of Air and Critical Care Transport (IAACCT), 2005.

Emergency Medical Service AMT should be an integral resource within a comprehensive Emergency Medical Service (EMS) system. Integration begins with the establishment of geographic service areas. Service areas may be determined based on program mission description, aircraft range and speed, the placement of specialty centers and receiving facilities, and the location and mission of air medical programs in adjacent regions. Population densities also are key factors. Helicopters are generally less useful in urban settings because of the proximity of health care facilities and a lack of open and safe landing zones. Paramedics, EMTs, and other public safety personnel should be provided with guidelines specifying when AMT should be considered. These protocols are best developed by EMS Medical Directors in close collaboration with their air medical colleagues.

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Page 5015

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Page 5016

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Marx: Rosen's Emergency Medicine: Concepts and Clinical Practice, 6th ed., Copyright © 2006 Mosby, Inc.

CLINICAL CONCEPTS AND PATIENT CARE Although virtually all types of patients have been transported by air medical services, definitive data indicating which patients benefit from flight are lacking. Many questions regarding the triage of patients to air or ground transport, the efficacy of air medical care, and the effects of AMT on morbidity and mortality in medical and surgical conditions remain unanswered. In an effort to ensure that AMT resources are used wisely, the Air Medical Physician Association has established a detailed medical condition list for the appropriate use of AMT.[14] A more general approach to the need for AMT is illustrated in Box 192-3 . BOX 192-3 Criteria for Air Medical Transport

1. 2. 3. 4. 5. 6. 7. 8.

Distance to the closest appropriate facility is too great for safe and timely transport by ground ambulance. Patient's clinical condition requires that the time spent in transport be as short as possible. Patient's condition is time critical, requiring specific or timely treatment not available at the referring hospital. Potential for transport delay associated with ground transport is likely to worsen the patient's clinical condition. Patient requires critical care life support during transport that was not available from the local ground ambulance service. Patient is located in an area inaccessible to regular ground traffic, impeding ambulance egress or access. Local ground units are not available for long-distance transport. Use of local ground transport services would leave the local area without adequate EMS coverage.

Courtesy of University of Chicago Hospitals Aeromedical Network (UCAN), 2001.

Trauma The effect of helicopter EMS on trauma patient outcomes has been a topic of much study. Many studies show that overall mortality in patients transported by air medical services is significantly reduced, but others show no mortality reduction. More refined efforts note that the major advantage in mortality lies in transport of moderately to severely injured patients. Mortality can be reduced 35% if air transport is used in the appropriate subset of patients. Patients with minor injuries or very severe injuries do not gain additional survival benefit by use of air transport. Generally, patients with prolonged ground transport time from the trauma center obtain the most benefit from air medical services.[]

Cardiac Disorders Hypoxia at altitude causes a compensatory increase in pulse and respiratory rate, and the increased myocardial oxygen demand may result in cardiac decompensation. Studies of patients with acute myocardial infarction and unstable angina revealed that complications (e.g., hypotension, dysrhythmias, exacerbation of chest pain) could be managed effectively aloft. No problems have been seen during transport in series of patients with pacemakers or immediately after thrombolysis for myocardial infarction or

Page 5017

stroke.[] Major in-flight events among cardiac patients occur 12% to 41% of the time and physicans play an important role in safe transport.[] It also has been documented that patients transported by air after resuscitation from cardiac arrest have improved outcomes over patients transported by ground crews.[]

Pregnancy AMT of a gravid woman is generally safe for the mother and fetus. Maternal inspired oxygen concentration is usually adequate to meet the metabolic demands of the fetus, but it may be prudent to provide maternal supplemental oxygen during flight. Transporting a woman in active labor is another major concern because delivery of the infant within the confines of the aircraft cabin may prove difficult.[30]

Neonates and Children Pediatric and neonatal specialty centers often depend on air medical services for prompt transport of critically ill or injured patients to tertiary care centers with specialized pediatric services. These flight crews must have the experience, training, and competency to care for critical pediatric or neonatal patients and the appropriate equipment and medications. The Task Force on Interhospital Transport of the American Academy of Pediatrics has established guidelines for air and ground transport of pediatric and neonatal patients.[31]

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Page 5018

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Chapter 21 – Nausea and Vomiting Leslie S. Zun Amardeep Singh

PERSPECTIVE Nausea and vomiting may represent the primary presentation of many gastrointestinal (GI) disorders (e.g., bowel obstruction, gastroenteritis) or the secondary presentation of numerous systemic conditions (1) caused by severe pain, especially visceral pain; (2) caused by or related to severe systemic illness, such as myocardial infarction, sepsis, or shock; or (3) related to specific conditions by specific mechanisms, such as pregnancy (hormones), increased intracranial pressure (central mechanism), and chemotherapy (chemoreceptor trigger zone [CTZ]). Additionally, vomiting may cause serious sequelae, such as aspiration pneumonia, Mallory-Weiss syndrome, esophageal rupture, volume depletion, and metabolic derangement. Classification by vomiting duration and acute, recurrent, chronic, or cyclic vomiting may assist in determination of the etiology.[1]

Epidemiology The most common causes of nausea and vomiting are acute gastroenteritis, febrile systemic illnesses, and drug effects. Acute viral gastroenteritis is the most common GI disease in the United States. In adult medicine, nausea and vomiting are caused most often by medications. Emesis associated with pregnancy is common, but hyperemesis gravidarum is not.

Pathophysiology The act of vomiting can be divided into three distinct phases: nausea, retching, and actual vomiting. Nausea may occur without retching or vomiting, and retching may occur without vomiting. Nausea is defined as a vague and extremely unpleasant feeling that often precedes vomiting. The exact neural pathways mediating nausea are not clear, but they are likely the same pathways that mediate vomiting. Mild activation of the pathways may result in nausea, whereas more intense stimulation results in vomiting. During nausea, there is an increase in tone in the duodenum and jejunum, with a concomitant decrease in gastric tone; this leads to reflux of intestinal contents into the stomach. There is often associated hypersalivation, repetitive swallowing, and tachycardia. Retching is characterized as rhythmic, synchronous contractions of the diaphragm, abdominal muscles, and intercostals, which occur against a closed glottis. There is a resultant increase in abdominal pressure with a concurrent decrease in intrathoracic pressure. This pressure gradient causes gastric contents to move up into the esophagus. Vomiting is the forceful expulsion of gastric contents through the mouth. There is contraction of the external oblique and abdominal rectus muscles, and the hiatal portion of the diaphragm relaxes; this increases the pressure in the abdominal and the thoracic compartments. There is contraction of the pyloric portion of the stomach. Simultaneously, there is relaxation of the gastric fundus, cardia, and upper esophageal sphincter as the vomitus is brought up and out the mouth. The glottis closes to prevent aspiration. The complex act of vomiting is coordinated by a vomiting center located in the lateral reticular formation of the medulla ( Figure 21-1 ). The efferent pathways from the vomiting center are mainly through the vagus, phrenic, and spinal nerves. These pathways are responsible for the integrated response of the diaphragm, intercostals, abdominal muscles, stomach, and esophagus. The vomiting center is activated by afferent stimuli from a variety of sources. These include vagal and sympathetic impulses directly from the GI tract. Direct irritation of the stomach causes vomiting in this way. Other GI sources of afferent impulses include the pharynx, small bowel, colon, biliary system, and peritoneum. Receptors also are found outside the GI tract in the vestibular system, heart, and genitalia.

Page 5019

Figure 21-1 Pathophysiology of nausea and vom iting. GI, gastrointestinal.

The other major source of impulses to the vomiting center is from the CTZ. The CTZ is located in the area postrema, the floor of the fourth ventricle. It is activated by medications or toxins in the circulation, including opiates, digitalis, chemotherapy agents, salicylate, syrup of ipecac, and dopamine neurotransmitters. The discovery of various neurotransmitters and their receptor sites within the medulla has improved the understanding and development of therapeutic agents. The CTZ area is rich in dopamine D2 receptors, which are antagonized by drugs such as prochlorperazine, metoclopramide, and droperidol. The serotonin receptor has been found widely in the area postrema and the GI tract. It may act directly and through the release of dopamine. Serotonin receptor antagonists, ondansetron and granisetron, have been shown to be effective in preventing chemotherapy-induced nausea and vomiting. Concentrations of cholinergic and histamine receptors are found in the lateral vestibular nucleus and are important in motion sickness. Meclizine, diphenhydramine, and scopolamine act by antagonizing these receptors. Rumination is regurgitation of ingested food that subsequently is reswallowed or ejected. Rumination syndrome is found in infants, children, and mentally challenged adults, but rarely in adults with normal intelligence.

DIAGNOSTIC APPROACH Differential Considerations The differential diagnosis for nausea and vomiting is particularly broad; almost any organ system can be involved ( Table 21-1 ). Vomiting also can result in complications; the causes and complications must be considered. The sequelae of vomiting may include the following: Table 21-1 -- Differential Diagnosis of Nausea and Vomiting Organ System Critical Diagnoses Emergent Diagnoses

Nonemergent Diagnoses

Gastrointestinal Boerhaave's syndrome Ischemic bowel

Gastric outlet obstructed Pancreatitis Cholecystitis Bowel obstruction/ileus Ruptured viscus Appendicitis Peritonitis

Intracerebral bleed Meningitis

Migraine CNS tumor Raised ICP

Gastritis Gastroparesis Peptic ulcer disease Gastroenteritis Biliary colic Hepatitis

Neurologic

Endocrine Pregnancy

DKA

Adrenal insufficiency Hyperemesis gravidarum

Thyroid Nausea and vomiting of pregnancy

Drug toxicity Tylenol Digoxin Aspirin Theophylline Therapeutic

Page 5020

Organ System Critical Diagnoses

Emergent Diagnoses

drug use

Nonemergent Diagnoses Aspirin Erythromycin Ibuprofen Chemotherapy

Drugs of abuse Narcotics Narcotic withdrawal Alcohol Genitourinary

Gonadal torsion Urinary tract infection Kidney stone

Miscellaneous Myocardial infarction Sepsis

Carbon monoxide Electrolyte disorders

Motion sickness Labyrinthitis

CNS , cent ral nerv ous syst em; DKA , diab etic keto acid osis; ICP, intra cran ial pres sure .

Hypovolemia is caused by loss of water and sodium chloride in the vomitus. The contraction of the extracellular fluid space leads to activation of the renin-angiotensin-aldosterone system. Metabolic alkalosis is produced by loss of hydrogen ions in the vomitus. Many factors serve to maintain the alkalosis, including volume contractions, hypokalemia, chloride depletion, and increased aldosterone. Hypokalemia is produced primarily by loss of potassium in the urine. The metabolic alkalosis leads to large amounts of sodium bicarbonate being delivered to the distal tubule. Secondary hyperaldosteronism from volume depletion causes reabsorption of sodium and excretion of large amounts of potassium in the urine. Mallory-Weiss tears typically follow a forceful bout of retching and vomiting. The lesion itself is a 1- to 4-cm tear through the mucosa and submucosa; 75% of cases occur in the stomach with the remainder near the gastroesophageal junction. Bleeding usually is mild and self-limited; however, 3% of deaths from upper GI bleeds are due to Mallory-Weiss tears. Boerhaave's syndrome refers to a perforation of all layers of the esophagus as a result of forceful retching

Page 5021

or vomiting. The overlying pleura is torn so that there is free passage of esophageal contents into the mediastinum and thorax; 80% of cases involve the posterolateral aspect of the distal esophagus. Boerhaave's syndrome is a surgical emergency. Mortality is 50% if surgery is not performed within 24 hours. Aspiration of gastric contents is a concern in patients who have altered mental status or pulmonary findings after an episode of vomiting. Patients with pulmonary findings after vomiting need further evaluation for aspiration.

Rapid Assessment and Stabilization The initial assessment is directed toward the patient's hemodynamic status and identifying the critical causes or sequelae of vomiting (see Table 21-1 ). Data gathered include duration of vomiting, whether blood is in the vomitus, symptoms of volume depletion, and associated symptoms pointing to serious underlying disease. Physical findings include level of consciousness, status of abdomen, rapid neurologic screen for focality, and serial vital signs. Initial stabilization may include intravenous access and fluid resuscitation if there are signs of volume depletion, cardiac monitoring, and therapeutic measures directed toward specific underlying diseases (e.g., blood pressure control in severe hypertension).

Pivotal Findings A thorough history and physical examination usually yield the underlying cause of nausea and vomiting.

History Content of the vomitus may provide clues. The presence of bile indicates a patent connection between the duodenum and the stomach and essentially rules out a gastric outlet obstruction. Regurgitation of undigested food can suggest achalasia, esophageal stricture, or Zenker's diverticulum. Feculent material usually suggests a distal bowel obstruction, but also may be seen with gastrocolic fistula or bacterial overgrowth of stomach contents in long-standing outlet obstruction. Timing of the vomiting may be important. An acute onset of nausea and vomiting suggests gastroenteritis, pancreatitis, cholecystitis, or a drug-related side effect. Symptoms occurring primarily in the morning suggest pregnancy, although this pattern also may be seen in uremia, alcohol ingestion, or increased intracranial pressure. Delayed vomiting more than 1 hour after eating suggests gastric outlet obstruction or gastroparesis. Vomiting of material eaten more than 12 hours previously is pathognomonic for outlet obstruction. Nausea and vomiting for more than 1 month are considered chronic. Associated symptoms may be helpful. Hypersalivation, defecation, tachycardia, bradycardia, atrial fibrillation, and termination of ventricular tachyarrhythmias are associated phenomena with nausea and vomiting. Chronic headaches with nausea and vomiting should raise the suspicion for an intracranial lesion. Also, vomiting without preceding nausea is typical of central nervous system pathology. The social history should include inquiries about alcohol or other substance abuse. The past medical history should include any GI disease or surgeries. Nutritional history is valuable in the consideration of failure to thrive in infancy. Finally, a thorough medication list, including over-the-counter drugs, should be included.

Physical Examination The important physical examination findings are outlined in Table 21-2 . During evaluation, findings of jaundice, lymphadenopathy, abdominal masses, and occult blood in stool can help determine the etiology of the disease. Orthostatic vital signs should be obtained in patients with signs of dehydration, lightheadedness, generalized weakness, or toxic appearance. It also is important to evaluate neurologic status to rule out a central cause of a patient's symptoms, which includes cranial nerves, funduscopic examination, and gait observation. Table 21-2 -- Physical Examination of Patient with Nausea and Vomiting Organ System Finding Suggested Diagnosis General

Dehydration Poor skin turgo r Dry muc ous me

Page 5022

Organ System

Finding

Suggested Diagnosis mbr anes

Vital signs

Fever Gast roent eritis , chol ecys titis, appe ndici tis, hepa titis Bow el perfo ratio n

HEENT

Tachycardia/orthostatic changes Nystagmus

Dehydration Laby rinthi tis Vert ebro -basi lar insuf ficie ncy Cere bella r infar ct or blee d CPA tumo r

Papilledema Incre ased ICP from CNS tumo r or blee ding Abdomen

Bowel obstruction, gastroparesis Abdo mina l diste

Page 5023

Organ System

Finding

Suggested Diagnosis ntion Peri stalti c wav es

High-pitched bowel sounds Decreased bowel sounds

Gastric outlet obstruction Bow el obstr uctio n Ileus

Hernias or surgical scars Peritoneal signs

Possible bowel obstruction Appe ndici tis, chol ecys titis Perf orate d visc us

Neurologic

CNS pathology Abno rmal ment al statu s Cere bella r findi ngs Cran ial nerv e findi ngs

CNS, central nervous system; CPA, cerebellar pontine angle; HEENT, head, eyes, ears, nose, throat; ICP, intracranial pressure.

Ancillary Studies

Page 5024

Because of the broad differential diagnosis of nausea and vomiting, there is no standard panel of laboratory tests. Appropriate testing is determined by the specifics of the history and physical examination. The following are general guidelines: Complete blood count: Most patients do not require a complete blood count. Elevated hemoglobin may suggest dehydration, but other tests are better for this purpose. An elevated white blood count is entirely nonspecific and of no discriminatory value. Serum electrolytes: Measurement of serum electrolytes is not indicated in most cases of vomiting. Severe, protracted vomiting can cause a hypochloremic, hypokalemic, metabolic alkalosis. Patients with this history or clinical findings of dehydration should have electrolyte testing ordered. In general, serum electrolyte testing is indicated only in patients with symptoms lasting longer than 3 days or who require intravenous fluid to replenish vascular volume. Blood urea nitrogen and creatinine: Classically a blood urea nitrogen-to-creatinine ratio greater than 20:1 implies significant dehydration. Serum lipase: Lipase is indicated in cases of suspected pancreatitis. Urine tests: A urine pregnancy test should be performed on all women of childbearing age. Nitrites, leukocyte esterase, white blood cells, and bacteria indicate a urinary tract infection. Ketones may support a diagnosis of diabetic ketoacidosis. Hematuria indicates a possible renal calculus. Liver function tests: Liver function tests are indicated in cases of suspected hepatitis or biliary disease. Serum drug levels: Serum drug levels may be important in patients on theophylline, digoxin, or salicylates, especially in elderly patients who are taking medication without supervision. Abdominal imaging: Flat and upright films are indicated only in cases of suspected bowel obstruction or ileus. Computed tomography scan of the abdomen has supplanted plain films in the evaluation of many patients with suspected obstruction because of the improved ability to discern the cause of the problem in addition to the presence of obstruction. An abdominal ultrasound study is indicated in cases of suspected choledocholithiasis or cholecystitis in adults, suspected pyloric stenosis, and intussusception in children. Electrocardiogram: Electrocardiogram is indicated in cases of suspected coronary ischemia.

DIFFERENTIAL DIAGNOSIS Clinical and diagnostic findings are helpful in differentiating the common and catastrophic causes of nausea and vomiting ( Table 21-3 ). An algorithmic approach to the assessment of nausea and vomiting is given in Figure 21-2 . Table 21-3 -- Differential Diagnoses in Patient with Vomiting History Prevalence Physical Examination Nause a and vomiti ng of pregn ancy (NVP)

Vomiting occurs predominantly in the morning. Associated breast tenderness and late menses. NVP typically starts in week 4–7, peaks in week 10–16, and disappears by week 20. Vomiting that begins after week 12 or continues past week 20 should prompt a search for another cause

Useful Tests

Benign abdomen Very com mon Affec ts 75% of all preg nanc ies

Urin e preg nanc y test Seru m elect rolyt es, urine keto nes to excl ude

Comments Consider NVP in all females of childbearing age. Prognosis for mother and infant is excellent. NVP is associated with a decreased risk of miscarriage, fetal growth retardation, and fetal mortality

Page 5025

History

Prevalence

Physical Examination

Useful Tests

Comments

hype rem esis gravi daru m Hyper emesi s gravid arum

Severe, protracted form of NVP. No universally accepted definition of the disease. Generally accepted hallmarks include 5% weight loss, ketonuria, and electrolyte disturbance. Hyperemesis is associated with multiple gestation, molar pregnancy, and nulliparity

Gastr Fever, diarrhea, oenter and crampy itis abdominal pain. Vomiting and pain occur early, followed by diarrhea within 24 hr

Unc om mon Affec ts < 1% of preg nanc ies

Very common

Gastrit Epigastric pain, Very common is belching, bloating, fullness, heartburn, and food intolerance. Use of NSAIDs or ETOH common Peptic Epigastric pain Very common ulcer present in 90% of diseas cases. Classically, e duodenal ulcer pain is relieved by food while gastric

Sign s of dehy drati on Beni gn abdo men

Benign abdomen

p HCG Urin alysi s for keto nes Seru m elect rolyt es Ultra soun d to excl ude mola r preg nanc y or multi ple gest ation

Most studies have found no adverse outcomes for the fetus. A few studies, however, have shown a correlation with fetal growth retardation

Early gastroenteritis, when only vomiting and periumbilical pain are present, may be confused with early appendicitis. Diarrhea must be present to make the diagnosis of gastroenteritis Mild epigastric Lipase and Removal of inciting tenderness may be pregnancy test agent along with present may be necessary antacid therapy will to exclude other resolve symptoms diagnoses in most patients

Mild epig astri c

Usually not necessary

Hem oglo bin if blee

Three major causes of PUD are NSAIDs, H. pylori infection, and hypersecretory states.

Page 5026

History

Prevalence

ulcer pain is made worse. Presence of severe pain should raise suspicion of perforation

Physical Examination tend erne ss Hem e posit ive stool

Biliary Abdominal pain Very common diseas may be e midepigastric or right upper quadrant (RUQ). Onset frequently after a fatty meal. May have history of similar episodes in the past

RUQ tenderness present in most cases. If instructed to breathe deeply during palpation in the RUQ, the patient experiences heightened tenderness and inspiratory arrest (Murphy's sign)

Myoca rdial infarcti on

Patients are often anxious and in distress from pain. No diagnostic examination findings

Patients typically have substernal chest pain that may radiate to left arm or jaw. Often associated with dyspnea, diaphoresis, or dizziness

Diabet Polydipsia and ic polyuria occur

Common

Common

Useful Tests

Comments

ding is susp ecte d Upri ght abdo mina l film if perfo ratio n is susp ecte d WB C Lipa se Seru m biliru bin Alkali ne phos phat ase RUQ ultra soun d ECG (new Q wav es, ST seg ment chan ges or T wav e inver sion s) CPK /trop onin

Normal temperature, WBC, and spontaneous resolution of symptoms suggest biliary colic. Fever, Murphy's sign, elevated WBC, and suggestive ultrasound indicate cholecystitis

Not all patients present with chest pain. A subset of patients, particularly diabetics and the elderly, may present with only nausea, vomiting, and epigastric discomfort

“Fruity” breath odor Serum glucose, DKA may be the results from serum urine ketones, ABG first manifestation

Page 5027

History

Prevalence

ketoac early. If not treated, idosis altered mental status and coma may develop. In long-standing diabetics, DKA may be triggered by infection, trauma, MI, or surgery

Pancr Patients present eatitis with epigastric pain, which often radiates to the back. Most cases are caused by gallstones or alcoholism. Other causes include hypercalcemia, hyperlipidemia, drugs (sulfas and thiazides), ERCP

Common

Physical Examination acetone. Tachypnea occurs as the patient attempts to blow off carbon dioxide to compensate for metabolic acidosis. Signs of dehydration may be present. Severe cases often present with altered mental status or coma Epigastric tenderness is present. Associated paralytic ileus may cause abdominal distention and decreased bowel sounds. Frank shock may be present in severe cases

Useful Tests

Comments of diabetes in some patients. These patients often do not recognize the importance of polydipsia and polyuria. They often present complaining only of nausea, vomiting, and epigastric pain

Lipa se WB C, seru m gluc ose, LDH, AST Hem atocr it, BUN , calci um, ABG

Crite ria corr elati ng with high er mort ality inclu de: At admi ssio n— Age >55, WB C >16, 000, gluc ose >200 , base defic it >4, LDH >350 , AST >250 Withi n 48 hour s— Hct drop of 10%, BUN incre

Page 5028

History

Prevalence

Physical Examination

Useful Tests

Comments ase of 5, PO2 < 60, calci um 6 L

Appen dicitis

Common Abdo mina l pain clas sicial ly begi ns in periu mbili cal regio n and later mov es to right lowe r quad rant Anor exia is com mon

Bowel Classically, Common obstru abdominal pain ction consists of intermittent cramps occurring at regular intervals. The frequency of the cramps varies with the level of the obstruction; the higher the level, the more frequent the cramps. The location of the pain also varies with the level of the obstruction; high

Localized tenderness over right lower quadrant. Low-grade fever may be present

Abdominal distention, mild diffuse tenderness, and high-pitched “tinkling” bowel sounds may be present. Thorough search for hernias should be performed

WB C Abdo mina l CT

Supi ne and uprig ht plain abdo mina l films Abdo mina l CT

Early appendicitis can be a difficult diagnosis to make. It is still frequently missed on the first physician encounter

Adhesions, hernias, and tumors account for 90% of bowel obstructions. Other causes include intussusception, volvulus, foreign bodies, gallstone ileus, inflammatory bowel disease, stricture, cystic fibrosis, and hematoma

Page 5029

History

Carbo n mono xide (CO) poison ing

Boerh aave's syndr ome

Prevalence

obstruction causes epigastric pain, mid-level obstruction causes periumbilical pain, colonic obstruction causes hypogastric pain Headache is Uncommon usually present. CO poisoning often occurs during winter months when furnaces are turned on. Family members may have similar symptoms if they also have been exposed Patients may have Uncommon neck, chest, or epigastric pain. Forceful, protracted vomiting usually causes the tear. Most cases follow a bout of heavy eating and drinking. Other reported causes include childbirth, defecation, seizures, and heavy lifting

Physical Examination

Useful Tests

Comments

No reliable signs of CO level early CO poisoning

Because CO is a tasteless, odorless gas, patients may not realize they have been exposed. It is important to keep a high index of suspicion during the winter months

Tachypnea, tachycardia, and hypotension may be present. Escaped air from the esophagus may produce subcutaneous emphysema. Air in the mediastinum produces a “crunching” sound as the heart beats (Hamman's sign)

The classic presentation includes forceful vomiting, severe chest pain, subcutaneous emphysema, and multiple CXR findings. There is a growing body of evidence that most cases do not have this “classic” picture. In more subtle presentations, the diagnosis can be difficult to make

CXR may show pleural effusion, widened mediastinum, pneumothorax, or pneumomediastinu m. Esophagogram using water-soluble contrast is definitive

ABG, arteria l blood gas; AST, aspart ate amino transf erase; p -hC G, p -hu man chorio nic gonad otropi n;

Page 5030

History

Prevalence

Physical Examination

Useful Tests

Comments

BUN, blood urea nitrog en; CPK, creati ne phosp hokina se; CT, comp uted tomog raphy; CXR, chest radiog raphy; DKA, diabeti c ketoac idosis; ECG, electr ocardi ogram ; ERCP , endos copic retrogr ade cholan giopan cre-at ograp hy; ETOH , ethyl alcoho l; LDH, lactate dehyd rogen ase; MI, myoc ardial infarcti on; NSAID , nonst eroidal

Page 5031

History

Prevalence

Physical Examination

Useful Tests

Comments

anti-inf lamm atory drug; PUD, peptic ulcer diseas e; WBC, white blood cell.

Figure 21-2 Algorithm ic approach to nausea and vom iting. IV, intravenous; ECG, electrocardiogram; CNS, central nervous system ; MI, m yocardial infarction; Psych, psychiatric origin.

PEDIATRIC CONSIDERATIONS The evaluation and management of pediatric patients with nausea and vomiting depends on age and probable etiologies ( Table 21-4 ). Mild degrees of reflux and associated regurgitation are common in the first few months of life, but vomiting in infancy can be associated with life-threatening illness. In the first week of life, obstructive lesions of the alimentary tract, inborn errors of metabolism, and serious infectious processes are associated with vomiting. After the first week of life, pyloric stenosis needs to be considered. The diagnosis of “feeding problems” should be considered a diagnosis of exclusion. After the first month of life, infections, metabolic diseases, cow's milk intolerance, and subdural hematoma from abuse should be prime considerations. Thereafter, recurrent cyclic vomiting of varying etiologies, acute surgical emergencies, food poisoning, toxic ingestion, Henoch-Schönlein purpura, pneumonia, and diabetic ketoacidosis are likely causes of nausea and vomiting. Anorexia nervosa should be considered in teenagers with recurrent vomiting.[] Table 21-4 -- Pediatric Etiologies by Age Newborn Infant

Child

Adolescent

Infectious

Gastroenteritis

Gastroenteritis, URI

Bezoars, chronic granulomatous disease

PUD, superior mesenteric syndrome

Anatomic

Gastrointestinal

Neurologic

Sepsis, meningitis, UTI, thrush Atresia and webs, malrotation, stenosis, meconium ileus, Hirschsprung's disease Reflux, overfeeding, gastric outlet obstruction, volvulus Subdural

Pneumonia, otitis media, thrush Pyloric stenosis, intussusception, Hirschsprung's disease

Reflux, gastritis, milk Appendicitis, Achalasia, hepatitis intolerance pancreatic, hepatitis, other food intolerance Subdural hematoma Neoplasia, migraine, Neoplasia, migraine,

Page 5032

Newborn

Infant

hematoma, hydrocephalus Metabolic

Organic or amino acidemias, urea cycle defects, galactosemia, hypercalcemia, phenylketonuria, kernicterus Idiopathic, cardiac failure

Other

Child

Adolescent

Reye syndrome, motion sickness, hypertension Diabetes, vitamin A excess

motion sickness, hypertension

Hereditary fructose intolerance, disorders of fatty acid metabolism, uremia, adrenal hyperplasia, kernicterus Rumination, cardiac Cyclic vomiting failure syndrome, toxins, food poisoning, Munchausen syndrome by proxy

Diabetes, pregnancy, acute intermittent porphyria

Psychogenic, anorexia

PUD, peptic ulcer disease; URI, upper respiratory infection; UTI, urinary tract infection. Adapted from Li BUK: Common symptoms and signs of gastrointestinal disease; and Dodge, JA: Vomiting and regurgitation. In Walker WA, Durie PR, Hamilton JR, et al (eds): Pediatric Gastroenterology. Philadelphia, BC Decker, 1991.

MANAGEMENT Management of patients with nausea and vomiting is outlined in Figure 21-2 . Decreased oral intake is a major cause of dehydration and malnutrition. Hypokalemia is rarely of clinical significance, but may be found with profound vomiting secondary to contraction alkalosis. Placement of a nasogastric tube is important in cases such as persistent vomiting or gastroparesis. The pharmacologic therapies available may be classified to allow the physician to make an appropriate choice for each patient ( Box 21-1 and Table 21-5 ).[ 4]

BOX 21-1 Antiemetic Therapy of Specific Diseases CTZ, chemoreceptor trigger zone; DKA, diabetic ketoacidosis; GI, gastrointestinal.

Phenothiazines or 5-HT Antagonists CTZ DKA Opia

Page 5033

tes Che moth erap y Theo phylli ne Digo xin

Antihistamines Vesti bular Moti on sick ness Laby rinthi tis

Phenothiazines or 5-HT Antagonists GI irritat ion Gast ritis Appe ndici tis Biliar y dise ase Gast roent eritis

Prokinetics Gast ropa resis Table 21-5 -- Symptomatic Treatment of Nausea and Vomiting Medication Dose Promethazine (Phenergan) Adult :

Comments May be repeated every 6 hr, until cessation of vomiting. Dry mouth, dizziness, blurred

Page 5034

Medication

Dose

Comments 12.5 –25 mg IV, IM, PO, or by rectu m Pedi atric: 0.5 mg/p ound IV, IM, PO, or by rectu m

Prochlorperazine (Compazine) Adult : 5– 10 mg IM, or PO; 2.5– 10 mg IV; 25 mg by rectu m Pedi atric: 2.5 mg PO or by rectu rm; 0.06 mg/p ound IM Haloperidol (Haldol) Adult : 0.5 –5 mg PO; 2–5 mg IM

vision

May be repeated every 4 hr by IV or IM or every 12 hr by rectum, until cessation of vomiting. Lethargy, hypotension, extrapyramidal effects

May be repeated every 8–12 hr, until cessation of vomiting. Known extrapyramidal effects, lethargy, confusion

Pedi

Page 5035

Medication

Dose

Comments atric: 0.07 5– 0.15 mg/k g/da y bid or tid

IM, intramuscular; IV, intravenous.

The phenothiazines are widely used as general-purpose antiemetics. These agents have multiple complex mechanisms of action. The antiemetic effect is apparently through blockage of the dopamine D2 receptor in the CTZ. Prochlorperazine (Compazine) and promethazine (Phenergan) are the most commonly used medications in this class. Mild to moderate side effects are fairly common and include dystonic reactions and feelings of restlessness. These side effects may be treated with diphenhydramine (Benadryl). Although prochlorperazine was found to be more effective in reducing vomiting than promethazine, prochlorperazine has been reported in association with a 16% incidence of akathisia and a 4% incidence of dystonia, and patients should be advised of this potential and its mitigation with diphenhydramine or benztropine (Cogentin). Neuroleptic malignant syndrome, blood dyscrasias, and cholestatic jaundice have been documented rarely with phenothiazines. The serotonin receptor antagonists, such as ondansetron, are a new class of agents that generated much interest because of their effect on chemotherapy-induced emesis. Their principal site of action is the area postrema, although they also affect receptors in the GI tract. Several small series have looked at their effect in overdoses of theophylline and acetaminophen. Both of these overdoses cause vomiting, and both require oral intake as part of therapy (multiple-dose charcoal and N -acetyl cysteine). It is well documented that the vomiting often prevents effective oral therapy in these patients. These small studies showed that ondansetron stopped the vomiting and allowed oral therapy to proceed. The dose was 8 mg given intravenously over 20 minutes. The side effects of the serotonin receptor antagonists are mild and include headache and constipation.[] The prokinetic agents are useful in patients with gastroparesis, gastroesophageal reflux disease, and other putative dysmotility syndromes. Metoclopramide (Reglan) has the most applicability in the emergency department. It has dopamine antagonist activity at the CTZ and anticholinergic and antiserotonin effects. The primary effect is increased gastric emptying; the exact mechanism for this is not understood. Metoclopramide has multiple antiemetic actions and may be used as a general-purpose agent. Newer prokinetic agents, such as cisapride (Propulsid), do not cross the blood-brain barrier. They are not useful as general-purpose antiemetics. Prokinetic agents are used in patients with isolated gastric motility disorders. The most common side effects of metoclopramide are restlessness, drowsiness, and diarrhea. These effects are usually mild and transient. Prophylactic administration of metoclopramide, prochlorperazine, or any other agent to prevent vomiting in the administration of opioid analgesics has been shown to be of no benefit and has fallen out of favor.[7] Antihistamines are useful in nausea and vomiting associated with motion sickness and vertigo. Agents such as dimenhydrinate (Gravol, Dramamine) and meclizine (Antivert) directly inhibit vestibular stimulation and vestibular-cerebellar pathways. Their anticholinergic effect also may contribute to their effectiveness in vertigo and motion sickness. Antihistamines have some use as general antiemetics, but are better in the prevention of motion sickness; for nausea and vomiting, they are less effective than the phenothiazines. The most common side effects of antihistamines are drowsiness, blurred vision, dry mouth, and hypotension. The anticholinergic agent scopolamine in a transdermal patch (Transderm ScJlp) is used for prophylaxis and treatment of motion sickness. It also has mild efficacy in preventing cytotoxic chemotherapy-related nausea and vomiting, but it is not a useful antiemetic agent in the emergency department. Many agents have been advocated for the treatment of nausea and vomiting in pregnancy. For severe symptoms, hospitalization, fluids, electrolyte replacement, thiamine supplementation, and administration of antiemetics including antihistamines (e.g., meclizine, and phenothiazines) may be used. Hyperemesis

Page 5036

gravidarum begins early in pregnancy, and other causes for severe vomiting after the first trimester must be considered. Metoclopramide, cisapride, serotonin receptor antagonists, domperidone, and bethanecol are commonly used in pediatric patients for nausea and vomiting. Domperidone blocks dopamine in the area postrema and in the gut. Bethanechol, a selective muscarinic ester, is used frequently in children with gastroesophageal reflux because of the reduction in vomiting episodes with its use.

DISPOSITION Admitting the patient to the hospital is appropriate when the patient has a significant underlying disease, the patient has an unclear diagnosis and responds poorly to fluid and antiemetic therapy, the patient has uncontrolled emesis refractory to medication, or the patient is at the extremes of age with poor response to treatment. A category subject to broad interpretation is when the diagnosis is unclear and there are poor prospects for timely follow-up (e.g., the patient has no family, no transportation, is indigent, is a drug abuser or an alcoholic, or has a language barrier). Patients are considered for discharge if no serious underlying illness is present, there is a good response to fluid and antiemetic therapy, the patient is able to take clear liquids before discharge, and there are good prospects for follow-up and observation at home. Close follow-up is arranged for all discharged patients, preferably with their primary physician, in 24 to 48 hours. At discharge, the gradual return to a normal diet is explained, as are doses of any prescribed medications. Clear instructions are given to return to the emergency department if recurrence, change or deterionation in symptoms occurs. Causes for nausea and vomiting frequently remain undiagnosed. Some cases declare themselves or resolve over time; re-evaluation and close follow-up are imperative. In patients with persistent symptoms, psychogenic causes or cyclic vomiting syndrome should be ruled out.

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Marx: Rosen's Emergency Medicine: Concepts and Clinical Practice, 6th ed., Copyright © 2006 Mosby, Inc.

EFFICACY AND COST-EFFICIENCY Traditional research in air medical care has identified what can be done in the AMT setting. Work has shifted the focus from simple observational studies to measurement of the value of the interventions. The most basic consideration is if AMT makes a difference to patient care. Older, subjective studies show a benefit to AMT in only 10% to 20% of patients flown. Where AMT appears beneficial, the advantage seems related to the provision of on-site advanced life support care rather than to a unique advantage of the helicopter.[32] AMT has long been assumed to save additional lives in trauma; however, it is now recognized that improvements in outcomes are more likely related to the provision of on-site ALS care within a comprehensive trauma system rather than to the aircraft itself. Studies have challenged the benefit of AMT in interfacility transports in urban areas.[] Although the speed of the aircraft is undoubtedly greater than that of any ground vehicles, small gains in transport time may be offset by higher costs without significant changes in patient outcome.[] Finally, there is increasing recognition that studies “proving” the efficacy of an AMT system must be taken within their own local contexts and that extrapolations and comparisons are often invalid. AMT systems must satisfactorily address operational needs for effective lines of referral and communication, smooth transfer processes, active clinical coordination, the availability of dedicated vehicles and equipment, and the integration of AMT services into a regional network of prehospital care.

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Marx: Rosen's Emergency Medicine: Concepts and Clinical Practice, 6th ed., Copyright © 2006 Mosby, Inc.

FUTURE OF AIR MEDICAL TRANSPORT AMT services work best when they are integral to and enhance an overall system of prehospital care. In most cases, the efficacy of AMT remains to be proven. Research into these issues is a key facet of the future of AMT. Efforts must be made to standardize research definitions and terms; explore novel uses of objective measures to evaluate components of AMT systems; and determine appropriate short-term, long-term, and comparative outcome measures for AMT.[] It also seems that advances in ground-based EMS are offsetting many of the assumed benefits of AMT, and, increasingly, the value of many prehospital interventions is being reassessed. Geographic issues, the regionalization of specialty services, the development of new highly time-sensitive therapies, and the need to transport patients quickly over long distances require systems to continue to assess the potential value of initiating or continuing AMT.

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Marx: Rosen's Emergency Medicine: Concepts and Clinical Practice, 6th ed., Copyright © 2006 Mosby, Inc.

REFERENCES 1. Jacobs LM, Jacobs BB, Schwartz R: A medical helicopter transportation system for Connecticut. Conn Med1985;49:489. 2. Rau W: Medical crew survey. AirMed1999;5. 3. Kaplan L, Walsh D, Burney RM: Emergency aeromedical transport of patients with acute myocardial infarction. Ann Emerg Med1987;16:55. 4. Schwartz RJ, Jacobs LM, Lee M: The role of the physician in a helicopter emergency medical service. Ann Emerg Med1988;17:426. 5. McCloskey KA, King WD: Pediatric critical care transports: Is a physician always needed on the team?. Ann Emerg Med1988;17:427. 6. Baxt WG, Moody P: The impact of a physician as part of the aeromedical prehospital team in patients with blunt trauma. JAMA1987;257:3246. 7. Myers KJ, Rodenberg H, Woodard D: Influence of the helicopter environment on patient care capabilities: Flight crew perceptions. Air Med J1995;14:21. 8. Hunt RC: Adverse effects of helicopter flight on the ability to palpate carotid pulses. Ann Emerg Med 1994;24:190. 9. Hunt RC: Inability to assess breath sounds during air medical transport by helicopter. JAMA 1991;265:1982. 10. Thomas SH, Stone CK, Bryan-Berge D: The ability to perform closed chest compressions in helicopters. Am J Emerg Med1994;12:296. 11. Fromm RE, Campbell E, Schlieter P: Inadequacy of visual alarms in helicopter air medical transport. Aviat Space Environ Med1995;66:784. 12. Wright MS, Bose CL, Stiles AD: The incidence and effects of motion sickness among medical attendants during transport. J Emerg Med1995;13:15. 13. Thomas SH, Williams KA, Claypool D: Medical director for air medical transport programs: Position paper of the National Association of EMS Physicians. Prehosp Emerg Care2002;6:455. 14. Air Medical Physician Association : Medical condition list and appropriate use of air medical transport: Position statement of the Air Medical Physician Association. Prehosp Emerg Care2002;6:464. 15. Baxt WG: Hospital-based rotorcraft aeromedical emergency care services and trauma mortality: A multicenter study. Ann Emerg Med1985;14:859. 16. Eckstein M: Helicopter transport of pediatric trauma patients in an urban emergency medical services system: A critical analysis. J Trauma2002;53:340. 17. Chappell VL: Impact of discontinuing a hospital-based air ambulance service on trauma patient outcomes. J Trauma2002;52:486. 18. Cocanour CS, Fischer RP, Ursic CM: Are scene flights for penetrating trauma justified?. J Trauma 1997;43:83. 19. Cunningham P: A comparison of the association of helicopter and ground ambulance transport with the outcome of injury in trauma patients transported from the scene. J Trauma1997;43:940. 20. Thomas SH: Trauma helicopter emergency medical services transport: Annotated review of selected outcomes-related literature. Prehosp Emerg Care2002;6:359. 21. Jacobs LM: Helicopter air medical transport: Ten-year outcomes for trauma patients in a New England program. Conn Med1999;63:677. 22. Phillips RT, Conaway C, Mullarkey D, Owen JL: One year's trauma mortality experience at Brooke Army Medical Center: Is aeromedical transportation of trauma patients necessary?. Milit Med1999;164:361. 23. Bellinger RL: Helicopter transport of patients during acute myocardial infarction. Am J Cardiol 1988;61:719. 24. Fromm RE: Bleeding complications following initiation of thrombolytic therapy for acute myocardial infarction: A comparison of helicopter-transported and non-transported patients. Ann Emerg Med 1991;20:892. 25. Schneider S: Critical cardiac transports: Air versus ground?. Am J Emerg Med1988;6:449. 26. Fromm RE: The incidence of pacemaker dysfunction during helicopter air medical transport. Am J Emerg Med1992;10:333.

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27. Chalela JA: Safety of air medical transportation after tissue plasminogen activator administration in acute ischemic stroke. Stroke1999;30:2366. 28. Werman HA: Helicopter transport of patients to tertiary care centers after cardiac arrest. Am J Emerg Med1999;17:130. 29. Stone CK: Interhospital transfer of cardiac patients: Does air transport make a difference?. Air Med J 1994;13:159. 30. Van Hook JW: Aeromedical transfer of preterm labor patients. Tex Med1998;94:88. 31. American Academy of Pediatrics Task Force on Interhospital Transport : Guidelines for Air and Ground Transportation of Neonatal and Pediatric Patients, 2nd ed. Elk Grove Village, Ill, American Academy of Pediatrics, 1999. 32. Kurola J: Paramedic helicopter emergency service in rural Finland—do benefits justify the cost?. Acta Anaesthesiol Scand2002;46:779. 33. Arfken CL: Effectiveness of helicopter versus ground ambulance services for interfacility transport. J Trauma1998;45:785. 34. Brampton WJ: Using helicopters for secondary transfer—does the patient benefit?. Anaesthesiol Reanimat2001;26:102. 35. Nicholl JP, Beeby NR, Brazier JE: A comparison of the costs and performance of an emergency helicopter and land ambulances in a rural area. Injury1994;25:145. 36. Fetter WPF: Neonatal transport by helicopter in the Netherlands: A 7-year overview. Eur J Emerg Med 1995;2:88. 37. Safford SD: A cost and outcomes comparison of a novel integrated pediatric air and ground transportation system. J Am Coll Surg2002;195:790. 38. Thompson CB, Schaffer J: Minimum data set development: Air transport time-related terms. Int J Med Informatics2002;65:121. 39. Rodenberg H: Effect of aeromedical aircraft on care of trauma patients: Evaluation using the revised trauma score. South Med J1992;85:1065. 40. Rodenberg H: The Revised Trauma Score: A means to evaluate aeromedical staffing patterns. Aviat Space Environ Med1992;63:308.

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Chapter 193 – Tactical Emergency Medical Support and Urban Search and Rescue Richard Schwartz John G. McManus Jeffrey Orledge

TACTICAL EMERGENCY MEDICAL SUPPORT Perspective Law enforcement agencies in the 21st century face an increase in terroristic threats and new challenges, including organized opposing forces, military-type weapons, direct fire, hostage and barricade situations, and potential toxic hazards. As these threats have increased, so has the recognition of the need for integrated medical support of tactical operations.[] Tactical emergency medical support (TEMS) is the specialty of emergency medical services established to maintain safety, health, and welfare of Special Operations law enforcement units, such as special weapons and tactics (SWAT) teams, hostage rescue teams, and special emergency rescue teams.[] These specially trained teams consist of highly trained and specially equipped law enforcement personnel who are tasked with mitigating and responding to many different high-risk criminal situations. Several emergency medical societies and programs have endorsed the practice of TEMS and have created training and education programs for emergency physicians, residents, and prehospital providers, enhancing their ability to provide preventive, urgent, and emergency care of patients in a functionally austere environment.[]

Tactical Medical History The principles of TEMS have largely been developed through lessons learned from military conflicts. Civilian TEMS structure most closely emulates the medical support structure of military special operations units such as Army Special Forces, Navy Seals, Army Rangers, and Air Force Pararescuemen.[7] These small, unique tactical units operate frequently outside the normal realm of military operations, remote from dedicated medical resources, often for long periods of time. Although modern TEMS units generally operate in the urban environment, where prompt evacuation to highly capable medical facilities is the rule, training must account for circumstances in which prolonged care must be provided on-site, when conflict circumstances preclude evacuation. In the civilian setting, snipers, mass demonstrations, riots, and fire bombings gained notoriety as new forms of urban conflict in America during the late 1960s and early 1970s. Many of these incidents occurred in Los Angeles during and after the Watts Riot, leading to the formation of the first SWAT unit. As of 1996, there are more than 5000 SWAT teams in the United States supporting local, state, and federal agencies.[11] With the evolution of these specialized law enforcement tactical teams, the need for military-style emergency medical services (EMS) support began to emerge.[1] Although the Los Angeles Sheriff's Department had utilized SWAT-trained medics since 1971, it was not recognized as a standard practice until the early 1980s.[4] Because of the dangerous environment, SWAT team members are at high risk for injury, with a casualty rate of 33 injuries per 1000 officer missions.[1] Suspects are injured at the rate of 18.9 injuries per 1000 officer missions, and bystanders are injured at the rate of 3.2 per 1000 officer missions. It was recognized that traditional EMS providers were not properly trained or equipped to enter these unique and sometimes remote austere environments to care for casualties.[] In fact, basic EMS training still emphasizes that personnel should wait until the “scene is safe” before rendering medical care to patients. Past incidents such as those occurring at the Columbine High School in Littleton, Colorado, Ruby Ridge in Idaho, University of Texas in Austin, and the Mormon Library in Salt Lake City proved that sequestering medical personnel far from the area of operations leads to delays in definitive trauma care, with potentially higher rates of morbidity and mortality.[] The tactical environment necessitates that the medical provider possess a unique training and skill subset to utilize a different set of field assessment and treatment priorities and strategies for

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monitoring and sustaining health maintenance. Provision of tactical medical care has now become an integral part of preplanning for federal, state, and local tactical teams in response to lessons learned.[]

Goals of Tactical Emergency Medical Support In the early years, the TEMS role was for care and evacuation of wounded. This role has now evolved with more emphasis on mission planning, primary care, preventive medicine, and emergency care of illness and injury. Although the primary goal of TEMS is to enhance the law enforcement mission, the tactical medical role involves a continuum of care to include maintenance of the team health, reconnaissance of environmental and situational aspects of the mission, coordination of local emergency medical support, creation of evacuation plan and routes, and assessment of future medical needs of the team, perpetrators, bystanders, and possible hostages.[] Implementation of an effective tactical medical support program is now directed at achieving several important goals ( Box 193-1 ). Today's tactical medical support is also expected to be tactically knowledgeable, mobile, and able to survive and provide and sustain appropriate care in a variety of hostile and adverse environments. BOX 193-1 Goals of Tactical Emergency Medical Services

{, {, {, {, {, {, {, {, {, {, {,

Enhance mission accomplishment Prepare medical threat assessment Monitor the medical effects of environmental conditions Reduce death, injury and illness, and related effects, among team members, innocents, and perpetrators Reduce line of duty injury and disability Reduce lost work time Maintain good team morale Maintain health of team and provide preventive medicine Coordinate with surrounding agencies and hospitals Decrease liability Possess basic forensic knowledge and crime scene preservation

Tactical Team Structure, Training, and Integrated Medical Support The structure and size of the SWAT team varies across the country according to location and purpose. Some teams have specific full-time roles for each individual, whereas other teams may have complete voluntary tactical teams with individuals serving several roles that rotate according to mission and availability of team members. The typical team is composed of assault teams, which make initial contact with suspects, and arrest teams, which support the assault team. There are also rescue teams, backup teams, and hostage and negotiation teams. A unit commander supervises the operation from a command post.[] The TEMS component of a tactical unit, like team structure, varies widely across the United States. Some SWAT teams use “standby” EMS personnel, and others have physician-only TEMS providers. Much like the military Special Forces, many civilian tactical law enforcement agencies are now integrating medical support into the tactical team to enhance mission success.[] Although not ideal, the minimal medical coverage at a tactical location should be the use of standby civilian EMS personnel in a predetermined location. The “standby” EMS personnel treat casualties that are brought to them but are unable to assist in medical preplanning or inner perimeter rescue. This minimal medical

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support for tactical missions may be inadequate for some missions, given the high degree of potential injury and delay in definitive care.[3] Law enforcement agencies using integrated medical support have varying medical qualifications. The use of EMT-Bs for medical coverage has the advantage of availability and modest cost. However, basic providers require medical control and have limited advanced life-saving skill capabilities. Medical directors may be able to train basic providers with an enhanced skill set to provide appropriate medical care for tactical support. Paramedic providers also require medical control and have an even higher educational requirement for initial certification maintenance above the basic provider. However, the increased skill set possessed by advanced prehospital providers makes them favorable in a TEMS environment.[3] In a small number of jurisdictions, emergency physicians and residents provide medical oversight for TEMS units and are also deployed as medical operators in the tactical environment.[] Although physician providers offer a broader scope of practice and do not require direct medical control, they usually have limited prehospital experience and also require tactical training.

Training Issues The tactical environment is different than the traditional EMS environment. Traditional EMS doctrine teaches personnel to ensure the scene is “safe” before attempting to render care.[18] This principle is not possible in some tactical situations. Tactical training needs to take into account team tactics and movement, cover and concealment, equipment issues, nuclear/biological/chemical (NBC) training, rappelling, weapons familiarity, noise, and light discipline training.[] Also, routine training needs to be done in basic rescue tactics, tactical room entries, open area rescues and tactics, movement under fire, cover and concealment, officer down drills, and, in some systems, firearm training ( Figure 193-1 ).

Figure 193-1 A, Special Response Team training for the extraction of an injured suspect. B, Note the suspect is secured with handcuffs to ensure the safety of the team and bystanders. ((Courtesy of Richard Schwartz.))

Although Advanced Trauma Life Support (ATLS) may be applicable to the emergency department management of trauma patients in both civilian and military hospitals, it was not created for combat or tactical medicine.[] ATLS was developed for physicians, not for out-of-hospital care. It assumes that hospital diagnostic and therapeutic equipment is available and, most importantly, does not recognize the existence of the tactical combat environment. The three goals of tactical combat care are (1) treat the casualty; (2) prevent additional casualties; and (3) complete the mission.[] Tactical combat casualty care is divided into three distinct phases to provide the correct medical interventions at the correct time in the continuum of field care ( Box 193-2 ).[31] BOX 193-2 Phases of Tactical Combat Care

1.

2.

3.

Care unde r fire Tacti cal field care Cas ualty evac

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uatio n care (CA SEV AC)

Care Under Fire In terms of medical delivery in the civilian tactical environment, the area is usually divided into three zones: cold, warm, and hot.[] These zones are based on tactical environment, threat level, and treatment options, which are based on a risk-benefit ratio relative to the medical provider and patient. The cold zone is a safe environment with no threat of injury. This zone is outside the inner perimeter, and regular EMS treatment principles usually apply. In the warm zone, threat is not considered immediate but still exists. Finally, the hot zone is characterized by possible direct exposure to hostile fire. Care under fire refers to care being rendered in the “hot zone.” In this zone, the medic and casualty are under direct effective hostile fire. Care in this phase is very limited, but not nonexistent. When care can be rendered, airway management, the first medical priority in routine prehospital medicine, is best deferred until the tactical field care phase due to difficulty maintaining the airway during evacuation under direct fire. Also, cardiopulmonary resuscitation and cervical spine immobilization have little to no role with treatment of penetrating injuries in this phase and are not a priority in the combat environment.[] Recommended care is limited to achieving adequate hemostasis and evacuation of the casualty if possible.

Tactical Field Care The second phase of care, tactical field care, is medical treatment rendered in the “warm zone.” In this zone, the medic and casualty are still under threat of injury but not under direct fire. Care in this phase focuses on several areas that have been shown to increase morbidity and mortality in tactical environments if not addressed.[] Airway establishment and maintenance is first addressed in this phase of treatment. Airway management depends on provider training, available equipment, time to evacuation, and type of environment. Next, breathing issues such as tension pneumothorax and open pneumothorax (sucking chest wound) need to be addressed in this phase of care. Circulatory issues such as tourniquet replacement with pressure dressings and correct fluid therapy are then addressed. Intravenous access needs to be established. The tactical environment often makes intravenous access difficult and alternate techniques and routes may be needed to establish access.[] There has also been much controversy in both the civilian and military literature involving optimal type and amount of fluid resuscitation in caring for the trauma patient with controlled or uncontrolled hemorrhagic shock.[] Advanced homostatic dressings can also be used for external hemorrhage not controlled with conventional therapy.[38] Adequate analgesia, prophylactic antibiotics, and appropriate use of cardiopulmonary resuscitation are also addressed in this phase.[13]

Combat Casualty Evacuation Care Combat casualty evacuation care (CASEVAC) is the third phase of care that is being rendered to casualties in the “cold zone” and while they are evacuated to definitive medical care. Care now begins to closely approximate ATLS guidelines.[] In the civilian setting, CASEVAC is provided en route via aero-medical transport or advanced life support ambulance and continued into the hospital setting, to which the casualties are transported as soon as they are evacuated from the hot or warm zone. Advanced life support care continues en route to the receiving facility, usually a level one trauma center ( Figure 193-2 ).

Figure 193-2 CASEVAC is usually provided via aerom edical transport or advanced life support am bulance in the civilian setting. ((Courtesy of the Augusta Chronicle, Andrew Davis/Tucker.))

Civilian Training Programs

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Multiple commercial, local, state, and federal training programs exist.[] One of the first and best known training programs for civilian tactical medical support is the Counter Narcotics and Terrorism Operational Medical Support Program. This program consists of a 58-hour course providing continuing education for prehospital providers having training at the emergency medical technician basic level or higher.[] There are multiple other TEMS training courses available of varying length, and some emergency medical graduate medical education programs are incorporating TEMS into their curriculum.

Tactical Emergency Medical Support Environment Training Practicing effective medical care in the tactical environment requires TEMS personnel to be well educated, trained, and equipped. Tactical EMS involves knowledge and skills that are not included in standard medical education. Integrated “team” training allows the medical support to understand their roles and learn all aspects of tactical law enforcement operations and fundamentals on how to approach the tactical medical arena. Unique medical scenario–driven protocols should be developed and rehearsed with the tactical team. These specialized protocols may require advanced practice and require medical control approval that should also satisfy state or federal regulations.[]

Equipment The TEMS personnel must be familiar with and use tactical, protective, medical, and evacuation equipment. Equipping a TEMS provider can be costly, with the price being greater than $6000 in 1997 for each medic assigned to the LA County Sheriff's SWAT team.[7] The personnel protective equipment includes body armor, helmets, eye armor, protective chemical mask, and clothing. Body armor and protective suits raise heat stress and water consumption requirements. Protective gear also limits vision, communication, sensory input, and the ability to perform medical assessment and treatment.[] The medical equipment selected and carried by TEMS providers varies and is based on usage, size, weight, budget, training, experience, and mission type. Conventional EMS medications and equipment with bright markings and color coding is often discouraged in the tactical environment to maintain concealment. To optimize amount of equipment available, many TEMS providers separate the medical equipment by use or zones of care. First, they carry a small medical kit or “entry” bag that contains basic supplies utilized in the “hot” or “warm” zone. This small entry bag usually contains equipment such as gloves, tourniquets, simple airway devices, large-bore intravenous needles, and compressive dressings. Next, a larger “aid” bag is used to store equipment used to augment the entry bag and provide a higher level of medical care. This bag is often located in the warm zone or at the command post, if not carried. The aid bag usually contains mission-specific medical equipment, which is determined by the threat assessment, as well as advanced trauma equipment and supplies. Finally, type and location of evacuation equipment for the potential casualties must also be considered. There are several devices and litters that teams can utilize to effectively and safely transport casualties out of the tactical environment.

Remote Patient Assessment Cases of hostages, barricaded suspects, and pinned down casualties, in which “hands-on” assessment is impossible, often prove to be challenging. Although assessment and management of casualties in these situations is difficult, it is not impossible. Remote patient assessment is another function of TEMS and is done when a person is injured and medical personnel must assess a patient from a distance. Several devices can aid in this remote assessment, including binoculars, gun scopes, night vision goggles, cameras, and microwave radar motion detectors. TEMS providers need to be trained to use visual assessment techniques.[41] If the scene presents a great risk to rescuers, then medical care may be limited to distant guidance and encouragement. Because military data have shown an inherent 20% mortality rate for medics who put themselves at risk, direct medical management should only be considered once the tactical situation permits.[19] An extension of remote patient assessment has been termed “medicine across the barricade” and involves indirect patient care through skilled communication with a non-health care provider on site.[41]

Hazardous Materials Incidents involving clandestine drug laboratories and weapons of mass destruction are also considerations in a TEMS environment. Decontamination becomes an issue if team members are exposed to a potential toxic substance. Rapid decontamination must be taught and practiced by tactical teams, because adequate decontamination is usually not available in the inner perimeter.[]

Forensic Science

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Basic knowledge of forensic science is important to recognize and preserve evidentiary items. Documentation of wound and blood patterns should be done. All evidence should be collected appropriately and the chain of custody honored.[44]

Medical Threat Assessment Medical threat assessment is the accounting for all variables that may affect the health and welfare of the tactical team, the perpetrators, nearby civilians, and possible hostages. The medical threat assessment is an essential component of the preplanning phase and should be integrated into the tactical operation.[] Medical information is gathered prospectively and continues “real time” during the entire operation. TEMS personnel help to advise the command on factors affecting medical conditions, such as current medical conditions of all personnel involved, environmental and terrain hazards (e.g., weather, obstacles), possible hostage scenarios, medical transport and communications, and potential toxic hazards (e.g., chemicals, plants, animals). The medical threat assessment also includes primary and secondary evacuation planning. Communication with local EMS elements about medical resources, casualty extrication and evacuation, routes of egress, and lines of communication should all be part of the medical assessment.[] Once the medical threat assessment is complete, a plan is then developed based on the medical intelligence, addressing each possible situation while recognizing that the plan may change as the mission evolves.

Preventive Medicine The maintenance of the tactical team's health is an important aspect of a TEMS program. Poor health has been shown to directly correlate with poor job performance and decreased mission accomplishment.[] Ensuring that team members are medically and physically fit to participate in missions is essential to improve chances of success.[49] Key preventive medicine issues include monitoring of disease states and stress levels, field hygiene, sleep-wake cycle management during missions, maintenance of immunizations, injury prevention, monitoring of environmental risks, and making physical training recommendations.

Liability Because special operations lends itself to high litigation and possible disability, TEMS providers need to ensure they have proper malpractice and disability coverage.[7] TEMS has become viewed as an essential component to provide “standard of care” tactical medicine. Both law enforcement and medical personnel have the responsibility of decreasing risk of injury.[2] Court cases have shown that officers who bring prisoners to health care institutions also have a duty to protect third parties from harm.[]

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KEY CONCEPTS {, {, {,

{,

The hostile environment that is intrinsic to urban SWAT team operations requires specialized training and planning for medical personnel. Integration of medical planning into both overall team preparation and specific mission planning is essential to an effective medical response in a threatening and dangerous environment. Determining medical capability for the hot, warm, and cold zones of a conflict area requires evaluation of local characteristics, the nature of the threat, team safety, and community resources. Appropriate use of tactical emergency medical support will aid in diminishing medical threats and improve overall chances of a successful mission.

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URBAN SEARCH AND RESCUE Perspective “It was hard to breathe. The air was thick and choking. It looked as though black snow had fallen, covering everything.” “It was as dark as a tunnel and the air was as thick as soup. Despite repeatedly scooping chunks of dust and debris from my mouth and nostrils, I inhaled and swallowed large quantities.” “It took an hour to wash off the layers of dust which by now had become like a layer of concrete.” Drs. Kelly and Prezant, New York City Fire Department, during the 9/11 attacks against the World Trade Center Urban Search and Rescue (US&R) is a relatively new concept. US&R is the science of responding to, locating, reaching, medically treating, and safely extricating victims entrapped by collapsed structures.[51] US&R is a “multi-hazard” discipline, because it can be needed in a variety of emergencies and disasters, including natural disasters (e.g., earthquakes, hurricanes) and human-made disasters (e.g., terrorist attacks, building and structure collapse, hazardous materials spills).[52] Prior to the 1980s, little information was available on the subject and the Federal Emergency Management Agency (FEMA) US&R teams had not yet been developed. However, since that time national awareness of disasters has increased and there is a demonstrated need for teams with specialized rescue and medical skills for the urban environment.[53] Reviews of worldwide disasters have helped us understand the injury patterns that can be expected in events such as earthquakes and collapsed structures.[] Immediately after a large earthquake or collapsed structure, there is usually a period of chaos. The local resources are overwhelmed, and most of the victims rescued at this time are rescued by uninjured bystanders. Patients requiring resuscitation during the “golden hour” unfortunately will likely not be reached in time.[] However, there may still be a large number of injured people trapped in the rubble who will require rescue. Their survival depends on extrication and medical treatment within a short 24- to 48-hour time period, termed “the golden day.”[54] After 48 hours, survival rates drop dramatically.[54] For responding resources to be effective, personnel must be highly trained, quickly deployable, mobile, and self-sufficient. The lessons learned have led to the development of the current US&R system in the United States.

History of Urban Search and Rescue in the United States The current FEMA US&R system started with the Office of US Foreign Disaster Assistance (OFDA). The OFDA sent responders to earthquakes in Mexico City (1985), El Salvador (1986), and Armenia (1988), and the experiences of these responses led to the development of a specialized team for earthquake response. The first equipped, fully integrated team deployment happened in July 1990, when the OFDA sent a Disaster Assistance Response Team to Luzon Province, in the Philippines. The experiences of this team led to the development of the framework for the current US&R task force.[51] Prior to 1990, FEMA was a disaster recovery agency. Hurricane Hugo and the Loma Prieta Earthquake focused national attention on the deficiency in disaster response. Since initial development, there have been a number of deployments of teams within the United States to various disasters, including hurricanes, earthquakes, and terrorist attacks.[51]

Components and Structure of an Urban Search and Rescue Team The responding team must mobilize quickly to accomplish its objectives and must not place additional demands on the already stressed infrastructure.[] An effective US&R team needs both properly trained personnel and appropriate equipment. The equipment cache should allow the task force to be totally self-sufficient for the first 72 hours and to be

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capable of 24-hour operation for 10 days.[] The FEMA equipment cache is divided into five groups: rescue equipment, medical equipment, technical equipment, communications equipment, and logistics equipment. The medical equipment cache was designed to treat the unique medical needs of trapped victims as well as the medical needs of the team itself. The medical cache contains enough supplies to be able to handle 10 critical cases, 15 moderate cases, and 25 minor cases. The cost of the entire cache is close to $2 million.[] Coordination and cooperation with local resources and other teams are critical.[] The US&R team is integrated into the Incident Command System at the disaster. The leader is responsible for managing and supervising all team operations and for coordinating the team's efforts with the incident commander.[] The search team is responsible for developing and implementing a plan to search the area for victims. The search team can be subdivided into two teams, a canine search team and a technical search team. The canine team uses specially trained dogs to locate trapped victims. The technical team uses specialized microphones, listening devices, cameras, and fiber optic devices to locate victims in confined spaces. The search team is responsible for locating victims and identifying probable areas where victims may be found.[ 60]

The rescue team is composed of rescue specialists. Once a victim or potential victim is located, the rescue team is responsible for breaching the area and creating a safe entrance to, and exit from, the victim's position. Team members utilize specialized equipment for extricating the victim and have training in collapsed building rescue and hazardous materials.[60] The technical team is composed of various specialists, including structural specialists, hazardous materials specialists, heavy rigging and equipment specialists, technical information specialists, and communications specialists.[60] These specialists work collaboratively to ensure a safe and efficient operation. The logistics team is responsible for all the equipment needs, including inventory, issuing, and record keeping.[60] Finally, there is the medical component, which is composed of medical personnel who are responsible for the medical needs of both the task force personnel and the victims. Typically, the medical personnel are emergency physicians and paramedics.[]

Medical Team Operations in Urban Search and Rescue A number of unique considerations must be addressed for US&R. As with TEMS, team physicians must realize that they will be operating outside of their usual environment and that they are not in charge overall. Typically, the physician on the team works with the team leader and the managers of the other components. To do this efficiently, the physician should be familiar with the capabilities and training of all the members on the team and the Incident Command System. Cross-training of team members is ideal.[]

Medical Team Tasks Predeployment. The job of the medical team in the predeployment phase is to ensure that the entire team is fit and functional for deployment and that the medical equipment cache is organized and up to date.[61] The perceived medical threats in the deployed area must also be addressed (e.g., endemic disease, water contamination, insect threats, existing medical support). A family and communication support system should also be set up before the deployment.

Deployment. The medical team is responsible for much more than just treating the victims. Medical intelligence information needs to be collected and addressed ( Box 193-3 ). A plan is required for transfer and transport of victims and for fatality management. BOX 193-3 Medical Intelligence Gathering Prior to Deployment

{,

Type of disaster and predicted numbers and types of potential victims

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{, {, {, {, {, {, {,

Capabilities of the team to deal with the medical aspects of the situation, including dealing with injured team members Local emergency departments level of functioning. Trauma center status and location Local EMS resources Location of planned triage staging area Communications with local resources (EMS, police, emergency departments, fire and rescue etc.) Weather, environment, or hazardous materials issues Availability of other resources (e.g., military, NDMS, DMAT)

DMAT, Disaster Medical Assistance Team; EMS, emergency medical service; NDMS, National Disaster Medical System. The medical action plan is critical for ensuring smooth operations and must be updated as conditions or knowledge change.[] The medical component of a US&R team needs to be able to provide care for its own team members, whose needs may exceed those of the victims. The medical team also needs to assess adequacy of team members' rest and sleep and the psychological effects of the situation.[] Public health issues, including integrity of food and water supply and waste management, are managed by the medical team. If there is a canine search component, the medical team should receive some sort of basic veterinary training before deployment.[]

Confined Space Issues A confined space is defined as any space with limited access and ventilation. The physician and medical team must be prepared to work in this setting during a deployment and must be aware of issues related to team and victim safety, air purification, and structural dynamics related to collapse or impending collapse.[]

Specific Disorders in Urban Search and Rescue Perspective The US&R teams will typically be responding to the aftermath of earthquakes, collapsed structures, terrorist bombings, hurricanes, and other natural and human-made disasters.[] Reviews of the literature have identified the types of medical problems and conditions that might be encountered.[] Most of the medical conditions are those encountered in the emergency department and are handled similarly. There are a few clinical problems that occur with much greater frequency in the US&R environment: crush syndrome, compartment syndrome, particulate inhalation, hazardous materials exposures, and blast injuries.[] Since the terrorist attacks of 9/11, there has also been an emphasis on preparing the US&R teams for the medical response to weapons of mass destruction.

Crush Injury and Crush Syndrome Perspective Compartment syndrome is defined as crush injury caused by swelling of tissue inside the confining fibrous sheath of a muscle compartment, which can cause further destruction of the intracompartment muscle and nerves (see Chapter 46 ). Fasciotomies in this setting are controversial; the potential benefit—to restore function and lessen rhabdomyolysis—has to be weighed against the much higher risks of infection and bleeding.[] Crush syndrome is defined as the systemic manifestations caused by crushed muscle tissue. This typically occurs when blood flow is restored to the crushed tissue and the toxins are released systemically. It is estimated that between 3% to 20% of earthquake victims and up to 40% of survivors of multistory building collapses will develop crush syndrome.[64] Early hydration of the victim in the rubble before, during, and after extrication can lessen the renal effects of crush syndrome. Crush injury and crush syndrome can result from objects that have fallen on the patient or from the patient's own body weight. The length of time needed to develop crush syndrome depends on both the amount of pressure and patient factors. It can occur within 1 hour if the pressure is severe but usually takes 4 to 6 hours to develop.

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Typically, crush syndrome occurs in the lower extremities, the buttocks, or an entire upper extremity and the associated pectoral area.[61]

Pathophysiology of Crush Syndrome The cause of muscular injury in crush injury is not fully understood and is controversial. It is thought that in crush injury, cellular blood flow at the local level is interrupted. These cells begin to function anaerobically, creating lactic acid and other toxins. The intracellular organelles' functions become disrupted and there is a shift of calcium into the cells.[] This shift can lead to systemic hypocalcemia. The influx of calcium into the cell is thought to activate phospholipase A2 and other enzymes that eventually lead to the cell's death. The intracellular contents of the cell include lactic acid, potassium, myoglobin, uric acid, enzymes, leukotrienes, thromboxane, phosphate, and others. Once the cell's membrane is disrupted, the intracellular contents leak out locally. There is also increased capillary permeability. This can lead to edema and third spacing of fluid.[] These effects occur locally until the tissue is released and reperfused. This is why victims can be trapped for days with severe crush injury and appear stable when reached by rescuers, only to deteriorate shortly after being rescued. There are reports of patients going into cardiac arrest shortly after rescue.[] When the crushed area is released, there is the release of all the intracellular contents that have been building up locally into the systemic circulation, causing systemic symptoms. Lactic acid can cause a severe metabolic acidosis. Since 75% of the body's potassium is intracellular, the potassium released may be cardiotoxic. Hyperphosphatemia can aggravate hypocalcemia and cause metastatic calcifications. Uric acid, myoglobin, purines, and others can cause renal failure. Leukotrienes and other cellular toxins can lead to acute respiratory distress syndrome.[] The major causes of early death due to crush syndrome are hypovolemia due to third spacing of fluid and dysrhythmias due to severe metabolic acidosis and hyperkalemia. Delayed causes of death include renal failure, acute respiratory distress syndrome, sepsis, ischemic organ injury, disseminated intravascular coagulation, and electrolyte disturbances.[]

Management of Crush Syndrome Early aggressive therapy is essential for prevention of crush syndrome and should begin before extrication.[ 66] All victims who have an obvious crush injury or are immobilized for 4 hours or longer should be considered to have crush injury. The severity of the crush syndrome may be related to the number of extremities with crush injury. In a Japanese study of earthquake victims, the incidence of acute renal failure due to crush syndrome was 50.5% with one extremity, 74.7% for two involved extremities, and 100% for three or more involved extremities.[64] Once a victim is located, the medical component needs to be actively involved with the rescue process and begin treatment before extrication. Cardiovascular instability is commonly seen in patients with crush syndrome.[67] As extrication is being done, continuous cardiac monitoring is recommended. Adequate hydration is recommended along with the usual management of hyperkalemia (insulin/glucose, ion exchange resins, p -agonists, and dialysis). The routine use of intravenous calcium in this setting is controversial. This is because not only is the potassium level elevated but there is also significant hyperphosphatemia. When additional calcium is given, there is the risk of forming metastatic calcifications of calcium phosphate. The current guidelines taught in the FEMA medical specialists course recommend intravenous calcium only for arrhythmias that do not respond to other measures or there is a documented severe hypocalcemia.[61] The mainstay of treatment for crush syndrome and prevention of renal complications is forced diuresis. The fluid of choice is normal saline. There is considerable debate over the amount of fluid to be given. Large amounts of fluids may be needed because of significant third spacing. One to 1.5 L/hr has been suggested as a starting rate to use during the extrication process, with the rate being titrated to the patient's clinical status. It has been suggested that an average-sized adult may require up to 12 L/day of fluids to sustain a forced diuresis of 8 L/day to prevent renal complications. Continued monitoring of the patient's vital signs, hydration status, and urine output should be done to guide fluid administration until more invasive monitoring is available.[63] Alkalinization of the urine to prevent renal failure has been recommended in crush syndrome but has not been subjected to proper study, and the effects of the alkalinization, if any, are impossible to separate from those of the volume fluid used. Rhabdomyolysis and its relationship to renal failure are discussed in Chapter 125 .

Other Medical Problems in Urban Search and Rescue Another unique medical problem in US&R is dust and airway contamination. In every earthquake and collapsed building, a tremendous amount of dust is released in the air. During the first 48 hours of rescue efforts at the World Trade Center, 90% of the 10,116 New York City Fire Department rescue workers evaluated at the site reported an acute cough, often accompanied by nasal congestion, chest tightness, or chest burning, but only three required hospitalization for respiratory symptoms ( Figure 193-3 ). During the 6

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months after the attacks, 322 firefighters and one EMS worker had site-related cough severe enough to require more than 4 weeks of leave.[69]

Figure 193-3 Massive am ounts of dust and contam inants can exacerbate existing medical conditions, such as asthm a and chronic obstructive pulm onary disease, during US&R operations. ((Photo b y Jeff Orledge.))

The victim of a collapsed structure should be assumed to have some sort of dust contamination. This contamination can exacerbate existing respiratory disease such as asthma. The physician should evaluate the airway for any evidence of burns or hazardous materials exposure. During the extrication process, the patient's airway should be monitored and deterioration expected. If intubation is being considered, it is better to do it early before edema obstructs the airway, which makes the procedure more difficult. Medical management of the victim reached after prolonged entrapment is very different from the typical trauma setting. The “scoop and run” approach of the trauma patient is not always appropriate or possible. Hypothermia can also be an issue for patients subjected to environmental conditions. Stabilization, extrication, and ongoing treatment should be directed at the prevention or reversal of hypothermia.

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KEY CONCEPTS {, {,

{, {,

Urban Search and Rescue Teams (US&R) have many integrated components. Typically, the medical component is the smallest part of the team but has some of the greatest responsibilities. To be an effective part of the medical team, one needs to understand the incident command system, how the medical component interacts with the team, and the value of a good medical action plan. In many deployments, medical care of team members may constitute a much greater component of the medical activity than medical care of victims of the incident. Medical problems will be encountered in US&R, including: Crush syndrome Compartment syndrome Exacerbation of respiratory illness Hypothermia

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REFERENCES 1. Heiskell LE, Carmona RH: Tactical emergency medical services: An emerging subspecialty of emergency medicine. Ann Emerg Med1994;23:778. 2. Vayer JS: Tactical emergency medicine. In: Hogan DE, Bernstein JL, ed.Disaster Medicine, Philadelphia: Lippincott Williams & Wilkins; 2002: 3. Casualty Care Research Center : Counter Narcotics and Terrorism Operational Medical Support Medical Director's Course Handbook, 3rd ed. Bethesda, MD, Casualty Care Research Center, 2004. 4. Murphy M: FBI, SWAT Paramedics. Tactical Edge J1989;7:22. 5. Yeskey KS, Llewellyn CH, Vayer JS: Operational medicine in disasters. Emerg Med Clin North Am 1996;14:429. 6. Rinnert KJ, Hall WL: Tactical emergency medical support. Emerg Med Clin North Am2002;20:929. 7. Vayer JA, Schwartz RB: Developing a tactical emer-gency medical support program. Topics Emerg Med 2003;25:282. 8. Heck JJ, Pierluisi G: Law enforcement special operations medical support. Prehosp Emerg Care 2001;5:403. 9. Bozeman WP: Tactical EMS: An emerging opportunity in graduate medical education. Prehosp Emerg Care2002;6:322. 10. Heck JJ, Pierluisi G: Law enforcement special operations medical support NAEMSP position paper. Prehosp Emerg Care2001;5:403. 11. Booth W: Exploding number of SWAT teams sets off alarms. Washington PostJune 17, 1997;A01. 12. Bellamy RF: The causes of death in conventional land warfare: Implications for combat casualty care research. Mil Med1984;149:55. 13. Butler FK, Hagmann J, Butler EJ: Tactical combat casualty care in special operations. Mil Med 1996;161(Suppl):3. 14. Mabry RL: United States Army Rangers in Somalia: An analysis of combat casualties on an urban battlefield. J Trauma2000;49:515. 15. Feero S: Does out-of-hospital EMS time affect trauma survival?. Am J Emerg Med1995;13:133. 16. Rasumoff D, Carmona R: Inside the perimeter: Evolving roles of the TEMS provider. Tactical Edge J 1997;15:57. 17. Rasumoff D, Carmona R: Inside the perimeter: Trends in TEMS. Tactical Edge J1996;14:52. 18. McSwain NE: The Basic EMT: Comprehensive Prehospital Care, St. Louis, Mosby, 1996. 19. DeLorenzo RA, Porter RS: Tactical Emergency Care, Upper Saddle River, NJ, Prentice-Hall, 1999. 20. Llewellyn CH: The antecedents of tactical emergency medical support. Topics Emerg Med2003;25:274. 21. Smith JP, Bodai BI: The urban paramedic's scope of practice. JAMA1985;253:544. 22. Honigman B: Prehospital advanced trauma life support for penetrating cardiac wounds. Ann Emerg Med 1990;19:145. 23. Krausz MM: ‘Scoop and run’ or stabilize hemorrhagic shock with normal saline or small-volume hypertonic saline?. J Trauma1992;33:6. 24. Butler FK: Tactical management of urban warfare casualties in special operations. Mil Med 2000;65(Suppl):1. 25. In: McSwain N, ed.Military Medicine: Prehospital Trauma Life Support, 5th ed. St Louis: Mosby; 2003: 316-331. 26. Arishita GI, Vayer JS, Bellamy RF: Cervical spine immobilization of penetrating neck wounds in a hostile environment. J Trauma1989;29:332. 27. Macmillian DS, Cone DC: Officer down. Prehosp Emerg Care2003;7:402. 28. Calkins MD, Fitzgerald G, Bentley TB, Burris D: Intraosseous infusion devices: A comparison for potential use in Special Operations. J Trauma2000;48:1068. 29. Dubrick MA, Holcomb JB: A review of intraosseous vascular access: Current status and military application. Mil Med2000;165:552. 30. Schwartz RB, Charity BM: Use of night vision goggles and low-level light source in obtaining intravenous access in tactical conditions of darkness. Mil Med2001;166:982. 31. Pepe PE, Mosesso VN, Falk JL: Prehospital fluid resuscitation of the patient with major trauma. Prehosp

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Emerg Care2002;6:81. 32. In: McSwain N, ed.Military Medicine: Prehospital Trauma Life Support, 5th ed. St Louis: Mosby; 2003: 316-331. 33. Bickell WH: Immediate versus delayed fluid resuscitation for hypotensive patients with penetrating torso injuries. N Engl J Med1994;331:1105. 34. Wade CE, Dubick MA, Grady JJ: Optimal dose of hypertonic saline/dextran in hemorrhaged swine. J Trauma2003;55:413. 35. Dubick MA, Atkins JL: Small-volume fluid resuscitation for the far-forward combat environment: Current concepts. J Trauma2003;55:413. 36. Holcomb JB: Fluid resuscitation in modern combat casualty care: Lessons learned from Somalia. J Trauma2003;55:413. 37. Rhee P, Koustova E, Alam HB: Searching for the optimal resuscitation method: Recommendations for the initial fluid resuscitation of combat casualties. J Trauma2003;54(5 Suppl):S52. 38. Pusateri AE: Advanced hemostatic dressing development program: Animal model selection criteria and results of a study of nine hemostatic dressings in a model of severe large venous hemorrhage and hepatic injury in swine. J Trauma2003;55:518. 39. Rasumoff D, Carmona R: An evaluation period for TEMS personnel: Do we need one?. Tactical Edge J 1995;13:83. 40. Law Enforcement Life Saver, Medical College of Georgia, 2003. 41. Emergency Medical Technician Tactical Course Manual, 14th ed. Bethesda, MD, Uniformed Services University and Health Sciences, 1995. 42. Heiskell LE, Tang DH: Medical aspects of clandestine drug labs. Tactical Edge J1994;12:51. 43. Heck JJ, Byers D: Chemical and biological agents: Implications for TEMS. Tactical Edge J2000;19:52. 44. Carmona RH, Rasumoff D: Forensic aspects of tactical emergency medical support. Tactical Edge J 1992;10:54. 45. Dressler FL: Operational planning for the law enforcement medic. Topics Emerg Med2003;25:333. 46. Rasumoff D, Carmona R: Inside the perimeter: Understanding the risks and benefits in selection of mission-specific personnel protective equipment. Tactical Edge J1993;11:68. 47. Rasumoff D, Carmona R: Inside the perimeter: Diet and performance in the tactical environment. Tactical Edge J1994;12:82. 48. Sanders N: Should physical fitness qualifications be required for SWAT?. Tactical Edge J1992;10:30. 49. Carmona R, Rasumoff D: Suggested Guidelines for TEMS Policy and SOP. Tactical Edge J1999;17:95. 50. Lessenger JE: Prisoners in the emergency department. Ann Emerg Med1985;14:179. 51. Barbera J, Cadoux C: Search, rescue, and evacuation. Crit Care Clin1991;7:321. 52. FEMA website. Available at www.fema.gov/usr/about.shtm 53. Barbera J, Lozano M: Urban Search and Rescue Medical Teams: FEMA Task Force System. Prehosp Disast Med1993;8:349. 54. Kunkle RF: Medical care of entrapped patients in confined spaces. Proceedings of the International Workshop on Earthquake Injury Epidemiology for Mitigation and Response July 10-12. 1989, Baltimore, MD: The Johns Hopkins University Press; 1989: 338-344. 55. Noji EK: Natural disasters. Disast Manag Crit Care Clin1991;7:271. 56. Barbera A, Macintyre A: Urban search and rescue. Emerg Med Clin North Am1996;14:399. 57. FEMA website: US&R past deployments. Available at www.fema.gov/usr/about.shtm 58. Cone D: Rescue from the rubble: Urban search and rescue. Prehosp Emerg Care2000;4:352. 59. FEMA National US&R Response System Task Force Equipment Cache List Approved Jan: 28, 2000. FEMA website. Available at www.fema.gov/usr/about.shtm 60. National Urban Search and Rescue Response System Field operations guide; US Department of Homeland Security: FEMA Sept 2003. FEMA website. Available at www.fema.gov/usr/about.shtm 61. FEMA US&R Response system Task Force Medical Team Training Manual April 1997: FEMA website. Available at www.fema.gov/usr/about.shtm 62. Hew P: Urban search and rescue. Topics Emerg Med2002;24:26. 63. Gans L, Kennedy T: Management of unique clinical entities in disaster medicine. Emerg Med Clin North Am1996;14:301. 64. Oda J: Analysis of 372 patients with crush syndrome caused by the Hansshin-Awaji earthquake. J Trauma Injury Infect Crit Care1997;42:470. 65. Kazancioglu R: The characteristics of infections in crush syndrome. Clin Microbiol Infect2002;8:1078. 66. Vandholder R: Acute renal failure related to crush syndrome: Towards an era of seismo-nephrology. Nephrol Dial Transplant2000;15:1517. 67. Michaelson M: Crush injury and crush syndrome. World J Surg1992;16:899. 68. Kikta M: Crush syndrome due to limb compression. Arch Surg1987;122:1078. 69. Centers for Disease Control and Prevention : Injuries and illnesses among New York City fire department

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rescue workers after responding to the World Trade Center attacks. MMWR2002;51.

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Marx: Rosen's Emergency Medicine: Concepts and Clinical Practice, 6th ed., Copyright © 2006 Mosby, Inc.

Chapter 194 – Disaster Preparedness[*] Carl H. Schultz Kristi L. Koenig Eric K. Noji * The views expressed in this chapter do not necessarily represent the views of the Department of Veterans Affairs or of the United States Governm ent.

PERSPECTIVE Disasters affect all parts of the globe and cause harm to people, property, infrastructures, economies, and the environment. Harm to people includes death, injury, disease, malnutrition, and psychological stress. Recent natural catastrophes have included earthquakes in Iran (2003) and Armenia (1988) ( Figure 194-1 ); a series of devastating hurricanes in the Caribbean (1998), including Hurricanes Mitch and Georges; severe flooding in Mozambique (2000), France (2003), and California (1998); tornadoes in Oklahoma and Texas (1999); and global adverse weather conditions related to the El Niño phenomenon (1997 and 1998). The future appears to be even more frightening. Increasing population density in floodplains and in earthquakeand hurricane-prone areas points to the probability of future catastrophic natural disasters with millions of casualties.

Figure 194-1 Natural catastrophes, such as this earthquake in Arm enia (1988), have the potential to cause m uch injury and psychological stress.

Factors that indicate an increasing probability of mass casualty incidents include (1) terrorist activity; (2) increasing population density in floodplains, seismic zones, and areas susceptible to hurricanes; (3) production and transportation of thousands of toxic and hazardous materials; (4) risks associated with fixed-site nuclear and chemical facilities; and (5) the possibility of catastrophic fires and explosions. For example, the U.S. Geological Survey has identified about 35 volcanoes in the western United States and Alaska that are likely to erupt in the future. Mt. Hood, Mt. Shasta, and the volcano underlying Mammoth Lakes in California are near population centers. Because of the rising population density in these areas, hazards from volcanic activity are increasing. Given this probability and the increasing role of emergency medicine in disaster preparation, mitigation, response, and recovery, this chapter discusses disaster planning and operations with emphasis on the role of the emergency physician. The emergency physician has extensive responsibilities for community disaster preparedness and disaster medical services, particularly regarding terrorism.[1] In its June 2001 position paper, the American College of Emergency Physicians outlined the scope of emergency medicine's involvement in preparedness and response to terrorism and stated its belief that “hospital emergency departments will be the first and most critical line of defense for detection, notification, rapid diagnosis, and treatment” and furthermore that “emergency department personnel will become the first responders to a covert biological attack.” A committed emergency department alone is insufficient to provide hospitals with a successful disaster preparedness program. Institutional commitment by every hospital department and the administration is necessary to coordinate effectively with system-wide resources for disaster management.

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NATURE OF DISASTERS Definitions One of the challenges facing those responsible for disaster preparation is that no standard definition of disaster exists. Some events that have been routinely classified as disasters clearly are not. For example, many would consider a plane crash a disaster, yet it may not even approach overwhelming the resources of the local responders. Because disaster medicine is multidisciplinary and depends on the integration of multiple levels of responders, the use of a common, precise terminology is essential. In general terms, an event can be considered a disaster when it overwhelms response capabilities. These response capabilities can change in diverse environments or even in the same location at different times of the day or days of the week. For example, a multiple-vehicle accident with 6 critically injured patients and 12 patients with minor injuries could overwhelm both the emergency medical services system and the hospital in a small rural community. In an urban area with multiple hospitals that participate in a trauma system, however, this same event could be handled with routine resources. Thus, it is the functional impact on the specific area that is the key concept in determining whether a disaster exists.

Classic Terminology Many terms have been used in an attempt to describe disasters. The words internal and external refer to a hospital setting to help distinguish whether an event has occurred within the hospital grounds (internal) or in the community (external). This concept distinguishes between preparing for casualties to arrive at the hospital versus dealing with casualties or resource problems within the hospital. This geographic distinction between internal and external may be useful, but it has severe limitations. Many events can be both internal and external to the facility at the same time (e.g., major earthquake or hurricane). Further, simply identifying the location of the event does not answer the critical question: How are response capabilities affected? An etiologic descriptor for an event is another customary classification. It does not matter whether a disruption in the ability of the hospital to respond is caused by nature or by humankind. The key consideration is what needs to be done to mitigate and then to rectify the situation. Some definitions have been based on the number of casualties. As previously described, the absolute number of patients is much less important than whether their needs exceed the resources to care for them. Another scheme divides disasters into three levels. Level I denotes a situation in which local resources are adequate to care for casualties. The 1999 attack on a Jewish community center by a lone gunman in California, for example, was handled effectively by local responders. Level II means that regional mutual aid is required to respond to the event. This was the case at the Hyatt Regency Hotel in Kansas City in 1981 when two skywalks collapsed, killing 114 people and injuring hundreds. Level III incidents require state and federal aid. The attack on the World Trade Center in 2001 ( Figure 194-2 ) and Hurricane Andrew in 1992 were such events, causing such massive destruction that federal disaster medical assistance teams were deployed to New York and Florida, respectively, to provide medical personnel and supplies.

Figure 194-2 The World Trade Center attack of 2001 overwhelm ed local resources and necessitated state and federal help.

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One model being proposed eliminates the word disaster and replaces it with the acronym for potential injury-creating event, PICE. [] The PICE nomenclature is an attempt to resolve the issue surrounding diverse meanings for disaster. Although not yet routinely accepted, this model is discussed here to help clarify important concepts in describing an event.

Potential Injury-Creating Event (PICE) Nomenclature The acronym PICE and its modifiers concisely describe the critical features of most types or degrees of disaster.[] The same occurrence can have different effects at different points in time; thus, as an event evolves over time, its description may change. Modifiers are chosen from a standardized group of prefixes along with a stage to indicate the need for outside medical assistance ( Table 194-1 ). The first prefix (column A) describes the potential for additional casualties. The second prefix (column B) describes whether local resources are overwhelmed and, if so, whether they must simply be augmented (disruptive) or whether they must first be totally reconstituted (paralytic). The third prefix (column C) shows the extent of geographic involvement.[] Table 194-1 -- Potential Injury-Creating Event (PICE) Nomenclature Prefix A

B

C

Static

Controlled Local

Dynami Disruptive Regional c Paralytic National

PICE stage Projected Need for Outside Aid

Status of Outside Aid

0

None

Inactive

I

Small

Alert

II

Moderate

Standby

Large

Dispatch

International III

The stage rating scale defines the likelihood that outside medical assistance will be needed either to augment or to completely reconstitute resources.[] Stage 0 means that there is little or no chance. Stage I means that there is a small chance and requires placing outside medical help on alert. Stage II means that there is a moderate chance and outside help should be placed on standby. Stage III means local resources are clearly overwhelmed and requires the dispatch of outside resources and commitment of personnel. For example, a multivehicle accident with a dozen injuries and several deaths in a large city would be a stage 0, whereas in a small rural town it might be stage III ( Table 194-2 ). Table 194-2 -- PICE Nomenclature Examples World Trade Center Attack, 9/11/01 Dynamic, paralytic, local PICE, stage III Los Angeles civil disturbance

Dynamic, paralytic, regional PICE, stage I

Northridge earthquake

Dynamic, disruptive, regional PICE, stage II

Oklahoma City bombing

Dynamic, disruptive, local PICE, stage I

A PICE can be either static or dynamic. Dynamic implies an evolving situation in which it is too soon after the incident to determine the number of casualties and the impact on the hospital. Alternatively, a static situation results if 10 people are injured in an accident and little potential for further harm exists.[] In some situations, enhancing routine operations is not sufficient or possible. A PICE can completely overwhelm the capability to mount a normal response, so that a substitute plan for recovery must be used. Situations that require significant reconstitution of critical resources are termed paralytic.[] Within the hospital, there are six critical elements necessary to provide a response ( Box 194-1 ).[] If one or more of these resources are compromised, they must be reconstituted or a substitute must be implemented. Such paralytic events can be either destructive or nondestructive ( Box 194-2 ).[3] BOX 194-1 Six Critical Substrates for Hospital Operations

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Physical plant Personnel Supplies and equipment Communication Transportation Supervisory managerial support BOX 194-2 Examples of Paralytic PICE

Destructive Bom b expl osio n Eart hqua ke Fire Civil unre st

Nondestructive Sno wsto rm Emp loye e strik e Pow er failur e Wat er supp ly cutof f

Hazards Analysis An important consideration in disaster planning is an awareness of the types of events for which the hospital or community is vulnerable. The classic example is the monumental risk from earthquakes in the central United States resulting from the combination of the New Madrid fault and the limited seismic safety requirements for buildings in that area. The planner must learn what types of support are available from outside agencies (e.g., hazardous materials decontamination from the fire departments, information from poison control centers). Although awareness of such resources is critical, contingency plans must be available when such assistance is not accessible.

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After performing a hazard vulnerability analysis, emergency planners should consider the most probable events and prepare for them. There must also be planning for events that are rare but catastrophic.[7] The major peacetime threat to life and limb in the United States is probably a large earthquake in a densely populated area or a terrorist attack. The disaster planner must proactively identify all such hazards and prepare contingency plans for each.

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Acknowledgments To our editors, for their enduring loyalty and dedication; to Karin, for her unwavering courage and grace; to my faculty and residents, who have given me so much; to Conner and Shelby, who have given me everything. JAM To Peter and the former editors for trusting us to continue their work; to the current authors and editors for the expertise, skill, and time they dedicated to this edition; to Ron for his critical thinking, enthusiasm, and much-needed sense of humor; to John for the few big things, the many small-but-important things, and the day-to-day leadership he provided as Editor-in-Chief; to my faculty, fellows, and residents for making each day an adventure; and to Patty, the love of my life. RSH With humble thanks to Peter, for his great vision in the creation of an extraordinary specialty and this compendium of its biology; to John and Bob, for their enduring friendship and collaboration; to the editors, for their sedulous attention to detail; and to Barb, Andrew, Blake, and Alexa, whose love defines me. RMW To my father, James J. Adams, whose strength will forever inspire me; to my mother Rita A. Adams, whose devotion to family will forever guide me; and to the many other members of my family: Cecelia, Joe, Jeff, Liz, Rob, David, Nicholas, Gregory, Leah, Katherine, and Sydney, whose support I rely on. JGA To all my former residents over the past 25 years from both Cincinnati and Michigan. I have been privileged to work with the best and I have learned a lot from all of you. I have to thank my children, David, Blake, and Anna, for keeping me thinking young and teaching me lots about life and family. My mom and dad have been a constant source of inspiration to me my entire life and they continue to be the role models I try to live up to. Most of all, I have to thank my wife and best friend, Mary, for her love and support over the past 30 years. She makes it all worthwhile. WGB To my family, friends, students, and teachers. I am continuously amazed, grateful, and humbled by your support and encouragement. Thank you. MHB To Joanna, Bags, Jules, and the Belties; and to our spry 91-year-old Floyds Knobs farmer neighbor, Odell Stiller, who quipped, “Doc, you'll never see my name or face in a book.” Gotcha. DFD I dedicate this book to my husband David and our children, Sarah, Jeremiah, and Katie for their patience, love, and support. MGH To Lynda, 35 years, a witnessed life, all because of a chance meeting in Ann Arbor just yesterday.

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GCH To emergency medicine residents and faculty everywhere, in their constant pursuit of knowledge but especially those at Hennepin County Medical Center for continuing to teach me. I am grateful to my parents, Rose and Joseph, for their commitment to education. Special thanks to Eric, Ali, Amanda, and, most of all, Beth for their love, patience, and understanding. LJL I would like to thank my teachers my parents and my children, professors and patients, colleagues and students who have patiently taught me about medicine and life; and my steadfast companion and wife Lynda, who has made the pursuit of wisdom possible. EJN

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REFERENCES 1. Quigley E, Hasler W, Parkman H: American Gastroenterological Association technical review on nausea and vomiting. Gastroenterology2001;120:263. 2. Koletzko S: Dysmotilities. In: Walker WA, ed.Pediatric Gastroenterology, Philadelphia: BC Decker; 2004: 1016-1030. 3. Sondheimer JM: Vomiting. In: Walker WA, ed.Pediatric Gastroenterology, Philadelphia: BC Decker; 2004: 203-209. 4. Allan S: Antiemetics. Gastroenterol Clin North Am1992;21:597. 5. Sage TA, Jones WN, Clark RF: Ondansetron in the treatment of intractable nausea associated with theophylline toxicity. Ann Pharmacother1993;27:584. 6. Reed M, Marx C: Ondansetron for treating nausea and vomiting in the poisoned patient. Ann Pharmacother1994;28:331. 7. Reynolds J, Putnam P: Prokinetic agents. Gastroenterol Clin North Am1992;21:567.

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TRIAGE Triage comes from the French verb, trier, meaning “to sort.” The concept of triage was used as far back as Napoleon's time to assign priorities to treatment of the injured when resources were limited. Priority is given to the most salvageable patients with the most urgent conditions. The emergency department uses triage in the hospital setting on a daily basis, but the focus of such triage must be changed under disaster conditions.[ 8] Standard emergency department triage is intended to identify the most seriously ill patients first and ensure that they receive rapid care. The goal of disaster triage is slightly different, that is, “to do the most good for the most people.” It can be very difficult for physicians to realize that, to achieve the goal of maximizing benefit to an entire population of patients, they may need to let some patients die with only comfort care. Under true disaster conditions, cardiopulmonary resuscitation should not be performed.[9]

Routine Multiple-Casualty Triage To assist in understanding triage techniques, it is useful to consider a routine prehospital event with multiple casualties (e.g., multivehicle accident). In such situations, rescue personnel often use a simple triage and rapid treatment (START) technique that depends on a quick assessment of respiration, perfusion, and mental status.[10] Initially, all victims who are able to walk are asked to move away from the immediate incident area. These patients are classified as green, or “walking wounded,” and are reassessed after the more immediately critical patients are triaged. As illustrated in Figure 194-3 , a rescuer can move through each patient in seconds, quickly checking respiratory rate, pulse, and ability to follow commands (mental status), and divide them into the remaining three categories: (1) red (immediate), (2) yellow (delayed), and (3) black (deceased). The only patient care interventions provided during this process are the opening of an obstructed airway and direct pressure on obvious external hemorrhage. At this point, patients are generally transported to a hospital for definitive care. Most often, patients arrive with a color-coded triage tag and are reassessed and retriaged by the hospital staff.

Figure 194-3 Sim ple triage and rapid treatm ent (START). Victim s who can walk are identified first and triaged into the “m inor” category. Those rem aining are triaged using the algorithm . ((Modified from Triage-START and SAVE. In Medical Disaster Response Training Course Syllab us. Dana Point, Calif, Medical Disaster Response, 1993.)Medical Disaster Response)

Catastrophic Casualty Management Triage during a widespread, catastrophic disaster differs from triage performed in routine prehospital and hospital settings. The number of victims is vastly increased, and medical resources are severely limited or even initially absent. Patients may remain on scene for an extended period and must be frequently reassessed. In addition, the triage process is decentralized, occurring at multiple sites, or compartments, simultaneously throughout the disaster zone. Rather than a single scene or localized disaster, this can be thought of as a compartmentalized disaster.[7] Lastly, patients tend to seek care at the closest hospital, a phenomenon known as convergence. Hospitals close to the disaster scene are overwhelmed, whereas

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hospitals located only a few miles away may receive few, if any, patients. To address these considerations, the secondary assessment of victim endpoint (SAVE) system of triage was proposed.[11] The SAVE triage system is designed to identify patients who are most likely to benefit from care available under austere field conditions. When combined with the START protocol, SAVE triage is useful for any scenario in which multiple patients experience a prolonged delay in accessing definitive care. The SAVE methodology is designed for use by health care providers within the disaster zone who begin caring for patients immediately but may not be able to transport patients to a definitive care facility for days. It is immediate and dynamic rather than delayed and static. Although there are many elements in common with other triage systems, rapid transport to a functional medical center within the ideal “golden hour” is impossible. The SAVE triage methodology divides patients into three categories: (1) those who will die regardless of how much care they receive; (2) those who will survive whether or not they receive care; and (3) those who will benefit significantly from “austere” field interventions. Only those patients expected to improve receive more than basic care and comfort measures. Using SAVE, patients are separated into these three categories so resources can be focused appropriately. The decision to place patients in a particular group is based on field outcome expectations derived from existing survival and morbidity statistics.[11] An example is a situation in which three victims require chest tubes (two victims require one tube each and one victim requires two tubes), but only two chest tubes are available. The SAVE principles guide providers to place their last two chest tubes into the two victims that need it rather than into the single victim requiring two tubes. During the triage process, individuals who would most benefit from early transport should be marked as “first out,” in case an evacuation opportunity occurs. These would be victims with medical problems readily treatable at a hospital but untreatable and fatal in the field. A patient requiring surgery for intra-abdominal hemorrhage is a common example. Since the issue of nuclear, biologic, and chemical terrorism has developed, new triage systems are under development. Responders must be protected from secondary contamination or exposure, and therefore, part of the triage algorithm must include a risk assessment and determination of whether, and what type of, personal protective equipment must be donned prior to assessing patients. A quick determination is critical to prevent patient deaths from traumatic injuries while awaiting medical care from responders concerned about their own health and safety. This is particularly true in a “combined event” scenario such as a radiologic dispersion device. Also associated with terrorism incidents are large numbers of psychogenic casualties, or those who believe they were exposed but actually were not. The emergency plan must include a mechanism to assess and sort these individuals so as not to overwhelm the emergency department. While performing triage, the emergency physician must also consider the effects of extremes of age, underlying disease, and multiple injuries when assessing the potential prognosis for a given patient.[12] The treatment of many nontraumatic emergencies fortunately can be accomplished with field interventions that do not consume extensive resources. Therefore, patients with such illnesses should usually be triaged to the treatment area.

Special Triage Categories To maximize personnel resources, disaster victims who would normally be triaged to the observation area can be triaged to the treatment area if they possess special skills valuable to the medical team (e.g., medical expertise, translation skills). By increasing the number of functional team members, the effectiveness of the overall response will improve. The guiding principle supports the disaster triage goal of maximizing benefit to the most people.

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PREHOSPITAL RESPONSE Emergency Medical Services System Protocols To prepare adequately, hospitals must be familiar with and involved in the development of county or regional plans. For example, some EMS systems use automatic systems such that each hospital may be expected to accept a predetermined number of critically ill or injured and minor patients without previous notification. Physicians working at hospitals should be familiar with community disaster management operations, including the function of the emergency operations center.[6] Mutual aid agreements with other hospitals or regions should be considered for situations in which the hospital becomes overwhelmed or needs to be evacuated.

Incident Command System The incident command system is a standard emergency management system used throughout the United States to provide a flexible command and control structure on which to organize a response.[13] By standardizing an organizational structure and using common terminology, the incident command system provides a management system that is adaptable to incidents involving a multiagency or multijurisdictional response. At the most basic level, there are five functional elements in the organizational structure: (1) incident command, (2) operations, (3) planning, (4) logistics, and (5) finance. The principles of the incident command system can also be applied to the hospital setting through the Hospital Emergency Incident Command System. With this type of organizational infrastructure and the flexibility to expand and collapse as needed, an orderly and efficient response to any incident can be accomplished. Since hospitals cannot anticipate every contingency, a system such as Hospital Emergency Incident Command System assists with planned improvisation. The Joint Commission on the Accreditation of Healthcare Organizations (JCAHO) standards require use of an incident management system.

Incident Command The incident commander has overall management responsibility for the incident. Physicians should understand that they are not in charge at the scene of a prehospital incident.[14] In general, prehospital providers can handle the scene, and physicians should remain at the hospital to provide definitive care. When a physician is on scene, the best way to assist is to ask the incident commander where medical help is most needed. The incident commander may choose to appoint a command staff to handle public information, safety, and interagency liaisons.[13] When an event involves multiple jurisdictions, a centralized command coordinates a common and consistent action plan to make the best use of available resources.

Operations Section The operations section has a chief who is responsible for the management of all incident tactical activities.[13 ] This section can be expanded and subdivided into branches (e.g., law, fire, medical) and divisions. Operations also manages the resources assigned to staging areas. Ambulances, personnel, and supplies must be staged outside the perimeter of the scene and directed in as needed rather than converging on the disaster site, potentially disrupting activities, and blocking the exodus of patients. It is under the Operations Section that all medical triage and care is provided.

Planning Section The planning section collects, evaluates, and disseminates information regarding incident operations and the status of resources. This section also develops action plans and conducts planning meetings.[13]

Logistics Section

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The logistics section's chief is responsible for providing facilities, services, and material in support of the incident. This includes procuring equipment and supplies, providing food and medical support, and meeting transportation needs.[13]

Finance Section The finance section is responsible for maintaining records on personnel and equipment time, providing payments to vendors for supplies and use of equipment, and determining the cost of various alternatives for strategic planning.

Organization of Prehospital Disaster Scene The disaster site is organized into several distinct areas. The command post is the nerve center of the operation and contains the incident commander and section chiefs. A staging area for incoming personnel and equipment should be established on the outer perimeter. If air evacuation is needed, a safe landing zone must be identified. A casualty collection point and morgue should be designated. In conjunction with an incident command system, this structure brings order to the response.

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PLANNING AND HOSPITAL RESPONSE Comprehensive Emergency Management The comprehensive emergency management all-hazard approach to disaster preparedness is now required by JCAHO. Comprehensive emergency management consists of four phases: (1) mitigation, (2) preparedness, (3) response, and (4) recovery.[] Mitigation involves taking actions to reduce the impact of identified hazards. Training, drills, and cataloging resources are examples of preparedness activities. Response includes assessment of the situation and coordinating resources. Finally, recovery consists of a return to normal operations and debriefing to critique the response and provide psychological support to the rescuers. As required by JCAHO, a hospital's disaster or “emergency management” plan must address events occurring both inside (internal) and outside (external) the institution.[15] Because some incidents trigger both internal and external plans, they should integrate seamlessly with each other.

Internal Disaster Plan An internal disaster is any event that disrupts daily, routine hospital functions. This can represent an infrastructure failure (e.g., loss of electric power and water) or a threat to the safety of patients and hospital personnel (e.g., labor dispute). Because the internal disaster response varies from postponing elective surgery to facility evacuation, every hospital department must participate in the planning process. At a minimum, the internal plan should (1) clearly delineate the circumstances under which the plan is activated; (2) identify the command structure with defined lines of authority and responsibility; (3) describe a response strategy for each anticipated incident; (4) estimate an incident's impact on safety and hospital function, providing for evacuation if necessary; and (5) list essential information, such as critical telephone numbers (elevators, key personnel, pay telephones), community agencies (emergency medical services, police, public health), and sources of vital supplies (water, oxygen, drugs).[14] After plan activation, the primary role of the emergency department is to assess and treat individuals with illness or injury. In the absence of casualties, other hospital departments primarily manage internal disasters. Nevertheless, the medical director of the emergency department should continuously monitor the response process. In the unlikely event that evacuation of the emergency department is necessary, evacuation routes and relocation destinations that have been planned in advance maximize safety and efficiency. When resources are plentiful, emergency department patients in critical condition are assigned the highest priority for evacuation and transport. Less ill patients receive a lower priority.[16] When resources are limited (e.g., large-magnitude earthquake), the reverse strategy applies. The least critically ill patients receive the highest priority for evacuation.

External Disaster Plan An external disaster is an event occurring in the community that results in a sudden influx of patients requiring emergency care at hospitals. This definition generally assumes that the incident has had no direct impact on hospital capacity or function. Participation in the planning and execution of the hospital disaster response is an important administrative responsibility.[9] Available data guiding development of disaster strategies are incomplete, but an effective disaster response can be created by reviewing the essential components of disaster plans and the previous experience of hospitals.[] A member of the emergency department must have a leadership role in the planning and implementation of the external disaster plan.

Basic Components of Hospital Comprehensive Disaster Response Plan Interdepartmental Planning Group

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The interdepartmental planning group has the responsibility for hazard identification and disaster preparedness activities. Frequently referred to as the disaster or emergency preparedness committee, it is composed of representatives from all departments vital to the hospital's response, including administration, medical staff, nursing, safety, security, the emergency department, and engineering. Additional input may occasionally be necessary from outside agencies (e.g., fire department, hospital suppliers of goods and services, emergency medical services agency). The committee must be structured to ensure that the plan is properly constructed, tested, and executed. Hospital resources must be provided to support the planning process and testing of the plan, and there must be a detailed educational program for all affected hospital staff.[]

Resource Management A full inventory of the hospital's resources must be available. In addition to equipment, space, and personnel within the institution, potential support from outside the hospital must be sought. It is also necessary to develop contingency plans to compensate for lost resources (e.g., failure of hospital computers during a power outage). Strong relationships with community agencies (e.g., fire department, regional emergency medical services system) are important to ensure a coordinated disaster response. Hospitals located near companies using large amounts of hazardous materials are required by Title III of the Superfund Amendments and Reauthorization Act to participate in local emergency planning committees.[21]

Command Structure An organized system establishing lines of authority and decision responsibility must be in place. This system should designate a command center where the disaster response can be coordinated and create a clear chain of command. This prevents confusion if certain individuals are missing, a common situation on nights and weekends. The command center should contain sufficient equipment to support command and control functions, even if the center must be moved as a result of hospital damage.

Media The media can be an important source of information but can also significantly disrupt the hospital's disaster response. Therefore, arrangements should be made in advance for a designated individual to coordinate all media interactions and for these briefings to occur in a predetermined location. Media coordinators should inform reporters of the time they will receive their next update so they do not intrude on response operations while trying to obtain information. A strong media liaison can facilitate dissemination of important information to the public, as, for example, that no blood shortage exists so that individuals refrain from coming to the hospital to donate blood. Security should be involved in managing the media response to the hospital and in preventing media from interfering with triage and treatment of patients.

Communication Communication systems are probably the most important, but also most vulnerable, component of a disaster plan.[] Redundant systems are a must. Those responsible for mobilizing the emergency response require access to at least one other communication system besides the telephone (which is frequently one of the first systems compromised during a disaster). Two-way radios are often used, as are pay telephones, independent fax lines, and cellular phones. Another option is the evolving technology utilizing satellite phones and wireless hand-held devices to transmit e-mail messages. Runners are useful for intrahospital communication if all else fails.

Personnel The disaster plan must include a roster of all critical positions and personnel and establish a reliable method for their mobilization. Several individuals should be assigned to each position in case some personnel cannot be reached. A protocol for managing volunteers is also crucial. A large group of uncontrolled volunteers descending on a hospital can be as disruptive as the disaster.[23] Some hospitals are credentialing volunteer health care providers in advance of a disaster so they will have emergency privileges should the need for their services arise.

Patient Management A systematic approach to patient management is necessary to maximize resources. This includes protocols for decontamination, triage, patient prioritization, evacuation, and control of patients' families. Alternative use of hospital facilities must be anticipated, such as the conversion of a parking lot into a clinic area for suturing lacerations or a decontamination zone. Provisions for patient identification and treatment documentation are

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also important to facilitate federal and third-party reimbursement at the conclusion of the disaster.

Training Exercises Disaster exercises are one of the more effective ways of familiarizing hospital staff with their responsibilities. All hospital departments should participate, and community agencies should be involved. The JCAHO requires two drills a year; these should mimic incidents that are likely to occur.

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REVIEW OF HOSPITAL AND COMMUNITY DISASTER RESPONSE EXPERIENCE Disaster plan implementation is complex and difficult. Much can be learned from reviewing previous disaster response experiences, resulting in improved implementation strategies. The following discussion highlights potential problem areas.

Focal Disasters Most disasters experienced by hospitals are focal in nature. Hospital function is typically unimpaired. The majority of problems encountered are related to a sudden increase in patient volume and acuity or arrival of patients with illnesses not usually treated at that facility (e.g., burns, radiation exposure, sudden acute respiratory syndrome). Hospitals frequently experience difficulty in effectively using and interfacing with community resources. Field triage must allocate patients rationally, and transfer agreements must be in place to facilitate interhospital movement of patients. Media access must be controlled. During the Loma Prieta earthquake in 1989, a news helicopter occupied a nearby community hospital's only landing zone, preventing the possibility of landing a medical helicopter. Redundant communication systems must be in place. Typical backup systems to the telephone are radios and cellular phones, but the frequencies can be overloaded in both systems. Two-way radios are reliable and should be part of the communications network.

Catastrophic Disasters In a large-scale disaster, paramedics may be unavailable to assist in patient transfers or hospital evacuations. Disaster medical assistance teams and urban search and rescue teams will deploy, but their time to arrival on scene may be variable. Each individual hospital may have to fend for itself for 48 to 72 hours. Generator problems are frequent; they either fail altogether (as they did in Loma Prieta) or supply insufficient power to meet emergency needs (as in Northridge).[] Evacuation plans must not require elevators for this reason. Telephone service will cease as lines are disrupted or deliberately restricted by the phone company. Cellular phones may function within a local area, but failure is likely if more distant sites within the city are dialed. Hospital radios designated for disaster use must have the hardware secured to prevent earthquake damage. Under catastrophic conditions, mobilizing personnel is more difficult. Because telephone communication is unreliable, at least one additional system for contacting personnel at home must be in place. An alternative is to institute an automatic response system. After earthquakes or explosions, immediate access to structural engineers is important. In the Northridge earthquake, eight hospitals in the Los Angeles area sustained enough damage to force evacuation of at least one patient. Four institutions completely evacuated their facilities in the first 24 hours, including two hospitals that met the most current structural earthquake standards. Further structural damage was subsequently identified and forced two additional hospitals to evacuate completely in the next 2 weeks. Ultimately, four of these hospitals were permanently closed and scheduled for demolition.[16] Catastrophic earthquakes can cause extensive casualties, including large numbers of patients with crush syndrome and lacerations. Up to 90% of the victims with serious but survivable injuries are rescued by local responders and volunteer citizens in the first 24 to 48 hours.[] Therefore, special medical teams such as disaster medical assistance teams and urban search and rescue teams may not significantly affect survival if they arrive after more than 48 to 72 hours. If hospitals are not functional and no backup plan exists,

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immediate advanced medical care will not be available, and many people will die. Therefore, planners must include a backup system to provide medical care at nonhospital sites.

Need for Local Response Currently, it is not possible for outside assistance to arrive in force during the crucial first 48 hours. Therefore, an alternative source of immediate, sophisticated medical care is necessary. It appears this is best provided by local responders who arrive shortly after the event.[] The Medical Disaster Response Project is the most advanced model of a local medical response to such a disaster. Developed by emergency physicians in southern California, the Medical Disaster Response Project has two components: (1) training of health care providers in the management of disaster victims under austere conditions, and (2) placement of sophisticated medical supplies at predesignated sites within the community.[] Under this plan, victims could receive rapid, advanced medical care from surviving volunteer health care providers even if hospitals were destroyed.

Toxic Disasters (Hazardous Material) Hospitals in the vicinity of major chemical industries, transportation corridors, or probable terrorist targets (e.g., Disneyland) should be aware of potential hazards from incidents involving chemical and radioactive substances and be prepared to decontaminate large numbers of individuals exposed to these hazardous substances. Effective decontamination of victims and the need for effective safety measures on the part of rescue personnel to prevent secondary contamination are critical.[29] Decontamination equipment must be stored near the emergency department and the staff must be trained in its use. This location must be known to personnel.[30] When such an emergency occurs, there is little time to search the hospital for the necessary supplies. Ideally, patients contaminated with hazardous chemicals should first be brought to a predesignated decontamination area containing a warm water shower with a container to hold drainage water. Rescuers and victims should remove all clothing. These are bagged, tagged, and stored. Contaminated patients must never be brought into regular patient care areas because of the danger of contaminating other patients, hospital staff, and equipment. In 1994, paramedics unsuspectingly transported a patient contaminated with a degradation product of dimethyl sulfoxide to an emergency department in Riverside, California. Before detecting the presence of the hazardous material, six health care workers were exposed, including an emergency physician. This emergency physician experienced a near-fatal exposure and required intubation and an extensive stay in the hospital's intensive care unit. Uncontrolled spread of the toxin resulted in evacuation and temporary closure of the emergency department.[31] The emergency department must close off the air intake vents in rooms containing contaminated patients so toxic products do not enter the ventilation system and circulate to other parts of the hospital. Rescue personnel and hospital staff should be protected by gowns, gloves, and masks, and, if necessary, supplied air respirators. The goals are to reduce the initial level of external contamination, contain the contamination that remains, and prevent further spread of these potentially dangerous substances to other patients and staff members.

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NUCLEAR, BIOLOGIC, AND CHEMICAL TERRORISM In addition to the familiar threat from hazardous materials, there is a new challenge: a potential attack by terrorists using nuclear, biologic, or chemical weapons (see Chapter 195 ). Although somewhat similar to hazardous materials situations, management of patients exposed to weapons of mass destruction (WMD) requires new knowledge and skills. The most likely radiation source used by terrorists will probably not come from the detonation of a nuclear weapon. Instead, simple radiologic devices, such as those used by hospitals for radiation therapy, are believed to be the source of choice. They do not explode and give no warning of their presence. Terrorists can also dismantle such devices and incorporate the radioactive source into an explosive radiologic dispersion device (“dirty bomb”). Therefore, providers must recognize the presentation of patients suffering from radiation exposure to make the diagnosis. Patients who are irradiated but not externally or internally contaminated pose no threat to emergency department personnel. One of the greatest challenges with respect to WMD is the detection of biologic weapons. Patients exposed to many of the biologic agents initially present with vague symptoms associated with flulike illnesses. Decontamination is not a priority unless the exposure is immediate; standard precautions are generally sufficient. Unlike radiologic or biologic weapons, chemical agents produce symptoms quickly. The challenge is decontamination and treatment. Approximately 80% of mass casualty decontaminations are performed at hospitals. Therefore, hospitals must be prepared to decontaminate patients outside the emergency department. Personal protective equipment is also an issue for responders because of the risk of exposure during the decontamination process.[32]

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DISASTER STRESS MANAGEMENT Emergency health care providers experience high levels of stress responding to the needs of disaster victims. If this excessive stress exceeds the capacity of normal coping mechanisms, it can potentially interfere with job performance and produce disturbing symptoms. These symptoms include depression, sleep disturbances, increased use of alcohol and drugs, irritability, and anxiety.[33] Posttraumatic stress disorder can result.[34] In an attempt to reduce the psychological impact of these events on medical responders, a technique known as critical incident stress debriefing was introduced in 1983.[33] Subsequently, other models have been introduced. In general, the longer the delay is between exposure to the critical incident and subsequent psychological intervention, the smaller the chance is for a successful outcome. Therefore, the critical incident stress debriefing process is designed for rapid implementation. During the incident, stress management staff or even a colleague can provide on-scene intervention. The goal is to assist the health care worker in regaining emotional control by facilitating communication of feelings and reactions through listening and support. If a critical incident has profoundly affected multiple participants, and if symptoms are still present many hours later, a debriefing is held, which is a more extensive and formal version of a defusing. Debriefings are coordinated by mental health and peer support staff and focus on education and venting of emotions.[35] Data from previous experiences suggest that such intervention can assist providers in maintaining job performance and satisfaction, resulting in improved patient care.[36]

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DISASTER RESPONSE ORGANIZATIONS Department of Homeland Security The Department of Homeland Security (DHS), a cabinet-level department formed after the terrorist attacks of September 11, 2001, is the federal government's lead organization for emergency management activities in the United States (the Federal Emergency Management Agency [FEMA] has been incorporated intact into DHS and retains its name). DHS has a coordinating responsibility for the entire spectrum of natural, technologic, and terrorist disasters. DHS assists state and local organizations to mitigate, prepare for, respond to, and recover from emergencies and is a major source of funding for these endeavors. Starting in 1992, the Federal Response Plan was used to coordinate federal assistance into 12 categories known as emergency support functions. Examples of emergency support functions include food, health and medical services, transportation, and communications. In 2003, the President of the United States directed that the DHS develop a National Incident Management System and a National Response Plan. Existing federal plans, including the Federal Response Plan, are being incorporated into the National Response Plan.

National Disaster Medical System The National Disaster Medical System (NDMS) is a federally coordinated initiative designed to augment the emergency medical response capability of the United States in the event of a catastrophic disaster. This system is a cooperative program of four agencies in the federal government: (1) Department of Defense, (2) Department of Health and Human Services (HHS), (3) DHS, and (4) Department of Veterans Affairs (VA). DHS has the lead for the NDMS via FEMA. The NDMS provides an interstate medical mutual aid system linking the federal government, state and local agencies, and private sector institutions to address the medical needs of victims from catastrophic disasters. Its medical response element includes dozens of volunteer civilian disaster medical assistance teams that supplement the local medical infrastructure. In a disaster, the NDMS is activated when state resources are overwhelmed and the governor makes a request for federal assistance. The disaster medical assistance teams must meet specific NDMS standards. Throughout the NDMS, emergency physicians are taking key roles in defining training standards, the deployment of clinical services, and the administration of field operations and in developing the concept of a civilian-federal disaster response capacity during national emergencies.[37]

Department of Veterans Affairs The VA has not traditionally been regarded as a disaster response entity. However, one of VA's four mandated missions is emergency management. A unique feature of VA is that its facilities and personnel are situated nationwide, and these are used to support federal health and medical assistance to state and local governments during disasters. VA has highly trained specialty personnel that can support disaster medical activities. In addition to the vast pool of human resources, VA provides vast amounts of the pharmaceuticals and expendable supplies for on-site disaster support. Support is coordinated through DHS and HHS, as the lead federal agency for health and medical response.

Urban Search and Rescue When a building collapses because of an earthquake, terrorist bombing, structural failure, or other reason, various challenges confront rescue and medical personnel.[] Some victims require field amputations to facilitate extrication,[39] and use of urban search and rescue teams and effective emergency medical care is essential for successful lifesaving efforts.[40] This national system of multidisciplinary task forces is designed for rapid deployment to the sites of collapsed structures.[] The medical team's responsibilities include caring for task force members, victims recovered by search and rescue activities, and the search team's dogs. There are now WMD-urban search and rescue teams trained by FEMA to respond to nuclear, biological, and chemical (NBC) terrorist attacks.

Centers for Disease Control and Prevention

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The Centers for Disease Control and Prevention, based in Atlanta, is a U.S. federal agency under HHS. Its major responsibilities include preparing for and responding to public health emergencies (e.g., disasters) and conducting investigations into the health effects and medical consequences of these events. The major aims of the Centers for Disease Control and Prevention researchers are to assess the risks of death and injury and to develop strategies for preventing or mitigating the impact of future disasters. Other responsibilities of Centers for Disease Control and Prevention staff in the area of emergency preparedness and response include: (1) rapid assessment of the health and medical needs of disaster victims in the immediate post-disaster period; (2) development and maintenance of national systems for acute environmental hazard surveillance; and (3) provision of epidemiologic, sanitary, laboratory, and other relevant scientific support services to agencies involved in disaster planning and response.[]

Metropolitan Medical Response Systems Metropolitan Medical Strike Teams (MMSTs) are highly trained, readily deployable, and fully equipped groups of medical, fire, and rescue professionals. As a component of the larger Metropolitan Medical Response System, they support other local personnel in treating the victims of a chemical, biologic, or nuclear attack. At least 25 such teams are currently planned throughout the United States. Although composed of local personnel, MMSTs are under the direction of HHS. Their goal is to enhance local planning and response capability. However, hospital and community planners must still create an independent response because MMSTs require 90 minutes or longer to deploy.[45] MMSTs are equipped with chemical agent monitoring devices, protective equipment, and pharmaceutical supplies.

The Military On April 17, 2002, Secretary of Defense Donald Rumsfeld announced the formation of the Northern Command, or NorthCom, to assume responsibility over all military forces that operate within the United States in response to external threats and in support of civil authorities. Furthermore, Secretary Rumsfeld stated that NorthCom will “help the department better deal with natural disasters, attacks on U.S. soil, or other civil difficulties. It will provide for a more coordinated military support to civil authorities such as FBI, FEMA and state and local governments.”

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FUTURE DIRECTIONS The field of disaster medicine has become a major subspecialty within emergency medicine, and a section for disaster medicine has been organized within the American College of Emergency Physicians. There are also several national and international forums for the presentation of disaster medical research results. Since the American College of Emergency Physicians first defined a disaster medicine curriculum suitable for residencies and fellowships, a number of disaster medicine fellowships have been established in the United States. In the 21st century, disaster medicine will continue to develop as a professional activity in the United States.

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KEY CONCEPTS {, {, {, {, {, {, {,

The increasing likelihood of mass casualty incidents and high public expectations for an appropriate and timely response mandate careful and complete interagency planning. Mass casualty planning must account for the fact that traditional transport and communications systems will break down. Field personnel must be specifically trained in mass casualty triage and stabilization because austere field conditions change management strategies. All plans must protect caregivers and rescue personnel. Critical incident stress management may be highly desirable after an event and must be planned for in advance. Planners should establish and exercise a hospital-based incident management system. A plan must be in place to manage convergence of volunteers, address credentialing issues, and work with the media.

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ACKNOWLEDGMENTS The authors thank Connie J. Boatright, MSN, RN, Director, Education and Research, VA Emergency Management Strategic Healthcare Group (EMSHG); Peter W. Brewster, Emergency Preparedness Planning Specialist, EMSHG; and David S. Teeter, PharmD, Clinical Training Manager, EMSHG, for their assistance in writing and reviewing this manuscript.

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Chapter 22 – Abdominal Pain[*] Kelly E. King John M. Wightman * All m aterial in this chapter is in the public dom ain, with the excep-tion of any borrowed figures or tables.

PERSPECTIVE The nature and quality of abdominal pain are often difficult for the patient to convey and may be subject to a wide range of patients' and physicians' perceptions. The physical examination is often not helpful. Pain perception may be remote from the site of pathology, and the examination can change over time as the disease process evolves. Seemingly routine symptoms and signs may stem from life-threatening problems, and benign processes can present with severe symptoms. All of these factors make the evaluation of patients with acute abdominal pain a continuing challenge in emergency care.

Epidemiology Abdominal pain is a common presenting complaint, accounting for up to 10% of all emergency department visits. Some of the most common causes of acute abdominal pain are listed in Table 22-1 . Many patients present with pain and other symptoms that are not typical of any specific disease process. A specific diagnosis may not be possible in about one in every four individuals presenting with this chief complaint.[1] In addition, two groups deserve special consideration: elderly people (age older than 65 years) and women of reproductive age. Table 22-1 -- Common Causes of Abdominal Pain Epidemiology Etiology Presentation

Physical Examination

Useful Tests Uncomplicated cases are treated with antacids or H2 blockers before invasive studies are contemplated. Gastroduodenoscopy is valuable in diagnosis and biopsy. Valuable in diagnosing H. pylori. Also blood test for H. pylori. US, barium enema, or CT with contrast may have diagnostic benefit. Leukocyte count usually elevated or may show left shift. Urine may show sterile pyuria. C-reactive proteins sensitive, but accuracy varies. CT is sensitive and specific. US may have use in women with RLQ pain.

Peptic ulcer

Occur in all age groups. Peak at age 50. Men affected twice as much as women. Severe bleeding or perforation in less than 1% of patients.

May be associated with Helicobacter pylori infection. Risk factors include COPD, NSAID use, tobacco and alcohol use.

Nonradiating epigastric pain that starts 1–3 hours after eating and is relieved by food or antacids. Pain frequently awakens patient at night.

Epigastric tenderness without rebound or guarding. Perforation or bleeding leads to more severe clinical findings.

Acute appendicitis

Peak age: adolescence and young adulthood. Less common in children and elderly. Higher perforation rate in women, children, and elderly. Mortality rate is 0.1% but

Appendiceal lumen obstruction leads to swelling, ischemia, infection, and perforation.

Epigastric or periumbilical pain migrates to RLQ over 8–12 hours (50%–60%). Later presentations associated with higher perforation rates. Pain, low-grade fever (15%), and anorexia (80%)

Mean temperature 38° C (100.5° F). Higher temperature associated with perforation. RLQ tenderness (90%–95%) with rebound

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Epidemiology

Etiology

increased to 2% –6% with perforation.

Biliary tract disease

Peak age 35– 60. Rare in patients younger than 20. Female-to-male ratio of 3:1. Risk factors include multiparity, obesity, alcohol intake, and birth control pills.

Passage of gallstones causes biliary colic. Impaction of a stone in cystic duct or common duct causes cholecystitis or cholangitis.

Ureteral colic

Average age 30 –40, primarily in men. Prior history or family history of stones is common.

Family history, gout, Proteus sp infections. Renal tubular acidosis and cystinuria lead to stone formation.

Diverticulitis

Incidence increases with advancing age; occurs in males more than females. Recurrences are common. Often called “left-sided” appendicitis.

Colonic diverticula become infected or perforated or cause local colitis Obstruction, peritonitis, abscesses, fistulas result from infection or swelling. Usually viral.

Acute Common gastroenteritis diagnosis. Seasonal. Most common misdiagnosis of appendicitis. May be seen in multiple family members.

Presentation

Physical Examination

Useful Tests

common; vomiting (40%–70%) in less common majority of (50%–70%). cases. Rectal tenderness in up to 30%. Crampy RUQ pain Temperature radiates to right normal in subscapular area. biliary colic, Prior history of elevated in pain is common. cholecystitis, Longer duration of cystitis, and pain favors cholangitis. diagnosis of RUQ cholecystitis or tenderness, cholangitis. rebound, and jaundice (less common) may be present. Acute onset of Vital signs flank pain radiating usually normal. to groin. Nausea, Tenderness on vomiting, and CVA pallor are percussion common. Patient with benign usually writhing in abdominal pain. examination.

Common to have change in stool frequency or consistency. Left lower quadrant pain is common. Associated fever, nausea/vomiting, rectal bleed may be seen.

Pain usually poorly localized. Intermittent, crampy diffuse pain. Diarrhea is key element in diagnosis, usually large volume, watery. Nausea and vomiting usually begin before pain. Sense of increased peristalsis may be noted.

WBC count elevated in cholecystitis and cholangitis. Amylase and liver function tests may help differentiate this from gastritis or ulcer disease. Ultrasound shows anatomy, stones, or duct dilatation. Hepatobiliary scintigraphy diagnoses gallbladder function. Urinalysis usually shows hematuria. Intravenous pyelography is the mainstay of diagnosis. Helical or spiral CT may be more appropriate in older patients or patients with elevated renal functions. US ± KUB with fluid bolus useful diagnostically. Fever usually Most testing usually low grade. Left normal. Plain films may lower quadrant show obstruction or pain without mass effect. Barium rebound is enema is often common. diagnostic. Stools may be heme positive.

Abdominal examination usually nonspecific without peritoneal signs. Watery diarrhea or no stool noted on rectal examination. Fever is usually present.

Usually symptomatic care with antiemetics and volume repletion. Key is not using this as a “default” diagnosis and missing more serious disease.

Page 5084

Epidemiology Nonspecific abdominal pain

Etiology

More common Unknown. in persons of young and middle age, women of childbearing years, or low social class and those with psychiatric disorders. Up to 10% of patients over 50 years of age prove to have intraabdominal cancer.

Presentation

Physical Examination

Useful Tests

Variable but tends Variable but no Variable and can often to be chronic or peritoneal be done on an recurrent. signs. outpatient basis.

COPD, chronic obstructive pulmonary disease; CT, computed tomography; CVA, costovertebral angle; KUB, kidney, ureters, and bladder; NSAID, nonsteroidal anti-inflammatory drug; RLQ, right lower quadrant; RUQ, right upper quadrant; US, ultrasonography; WBC, white blood cell.

Elderly patients with acute abdominal pain are more likely to have a life-threatening process as the cause of their pain, which can also be more rapidly progressive. Atypical symptoms and clinical findings in elderly patients make specific diagnoses difficult to determine. Decreased diagnostic accuracy, coupled with increased probability of severe disease, results in increased mortality in elderly patients with abdominal pain. [2]

Pain in pelvic organs is commonly perceived as abdominal in origin. The possibility of ectopic pregnancy in women of reproductive age greatly increases the risk of serious disease with a high potential for misdiagnosis. During pregnancy the uterus becomes an abdominal rather than pelvic organ. It may displace the normal intraperitoneal contents, adding complexity to the evaluation of these patients.[3]

Pathophysiology Pathology in the gastrointestinal and genitourinary tracts remains the most common source of pain perceived in the abdomen. Also, pain can arise from a multitude of other intraabdominal and extraabdominal locations ( Box 22-1 ). Abdominal pain is derived from one or more of three distinct pain pathways: visceral, somatic, and referred. BOX 22-1 Important Extraabdominopelvic Causes of Abdominal Pain

Thoracic Myocardial infarction/unstable angina Pneumonia Pulmonary embolism Herniated thoracic disc (neuralgia)

Genitourinary

Page 5085

Testicular torsion

Abdominal Wall Muscle spasm Muscle hematoma Herpes zoster

Infectious Strep pharyngitis (more often in children) Rocky Mountain spotted fever Mononucleosis

Systemic Diabetic ketoacidosis Alcoholic ketoacidosis Uremia Sickle cell disease Porphyria Systemic lupus erythematosus Vasculitis Glaucoma Hyperthyroidism

Toxic Methanol poisoning Heavy metal toxicity Scorpion bite Black widow spider bite Adapted from: Purcell TB: Nonsurgical and extraperitoneal causes of abdominal pain. Emerg Med Clin North Am 7:721, 1989.

Visceral pain results from stimulating autonomic nerves invested in the visceral peritoneum surrounding internal organs. It is often the earliest manifestation of a particular disease process. Hollow-organ distention by fluid or gas and capsular stretching of solid organs from edema, blood, cysts, or abscesses are the most common stimuli. This discomfort is poorly characterized and difficult to localize. If the involved organ is affected by peristalsis, the pain is often described as intermittent, crampy, or colicky. In general, visceral pain is perceived from the abdominal region that correlates with the embryonic somatic segment: {,

{,

Foregut structures (stomach, duodenum, liver, and pancreas) cause upper abdominal pain. Midgut derivatives (small bowel, proximal colon, and appendix) cause periumbilical pain.

Page 5086

{,

Hindgut structures (distal colon and genitourinary tract) cause lower abdominal pain.

Visceral pain can be perceived in a location remote from the actual disease process. Localization occurs with the extension of the disease process beyond the viscera. A classical example is the early periumbilical pain of appendicitis (midgut). When the parietal peritoneum becomes involved, the pain localizes to the right lower quadrant of the abdomen, the usual location of the appendix. Somatic pain occurs with irritation of the parietal peritoneum. This is usually caused by infection, chemical irritation, or other inflammatory processes. Sensations are conducted by the peripheral nerves and are better localized than the visceral pain component. Figure 22-1 illustrates some more typical pain locations corresponding to specific disease entities. Somatic pain is often described as intense and constant. As disease processes evolve to peritoneal irritation with inflammation, better localization of the pain to the area of pathology generally occurs.

Figure 22-1 Differential diagnosis of acute abdom inal pain. ((From Wagner DK: Approach to the patient with ab dom inal pain Curr Top 1:3, 1978, with perm ission))

Referred pain is defined as pain felt at a distance from its source because peripheral afferent nerve fibers from many internal organs enter the spinal cord through nerve roots that also carry nociceptive fibers from other locations. This makes interpretation of the location of noxious stimuli difficult for the brain. Both visceral pain and somatic pain can manifest as referred pain. Two examples of referred pain are the epigastric pain associated with an inferior myocardial infarction and the shoulder pain associated with blood in the peritoneal cavity irritating the diaphragm. Gynecologic and obstetric presentations are discussed in other chapters. Notably, any abdominal pain in a female could be referred pain from pelvic structures or an extension of a pelvic process, as in the case of perihepatic inflammation with pelvic inflammatory disease.

DIAGNOSTIC APPROACH The clinical approach should focus on early stabilization, history, physical examination, and any ancillary tests collectively facilitating appropriate management and disposition plans.

Differential Considerations Classically, potential diagnoses are divided into intraabdominopelvic (intraperitoneal, retroperitoneal, and pelvic) causes (e.g., appendicitis, cholecystitis, pancreatitis) and extraabdominopelvic processes (e.g., pneumonia, myocardial infarction, ketoacidosis). Although significant morbidity and mortality can result from many causes of abdominal pain, a few processes warrant careful consideration in the emergency department. Table 22-2 lists the six most important potentially life-threatening nontraumatic causes of abdominal pain. This group represents the major etiologies likely to arise with hemodynamic compromise and for which early therapeutic intervention is critical. Table 22-2 -- Potentially Life-Threatening Causes of Abdominal Pain Cause Epidemiology Etiology Presentation Physical Examination

Useful Tests

Ruptured ectopic Occurs only in pregnancy females of

bHCG testing necessary for all

Risk factors Severe, sharp include nonwhite constant pain

Shock or evidence of

Page 5087

Cause

Epidemiology

Etiology

Presentation

Physical Examination

Useful Tests

(critical)

childbearing age without bilateral oophorectomy. No method of contraception prevents ectopic pregnancy. Approximately 1 in every 100 pregnancies.

race, older age, history of STD or PID, infertility treatment, intrauterine contraceptive device within the last year, tubal sterilization, and previous ectopic pregnancy.

localized to the affected side. More diffuse abdominal pain with intraperitoneal hemorrhage. Signs of shock may be present. Midline pain tends not to be ectopic pregnancy.

peritonitis may be present. Lateralized abdominal tenderness. Localized adnexal tenderness or cervical motion tenderness increase the likelihood of ectopic pregnancy. Vaginal bleeding does not have to be present.

Ruptured or leaking abdominal aneurysm (critical)

Incidence increases with advancing age. More frequent in men. Risk factors include HTN, DM, smoking, COPD, and CAD.

Atherosclerosis in over 95%. Intimal dissection causes aortic dilatation and creation of a false lumen. Leakage or rupture causes shock.

Patient often asymptomatic until rupture. Acute epigastric and back pain often associated with or followed by syncope or signs of shock. Pain may radiate to back, groin, or testes.

Mesenteric ischemia (emergent)

Occurs most commonly in elderly people with CV disease, CHF, cardiac dysrhythmias, DM, sepsis, and dehydration. Responsible for 1 of 1000 hospital admissions. Mortality 70%. Mesenteric venous thrombosis associated with hypercoagulable states, hematologic inflammation,

20%–30% of lesions are nonocclusive. The causes of ischemia are multifactorial, including transient hypotension tension in the presence of preexisting atherosclerotic lesion. The arterial occlusive causes (65%) are secondary to emboli (75%) or acute arterial thrombosis (25%).

Severe pain, colicky, that starts in periumbilical region and then becomes diffuse. Often associated with vomiting and diarrhea.

Vital signs may be normal (in 70% of patients) to severely hypotensive. Palpation of a pulsatile mass is usually possible in aneurysms 5 cm or greater. If suspected, the physical examination should not be relied on only. CT or US usually indicated. Bruits or inequality of femoral pulses may be evident. Early examination results can be remarkably benign in the presence of severe ischemia. Bowel sounds often still present. Rectal examination important because mild bleeding with positive guaiac stools can be present.

women of childbearing ages (10–55). This combined with ultrasonography, preferably transvaginal, is usually diagnostic. Culdocentesis reserved for circumstances where other more sophisticated testing is not available. Abdominal plain films abnormal in 80% of cases. Lateral abdominal film may be helpful. Ultrasound can define diameter and length but limited by obesity and gas. Spiral CT test of choice if patient is stable.

Often a pronounced leukocytosis is present. Elevations of amylase and creatine phosphokinase levels are seen. Metabolic acidosis due to lactic acidemia is often seen with infarction. Plain films of limited benefit. CT, MRI, and angiography are accurate to varying degrees.

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Cause

Intestinal obstruction (urgent)

Perforated viscus (urgent)

Acute pancreatitis (urgent)

Epidemiology and trauma. Peaks in infancy and elderly. More common with history of previous abdominal surgery.

Etiology

Presentation

Physical Examination

Adhesions, carcinoma, hernias, abscesses, volvulus, and infarction. Obstruction leads to vomiting, third spacing of fluid, strangulation, and necrosis of bowel.

Crampy diffuse abdominal pain associated with vomiting.

Vital signs usually normal unless dehydration or bowel strangulation has occurred. Abdominal distention, hyperactive bowel sounds, and diffuse tenderness. Local peritoneal signs indicate strangulation.

Useful Tests

WBC count may indicate strangulation if elevated. Electrolytes may be abnormal if associated with vomiting or prolonged symptoms. Abdominal films are useful for identifying level of obstruction. US or CT rarely needed to make diagnosis. Incidence More often a Acute onset of Fever, usually WBC count increases with duodenal ulcer epigastric pain is low grade, is usually elevated advancing age. that erodes common. common, higher due to peritonitis. History of peptic through the Vomiting in 50%. fever occurs with Amylase may be ulcer disease or serosa. Colonic Fever may be time. elevated as well. diverticular diverticula, large present later. Tachycardia is LFT results are disease bowel, small Pain may common. variable. Upright common. bowel, and localize with Abdominal view of gallbladder omental walling examination radiographs perforations are off of peritonitis. reveals diffuse reveals free air in rare. Spillage of Shock may be guarding and 70%–80% of bowel contents present with rebound. A cases with causes bleeding or “boardlike” perforated peritonitis. sepsis. abdomen in later ulcers. stages. Bowel sounds are decreased. Peak age in Alcohol, Acute onset of Low-grade fever Lipase is test of adulthood. Rare gallstones, epigastric pain common. Patient choice. Amylase in childhood and hyperlipidemia, radiating to the may be 3× normal more elderly. Male hypercalcemia, back. Nausea hypotensive or specific for preponderance. or endoscopic and vomiting tachypneic. diagnosis. Alcohol abuse retrograde common. Pain Some epigastric Ultrasound may and biliary tract pancreatography disproportionate tenderness show edema or disease are risk causes to physical usually present. pseudocyst. CT factors. pancreatic findings. Since scan may show damage, Adequate retroperitoneal abscesses, saponification, volume repletion organ, guarding necrosis, and necrosis. is important in or rebound not hemorrhage, or ARDS, sepsis, the initial present unless pseudocysts. CT hemorrhage, and therapy. severe. Flank is ordered if renal failure are ecchymoses severe acute secondary. may be seen if pancreatitis is hemorrhagic. suspected.

CAD, coronary artery disease; CHF, congestive heart failure; COPD, chronic

Page 5089

Cause

Epidemiology

Etiology

Presentation

Physical Examination

Useful Tests

obstructive pulmonary disease; CV, cardiovascular; DM, diabetes mellitus; HTN, hypertension; PID, pelvic inflammatory disease; STD, sexually transmitted disease.

Rapid Assessment and Stabilization As with any complaint, triage is the first critical step in management. Most patients presenting with abdominal pain do not have hemodynamic instability, but up to 7% of these patients may have a life-threatening process. This percentage is higher in elderly and immunocompromised patients.[1] Physiologically compromised patients should be brought to a treatment area immediately and resuscitation initiated. Profound shock or protracted emesis can lead to airway compromise and require intubation. Volume repletion, if necessary for the patient's stabilization, is usually accomplished with an isotonic crystalloid solution and titrated to a physiologic endpoint. Extreme conditions such as ruptured abdominal aortic aneurysm, massive gastrointestinal hemorrhage, ruptured spleen, and hemorrhagic pancreatitis may require blood or blood product replacement. Bedside ultrasonography can be used to establish the presence of free intraperitoneal fluid quite rapidly and can aid in directing the initial stabilization phase. Because all of the immediately life-threatening entities could require surgical intervention or management, early surgical consultation is necessary.

Pivotal Findings History A careful and focused history is central to unlocking the puzzle of abdominal pain. Box 22-2 lists some historical questions with high yields for serious pathology. Language and cultural differences may influence accurate communication and mutual understanding. BOX 22-2 High-Yield Historical Questions

1.

How old are you ? Adva nced age mea ns incre ased risk.

2.

Whi ch

Page 5090

3.

4.

cam e first — pain or vom iting ? Pain first is wors e (i.e., mor e likely to be caus ed by surgi cal dise ase). How long have you had the pain ? Pain for less than 48 hour s is wors e. Hav e you ever had abd omi nal surg ery? Con sider obstr uctio n in patie nts who

Page 5091

5.

6.

7.

repo rt previ ous abdo mina l surg ery. Is the pain con stan t or inter mitt ent? Con stant pain is wors e. Hav e you ever had this befo re? A repo rt of no prior epis odes is wors e. Do you have a hist ory of canc er, dive rticu losis , pan crea titis, kidn ey failu

Page 5092

8.

9.

re, galls tone s, or infla mm ator y bow el dise ase? All are sugg estiv e of mor e serio us dise ase. Do you have hum an imm uno defi cien cy viru s (HIV )? Con sider occu lt infec tion or drug -relat ed panc reatit is. How muc h alco hol do you drin k per day

Page 5093

10.

11.

12.

? Con sider panc reatit is, hepa titis, or cirrh osis. Are you preg nant ? Test for preg nanc y— cons ider ecto pic preg nanc y. Are you taki ng anti bioti cs or ster oids ? Thes e may mas k infec tion. Did the pain start cent rally and migr ate to the right lowe r qua

Page 5094

13.

dran t? High spec ificity for appe ndici tis. Do you have a hist ory of vasc ular or hear t dise ase, hyp erte nsio n, or atria l fibril latio n? Con sider mes enter ic isch emia and abdo mina l aneu rysm .

From Colucciello SA, Lukens TW, Morgan DL: Abdominal pain: An evidence-based approach. Emerg Med Pract 1:2, 1999.

Abrupt onset is often indicative of a more serious cause; however, delayed presentations may also represent a surgical condition. Surgical causes of abdominal pain are more likely to arise with pain first followed by nausea and vomiting, rather than nausea and vomiting followed by pain. Localization and pain migration are also helpful. Diffuse pain is generally nonsurgical, but it may represent the early visceral component of a surgical process. The severity and descriptive nature of the pain are the most subjective aspects of the pain history, but there are a few classical descriptions, such as the following: {,

The diffuse, severe, colicky pain of bowel obstruction

Page 5095

{,

The “pain out of proportion to examination” observed in patients with mesenteric ischemia The radiation of pain from the epigastrium straight through to the midback associated with pancreatitis, either related to primary organ inflammation or secondary to a penetrating ulcer

{,

Physical Examination The objective evaluation begins with measurement of the vital signs. Significant tachycardia and hypotension are indicators that shock may be present. Tachypnea may be an indication of metabolic acidosis from gangrenous viscera or sepsis, hypoxemia from pneumonia, or simply a catecholamine-induced reaction to pain. Elevated temperature is often associated with intraabdominal infections. However, fever does not accurately predict significant abdominal pathology. For example, the temperature is often normal in elderly patients with laparotomy-proven intraperitoneal infections.[4] The abdomen and pelvis are examined to identify the area of maximal tenderness, anticipating some correspondence with the location of the diseased organ. This can be true, but it is often not the case. Although 80% of suspected appendicitis cases manifest right lower quadrant abdominal tenderness, 20% of patients with proven appendicitis do not.[5] Rectal examination may have limited use in abdominal pain, except when associated with intraluminal gastrointestinal hemorrhage, prostatitis, and perirectal disease. Its main utility is in the detection of heme-positive stool. Rectal examination has not been shown to increase diagnostic accuracy for appendicitis when added to external physical examination of the abdomen.[6] The abdominal evaluation should include a pelvic examination in female patients with lower abdominal pain or an otherwise uncertain diagnosis. Male patients should receive a genital examination as well as evaluation for the presence of inguinal or femoral hernias. Given the evolving nature of abdominal pain, repetitive examinations may be used. This is common practice with respect to suspected appendicitis and has improved the diagnostic accuracy in patients whose presentations were atypical.[2]

Ancillary Testing Urinalysis and testing for pregnancy are perhaps the most time- and cost-effective adjunctive laboratory tests available ( Table 22-3 ). Results can often be obtained quickly, so the former can lead to an early diagnosis and the latter may significantly affect further evaluation and management approaches. It is necessary to interpret urinalysis results within the entire spectrum of the patient's clinical picture. Pyuria, with or without bacteriuria, is often present in a variety of conditions besides a simple urinary tract infection. Hematuria can also be misleading. Up to 30% of patients with appendicitis have an abnormal urinalysis.[7] Table 22-3 -- Diagnostic Studies for Common Abdominal Presentations Common CBC Lytes UA Plain Films U/S Testing Abdominal aortic aneurysm A Appendicitis Y Biliary tract disease A Bowel obstruction, perforation A Cholecystiti A

CT Scan

A A

Y Y

Y Y

A

Y[*]

Y

Y

Y

Y[*]

Y

A A

Y[*]

Other Angiography , MR imaging[*] C-reactive protein HIDA scan

Page 5096

Common CBC Testing s Diverticulitis A

Ectopic pregnancy A Gastroenteri Y tis Hernia

Lytes

Y

Testicular torsion

A

Y

A A

Y[*]

A

A

A Y

A A

Y

Y

A

Plain Films U/S

CT Scan

Other

Y

Barium enema HCG, progesteron e Fecal leukocytes Physical examination Angiography , ECG, MR imaging Doppler ultrasound

A

Intestinal A infarction/isc hemia Ovarian Y torsion Pancreatitis Pelvic inflammator y disease Pyelonephrit is Renal colic

UA

Y

A

Y

Y

Y A

Y

Y

A

Y

Y

Y

Lipase[*], amylase ESR, CRP

Helical CT, IVP Doppler, nuclear scan

Urinary tract infection Y Y[*] A From Gaff LG, Robinson D: Abdominal pain and the emergency department evaluation. Emerg Med Clin North Am 19(1), 2001. A, helpful adjunct to testing for disease but not necessarily indicated; Y, indicated for establishing diagnosis. CT, computed tomography; CRP, C-reactive protein; ECG, electrocardiogram; ESR, erythrocyte sedimentation rate; hCG, human chorionic gonadotropin; HIDA, hepatoiminodiacetic acid; IVP, intravenous pyelography; MR, magnetic resonance. *

Diagnostic test of choice to detect the particular disease entity.

Complete blood counts are frequently ordered for patients with abdominal pain. Despite elevated white blood cell (WBC) counts being associated with many infectious and inflammatory processes, the WBC count is neither sufficiently sensitive nor specific to be considered a discriminatory test to help establish the cause of the abdominal pain. Even serial WBC counts have failed to differentiate surgical versus nonsurgical conditions. The WBC count is, therefore, not helpful for diagnosis. Serum electrolytes, even in the presence of protracted emesis or diarrhea, are abnormal in less than 1% of patients. These studies are not indicated for most patients in the absence of another indication. Blood urea nitrogen concentrations can be elevated in gastrointestinal hemorrhage and dehydration, but such conditions are better detected and quantified by history and physical examination. Increased serum creatinine is usually indicative of renal dysfunction. Blood glucose, anion gap, and serum ketone determinations are useful in diabetic ketoacidosis, one cause of acute abdominal pain and tachypnea. Liver enzymes and coagulation studies are helpful only in a small subset of patients with suspected liver disease.[8] If pancreatitis is suspected, the most useful diagnostic result is serum lipase elevated to at least double the normal value because it is more specific and more sensitive than serum amylase for this

Page 5097

process. There is no value to obtaining a serum amylase if a serum lipase level is available.[9] Serum phosphate and serum lactate levels are elevated late in bowel ischemia and may be useful if this entity is suspected but cannot be considered either sufficiently sensitive or specific to establish or exclude the diagnosis on their own. Plain radiography of the abdomen has limited utility in the evaluation of acute abdominal pain. Suspected bowel obstruction, foreign body, and perforated viscus are the main indications. Helical computed tomography of the abdomen has become the imaging modality of choice with respect to nonobstetric abdominal pain. It allows visualization of both intraperitoneal and extraperitoneal structures and has a high degree of accuracy, establishing a diagnosis in more than 95% of cases in one study[10] and increasing the confidence of diagnosis in another.[11] In the elderly subpopulation, computed tomography results changed management or disposition decisions in a significant proportion of patients.[12] Transabdominal and transvaginal ultrasonography have emerged as extremely useful adjuncts. Bedside emergency department ultrasonography applications with utility in life-threatening abdominopelvic processes include the following: {,

{,

{,

Identification of an intrauterine pregnancy, effectively lowering the chances of an ectopic pregnancy to less than 1 in 20,000 Measurement of the cross-sectional diameter of the infrarenal aorta to determine whether an abdominal aortic aneurysm exists Detection of free intraperitoneal fluid indicating hemorrhage, pus, or extrusion of gut contents

Uses as a diagnostic aid in non–life-threatening conditions include the following: {,

{,

Detection of gallstones or a dilated common bile duct, which may aid in diagnosis of cholecystitis Detection of free intraperitoneal fluid indicating ascites

The results of sonographic examinations are operator dependent and misdiagnosis can occur because of failure to detect or identify pathology, incorrect identification of normal anatomy as pathologic, and overinterpretation of correctly identified findings (e.g., the mere presence of gallstones does not indicate that cholelithiasis is the etiology of the pain).

DIFFERENTIAL DIAGNOSIS A simple algorithmic approach to acute abdominal pain is difficult, given the broad range of potential etiologies. The differential considerations include a significant number of potentially life- or organ-threatening entities, particularly in the setting of a hemodynamically unstable or toxic-appearing patient. This is particularly important when dealing with elderly or potentially pregnant patients (see Tables 22-1 and 22-2 ). Traditionally, despite the limitations already described, the approach to the differential diagnosis of abdominal pain is based on the location of maximal tenderness. Figure 22-1 shows locations of subjective pain and maximal tenderness on palpation related to various underlying causes. Women of reproductive age should undergo pregnancy testing early, and a known pregnancy or a positive urine or serum pregnancy test in the emergency department should be considered to represent an ectopic pregnancy until proved otherwise. If evi-dence of blood loss is present, early obstetric consultation and diagnostic ultrasonography should be promptly sought. Bedside, transabdominal sonography may identify free intraperitoneal fluid during the evaluation of shock, which may be sufficient evidence to justify operative intervention in the context of a positive pregnancy test and appropriate history and physical findings.

Page 5098

In patients who are hemodynamically normal and stable, including women with a negative pregnancy test, the diagnostic algorithm then proceeds to identify the general region of the abdomen that contains the point of maximal tenderness. In the hemodynamically stable patient, a positive pregnancy test may indicate ectopic pregnancy, but the entire spectrum of intraabdominal conditions remains in the differential diagnosis, as for the nonpregnant patient. When the very broad differential list is compartmentalized by both history and physical examination, ancillary testing should proceed to either confirm or support the clinical suspicion. Table 22-3 lists the ancillary tests used in the evaluation of specific causes of abdominal pain. Despite the significant variety of tests available, close to one half of the patients presenting to the emergency department with acute abdominal pain have no conclusive diagnosis. It is incumbent upon the clinician to reconsider the extraabdominal causes of abdominal pain (see Box 22-1 ), with special consideration for the elderly and the immunocompromised patient subsets, before arriving at the diagnosis of “nonspecific abdominal pain.”

EMPIRICAL MANAGEMENT The main therapeutic goals in managing acute abdominal pain are physiologic stabilization, mitigation of symptoms (e.g., emesis control, pain relief), and expeditious diagnosis, with consultation, if required ( Figure 22-2 ). A

B

Figure 22-2 Managem ent algorithm for acute abdom inal pain. p -hCG, p subunit of hum an chorionic gonadotropin; ED, em ergency departm ent; EMTALA, Em ergency Medical Treatm ent and Active Labor Act; GI, gastroenterology; IUP, intrauterine pregnancy; Ob/Gyn, obstetrics and gynecology; US, ultrasonography.

Gastric emptying by nasogastric tube with suction is appropriate for suspected small bowel obstruction. Antiemetics, such as promethazine or trimethobenzamide, can be useful for intractable vomiting, but they can also cause mental status changes in some patients. Granisetron and ondansetron are alternative antiemetics with less potential for mental status changes, but these agents are more expensive. If intraabdominal infection is suspected, broad-spectrum antibiotic therapy should be initiated promptly. Abdominal infections are often polymicrobial and coverage for enteric gram-negative, gram-positive, and anaerobic bacteria must be included. In the choice of antibiotic or combination, the following should be considered: {,

Unless local antibiotic resistance surveillance indicates otherwise, second-generation cephalosporins (e.g., cefamandole, cefotetan, cefoxitin) may be combined with metronidazole for the initial dose of antibiotics in the emergency department. Other noncephalosporin, p -lactam agents with p -lactamase antagonists (e.g., ampicillin-sulbactam, piperacillin-tazobactam, ticarcillin-clavulanate) are

Page 5099

{,

alternatives. Many enteric gram-negative bacilli mutate rapidly to produce p -lactamases that are poorly antagonized by specific drug combinations containing clavulanate, sulbactam, or tazobactam. A carbapenem (e.g., imipenem, meropenem) or cefepime is an alternative for patients who may have recently received other antibiotics.[]

The need to cover Enterococcus species is still a subject of debate, and the decision to treat these bacteria specifically can be made after consultation. Immunocompromised patients may require antifungal agents. There is no evidence to support withholding analgesics for patients with acute abdominal pain to prevent potentially limiting the effectiveness of subsequent physical examinations by consultants not present in the emergency department. Pain relief may facilitate the diagnosis in patients ultimately requiring surgery.[] In the acute setting, analgesia is usually accomplished with intravenously titrated opioids. Meperidine (Demerol) has an unfavorable side-effect profile and should be avoided. Intravenous ketorolac, the only parenteral nonsteroidal anti-inflammatory drug available in North America, is useful for both ureteral and biliary colic,[] as well as some gynecologic conditions, but is not indicated for general treatment of undifferentiated abdominal pain. Relative to patients with gastrointestinal hemorrhage and potential surgical candidates, ketorolac has been shown to increase bleeding times in healthy volunteers.[19] Aside from analgesics, a variety of other medications may be helpful to patients with abdominal pain. The burning pain caused by gastric acid may be relieved by antacids.[20] Intestinal cramping may be diminished with oral anticholinergic agents such as atropine-scopolamine-hyoscyamine-phenobarbital (Donnatal).

DISPOSITION Because up to 40% of patients presenting with acute abdominal pain receive the diagnosis of nonspecific abdominal pain, the dispositions of patients with abdominal pain can be as difficult as their diagnoses. Categories for disposition may include surgical versus nonsurgical consultation and management, admission for observation, and discharge to home with follow-up evaluation.[21] The decision to admit a patient to an observation unit or a hospital bed must factor in the following: {,

{, {,

{,

Information gained from the history, physical examination, and test results The likelihood of any suspected disease Any potential ramifications, if a known disease progresses or the patient is incorrectly diagnosed or managed Whether follow-up evaluation can occur in a timely manner if the patient is discharged home

Clinically stable patients may be discharged from the emergency department with appropriate follow-up care, possibly to include repeated or additional diagnostic imaging. In the case of nonspecific abdominal pain that is considered potentially worrisome, it is prudent to have the patient reevaluated after 8 to 12 hours. This can be done through a return visit to the emergency department, an appointment with a primary care physician, or an observation unit protocol. If a patient is to be discharged home without a specific diagnosis, clear instructions to the patient must

Page 5100

include the following information: {,

{,

{,

What the patient has to do to improve his or her symptoms or chances of resolving the condition (e.g., avoiding exacerbating food or activities, taking medications as prescribed) Under what circumstances, with whom, and in what time frame to seek follow-up evaluation, if all goes as desired on the basis of what is known when the patient is in the emergency department Under what conditions the patient should seek more urgent care, if there are unexpected changes in his or her condition (e.g., natural progression of the process before improvement, incorrect diagnosis made in the emergency department, untoward reactions to medications)

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Marx: Rosen's Emergency Medicine: Concepts and Clinical Practice, 6th ed., Copyright © 2006 Mosby, Inc.

REFERENCES 1. Waeckerle JF: Executive summary: Developing objectives, content, and competencies for the training of emergency medical technicians, emergency physicians, and emergency nurses to care for casualties resulting from nuclear, biological, or chemical (NBC) incidents. Ann Emerg Med2001;37:587. 2. Bosner L: Catastrophic events. In: Kuehl AE, ed.Prehospital Systems and Medical Oversight, St. Louis: Mosby; 1994: 3. Koenig KL, Dinerman N, Kuehl AE: Disaster nomenclature: A functional impact approach: The PICE system. Acad Emerg Med1996;3:723. 4. Chaff L: Emergency preparedness. Safety Guide for Health Care Institutions, 5th ed. Chicago, American Hospital Publishing, 1994. 5. Callum JR, Dinerman NM: Disaster preparedness. In: Sheehy S, ed.Emergency Nursing: Principles and Practice, 3rd ed. St Louis: Mosby; 1992: 6. Aufderheide E: Resource management. Disaster Response: Principles of Preparation and Coordination, St Louis, Mosby, 1989. 7. Koenig KL, Schultz CH: Disaster medicine: Advances in local catastrophic disaster-response. Acad Emerg Med1994;1:133. 8. Koenig KL: Triage: Do we need new concepts? [abstract]. Trauma Care2003;13:44. 9. Waeckerle JF: Disaster planning and response. N Engl J Med1991;324:815. 10. Super G: START: Simple Triage and Rapid Treatment Plan, Newport Beach, Calif, Hoag Memorial Hospital Presbyterian, 1994. 11. Benson M, Koenig KL, Schultz CH: Disaster triage: START then SAVE—a new method of dynamic triage for victims of a catastrophic earthquake. Prehosp Disaster Med1996;11:117. 12. Milzman DP: Pre-existing disease in trauma patients: A predictor of fate independent of age and injury severity score. J Trauma1992;32:236. 13. Irwin RL: The incident command system (ICS). In: Aufderheide E, ed.Disaster Response: Principles of Preparation and Coordination, St Louis: Mosby; 1989: 14. Schultz CH, Mothershead JL, Field M: Bioterrorism preparedness I: The emergency department and hospital. Emerg Med Clin North Am2002;20:437. 15. Joint Commission on the Accreditation of Healthcare Organizations : Accreditation Manual for Hospitals, Oak Brook Terrace, Ill, Joint Commission, 2001. 16. Schultz CH, Koenig KL, Lewis RJ: Implications of hospital evacuation after the Northridge, California, Earthquake. N Engl J Med2003;348:1349. 17. Kai T, Pretto E: Hospital preparedness in Osaka, Japan. Prehosp Disaster Med1993;8:S91. 18. Aufderheide E: Community Medical and Hospital Disaster Planning Guidelines: An Interrogatory Format, Dallas, American College of Emergency Physicians, 1995. 19. Drabek TE: Emergency Management: The Human Factor, Emmitsburg, Md, Federal Emergency Management Agency National Emergency Training Center, 1985. 20. The San Mateo County Health Services Agency : Emergency Medical Services: Hospital Emergency Incident Command System, 3rd ed. San Mateo, Calif, The San Mateo County Health Services Agency, 1998. 21. O'Neil K: Emergency department planning for hazardous materials victims: Getting started. J Emerg Nurs1994;20:41. 22. Estess PA, Angell LS: Watsonville Community Hospital responds to the 1989 Loma Prieta earthquake. Plant Technol Safety Management Series1990;2:21. 23. Cone DC, Weir SD, Bogucki S: Convergent volunteerism. Ann Emerg Med2003;41:457. 24. Earthquake Engineering Research Institute : Northridge Earthquake: Preliminary Reconnaissance Report—January 17, 1994, El Cerrito, Calif, The Institute, 1994. 25. Noji EK, Jones NP: Hospital preparedness for earthquakes. Plant Technol Safety Manage Series 1990;2:13. 26. Pretto EA: Disaster reanimatology potentials: A structured interview study in Armenia. III. Results, conclusions, and recommendations. Prehosp Disaster Med1992;7:327. 27. Noji EK: Evaluation of the efficacy of disaster response: research at the Johns Hopkins University.

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UNDRO News July-August1987;11. 28. Schultz CH, Koenig KL, Noji EK: A medical disaster response to reduce immediate mortality following an earthquake. N Engl J Med1996;334:438. 29. Borak J, Callan M, Abbott W: Hazardous Materials Exposure, Englewood Cliffs, NJ, Brady, 1991. 30. Agency for Toxic Substances and Disease Registry: Managing Hazardous Materials Incidents: Hospital Emergency Departments—A Planning Guide for the Management of Contaminated Patients, Atlanta, 1992. Agency for Toxic Substances and Disease Registry. 31. Boodman SG: Health. Washington PostSept 13, 1994; 32. Koenig KL: Strip and shower: The duck and cover for the 21st century. Ann Emerg Med2003;42:391. 33. Mitchell J: When disaster strikes… the critical incident stress debriefing process. J Emerg Med Serv 1983;8:36. 34. Burkle FM: Acute-phase mental health consequences of disasters: Implications for triage and emergency medical services. Ann Emerg Med1996;28:119. 35. Oster NS, Doyle CJ: Critical Incident Stress. In: Hogan DE, Burstein JL, ed.Disaster Medicine, Philadelphia: Lippincott Williams & Wilkins; 2002: 36. Mitchell JT: Stress: The history, status and future of critical incident stress debriefings. JEMS 1988;13:46. 37. Roth PB: Status of a national disaster medical response. JAMA1991;266:1266. 38. Kunkle RF: Medical care of entrapped patients in confined spaces. Proceedings of the International Workshop on Earthquake Injury Epidemiology: Implications for Mitigation and Response, Baltimore, Johns Hopkins University, 1989. 39. Koenig KL, Schultz CH: The crush injury cadaver lab: A new method of training physicians to perform fasciotomies and amputations on survivors of a catastrophic earthquake [abstract]. Ann Emerg Med 1992;21:613. 40. Noji EK: Medical consequences of earthquakes: Coordinating medical and rescue response. Disaster Management1991;4:32. 41. Better OS, Stein JH: Early management of shock and prophylaxis of acute renal failure in traumatic rhabdomyolysis. N Engl J Med1990;322:825. 42. Barbera JA, Lozano M: Urban search and rescue medical teams: FEMA task force system. Prehosp Disaster Med1993;8:349. 43. Patrick P: The American Red Cross-Centers for Disease Control Natural Disaster Morbidity and Mortality Surveillance System [letter]. Am J Public Health1992;82:1690. 44. Noji EK: Role of the Centers for Disease Control in disaster preparedness and response [letter]. Ann Emerg Med1991;20:1397. 45. Institute of Medicine-National Research Council : Chemical and Biological Terrorism: Research and Development to Improve Civilian Medical Response, Washington, DC, National Academy Press, 1999.

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Chapter 195 – Weapons of Mass Destruction[*] Carl H. Schultz Kristi L. Koenig * The views expressed in this chapter do not necessarily represent the views of the Department of Veterans Affairs or of the United States Governm ent.

PERSPECTIVE The practice of emergency medicine now has another challenge: the possibility of an attack by terrorists using nuclear, biologic, chemical, or high-explosive weapons. Although conventional explosives remain the most common weapon used by terrorists, the risk from nuclear, biologic, and chemical agents will increase over time. The nomenclature for these weapons remains controversial. Some authors have proposed the use of weapons of mass effect or weapons of mass disruption. The military uses the acronym CBRNE, pronounced “see-burn-ee” and referring to chemical, biologic, radiologic, nuclear, and explosive. This chapter uses weapons of mass destruction (WMD) because of its wide acceptance. The results of an attack with WMD, although admittedly of low probability, are potentially catastrophic. According to a World Health Organization estimate, 50 kg of anthrax spores aerosolized above a city of 5 million people would result in 100,000 deaths, with an additional 150,000 people seriously infected. The cost of managing 100,000 cases of anthrax exposure is estimated at $26 billion by the Centers for Disease Control and Prevention (CDC).[1] Given these considerations, most authorities believe that preparedness for such threats must be improved. Children are particularly vulnerable to these weapons. They breathe at a faster rate than adults, increasing their relative exposure to aerosolized agents. Some chemicals, such as sarin, are heavier than air, so tend to accumulate at the level where children are more likely to inhale them. Children have a greater surface-area-to-volume ratio and their skin is thinner. This makes them more susceptible to agents that act on or through the skin. They have smaller fluid reserves and higher metabolic rates. Therefore, they are more vulnerable to dehydration from vomiting and diarrhea and suffer increased toxicity from a given exposure, such as to I131. The use of biologic and chemical agents dates back to biblical times, although the threat from radiation and nuclear detonation is relatively new. Assyrians poisoned the wells of their enemies using rye ergot in the 6th century BC. The Mongols catapulted bodies infected with bubonic plague over the walls of Caffa in the 14th century. A British officer proposed giving American Indians blankets taken from individuals infected with smallpox during Pontiac's Rebellion in 1763. During World War I, the Germans effectively used chlorine and mustard agent against the advancing Allied armies. The Japanese killed hundreds to thousands of Chinese citizens with bubonic plague during World War II by spraying towns with fleas infected with Yersinia pestis. Saddam Hussein employed mustard agent against the Iranians during the 1980s' Iran-Iraq War. The use of WMD has been predominantly by the military during times of conflict. Recently, however, the use of these agents has taken an ominous turn. Nonaffiliated groups have begun using WMD directed at civilians to achieve political ends. The Bhagwan cult sprayed salad bars in Oregon with Salmonella in an attempt to influence an election in 1984.[2] The Aum Shinrikyo used the nerve agent sarin in an unsuccessful 1994 assassination attempt on three judges in Matsumoto, Japan. This same group used sarin again in the 1995 Tokyo subway attack that killed 11 people.[3] The United States experienced multiple anthrax hoaxes during 1997 and 1998, motivated by personal or political agendas. An actual anthrax attack using the U.S. mail occurred in the fall of 2001 and resulted in 11 deaths. The perpetrator's identity and motivation remain unknown. No one has yet used radiologic or nuclear devices in a successful terrorist attack, but at least one attempt has occurred. In addition, several highly radioactive sources have been stolen from U.S. medical facilities. Many agents are potential candidates for weaponization, and some represent a substantial risk ( Box 195-1

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). Management strategies for patients exposed to WMD are frequently similar to strategies for hazardous materials exposure. However, several features associated with WMD make these events unique ( Box 195-2 ). Additional knowledge and skills are required in the evaluation and treatment of WMD victims. These plans represent only one small part of an overall comprehensive emergency management strategy for all hazards (see Chapter 194 ). A list of departments, bureaus, and agencies that can assist with planning and response to WMD events are listed in Table 195-1 . BOX 195-1 Agents Currently Considered Likely Candidates for Use in Weapons of Mass Destruction

Chemical Nerve agents Sarin Soman Tabun VX Mustard agent

Biologic Anthrax Plague Smallpox

Radiologic Simple device Dispersal device BOX 195-2 Features of Weapons of Mass Destruction Threat

Fear Lack of training for hospital personnel Lack of equipment, including personal protection and diagnostic aids Potential for mass casualties Psychologic casualties Crime scene requiring evidence collection and interaction with FBI Potential for ongoing morbidity and mortality (dynamic situation) Table 195-1 -- Resources and Contacts for Planning and Response to Events Involving Weapons of Mass Destruction Organization

Website

Telephone

The Radiation Emergency Assistance Center/Training Site (REAC/TS) State and local health departments

www.orau.gov/reacts

865-576– 3131

www.statepublichealth.org/index.php

www.cdc.gov/other.htm#states

Page 5105

Organization

Website

Telephone

Centers for Disease Control and Prevention (CDC) www.bt.cdc.gov Federal Bureau of Investigation (FBI) www.fbi.gov

770-488– 7100

Federal Emergency Management Agency (FEMA)

www.fema.gov

U.S. Army Medical Research Institute of Chemical Defense

202-646– 4600

www.chemdef.apgea.army.mil/

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NUCLEAR AND RADIOLOGIC DEVICES Terrorists selecting radiation as a means to inflict casualties are unlikely to employ nuclear weapons. These devices are heavily guarded, difficult to move due to their size and weight, and easy to detect. Although Russia acknowledges that 50 to 100 of its 1-kiloton “suitcase” nuclear weapons are missing, the problems of purchasing, moving, and detonating these devices are formidable. Sabotage at nuclear power stations is possible, but given tight security, multiple safety systems, and thick concrete housings surrounding the reactors, the threat is probably low. Instead, simple radiologic devices, such as those used by hospitals for radiation therapy, are thought to be the source of choice. These sources are plentiful. They do not detonate on their own and give no warning of their presence, unless dispersed by a conventional explosive (radiologic dispersal device). Thefts of radiotherapy sources have occurred in the United States. Accidental dispersion from a stolen hospital therapy source in Brazil resulted in the screening of 112,000 people for contamination and found 249 exposed persons. Four ultimately died.[2] Placement of such a device at an information kiosk in a crowded mall during a busy holiday shopping season would silently expose countless persons to significant radiation. Ionizing radiation, regardless of its type, causes injury at the cellular level, usually by damaging DNA. Rapidly dividing cells are the most sensitive. Patients develop symptoms within hours to days, depending on the dose. Common syndromes associated with radiation exposure include dermal burns, bone marrow failure, and gastrointestinal dysfunction (e.g., vomiting, gastrointestinal bleeding) (see Chapter 144 ). A U.S. Department of Homeland Security task force developed an expert consensus document on medical treatment of radiologic casualties.[4] A basic emergency department radiation protocol must address decontamination, triage, staff safety, personal protective equipment (PPE), and diagnostic procedures that emphasize radiation monitoring. Victims presenting to the emergency department will suffer from three types of exposure: irradiation, internal contamination, and external contamination. Irradiated victims have been exposed to a beam of radiation, similar to someone undergoing a chest x-ray. They are not radioactive and pose no threat to emergency department personnel. Contaminated patients are more problematic, and early involvement of the radiation safety officer is critical. This individual evaluates the degree of the victim's contamination and monitors radioactivity levels throughout the decontamination process. Internally contaminated patients present a therapeutic challenge because they have radioactive material inside their bodies (lungs, gastrointestinal tract) or incorporated into their cells. They should be placed in an isolation room, where all secretions and bodily fluids can be collected. Various medications are available for administration to internally contaminated patients and can limit uptake or facilitate removal of certain radioactive elements. These medications include Radiogardase (Prussian blue) for cesium and thallium ingestions and diethylenetriamine pentaacetic acid (DTPA) for plutonium exposure. Health care providers can receive assistance by calling the Radiation Emergency Assistance Center/Training Site (REAC/TS) at 865-576-3131. Externally contaminated victims have radioactive material on their skin or clothing and are decontaminated by removal of clothing and washing with soap and water. Washing by protected personnel must continue until monitoring by the radiation safety officer demonstrates absence of radioactivity. If present, wounds are decontaminated first. After the wounds are covered with a sterile, waterproof dressing, the remaining skin is washed. Hospitals must be prepared to decontaminate patients, because historical data suggest that up to 80% of patients do not receive this intervention before arrival.[2] Decontamination before hospital entry is crucial, because these individuals can expose caregivers to radiation and contaminate the entire hospital through the ventilation system. In such cases, decontamination takes precedence over emergency care. Removal of clothing and covering the head with a surgical cap can reduce contamination by 80% to permit stabilization in the decontamination unit, but complete decontamination should occur before exposure of

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unprotected staff to the patient. Initial triage of radiation casualties is based on their overall pathologic condition, not on exposure. Even patients who have received a lethal dose of radiation do not die immediately. Therefore, a patient in acute distress from a myocardial infarction or urosepsis would be triaged ahead of a radiation victim with stable vital signs, regardless of the dose received. If a radiation casualty also suffers a severe injury or illness, immediate intervention is required. For example, most morbidity and mortality related to a radiologic dispersion device would be related to traumatic injuries from the explosion and not to radiation exposure. In addition to patient contamination, the radiation safety officer is responsible for monitoring the exposure of hospital staff. All personnel involved in the care of contaminated patients should wear dosimeters, which measure the amount of radiation received by the wearer. The safety officer tracks the amount of radiation received by each staff member and can remove a health care worker from the area if the exposure is too high. Radiation monitoring is complex, and the radiation safety officer should be involved as early as possible. Hospitals should consider conducting disaster drills that include casualties suffering radiation injuries. Although many radioactive elements are candidates for use in a terrorist attack, radioactive iodine (131I) and related isotopes deserve additional discussion because of heightened interest. 131I is found only after a nuclear detonation or in reactor fuel rods. While not impossible, the probability that terrorists could tap either of these sources is very small. The use of 131I in a radiologic dispersal device is very unlikely, owing to its short half-life (8 days). Even if such a device could be made, it is extremely unlikely that the radiologic dispersal device could disperse sufficient radioactive material to pose an immediate health hazard.[5] Given these facts, the probability that any significant exposure of the population (especially children) to 131I will occur is equally small. The large number of childhood thyroid cancers that occurred after the accident at the Chernobyl nuclear power plant was due mostly to situations that will not occur in the United States. These include delayed reporting of a breach in the reactor containment vessel preventing timely evacuation, failure to quarantine contaminated milk and vegetables, and significant iodine deficiency in the exposed children.[6] Nonetheless, concern regarding treatment to prevent thyroid cancer after potential exposure to 131I remains. Current recommendations for treatment with potassium iodide, which blocks uptake of 131I by the thyroid, are listed in Table 195-2 Caveats for using this table include increasing the amount of potassium iodide for adolescents approaching 70 kg to the adult dose (130 mg), and monitoring thyroid-stimulating hormone and free T4 levels in neonates when possible. Nonpregnant adults older than 40 years are unlikely to benefit from this intervention. Table 195-2 -- Treatment with Potassium Iodide (KI) for Radioactive Iodine Exposure Subpopulation

Predicted Exposure (rad)

KI Dose (mg)

Number of 130-mg Tablets

Adults >40 years

>500

130

1

Adults 18-40 years

≥10

130

1

Pregnant/lactating women ≥5

130

1

Children 3-18 years

≥5

65

½

Children 1 month–3 years ≥5

32

¼

Neonates, birth–1 month

16

≥5

`"

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BIOLOGIC WEAPONS By convention, biologic weapons are divided into three groups: bacteria, viruses, and toxins. A characteristic shared by these agents is their ability to be dispersed as an aerosol. Since this is the most effective means to expose a large population, aerosol dispersal is the most likely route that terrorists will use to deploy such weapons. Therefore, victims will have respiratory signs and symptoms. Dermal contact and ingestion are also potential pathways for exposure, and some agents are effective by these routes. People infected in the 2001 U.S. anthrax attack were inoculated via aerosol and dermal exposures. However, it is logistically more difficult to produce large casualty numbers using nonrespiratory portals of entry, so agents spread primarily by injection or through the gastrointestinal tract are less likely candidates for wide deployment. If the goal is to disrupt the economy or spread fear among the population, then almost any type of release will suffice, whether or not people actually die. Patients exposed to biologic agents usually present with vague symptoms associated with flulike illnesses. Unless a biologic attack is announced or suspected, the emergency department staff may not realize they are treating victims. Indeed, it is not always possible to distinguish naturally occurring from engineered outbreaks of diseases. Therefore, personnel must be vigilant and at least consider the possibility of a bioweapon exposure when warning signs are present ( Box 195-3 ). For example, large numbers of patients suddenly presenting with the “flu” not during flu season should cause concern. For these reasons, health surveillance will be paramount in identifying agents and potential sources. The emergency department must have a working relationship with local and state health departments as well as local law enforcement and stay appraised of CDC guidelines. BOX 195-3 Signs Suggesting Biologic Weapon Deployment

Syndromes Pulmonary symptoms Rashes Sepsis syndrome Influenza symptoms

Epidemiology Multiple, simultaneous events Dead animals Large patient numbers with high toxicity and death rate Several infectious agents with potential for use as biologic weapons can spread in a hospital environment. Examples include Ebola and smallpox.[] Hospitals need protocols for PPE and patient isolation to ensure a safe environment. Fortunately, such protocols are similar to those applied to other infectious diseases ( Box 195-4 ). Implementation of such precautions is credited with halting the in-hospital spread of the Ebola virus in the 1995 Zaire outbreak. Decontamination is not a priority unless the exposure is immediate. Standard (universal) precautions are generally sufficient, and special suits (e.g., levels A, B, and C) are unnecessary.[ 8]

BOX 195-4

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Recommendations for Prevention of In-Hospital Transmission of Contagious Agents

1. 2. 3. 4. 5.

Isolate patient in single room with adjoining anteroom. Have handwashing facilities and personal protective equipment (PPE) available in anteroom. Use negative air pressure if possible. Use strict barrier precautions: PPE, gowns, gloves, HEPA filter masks, shoe covers, protective eyewear. Alert hospital departments that generate aerosols: laboratory (centrifuges), pathology (autopsies).

Current assessment suggests that three biologic agents—anthrax, plague, and smallpox—represent the greatest threat.

Anthrax Bacillus anthracis, a gram-positive spore-forming bacterium, is the causative agent of anthrax (“woolsorters' disease”). The spores are extremely hardy and can survive for years in the environment. The disease is caused by exposure to the spores, not the bacilli in their vegetative state. It is normally a disease of sheep, cattle, and horses and is rarely seen in developed countries because of animal and human vaccination programs. Disease in humans can occur when spores are inhaled, ingested, or inoculated into the skin. The spores germinate into bacilli inside macrophages. The bacteria then produce disease by releasing toxins (protective antigen, edema factor, and lethal factor) that cause edema and cell death. Russia and the United States have successfully developed anthrax into a biologic weapon. The effectiveness of this agent was clearly demonstrated by two events: an accidental release of spores from a biologic weapons facility in the former Soviet Union town of Sverdlovsk in 1979 and the intentional distribution of anthrax spores through the mail along the eastern seaboard of the United States in 2001. After the Sverdlovsk release, at least 66 people died downwind from the compound during the next several weeks, and animal cases of anthrax were reported 30 miles away.[] The ability of non-state-sponsored terrorist groups to develop anthrax as a weapon is uncertain. The Japanese organization Aum Shinrikyo made several attempts to disperse anthrax throughout Tokyo without success.[1] The perpetrator of the U.S. anthrax attack remains unidentified. However, many experts speculate that this individual was not a foreign national, given that the strain of anthrax used in the attack (Ames strain) was developed by the U.S. government. Inhalational anthrax is the most lethal form of the disease and is caused by inhaling spores into the lungs. The mortality rate was thought to exceed 90%. However, the data from the 2001 anthrax exposure calls this figure into question (5 deaths in 11 cases). Although the actual mortality rate is unknown, it is probably in the 50% range.[] The minimum number of spores required to produce disease is currently unknown. The original number quoted in the literature, 10[4] spores, appears high given recent experience.[13] After phagocytosis by macrophages, the spores germinate and are transported to the tracheobronchial lymph nodes, where the bacteria multiply. Over 2 to 10 days, patients develop a flulike illness, with malaise, fever, and nonproductive cough. This initial phase can be delayed for more than a month in some patients. Within 24 to 48 hours, abrupt deterioration occurs, with overwhelming sepsis, shock, hemorrhagic mediastinitis, dyspnea, and stridor. A chest radiograph obtained at this time may show a widened mediastinum and hilar adenopathy, but typical radiographic findings are not dramatic and could be missed ( Figure 195-1 ). Computed tomography scanning of the chest is more sensitive and should be performed if the disease is suspected. Bloody pleural effusions can also occur, and examination of the lung fields frequently reveals consolidation. This can easily be confused with pneumonia ( Figure 195-2 ). Death usually results within 3 days, and 50% of patients develop hemorrhagic meningitis. Human-to-human transmission has not been reported with inhalational anthrax.

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Figure 195-1 Chest radiograph of anthrax patient showing diffuse left lung consolidation consistent with pneumonia. There is no m ediastinal widening. ((Courtesy of the U.S. Centers for Disease Control and Prevention.))

Figure 195-2 Chest com puted tom ography scan of an anthrax patient showing pulm onary consolidation and effusions. ((Courtesy of the U.S. Centers for Disease Control and Prevention.))

Initial diagnosis is generally made clinically, based on a flulike or septic illness, a suspicious chest radiograph or computed tomography scan demonstrating hilar adenopathy, infiltrates, or pleural effusions, and a reason to consider anthrax in the first place (e.g., current outbreak, warning from authorities). Several clinical algorithms exist that attempt to separate patients with influenza from those with anthrax.[] Unfortunately, they are based on a handful of anthrax cases, and their usefulness remains in doubt.[12] Sputum culture, Gram stain, and blood cultures are not helpful until late in the course of the disease. Tests to confirm the diagnosis of inhalational anthrax include the polymerase chain reaction for identification of anthrax markers in pleural fluid, serologic detection of immunoglobulin to protective antigen, and immunohistochemical testing of biopsy specimens. In addition to inhalational anthrax, dermatologic anthrax can occur in any area where large numbers of spores are released, as was the case in the United States in 2001. This form of the disease occurs when spores are introduced into the skin, usually through open wounds or abrasions. The mortality rate is approximately 20% without treatment and 1% with treatment. Antibiotics do not affect the course of local disease but are used to prevent dissemination and death. After an incubation period of 1 to 5 days, a papule develops, progressing to form a large vesicle over the next several days. Severe edema occurs around the lesion and is associated with regional lymphadenitis. The lesions are not tender, and the patient may or may not be febrile ( Figure 195-3 ). After about 1 week, the lesion ruptures, forming a black eschar (thus the name anthrax, Greek for “coal”). In the next 2 to 3 weeks, either the eschar sloughs off and the illness is over, or the organism disseminates and the patient dies. As with inhalational anthrax, the diagnosis is predominantly clinical. Confirmation is established by culturing of the lesion, punch biopsy, or serologic testing. A total of 11 cutaneous anthrax cases occurred in the United States after the 2001 attack.[16]

Figure 195-3 Child with cutaneous anthrax. ((From Roche KJ, Chang MW, Lazarus H: Im ages in clinical m edicine: Cutaneous anthrax infection. N Engl J Med 345:1611, 2001.))

A few cases of gastrointestinal anthrax and oropharyngeal anthrax are also likely after a terrorist attack. These rare manifestations usually occur with the ingestion of insufficiently cooked, contaminated meat. The mortality rate is approximately 50%. After ingestion, the spores are transported to regional lymphatic tissue, where symptoms develop after a 2- to 5-day incubation period. Patients with oropharyngeal anthrax present with sore throat and neck swelling from cervical and submandibular lymphadenitis. The tonsils also are frequently involved, and symptoms are associated with fever and toxicity. Dysphagia and respiratory distress often follow. Gastrointestinal anthrax begins with nausea, vomiting, and fever associated with mesenteric

Page 5111

lymphadenitis. Patients then experience severe abdominal pain, hematemesis, ascites, and bloody diarrhea and may present with an acute abdomen.

Treatment Traditional treatment for anthrax infection has been penicillin. However, weapons-grade anthrax is probably resistant to penicillin (although this was not the case with the U.S. attack). Current treatment recommendations reflect this fact ( Box 195-5 ).[] These consensus recommendations include fluoroquinolones and tetracycline for all children, regardless of age. Balancing the potential risks of such drugs against the consequences of infection by drug-resistant anthrax strains, the benefits justify the recommendations. Nontoxic victims with cutaneous anthrax can be treated as outpatients with oral ciprofloxacin or doxycycline for 7 to 10 days. Victims with inhalational, cutaneous, or gastrointestinal disease and toxicity require intravenous therapy with ciprofloxacin or doxycycline plus at least two other antibiotics (such as rifampin, clindamycin, imipenem, or an aminoglycoside). Patients can be switched to oral antibiotics when toxicity resolves. Other modalities that may be helpful include chest tube drainage of pleural effusions and possibly tracheal intubation and mechanical ventilation.[16] Surprisingly, the latter intervention did not improve mortality. All patients intubated after the U.S. anthrax attack died.[] BOX 195-5 Treatment for Anthrax

Cutaneous Anthrax without Toxicity Adul Cipr ts oflox acin, 500 mg PO bid or Dox ycyc line, 100 mg PO bid or Amo xicilli n, 500 mg PO tid Chil Cipr dren oflox acin, 20-3 0 mg/ kg/d ay PO divid ed bid (ma x1 g)

Page 5112

or Dox ycyc line, 4.4 mg/ kg/d ay PO divid ed bid (ma x 200 mg) or Amo xicilli n, 20-4 0 mg/ kg/d ay PO divid ed tid (ma x 150 0 mg)

All dose s give n for 7-10 days .

Inhalational, Cutaneous, or Gastrointestinal Anthrax with Toxicity Adul Cipr ts oflox acin, 400 mg IV q12 h or Dox

Page 5113

ycyc line, 100 mg IV q12 h or Peni cillin G, 4 milli on units IV q4h Chil Cipr dren oflox acin, 20-3 0 mg/ kg/d ay IV divid ed q12 h (ma x1 g) or Dox ycyc line, 4.4 mg/ kg/d ay IV divid ed q12 h (ma x 200 mg) or Peni cillin G, 100 000400 000 U/kg /day IV divid

Page 5114

ed q4h (ma x 24 × 10 6 )

All dose s give n until toxici ty resol ves. Then swit ch to oral form . Trea t for 60 days or until patie nt recei ves three dose s of vacc ine.

Postexposure Prophylaxis

Sam e drug s and dosa ge as for cuta neou s anthr ax

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witho ut toxici ty. Trea t for 60 days or until patie nt recei ves three dose s of vacc ine. Treatment must continue for 60 days or until the patient has received three doses of the anthrax vaccine, given on days 0, 14, and 28. The complete vaccine course requires 18 months. This treatment regimen is also recommended for children and pregnant women. If the anthrax strain proves susceptible, patients can be switched to intravenous penicillin or oral amoxicillin. In vitro studies suggest that ofloxacin or levofloxacin can be substituted for ciprofloxacin.[1] For postexposure prophylaxis, oral ciprofloxacin (500 mg) or doxycycline (100 mg) twice a day is recommended. Amoxicillin can be substituted if sensitive strains are identified. Antibiotic prophylaxis must continue for 60 days or until patients have received at least three doses of the vaccine. The vaccine is approved by the U.S. Food and Drug Administration for adults but not for children. A recent review by the Institute of Medicine found the vaccine both safe and effective for prophylaxis against inhalational anthrax.[17]

Plague Plague has been a human pathogen since antiquity. Many regions of the world, including Asia and India, are currently witnessing the third pandemic of plague, and this affliction is endemic in the western half of the United States. Plague is caused by Yersinia pestis, a gram-negative bacillus. It is normally a disease of rodents that is transmitted to humans through the bite of an infected flea or by inhalation. Three forms of the disease exist: pneumonic, bubonic, and septicemic plague. The bacteria do not form spores and die rapidly in the environment. However, they are viable for days in dry sputum, flea feces, and human remains. Dogs are relatively resistant to infection, but cats are highly susceptible and could form a reservoir for maintaining the disease in a human population. Recovery is followed by temporary immunity. Primary pneumonic plague results when bacilli are inhaled into the lungs. It has a mortality rate approaching 100% if not treated early. Pneumonic plague will be the most frequently encountered form of the disease, since terrorists are likely to use aerosolization as the method of dispersal. After an incubation period of 2 to 3 days, victims develop sudden onset of fever, chills, and a flulike illness. This is followed within 24 hours by a fulminant pneumonia associated with hemoptysis, systemic toxicity, respiratory failure, circulatory collapse, and death. The pneumonia is classically lobar, but any x-ray pattern is possible, including acute respiratory distress syndrome. Six to 10% of victims develop plague meningitis. Coagulation abnormalities and hepatocellular injury occur. The coagulopathy is characterized by ecchymoses, disseminated intravascular coagulation, and acral gangrene (“black death”). The gangrene is caused by bacterial production of the coagulase enzyme in areas of the body where the temperature drops below 37° C. This causes blood to clot in fingers, toes, and the nose, with resultant infarction and gangrene. If the victims survive, long-term rehabilitation is required. Pneumonic plague is transmissible human to human. Bubonic plague occurs when organisms are inoculated into the skin, usually from a flea bite. During the 2- to 3-day incubation period, the bacilli migrate to regional lymph nodes, where they multiply and cause inflammation and necrosis of lymphatic tissue, resulting in large, tender nodes, or buboes. Typically, buboes develop in the groin, axilla, or cervical region and are so painful that the patient will refrain from moving the affected area ( Figure 195-4 ). Individuals experience fever, chills, and weakness. In approximately 25% of patients, vesicles or ulcerations occur at the site of the flea bite. The buboes are usually nonfluctuant but rarely can suppurate. Organisms can be aspirated from the nodes for diagnosis, but incision and drainage is

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not recommended because the lymphadenitis resolves with antibiotic treatment, and practitioners could become infected if exposed during the procedure.

Figure 195-4 Child with bubonic plague dem onstrating axillary bubo. ((Courtesy of Frederick M. Burkle, Jr., MD, MPH.))

Over the next week or more, the bacteria disseminate in approximately 50% of patients with bubonic plague. These victims develop septicemic plague or secondary pneumonic plague and die if untreated. Those with septicemic plague experience endotoxemia, shock, disseminated intravascular coagulation, and coma. If bacteremia does not occur, most victims recover. A small percentage of those infected by fleas develop septicemic plague without detectable buboes. Direct human-to-human transmission does not occur with bubonic or septicemic plague. However, both these conditions can lead to secondary pneumonic plague, which is communicable. Therefore, initial isolation is recommended for all patients with plague.

Differential Diagnosis The preliminary diagnosis of plague is clinical. Few diseases other than plague cause fulminant gram-negative pneumonia associated with hemoptysis in previously healthy individuals. The same can be said for diseases that cause lymphadenopathy. Cat-scratch disease, tularemia, and staphylococcal or streptococcal infections are all in the differential diagnosis. However, the extremely tender nature of the lymphadenopathy and the toxicity of the patient strongly suggest plague. Once the disease is suspected, Gram stain and culture of sputum, blood, cerebrospinal fluid, or lymph node aspirate are helpful. State health departments or the CDC can test specimens for the presence of the capsular antigen using direct fluorescent antibody staining. Polymerase chain reaction also holds promise. Unfortunately, all laboratory tests require several days to complete, so initial management decisions must be based on clinical findings.

Treatment Antibiotic treatment is essentially the same for all three types of plague ( Box 195-6 ).[18] The same caveats for the use of fluoroquinolones and tetracycline in children with anthrax also apply to plague. In the case of pneumonic and septicemic plague, treatment must be started within 24 hours of symptoms to improve outcome. Antibiotics are given for a minimum of 10 days. As patients improve, oral antibiotics are substituted for intravenous therapy to complete the course. Respiratory isolation of patients with pneumonic plague is necessary for 4 days after beginning antibiotics to guarantee sterilization of sputum. Patients with septicemic and bubonic plague require isolation for 48 hours. If they do not develop pneumonia or draining lesions during this time, isolation can be discontinued. Nonseptic patients with mild bubonic plague can be treated at home with oral doxycycline or tetracycline for 10 days. BOX 195-6 Treatment for Plague

Parenteral Therapy Adul Stre ts pto myci n, 1 g IM bid Gent ami cin, 5 mg/ kg onc e

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daily IM or IV Dox ycyc line, 100 mg IV bid Cipr oflox acin, 400 mg IV bid Chlo ram phe nicol , 25 mg/ kg IV qid Chil Stre dren pto myci n, 15 mg/ kg IM bid (ma x2 g/da y) Gent ami cin, 2.5 mg/ kg IM or IV tid Dox ycyc line, 2.2 mg/ kg IV bid (ma x 200 mg/ day) Cipr

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oflox acin, 15 mg/ kg IV bid (ma x1 g/da y) Chlo ram phe nicol , 25 mg/ kg IV qid

Preg nant wom en: sam e as abov e but excl ude strep tomy cin and chlor amp heni col.

Oral Therapy Adul Dox ts ycyc line, 100 mg bid Cipr oflox acin, 500 mg bid Chlo ram phe nicol

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, 25 mg/ kg qid Chil Dox dren ycyc line, 2.2 mg/ kg bid (ma x 200 mg/ day) Cipr oflox acin, 15 mg/ kg bid (ma x1 g/da y) Chlo ram phe nicol , 25 mg/ kg qid

Preg nant wom en: sam e as abov e but excl ude chlor amp heni col. The mainstay of prophylaxis against plague remains oral antibiotics. A vaccine exists but has no value in an acute outbreak. It is effective only against bubonic disease and requires several months to impart immunity. The drugs for prophylaxis are tetracycline, doxycycline, ciprofloxacin, chloramphenicol, and possibly trimethoprim-sulfamethoxazole for children. The doses are the same as those listed in Box 195-5 , except the duration of treatment is 7 days, not up to 10 days. Levofloxacin and ofloxacin can be substituted for ciprofloxacin.

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Smallpox Smallpox was eradicated in 1980 as a naturally occurring disease. The only known repositories of the variola virus, the etiologic agent of smallpox, are in the United States and Russia. However, the Russians were successful in weaponizing the virus, which may have been sold or smuggled out of the country.[7] The effectiveness of their weaponized strain was demonstrated in 1971, when an individual became infected while traveling on a ship 15 km downwind from a Soviet bioweapons test site (Vozrozhdeniye Island in the Aral Sea).[19] In addition, most of the world's population is no longer immune to infection because vaccination against smallpox ceased 20 years ago. Given its high infectivity and lethality, this makes smallpox an excellent biologic weapon. The variola virus is spread as an aerosol. It can survive for 24 hours, possibly 48 hours, in the environment. The occurrence of smallpox in hospital employees whose only exposure was handling laundry from infected persons is testimony to its viability. Approximately 30% of exposed persons become ill. One infected person has the potential to infect up to 20 other individuals. Persons are infectious from the time the rash first appears until the scabs fall off (1-2 weeks). Anyone exposed to smallpox must be observed for 17 days to rule out infection. The disease manifests clinically in several forms. Variola major and variola minor represent 90% of the cases. Variola major is the classic form, a more severe illness with a mortality rate of 30%. Variola minor is a milder form, with less toxicity, fewer pox, and a mortality rate of 1%. Two other forms of the disease, hemorrhagic and malignant (or flat) smallpox, are seen in 10% of cases; the mortality rate is greater than 90%. Patients with hemorrhagic smallpox develop symptoms earlier and become toxic quickly. Instead of pox, their rash is characterized by petechiae and hemorrhage. Death occurs in 5 to 6 days. Those with malignant smallpox have a similar course, but their rash is characterized by soft, flattened lesions that never progress to pustules. If they survive, the lesions resolve without forming scabs. The infection begins when the virus is inhaled. After migrating to regional lymph nodes, the virus replicates for 3 to 4 days, then asymptomatically spreads to the spleen, bone marrow, other lymphoid tissue, and liver. A second viremia occurs 8 to 12 days later and is associated with fever, prostration, and headache. Mental status changes can occur. During this phase, lasting 2 to 3 days, the virus localizes to the skin and pharyngeal mucosa. A maculopapular rash soon appears, which becomes vesicular and finally pustular. The rash first appears on the face and forearms, later spreading to the legs and trunk. All the lesions in any one area of the body are the same age ( Figure 195-5 ). Over the next 8 to 14 days, the pustules crust over and separate from the skin, leaving pitted scars.

Figure 195-5 Man with sm allpox. ((From the U.S. Centers for Disease Control and Prevention Pub lic Health Im age Lib rary. http://phil.cdc.gov.ezproxy.hsclib .sunysb .edu/phil/detail.asp?id=131.))

A clinical algorithm developed by the CDC can assist in assessing the probability that an individual has smallpox. It relies on three major and five minor criteria. The major criteria are a febrile prodrome, classic smallpox lesions, and lesions in the same stage of development. The minor criteria are centrifugal distribution of pustules; first lesions on the oral mucosa, face, or forearms; toxic appearance; slow evolution of lesions; and pustules on the palms and soles. A patient with all three major criteria is at high risk and should be isolated and reported immediately. Patients with the febrile prodrome and either four minor criteria or one other major criteria are at moderate risk. Consultation with infectious disease and dermatology specialists should be sought and tests ordered to confirm varicella. If smallpox cannot be ruled out after these interventions, the patient should be treated as high risk. If a patient does not have the febrile prodrome or has the prodrome but no other major criteria and has fewer than four minor criteria, the individual is at low risk for smallpox. These patients can be managed as clinically indicated.[20]

Differential Diagnosis As with anthrax and plague, the initial diagnosis of smallpox is clinical. The other illnesses resembling smallpox include chickenpox, herpes simplex, and monkeypox (now in the differential diagnosis because of

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a recent outbreak in the Midwest). Unlike variola, the rash associated with chickenpox (varicella) is seen first on the trunk, then spreads to the extremities and face. In addition, the pustules are in different stages of evolution in any one area of the body. If the first case seen is hemorrhagic or malignant smallpox, the diagnosis will probably be missed until more typical cases present. To confirm the diagnosis, vesicular fluid or scabs were traditionally sent for electron microscopic examination. Now, polymerase chain reaction techniques appear promising for rapid viral identification, with sensitivities and specificities in the 96% to 99% range.[21]

Treatment No effective therapy currently exists for victims infected with smallpox who become symptomatic. However, potential antiviral agents, such as cidofovir, show promise. In mice exposed to a lethal cowpox challenge, administration of an oral lipid prodrug of cidofovir in modest doses once a day for 5 days produced 100% survival.[22] Vaccinia immunoglobulin (VIG) has no role in the treatment of active disease. Some practitioners suggest that most smallpox patients should be isolated at home or other nonhospital facilities, since the virus spreads easily in a hospital environment and the disease is currently untreatable.[7] The best strategy for containing the disease is vaccination of the susceptible population. Vaccinating an immunocompetent individual within 3 days of exposure will prevent or significantly ameliorate illness. Vaccination up to 7 days may prevent death. Complications from vaccination with vaccinia virus occur and can be fatal. Groups at risk for these adverse consequences include pregnant women and those with eczema, human immunodeficiency virus infection, and immunosuppressive conditions (e.g., malignancy, steroid administration, hereditary immunodeficiencies). Given the seriousness of the disease, the current recommendation is to vaccinate these individuals and simultaneously administer 0.3 mg/kg of VIG intramuscularly. For persons developing complications from the vaccine (e.g., progressive vaccinia, ocular autoinoculation, eczema vaccinatum), the dose of VIG is 0.6 mg/kg IM and is divided over 24 to 36 hours. Ribavirin can be administered but is considered experimental. VIG is not indicated for vaccinia-associated encephalitis. The smallpox vaccine supply situation has improved dramatically in the United States. The CDC now has 100 million doses of the traditional smallpox vaccine (Dryvax). These vials can be diluted 5:1 to produce a total of 500 million doses without any decrement in the vaccine's efficacy.[23] In early 2004, a British company delivered an additional 209 million doses of a second-generation vaccine derived from the same vaccinia virus used in Dryvax but grown in cell cultures. In addition, work is commencing on production of an improved modified vaccinia ankara vaccine. The virus used in the modified vaccinia ankara vaccine is so attenuated, it does not replicate in a human host. Officials hope this will make it safe for administration to immunocompromised individuals.

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CHEMICAL WEAPONS Unlike victims of biologic weapons, casualties exposed to chemical agents manifest symptoms quickly, from immediately to a few hours after contamination. Therefore, surveillance and recognition are less problematic. The challenge is decontamination and treatment. Terrorism with chemical weapons produces casualties similar to those seen in hazardous materials incidents, and medical management is comparable. However, the unique features of such events, including the volume of patients and the risk of hospital contamination, necessitate additional preparation. For example, the Tokyo subway attack using sarin in 1995 resulted in 11 deaths and more than 5000 patients converging on local emergency departments. Although the majority of these patients had subclinical exposure or psychological symptoms alone, the health care system was severely taxed. Secondary contamination by direct contact or vaporization occurred in ambulances and at the hospitals.[3] Health care facilities must have protocols in place to deal with the eventuality of chemically contaminated patients ( Box 195-7 ).[] Current recommendations for levels of PPE and types of decontamination facilities necessary in a hospital setting are inconclusive.[26] BOX 195-7 Emergency Department Preparedness for Chemical Weapons of Mass Destruction

Community-based hospital planning Personnel trained in recognition, mass casualty triage, and treatment Decontamination facility with protocols (runoff water, warm water, etc.) Personal protective equipment readily accessible and compliant with regulations Rapid access to antidotes, cyanide kits, and anticonvulsants Hospital incident management system in place Knowledge of how to access experts quickly The four basic classes of chemical agents are (1) nerve, (2) vesicant (blistering), (3) blood, and (4) pulmonary (choking). Although all have potential for use as weapons, the nerve agents and vesicants are thought to represent the greatest threat.

Nerve Agents (Sarin, Tabun, Soman, VX) Nerve agents are organophosphates. They inhibit the enzyme acetylcholinesterase, blocking the degradation of acetylcholine at the postsynaptic membrane. Acetylcholine accumulates, resulting in overstimulation of muscarinic and nicotinic receptors. Symptoms are receptor dependent. Stimulation of muscarinic receptors produces miosis, salivation, rhinorrhea, lacrimation, bronchorrhea, bronchospasm, vomiting, and defecation. The major life threat associated with this syndrome is ventilatory compromise from profound bronchorrhea and bronchoconstriction. Stimulation of nicotinic receptors produces muscle fasciculations, flaccid paralysis, tachycardia, and hypertension. Unlike typical organophosphates, exposure to nerve agents has not been associated with urination. In addition, bradycardia is rare, and miosis does not respond to systemic therapy.[9] Nerve agents also cause direct central nervous system toxicity that manifests as seizures, coma, and apnea. In survivors, residual central nervous system effects manifest as psychological changes that can last for 4 to 6 weeks. These manifestations are caused by chemical effects, not stress. A preliminary diagnosis of nerve agent exposure is based on clinical findings. Important features include

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muscle fasciculations and miosis, which are sufficient to justify treatment pending further evaluation. Diagnosis is confirmed by measuring red blood cell cholinesterase levels. This test is not readily available, however, so treatment must begin before test results are known. The nerve agents most likely to be employed by terrorists are sarin (designated GB) and VX. Sarin exists as a liquid at room temperature but represents primarily a vapor threat because of its high volatility. Symptoms occur within seconds after inhaling vapor and peak at 5 minutes. There are no delayed effects; patients remaining asymptomatic 1 hour after possible exposure have not been contaminated. They can be sent home. VX is a thick liquid with low volatility. It represents a liquid threat only. Victims generally develop symptoms after skin exposure. The median lethal dose (LD50) for VX is 10 mg, a droplet slightly larger than a pinhead. Death from doses of this size occurs in less than 30 minutes. Delayed symptoms occur, so individuals must be observed for 18 hours before potential contamination can be ruled out. Decontamination of victims exposed to sarin vapor requires only removal of clothing. Persons contaminated with VX or liquid sarin must have their clothing removed and then must be decontaminated using showers. When the level of exposure or the involved agent is uncertain, full decontamination is prudent. Responders caring for patients in the presence of liquid sarin exposure may require level A or B protective suits.

Treatment The treatment of nerve agent victims depends on the form, liquid or vapor, and level of exposure: mild, moderate, or severe ( Box 195-8 ). Three drugs are the mainstay of treatment: atropine for the muscarinic effects (improves ventilation), pralidoxime chloride (2-PAM) for the nicotinic effects (reverses paralysis), and diazepam for the prevention and treatment of seizures ( Box 195-9 ). If diazepam is unavailable, other benzodiazepines can be used. 2-PAM is most effective if administered within 4 to 6 hours of sarin exposure. After this period, the drug's impact wanes due to “aging,” defined as the permanent attachment of sarin to the acetylcholinesterase enzyme. Hypertension can occur during 2-PAM administration and is controlled by intravenous phentolamine, 5 mg for adults and 1 mg in repeat doses for children. BOX 195-8 Type and Degree of Nerve Agent Exposure

Vapor Exposure (Sarin) Mild:

Rhinorrhea and miosis

Moderate: Mild symptoms plus increased secretions, wheezing/dyspnea, muscle weakness/fasciculations, or gastrointestinal effects Severe:

Apnea, seizures, loss of consciousness, flaccid paralysis, or major involvement of two organ systems

Liquid Exposure (VX) Mild:

Localized sweating and fasciculations where a drop touches the skin; no miosis; may be delayed for 18 hours

Moderate: Gastrointestinal effects; miosis uncommon; may be delayed for 18 hours Severe:

Apnea, seizures, loss of consciousness, flaccid paralysis, or major involvement of two organ systems; occurs in less than 30 minutes at or above LD50

BOX 195-9 Treatment for Nerve Agent Exposure[*]

Vapor Mild: Observe for 1 hour, then release; no treatment Moderate: One or two Mark I kits IM or Atropine, 2-4 mg IV, may repeat every 5-10 minutes as needed, and 2-PAM, 1g IV over 30 minutes, may repeat every hour as needed Severe: Three Mark I kits IM and one diazepam autoinjector IM or Atropine, 6 mg IV, may repeat 2 mg boluses IV every 5-10 minutes, and 2-PAM, 1g IV over

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30 minutes, repeat every hour for total of 3 g, and diazepam, 5 mg IV, may repeat as needed

Liquid Mild:

One Mark I kit IM or Atropine, 2 mg IV, and 2-PAM, 1 g IV over 30 minutes

Moderate: Same as for vapor Severe:

Same as for vapor

Pediatric Doses Atropine, 0.02 mg/kg IV 2-PAM, 15 mg/kg IV over 20-30 minutes Diazepam, 0.2-0.3 mg/kg IV * Give atropine before attempting intubation. Otherwise, airway resistance will inhibit ventilation. Continue atropine until secretions are dry (usually ≤20 m g). In hypoxic patients, IV atropine has been reported to cause ventricular fibrillation, so consider using IM atropine.

An autoinjector kit (Mark I) approved by the Food and Drug Administration consists of two cartridges, one containing atropine (2 mg) and the other 2-PAM (600 mg). Mark I kits are available as part of civilian pharmaceutical caches strategically located throughout the United States. An autoinjector containing 10 mg of diazepam also is available. Doses should be adjusted for pediatric and elderly patients. Using the Mark I kits to treat these populations can be problematic because of difficulty in adjusting the dose. An alternate solution is to inject the medication into a sterile vial. The drug can then be reaspirated in an appropriate amount for the patient's weight or age and administered.[27]

Vesicants (Mustard) Vesicants (blistering agents) are chemical warfare agents that induce blister formation when contacting skin. Terrorists could use several of these compounds, but mustard is considered the chemical of choice. Mustard is a liquid at room temperature but has both liquid and vapor toxicity. Injury from mustard exposure occurs in 1 to 2 minutes, but symptoms do not develop for 4 to 8 hours. The exact mechanism is unknown, but the agent damages DNA, causing eventual cell death. Mustard has both local and systemic toxicity. Local effects occur from direct exposure to the skin, eyes, and airway. Systemic effects result from the impact of absorbed mustard on the bone marrow. Treatment is supportive and includes decontamination (to prevent secondary contamination) and airway maintenance. Although no specific antidote for mustard is currently available, a topical iodine preparation shows promise. When applied within 1 hour after mustard exposure to the skin of guinea pigs, an iodine-tetraglycol solution reduced vesicle formation and signs of inflammation.[28] Application more than 1 hour after exposure was not effective. Eye damage from mustard exposure varies from conjunctivitis to corneal ulcer and perforation; however, only 1% of patients have permanent eye damage. Severe pain is frequently associated with mustard injury and causes significant blepharospasm. Irrigation is beneficial if performed within minutes of exposure but ineffective once symptoms occur. Standard treatment includes mydriatics, topical antibiotics, oral analgesics, and petroleum jelly applied to the lids to prevent adhesions. Topical steroids are indicated only within the first 24 hours. The hallmark of mustard injury is skin blisters resembling second-degree burns. Within 4 to 8 hours of exposure, erythema and burning occur, followed by vesicle and bulla formation. Most vapor injuries do not involve the entire dermis, so wounds will not require skin grafting. If liquid exposure occurs to skin, full-thickness burns may result. The patient should be decontaminated by removing clothing and washing with water or a dilute bleach (1:10 hypochlorite) solution. Decontamination immediately after exposure prevents further injury to the patient, but delayed decontamination is indicated to protect staff. Treatment is supportive and includes standard burn wound management, analgesia, and tetanus prophylaxis. An important exception is fluid resuscitation. Fluid losses from mustard injury are much less than those associated with thermal burns. Therefore, standard burn formulas for fluid administration do not apply, and caution must be used to avoid overhydration.

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The degree of airway injury after mustard exposure is dose dependent. Mild exposure causes irritation of the nose, sinuses, and pharynx and can be treated with cool, humidified mist. Moderate exposure extends to the larynx and upper trachea and may require treatment with oxygen, continuous positive airway pressure, or even intubation. Severe exposure involves the lungs, producing hemorrhagic necrosis of the bronchioles. Pulmonary edema is rare. Intubation is usually required, and patients may benefit from positive end-expiratory pressure and in-line bronchodilators. Steroids are of questionable benefit, and antibiotics should only be given for established infection. Systemic toxicity from mustard is caused by bone marrow suppression. Absorbed mustard kills stem cells, causing the white blood cell count to fall after 3 to 5 days. Survival is rare if the white blood cell count falls below 200, which generally occurs when greater than 50% of the total body surface area is involved from exposure to liquid agent. Death after mustard exposure usually results from secondary infection.

Blood Agents (Cyanide) Blood agents such as cyanide bind to cytochromes within mitochondria and inhibit cellular oxygen use. Low-dose exposures result in tachypnea, headache, dizziness, vomiting, and anxiety. Symptoms subside when the patient is removed from the source. At higher doses, the symptoms progress to seizures, respiratory arrest, and asystole within minutes of exposure. Victims should be removed from the area, should have their clothing discarded, and should receive oxygen. If no improvement occurs, the cyanide anti-dote is given (amyl nitrate, sodium nitrite, sodium thiosulfate).

Pulmonary Agents (Phosgene, Chlorine) Pulmonary or choking agents cause an inflammatory reaction when they come into direct contact with the eyes and upper airway. They can be life threatening if inhaled. No specific antidote exists. Treatment is mainly supportive and consists of removing the patient from the source, decontamination, airway maintenance, bronchodilators, and eye irrigation.

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KEY CONCEPTS {,

{, {, {, {, {, {,

Emergency department preparedness for a radiation incident must address decontamination (an external, free-standing decontamination unit is best), triage, staff safety, PPE, and diagnostic procedures that emphasize radiation monitoring. The emergency personnel should make sure they know their radiation safety officer. Management of acute, life-threatening conditions takes priority over radiation-associated issues. Aerosol dispersal is a likely route that terrorists will use to deploy biologic weapons, so victims will present primarily with respiratory complaints. In addition to “flulike” symptoms, anthrax typically causes mediastinal widening, pulmonary consolidation, and pleural effusions best seen on chest computed tomography scans. Smallpox can spread in a hospital environment; thus, patients suspected of having smallpox should be admitted to locations separated from the rest of the hospital. Decontamination is a key activity in the management of patients exposed to chemical agents, and hospitals must provide this intervention. Nerve agents are organophosphates, and patients exposed to these agents are treated with large doses of atropine, repeated frequently, and pralidoxime.

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REFERENCES 1. Inglesby TV: Anthrax as a biological weapon: Medical and public health management. JAMA 1999;281:1735. 2. Domestic Preparedness Training Program: Hospital Provider Manual, Edgewood Arsenal, Md, Chemical and Biological Defense Command, 1999. 3. Okumura T: Report on 640 victims of the Tokyo subway sarin attack. Ann Emerg Med1996;28:129. 4. Koenig KL, Hatchett R. (eds.) Department of Homeland Security Working Group on Radiological Dispersal Device (RDD) Preparedness, Medical Preparedness and Response Sub-Group: Medical Response to Radiologic Casualties, May 2003. Available at http://www.va.gov/emshg . 5. Guidance for Protective Actions following a Radiological Terrorist Event: Position Statement of the Health Physics Society, Mclean, Virginia. Available at http://hps.org/hpspublications/papers.html#position January 2004 Accessed February 24, 2004. 6. Balk S, Miller RW: FDA Issues KI Recommendations. AAP News2002;20(3):99. 7. Henderson DA: Smallpox as a biological weapon: Medical and public health management. JAMA 1999;281:2127. 8. Schultz CH, Mothershead JL, Field M: Bioterrorism preparedness I: The emergency department and hospital. Emerg Med Clin North Am2002;20:437. 9. Friedlander AM: Anthrax. In: Zajtchuk R, Bellamy RF, ed.Textbook of Military Medicine, Washington, DC: Office of the Surgeon General, US Army; 1997: 467-478. 10. Dixon TC: Anthrax. N Engl J Med1999;341:815. 11. Jernigan JA: Bioterrorism-related inhalational anthrax: The first 10 cases reported in the United States. Emerg Infect Dis2001;7:933. 12. Schultz CH: Chinese curses, anthrax, and the risk of bioterrorism. Ann Emerg Med2004;43:329. 13. Centers for Disease Control and Prevention : Update: Investigation of Bioterrorism-Related Inhalational Anthrax—Connecticut, 2001. MMWR Morb Mortal Wkly Rep2001;50:1029. 14. Hupert N, Bearman GML, Mushlin AI, Callahan MA: Accuracy of screening for inhalational anthrax after a bioterrorist attack. Ann Intern Med2003;139:337. 15. Kuehnert MJ: Clinical features that discriminate inhalational anthrax from other acute respiratory illnesses. Clin Infect Dis2003;36:328. 16. Conference Summary: Clinical issues in the prophylaxis, diagnosis, and treatment of anthrax. Emerg Infect Dis2002;8:222. 17. Joellenbeck LM: The anthrax vaccine—Is it safe? Does it work? Committee to Assess the Safety and Efficacy of the Anthrax Vaccine, Washington, DC: Institute of Medicine, National Academy Press; 2002: 288. Available at http://www.nap.edu.ezproxy.hsclib.sunysb.edu/catalog/10310.html Accessed February 26, 2004. 18. Inglesby TV: Plague as a biological weapon: Medical and public health management. JAMA 2000;283:2281. 19. Tucker JB, Zilinskas RA: The 1971 Smallpox Epidemic in Aralsk, Kazakhstan, and the Soviet Biological Warfare Program. Occasional Paper No. 9. Chemical and Biological Weapons Nonproliferation Project, Center for Nonproliferation Studies, Monterey Institute of International Studies, Monterey, California, July 2002. 20. Evaluating patients for smallpox: Acute, generalized vesicular or pustular rash illness protocol. Available at http://www.bt.cdc.gov.ezproxy.hsclib.sunysb.edu/agent/smallpox/diagnosis/pdf/spox-poster-full.pdf Accessed February 27, 2004. 21. Sofi IM: Real-time PCR assay to detect smallpox virus. J Clin Microbiol2003;41:3835. 22. De Clercq E: Cidofovir in the therapy and short-term prophylaxis of poxvirus infections. Trends Pharmacol Sci2002;23:456. 23. Frey SE: Clinical responses to undiluted and diluted smallpox vaccine. N Engl J Med2002;346:1265. 24. Macintyre AG: Weapons of mass destruction events with contaminated casualties: Effective planning for health care facilities. JAMA2000;283:242.

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25. Burgess JL: Emergency department hazardous material protocol for contaminated patients. Ann Emerg Med1999;34:205. 26. Koenig KL: Strip and shower: The duck and cover for the 21st century. Ann Emerg Med2003;42:391. 27. Henretig FM, Mechem C, Jew R: Potential use of autoinjector-packaged antidotes for treatment of pediatric nerve agent toxicity. Ann Emerg Med2002;40:405. 28. Wormser U: Topical iodine preparation as therapy against sulfur mustard-induced skin lesions. Toxicol Appl Pharmacol2000;169:33.

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Marx: Rosen's Emergency Medicine: Concepts and Clinical Practice, 6th ed., Copyright © 2006 Mosby, Inc.

PART SEVEN - The Practice of Emergency Medicine Section I - Clinical Practice and Administration Chapter 196 – Guidelines in Emergency Medicine J. Stephen Bohan The essential daily work of the emergency physician consists of only three areas: acquiring data, making decisions, and performing procedures. Numerous other tasks are associated with each patient visit but none requires professional medical expertise. Because of the many reasons for emergency department visits, the level of thought or decision making required varies accordingly. A few presentations (e.g., cardiac arrest, apnea) require almost reflexive action, after which further thought is required. Most visits require only a modest amount of information and rule-based action. As the population ages and is sustained by medical advances, the practice of emergency medicine is evolving from caring for relatively simple conditions (e.g., injuries, asthma, minor gastrointestinal complaints) to dealing with much more complex problems (e.g., altered cognition, medication interactions, multisystem failure). Decision making in this setting changes as well, moving from rule-based to integrative, employing substantive probabilistic reasoning. The patient history dictates the course of the visit and directs all subsequent evaluation. The form of the patient's delivery of the history (e.g., coherent, interrupted by need to breathe, “raced”) is as important as the content. Hypotheses are constantly formed and rejected by the interviewer during this process as the elements of the history are fed into and integrated with the database in the clinician's mind. This is an imperfect process for a variety of reasons. The story may be incomplete (in fact, an essential part of the assessment is to judge the level of completeness) and expressed in unfamiliar terms, tempered by gender or ethnicity, or affected by emotional or physical pain. The physician's knowledge base may also be inadequate. The data on even the most common diseases and interventions are often ambiguous and may be derived from a patient base outside the emergency department. Even the best evidence gleaned from careful studies is often outdated at the time of publication or made irrelevant by the interim development of new medicines or tests. Finally, questions answered by research projects are not often the clinical question, for example, “Does this patient have coronary heart disease?” versus “Is it safe to send this patient home?” Physicians acquire experience over time, which becomes the filter for information received and sent in the integrative process. More experience reduces the amount of information received and the number of hypotheses generated. Hypothesis selection is equally hampered by the lack of complete follow-up data. Emergency physicians may not be aware of the outcome of admitted patients and often do not know the outcome of discharged patients. These impediments are largely structural, inherent in the nature of the clinical practice in an area of expanding knowledge. Adding to the increasing complexity of emergency medicine is the format of the patient-doctor interaction. In this multiple simultaneous patient model, the number of data sets to be

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managed grows proportionally but the capacity of the human mind to deal with them does not. To deal with many data sets, physicians seek guidance from external sources, traditionally drawing from texts and teachers. Statements of authorities remained the only decision-making aids for millennia. Aggregation of expert opinions into consensus statements has a relatively short tradition in this country, dating from 1938 when the American Academy of Pediatrics published recommendations for management of infectious diseases.[1] Advances in science and technology since 1938 have created the demand for better decision-making aids. Some of these tools are cumbersome to use (e.g., differential diagnosis programs) and thus not of practical use to the emergency physician, whereas others (e.g., electrocardiographic interpretation programs in electrocardiographic machines) are simple and useful.

GUIDELINES Published statements that make recommendations for action go by various names: clinical policy, pathway, guideline. These are often used interchangeably. Generically, they are “systematically developed statements to assist practitioners and patient decisions about appropriate health care for specific clinical circumstances.”[2] Clinical decision rules are related recommendations that can be included in guidelines. In general, the word policy carries the connotation of an inflexible rule, pathway suggests some time element, and guideline implies a recommendation. Guidelines can be applied to diagnostic or therapeutic interventions and often contain reminders about elements necessary before making a decision (e.g., contraindications). At best, these documents are distillations of evidence and expert opinion supporting practices that have been shown to improve patient outcomes. At their worst, they are amalgamations of opinion often dubious in origin and execution, colored by political interests and of unproven benefit. Guidelines have remarkable potential to benefit the patient-physician encounter.[3] They can promote interventions of proven benefit and discourage ineffective measures. They have the potential to reduce morbidity and mortality and to benefit health outcomes. They can reduce variation in practice, allowing optimal outcomes irrespective of which practitioner is consulted or where the consultation takes place. Guidelines can provide explicit recommendations when uncertainty exists about which test or treatment is best. This assistance can substantially reduce emergency physicians' intellectual and emotional burden. Guidelines provide the basis for consensus building on the quality of the activity or endeavor. Quality improvement activities can then focus on adherence to or deviation from best practices. Adherence strongly affirms commitment to quality. Guidelines may be inadequately or improperly developed, promoting untested or unproven interventions and encouraging ineffective or harmful care. Contradictory recommendations can be the source of conflict between patient and physician or among treating physicians. Guidelines may be overly influenced by opinion and may have goals other than patient benefit. Inflexible guidelines may serve the needs of populations but not the needs of the individual patient. A lack of flexibility can also disrupt the physician-patient relationship. Patients may interpret a guideline as an absolute and feel deprived of a test or treatment that is actually not suitable for their individual circumstance. Even if the content is coherent and reliable, guidelines may be poorly expressed or cumbersome to use and distracting to the user. Their presence may prevent the physician from considering alternative causes for symptoms or the patient's preferences. Guidelines may increase resource consumption or, when used for political advocacy, result in an inappropriate reallocation of resources. Lingering behind every guideline, despite disclaimers, is the threat of its use for legal purposes. Despite these concerns, guidelines are proliferating at a rapid rate and becoming embedded in clinical practice. The decision to use a guideline is usually multifactorial. Commonly cited reasons are reduced variation, improved efficiency, improved heath outcomes, reduced costs, or some combination of these. Successful use of guidelines requires clear recognition and acknowledgment of the reason to use them.

Development The first step is to choose whether to develop a new guideline or adopt an already existing one. As guidelines become more sophisticated, their development becomes more difficult and is often beyond the scope of competence of a single individual. The skills of the group assembled must be multifaceted and include the following: (1) literature search and retrieval, (2) epidemiology, (3) biostatistics, (4) health services research, (5) clinical practice, (6) group process, and (7) writing and editing.[4]

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This group must be able to assess the nature of the evidence, the applicability of the evidence to the population of interest, and the fiscal implications of recommendations, including cost benefit and cost-effectiveness. Health policy expertise is required to assess the effect of the guideline on the health system. The group of experts needs both technical and administrative support to be effective. A checklist of the essential characteristics of valid guidelines has been assembled by an expert group.[5] The question to be answered (e.g., “What should the practitioner do in this situation?”) needs to be explicitly stated and highly refined, as do the questions that relate to the intermediate steps. Evidence that will form the answer to the questions must be gathered, assessed, graded, and translated into recommendations with each step guided by explicit criteria. There are several schemes for grading evidence and assessing the strength of recommendations, none proven better than another. The one most commonly used in the emergency medicine literature is that employed by the American College of Emergency Physicians. The literature on which recommendations are based is rated as class 1, 2, or 3 depending on the quality of the study and its applicability to the question at hand. The best evidence (class I) is that drawn from randomized trials and meta-analyses of such trials. The Cochrane Library (www.cochrane.org ) is a repository of such trials and analyses. The recommendation is then made and given a “strength” rating of level A (a high degree of certainty based principally on class 1 evidence), level B (a moderate degree of certainty as the result of mostly class 2 evidence), or level C (based on absent, inconclusive, or conflicting evidence).[6] The American College of Cardiology (www.ACC.org ), working with the American Heart Association and the European Society of Cardiology, has developed a variety of guidelines for care of conditions, some of which are particularly relevant to emergency medicine practice. Their development process is rigorous and includes members of other specialties and community practitioners.[] While the levels of evidence approximate those of the American College of Emergency Physicians, the classes of recommendations differ significantly, being distributed over four levels, the last being “not useful/effective and may be harmful” ( Figure 196-1 ). A summary ( Figure 196-2 ) shows how these levels of evidence (“precision of estimate of treatment effect”) relate to the classes of recommendations (“size of treatment effect”) and demonstrates how the two elements come together to form a recommendation for best practice.

Figure 196-1 Classes of recom m endations and level of evidence used in Am erican College of Cardiology/Am erican Heart Association clinical practice guidelines. RCT, randomized controlled trial. ((From Gib b ons RJ, Sm ith S, Antm an E: Am erican College of Cardiology/Am erican Heart Association Clinical Practice Guidelines: Part 1: Where do they come from ? Circulation 107:2979, 2003.))

Figure 196-2 A sum m ary shows how levels of evidence (precision of estim ate of treatm ent effect) relate to the classes of recom m endations (size of treatm ent effect) and dem onstrates how the two elem ents com e together to form a recom m endation for best practice. ((From Gib b ons RJ, Sm ith S, Antm an E: Am erican College of Cardiology/Am erican Heart Association Clinical Practice Guidelines: Part 1: Where do they com e from ? Circulation 107:2979, 2003.))

After the evidence is gathered and collected, there will be gaps in the knowledge base required to make recommendations. The method for incorporating opinion to fill these gaps needs to be made explicit, lest the

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process be suspect for bias. Finally, the guideline needs to have external review for content validity, clarity, and applicability.

Clinical Decision Rules “A Clinical Decision Rule (CDR) is a clinical tool that quantifies the individual contributions that various components of the history, physical examination, and basic laboratory results make toward the diagnosis, prognosis, or likely response to treatment in a patient.”[9] CDRs are an attempt to guide clinicians by simplifying and improving diagnostic accuracy and efficiency. Central to their development and use is their ability to establish pretest probability if certain conditions are met. This allows an estimate of risk for performing or not performing an action. Prior to use, CDRs need to be validated in multiple settings and their impact needs to be assessed, including their ease of use, rate of use, and effect on patient satisfaction.[10] CDRs are ranked as level 1, 2, or 3 depending on their compliance with these standards.[9] The Ottawa Ankle Rules is the only CDR to meet level 1 criteria. Other rules applicable to emergency medicine that have the potential of reaching level 1 and having a significant impact on practice habit are the San Francisco Syncope Rule,[11] the Canadian Head CT Rules,[12] the Canadian C Spine Rules,[13] and the NEXUS C Spine rule,[14] the latter two of which have been tested against each other.[15]

Sources and Adoption The process of developing a guideline is dependent on the physical and fiscal capability (up to $1.2 million) of large organizations.[5] As a result, most smaller organizations (individual hospitals and professional groups) adopt guidelines already developed by other organizations. This process, while simpler and quicker, must be no less careful. There are multiple sources and repositories of guidelines developed by government agencies, professional organizations, and individual institutions. Searches for guidelines should start with published databases and websites of the repositories ( Table 196-1 ). The American Medical Association publishes a compendium, which now contains more than 1800 policies contributed by more than 75 different organizations.[16] This compendium also delineates attributes that can guide the development and evaluation of practiced guidelines. Table 196-1 -- Finding Guidlines Databases Medline

“guideline” (publication type)

Healthstar

“Consensus Development Conference” (publication type)

EMBASE

“practice guidelines” (subject heading)

Websites www.ahrq.gov

Agency for Healthcare Research and Quality (formerly AHCPR)

www.guideline.gov

National Guideline Clearing House

www.acep.org

American College of Emergency Physicians

www.acc.org

American College of Cardiology

www.mssm.ecu

Mount Sinai School of Medicine

www.east.org

Eastern Association for the Surgery of Trauma

The National Guideline Clearing House ( Table 196-2 ) is a repository and also offers comparisons of various guidelines on the same subject. The comparison of guidelines on pharyngitis is particularly illustrative, highlighting the various classifications of evidence used and noting the similarities and differences in recommendations and their implications. Table 196-2 -- Classificaton Schemes for Standards of Evidence in Emergency Medicine

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Recommendation Schema I Class I Always acceptable, safe

Level of Evidence

One or more large prospective studies are present (with rare exceptions)

Definitely useful Proven in both efficacy and effectiveness Study results consistently positive and compelling Must be used in the intended manner for proper clinical indications Class IIa Safe, acceptable Generally higher levels of evidence Clinically useful Results are consistently positive Considered treatment of choice Class IIb Safe, acceptable Generally lower or intermediate levels of evidence Clinically useful Generally, but not consistently, positive results Considered optional or alternative treatments Class III Unacceptable No positive high-level data Not useful clinically Some studies suggest or confirm harm May be harmful Intermediate Continuing area of research Evidence not available No recommendations until further research Higher studies in progress Results inconsistent, contradictory Results not compelling Schema II Evidence-Based Standards Generally accepted principles for patient Strength of Evidence A—Interventional studies management that reflect a high degree of clinical including clinical trials, observational studies certainty (i.e., based on “strength of evidence A” or including prospective cohort studies, aggregate overwhelming evidence from “strength of evidence B” studies including meta-analyses of randomized studies that directly address all the issues). clinical trials only. Guidelines Recommendations for patient management that may Strength of Evidence B—Observational studies identify a particular strategy or range of management including retrospective cohort studies, strategies that reflect moderate clinical certainty (i.e., case-controlled studies, aggregate studies including based on “strength of evidence B” that directly meta-analyses. addresses the issue, decision analysis that directly addresses the issue, or strong consensus of “strength of evidence C”). Options Other strategies for patient management based on Strength of Evidence C—Descriptive cross-sectional preliminary, inconclusive, or conflicting evidence, or, studies, observational reports including case series, in the absence of any published literature, based on case reports; consensual studies including panel consensus. publishing panel consensus by acknowledged groups of experts. Data in Schema I modified from American Heart Association by Pinnacle Publishing; data in Schema II from the American College of Emergency Physicians in its clinical policies.

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The Eastern Association for the Surgery of Trauma produces exceptionally detailed and rigorously supported guidelines for management of trauma patients.[17] Once obtained, the guideline should be assessed for validity. The methods for such assessments are published.[18] If the criteria for validity are comprehensive and rigorous and include not only the content but also explicitness about the development process, most published guidelines will not meet this standard. Fifty percent of a selection of guidelines developed in 1997 did not meet standards set by experts in guideline development. Only 40% specified outcomes of interest, and none met all 25 criteria for adequacy.[19] Adoption should incorporate modifications to meet local needs, acknowledging any changes in strong recommendations. Attention should be paid to the reference population and how closely it mirrors the population (both of care givers and care receivers) to whom it will be applied.[20] The American College of Emergency Physicians is explicit as to the “Scope of Application,” “Inclusion,” and “Exclusion Criteria” for its clinical policies.[6] Guidelines should be reassessed for validity every 3 years.[21]

CONCEPT TO PRACTICE: CLINICAL PATHWAYS Clinical pathways, also known as critical paths, critical pathways, care paths, or care maps, are the translation of guidelines into locally developed, functional tools that guide the process of care. They are the link between the establishment of a guideline and its use, usually employing printed management plans that display goals for patients and provide the sequence and timing of actions necessary to achieve these goals with optimal efficiency.[] They have their origin in industrial management, where they are employed to increase efficiency in manufacturing by reducing variance. The focus is on the rate-limiting step in the manufacturing process. Pathways differ from protocols in that the single purpose of protocols is to monitor and increase adherence to guidelines. Protocols often are often aimed at improving the quality of the care while pathways are predominately directed at promoting efficiency and reducing cost. Pathways are further distinguished by an element of constant monitoring and data evaluation intended to study not only compliance with the recommended action but also the process that links one action to another.[24] Since the process of care involves a variety of professional and nonprofessional staff, the development of pathways is characteristically multidisciplinary. The course of development for a pathway is similar to that of guidelines with the convening of a group, isolation of the issue to be addressed, gathering the evidence, reaching consensus, publication, and pilot implementation. A comprehensive description of one emergency department's experience, including examples of documentation tools, is available.[25] In their most sophisticated expression, clinical pathways describe the tasks to be performed, timing and sequence of these tasks, and the people responsible for completing the task. This document is part of the patient's record. The goals here are simplicity, efficiency, increase in communication among members of the team, reduction of variation, and ease of audit. Often the record demands explanation of variance. Clinical pathways have been an instrument in guiding and measuring emergency departments' response to the emergence of time-dependent therapies, particularly vascular emergencies. When goals such as “door to open artery time” become a standard, the response to such patients needs to be reworked and measured. Clinical pathways are important tools in achieving and maintaining a timely response, particularly when the description of the steps, the statement of important time intervals, and the necessary documentation are in a single document ( Figure 196-3 ). A

B

C

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Figure 196-3 Pathway (A) and standardized order set (B, C) for managem ent of acute coronary syndrom es with interventions supported by evidence annotated as “strong consideration.” ((From Herzog E, et al: The PAIN pathway as a tool to b ridge the gap b etween evidence and m anagem ent of acate coronary syndrom e. Critical Pathways in Cardiology 3:20, 2004.))

Clinical pathways are subject to the same criticism as guidelines in general: the tension between structure and flexibility, the surreptitious setting of “standards of care,” and the demand for explanations of variance. Pathways carry the cost of development and implementation, are even less frequently validated than guidelines, and appear better suited to simple straightforward problems (e.g., procedures) than to complicated medical cases.

IMPLEMENTATION AND OUTCOMES Before any beneficial outcome can be achieved, the guideline, pathway, or clinical decision rule must be used, and while the development or adoption of a guideline does not require a change in behavior, behavioral change is necessary for individuals to use and adhere to the guideline.[] The literature is replete with failed efforts to achieve such change, which has brought attention to implementation. Simple dissemination is ineffective in modifying behavior in any meaningful way.[] Even more elaborate strategies often fail.[8] For example, the Joint National Committee on Hypertension first published its recommendations in 1977 and is currently on the seventh iteration of its guideline for management of blood pressure. Its recommendations are supported by the strongest of evidence. When primary care physicians were surveyed about their knowledge of the guidelines, about 40% of respondents were unaware of the guidelines. Of those who were aware, 75% stated that they would behave differently than the recommended guideline.[31] Emergency physicians failed to adhere to evidence-based guidelines for the treatment of “isolated benign headache” 75% of the time.[32] One could assume that this was due to lack of awareness of the existence or content of the guideline, but the above-referenced study would belie that assumption. This problem is not isolated to large national efforts. Dealing with only one intensive care unit, one group spent 4 months educating the staff on a version of guidelines for use of sedative and paralytic drugs based on the evidence-based guidelines of the Society of Critical Care Medicine. On review, only 23 of 100 consecutive patients were treated in a manner consistent with the guidelines. Expanding the definition of compliance to include even partial compliance yielded only 58% treated in a compliant manner. The majority of practitioners actually thought they were following the guidelines.[33] In managing cystitis, a managed care organization was successful in reducing resource use (urine analysis and high cost antibiotics) by shifting the central point of care away from the physician to a nurse, holding small group discussions, providing opinion leaders as educators and educating the (closed panel) patient population. They also pilot-tested the guideline to establish its acceptability and practicality. Despite these efforts, the guideline was not used in 47% of patient cases.[34] The Ottawa Ankle Rules present a sobering example: “Clinicians expert in the use of the Ottawa Ankle Rules trained 16 other individuals to teach the use of the rules. These individuals returned to their Emergency Departments armed with slides, overheads, a 13 minute instructional video, and a mandate to train their colleagues locally and regionally in the use of the rules. Unfortunately, this program led to no change in the use of radiography.”[9] Despite one expert's apparently justified pessimism (“Modification of physician behavior has proven to be so daunting that no durable resolution of this problem seems likely in the near term.”), successful implementations do occur.[] Strategies that have been shown to achieve at least limited success in changing physician behavior require intensive and broad-reaching use of resources (The Cochrane Library contains the collection of literature on this subject in The Cochrane Effective Practice and Organization of Care Group). Multiple dimensions, both internal (knowledge, attitude, and behavior) and external (barriers), need to

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be addressed.[] All concerned parties need to be involved, barriers need to be identified and removed, reminders need to be regular and appropriately timed, and social influence used. “Academic detailing” is of demonstrated utility, as are public statements by opinion leaders.[39] Marketing of guidelines can be directed to the patient as well as the physician, a strategy with successful precedent in the direct-to-patient advertisements of pharmaceutical companies. In some form and in some circumstances, the following have been effective in changing behavior: remuneration; restriction of resources (e.g., no expensive antibiotic without ID consult); and practice aids, including chart (paper or computer) reminders or different charting forms and chart audit.[39] Postimplementation interviews can be particularly revealing. Using computer-based order entry systems has been particularly effective. Compliance with a guideline for unstable angina was associated with dramatically improved outcomes.[40] However, this association was not directly linked to dissemination of the guideline as distinct from changes in practice made for other reasons. A group of physicians practicing in urgent care clinics of a large health system radically altered the number of hospital admissions in patients with community-acquired pneumonia when provided with an 8 × 11 inch form that required only summing “risk factors” to arrive at recommendations.[41] A home nurse visit was also made available and the logic was pilot-tested before implementation. The form was used in 90% of cases and admissions were halved without any increase in mortality. The simplicity of the decision aid was noted in an analysis of the high compliance rate. However, the relative effect of the use of the guideline as opposed to the availability of the home nurse was not assessed. This beneficial effect of the provision of simple tools has been confirmed in a controlled multihospital myocardial infarction care effort. Care measures were improved overall compared to nonintervention hospitals, but all of the benefit came from those who used the “tool kit” provided.[42] In an emergency department where symptom-based (as opposed to diagnosis-based) order sets and pathways resulted in fewer tests, fewer admissions, and shorter emergency department stays for subject patients compared to both historical controls with the same symptom presentation and contemporaneously when compared to symptoms not being studied.[43] None of these successes have been tested for persistence of effect, nor were cost-benefit analyses done. Norway, with a national hospital system, was successful in implementing a management guideline for mild head injuries and attributed the success of the project in part to targeting medical students and trainee physicians, as opposed to established practitioners, supporting the contention of the “old horse/new tricks” cliché.[44] The conclusion is that interventions need at the very least to be focused, multimodal, easy for the user, and possibly accompanied by restrictions. They should be pilot-tested as well as accompanied by some reward, even if that is only feedback. Success may depend on the subject matter and the characteristics of the subject group, including demographics, qualifications, and even learning styles.[45] “…Even carefully designed educational interventions may not achieve the magnitude of change in behavior that was expected…. Practice behavior seems to be influenced by a wide range of factors other than research evidence.”[46]

COMPUTER-BASED PROTOCOLS The 4th century Greek philosopher Plato, in discussing the nature of political leadership, distinguished between task-based jobs and jobs centered on expertise, emphasizing flexibility and improvisation.[47] Using physicians as an example, he assessed the effect of codifying consensus and making it a rule. He concluded that it would be less than satisfactory because the rule would presuppose an average patient, not the individual sitting before the physician. This same reservation has resurfaced 17 centuries later.[48] Additionally, the mode of the rule would reflect the thinking of the developer, not the thought processes of the clinician. This tension between constraint and freedom, between best practice and clinical judgment, remains today as one of the major impediments to successful implementation of guidelines. The challenge lies in reducing the opportunity for variability while simultaneously making allowances for patient individuality. Computers can go a long way in achieving this concept of “flexibility within boundaries.” Such a system has been demonstrated in the treatment of critical care unit patients, both in their need for hemodynamic support and in treatment of respiratory failure.[49] Decision support protocols are built into the computer order entry system at the patient's bedside. This system receives real-time physiologic data from

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monitoring equipment. The protocol is driven by the patient's physiologic parameters, and inappropriate options are not offered. No alternative method of entering orders exists, although overrides are possible, necessitating, however, an explanation of the reason for the override. Subjectivity in assessment of the patient's condition with respect to the question at hand (e.g., PEEP vs. no PEEP) is absent, in contradistinction to guidelines that simply provide recommendations and depend on the practitioner changing to the recommended behavior. In this model, the recommended action is the default one and the practitioner must take action to behave differently. Most paper-based guidelines require initiative to move to the recommended action while computer-based order entry systems that structure the care require initiative to deviate from the recommendation. Physician compliance with the recommended path of treatment was in the 95% range and reproducible over a wide number of hospitals. Given the nature of clinical practice, computerized protocols must be explicit and unambiguous and include all possible outcomes under the rules. The site of operation must be the point of care, as the clinical decisions depend on accurate, precise, and timely data. Such data must be delivered to the practitioner in a convenient fashion that requires little or no effort while continuous collection of performance data allows for feedback to the user and iterative refinement to the developer. Simplicity and convenience are the hallmarks of such a system. Computer-based systems have the potential to overcome many if not most of the deficiencies and objections of the traditional paper-based method. Variability of the patient's history is difficult to overcome; controlling the site of entry to diagnostic tests and therapies holds substantive promise for reducing variation and improving outcomes. Useful tests and preferred drugs can be displayed on the top screen while those of doubtful utility or those that are less cost-effective can only be accessed deeper in the system ( Figure 196-4 ). Computer order entry has been shown, for instance, to dramatically reduce medication errors in hospitals.[ 50] When five emergency departments were asked to comply with a set of standards for six common chief complaints, the one department that embedded the standards in its electronic record performed the best by a considerable margin.[51] In this arrangement, the order sets become the pathways.

Figure 196-4 Order entry tem plate for sexual assault.

LEGAL AND ETHICAL CONSIDERATIONS Guidelines have traditionally provided recommendations, not prescriptions, with most containing disclaimers that they are not standards. Large health care organizations support this approach. In Britain, the National Health Service states explicitly that “guidelines…cannot be used to mandate, authorize or outlaw treatment options. Regardless of the strength of the evidence, it will remain the responsibility of the practicing clinicians to interpret their application.”[52] The World Health Organization similarly notes that “guidelines should provide extensive, critical and well balanced information on benefits and limitations of the various diagnostic and therapeutic interventions so that the physician may exert the most careful judgment in individual cases.”[ 53] Statements such as these give comfort to the physician who feels constrained to do more or less than the guideline recommends. This latitude is usually intended specifically for the physician but in fact may be even more important for the patient. Recently, this latitude appears to be waning. This may be the result of gradual accumulation of grade A evidence of sufficient magnitude to establish a clear and unequivocal standard. The most recent Advanced Cardiovascular Life Support Guidelines, now strictly evidence based, are more explicit: “Our guidelines are no longer just descriptive—‘This is how we do it here’—but can now be prescriptive—‘ This is how we should be doing it in the future.’”[54] The implications of such a change in the role of guidelines on the practice of emergency medicine are substantial. Whether following guidelines provides a degree of immunity from accusations of malpractice is unknown, as is the converse, whether deviations from guidelines expose one to increased liability. Guidelines played a “relevant or pivotal role in the proof of negligence” in less than 7% of malpractice actions

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in this country.[55] The latitude granted in all but the most recent guidelines was always directed at physician judgment, allowing discretion to suit the individual medical needs of the patient. The growth of patient autonomy brings new perspective to this latitude and to guidelines in general. What should happen if, in the face of guidelines on who may or may not receive renal dialysis, a patient demands the treatment? What duty does the patient's personal physician and the health system have to meet his demand? Likewise, should the answer be different if the patient's care for the potential treatment is to be paid for by the government, a private insurer, or the patient himself? An example more relevant to emergency medicine might be the situation in which the department has a guideline on using computed tomography in a head injury case and a patient who does not meet eligibility criteria demands the test. Should the answer differ depending on the payer, time of day (scanner not busy versus scanner backed up), or strength of the demand? When, in fact, do expert recommendations become covert rationing and could such accusations be tempered by the inclusion on the development panel of lay persons as public representatives?[56] In the future, the incorporation of all stakeholders in the development and use of guidelines might produce a process that is inclusive of available evidence and considerate of the opinion of those most affected by the document, the patients.

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Use of this content is subject to the Term s and Conditions of the MD Consult web site.

Marx: Rosen's Emergency Medicine: Concepts and Clinical Practice, 6th ed., Copyright © 2006 Mosby, Inc.

REFERENCES 1. Drake L: American Academy of Dermatology Guidelines of Care: Development and Process. Arch Dermatol1997;33:1369. 2. Field MJ, Lohr KN: Clinical Practice Guidelines: Direction of a New Program, Washington, D.C., National Academy Press, 1999. 3. Woolf S: Clinical Guidelines: Potential benefit, limitations, and harms of clinical guidelines. BMJ 1999;318:527. 4. Shekelle P: Clinical guideline: Developing guidelines. BMJ1999;318:593. 5. Shiffman RN: Standardized Reporting of Clinical Practice Guidelines: A Proposal from the Conference on Guideline Standardization. Ann Intern Med2003;139:493. 6. ACEP Clinical Policy Committee : Clinical Policy: Critical issues in the evaluation of adult patients presenting to the emergency department with acute blunt abdominal trauma. Ann Emerg Med2004;43:278. 7. Gibbons RJ, Smith S, Antman E: American College of Cardiology/American Heart Association Clinical Practice Guidelines: Part 1: Where do they come from?. Circulation2003;107:2979. 8. Gibbons RJ, Smith S, Antman E: American College of Cardiology/American Heart Association Clinical Practice Guidelines: Part II: Evolutionary Changes in a Continuous Quality Improvement Project. Circulation 2003;107:3101. 9. McGinn TG: User's guides to the medical literature XXII: How to use articles about clinical decision rules. JAMA2000;284:79. 10. Gallagher EJ: Shooting an elephant. Ann Emerg Med2004;43:233. 11. Quinn JV: Derivation of the San Francisco Syncope Rule to predict patients with short term serious outcomes. Ann Emerg Med2003;43:224. 12. Stiel IG: The Canadian CT Head Rule for patient with minor head injury. Lancet2001;357:391. 13. Stiell IG: Canadian C-spine rule study for alert and stable trauma patients. JAMA2001;286:1841. 14. Hoffman JR: Validity of a set of clinical criteria to rule out injury to the cervical spine in patients with blunt trauma. N Engl J Med2001;343:94. 15. Stiell IG, Clement CM, McKnight RD: The Canadian C spine rule versus the Nexus low-risk criteria in patients with trauma. N Engl J Med2003;349:2510. 16. American Medical Association : Policy Compendium, Chicago, The Association, 1997. 17. Dunham DM: Guidelines for emergency tracheal intubation immediately after traumatic injury. J Trauma 2003;55:162. 18. Hayward RS: Users' guides to the medical literature. VIII. How to use clinical practice guidelines: A. Are the recommendations valid?. JAMA1995;274:574. 19. Shaney F: Are guidelines following guidelines? The methodological quality of clinical practice guidelines in the peer reviewed medical literature. JAMA1999;281:1900. 20. Alrich R: Using socioeconomic evidence in clinical practice guidelines. BMJ2003;327:1283. 21. Shakelle PG, Ortiz E, Rhodes D: Validity of the agency for Health Care Research and Quality Clinical Practice Guidelines: How quickly do guidelines become outdated. JAMA2001;286:1461. 22. Campbell H, Hotchkiss R, Bradshaw N: Integrated care pathways. BMJ1998;316:133. 23. Pearson S, Goulart-Fisher D, Lee T: Critical pathways as a strategy for improving care: Problems and potential. Ann Intern Med1995;123:941. 24. Every N, Hochman J, Becker R: Critical pathways: A review. Circulation2000;101:461. 25. Bridgeman T, Flores M, Rosenblath J: One emergency department's experience: Clinical algorithms and documentation. J Emerg Nursing1997;23:316. 26. Eccles M: Effect of computerized evidence based guidelines on management of asthma and angina in adults in primary care: Cluster randomized controlled trial. BMJ2002;325:941. 27. Mendis D: Management of spontaneous pneumothorax: Are British Thoracic Society guidelines being followed?. Post Grad Med J2002;78:80. 28. Lewis L, Lasater L, Ruoff B: Failure of a chest pain policy to modify physician evaluation and management. Ann Emerg Med1995;259. 29. McGinn T, Guyatt G, Wyer P: Users' guides to the medical literature: XXII. How to use articles about clinical decision rules. JAMA2000;284:79.

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30. Oxman A: No magic bullets: A systemic review of 102 trials of interventions to improve professional practice. Can Med Assoc J1997;153:1432. 31. Hyman D, Paulik V: Self-reported hypertension treatment practices among primary physicians. Arch Intern Med2000;160:2281. 32. Vinson DR: Treatment patterns of isolated benign headache in US emergency Departments. Ann Emerg Med2003;39:215. 33. Bair N: Introduction of sedative, analgesic and neuromuscular blocking agent guidelines in a medical intensive care unit: Physician and nurse adherence. Crit Care Med2000;28:707. 34. Saint S: The effectiveness of a clinical protocol guideline for the management of presumed uncomplicated urinary tract infection in women. Am J Med1999;106:636. 35. Gallagher EJ: How well do clinical practice guidelines guide clinical practice. Ann Emerg Med 2002;40:394. 36. Grimshaw J, Russell I: Effect of clinical guidelines on medical practice: A systemic review of rigorous evaluations. Lancet1993;342:1317. 37. Cabana MD: Why don't physicians follow clinical practice guidelines? A framework for improvement. JAMA1999;282:1458. 38. Grol R: Beliefs and evidence in changing clinical practice. BMJ1997;315:418. 39. Tamblyn R, Battista R: Changing clinical practice: Which interventions work?. J Contin Educ Health Prof 1993;13:273. 40. Giugliano R: Association of unstable guidelines and with improved survival. Arch Intern Med 2000;160:1775. 41. Dean N: Implementation of admission decision support for community-acquired pneumonia: A pilot study. Chest2000;117:1368. 42. Mehta R: Improving quality of care for acute myocardial infarction: The guidelines applied in practice (GAP) initiative. JAMA2002;287:1269. 43. Armon K: The impact of presenting problem based guidelines for children with medical problems in an accident and emergency department. Arch Dis Child2004;89:159. 44. Muller K: Minor head injuries: Impact of a national strategy for implementation of management guidelines. J Trauma2003;55:1029. 45. Stross J: Guidelines have their limits. Ann Intern Med1999;131:304. 46. Gunderson L: The effect of clinical practice guidelines on variations in care. Ann Intern Med 2000;133:317. 47. In: Annas J, Waterfield R, ed.Plato: Statesman, Cambridge: Cambridge University Press; 1995: 48. Wears RL: Headaches from practice guidelines. Ann Emerg Med2002;39:334. 49. Morris A: Developing and implementing computerized protocols for standardization of clinical decisions. Ann Intern Med2000;132:373. 50. Bates DW, Leape L, Culen DJ: Effect of computerized physician order entry and a team intervention on prevention of serious medication errors. JAMA1998;280:1360. 51. Burnstin H: Benchmarking and quality improvement: The Harvard Emergency Department Quality Study. Am J Med1999;107:437. 52. NHS Executive Clinical Guidelines, Leeds, NHSE, 1986. 53. Subcommittee of WHO/ISH, Mild Hypertension Liaison Committee: Summary of 1993 WHO/ISH guidelines for the management of mild hypertension. BMJ1993;707:1541. 54. American Heart Association: Part 6: Advanced cardiovascular life support, Section 1. Introduction to ACLS 2000: Overview of recommended changes in ACLS from Guidelines 2000 Conference. Circulation 2000;102:1. 55. Hyams A: Practice guidelines and malpractice litigation: A two way street. Ann Intern Med1995;122:450. 56. Norheim O: Health care rationing: Are additional criteria needed for assessing evidence based clinical practice guidelines?. BMJ1999;319:1426.

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Marx: Rosen's Emergency Medicine: Concepts and Clinical Practice, 6th ed., Copyright © 2006 Mosby, Inc.

Chapter 197 – Medical Literature and Evidence-Based Medicine Kelly D. Young Roger J. Lewis

PERSPECTIVE Medicine is an empiric science based on the experiences and insights of past and contemporary practitioners. Because the clinical experience of an individual physician is a small fraction of the experience of the medical profession as a whole, the advancement of medical science depends on physicians' abilities to assemble, organize, and disseminate information in order to learn from the experience of others.

The Medical Literature During the last several decades, medical literature has exploded.[] Thirty years ago, physicians could understand most medical publications. Currently, reports frequently use sophisticated statistical analyses that are unfamiliar to most clinicians.[] Emergency physicians and other practitioners are increasingly aware that the quality of the research reported must be evaluated before the results can be considered valid and clinical practice altered. Also, the results of quality research may not be applicable if the population studied differs greatly from the patient population in the emergency physician's clinical practice. Even a clinician who possesses the analytical skills necessary to understand the modern medical literature will find it difficult to remain current, given the rate at which medical studies relevant to emergency medicine are published. Thus, the emergency physician must have a plan to identify, select, and read high-quality, relevant articles. Furthermore, the emergency physician must understand a number of principles to be able to analyze published studies critically. The first step toward achieving these goals is to identify a small number of journals on which to focus.[5] Most high-quality studies relevant to emergency medicine are published in fewer than a dozen journals. Once a list of 6 to 12 journals is compiled, back issues can be skimmed to determine the average number of relevant articles in each issue. Those journals that publish the highest number of articles directly relevant to an emergency physician's clinical practice should then be selected.[5] An emergency physician in full-time clinical practice should probably focus on two to six journals per month. Regular pamphlet or audiotape updates reviewing recent literature relevant to emergency medicine can be purchased and used as a supplement to journal review. Articles should be pulled and read in full, however, before results are accepted and clinical practice altered. Possible articles should then be screened to evaluate the relevance of the study question and population and to determine whether the methodology is of sufficient quality to warrant reading the article in more detail. Quality and clinical relevance vary greatly in the peer-reviewed literature.[5] Only articles that meet high standards for methodologic quality should be read in detail.[] The emergency physician must learn to differentiate high-quality studies from poor-quality studies with unreliable results. Practitioners who understand the concepts presented in this chapter will have the basic foundation to differentiate good from poor studies and to focus their reading on those studies most likely to yield results that warrant a change in clinical practice.[6] Additional guidance can be obtained from the Journal of the American Medical Association's Users' Guides to the Medical Literature series ( http://medicine.ucsf.edu/resources/guidelines/users.html

).[6]

A steadily increasing amount of attention is being paid to the importance of rigorous methodology in the design and execution of clinical trials.[] A poorly designed statistical analysis can yield misleading results, but a trial is more likely to be weakened by a poorly chosen question, an inappropriate study population, or other methodologic errors that bias the results.[] Thus, although some degree of statistical literacy is important, the

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practitioner must also understand nonstatistical issues in the design and analysis of clinical studies.[]

TYPES OF CLINICAL STUDIES Studies can be divided into two categories, cross-sectional and longitudinal (cohort), based on when the measurements are made on the study population.[12] In a cross-sectional study, data are obtained from a population of patients at a single point in time, whereas in a longitudinal study, data are obtained from a population of patients over a period of time.

Cross-Sectional Studies Many epidemiologic studies are cross-sectional. Although a cross-sectional study cannot prove a causal relationship between a risk factor or treatment and an outcome, strong associations between identified variables in cross-sectional studies are suggestive of such effects.[18] Many important observations can only be made using cross-sectional studies because, for practical and ethical reasons, some variables cannot be artificially manipulated to determine their effect on patient outcome.[18] Furthermore, the effect may be so delayed that a longitudinal study is impractical. An example is a study examining the association between cigarette use and lung cancer. It would be unethical to expose a nonsmoking population to the effects of cigarettes, and, even if one were to identify a population that voluntarily would use cigarettes, it would be impractical to observe subjects long enough for malignancies from cigarette smoking to appear. However, a cross-sectional study of self-reported cigarette use and the diagnosis of lung cancer that examines a population of subjects at a single point in time can easily demonstrate an association.

Longitudinal Studies In a longitudinal, or cohort, study, a population of patients is enrolled in the study and measurements are made over a period of time.[] Longitudinal studies can be observational, if no intervention is made, or they can be interventional.

Longitudinal Observational Studies In a longitudinal observational study, data are collected from a group, or cohort, of patients over time, but no intervention is made. A longitudinal observational study can be either prospective or retrospective. In a prospective observational study, patients who meet specific eligibility criteria are identified, and data are prospectively gathered over time.[12] Prospective observational studies are valuable for defining the course of a particular disease treated with standard therapies and for identifying subgroups of patients with differing prognoses. If an association is noted between treatment and outcome in a prospective observational study, the association should be verified in a prospective interventional randomized clinical trial. Although an observational study cannot prove a causal relationship, associations between initial patient characteristics or specific treatments and subsequent outcome can be detected. Such associations can be measured more accurately in a prospective longitudinal study than in a cross-sectional study, because both the original patient characteristics and the subsequent outcome are determined prospectively. When both the original patient characteristics and the outcome are determined prospectively, any associations observed are more likely to be true and not a result of bias. In a retrospective observational study, medical records of patients with certain initial characteristics who are treated over time are reviewed and data abstracted. As with all retrospective studies, retrospective observational studies are subject to recording bias, problems with missing information, and other methodologic limitations. Because retrospective studies have these additional sources of bias and limitations, prospective studies provide higher quality evidence than retrospective studies. Prospective studies, however, are usually more difficult and time-consuming to perform.

Longitudinal Interventional Studies (Clinical Trials) Interventional studies, which must be prospective, involve the artificial manipulation of a patient's therapy to determine the effect of an investigational treatment.[] An interventional study can be controlled or uncontrolled, and, if controlled, it should be randomized. In an uncontrolled interventional study, all patients who meet defined eligibility requirements are given the investigational therapy, and their outcomes are determined. Although such studies are useful for defining the rate of successful therapy in a well-defined population of subjects, the lack of a control group makes it difficult to estimate the relative effectiveness of the new therapy compared with another therapy. Previous experience with the standard treatment, in the form of a historical control group, can be used for comparison

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to the group receiving the new therapy. The use of such historical control groups is unreliable and often leads to an overestimate of the relative effectiveness of the new investigational therapy.[16] Medical care generally is becoming more effective, and thus the results of modern studies tend to yield better patient outcomes, even if the investigational treatment has no inherent advantage over the therapy received by the historical control patients.[16] In a controlled clinical trial, some patients are given the new investigational treatment, and some patients ( control group) are given a standard treatment.[] The purpose of the control group is to define the effectiveness of the standard therapy in a group of patients as similar as possible to the group receiving the investigational therapy. To obtain two groups of patients who are nearly identical with respect to all characteristics that might influence the outcome of their disease, it is important that no external or subjective factors influence the assignment of treatment.[] Each patient must have the same chance of receiving each therapy. For this reason, assignment to control or therapy groups should be randomized. It is extremely important that control patients be given a therapy that is at least as effective as the best currently available treatment. It is unethical for a control group to receive an inferior treatment simply to demonstrate that a new treatment has some effectiveness.[] In general, longitudinal interventional studies provide the highest quality evidence, although this is controversial.[]

RANDOMIZED LONGITUDINAL INTERVENTIONAL STUDY (CLINICAL TRIAL) The steps in a randomized clinical trial assume that a worthwhile research question has been defined ( Figure 197-1 ). No matter how well designed the study, if the research question is not well defined and not clinically useful, the intended audience will not find the study's results valuable.[26] The research question must also be prospectively defined; it is not appropriate to gather data and then devise a research question to fit the data. A good research question clearly defines four elements: (1) patient population and problem to be studied, (2) intervention to be applied to the treatment group, (3) comparison (control) intervention, and (4) outcome of interest.

Figure 197-1 Im plem entation and analysis of a prospective, random ized, controlled clinical trial.

Even if these four elements are well defined, the research question must still have relevance for the emergency physician. For example, a study that compares oral and parenteral antibiotics (treatment and comparison interventions) for the prevention of meningitis (outcome) in well-appearing febrile children with occult bacteremia confirmed by positive blood culture (patient population) is less useful to the emergency physician than a similar study including all well-appearing febrile children, since results of blood cultures are not typically available in the emergency department.

Step 1: Definition of Patient Population Assuming an appropriate research question has been selected, the first step is to define the patient population to be studied.[] The original patient population defined in the research question may be modified slightly by practical factors in study design. For example, although an investigator may want to study all asthmatic patients presenting to the emergency department, it may only be practical to study those presenting when investigators are available (convenience sample). Explicit inclusion and exclusion criteria must be defined before enrolling any patients, and these criteria must be uniformly applied in determining which patients are eligible to participate in the study. For the study to be most applicable to emergency medicine, the population should be defined in terms of clinical characteristics that are observable in the emergency department. On the other hand, groups of patients defined by their clinical characteristics in the emergency department are highly heterogeneous.[13] Some patients in the population may have more severe disease than other patients or may have a completely different cause for their symptoms. When reading a study, one should look to see that the patient population is well defined and reasonably

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comparable to one's own patient population.[6] If important segments of the population are excluded (e.g., those with severe disease), the study results are not applicable to this subgroup. Researchers should not generalize their conclusions to patients not included in their study population.

Step 2: Recruitment and Enrollment of Patients Once a patient population is defined, the next step is to recruit patients for enrollment in the study. To the extent possible, all patients meeting the predefined eligibility requirements for the study should be enrolled. The method of recruitment and enrollment should ensure that there is no systematic tendency to exclude a subgroup of patients from the study who meet the inclusion criteria. If such a selection bias exists, it will make the results of the study inapplicable to the types of patients that were excluded.[] For example, if a study of head trauma patients specifies that informed consent must be obtained from the patient within the first half hour of presentation to the emergency department, there will be a systematic tendency to exclude patients with head trauma severe enough to result in an altered level of consciousness. Even in a study that is appropriately designed, patients may self-select, resulting in selection bias. For example, patients of low socioeconomic status may be less likely than patients of high socioeconomic status to give consent for participation in clinical studies. Thus, although the disease itself may affect people in all socioeconomic strata, the study results may apply only to patients of high socioeconomic status similar to those who participated in the study. To minimize selection bias, studies should aim to achieve consecutive enrollment of all patients who meet inclusion criteria. Furthermore, patients who meet eligibility criteria but are not subsequently enrolled should be counted to allow an estimation of the possible extent of any selection bias that might exist.[10] When reading a study, one should look for information on eligible patients who were not enrolled. A significant number of such patients may indicate selection bias. Researchers should explain why these patients were missed and should justify the validity of their results despite missed patients by showing, for example, that demographics and disease characteristics of missed patients were similar to those of enrolled patients.

Step 3: Randomization The third step in conducting a clinical trial is to randomize enrolled patients to the different treatments being compared. The purpose of this randomized allocation is to create two groups of patients who, other than receiving different treatments, are as nearly identical as possible.[11] Stratified randomization can be used to ensure that important confounding factors are equally distributed in the control and test groups.[11] In a stratified randomization, patients with the stratifying characteristic are randomized independently of those without the characteristic. For example, in a study of therapy for closed head injury, patients with severe closed head injury as defined by a low Glasgow Coma Scale score could be randomized independently of those patients with a higher Glasgow Coma Scale score. This would help ensure that the control and test groups have equal fractions of patients with severe and mild closed head injury. Whenever possible, both the patient and the treating physician should be “blinded” (double blinding) to the therapy given.[11] Such blinding is important to ensure that both the patient and the investigating physician can make unbiased estimates of endpoints, including the occurrence of undesirable side effects. Recently, increasing importance has been placed on subjective outcomes, such as quality-of-life assessments made by the patient. Blinding is especially important to ensure that the patients' expectations regarding the effect of the new therapy do not influence their assessment of this type of outcome. The quality of the randomization in a controlled clinical trial is important because studies that are inadequately randomized are more likely to “find” a positive treatment effect.[30] Similarly, studies in which blinding is inadequate, so that the patient or the treating physician might be able to determine the treatment the patient actually receives, are more likely to yield false-positive results.[15] When reviewing a clinical trial, one should look for truly random treatment assignment and adequate blinding procedures. For example, in a trial in which patients are enrolled if determined to be sufficiently “stable” by the physician and assignment to therapy or control is alternated, a physician with the bias that the therapy is not efficacious may avoid enrolling a patient by deeming the patient unstable if the physician knows that the next patient will be assigned to the treatment group. A better method of randomization would be assignment by a computerized randomization program, such that no pattern of assignment can be discerned by the enrolling personnel.

Step 4: Measurement of Baseline Characteristics The fourth step is to measure the characteristics of patients enrolled in the study before therapy. The

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purpose of these baseline measurements is to detect imbalance between the control and test groups in characteristics that might influence each patient's chance for a successful outcome. Factors that might influence patient outcome and that are not controlled by the investigators are termed confounding variables. For example, the initial cardiac rhythm is a confounding variable in a study that compares different treatments for out-of-hospital cardiac arrest. If one group includes more patients in ventricular fibrillation while the other group has more patients in asystole, the intervention given to the first group will appear to be more efficacious. The influence of confounding characteristics must be anticipated, and those characteristics should be prospectively measured for all patients enrolled in the study. Subgroups of the overall patient population often have specific confounding characteristics (see Figure 197-1 ). If a clinically significant difference in outcome is ultimately detected between the two treatment groups, the baseline characteristics of the treatment groups should be compared to ensure that the observed difference in outcome did not occur because the two patient groups were not initially equivalent.[11] When reading a study, one should look to see that important confounders were measured and that they did not differ significantly between the groups studied.

Step 5: Treatment or Intervention The next step is to administer the experimental treatment to the test group and the control treatment to the control group. Although the control and test patients should be nearly identical in their underlying characteristics, the two groups often have unequal compliance with therapy. For example, in a placebo-controlled study of an oral medication, those patients taking the active drug may find that it causes gastrointestinal discomfort, whereas those taking the placebo treatment might not experience such an effect. Therefore, patients taking the active agent may be less compliant with therapy. Unequal compliance complicates the interpretation of the outcome data.

Step 6: Collection of Data on Outcome The sixth step is to determine the outcome of each patient. Definitions of treatment success and treatment failure must be explicitly defined before any data are collected. Sometimes a trial is initially designed to investigate the effects of therapy on one outcome, but during data analysis investigators notice an apparently significant effect on a different outcome. Such a serendipitous finding may be true but can also result from chance, because there are generally many such possible findings, and the study was not originally designed to investigate each of these possible outcomes. Such findings can be reported as interesting and warranting further investigation but should not be reported as reliable conclusions. A difficulty with the collection of outcome data arises if too many subjects are lost to follow-up. This is more likely to occur in studies that evaluate the long-term effects of therapy. Patients who are lost to follow-up may have different characteristics than those patients who keep their follow-up appointments. For this reason, lack of complete follow-up in the study population can bias the results of the study. Ensuring high rates of follow-up in studies of outpatient therapy is notoriously difficult. One approach is to create a multistep plan to obtain follow-up, with specific procedures to be followed if patients miss their first, second, or even third follow-up appointment. When reading a study, one should look at the percentage of patients lost to follow-up and look for a systematic effort to maintain good follow-up.

Step 7: Data Management Once patients have been enrolled and have had their baseline characteristics measured, treatments administered, and outcomes determined, all this information must be organized and stored in a format that allows analysis of the data. Data should be collected on a form that limits and organizes the information. In general, information to be recorded on the data form should be highly structured, with categorical variables limited to a small number of possibilities and with very little (or no) unformatted “fill-in-the-blank” information requested. Such structure is required if the resulting data are to be analyzed statistically. Errors may be introduced when data are entered into the database from data sheets. Bias can be introduced if certain types of data (e.g., written phrases in a patient questionnaire) must be reduced to a smaller number of categoric responses during the data entry procedure. Databases should be designed to ensure that the data listed are reasonable. For example, the electronic database should not allow entry of patient temperatures that are incompatible with life or negative blood pressures. When reviewing a study, one should look for data categorizations that are clear and clinically useful. For example, a study of post-resuscitation neurologic outcomes would be most useful to the emergency physician if patients were categorized as “normal,” “mildly impaired,” “severely impaired,” or “dead,” versus the more vague terms “good” or “poor” or by the results of a detailed neuropsychological battery of tests.

Step 8: Statistical Analysis

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The next step is to analyze the data. Careful planning of the statistical analysis to be performed is required to minimize the chance of erroneous conclusions. Only a small number of comparisons should be made, and the study should be designed to have an adequate sample size to reliably detect a clinically important treatment effect.[] The comparisons to be conducted must be defined prospectively, as well as any specific subgroups of patients that will be considered separately. Any imbalance in confounding baseline characteristics should be accounted for in the statistical analysis. Specific statistical tests are discussed later.

Step 9: Presentation and Publication of Results Once the clinical trial data have been statistically analyzed, conclusions can be drawn from the results of the study. During the preparation of a manuscript describing the study and its conclusions, the investigators must be careful not to overextrapolate the results. Care must be taken to explain limitations in the study design and to enumerate factors that might bias the results of the study, or at least limit its applicability to different patient populations. One purpose of the peer review process is to ensure that appropriate care is taken in interpreting the clinical trial results. The enthusiasm of most investigators and clinicians for the results of a clinical trial are partly determined by the direction of the results.[36] For example, a trial that shows a highly effective new therapy for a serious disease is interesting and exciting. On the contrary, a trial that shows that a previously unstudied therapy has no advantage over the currently accepted treatment may be less interesting. Because positive results are inherently more interesting, it is commonly believed that clinical trials yielding positive results are more likely to be published than those with negative results. This effect is termed publication bias.[] Recent studies, however, have shown that trials with negative results may be less likely to be submitted for publication but, once submitted, are as likely to be published as trials with positive results.[] Thus publication bias may be the result of a file drawer problem, meaning that the results of studies with negative results sometimes end up in the file drawer, instead of in manuscripts submitted for publication.[40] Publication bias and the file drawer problem are serious threats to the validity of the medical literature taken as a whole. If negative trials are selectively excluded from the medical literature, an ineffective treatment may appear to be at least partially effective because those (possibly poorly designed) studies that show some positive treatment effect are selectively submitted for publication. Meta-analyses or systematic reviews often utilize only published research. It may be unethical to subject patients to the risks and discomforts of participation in a clinical study and not publish the results, especially if participation did not result in any direct benefit to the patient. Publication bias and other sources of bias can be especially problematic in pharmaceutical or commercially sponsored clinical research. Commercial studies are less likely to report unfavorable conclusions.[41] Data from industry-sponsored research may go unpublished or may be difficult to obtain for subsequent review.[42 ] When reading a clinical trial, one should look to see what agency or company funded the research and consider what biases, if any, might have been introduced.

DATA ANALYSIS Classical Hypothesis Testing Data from clinical trials are usually analyzed using P values and classical hypothesis testing.[] In classical hypothesis testing, two hypotheses that might be supported by the data are considered. The first, called the null hypothesis, states that no difference exists between the groups being compared with respect to the measured outcome of interest.[7] For example, in a study examining the use of a new sympathomimetic agent for blood pressure support in patients with sepsis, the null hypothesis might be that there is no difference between the average systolic blood pressure achieved with the test agent and that achieved with the control agent. The alternative hypothesis states that the groups being compared are different.[7] In this example study, the alternative hypothesis might be that the test agent results in a 10 mm Hg greater average systolic blood pressure than the control agent. The magnitude of the difference between the two groups defined by the alternative hypothesis is called the treatment effect ( Tables 197-1 and 197-2 ). Table 197-1 -- Steps in Classical Hypothesis Testing Step hypothesis

Description

Define the null

There is no difference between the groups being compared. For example, in a clinical trial the null

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Step hypothesis

Define the alternative hypothesis

Calculate a P value

Accept or reject the null hypothesis

Accept the alternative hypothesis

Description hypothesis might be that the response rate in the treatment group is equal to that in the control group. The alternative hypothesis might be that the response hypothesis rate in the treatment group is greater than that in the control group by a given amount. This calculation assumes that the null hypothesis is true. One determines the probability of obtaining the results found in the data, or other results even more inconsistent with the null hypothesis. This probability is the P value. If the probability of observing the actual data, or more extreme results, under the null hypothesis is small (P < p ), then we should doubt that hypothesis. The idea is that if the probability under the null hypothesis of observing the actual results is very small, then there is a conflict between the null hypothesis and the observed data, and we should conclude that the null hypothesis is not true. If we reject the null hypothesis, we accept the alternative hypothesis by default.

Table 197-2 -- Terms Used in Design of Clinical Trials Term Definition p

Maximum P value to be considered statistically significant; the risk of committing a type I error p error Type I error Alternative hypothesis Hypothesis considered an alternative to the null hypothesis; usually the alternate hypothesis is that there is an effect of the studied treatment on the measured variable of interest; also called test hypothesis p Risk of committing a type II error p error Type II error Null hypothesis Hypothesis that there is no effect of the studied treatment on the measured variable of interest Power Probability of detecting a treatment effect the size of the treatment effect sought (i.e., obtaining a P value