As a Refresher Course in Anesthesiology 2005

R E FRE SHE R C OURSE S IN ANE STHE SIOLOGY Peer-R eviewed E DIT OR : ALAN JAY S CHWAR T Z, M.D., M.S.E D. ASSOCIATE SS...

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R E FRE SHE R C OURSE S IN ANE STHE SIOLOGY Peer-R eviewed

E DIT OR : ALAN JAY S CHWAR T Z, M.D., M.S.E D. ASSOCIATE SSOCIATE E DITORS DITORS: M. JANE ANE MATJASK ATJASKO O, M.D. JEEFFRE FFREYY B. GROSS ROSS, M.D.

The American S ociety of Anes thes iologis ts , Inc. V

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FOREWORD

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dvancing the science of anesthesiology by encouraging education and research was a high priority for the physicians who founded the organization that was to become the ASA. This year of our centennial is an appropriate time to note that the ASAÕs educational offerings have reached an outstanding level of excellence, both in variety and number, through the tradition of each successive generation of anesthesiologists building on the achievements of its predecessors. It is interesting to review the origins of this publication. The Þrst Editor-in-Chief, S. C. Hershey, M.D., published Volume 1 in 1973 with an introduction by ASA President E. S. Siker, M.D. The Associate Editors were Drs. Phillip O. Bridenbaugh and Charles Court Tandy. Dr. Siker explained the rationale for the format of the new educational offering: Few would argue that there are basic differences between written and spoken methods for conveying information, although the information to be conveyed may be identical. While the lecture form is, and will continue to be, widely practiced, most educators would now agree that written formats are probably more successful as teaching instruments. It would be a dull academic world indeed, however, if the sonorous rhetoric of the inspired and inspiring lecturer were put on the shelf because the written word was a better teaching device. Additionally, the lecture form offers advantages that no written text can provide: the rapport between lecturer and student, the opportunity for the lecturer to answer questions, to develop word explanations and to defend premises. The unanswering printed page can do none of these things.É

We are all indebted to the current and past Editorial Boards of this publication for its exceptional quality. Because of their dedication, it continues to be a core resource among this SocietyÕs educational offerings, and the ASA remains the best source of continuing professional education for its members.

E UGENE SINCLAIR , M.D. President American Society of Anesthesiologists

TABLE OF CONTENTS VOLUME 33 Foreword

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S upratentorial Tumors : Anes thetized, Awake, and Computer-as s is ted Management AudrŽe A. Bendo

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Chemical Dependence: Unders tanding the Dis eas e and Its Treatment Arnold J. Berry

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R ecognition and Treatment of Malignant Hyperthermia Barbara W. Brandom

21

Anticoagulation and R egional Anes thes ia Lynn M. Broadman

31

Anes thes ia for B ariatric S urgery Jay B. Brodsky

49

Problems with Anes thes ia Gas Delivery S ys tems James B. E isenkraft

65

Preoperative As s es s ment of the Patient with Cardiac Dis eas e Lee A. Fleisher

79

Pos tdural Puncture Headache: Whos e Headache Is It? Robert R. Gaiser

89

Les s Jolts from Your Volts : Electrical S afety in the Operating R oom Jeffrey B. Gross

101

Lower Extremity Peripheral Nerve B locks Admir Hadzic, Tony Tsai, Takashige Iwata, and K ayser E nneking

115

Anes thes ia for the Pregnant Patient Undergoing Nonobs tetric S urgery Joy L. Hawkins

137

Anes thetic Cons iderations for Interventional Neuroradiology Chanhung Z. Lee and William L. Young

145

Anaphylaxis and Advers e Drug R eactions Jerrold H. Levy

155

The Graying of America: Anes thetic Implications for Geriatric Outpatients K athryn E . McGoldrick

165

Pain R elief without S ide Effects : Peripheral Opiate Antagonis ts Jonathan Moss and Joseph Foss

175

Perioperative Management of the Patient Undergoing Aortic Vas cular S urgery E dward J. Norris

187

Management of the Patient with Pulmonary Hypertens ion and R ight Ventricular Failure George F. Rich

203

Hematologic As pects of Cardiac S urgery Linda Shore-Lesserson

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Clinical Monitoring of the B rain and S pinal Cord Tod Sloan

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Anes thes ia for Ces arean Delivery Lawrence C. Tsen

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CHAPTER 1

V O L U M E

T H I R T Y - T H R E E

SUPRATENTORIAL TUMORS: ANESTHETIZED, AWAKE, AND COMPUTER-ASSISTED MANAGEMENT AUDRÉE A. BENDO, M.D. PROFESSOR AND VICE CHAIR FOR EDUCATION DEPARTMENT OF ANESTHESIOLOGY SUNY/DOWNSTATE MEDICAL CENTER BROOKLYN, NEW YORK

EDITOR: ALAN JAY SCHWARTZ, M.D., M.S.ED. ASSOCIATE EDITORS: M. JANE MATJASKO, M.D. JEFFREY B. GROSS, M.D.

The American Society of Anesthesiologists, Inc.

© 2005

The American Society of Anesthesiologists, Inc. ISSN 0363-471X ISBN 0-7817-8646-0 An educational service to the profession under the auspices of The American Society of Anesthesiologists, Inc. Published for The Society by Lippincott Williams & Wilkins 530 Walnut Street Philadelphia, Pennsylvania 19106-3621 Library of Congress Catalog Number 74-18961.

PERMISSION TO PHOTOCOPY ARTICLES: This publication is protected by copyright. Permission to reproduce copies of articles for noncommercial use must be obtained from the Copyright Clearance Center, 222 Rosewood Dr., Danvers, MA 01923; (978) 750-8400, FAX: (978) 750-4470, www.copyright.com.

Supratentorial Tumors: Anesthetized, Awake, and Computer-assisted Management Audrée A. Bendo, M.D. Professor and Vice Chair for Education Department of Anesthesiology SUNY/Downstate Medical Center Brooklyn, New York

Each year, more than 200,000 people in the United States are diagnosed with brain tumors.1 Primary brain tumors comprise approximately 40,000 of these diagnoses. Most brain tumors are metastatic, usually from breast and lung cancer. Brain tumors are the leading cause of cancer death in children less than 20, now surpassing acute lymphocytic leukemia, and the second leading cause of cancer death in males ages 20 to 29.1 The distribution of all primary brain and central nervous system (CNS) tumors by site reveals that the majority are supratentorial.1

Pathophysiology Supratentorial tumors (meningiomas, gliomas, and metastatic lesions) change intracranial dynamics predictably. Initially, when the lesion is small and slowly expanding, volume–spatial compensation occurs by compression of the cerebrospinal fluid (CSF) compartment and nearby cerebral veins, which prevents increases in intracranial pressure (ICP). As the lesion grows, compensatory mechanisms become exhausted, and any further increase in tumor mass will cause progressively greater increases in ICP. Primary or metastatic tumors or chronic subdural hematomas can present as chronic mass lesions. Because of the ability of the intracranial compartment to compensate up to a point, patients may exhibit minimal neurologic dysfunction despite the presence of a large mass, elevated ICP, and shifts in the position of brain structures. Significant changes in ICP can occur with supratentorial tumors if they develop a central area of hemorrhagic necrotic tissue or a wide border of brain edema. As the tumor enlarges, it can outstrip its blood supply, developing a central hemorrhagic area that may expand rapidly, increasing ICP. Brain edema surrounding the tumor increases the effective bulk of the tumor and represents an additional portion of the brain that is not autoregulating. In such situations of compromised intracranial compliance, small increases in arterial pressure may produce large increases in cerebral blood flow (CBF), which can markedly increase intracranial volume and ICP with its attendant complications, that is, cerebral ischemia and herniation. In addition to hypertension, other causes of increased cerebral blood volume such as hypercarbia, hypoxia, vasodilating agents, and jugular venous obstruction can adversely affect cerebral hemodynamics and must be avoided perioperatively.

Anesthetic Techniques and Drugs The goal of neuroanesthetic care for patients with supratentorial tumors is to maximize therapeutic modalities that reduce intracranial volume. ICP must be controlled 1

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before the cranium is opened and optimal operating conditions obtained by producing a slack brain that facilitates surgical dissection. Various maneuvers and pharmacologic agents have been used to reduce brain bulk (Table 1). For example, administration of diuretics or steroids, hyperventilation, and systemic blood pressure control may be implemented preoperatively to reduce cerebral edema and brain bulk, thereby reducing ICP. The application of these methods selectively or together, when necessary, is often accompanied by marked clinical improvement.

Clinical Control of Intracranial Hypertension Rapid brain dehydration and ICP reduction can be produced by administering the osmotic diuretic, mannitol, or the loop diuretic, furosemide. Mannitol is given as an intravenous infusion in a dose of 0.25 to 1.0 g/kg−1. Its action begins within 10 to 15 minutes and is effective for approximately 2 hours. Larger doses produce a longer duration of action but do not necessarily reduce ICP more effectively. Furthermore, larger doses and repeated administration can result in metabolic derangement. Mannitol is effective when the blood–brain barrier is intact. By increasing the osmolality of blood relative to the brain, mannitol pulls water across an intact blood–brain barrier from brain to blood to restore the osmolar balance. When the blood–brain barrier is disrupted, mannitol may enter the brain and increase its osmolality. Mannitol could pull water into the brain as the plasma concentration of the agent declines and cause a rebound increase in ICP. This rebound increase in ICP may be prevented by maintaining a mild fluid deficit. Mannitol has been shown to cause vasodilation of vascular smooth muscle, which is dependent on dose and rate of administration. Mannitol-induced vasodilation affects intracranial and extracranial vessels and can transiently increase cerebral blood volume TABLE 1.

Clinical Control of Intracranial Hypertension

Diuretics:

Osmotic: Mannitol (0.25 to 1 g/kg IV), hypertonic saline (under investigation). Furosemide: (0.5 to 1 mg/kg IV alone or 0.15 to 0.3 mg/kg IV in combination with mannitol).

Corticosteroids:

Dexamethasone (effective for localized cerebral edema surrounding tumors; requires 12 to 36 hours).

Adequate ventilation:

PaO2 ≥ 100 mm Hg, PaCO2 33 to 35 mm Hg; hyperventilation on demand.

Optimize hemodynamics (MAP, CVP, PCWP, HR): Target normotension and maintain cerebral perfusion pressure (CPP = MAP − ICP) to avoid cerebral ischemia. Fluid therapy:

Target normovolemia before anesthetic induction to prevent hypotension. Use glucose-free isoosmolar crystalloid solutions to prevent increases in brain water content (from hypoosmolality) and ischemic damage (from hyperglycemia).

Position to improve cerebral venous return (neutral, head-up position). Drug-induced cerebral vasoconstriction (e.g., thiopental, propofol). Temperature control:

Avoid hyperthermia perioperatively. Consider using mild intraoperative hypothermia. Cerebral spinal fluid drainage to acutely reduce brain tension. IV = intravenous; MAP = mean arterial pressure; CVP = central venous pressure; PCWP = pulmonary capillary wedge pressure; HR = heart rate; CPP = cerebral perfusion pressure; ICP = intracranial pressure.

SUPRATENTORIAL TUMORS

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and ICP while simultaneously decreasing systemic blood pressure. Because mannitol may initially increase ICP, it should be given slowly (≥10-minute infusion) and in conjunction with maneuvers that decrease intracranial volume (for example, steroids or hyperventilation). Prolonged use of mannitol may produce dehydration, electrolyte disturbances, hyperosmolality, and impaired renal function. Hypertonic saline, another osmotic diuretic, is currently under investigation as an agent to control ICP.2 Hypertonic saline solutions have been shown to reduce ICP in animal models and in human studies and may be more effective than other diuretics in certain clinical conditions, for example, patients with refractory intracranial hypertension or in those who require brain debulking and maintenance of intravascular volume.2,3 Hypertonic saline also can be used as an alternative or adjunct to intraoperative use of mannitol. There are several potential adverse effects of hypertonic saline therapy (Table 2). Significant complications such as central pontine myelinolysis and intracranial hemorrhage have not been reported in human studies. Different types of hypertonic saline solutions with different methods of infusion (bolus and continuous) have been reported in the literature. Published data are encouraging, but more studies are required to determine dose–response curves and the safety and efficacy of these solutions. Hypertonic agents, either mannitol or hypertonic saline, should be administered cautiously in patients with preexisting cardiovascular disease. In these patients, the transient increase in intravascular volume may precipitate left ventricular failure. Furosemide may be a better agent to reduce ICP in patients with impaired cardiac reserve. The loop diuretic furosemide reduces ICP by inducing a systemic diuresis, decreasing CSF production, and resolving cerebral edema by improving cellular water transport. Furosemide lowers ICP without increasing cerebral blood volume or blood osmolality; however, it is not as effective as mannitol in reducing ICP. Furosemide can be given alone as a large initial dose (0.5 to 1 mg/kg−1) or as a lower dose with mannitol (0.15 to 0.30 mg/kg−1). A combination of mannitol and furosemide diuresis has been shown to be more effective in reducing ICP and brain bulk than mannitol alone, but causes more severe dehydration and electrolyte imbalances. With combined therapy, it is necessary to monitor electrolytes intraoperatively and replace potassium as indicated. Corticosteroids reduce edema around some brain tumors; however, steroids require many hours or days before a reduction in ICP becomes apparent. The administration of steroids preoperatively frequently causes neurologic improvement that can precede the ICP reduction. One explanation for this is that the neurologic improvement is accompanied by partial restoration of the previously abnormal blood–brain barrier.

TABLE 2.

Hypertonic Saline: Potential Adverse Effects of Intravenous Administration

Central Nervous System

Systemic

Decreased level of consciousness Seizures *Central pontine myelinolysis *Subdural and intraparenchymal hemorrhage Rebound cerebral edema

Hyperosmolality Hypernatremia Congestive heart failure Hypokalemia Hyperchloremic acidosis Coagulopathy Phlebitis Renal failure

*Not reported in human studies.

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Postulated mechanisms of action for steroidal reduction in brain edema are brain dehydration, blood–brain barrier repair, prevention of lysosomal activity, enhanced cerebral electrolyte transport, improved brain metabolism, promotion of water and electrolyte excretion, and inhibition of phospholipase A2 activity. The potential complications of continuous perioperative steroid administration are hyperglycemia, glucosuria, gastrointestinal bleeding, electrolyte disturbances, and increased incidence of infection. Therefore, the potential risks and benefits of continuous steroid administration need to be evaluated in these patients. Hyperventilation reduces brain volume by decreasing CBF through cerebral vasoconstriction. For every 1-mm Hg change in PaCO2, CBF changes by 1 to 2 mL/100 g−1/min−1. The duration of effectiveness of hyperventilation for lowering ICP may be as short as 4 to 6 hours, depending on the pH of the CSF. Hyperventilation is only effective when the CO2 reactivity of the cerebrovasculature is intact. Impaired responsiveness to changes in CO2 tension occurs in areas of vasoparalysis, which are associated with extensive intracranial disease such as ischemia, trauma, tumor, and infection. The typical target PaCO2 is 30 to 35 mm Hg. A PaCO2 less than 25 to 30 mm Hg in some pathologic conditions may be associated with ischemia caused by extreme cerebral vasoconstriction.4,5 By monitoring global cerebral oxygenation with jugular venous oxygen saturation (SjvO2), for example, the therapeutic effectiveness of hyperventilation can be determined and more safely applied. The autoregulation of CBF has been discussed, as has the relationship between blood pressure and ICP when autoregulation is disturbed. The therapeutic goals are to maintain CPP and to control intracranial dynamics so that cerebral ischemia, edema, hemorrhage, and herniation are avoided. Severe hypotension results in cerebral ischemia and should be treated with volume replacement, inotropes, or vasopressors as dictated by clinical need. Severe hypertension, conversely, can worsen cerebral edema and cause intracranial hemorrhage and herniation. The β-adrenergic blockers, propranolol and esmolol, and the combination α- and β-adrenergic blocker, labetalol, are effective in reducing systemic blood pressure in patients with raised ICP resulting in minimal or no effect on CBF or ICP. Restricted fluid intake was a traditional approach to intracranial decompression therapy but is now rarely used to lower ICP. Severe fluid restriction over several days is only modestly effective in reducing brain water content and can cause hypovolemia, resulting in hypotension, inadequate renal perfusion, electrolyte and acid-base disturbances, hypoxemia, and reductions in CBF. In patients who are dehydrated preoperatively, intravascular volume must be restored to normal before induction of anesthesia to prevent hypotension in response to anesthetic agents and positive-pressure ventilation. Fluid resuscitation and maintenance fluids in the routine neurosurgical patient are provided with glucose-free isoosmolar crystalloid solutions to prevent increases in brain water content from hypoosmolality. For routine craniotomy, the patient receives hourly maintenance fluids and replacement of urine output. Blood loss is replaced at approximately a 3:1 ratio (crystalloid:blood) down to a hematocrit of approximately 25% to 30% depending on the patient’s physiological status. Solutions containing glucose are avoided in all neurosurgical patients with normal glucose metabolism, because these solutions exacerbate ischemic damage and cerebral edema. Hyperglycemia augments ischemic damage by promoting neuronal lactate production, which worsens cellular injury. Intravenous fluids containing glucose and water (D5W0.45%, NaCl or D5W) are particularly problematic because the glucose is metabolized and the free water remains in the intracranial fluid compartment, resulting in brain edema. Brain water can interfere with surgical exposure and, after closure


5

of the skull, can compromise cerebral perfusion. In normal patients, both preoperative dexamethasone treatment and general anesthesia-induced gluconeogenesis may increase resting glucose levels. Therefore, blood glucose levels should be monitored during craniotomy and maintained at near low-normal range. This should be accomplished mainly by withholding glucose. For most neurosurgical patients, a neutral head position, mildly elevated to 15° to 30°, is recommended to decrease ICP by improving venous drainage. Flexing or turning of the head may obstruct cerebral venous outflow, causing a dramatic ICP elevation that has been shown to resolve with resumption of a neutral head position. Lowering the head impairs cerebral venous drainage, which can quickly result in an increase in brain bulk and ICP. The application of positive end-expiratory pressure (PEEP) to mechanically ventilated patients can potentially increase ICP. This effect occurs when PEEP increases mean intrathoracic pressure, impairing cerebral venous outflow and cardiac output. When PEEP is required to maintain oxygenation, it should be applied cautiously and with appropriate monitoring to minimize decreases in cardiac output and increases in ICP. PEEP levels of 10 cm H2O or less have been used without significant increases in ICP or decreases in CPP. When higher levels of PEEP are required to optimize the PaO2–PEEP–CPP relationship, both central venous pressure (CVP) and ICP monitoring are indicated. The administration of pharmacologic agents that increase cerebral vascular resistance can acutely reduce ICP. Thiopental and propofol are potent cerebral vasoconstrictors that can be used for this purpose. These agents are usually administered during induction of anesthesia but may also be administered in anticipation of noxious stimuli or to treat persistently elevated ICP in the intensive care unit. Although rarely used to reduce ICP, hypothermia does this by decreasing brain metabolism, CBF, cerebral blood volume, and CSF production.6 Drugs that centrally suppress shivering, muscle relaxants, and mechanical ventilation are required when hypothermic techniques are used. Intraoperatively, a modest degree of hypothermia, approximately 34°C, has been recommended as a way to confer neuronal protection during focal ischemia. Hypothermic techniques are also used to cool febrile neurosurgical patients. Hyperthermia is particularly dangerous in neurosurgical patients because it increases brain metabolism, CBF, and the propensity for cerebral edema. To acutely reduce brain tension, CSF drainage either by direct surgical puncture of the lateral ventricle or by lumbar spinal catheter can be used. Lumbar CSF drainage should be used cautiously and only when the dura is open and the patient is at least mildly hyperventilated to prevent acute brain herniation. Brain tension can be effectively reduced by draining 10 to 20 mL of CSF.

Premedication Lethargic patients do not receive premedication. Patients who are alert and anxious may receive an anxiolytic (for example, 5 mg midazolam orally) before coming to the operating room. If there is any doubt about the patient’s level of consciousness, the patient may be given sedation or analgesics in the operating room after an intravenous route is established. For the preinduction insertion of invasive monitoring devices in an awake, conversant patient, premedicants (for example, small doses of opioids) should be considered to alleviate the discomfort from needle punctures.

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Monitoring In addition to the routine monitors, measurement of intraarterial blood pressure, arterial blood gases, CVP, and urine output is recommended for all major neurosurgical procedures. An arterial cannula is inserted before induction of anesthesia to continuously monitor blood pressure and to estimate CPP. When the arterial pressure transducer is at midhead level (usually the level of the external auditory meatus), mean arterial pressure (MAP) approximates the pressure at the level of the circle of Willis. Cerebral perfusion pressure is calculated as the difference between MAP and CVP in patients without intracranial hypertension or the ICP in those with intracranial hypertension. When the cranium is open, ICP equals atmospheric pressure and CPP equals MAP. With direct arterial pressure monitoring, the hemodynamic consequences of the pharmacologic agents administered during anesthesia are recognized instantly. In addition, the arterial catheter provides ready access for intraoperative measurement of arterial blood gases, hematocrit, serum electrolytes, glucose, and osmolality. Arterial blood gas measurement is necessary to verify the adequacy of hyperventilation. In the elderly and those with ventilation/perfusion mismatch, end-tidal CO2 may correlate poorly with the PaCO2. Therefore, the difference between PaCO2 and end-tidal CO2 must be determined for a given patient in a given position. Radial, femoral, or brachial arteries are suitable for short-term cannulation; however, after ulnar artery collateral blood flow is tested, cannulation of the radial artery is preferred. Because most neurosurgical patients are dehydrated preoperatively and then subjected to intraoperative diuresis, the measurement of cardiac preload and urine output is important. A right atrial catheter reflects cardiac preload and is used to determine the preoperative fluid deficit and rate of intraoperative fluid infusion. When possible, the CVP catheter should be inserted through an antecubital vein instead of the jugular or subclavian veins. This avoids increased ICP from both the head-down position and decreased cerebral venous outflow. The position of the antecubital placed CVP catheter can be verified by chest x-ray, transducer pressure waveform, or p-wave configuration on the electrocardiogram. Urine output is also measured as an indicator of perioperative fluid balance. During craniotomy, a diuresis occurs initially after the administration of osmotic or loop diuretics. Reduced urine output may reflect either hypovolemia or release of antidiuretic hormone. Preoperative ICP monitoring is rarely used in patients for elective supratentorial tumor operations. ICP monitoring is an invasive procedure that can cause bleeding or infection. When performed with local anesthesia before induction, the procedure can be uncomfortable to the patient.

Induction, Maintenance, and Emergence When the patient is brought into the operating room, a gross neurologic examination should be repeated and documented because changes in the patient’s neurologic status can occur overnight. In patients with elevated ICP by clinical examination, computed tomography scan, and/or ICP measurement, osmotherapy may be indicated before induction of anesthesia. After appropriate monitoring devices are applied, the cooperative patient is asked to hyperventilate while preoxygenation is provided. Before laryngoscopy and intubation of the trachea, the patient is smoothly and deeply anesthetized with agents that reduce ICP. In the presence of elevated ICP,


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thiopental is commonly used to induce anesthesia; however, alternative agents such as propofol or midazolam can be used depending on the patient’s medical condition. The following induction sequence is suggested: The intravenous administration of thiopental (3 to 5 mg/kg−1) or propofol (1.25 to 2.5 mg/kg−1) is followed by an opioid (3 to 5 µg/kg−1 fentanyl) and muscle relaxant. If no airway difficulties are anticipated, a nondepolarizing muscle relaxant is administered while controlled hyperventilation with 100% oxygen is instituted. In patients who have been vomiting because of elevated ICP, cricoid pressure is applied during mask ventilation. To deepen the anesthetic, fentanyl is administered in 50 µg increments to a total dose of 10 µg/kg−1, depending on the blood pressure response. Lidocaine (1.5 mg/kg−1) is also administered intravenously 90 seconds before intubation to suppress laryngeal reflexes. When the peripheral muscle twitch response disappears, an additional 2 to 3-mg/kg−1 bolus of thiopental is administered, and tracheal intubation is performed as rapidly and smoothly as possible. An esmolol infusion or bolus may also be used to reduce the heart rate and blood pressure response to laryngoscopy and intubation. After induction of anesthesia, ventilation of the lung is controlled mechanically. Arterial blood gases are measured after intubation to establish the arterial–end-tidal CO2 gradient. Routine institution of hyperventilation is no longer recommended in neurosurgical patients because of the risk of cerebral ischemia in some pathologic conditions. Surgical conditions should define the PaCO2 level for each patient. For example, in patients with significant intracranial hypertension or when using volatile agents, PaCO2 is usually adjusted between 30 and 35 mm Hg to reduce brain bulk.7 After direct visualization of the brain and/or discussion with the neurosurgeon, the PaCO2 level should be adjusted as necessary. Because anesthetics affect the intracranial environment, there continues to be controversy over the best choice of anesthetic technique for neurosurgical patients, that is, intravenous- or volatile-based techniques. In practice, the anesthetics most frequently administered to neurosurgical patients are either propofol–opioid or isoflurane–opioid.8 The opioids selected are usually fentanyl or remifentanil. There have been no large clinical outcome studies conducted comparing anesthetic techniques. Our choice of anesthetics has been based primarily on information derived from experimental and clinical studies of cerebral hemodynamics (CBF, CMRO2), ICP, and recovery characteristics of different agents. A popular maintenance technique for neurosurgical patients is the continuous infusion of propofol with remifentanil or fentanyl. In patients with brain tumors, this technique has been shown to reduce ICP more effectively than either isoflurane or sevoflurane,8 and in nonneurosurgical patients, propofol with remifentanil produced a quicker emergence than either desflurane or sevoflurane.9 This technique would seem ideal for neurosurgical patients; however, questions have been raised regarding the risk of cerebral hypoperfusion with propofol anesthesia.10,11 Studies suggest that propofol anesthesia produces a reduction of CBF larger than a reduction of cerebral metabolic rate (CMR), resulting in a decrease of the CBF/CMR ratio.11,12 In susceptible patients, the risk of cerebral hypoperfusion may be even greater when patients are hyperventilated under propofol anesthesia.11,12 Nitrous oxide, 50% to 70% in oxygen, is administered by some to decrease the total dose of intravenous agent or the required concentration of volatile agent. The cerebrovascular effects of nitrous oxide are not benign,6,13 and studies report that at equipotent doses, isoflurane has less adverse effects on ICP and CBF than nitrous oxide.6 In patients with elevated ICP or low compliance, some clinicians avoid the administration of either nitrous oxide or high concentrations of isoflurane (that is, greater than 1.0%).

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Alternatively, an opioid—thiopental or propofol anesthetic technique may be used with midazolam or low-dose isoflurane added for amnesia. When severe intracranial hypertension exists and the brain is tight despite adequate hyperventilation and the administration of steroids and diuretics, a totally intravenous technique using a thiopental infusion (2 to 3 mg/kg−1/hr−1) and fentanyl boluses or infusion (1 to 4 µg/kg−1/hr −1) is recommended. In the usual craniotomy for excision of a supratentorial tumor, the conduct of the anesthetic is aimed at awakening and extubating the patient at the end of the procedure to permit early assessment of surgical results and postoperative neurologic follow up. The risks and benefits of an early versus delayed recovery in neurosurgical patients have been reviewed.14 The authors recommend extubation of the neurosurgical patient only when there is complete systemic and brain homeostasis. There are several conditions listed in Table 3 that can delay awakening in neurosurgical patients and should be considered before developing an extubation plan. Intracranial hematoma and major cerebral edema are the most feared complications after intracranial surgery. In a retrospective study of 11,214 craniotomy patients, a relationship was demonstrated between perioperative hypertension and the development of postoperative hematomas.15 Therefore, emergence from anesthesia should be as smooth as possible, avoiding straining or bucking on the endotracheal tube. Bucking can cause arterial hypertension and elevated ICP, which can lead to postoperative hemorrhage and cerebral edema. To avoid bucking, muscle relaxants are not reversed until the head dressing is applied. Intravenous lidocaine (1.5 mg/kg−1) can be administered 90 seconds before suctioning and extubation to minimize cough, straining, and hypertension. Antihypertensive agents such as labetalol and esmolol also are also administered during emergence to control systemic hypertension. The patient is extubated only when fully reversed from paralysis, and when he or she is awake and following commands. If the patient is not responsive, the endotracheal tube remains in place until the patient is awake and following commands. A brief neurologic examination is performed before and after extubation of the trachea. The patient is positioned with the head elevated 15° to 30° and transferred to the recovery room or intensive care unit (ICU) with oxygen by mask, oxygen saturation monitoring, and continued hemodynamic monitoring. Close monitoring and care, including frequent neurologic examinations, are continued in the recovery room (ICU).

Awake Craniotomy Awake craniotomy with functional mapping is recommended for removal of tumors involving the eloquent cortex. Functional mapping is performed by stimulating the TABLE 3.

Causes of Delayed Awakening

Preoperative decreased level of consciousness Large intracranial tumor Residual anesthetics Metabolic or electrolyte disturbances Residual hypothermia Surgical complications Seizures Cerebral edema Hematoma Pneumocephalus


9

brain with a small electrical charge. A neuropsychologist then performs neurocognitive testing and/or monitors motor responses during mapping and later tumor resection. This technique allows maximal tumor resection with minimal postoperative neurologic deficits from retraction, edema, and/or resection of eloquent tissue. Other advantages include avoidance of general anesthesia and need for more intensive monitoring intraoperatively and postoperatively, a low complication rate, and reduction in resource utilization (for example, shorter intensive care time and total hospital stay).16,17 Preoperative selection, evaluation, and preparation of the patients for awake craniotomy are slightly different than for general anesthesia. The patient must be cooperative and able to participate in neurocognitive testing. In addition, the patient must have an uncomplicated airway and be a candidate for general anesthesia. Most centers provide the patient with detailed information about the procedure and what to expect in verbal, written, and visual form. In the operating room, there are several challenges for the anesthesiologist. Like with any craniotomy, optimal operating conditions providing adequate surgical exposure and brain relaxation are required. For the awake craniotomy, the patient must be positioned very comfortably with bolsters and additional padding. Adequate analgesia and sedation are needed for head frame application, skin incision, craniotomy, and opening of the dura. During cortical mapping and tumor resection, the patient must be fully alert, cooperative, and able to participate in complex neurocognitive testing. Several different anesthetic protocols have been reported for awake craniotomy.16 These include neurolept anesthesia, propofol with or without opioid infusions, and asleep, awake, asleep techniques using laryngeal mask airways. Dexmedetomidine, a highly specific α-2 adrenoreceptor agonist, has been recommended for use during awake craniotomy.18 It has the advantage of providing sedation and analgesia without respiratory depression. All awake procedures with sedation run the risk of respiratory depression and poor patient cooperation. Complications such as seizures, increased ICP, hypertension, nausea, and vomiting, which are more likely to occur during craniotomy, also require prompt treatment.16,19 Most anesthetic protocols include prophylaxis with antihypertensives, anticonvulsants, and antiemetics.

Neuronavigation/Computer-assisted Surgery Neuronavigation allows precise anatomic mapping and orientation of tumors before the operation and throughout the procedure.20–23 Image-guided surgery can be performed with a magnetic resonance image (MRI) in the operating room or in a “twin operating theater,” the MRI suite is in close proximity to the conventional operating room. A study comparing the impact of neuronavigation on patients undergoing glioblastoma surgery found that absolute and relative residual tumor volumes were significantly lower with neuronavigation.24 Furthermore, radical tumor resection was associated with a highly significant prolongation in survival. In another study, imageguided resection of meningiomas was associated with less complications and shorter hospital stays when compared with conventional surgery.25 Anesthetic management concerns regarding intraoperative MRI have been discussed in recent articles.26–28 Along with concerns of administering an anesthetic in a remote location and using MRI-compatible anesthesia equipment, neuroanesthetic principles must also be applied when caring for these patients.

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Summary There are several challenges to anesthetizing patients with an intracranial mass lesion. The anesthesiologist must balance the needs of the patient (for example, optimizing cerebral homeostasis and cardiorespiratory status) with those of the surgeon (for example, unusual position, brain exposure without retraction, early emergence for neurologic examination). Appropriate selection of anesthetics and monitoring with meticulous general management of the patient’s respiration, circulation, fluid replacement, and positioning are all essential to improving outcome.

References 1. Brain Tumor Society: Brain Tumor Facts & Statistics, 2004; Central Brain Tumor Registry of the United States, Chicago, 2002–2003. Available at: www.cbtrus.org. Accessed April 26, 2004. 2. Qureshi AI, Suarez JI: Use of hypertonic saline solutions in treatment of cerebral edema and intracranial hypertension. Crit Care Med 2000; 28:3301–13. 3. Vialet R, Albanese J, Thomachot L, et al.: Isovolume hypertonic solutes (sodium chloride or mannitol) in the treatment of refractory posttraumatic intracranial hypertension: 2 mg/kg 7% saline is more effective than 2 ml/kg 2% mannitol. Crit Care Med 2003; 31:1683–7. 4. Obrist WD, Langfitt TW, Jaggi JL, et al.: Cerebral blood flow and metabolism in comatose patients with acute head injury. Relationship to intracranial hypertension. J Neurosurg 1984; 61:241–53. 5. Coles JP, Minhas PS, Fryer TD, et al.: Effect of hyperventilation on cerebral blood flow in traumatic head injury: Clinical relevance and monitoring correlates. Crit Care Med 2002; 30:1950–9. 6. Bendo AA, Kass IS, Hartung J, Cottrell JE: Anesthesia for Neurosurgery. In: Barash PG, Cullen BF, Stoelting RK, eds. Clinical Anesthesia, 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2001:743–89. 7. Kaye A, Kucera IJ, Heavner J, et al.: The comparative effects of desflurane and isoflurane on lumbar cerebrospinal fluid pressure in patients undergoing craniotomy for supratentorial tumors. Anesth Analg 2004; 98:1127–32. 8. Peterson KD, Landsfeldt U, Cold GE, et al.: Intracranial pressure and cerebral hemodynamic in patients with cerebral tumors: A randomized prospective study of patients subjected to craniotomy in propofol-fentanyl, isoflurane-fentanyl or sevoflurane–fentanyl anesthesia. Anesthesiology 2003; 98:329–36. 9. Larsen B, Seitz A, Larsen R: Recovery of cognitive function after remifentanil–propofol anesthesia: A comparison with desflurane and sevoflurane anesthesia. Anesth Analg 2000; 90:168–74. 10. Cenic A, Craen RA, Lee T-Y, et al.: Cerebral blood volume and blood flow responses to hyperventilation in brain tumors during isoflurane or propofol anesthesia. Anesth Analg 2002; 94:661–6. 11. Jansen GFA, van Praagh BH, Kadaria MB, et al.: Jugular bulb oxygen saturation during propofol and isoflurane/nitrous oxide anesthesia in patients undergoing brain tumor surgery. Anesth Analg 1999; 89:358–63. 12. Kawano Y, Kawaguchi M, Horiuchi T, et al.: Jugular bulb oxygen saturation under propofol or sevoflurane/nitrous oxide anesthesia during deliberate mild hypothermia in neurosurgical patients. J Neurosurg Anesthesiol 2004; 16:6–10. 13. Pelligrino DA, Miletich DJ, Hoffman WE, et al.: Nitrous oxide markedly increases cerebral cortical metabolic rate and blood flow in the goat. Anesthesiology 1984; 60:405–12. 14. Bruder N, Ravussin P: Recovery from anesthesia and postoperative extubation of neurosurgical patients: A review. J Neurosurg Anesthesiol 1999; 11:282–93. 15. Basali A, Mascha EJ, Kalfas I, et al.: Relation between perioperative hypertension and intracranial hemorrhage after craniotomy. Anesthesiology 2000; 93:48–54. 16. Manninen PH, Tan TK: Postoperative nausea and vomiting after craniotomy for tumor surgery: A comparison between awake craniotomy and general anesthesia. J Clin Anesth 2002; 14:279–83.


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17. Bendo AA: Supratentorial tumors: Anesthetized, awake and computer-assisted management. In: Annual Meeting Refresher Course Lectures, ASA 2004, no. 138, pp 1–7. 18. Mack PF, Perrine K, Kobylarz E, et al.: Dexmedetomidine and neurocognitive testing in awake craniotomy. J Neurosurg Anesth 2004; 16:20–5. 19. Sarang A, Dinsmore J: Anesthesia for awake craniotomy–evolution of a technique that facilitates awake neurological testing. Br J Anaesth 2003; 90:161–5. 20. Meyer FB, Bates LM, Goerss SJ, et al.: Awake craniotomy for aggressive resection of primary gliomas located in eloquent brain. Mayo Clin Proc 2001; 76:677–87. 21. Haberland N, Ebmeier K, Hliscs R, et al.: Neuronavigation in surgery of intracranial and spinal tumors. J Cancer Res Clin Oncol 2000; 126:529–41. 22. Tuominen J, Yrjana SK, Katisko JP, et al.: Intraoperative imaging in a comprehensive neuronavigation environment for minimally invasive brain tumor. Acta Neurochir Suppl 2003; 85:S115–20. 23. Bernstein M, Al-Anazi AR, Kucharczyk W, et al.: Brain tumor surgery with the Toronto-open magnetic resonance imaging system: Preliminary results for 36 patients and analysis of advantages, disadvantages, and future prospects. Neurosurgery 2000; 46:900–7. 24. Wirtz CR, Albert FK, Schwadarer M, et al.: The benefit of neuronavigation for neurosurgery analyzed by its impact on glioblastomas surgery. Neurol Res 2000; 22:354–60. 25. Paleologos TS, Wadley JP, Kitchen ND, et al.: Clinical utility and cost-effectiveness of interactive image-guided craniotomy: Clinical comparison between conventional and imageguided meningioma surgery. Neurosurgery 2000; 47:40–7. 26. Manninen PH, Kucharczyk W: A new frontier: Magnetic resonance imaging-operating room. J Neurosurg Anesth 2000; 12:141–8. 27. Archer DP, McTaggart Cowan RA, et al.: Intraoperative mobile magnetic resonance imaging for craniotomy lengthens the procedure but does not increase morbidity. Can J Anesth 2002; 49:420–6. 28. Schmitz B, Nimsky C, Wendel G, et al.: Anesthesia during high-field intraoperative magnetic resonance imaging experience with 80 consecutive cases. J Neurosurg Anesth 2003; 15:255–62.

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CHEMICAL DEPENDENCE: UNDERSTANDING THE DISEASE AND ITS TREATMENT ARNOLD J. BERRY, M.D., M.P.H. PROFESSOR OF ANESTHESIOLOGY DEPARTMENT OF ANESTHESIOLOGY EMORY UNIVERSITY SCHOOL OF MEDICINE ATLANTA, GEORGIA



© 2005



Chemical Dependence: Understanding the Disease and Its Treatment Arnold J. Berry, M.D., M.P.H. Professor of Anesthesiology Department of Anesthesiology Emory University School of Medicine Atlanta, Georgia

Substance abuse and chemical dependence* are major causes of physician impairment.1,2 Although substance abuse represents a maladaptive pattern of use of a psychoactive drug, chemical dependence is a chronic disease characterized by compulsive use of the addictive substance (Table 1). With chemical dependence, there is loss of control and such an irrepressible craving of the substance that the individual’s behavior is changed. Drug use continues despite the health, social, and economic problems that inevitably occur. The addicted individual is unsuccessful in attempting to control or limit the drugs being used. They must spend considerable time obtaining drugs, and this behavior interferes with social, occupational, and recreational activities.

Chemical Dependence Is a Disease Chemical dependence is a disease that has biologic, behavioral, and social-context components. Any effective treatment must address all of these issues. Chronic use of addicting substances produces specific effects on the mesocorticolimbic dopaminergic reward system of the brain, the pathway that extends from the ventral tegmental area (VTA) of the midbrain to the nucleus accumbens and includes projections to the limbic system, amygdala, and orbitofrontal cortex3 (Fig. 1). This neural pathway is involved in rewarding and reinforcing the effects of positive natural stimuli for survival such as food and reproduction. The VTA–nucleus accumbens pathway serves to evaluate how rewarding an event is, the amygdala perceives whether an event is pleasurable, and the frontal cortex processes the information to determine what behavior to take. Although rodent models have been used for much of the work characterizing neural pathways affected by chemical dependence, positron emission tomography (PET) scans in humans are consistent with the laboratory animal findings. Addictive drugs, like natural rewards, stimulate dopamine release from neurons in the presynaptic VTA and produce euphoria. Repeated doses of addictive drugs stimulate the release of dopamine, producing pleasurable responses, and result in a learned association between the stimulus and the anticipation of the rewarding effects. Ethanol and benzodiazepines produce their effects by binding to GABA type A receptors. Ethanol also inhibits NMDA-sensitive glutamate receptors. Opioid effects are mediated through G-protein-coupled receptors. The opioid µ-receptor is required for analgesia and withdrawal symptoms. *The American Psychiatric Association uses the term “substance dependence,” whereas others use “addiction.”

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TABLE 1.

Criteria for Substance-related Disorders*

Substance abuse: A maladaptive pattern of substance use leading to clinically significant impairment as manifested by one or more of the following: • Failure to fulfill major role obligations; • Recurrent substance use in situations in which it is physically dangerous; • Substance-related legal problems; or • Continue substance use despite having recurrent social or interpersonal problems caused by the effects of the substance. Substance dependence: A maladaptive pattern of substance use leading to clinically significant impairment as manifested by three or more of the following: • Tolerance (a need for increased amounts of the substance to achieve the desired effect); • Withdrawal symptoms; • Substance is taken in larger amounts or over a longer period than was intended; • Unsuccessful efforts to control substance use; • A great deal of time is spent to obtain the substance; • Important social, occupational, or recreational activities are given up or reduced; or • Substance use is continued despite knowledge of having a physical or psychological problem caused by the substance. *Modified from DSM-IV Criteria, American Psychiatric Association’s Website. Available at: http:// www.psych.org/psych_pract/treatg/pg/pg_substance_2.cfm?pf=y. Accessed November 11, 2004.

FIG. 1. Neural pathways of the mesocorticolimbic dopamine (DA) system are important in the reinforcing effects of drugs of abuse. This representation of the rat brain demonstrates the projections of dopamine, norepinephrine (NE), glutamine (GLU), γ-aminobutyric acid (GABA), and serotonergic (5-HT) neurons and the proposed sites of actions of drugs of abuse. Reproduced with permission from Cami J, Farre M: Drug addiction. N Engl J Med 2003; 349:975–86. Copyright © 2003, MA Medical Society. All rights reserved.

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With initial use, opioids activate µ-receptors, which inhibit adenyl cyclase, lowering cAMP levels.3 Repeated administration of narcotics desensitizes opioid receptors, and tolerance seems to be associated with a decrease in the number of opioid receptors. Chronic stimulation of opioid receptors results in upregulation of cAMP pathways and an increase in factors that regulate gene transcription (phosphorylation of CREB [cAMP-responsive element-binding protein] and ∆Fos).4,5 Synaptic remodeling of neurons occurs in response to ∆Fos, and these changes persist for weeks or months after sobriety. When opioid levels decrease after periods of chronic administration, physical signs of withdrawal are produced by an increase in adrenergic output from rapidly firing neurons in the locus ceruleus. Alterations in neurotransmitter function result in tolerance whereby the individual must increase the dose of drug or reduce the intervals between doses to obtain the desired pleasurable effects. When symptoms of withdrawal occur, resumption of drug use will prevent or reduce the unpleasant physical symptoms and dysphoria. Neuronal remodeling in brain pathways may persist for 2 years or more after stopping drugs. Therefore, chemical dependence is a chronic, relapsing disorder.5 An understanding of the changes in neural pathways associated with chemical dependence holds promise for creating specific therapies targeted at affected neurons and their receptors. Genetic factors play a role in predisposition and susceptibility to chemical dependence. There is increased likelihood of alcoholism in the children of alcoholic parents, and an allele of a dopamine receptor gene has been linked to alcohol and opioid dependence. A large body of research has demonstrated that psychosocial factors also play a role in chemical dependence. Because psychiatric disorders may frequently coexist with chemical dependence, effective treatment must address both conditions.6,7 Finally, environmental factors may serve as stressors in susceptible individuals.8 Initial pleasurable responses to addicting drugs are linked to environmental cues leading to conditioned responses.9 The environmental cues then become associated with a craving for the drug or with symptoms of withdrawal.

Substance Abuse in Anesthesiologists Anesthesiologists work in an environment where they have ready access to controlled substances and are unique among physicians because they are responsible for administering these powerful drugs directly to patients. Data from treatment facilities indicates that polydrug use is common in anesthesiologists with chemical dependence.10 Alcohol may often be used along with another substance. All classes of substances, including propofol and volatile anesthetic agents, have been abused, but fentanyl and sufentanil remain the injectable agents most commonly used by anesthesiologists.10,11 Fentanyl is easily accessible, is difficult to detect on standard, random urine screens, and has a rapid onset of action. Doses can be easily titrated, and it has a short duration of action, making it compatible for use while on duty. There have been several studies attempting to determine the incidence of chemical dependence in practicing anesthesiologists and trainees.11–14 In one of the more recent investigations, a postal survey was sent to 133 academic anesthesiology programs to assess data for residents and faculty from 1990 to 1997.11 The information from respondents indicated a prevalence of controlled substance abuse of 1.6% among residents (133 of 8,111) and 1.0% among faculty (34 of 3,555). Thirty of the 167 affected individuals (18%) died or required emergent resuscitation as a result of their chemical dependence. Additional data collected from the academic training

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programs demonstrated that there was no difference in the amount of education regarding substance abuse between the programs who reported no abuse and those who had one or more users. Booth et al.11 noted that the prevalence of substance abuse was similar to that in previous reports from 1970 and 1980.13,15 The data from this study indicate that implementation of educational programs and methods to manage distribution of controlled substances (that is, satellite pharmacy, accounting policies, and drug-dispensing machines) were not successful in eliminating diversion of drugs by individuals with chemical dependence. A survey of 260 anesthesiologists trained at the Medical College of Wisconsin from 1958 through 1988 demonstrated a 15.8% (29 of 183) prevalence of substance dependence in anesthesiologists.12 The data included six individuals with opioid use, 19 with alcohol abuse, and four with both. The prevalence rate for substance dependence was greater for individuals trained before 1975. Substance abuse was more prevalent in the parents of impaired anesthesiologists (36%) than those without impairment (8%).

Identification and Treatment Chemical dependence can occur in all groups of anesthesia professionals, including physicians in practice, residents in training, anesthetists (CRNAs and anesthesiologist assistants), and student anesthetists.16 Activities may be directed at preventing substance abuse and toward early detection. Prevention efforts include educational programs to provide information for both anesthesia professionals as well as their spouses and significant others and implementation of pharmacy policies to prevent drug diversion (strict accounting of controlled substances and random testing of returned syringes), policies that permit random drug screening (see subsequently), and strategies to promote healthy lifestyles (work schedules that encourage adequate sleep and stress reduction). Because chemical dependence is a disease, prevention strategies are likely to be relatively ineffective. Therefore, greater effort should be directed toward early identification of individuals with the disease so that they can receive appropriate treatment and counseling. Identification of individuals with chemical dependence may be difficult, but as the disease progresses, they are likely to demonstrate one or more characteristic findings (Tables 2 and 3). Unfortunately, friends, spouses, and colleagues frequently deny that any problem exists with the chemically dependent individual and instead, will accept seemingly plausible explanations even though they are contradictory to their personal observations. Anesthesia professionals with the disease must spend an extraordinary portion of their free time in the hospital because this is where they have access to drugs. Professional responsibilities are often the last to be affected. Spouses and significant others outside the workplace must receive information regarding the signs and symptoms of chemical dependence because they are likely to be the first to observe the changes associated with the disease. Although random drug testing has been used in the military and in many industries to prevent substance abuse, the use of random testing as a prevention strategy for anesthesiology is associated with several issues.17 Routine toxicology screening tests usually will not detect fentanyl and its derivatives; identification of these opioids requires special laboratory testing at significantly increased cost. There must be a rigorous chain of custody for all collected samples. “Clean” urine can be purchased in many venues, and false-negative urine samples are possible even with directly observed collection. In addition, there are many causes of false-positive results, and these must be

CHEMICAL DEPENDENCE TABLE 2.

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Signs of Substance Abuse and Dependence: What to Look for Outside the Hospital

1. Addiction is a disease of loneliness and isolation. Addicts quickly withdraw from family, friends, and leisure activities. 2. Addicts have unusual changes in behavior, including wide mood swings, periods of depression, anger, and irritability alternating with periods of euphoria. 3. Unexplained overspending, legal problems, gambling, extramarital affairs, and increased problems at work are commonly seen in addicts. 4. An obvious physical sign of alcoholism is the frequent smell of alcohol on the breath. 5. Domestic strife, fights, and arguments may increase in number and intensity. 6. Sexual drive may significantly decrease. 7. Children may develop behavioral problems. 8. Some addicts frequently change jobs over a period of several years in an attempt to find a “geographic cure” for their disease or to hide it from coworkers. 9. Addicts need to be near their drug source. For a healthcare professional, this means long hours at the hospital, even when off duty. For alcoholics, it means calling in sick to work. Alcoholics may disappear without any explanation to bars or hiding places to drink secretly. 10. Addicts may suddenly develop the habit of locking themselves in the bathroom or other rooms while they are using drugs. 11. Addicts frequently hide pills, syringes, or alcohol bottles around the house. 12. Persons who inject drugs may leave bloody swabs and syringes containing blood-tinged liquid in conspicuous places. 13. Addicts may display evidence of withdrawal, especially diaphoresis (sweating) and tremors. 14. Narcotic addicts often have pinpoint pupils. 15. Weight loss and pale skin are common signs of addiction. 16. Addicts may be seen injecting drugs. 17. Tragically, some addicts are found comatose or dead before any of these signs have been recognized by others. Adapted from Farley WJ, Arnold WP: VIDEOTAPE: Unmasking Addiction: Chemical Dependency in Anesthesiology. Produced by David’s Productions, Parsippany, NJ, funded by Janssen Pharmaceutica, Piscataway, NJ, 1991. Reprinted with permission from American Society of Anesthesiologists: Task Force on Chemical Dependence of the Committee on Occupational Health of Operating Room Personnel: Chemical Dependence in Anesthesiologists: What You Need to Know When You Need to Know It. Park Ridge, IL: American Society of Anesthesiologists, 1998.

followed up with further testing. Before implementing any policies for random drug testing, it is important to consult with legal counsel regarding hospital policy as well as federal, state, and local laws and regulations. Chemical dependence, if undetected, may result in death. A cause-specific mortality study comparing causes of death in anesthesiologists with a matched cohort of internists used data from 1979 through 1995 contained in the National Death Index.18 Compared with internists, anesthesiologists had an increased risk of suicide (rate ratio [RR] = 1.45), drug-related suicide (RR = 2.21), and all drug-related deaths (RR = 2.79). The years of life lost before age 65 (premature death) for anesthesiologists attributable to all drug-related causes was 2,108 life-years. These data demonstrate the significant impact that chemical dependence has on anesthesiologists. Early data from one treatment program for impaired physicians suggested that anesthesiologists may have a greater rate of chemical dependence than other physician specialists.19 Talbott reported that although anesthesiologists represented only approximately 4% of all physicians in the United States, 12% of physicians being treated in his program for chemical dependence were anesthesiologists. The data from this treatment center were insufficient to determine whether this overrepresentation was the result of better methods to identify chemically dependent anesthesiologists or whether it truly represented an increased risk associated with the specialty. More recent data on

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BERRY Signs of Substance Abuse and Dependence: What to Look for Inside the Hospital

1. Addicts sign out ever-increasing quantities of narcotics. 2. Addicts frequently have unusual changes in behavior such as wide mood swings, periods of depression, anger, and irritability alternating with periods of euphoria. 3. Charting becomes increasingly sloppy and unreadable. 4. Addicts often sign out narcotics in inappropriately high doses for the operation being performed. 5. They refuse lunch and coffee relief. 6. Addicts like to work alone to use anesthetic techniques without narcotics, falsify records, and divert drugs for personal use. 7. They volunteer for extra cases, often where large amounts of narcotics are available (for example, cardiac cases). 8. They frequently relieve others. 9. They are often at the hospital when off duty, staying close to their drug supply to prevent withdrawal. 10. They volunteer frequently for extra call. 11. They are often difficult to find between cases, taking short naps after using. 12. Addicted anesthesia personnel may insist on personally administering narcotics in the recovery room. 13. Addicts make frequent requests for bathroom relief. This is usually where they use drugs. 14. Addicts may wear long-sleeved gowns to hide needle tracks and also to combat the subjective feeling of cold they experience when using narcotics. 15. Narcotic addicts often have pinpoint pupils. 16. An addict’s patients may come into the recovery room complaining of pain out of proportion to the amount of narcotic charted on the anesthesia records. 17. Weight loss and pale skin are common signs of addiction. 18. Addicts may be seen injecting drugs. 19. Untreated addicts are found comatose. 20. Undetected addicts are found dead. Adapted from Farley WJ, Arnold WP: VIDEOTAPE: Unmasking Addiction: Chemical Dependency in Anesthesiology. Produced by David’s Productions, Parsippany, NJ, funded by Janssen Pharmaceutica, Piscataway, NJ, 1991. Reprinted with permission from American Society of Anesthesiologists: Task Force on Chemical Dependence of the Committee on Occupational Health of Operating Room Personnel: Chemical Dependence in Anesthesiologists: What You Need to Know When You Need to Know It. Park Ridge, IL: American Society of Anesthesiologists, 1998.

108 physicians being evaluated for substance use disorders demonstrated that 4.6% were anesthesiologists and that the specialty was not overrepresented in this sample.7 A study of substance use by residents in 11 medical specialties indicated that anesthesiology residents did not have unexpectedly high rates of use and that the greatest rates occurred among emergency medicine and psychiatry residents.20 When there are sufficient data to demonstrate that an individual is chemically dependent, evaluation and treatment should be undertaken at a treatment center with expertise in caring for physicians with chemical dependence.1,21,22 It is rare that physicians with chemical dependence will self-refer to initiate treatment, and therefore, an intervention is usually required to demonstrate to the chemically dependent individual that they have the disease and are in need of treatment. The intervention must be carefully planned and executed by an experienced individual. Records and documentation should be available to present to the chemically dependent individual. Family, colleagues, and recovering physicians are often included to demonstrate support and caring for the affected individual. Arrangements should be in place for immediate evaluation and treatment of the individual. They should not be left alone after the intervention.

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Treatment usually includes diagnostic evaluation, detoxification, education, psychotherapy, and integration into a self-help group such as Alcoholics Anonymous or Narcotics Anonymous.21 Physicians may have difficulty accepting that they have the disease of chemical dependence, and therefore, a treatment center that has experience in caring for physicians is most desirable. After an inpatient phase of treatment, the recovering individual will participate in outpatient day or evening programs, usually in a peer group setting. Finally, there is a phase of extended aftercare that includes monitoring for abstinence and regular attendance at support group meetings. The individual selects a sponsor and participates in 12-step meetings. Random urine monitoring is begun, and some individuals may be prescribed daily naltrexone23 or disulfiram. There should also be contact established with the hospital or local medical society’s wellness committee. Because of the risk for relapse, the decision to return to work and the drugcontaining environment must be made by the treating physician and should be based on several criteria.21 Reentry is most successful when the affected individual has a good understanding of their disease, bonds and actively participates in Alcoholics Anonymous or Narcotics Anonymous, has strong family support, has no psychiatric disease or personality disorder, and has an anesthesiology department with good support from staff.24 Relapses are most commonly associated with concomitant psychiatric diagnoses, a dysfunctional family, multiple addictions, and problems coping with stress.6 Some affected anesthesiologists may never be able to return to their former employment. Special consideration should be undertaken for recovering anesthesia residents because they may be better served by a recommendation to enter another medical specialty. When it has been decided that an anesthesiologist may return to the workplace, a reentry contract is used to define the process and to set rules for both parties. (Information regarding chemical dependence can be found on the American Society of Anesthesiologists web site: http://www.asahq.org/publicationsAndServices/chemical.html and http://www.asahq.org/clinical/curriculum.pdf.)

Legal Issues Because diversion and illicit use of controlled substances are felonies, there are significant legal issues that must be addressed. State medical societies and hospitals usually have impaired physician/wellness committees to advise employers and to buffer the legal impact on the impaired physician. (The American Society of Anesthesiologists Executive Office can be contacted at 847-825-5586 to obtain the addresses and telephone numbers for state medical society programs and services that assist impaired physicians.) Usually, when an impaired physician willingly undergoes treatment, the legal impact is less severe. The Americans with Disabilities Act (ADA) may also be pertinent to the management of impaired physicians in the workplace. The ADA protects former drug users who are participating in or who have completed treatment as well as individuals legally using prescribed drugs. The ADA does not protect current users of illegal drugs. Because of the complexity of federal and state laws, departmental leaders should consult legal counsel when making decisions regarding impaired physicians.

Conclusions Chemical dependence is a complex illness, but many treatment opportunities are available for impaired physicians. Because of the serious consequences resulting from

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failure to detect chemical dependence, we must be vigilant for signs and symptoms of the disease in our colleagues.

References 1. Silverstein JH, Silva DA, Iberti TJ: Opioid addiction in anesthesiology. Anesthesiology 1993; 79:354–75. 2. Boisaubin EV, Levine RE: Identifying and assisting the impaired physician. Am J Med Sci 2001; 322:31–6. 3. Cami J, Farre M: Drug addiction. N Engl J Med 2003; 349:975–86. 4. Nester EJ, Malenka RC: The addicted brain. Sci Am 2004; March:78–85. 5. Nester EJ: Molecular basis of long-term plasticity underlying addiction. Nat Rev Neurosci 2001; 2:119–28. 6. Angres DH, McGovern MP, Rawal P, Shaw M: Psychiatric comorbidity and physicians with substance use disorders: Clinical characteristics, treatment experiences, and post-treatment functioning. Addict Disord Their Treatment 2002; 1:89–98. 7. McGovern MP, Angres DH, Leon S: Characteristics of physicians presenting for assessment at a behavioral health center. J Addict Dis 2000; 19:59–73. 8. Siegel S, Ramos BM: Applying laboratory research: Drug anticipation and the treatment of drug addiction. Exp Clin Psychopharmacol 2002; 10:162–83. 9. Schulteis G, Ahmed S, Morse AC, Koob GF, Everitt BJ: Conditioning and opiate withdrawal. Nature 2000; 405:1013–4. 10. Gallegos KV, Browne CH, Veit FW, Talbott GD: Addiction in anesthesiologists: Drug access and patterns of substance abuse. QRB 1988; 14:116–22. 11. Booth JV, Grossman D, Moore J, et al.: Substance abuse among physicians: A survey of academic anesthesiology programs. Anesth Analg 2002; 95:1024–30. 12. Lutsky I, Hopwood M, Abram S, et al.: Psychoactive substance use among American anesthesiologists: A 30-year retrospective study. Can J Anaesth 1993; 40:1993–7. 13. Ward CF, Ward GC, Saidman LJ: Drug abuse in anesthesia training programs. A survey: 1970 through 1980. JAMA 1983; 250:922–5. 14. Gravenstein JS, Kory WP, Marks RG: Drug abuse by anesthesia personnel. Anesth Analg 1983; 62:467–72. 15. Menk EJ, Baumgarten RK, Kingsley CP, Culling RD, Middaugh R: Success of reentry into anesthesiology training programs by residents with a history of substance abuse. JAMA 1990; 263:3060–2. 16. Aach R, Girard D, Humphrey H: Alcohol and other substance abuse and impairment among physicians in residency training. Ann Intern Med 1992; 116:245–54. 17. Scott M, Fisher KS: The evolving legal context for drug testing programs. Anesthesiology 1990; 73:1022–7. 18. Alexander BH, Checkoway H, Nagahama SI, Domino KB: Cause-specific mortality risks of anesthesiologists. Anesthesiology 2000; 93:922–30. 19. Talbott GD, Gallegos KV, Wilson PO, Porter TL: The Medical Association of Georgia’s Impaired Physicians Program: Review of the first 1000 physicians. Analysis of specialty. JAMA 1987; 257:2927–30. 20. Hughes PH, Baldwin DC, Sheehan DV, Conard S, Storr CL: Resident physician substance use, by specialty. Am J Psychiatry 1992; 149:1348–54. 21. Angres DH, Talbott GD, Bettinardi-Angres K: Healing the Healer: The Addicted Physician. Madison, CT: Psychosocial Press; 1998. 22. American Society of Anesthesiologists Task Force on Chemical Dependence: Chemical Dependence in Anesthesiologists: What You Need to Know When You Need to K. Park Ridge, IL: American Society of Anesthesiologists; 1998. 23. Modesto-Lowe V, Van Kirk J: Clinical uses of naltrexone: A review of the evidence. Exp Clin Psychopharmacol 2002; 10:213–27. 24. May JA, Warltier DC, Pagel PS: Attitudes of anesthesiologists about addiction and its treatment: A survey of Illinois and Wisconsin members of the American Society of Anesthesiologists. J Clin Anesth 2002; 14:284–9.



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RECOGNITION AND TREATMENT OF MALIGNANT HYPERTHERMIA BARBARA W. BRANDOM, M.D. PROFESSOR, DEPARTMENT OF ANESTHESIOLOGY UNIVERSITY OF PITTSBURGH SCHOOL OF MEDICINE DEPARTMENT OF ANESTHESIOLOGY CHILDREN’S HOSPITAL OF PITTSBURGH UNIVERSITY OF PITTSBURGH MEDICAL CENTER PITTSBURGH, PENNSYLVANIA



© 2005



Recognition and Treatment of Malignant Hyperthermia Barbara W. Brandom, M.D. Professor, Department of Anesthesiology University of Pittsburgh School of Medicine Department of Anesthesiology Children’s Hospital of Pittsburgh University of Pittsburgh Medical Center Pittsburgh, Pennsylvania

Recognition of a clinical episode of malignant hyperthermia (MH) remains a problem for the anesthesiologist. With current anesthetic techniques, the onset of a MH episode may be slow.1 Halothane has more effect on the opening of the ryanodine receptor and therefore allows more calcium to enter the myoplasm from the sarcoplasmic reticulum than do the newer inhalation anesthetics. Succinylcholine may make the episode more severe because it depolarizes the muscle cell. When these drugs are not given, fewer cases of MH occur and they may occur later in the course of the anesthetic. Many cases of MH have occurred in which anesthesia was uncomplicated for an hour or more before the occurrence of MH signs.2–4 The sine qua non of MH is an unexplained increase in carbon dioxide production. Initially, increased minute ventilation may compensate for increased production and end-tidal carbon dioxide may remain constant.2 However, as energy stores in the muscle are depleted and intracellular calcium continues to rise in muscle, carbon dioxide production and temperature become greater (Fig. 1).5 Then critical temperature and cardiovascular collapse may occur. Acute episodes of MH are more common in males. Large muscle bulk and recent exercise are also common in patients developing acute MH. Temperature monitoring can be vital in such cases because the duration of core temperature elevation is extremely important. There is a critical temperature above which multiorgan system failure is expected to occur in anyone.6 The signs of MH may be lessened by removal of inhalation anesthetics, treatment with dantrolene, and general supportive measures. However, there have been cases in which core temperature elevation was followed by central nervous system injury, although treatment of MH otherwise appeared adequate. Other causes of critical temperature such as allergic drug reactions, exogenous overheating, baclofen withdrawal, excessive motor activity, and impaired temperature regulation, like may occur in cases of severe cerebral palsy, should be differentiated from MH. These causes of critical temperature are not related to an autosomal-dominant occult myopathy.

Presumptive Diagnosis and Initial Evaluation When an MH episode is suspected, the minute ventilation and end-tidal carbon dioxide should be documented. Muscle tone should be noted. All vital signs, including core temperature, should be documented. Esophageal, tympanic, or nasal temperature probes can often be inserted easily during the course of anesthesia. An axillary temperature probe will be falsely low unless it is close to the axillary artery. Venous 21

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FIG. 1. An adolescent received propofol, mivacurium, and isoflurane for more than 2 hours when malignant hyperthermia was suspected and treated. From Nelson TE.5

blood gases from the antecubital or femoral vein may reveal respiratory acidosis, increased lactate and hyperkalemia before these abnormalities are observable in arterial blood. After dantrolene is given, documentation of changes in vital signs and laboratory values should be repeated. Response to dantrolene suggests, but does not prove, that the cause of the problem was classic MH. Dantrolene can reduce intracellular calcium and thus muscle metabolism in normal muscle. Dantrolene can reduce the force of contraction of normal muscle to 30% of baseline. Thus, dantrolene can reduce carbon dioxide production and heat production in normal individuals. However, the response during an MH episode is usually more dramatic (Fig. 1). Creatine kinase (CK) measurements should be repeated every 12 to 24 hours until they decrease to normal. This may require more than several days. An episode of acute MH may occur in the presence of minimal CK elevation. So a perioperative CK of 300 IU is not necessarily evidence against the diagnosis of mild or abortive MH. The MH Hotline, 1-800-644-9737, 1-800-MH HYPER, is staffed 24 hours a day by anesthesiologists who volunteer to help with the diagnosis and treatment of acute MH episodes. Acute MH episodes should be reported to the MH Registry on Adverse Metabolic Reaction to Anesthesia (AMRA) forms. These reports are sent to the physicians who called the Hotline. AMRAs may be obtained more quickly by calling the MH Registry at 412-692-5464. The AMRA can be seen at www.mhreg.org, but online submission was not yet available in 2004. There are no facts that can identify the patient on the AMRA report. The affected patient can be “registered” after that individual calls the MH Registry, completes consent to participate in the Registry, and places relevant

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information on an “AKA” form. These documents are also available for reading and printing at www.mhreg.org. The consenting participants in the Registry can get access to their AKA and AMRA forms thereafter by calling the Registry. MH-like symptoms can occur without exposure to anesthetic drugs. MH may occur in humans,7–9 like it has in susceptible animals, associated with exercise rather than anesthesia. Similarly, there are some rare cases of nonanesthetic drug-induced rhabdomyolysis in individuals with underlying abnormality of muscle function.10 Although some of these cases are not “classic MH,” the same decisions regarding diagnosis and treatment are relevant. These cases can also be reported on AMRAs.

Diagnosis and Definitive Evaluation After emergency treatment, a plan for definitive diagnosis of a potential myopathy should be made. This should include referral to one of the several malignant hyperthermia diagnostic centers functioning in North America where in vitro contracture testing with exposure to halothane and caffeine can be performed. This is the only test that can result in the diagnosis of NOT MH susceptible. In 2000 to 2001, there were 12 such centers available to patients in the United States and Canada. In 2005, there are two centers in Canada, in Ottawa and Toronto; and six in the United States, at the University of California at Los Angeles and at Davis, the University of Minnesota, the Uniformed Services University of the Health Sciences, Wake Forest University, and Thomas Jefferson University. See www.mhaus.org for addresses of MH diagnostic centers.

Adverse Anesthetic Events in Other Muscular Diseases Although a patient may undergo a muscle biopsy at any hospital, it is not the case that muscle obtained in any hospital will be suitable for contracture testing. If muscle is sent for routine pathologic examination with the expectation that a definitive diagnosis regarding MH susceptibility will be made, you will be disappointed. However, evaluation of the patient by a neurologist may be useful for several reasons. There are a few muscle disorders, central core disease and hypokalemic periodic paralysis in particular, that have been associated with MH episodes and positive contracture tests. Myotonia during anesthesia can produce many of the signs of MH. In some myopathies such as dystrophinopathies and other abnormalities of the structural proteins in the muscle membrane (Fig. 2), there is chronic elevation of CK indicating chronic rhabdomyolysis. Rarely anesthesia, more often inhalation anesthetics, but even total intravenous anesthetics without succinylcholine, have been associated with intraoperative or postoperative exacerbation of muscle breakdown and hyperkalemic cardiac arrest. Many cases of hyperkalemic cardiac arrest after administration of succinylcholine to boys and girls with occult myopathy have been recorded. These cases are not the same as classic MH but many of the signs are similar. Therefore, it is useful for the patient to be evaluated by a neurologist for the presence of occult myopathy. The implications of a diagnosis of X-linked myopathy, myotonia, or autosomal-dominant ryanodine receptor mutation are quite different for the rest of the family. Contracture testing for diagnosis of MH susceptibility must be arranged in advance with one of the active MH diagnostic centers. The patient must travel to the MH diagnostic center to undergo biopsy and contracture testing so that the test can be performed within 4 hours of excision of muscle from the patient.

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FIG. 2. There are many proteins in the sarcolemma that extend out into the extracellular matrix or inward toward the contractile apparatus of the muscle cell. When proteins that connect the sarcolemma with the extracellular matrix and contractile proteins are abnormal, congenital myopathy or muscular dystrophy (e.g., DMD/BMD/LGMD, merosin deficiency) may occur. CMD: congenital muscular dystrophy; DMD/BMD: Duchenne’s/Becker’s muscular dystrophy; LGMD: limb girdle muscular dystrophy with types 1C to F; MM: Miyoshi myopathy.

Rationale for Contracture Testing It is important that individuals who have experienced episodes consistent with MH undergo further evaluation because a large proportion of these cases are found to be MHN, not susceptible to MH.11 This is an important fact for the family. If the index case is shown to be MHN, the rest of the family is also MHN. However, there may be an enzyme deficiency such as carnitine palmitoyltransferase deficiency or a structural myopathy such as preclinical Duchenne or Becker dystrophinopathy that is responsible for the significant adverse anesthetic events. Such cases have many findings that overlap with MH. In some cases, the only diagnosis that is given to the young female is idiopathic hyperCKemia. Such a patient can be MHN or MH susceptible (MHS) on contracture testing. Perhaps that proband will always be treated as MHS during anesthesia whether or not the need for this precaution is confirmed by contracture testing, but different tests are needed to evaluate the health and risks of the rest of the family when the diagnosis of the index case is known to be one of these conditions rather than simply suspected MH. When muscle does produce a significant contracture, indicating that classic MH susceptibility is present, the tissue may contain a mutation that is recognized to be causative for MH. If a mutation known to be causative for MH is found in the index case or a first-


25

degree relative with a positive contracture test, then genetic testing for MH susceptibility can be the first step in the evaluation of other relatives. First-degree blood relatives, siblings, parents, and offspring of the index case should be evaluated first.

Genetic Testing of Malignant Hyperthermia Susceptibility In the European Union, genetic testing is now available under restricted conditions. When a mutation agreed to be causative for MH is identified in an individual shown to be MH susceptible by contracture testing, family members may undergo genetic evaluation before contracture testing.12 The chance of a first-degree relative, parent, sibling, or offspring sharing the MH causative mutation is 50%.13 If the relative carries the MH-causative familial mutation, that individual is diagnosed MH susceptible without contracture testing. If the familial mutation is not present, then the patient should undergo contracture testing. The diagnosis of MHN, ie, NOT MH susceptible, can be made securely only by a negative contracture test. Only 19 of 20 patients in Switzerland in whom the familial mutation could not be found also had completely negative muscle contracture tests confirming MHN status.13

More Details of the Genetics of Malignant Hyperthermia More than 100 mutations have been reported in the ryanodine receptor gene, RYR1. RYR1 on chromosome 19q13.2 is the major locus of MH susceptibility, but there are also several other loci.14 For example, the CACNA1S gene on chromosome 1q encoding the α1 subunit of the dihydropyridine receptor is another MH locus.15 Given the observed genetic heterogeneity of MHS, it is difficult to estimate the sensitivity of a genetic test for this condition based on RYR1. Current European MH Group (EMHG) guidelines recognize only 22 causative mutations. These guidelines demand that there be experimental evidence demonstrating that a mutation results in altered calcium control in response to RYR1 agonists, that the mutation is found in more than one MHS family, and that other criteria of genetic causation are met before that mutation is accepted as causative. (See www.emhg.org.) The genetics of MH susceptibility has not been studied in as many patients in North America as in Europe. However, in the ∼200 North American cases in which the mutational hot spots in the RYR1 have been examined, the most frequent mutations are the same as those found in Germany and England; amino acid changes of Arg614Cys and Gly2434Arg in RYR1 exons 17 and 45, respectively.16 In 30 patients with MHS from North America, the entire coding sequence of the RYR1 was examined. Mutations were found in 70%, but half of these were novel mutations, found for the first time in that MHS individual.17 A few nonpathologic polymorphisms were also identified. It is suggestive that these novel mutations are truly causative of MH, but this is not yet proven by the standard criteria. Genetic testing of the ryanodine receptor gene should be available in North America in 2005. MHAUS is planning to support the development of this test at the Center for Medical Genetics in the University of Pittsburgh. As discussed in 2002,18,19 a panel of exons, rather than the entire gene, will be examined in this clinical test. This group of exons was examined in 124 unrelated North American patients with MHS. Seventy percent of the causative MH mutations found were in the central of the three “hot spots” in the RYR1.20 However, MH-causative mutations were identified in only 23% of these people.20 This percentage of positive findings is similar to that in the Swiss population.13

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Genetic testing of MH susceptibility will have the highest yield, approximately 50%, in families in which a causative MH mutation has been identified in an individual who is known to be MHS by contracture testing. Until many more of the mutations in the RYR1 have been identified and other MHS genetic loci described more thoroughly, the chance of an individual suspected of MH susceptibility having a positive finding that can confirm MH susceptibility by a genetic test will be relatively low. Genetic testing is attractive because it will cost approximately 10% of the contracture test. Genetic testing will not require travel. A genetic test can be performed in any age patient. However, careful interpretation of a genetic test of MH susceptibility is necessary. Genetic testing for MH susceptibility will require a physician’s prescription, informed consent, genetic counseling with detailed medical history-taking by the Center for Medical Genetics at UPMC, and referral to a MH diagnostic biopsy center for further evaluation if the genetic result is negative. Biopsy centers may choose to refer patients for genetic testing before performance of the muscle biopsy and contracture test because a positive genetic result will provide the diagnosis, MHS, without surgery. Discordance between the presence of a RYR1 mutation and a positive contracture test has been described.21,22 The suggestion has been made that in some cases, discordance is the result of the effect of more than one gene.23 For these reasons, studies of MH susceptibility based on muscle function are still necessary.

Alternative Tests of Malignant Hyperthermia Susceptibility? Many alternative tests have been proposed, but none of these have yet been adequately validated as substitutes for contracture testing of viable muscle. Microdialysis was used to detect increases in carbon dioxide that followed the injection of caffeine directly into MHS muscle in vivo.24 This technique can separate MHS from MHN patients, but it requires specialized equipment and has not been widely replicated yet. Repetitive nerve stimulation may be able to produce electromyographic and force responses that are sufficiently different to separate MHS and MHN patients. This technique has the advantage of being less invasive, but it may always require regional anesthesia of some kind.25 RYR1 is expressed on β lymphocytes and in patients with MHS, these cells respond differently than normal to RYR1 agonists.26 Similar tests of lymphocytes might be able to identify many patients with MHS. However, not all significant mutations in RYR1 are expressed in lymphocytes to the extent that they are expressed in muscle.27

Treatment The key to successful treatment of MH remains rapid treatment with dantrolene, elimination of triggering agents, and aggressive supportive care. The initial dose of dantrolene, 2.5 mg/kg, should be repeated as needed to control the signs and acidosis of MH. Review of the ∼500 AMRA cases in the MH Registry supports the statement that the average dose of dantrolene needed for initial treatment is 2.5 mg/kg, but as much as 10 mg/kg has been required occasionally for effective treatment.28 Assistants should be called to help administer dantrolene, to cool the patient with intravenous fluids and ice packs, to insert catheters in the bladder, arteries, and central veins, and to repeat laboratory tests and obtain blood for CK measurement, creatinine, and clotting function tests. It has been shown that dantrolene is more than six times more soluble in water at 40°C than at 20°C.29 Warming the diluent may be very useful when many vials of dantrolene must be reconstituted quickly.


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Support from the Malignant Hyperthermia Association of the United States A booklet that describes all the useful roles and customizes telephone numbers for the local hospital or ambulatory surgery center can be obtained from the Malignant Hyperthermia Association of the United States (MHAUS). See www.mhaus.org for details.

Benefits and Risks of Dantrolene After the initial treatment has produced stable, normal vital signs and normal acid base status with no evidence of rigidity, 1 mg/kg of dantrolene should be given every 6 hours for a total of four to eight doses. Relapse or recrudescence of MH occurs in 25% of cases within 24 hours of initial dantrolene administration. Continuing dantrolene for 24 to 48 hours may preclude recrudescence and worsening of rhabdomyolysis. The most common complication of the administration of dantrolene is muscle weakness. In extreme cases, positive pressure ventilation may be required. Weakness is reported in ∼25% of patients treated with dantrolene. This may be the result of the effects of dantrolene, muscle injury from the episode, or both. Perhaps weakness can be confused at times with the delayed awakening often reported by patients after an MH episode. Phlebitis is reported in ∼11%.28 Administration of dantrolene by infusion pump rather than by gravity drip may be associated with greater likelihood of phlebitis. It is necessary to ensure that dantrolene does not extravasate. Mannitol, 3 g in each 20-mg vial of dantrolene, can initiate a compartment syndrome. However, compartment syndrome can complicate MH under other circumstances also.30

Supportive Treatment In cases of exercise-induced rhabdomyolysis, like in cases of suspected MH, it is necessary to apply all measures possible, including generous administration of isonatremic intravenous fluid, to decrease a critical temperature rapidly. When myoglobinuria from any cause is noted, increased flow of alkaline urine will help to protect the kidneys against renal failure. Multiorgan system failure can occur if treatment is delayed. Prolonged rehabilitation with muscle pain and weakness can follow an acute MH episode. Referral for physical therapy can be very helpful in such circumstances. At this time, there is only anecdotal evidence that a chronic slowly progressive myopathy exists in some MHS individuals. Yet some of the mutations in RYR1 are associated with central core disease, a chronic slowly progressive myopathy (Table 1). Chronic treatment with low-dose oral dantrolene was prescribed in the past for some MHS individuals. The risks and benefits of this therapy are yet to be demonstrated. TABLE 1.

Some Genotypes of RYR1 Associated with Malignant Hyperthermia Susceptibility CCD

EMHG Incidence

Exon

Mutation

RYR1 aa

6 11 17 39 39 45 45

C487T G1021A C1840T G6488A G6502A G7303A G7307T

R163C + 2–7% G341R 6–17% R614C 4–45% R2163H + 1% V2168M + 8% G2434R 4–10% R2435H + 2–3% Greatest Contractures Central core disease identified, +

NAMHR No. of Families 2 1 6 0 1 9 1

CCD = central core disease; EMHG = European Malignant Hyperthermia Group; NAMHR = North American Malignant Hyperthermia Registry.

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References 1. Hoenemann CW, Halene-Holtgraeve TB, Booke M, et al.: Delayed onset of malignant hyperthermia in desflurane anesthesia. Anesth Analg 2003; 96:165–7. 2. Karan SM, Crowl F, Muldoon S: Malignant hyperthermia masked by capnographic monitoring. Anesth Analg 1994; 78:590–2. 3. Johnson IAT, Andrzejowski JC, Curries JSA: Lower limb compartment syndrome resulting from malignant hyperthermia. Anaesth Intensive Care 1999; 27:292–4. 4. Short JA, Cooper CM: Suspected recurrence of malignant hyperthermia after post-extubation shivering in the intensive care unit, 18 h after tonsillectomy. Br J Anaesth 1999; 82:945–7. 5. Nelson TE: Malignant hyperthermia: A pharmacogenetic disease of Ca++ regulating proteins. Curr Mol Med 2002; 2:347–69. 6. Bouchama A, Knochel JP: Heat stroke. N Engl J Med 2002; 346:1978–88. 7. Kochling A, Wappler F, Winkler G, Schulte am Esch JS: Rhabdomyolysis following severe physical exercise in a patient with predisposition to malignant hyperthermia. Anaesth Intensive Care 1998; 26:315–8. 8. Tobin JR, Jason DR, Challa VR, Nelson TE, Sambuughin N: Malignant hyperthermia and apparent heat stroke. JAMA 2001; 286:168–9. 9. Davis M, Brown R, Dickson A, et al.: Malignant hyperthermia associated with exerciseinduced rhabdomyolysis or congenital abnormalities and a novel RYR1 mutation in New Zealand and Australian pedigrees. Br J Anaesth 2002; 88:508–15. 10. Guis S, Bendahan D, Kozak-Ribbens G, et al.: Rhabdomyolysis and myalgia associated with anticholesterolemic treatment as potential signs of malignant hyperthermia susceptibility. Arthritis Rheum 2003; 49:237–8. 11. Ruffert H, Olthoff D, Deutrich C, Froster UG: Current aspects of the diagnosis of malignant hyperthermia. Anaesthetist 2002; 51:904–13. 12. Urwyler A, Deufel T, McCarthy T, West S: Guidelines for the molecular detection of susceptibility to malignant hyperthermia. Br J Anaesth 2001; 86:283–7. 13. Girard T, Treves S, Voronkov E, Siegemund M, Urwyler A: Molecular genetic testing for malignant hyperthermia susceptibility. Anesthesiology 2004; 100:1076–80. 14. Jurkat-Rott K, McCarthy T, Lehmann-Horn F: Genetics and pathogenesis of malignant hyperthermia. Muscle Nerve 2000; 23:4–17. 15. Monnier N, Stieglitz P, Procaccio V, Lunardi J: Malignant hyperthermia susceptibility is associated with a mutation of the alpha-1 subunit of the human dihydropyridine sensitive L-type voltage dependent calcium channel receptor in skeletal muscle. Am J Hum Genet 1997; 60:1316–25. 16. Sambuughin N, Sei Y, Gallagher KL, et al.: North American malignant hyperthermia population: Screening of the ryanodine receptor gene and identification of novel mutations. Anesthesiology 2001; 95:594–9. 17. Sambuughin N, Holley H, Muldoon S, et al.: Screening of the entire ryanodine receptor type 1 coding region for sequence variants associated with malignant hyperthermia susceptibility in the North American population. Anesthesiology 2005 (In press). 18. Sei Y, Sambuughin N, Muldoon S: Malignant hyperthermia genetic testing in North America working group meeting. Anesthesiology 2004; 100:464–5. 19. Nelson TE, Rosenberg H, Muldoon SM: Genetic testing for malignant hyperthermia in North America. Anesthesiology 2004; 100:212–4. 20. Sei Y, Sambuughin NN, Davis EJ, et al.: Malignant hyperthermia in North America: Genetic screening of the three hot spots in the type I ryanodine receptor gene. Anesthesiology 2004; 101:824–30. 21. Brown RL, Pollock AN, Couchman KG, et al.: A novel ryanodine receptor mutation and genotype-phenotype correlation in a large malignant hyperthermia New Zealand Maori pedigree. Hum Mol Genet 2000; 9:1515–24. 22. Robinson RL, Anetseder MJ, Brancadoro V, et al.: Recent advances in the diagnosis of malignant hyperthermia susceptibility: How confident can we be of genetic testing? Eur J Hum Genet 2003; 11:342–8. 23. Monnier N, Krivosic-Horber R, Payen J-F, Lunardi J: Presence of two different genetic traits in malignant hyperthermia families: Implication for genetic analysis, diagnosis, and incidence of malignant hyperthermia susceptibility. Anesthesiology 2002; 97:1067–74.


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24. Anetseder M, Hager M, Muller CR, Roewer N: Diagnosis of susceptibility to malignant hyperthermia by use of a metabolic test. Lancet 2002; 359:1517–80. 25. Hoyer A, Veeser M, Schaupp F, Albrecht Y, Roewer N: Compound muscle action potentials of malignant hyperthermia-susceptible and non-susceptible human muscles differ distinctly under the influence of repetitive stimulation in vivo. ASA Meeting Abstracts 2002:A-997. 26. Sei Y, Brandom BW, Bina S, et al.: Patients with malignant hyperthermia demonstrate an altered calcium control mechanism in B lymphocytes. Anesthesiology 2002; 97:1045–6. 27. Monnier N, Ferreiro A, Marty I, Labarre-Vila A, Mezin P, Lunardi J: A homozygous splicing mutation causing a depletion of skeletal muscle RYR1 is associated with multi-minicore disease congenital myopathy with ophthalmoplegia. Hum Mol Genet 2003; 12:1171–8. 28. Brandom BW, Larach MG: Reassessment of the safety and efficacy of dantrolene. ASA 2002 Annual Meeting Abstract #650902. 29. Mitchell LW, Leighton BL: Warmed diluent speeds dantrolene reconstitution. Can J Anaesth 2003; 50:127–30. 30. Green G: A fatal case of malignant hyperthermia complicated by generalized compartment syndrome and rhabdomyolysis. Acta Anaesth Scand 2003; 47:619–21.



CHAPTER 4

V O L U M E


ANTICOAGULATION AND REGIONAL ANESTHESIA LYNN M. BROADMAN, M.D. PROFESSOR OF ANESTHESIA AND PEDIATRICS WEST VIRGINIA UNIVERSITY SCHOOL OF MEDICINE MORGANTOWN, WEST VIRGINIA



© 2005



Anticoagulation and Regional Anesthesia Lynn M. Broadman, M.D. Professor of Anesthesia and Pediatrics West Virginia University School of Medicine Morgantown, West Virginia

Why Regional Anesthesia for Joint Replacement and Hip Fracture Surgery? A recent metaanalysis by Rodgers et al. involving a total of 9,559 patients and 141 studies has clearly demonstrated that outcomes are better if one uses regional rather than general anesthesia for total hip replacement (THR), total knee replacement (TKR), and hip fracture surgery (HFS).1 In this metaanalysis, there were one third fewer myocardial infarctions in the patients who received regional anesthesia and there was a 59% reduction in the incidence of respiratory depression. Pulmonary embolism (PE) is the leading cause of death in patients undergoing THR, and current evidence suggests that this PE-related mortality can be reduced with regional anesthesia. Furthermore, an older study by Modig et al.2 suggests that there is a significant reduction in operative blood loss and need for perioperative transfusions in patients who have their hip replacement surgery performed under epidural anesthesia rather than a general anesthetic.

Why Do Our Surgical Colleagues Insist That They Need to Anticoagulate All Patients Undergoing Joint Replacement and Hip Fracture Surgery? The incidence of deep vein thrombosis (DVT) as determined by postoperative venography ranges from 36% to 84% in control or placebo patients who did not receive the benefit of anticoagulation or antiplatelet therapy after THR, TKR, or HFS.3 In addition, the incidence of fatal PE can run as high as 12.9% after HFS in patients who do not receive DVT prophylaxis.3 Therefore, it is imperative that all patients presenting for HFS, THR, and TKR receive some form of perioperative anticoagulation therapy.

What Are the Risks of Epidural Hematoma Formation When Perioperative Anticoagulation Is Used in Conjunction With Spinal Anesthesia? In the classic review article by Vandermeulen et al.,4 they reported the occurrence of 61 spinal hematomas in patients receiving neuraxial anesthesia between 1906 and 1994 (Table 1). 31

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BROADMAN TABLE 1.

Published Spinal/Epidural Hematomas from 1906–1994 in 61 Anticoagulated/Coagulopathic Patients

Type of Block

Single Shot epi (6/61)

Block difficulty

Difficult (15/61)

Bloody (15/61)

Coagulation Unfractionated status heparin or lowmolecularweight heparin (25/61)

Unfractionated heparin (5/61)

Epi with Catheter (32/61)

Epi Type Unknown (8/61)

Spinal 15/61

Total Blocks (n = 61) Risk ratio (30/61)

Other medications/ disease (12/61)

Risk ratio (42/61)

Table derived from the retrospective analysis performed by Vandermeulen and colleagues4 of all spinal/ epidural hematomas (Epi) reported in the literature from 1906 to 1994 noting the relationship between hematoma formation and the type of block performed, the coagulation status, and block difficulties. The table reads in rows from left to right and each column has no relationship to the material above or below it.

Synopsis of the Vandermeulen Findings At the time of anesthetic administration, 42 of 61 (69%) of the patients developing a spinal hematoma had impaired coagulation. In 25 of the cases, some form of heparin therapy was implicated. In addition, five of the patients had undergone a major vascular procedure in which heparin was likely used, but its use was not reported on their anesthetic record. The remaining 12 patients had a variety of conditions that could have altered their coagulation profile. Some of the conditions were thrombocytopenia, hepatic dysfunction, renal insufficiency, or the administration of another anticoagulant or platelet-altering agent. Needle placement was reported as difficult in 15 (25%) and/or bloody in 15 (25%) of the cases. Multiple punctures were reported in 12 (20%) of the cases. Pregnancy was noted in only five (8%) of the cases. Anatomic abnormalities such as spina bifida occulta or the presence of a vascular tumor were present in four (6.5%) of the cases.

A Rational Approach to the Use of Anticoagulants, Antiplatelet Agents, Nonsteroidal Antiinflammatory Drugs, and Neuraxial Anesthesia There are valid concerns regarding performing a spinal anesthetic in an anticoagulated patient. However, numerous studies, review articles, and consensus statements have documented the safety of spinal anesthesia and analgesia in the anticoagulated patient. The safe management of patients who will be receiving a neuraxial block and perioperative anticoagulation therapy can be improved by coordinating the timing of needle placement and catheter removal with the administration of the anticoagulant, and having a knowledge of the literature pertaining to patients receiving spinal anesthesia while using these drugs.

The Hemostatic Process The blood clotting system, or coagulation pathway, is a proteolytic cascade. Each enzyme of the pathway is present in the plasma as a zymogen, an inactive form, which on activation undergoes proteolytic cleavage to release the active factor from the pre-

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cursor molecule. The pathway functions as positive and negative feedback loops that control activation of this process. The ultimate goal of the pathway is to produce thrombin, which then converts soluble fibrinogen into fibrin, facilitating clot formation. The generation of thrombin can be divided into three phases, the intrinsic and extrinsic pathways that provide alternative routes for the generation of factor X and the final common pathway that results in thrombin formation.5

The Coagulation Cascade The launching of the cascade may result from activation of either the intrinsic or extrinsic pathways, which provide alternate routes for the generation of factor X, and the subsequent activation of the final common pathway, which results in thrombin formation. The intrinsic pathway is activated when blood comes into contact with subendothelial connective tissue. Quantitatively, it is the more important of the two pathways, but it cleaves fibrin more slowly than the extrinsic pathway.6 This pathway primarily involves the activation of factors XII and XI, and the ultimate activation of factor X.7 The first step in the intrinsic pathway is the binding of factor XII to a subendothelial surface exposed by an injury. The intrinsic pathway is primarily inhibited by the heparins. The extrinsic pathway provides a very rapid response to tissue injury, generating activated factor X almost instantaneously, compared with the seconds or even minutes required for the intrinsic pathway to activate factor X.5 The vitamin K-dependent factors II, VII, IX, and X are involved in the triggering of this pathway. The extrinsic pathway, in North America, is primarily inhibited by warfarin. The final common pathway involves the activation of factors X, II, and the ultimate formation of a clot through the formation of fibrin. The final common pathway will become more important in the future as the new pentasaccharide anticoagulants such as fondaparinux exert their effects on this limb of the coagulation cascade. The major anticoagulant effect of unfractionated heparin (UH), low-molecular-weight heparin (LMWH), and fondaparinux (FONDA) may be attributed to the pentasaccharide unit that possesses high affinity binding to antithrombin III (ATIII).8,9 Binding of this pentasaccharide unit to ATIII accelerates its ability to inactivate thrombin formation (factor IIa), as well as factors Xa, IXa, XIa, and XIIa.10 The inactivation of IIa formation by the ATIII/ heparin complex requires a chain length of at least 18 saccharide units and is the basis for the differences among LMWH, FONDA, and UH.11 LMWH is primarily comprised of the pentasaccharide sequence and lacks the long polysaccharide unit required to bind to IIa and ATIII simultaneously. LMWH has a Xa:IIa affinity ratio of approximately 3:1 and primarily inactivates Xa. FONDA is totally devoid of IIa activity because it is composed of only the pentasaccharide unit and does not possess the long tail needed to wrap around both the IIa and ATIII units.

Protamine Will Reverse the Effects of Unfractionated Heparin But Why Will It Not Reverse Either Low-Molecular-Weight Heparin or Fondaparinux Activity? Protamine is a strongly basic protein that binds to and neutralizes heparin.12 Protamine is a positively charged protein derived from salmon sperm. When administered

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intravenously in the presence of heparin, the positively charged protamine interacts with the negatively charged portion of the heparin molecule and forms a stable complex. The long polysaccharide chains of higher molecular-weight UH appear to increase their attraction to the protamine molecules.12 Moreover, the reversal action of protamine occurs primarily at the II to IIa cascade site. As such, protamine will reverse UH, it has limited ability to reverse LMWH, and has absolutely no ability to reverse the anticoagulation activity of FONDA.13

Monitoring of Anticoagulation in Patients Receiving Heparin Therapy Monitoring of the therapeutic anticoagulation of patients receiving UH is achieved through the activated partial thromboplastin time (aPTT). Normal values of the aPTT range from 24.3 to 35.0 seconds.14 The aPTT does not specifically measure anti-Xa activity.15 The aPTT should not be used to monitor either LMWH16 or FONDA therapy.13 In fact, at this time, there is no accurate way to monitor therapy with either of these agents.

Heparin-induced Thrombocytopenia and Thrombosis Both UH and LMWH are derived from animal sources. This explains the uncommon, but serious, occurrence of heparin-induced thrombocytopenia and thrombosis (HITT). The HITT syndrome is an IgG-mediated decrease in platelets to less than 150,000, which usually occurs 5 days after initiating heparin therapy and may be complicated by pathologic thrombosis.17 In randomized clinical trials, it has been shown to occur at a rate of approximately 3%. Warkentin et al.17 found that in a group of 665 patients randomized to receive either UH or LMWH, nine of 665 patients tested developed HITT. In this study, 332 received UH and 333 received LMWH. None of the patients receiving LMWH developed HITT, whereas nine of the patients receiving UH developed clinically significant HITT (2.7%). Furthermore, eight of the nine patients who developed HITT (89%) also had significant thrombotic complications. Patients with a history of HITT syndrome should not receive LMWH, because it is also derived from animal sources and there is a high incidence of crossreactivity. Unfractionated heparin clearly has a higher incidence of HITT syndrome than LMWH. On the other hand, FONDA is not derived from animal products. It is a synthetic compound and carries no risk of precipitating HITT.

Unfractionated Heparin The Efficacy versus Risks of Using Unfractionated Heparin to Prevent Deep Vein Thrombosis/Pulmonary Embolism Formation in Patients Receiving Spinal Anesthesia Administration of 5,000 units of UH subcutaneously every 8 to 12 hours has been used extensively and effectively for the prevention of DVT. In a review of 11 trials, Geerts et al.3 found that the overall risk of DVT in patients undergoing THR was 30% with low-dose UH, compared with 54% in controls. With this protocol, the aPTT often remains within the normal range.


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Abridged ASRA Guidelines for Use of Neuraxial Techniques in Patients Receiving Low-dose Subcutaneous Unfractionated Heparin During subcutaneous minidose prophylaxis (5,000 units 2 hours before surgery), there is no contraindication to the use of neuraxial techniques. The risk of neuraxial bleeding may also be reduced by delaying the heparin injection until 1 to 2 hours after placement of the neuraxial block. There may be an increased risk of neuraxial bleeding in debilitated patients or in patients who have received prolonged UH therapy. Because HITT may occur during heparin administration, patients receiving heparin for greater than 4 days should have a platelet count assessed before neuraxial block. 1. Avoid neuraxial techniques in patients with other coagulopathies. 2. Heparin administration should be delayed for 1 hour after needle placement. 3. Remove the catheter 1 hour before any subsequent heparin administration or 2 to 4 hours after the last heparin dose. 4. Monitor the patient postoperatively to provide early detection of motor blockade and consider the use of minimal concentrations of local anesthetics to facilitate the early detection of a spinal hematoma. 5. Although the occurrence of a bloody or difficult neuraxial needle placement may increase risk, there are no data to support mandatory cancellation of a case. Clinical judgment is needed. If a decision is made to proceed, full discussion with the surgeon and careful postoperative monitoring is warranted.

The European Guidelines for Patients Who Are Receiving or Will Receive Unfractionated Heparin and a Neuraxial Block The only substantial difference between the European19 and ASRA18 guidelines is the fact that the Europeans suggest that one wait 4 hours versus 2 hours after the subcutaneous injection of 5,000 units of UH before placing a neuraxial block.

The Safety of Neuraxial Anesthesia in the Patient Receiving Therapeutic and Full Anticoagulation With Unfractionated Heparin (20,000 to 30,000 Units Intravenously) In 1998, Sanchez and Nygard20 reported 558 cardiac surgery patients who had epidural catheters placed following strict guidelines. These included placement of the epidural catheters the day before the surgery and limiting attempts at catheter placement to two attempts. There was a zero incidence of spinal hematoma formation in this study.

Abridged ASRA Guidelines for the Administration of Neuraxial Anesthesia in the Patient Fully Anticoagulated with Unfractionated Heparin Currently, insufficient data and experience are available to determine if the risk of neuraxial hematoma is increased when combining neuraxial techniques with the full anticoagulation effects required during cardiac surgery. Prolonged therapeutic anticoagulation appears to increase the risk of spinal hematoma formation, especially if combined with other anticoagulants or thrombolytics. Therefore, neuraxial blocks should be avoided in this clinical setting. If systemic anticoagulation therapy is begun with an epidural catheter in place, it is recommended that one delay catheter removal for 2 to 4 hours after therapy discontinuation and evaluation of coagulation status.

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Low-Molecular-Weight Heparin Enoxaparin was the first commercially available LMWH and it remains the most widely used LMWH in North America. In this Refresher Course, the author only discusses enoxaparin. The mechanism of action for LMWH is quite similar to that of UH; however, because most of the polysaccharide chain lengths are too short to reach the IIa-binding site, LMWH does not prolong the aPTT to supranormal levels.

Low-Molecular-Weight Heparin Dosing Regimens In the United States, the usual dosing regimen for postsurgical DVT prophylaxis with enoxaparin is 30 mg, injected subcutaneously, every 12 hours, with the initial dose administered 12 to 24 hours postoperatively. An alternative dosing regimen is the European enoxaparin dosing protocol, or 40 mg subcutaneously per day, with the first dose administered 12 hours before surgery and the first postoperative dose given 12 to 24 hours after surgery.21 The European regimen is associated with a much lower incidence of epidural and wound hematoma formations21 (Table 2), but it may not be as effective as the U.S. protocol in preventing DVT formation.22,23

Abridged ASRA Guidelines for the Safe Use of Neuraxial Anesthesia in the Patient Who Has Received Preoperative Low-Molecular-Weight Heparin or Will Receive It in the Postoperative Period The presence of blood during needle and catheter placement does not necessitate postponement of surgery. However, initiation of LMWH therapy in this setting should be delayed for 24 hours after surgery. Antiplatelet or oral anticoagulant medications administered in combination with LMWH may increase the risks of spinal hematoma formation. A single-injection spinal anesthetic may be the safest neuraxial technique in patients receiving preoperative LMWH in accordance with the European protocol for thromboprophylaxis (40 mg/day). In these patients, needle placement should occur at least 10 to 12 hours after the last LMWH dose and neuraxial techniques should be avoided in patients administered a dose of LMWH 2 hours preoperatively (general surgery patients), because needle placement would occur during peak anticoagulant activity. With this protocol, indwelling catheters may be safely maintained. However, the catheter should be removed a minimum of 10 to 12 hours after the last dose of LMWH. Subsequent LMWH dosing should occur at least 2 hours after catheter removal.

TABLE 2.

The Relationship between Enoxaparin Dose and Hematoma/Thrombosis Rates

Enoxaparin Dose 60 mg2/day (n = 50) 30 mg2/12 h (n = 28) 40 mg2/day (n = 50) 20 mg2/12 h (n = 100)

Wound Hematoma Formation Rate

Thrombosis Rate

12% 22%† 6% 2%

6% 8% 8% 8%

Table derived from a study by Planes et al.21 and shows the relationship between various dosing regimens for enoxaparin and wound hematoma formation and deep vein thrombosis (DVT) rates. There are no statistically significant differences between any of the treatment groups with regard to DVT formation rates; all of the treatment regimens would appear to be equally effective in preventing DVT formations.† In groups I, III, and IV hematoma formations only delayed wound closures, but in group II they were quite severe and this arm of the study was closed at 28 patients.


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If one elects to use twice-daily dosing as per the U.S. protocol (30 mg every 12 hours), the first dose of LMWH should be administered no earlier than 24 hours postoperatively, regardless of anesthetic technique, and only in the presence of adequate hemostasis. This dosage may be associated with an increased risk of spinal hematoma. Indwelling catheters should be removed before initiation of LMWH thromboprophylaxis. If a continuous technique is selected, the epidural catheter may be left indwelling overnight and removed the next day, with the first dose of LMWH administered 2 hours after catheter removal.

Fondaparinux Fondaparinux is a pentasaccharide and the first in a series of synthetic oligosaccharides with antithrombotic effects.24 It is a selective factor Xa inhibitor and has no direct antifactor IIa activity.24 The pentasaccharide unit found in FONDA is the same subunit found in both UH and LMWH and is the subunit that causes inhibition of factor Xa.24 Because FONDA is a synthetic agent and not derived from animals, it does not induce the formation of antiplatelet antibodies and has no known effects on platelet function. However, nonantibody-mediated thrombocytopenia can occur with the administration of FONDA, and platelet counts should be closely monitored.13 Fondaparinux therapy should be discontinued if the platelet count falls less than 100,000 mm3. The daily dose of FONDA is 2.5 mg subcutaneously, with the first dose given 6 to 8 hours after the completion of surgery.24 The second, and all subsequent doses, should be administered at 24-hour intervals.

The Efficacy of Fondaparinux When Compared with Enoxaparin To date, five double-blind prospective trials involving more than 8,000 patients have been undertaken to compare the efficacy and safety of FONDA when compared with enoxaparin (ENOX).22–26 All of these studies22–26 follow a similar protocol. FONDA was shown in four of five prospective trials to be superior to ENOX in preventing DVT formation.22,24–26 Following THR, the risk reduction was 82%24 and in HFS the risk reduction was 56.4%.25 In TKR, the risk reduction was 55.2%.26 FONDA is presently the only anticoagulant approved by the U.S. Food and Drug Administration for DVT prophylaxis in patients undergoing HFS.13

Abridged ASRA Guidelines for the Safe Use of Neuraxial Anesthesia in the Patient Who Will Be Receiving Fondaparinux in the Postoperative Period Extreme caution is warranted given the sustained antithrombotic effect, early postoperative dosing, and irreversibility of this agent. Until further clinical experience is available, the performance of neuraxial techniques should occur under the same conditions that were used in clinical trials (single needle pass, atraumatic needle placement, avoidance of indwelling neuraxial catheters). If this is not possible, an alternate method of prophylaxis should be used.

The Author’s Recommendations for the Use of Fondaparinux in Conjunction with Neuraxial Anesthesia This author believes that the four large prospective studies conducted to date involving 2,277 patients, all having received some form of regional anesthesia, suggests that regional anesthesia may be safely used as the surgical anesthetic when FONDA is

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administered in a dose of 2.5 mg subcutaneously, and the first dose is administered 8 or more hours after the completion of surgery.22,24–26 The one case of spinal hematoma formation reported in the literature27 involved a patient who had had an attempted epidural catheter placement, which involved five or more needle passes and the subsequent administration of 6 mg of FONDA after the completion of surgery (the patient was a subject in a dose–response trail). This was more than twice the recommended dose of FONDA.13 Although the surgery was ultimately performed under general anesthesia, this case report would suggest that epidural anesthesia may carry more risk than spinal anesthesia performed with a fine-gauge needle (25–29 g). If epidural anesthesia is administered, it is imperative that the catheter be removed immediately after the completion of surgery and catheters should not be retained for the administration of postoperative analgesia. Finally, if one should experience difficulty in placing a spinal or epidural block, more than two needle passes, or if the lumbar puncture was bloody, one must communicate these facts with one’s surgical colleague. Discuss with the surgeon the risks and benefits of using FONDA as the antithrombotic in such cases and suggest alternatives. Although warfarin may be less efficacious,3 it may be the safer alternative after a traumatic lumbar puncture. The optimum time to the administration of the first dose of FONDA has been determined to be between 6 and 8 hours after surgery.13,24 This time interval to the first dose was based on the outcomes from five studies.22–26 However, this author suggests that clinicians use the upper recommended time limit and wait 8 hours after the completion of surgery before administering the first dose of FONDA. One spinal hematoma has already been reported using this time interval in a patient receiving twice the recommended dose of FONDA.27 As previously mentioned, this FONDA related hematoma occurred in a patient who had had an attempted epidural catheter placement.27 Schroeder suggests that the incidence of spinal hematoma in patients receiving LMWH is estimated to be approximately one in 3,000 in patients receiving continuous epidural anesthesia compared with one in 40,000 for spinal anesthesia.28 The fact that the first FONDA spinal hematoma was epidural-related may not be a coincidence, and spinal anesthesia may be the safer alternative when postoperative FONDA therapy is anticipated.

Vitamin K Antagonists In North America, warfarin is the most widely used vitamin K antagonist; therefore, I only discuss warfarin in this review.

How Warfarin Works and Its Basic Pharmacology Warfarin inhibits vitamin K epoxide reductase, which in turn limits the γ-carboxylation of the vitamin K-dependent coagulation factors: prothrombin (factor II), factor VII, factor IX, and factor X.29,30 The anticoagulation effect of warfarin is delayed until the clotting factors already circulating have been cleared.31 An anticoagulation effect occurs within 24 hours of instituting warfarin therapy as a result of the inhibition of the production of factor VII, which has a half-life of 6 to 7 hours; but, peak anticoagulation activity is delayed for 72 to 96 hours because of the longer plasma half-lives of factors II, IX, and X.32


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Warfarin also results in the depletion of the anticoagulation proteins (protein C and protein S). Protein C also has a relatively short half-life, like factor VII. Therefore, there is a potential for the anticoagulation effects of factor VII depletion to be countered by the thrombogenic effects of reduced protein C activity during the first 24 to 48 hours of warfarin therapy. Therefore, one must keep in mind that there may actually be a thrombogenic effect to warfarin therapy during the first 24 to 48 hours of therapy.33

Evidence and Guidelines for Performing Neuraxial Blocks in Patients Who Are Receiving Chronic Warfarin Therapy The Fully Anticoagulated Patient. There are no studies that establish the safety of placing a spinal or epidural block in the patient who is fully anticoagulated with warfarin or another vitamin K antagonist. However, there is the strong recommendation from two authorities in this field, Vandermeulen4 and Wille-Jorgensen,34 that neuraxial blocks should be withheld in all patients treated with therapeutic doses of vitamin K antagonists. It is the opinion of this author that full anticoagulation with warfarin or another vitamin K antagonist without international normalized ratio (INR)-documented reversal is an absolute contraindication to the placement of both spinal and epidural neuroblockade. The Fully Anticoagulated Patient Presenting for Urgent or Emergent Surgery and a Neuraxial Block Is the Anesthetic of Choice. Spinal anesthesia may be the anesthetic of choice for many elderly patients presenting for emergent hip fracture surgery.1 However, many of these patients may also be receiving chronic anticoagulation therapy with warfarin because of underlying medical conditions such as atrial fibrillation, chronic venous stasis, or heart valve replacement. If the surgery is emergent, one can rapidly reverse the warfarin-induced anticoagulation through the administration of fresh-frozen plasma, vitamin K, or prothrombin complex concentrate.4 More recently, recombinant factor VIIa has become available for use in the care of patients with hemophilia. Reports of off-label use of this agent35 suggest that it is very effective in reversing uncontrolled bleeding as a result of a variety of causes. Theoretically, recombinant factor VIIa should be very effective in reversing warfarin-induced anticoagulation. Although recombinant factor VIIa is quite expensive, it may be the drug of choice in patients who will not tolerate the fluid load created by the infusion of several units of fresh-frozen plasma or tolerate the 12- to 24-hour surgical delay, while vitamin K is allowed sufficient time to reverse the action of a vitamin K-depleting agent. Such delays will also increase the surgical risks for many elderly patients because they will miss the 24-hour “Golden Period” for hip fracture repair. In all cases, the INR should be monitored and the value should be 1.5 or less before placing any neuraxial block or performing surgery.36 Kearon and Hirsh,36 in their 1997 review article, have alluded that it is safe to perform surgery on patients who have been receiving chronic warfarin therapy and in whom warfarin therapy was discontinued 4 days before surgery, and the INR was then allowed to return to a value of 1.5 or less. They base “the safe INR value” on their own experience and on two older studies involving a limited number of patients. Kearon and Hirsh never mention that it may be safe to perform a spinal or epidural anesthetic in patients in whom the INR has returned to a level of 1.5 or less. We anesthesiologists have simply extrapolated this value to meet our needs and we have used the logic “that if an INR of 1.5 or less is a safe value at which one can perform surgery, it must also be a safe level at which one can perform a neuraxial block.”

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Abridged ASRA Guidelines for the Regional Anesthetic Management of the Patient Who Is Taking an Oral Anticoagulant For patients on chronic oral anticoagulation, the anticoagulant therapy must be stopped (ideally 4–5 days before the planned procedure). The PT/INR should be measured and should be allowed to reach a level of 1.5 or less before the initiation of neuraxial block. For patients receiving an initial dose of warfarin before surgery, the PT/INR should be checked before neuraxial block placement if the first dose was given more than 24 hours earlier or a second dose of oral anticoagulant has been administered. Patients receiving low-dose warfarin therapy during epidural analgesia should have their PT/INR monitored on a daily basis and checked before catheter removal if the initial dose of warfarin was administered more than 36 hours preoperatively. Neuraxial catheters should be removed when the INR is 40 kg/m2 is generally considered “morbid obesity.” A patient with a BMI >36 kg/m2 who has multiple medical comorbidities is also considered to be “morbidly obese” and hence a candidate for bariatric surgery. Probably as a reflection of the current trend toward bigger and bigger patients, new categories of obesity have been described. Superobese is used for a patient with a BMI >50 kg/m2 and supersuperobese for those with a BMI >60 kg/m2.

TABLE 1.

Ideal Body Weight (IBW) Formulas

Men Kilograms Height (cm)—100 50 kg (60 inches) + 2.3 kg for each additional inch 52 kg (60 inches) + 1.9 kg for each additional inch 56.2 kg (60 inches) + 1.41 kg for each additional inch Pounds 135 (63 inches) + 3 lbs each additional inch Women Kilograms Height (cm)—105 45.5 kg (60 inches) + 2.3 kg for each additional inch 49 kg (60 inches) + 1.7 kg for each additional inch 53.1 kg (60 inches) + 1.36 kg for each additional inch Pounds 119 (60 inches) + 3 lbs each additional inch

ANESTHESIA FOR BARIATRIC SURGERY TABLE 2.

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Metabolic Syndrome

To establish a diagnosis, three or more of the following must be present: Waist circumference >102 cm (men), >88 cm (women) Serum triglycerides ≥150 mg/dL High-density lipoprotein cholesterol 10 seconds’ cessation of air flow despite

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continuous respiratory effort against a closed airway) and hypopnea (50% reduction in air flow or reduction associated with a decrease of SpO2 >4%). Patients may not be aware of these symptoms, so it is important to interview their spouses. If OSA is present, they will describe loud snoring followed by silence as air flow stops with obstruction, and then gasping or choking as the patient awakes and air flow restarts. A definitive diagnosis of OSA can only be confirmed by polysomnography in a sleep laboratory. Because of fragmented sleep patterns, patients with OSA may have daytime sleepiness and headaches. Chronic OSA leads to secondary polycythemia, hypoxemia, and hypercapnia, all of which increase the risk of cardiac and cerebral vascular disease. Obese patients with a history of snoring or a diagnosis of OSA are often difficult to ventilate by mask, and their tracheas may be more difficult to intubate than obese patients without OSA. Patients using nasal continuous positive airway pressure (N-CPAP) devices at home should be instructed to bring them to the hospital to use in the postanesthesia care unit (PACU) after surgery. A few patients experience “obesity hypoventilation syndrome” characterized by somnolence, cardiac enlargement, polycythemia, hypoxemia, and hypercapnia. Hypoventilation is central and independent of intrinsic lung disease and is probably the result of a progressive desensitization of the respiratory center to hypercapnia from nocturnal sleep disturbances. Its most severe form, “Pickwickian syndrome,” it is characterized by marked obesity, hypersomnolence, hypoxia, hypercapnia, pulmonary hypertension, right ventricular enlargement, and hypervolemia. Patients rely on a hypoxic ventilatory drive and may hypoventilate or even stop breathing after emergence from general anesthesia when given mask O2 to breathe. Although patients with significant preoperative pulmonary dysfunction have a higher operative morbidity, bariatric surgery is usually recommended because weight loss is associated with significant improvements in sleep apnea, arterial blood gases, pulmonary hypertension, left ventricular function, lung volumes, and polycythemia. A careful preoperative assessment of a patient’s upper airway is always required because mask ventilation and tracheal intubation can be a challenge in some obese patients (see “General Anesthesia: Tracheal Intubation”). A review of the patient’s anesthetic records is extremely useful to see if airway problems had been encountered during previous surgical procedures.

Gastrointestinal and Urinary Systems It was once widely believed that morbidly obese patients were at greater risk for acid aspiration during induction of general anesthesia. Risk factors include increased intraabdominal pressure, a high incidence of gastroesophageal reflux disease (GERD) and hiatal hernia, and increased gastric volume with low gastric fluid pH. Recent work has challenged this belief.4 There were no differences in gastric volume or pH between lean and moderately obese surgical patients. Obese patients without symptoms of GERD have relatively normal gastroesophageal sphincter tone and may have faster gastric-emptying time. Patients at particular risk for gastric acid aspiration may be those with diabetes and gastroparesis. Nonalcoholic steatohepatitis (NASH, “fatty hepatitis”), with or without liver dysfunction, is extremely common. Histologic liver abnormalities are present in the livers of as many as 90% of morbidly obese patients. Preoperative liver function tests should be obtained, but they often do not reflect the actual severity of liver disease. Alanine aminotransferase (ALT) is the most commonly elevated liver enzyme. Surprisingly, liver clearance of many anesthetic agents is usually not altered with NASH.

ANESTHESIA FOR BARIATRIC SURGERY

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Obesity is associated with increased renal blood flow and an increased glomerular filtration rate (GFR). Renal clearance of drugs may be greater compared with the normalweight patient. The most common renal abnormality seen is proteinuria.

Operative Considerations Premedication In general, preoperative sedation is avoided. For the very anxious patient, small amounts of midazolam (1 to 2 mg intravenously) are administered. If a fiberoptic bronchoscopic (FOB) airway intubation is planned, atropine or glycopyrrolate should be given to decrease oral secretions. Most medications for chronic hypertension are continued before surgery. An exception is angiotensin-converting enzyme inhibitors, which should be stopped preoperatively because their presence can lead to profound hypotension after induction of anesthesia. Diabetic medications (insulin, oral hypoglycemics) are usually withheld on the morning of surgery, but blood sugar levels must be closely monitored before, during, and after the operation. Antibiotic prophylaxis for wound infection and heparin prophylaxis for deep venous thrombosis (DVT) are usually administered before surgery. Because of concern about a possible increased risk of acid aspiration, H2-receptor antagonists, proton pump inhibitors, metoclopramide, and nonparticulate antacids can be administered alone or in combination before induction of general anesthesia.5

Positioning Our practice is to have the unpremedicated patient climb off the gurney and position him- or herself on the operating room table. All pressure points must be carefully padded to avoid pressure sores and neurologic injury. Occasionally, two conventional operating room tables are placed together to accommodate a particularly large patient. Special tables strong enough to support a 1000-pound patient are commercially available. In the supine position, FRC is markedly reduced causing further ventilation/perfusion (V/Q) mismatch and significant increases in O2 consumption, cardiac output, and PAP.6 The reverse Trendelenburg position (RTP) is better tolerated because the diaphragm is “unloaded.” A left lateral tilt will further help to prevent inferior vena cava compression. The Trendelenburg position (TP) and lithotomy positions exaggerate and decrease lung volume. In the prone position, if the abdomen is compressed, ventilation will be restricted. However, when the prone obese patient is properly supported with the abdomen allowed to hang freely, ventilation is actually improved.7 The lateral decubitus position is tolerated if the panniculus is displaced off the abdomen.

Monitoring Standard monitors (ECG, blood pressure cuff, pulse oximetry, end-tidal capnography, temperature probe) are applied. Noninvasive cuff pressure may be inaccurate if the wrong size cuff is used. If the anatomy of the upper arm does not allow a proper fit, cuff pressures may need to be obtained from the wrist or ankle. A radial artery is often cannulated for accurate pressure monitoring. Central venous lines (CVP, PA) can be useful for major abdominal and thoracic procedures but may be technically difficult to obtain. Because venous access is often limited, a central line can be helpful for intraand postoperative needs. A nerve stimulator is used to assess neuromuscular blockade.

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Excess fat may make surface electrodes inaccurate, so needle electrodes are recommended. A bispectral index (BIS) monitor or another “depth of anesthesia” device can be helpful, but their role in routine bariatric anesthesia is yet to be determined.

Pharmacologic Considerations The physiological changes in obesity affect the distribution, binding, and elimination of the various anesthetic agents (Table 5). In routine anesthetic practice, drugs are usually administered on the basis of dose per unit body weight. This assumes that clearances and distribution volumes are proportional to weight, assumptions that may not be valid in the morbidly obese patient. Obese patients have a smaller than normal fraction of total body water, increased blood volume, and cardiac output, greater than normal adipose content, increased LBW, and changed tissue protein binding from increased concentrations of free fatty acids, triglycerides, lipoproteins, cholesterol, TABLE 5. Agent

Weight-based Dosing for Bariatric Patients

Dosing

Propofol

Induction—LBW Maintenance—TBW

Systemic clearance and Vd at steady state correlates with TBW; high affinity for excess fat; high hepatic extraction and conjugation relates to TBW

Thiopental

Induction—LBW

Increased Vd, increased blood volume, cardiac output, and muscle mass means increased absolute dose; prolonged duration of action; cardiovascular depression—limits dosage

Midazolam

TBW

Increased Vd; prolonged sedation because larger initial doses are needed to achieve adequate serum concentrations

Succinylcholine

LBW

Plasma cholinesterase activity increases with TBW

Vecuronium

IBW

Recovery may be delayed if given according to TBW because of increased Vd and impaired hepatic clearance

Rocuronium

IBW

Faster onset and longer duration of action, pharmacokinetics and pharmacodynamics are not altered in obese subjects

Atracurium cisatracurium

TBW

Absolute clearance, Vd, and elimination half-life do not change; unchanged dose per unit body weight without prolongation of recovery because of organ-independent elimination

Fentanyl

TBW

Increased Vd and elimination half-time, which correlates with TBW

Sufentanil

TBW Maintenance—IBW

Increased Vd and elimination half-time, which correlates with degree of obesity; distributes as extensively in excess body mass as in lean tissues; dose should account for total body mass

Remifentanil

IBW

Pharmacokinetics are similar in obese and nonobese patients

Modified from Ogunnaike BO, et al.: Anesthetic considerations for bariatric surgery. Anesth Analg 2002; 95:1793–805. LBW = lean body weight; IBW = ideal body weight; TBW = total body weight; Vd = volume of distribution.


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and other serum constituents. In addition, renal blood flow and glomerular filtration rate are increased, whereas cardiopulmonary function may not be optimal. Hepatic clearance is usually normal or even increased in obese patients despite the presence of NASH. Highly lipophilic medications (barbiturates, benzodiazepines) have a significant increase in volume of distribution (Vd) compared with nonobese patients, and the loading dose of these drugs is usually increased. Because their elimination half-lives are longer, maintenance dosing should be decreased to reflect IBW.8 Non- or weakly lipophilic drugs are given based on LBW.9 For a morbidly obese patient, LBW can be calculated by adding 20% to 30% to estimated IBW. Systemic absorption of oral medications is not significantly affected by obesity.

Inhalational Agents Obese patients metabolize halogenated inhalational anesthetic agents to a greater extent than nonobese patients. Serum fluoride levels reach high concentrations after enflurane anesthesia, are elevated after isoflurane, but are similar in obese and nonobese patients after sevoflurane. There is a belief that slow release of volatile anesthetic agents from the excess adipose tissue results in a prolonged emergence from anesthesia. Sevoflurane and desflurane have lower lipid solubility than isoflurane, and both of these agents have been recommended for bariatric surgery.10,11 Although reduction in blood flow to adipose tissue may limit the initial delivery of volatile agent to the fat and liver and inhalational anesthetics are stored in the fat long after completion of surgery, all inhalational anesthetics are rapidly eliminated from the well-perfused brain and lungs once the anesthetic is discontinued. Despite claims that one agent is superior to another for bariatric operations, with proper timing, recovery from general anesthesia is similar with any inhalation agent or total intravenous anesthesia (TIVA) technique.12

Induction Agents Larger than normal doses of propofol or thiopental are needed as a result of increases in fat content, blood volume, and cardiac output. The dosing regimen for propofol, in theory, should be based on actual weight. However, the cardiovascular effects of very large doses limit the absolute amount that can be given in morbidly obese patients. Although obese patients require more induction agent than normal patients, they are also more sensitive to these agents and should receive dosages based on LBW.

Muscle Relaxants Because pseudocholinesterase levels and extracellular fluid space are both increased in obesity, higher doses of succinylcholine (1.5 to 2.0 mg/kg IBW) are used for rapid sequence anesthetic induction. Complete paralysis is especially important during laparoscopy to facilitate ventilation and to provide adequate space for visualization and maneuvering of the surgical equipment. Loss of pneumoperitoneum may indicate incomplete paralysis. Because muscle relaxants are hydrophilic, there is limited distribution in the added adipose tissue. There are no clinical advantages between any of the nondepolarizing relaxants. Neuromuscular recovery time is similar in obese and nonobese patients with atracurium, vecuronium, or rocuronium.13 Most muscle relaxants are administered in incremental doses based on IBW. Neuromuscular blockade must be completely reversed before extubation of the trachea.

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Opioids For opioids that are highly lipophilic agents, in theory, their loading doses should be based on TBW. There is no clinical evidence that lipophilic opioids last longer in morbidly obese patients.14 Generous use of long-acting opioid analgesics (morphine, demerol, hydromorphone) can be dangerous because respiratory depression must be strictly avoided. The Vd of remifentanil in obese patients is less than expected, probably because of hydrolysis by blood and tissue esterases, so dosing of this drug is based on IBW.

Fluids Intraoperative fluid requirements are usually greater than would be anticipated in a normal weight patient. Several liters of crystalloid are required during an average laparoscopic bariatric procedure.

General Anesthesia Tracheal Intubation During surgery, morbidly obese patients cannot breathe adequately on their own while in the supine or in lithotomy positions, and they may also be at an increased risk for gastric aspiration. Therefore, tracheal intubation should be considered even for short surgical procedures. Potential airway management problems (fat face and cheeks; limited range of motion of the head, neck, and jaw; small mouth and large tongue; excessive palatal and pharyngeal tissue; short, large neck; high Mallampati [III or IV] score) should all be evaluated during the preoperative visit. High Mallampati score (limited visibility of the pharynx) and large neck circumference are the most reliable predictors of potential intubation difficulties in morbidly obese patients.15 If problems are anticipated, an “awake intubation” with a FOB is recommended. Supplemental O2 must be given and sedation kept to a minimum during the intubation sequence. Increasing weight or BMI is not a risk factor for difficult laryngoscopy.16 Proper positioning with the head, neck, and shoulders elevated (“stacked” or “ramped”) so that the patient’s ear is level with their sternum facilitates direct laryngoscopy so FOBassisted tracheal intubation is seldom necessary17 (Fig. 1A, B). Despite conflicting evidence that morbidly obese patients are at greater risk for acid aspiration, it still remains prudent to establish a secure airway as quickly and as safely as possible. Patients should be preoxygenated in the reverse Trendelenburg position until their SpO2 is 100% for several minutes.18 An apneic obese patient’s hemoglobin will desaturate very quickly because FRC is reduced and O2 reserves are limited. For the majority of patients, a rapid intravenous induction using propofol and succinylcholine, combined with cricoid pressure, is the best means of establishing an airway. A second trained individual who is experienced with airway management, preferably another anesthesiologist, must always be present to assist if difficulty is encountered with mask ventilation or tracheal intubation. Aids for difficult intubation should always be readily available. These include a short laryngoscope handle and a variety of laryngoscope blades, a gum elastic bougie, and a light wand. A Pro-Seal or intubating LMA can serve as a “bridge” until an endotracheal tube is placed if difficulty with intubation is encountered.19 Rarely is there a need for cricothyroidotomy and transtracheal jet ventilation.


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A

B

FIG. 1. (A) The supine position is usually poorly tolerated by a morbidly obese patient. Head elevation with a conventional 8-cm cushion may not optimize conditions for direct laryngoscopy. (B) Elevating the head, neck, and shoulders (“stacked” or “ramped” position) so that the patient’s ear is level with their sternum greatly facilitates direct laryngoscopy.

Ventilation Obese patients should be mechanically ventilated with at least 50% O2 and a tidal volume (Vt) 12 to 15 mL/kg IBW preferably in the reverse Trendelenburg position.20 A larger Vt will only marginally improve oxygenation while producing severe hypocapnia and may potentially injure the lung.21 With mechanical ventilation, especially during

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laparoscopy, peak ventilatory pressures and end-tidal CO2 levels will increase. Positive end-expiratory pressure (PEEP) superimposed on a large Vt can actually worsen hypoxemia by depressing cardiac output, which in turn will reduce O2 delivery to the tissues. Placement of subdiaphragmatic packs or retractors or changing to lithotomy or the Trendelenburg position will also worsen hypoxemia. The panniculus can be mechanically displaced to improve compliance. Most bariatric and gallbladder procedures are now performed laparoscopically. Obese patients tolerate abdominal insufflation without serious impairment of respiratory mechanics.22 Although absorption of insufflated CO2 can worsen hypercarbia and produce acidosis, these changes are temporary and are usually well tolerated and need not be corrected. The surgical pneumoperitoneum can also displace the diaphragm cephalad causing the position of the endotracheal tube position to change, with the tip entering a bronchus. Tube displacement should always be considered in the differential diagnosis of hypoxemia developing during laparoscopic bariatric surgery.23

Hemodynamic Changes Pulmonary capillary wedge and PA pressures may be elevated secondary to increased pulmonary blood volume and chronic hypoxemia. The reverse Trendelenburg position can improve oxygenation but may also cause pooling of blood and hypotension.24

Regional Anesthesia Performance of regional blocks in obese patients can be technically challenging. Special long epidural and spinal needles may be needed. Insulated needles and a nerve stimulator can be used to identify the appropriate nerves for peripheral nerve blocks. Neuraxial spread of local anesthetics is directly related to BMI.25 Increased abdominal pressure shifts blood from the inferior vena cava into the epidural venous system decreasing the volume of the epidural and subarachnoid spaces. Epidural fat further reduces the potential capacity of the epidural space. For epidural and spinal blocks, local anesthetic dose requirements are reduced by 20% to 25%.26

Anesthetic Technique For laparotomy and thoracotomy, a combination of general anesthesia with epidural analgesia produces a lower incidence of postoperative respiratory complications and shorter hospital stays. Postoperative epidural opioid analgesia, with or without local anesthetics, is recommended. The epidural catheter is usually placed in an awake patient before induction of general anesthesia, and the epidural is then used during the procedure. General anesthesia is maintained with an inhalational anesthetic. Longacting opioids are used with caution or avoided completely to decrease the risk of postoperative respiratory depression. Laparoscopic bariatric surgery is now the preferred operative approach. More than 140,000 procedures were performed in the United States in 2004. Surgical options currently include either strictly restrictive procedures (vertical banded gastroplasty, gastric banding) that limit the stomach capacity or operations that combine gastric restriction and malabsorption (Roux-en-Y gastric bypass [RGB], biliary–pancreatic diversion). Laparoscopy has many advantages, including less postoperative pain, earlier recovery, and reduced risk of postoperative pulmonary complications compared with open bariatric operations.


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For laparoscopy, we use a short-acting opioid infusion (remifentanil, alfentanil) with small amounts of intravenous fentanyl. The patient is ventilated with an inhalational anesthetic agent and 100% O2, and nitrous oxide is avoided. During laparoscopic bariatric procedures, the anesthesiologist is responsible for placement of an oral or nasogastric tube to help decompress the stomach and allow the surgeon to size the gastric pouch. In addition, the anesthesiologist may be asked to help perform a leak test for anastomotic integrity either by gas insufflation through the gastric tube or by placement of saline or dye into the gastric tube. It is extremely important that the gastric tube and anything else in the esophagus (such as a temperature probe or esophageal stethoscope) be completely withdrawn before the gastric pouch is stapled.

Postoperative Considerations Position The semirecumbent and reverse Trendelenburg positions maximize oxygenation because FRC is increased. If hemodynamically stable, patients should have their airway extubated with their upper body elevated 30° to 45° and then be transferred from the operating room in that same position.

Oxygenation Postoperative mechanical ventilation is rarely needed, especially after an uncomplicated laparoscopic procedure. Factors that may necessitate ventilatory support include extremes of age, coexisting cardiac disease, CO2 retention, fever or infection, and an uncooperative or extremely anxious patient. General anesthesia in morbidly obese patients predictably results in a significant incidence of postoperative atelectasis.27 Hypoxemia will be avoided if supplemental O2 is administered. Restoration of normal pulmonary function after abdominal surgery may take several days, so all patients should receive nasal or mask O2. For patients with OSA, N-CPAP should be considered in the immediate recovery period.28 Patients who fail to respond to N-CPAP may do better with bilevel positive airway pressure (BiPAP). BiPAP combines pressure support ventilation and PEEP through nasal mask, allowing alveolar recruitment during inspiration, and prevents alveolar collapse during expiration.29 In theory, N-CPAP could distend the gastric pouch and cause an anastomotic leak. However, this complication has not been reported and should not be a contraindication for N-CPAP in the PACU.

Hemodynamic Problems A significant decrease in left ventricular function may occur in the immediate postoperative period. Patients must be closely monitored and inotropic agents given when indicated, especially if the patient is receiving epidural local anesthetics.

Antithrombosis Thromboembolism is a major cause of postoperative mortality. Pulmonary emboli occur in up to 5% of obese patients after laparotomy. Prolonged immobilization can lead to phlebothrombosis. The risk of thrombosis is further increased because of the greater blood volume and relative polycythemia that is common in obesity. Other risk factors include high fatty acid levels, hypercholesterolemia, and diabetes. In addition, morbidly obese patients demonstrate accelerated fibrin formation, fibrinogen–

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platelet interaction, and platelet function. Anticoagulation or other prophylactic measures such as an inferior vena cava filter should be considered.30

Analgesia Local anesthetic is usually infiltrated into the trocar sites during laparoscopy, so incision pain in the PACU is minimal. Opioid patient-controlled analgesia (PCA) dosed on the basis of IBW is satisfactory for most laparoscopic procedures. Opioid epidural analgesia, alone or combined with local anesthetics, is preferred after laparotomy or thoracotomy. The insufflated CO2 that is used to create the surgical pneumoperitoneum causes pain not alleviated by analgesics. Despite attempts at warming and humidifying the CO2, postoperative discomfort in the PACU is common after laparoscopic procedures.31 Large doses of any opioid should be avoided after surgery. The use of nonopioid analgesic adjuncts should be instituted early. Nonsteroidal antiinflammatory drugs are helpful initially but should be discontinued within a day or 2 to avoid the potential complication of gastric ulceration.

References 1. Frigg A, Peterli R, Peters T, Ackermann C, Tondelli P: Reduction in co-morbidities 4 years after laparoscopic adjustable gastric banding. Obes Surg 2004; 14:216–23. 2. Alpert MA, Hashimi MW: Obesity and the heart. Am J Med Sci 1993; 306:117–23. 3. Pelosi P, Croci M, Ravagnan I, et al.: The effects of body mass on lung volumes, respiratory mechanics, and gas exchange during general anesthesia. Anesth Analg 1998; 87:654–60. 4. Maltby JR, Pytka S, Watson NC, Cowan RA, Fick GH: Drinking 300 mL of clear fluid two hours before surgery has no effect on gastric fluid volume and pH in fasting and non-fasting obese patients. Can J Anaesth 2004; 51:111–5. 5. Lam AM, Grace DM, Manninen PH, Diamond C: The effects of cimetidine and ranitidine with and without metoclopramide on gastric volume and pH in morbidly obese patients. Can Anaesth Soc J 1986; 33:773–9. 6. Brodsky JB: Positioning the morbidly obese patient for anesthesia. Obes Surg 2002; 12:751–8. 7. Pelosi P, Croci M, Calappi E, et al.: Prone positioning improves pulmonary function in obese patients during general anesthesia. Anesth Analg 1996; 83:578–83. 8. Servin F, Farinotti R, Haberer JP, Desmonts JM: Propofol infusion for the maintenance of anesthesia in morbidly obese patients receiving nitrous oxide. Anesthesiology 1993; 78:657–65. 9. Ogunnaike BO, Jones SB, Jones DB, Provost D, Whitten CW: Anesthetic considerations for bariatric surgery. Anesth Analg 2002; 95:1793–805. 10. Torri G, Casati A, Albertin A, et al.: Randomized comparison of isoflurane and sevoflurane for laparoscopic gastric banding in morbidly obese patients. J Clin Anesth 2001; 13:565–70. 11. Juvin P, Vadam C, Malek L, et al.: Postoperative recovery after desflurane, propofol, or isoflurane anesthesia among morbidly obese patients: a prospective, randomized study. Anesth Analg 2000; 91:714–9. 12. Cork RC, Vaughan RW, Bentley JB: General anesthesia for morbidly obese patients—An examination of postoperative outcomes. Anesthesiology 1981; 54:310–3. 13. Varin F, Ducharme J, Theoret Y, et al.: Influence of extreme obesity on the body disposition and neuromuscular blocking effect of atracurium. Clin Pharmacol Ther 1990; 48:18–25. 14. Gaszynski TM, Strzelczyk JM, Gaszynski WP: Post-anesthesia recovery after infusion of propofol with remifentanil or alfentanil or fentanyl in morbidly obese patients. Obes Surg 2004; 14:1–7. 15. Brodsky JB, Lemmens HJ, Brock-Utne JG, Vierra M, Saidman LJ: Morbid obesity and tracheal intubation. Anesth Analg 2003; 94:732–6. 16. Ezri T, Medalion B, Weisenberg M, et al.: Increased body mass index per se is not a predictor of difficult laryngoscopy. Can J Anesth 2003; 50:179–83. 17. Collins JS, Lemmens HJM, Brodsky JB, Brock-Utne JG, Levitan RM: Laryngoscopy and morbid obesity: A comparison of the ‘sniff’ and “ramped” positions. Obes Surg 2004; 14:1171–5.


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18. Jense HG, Dubin SA, Silverstein PI, O’Leary-Escolas U: Effects of obesity on safe duration of apnea in anesthetized humans. Anesth Analg 1991; 72:89–93. 19. Keller C, Brimacombe J, Kleinsasser A, Brimacombe L: The Laryngeal Mask Airway ProSeal™ as a temporary ventilatory device in grossly and morbidly obese patients before laryngoscope-guided tracheal intubation. Anesth Analg 2002; 94:737–40. 20. Perilli V, Sollazzi L, Bozza P, et al.: The effects of the reverse Trendelenburg position on respiratory mechanics and blood gases in morbidly obese patients during bariatric surgery. Anesth Analg 2000; 91:1520–5. 21. Bardoczky GI, Yernault JC, Houben JJ, d’Hollander AA: Large tidal volume ventilation does not improve oxygenation in morbidly obese patients during anesthesia. Anesth Analg 1995; 81:385–8. 22. Dumont L, Mattys M, Mardirosoff C, et al.: Changes in pulmonary mechanics during laparoscopic gastroplasty in morbidly obese patients. Acta Anaesthesiol Scand 1997; 41:408–13. 23. Ezri T, Hazin V, Warters D, Szmuk P, Weinbroum AA: The endotracheal tube moves more often in obese patients undergoing laparoscopy compared with open abdominal surgery. Anesth Analg 2003; 96:278–82. 24. Perilli V, Sollazzi L, Modesti C, et al.: Comparison of positive end-expiratory pressure with reverse Trendelenburg position in morbidly obese patients undergoing bariatric surgery: Effects on hemodynamics and pulmonary gas exchange. Obes Surg 2003; 13:605–9. 25. Pitkanen MT: Body mass and spread of spinal anesthesia with bupivacaine. Anesth Analg 1987; 66:127–31. 26. Taivainen T, Tuominen M, Rosenberg PH: Influence of obesity on the spread of spinal analgesia after injection of plain 0.5% bupivacaine at the L3–4 or L4–5 interspace. Br J Anaesth 1990; 64:542–6. 27. Eichenberger A, Proietti S, Wicky S, et al.: Morbid obesity and postoperative pulmonary atelectasis: An underestimated problem. Anesth Analg 2002; 95:1788–92. 28. Rennotte MT, Baele P, Aubert G, Rodenstein DO: Nasal continuous positive airway pressure in the perioperative management of patients with obstructive sleep apnea submitted to surgery. Chest 1995; 107:367–74. 29. Joris JL, Sottiaux TM, Chiche JD, Desaive CJ, Lamy ML: Effect of bi-level positive airway pressure (BiPAP) nasal ventilation on the postoperative pulmonary restrictive syndrome in obese patients undergoing gastroplasty. Chest 1997; 111:665–70. 30. Eriksson S, Backman L, Ljungstrom KG: The incidence of clinical postoperative thrombosis after gastric surgery for obesity during 16 years. Obes Surg 1997; 7:332–5. 31. Farley DR, Greenlee SM, Larson DR, Harrington JR: Double-blind, prospective, randomized study of warmed humidified carbon dioxide insufflation vs standard carbon dioxide for patients undergoing laparoscopic cholecystectomy. Arch Surg 2004; 139:739–43.



CHAPTER 6

V O L U M E


PROBLEMS WITH ANESTHESIA GAS DELIVERY SYSTEMS JAMES B. EISENKRAFT, M.D. PROFESSOR OF ANESTHESIOLOGY MOUNT SINAI SCHOOL OF MEDICINE ATTENDING ANESTHESIOLOGIST THE MOUNT SINAI MEDICAL CENTER NEW YORK, NEW YORK



© 2005



Problems with Anesthesia Gas Delivery Systems James B. Eisenkraft, M.D. Professor of Anesthesiology Mount Sinai School of Medicine Attending Anesthesiologist The Mount Sinai Medical Center New York, New York

The anesthesia gas delivery system consists of the anesthesia machine, vaporizers, a ventilator, a breathing system (patient circuit), and a waste gas scavenging system. Failure of the anesthesia gas delivery system is a rare cause of anesthesia-related injury to or death of a patient. More commonly, the delivery system is misused, the anesthesia caregiver makes an error, or the delivery system fails while the user is unaware that a failure has occurred. This refresher course reviews the types of failures and complications that can occur with delivery systems for inhaled anesthetics, considers how such failures may be detected, and thereby how an adverse outcome for the patient might be prevented.

Perspective The critical incident (CI) technique, first described by Flanagan in 1954, was developed for training situations to analyze critical events and ultimately decrease the loss of military pilots and aircraft in real-life situations.1 This technique involved the investigation of near misses to develop strategies designed to prevent recurrences. The CI technique was modified and introduced into anesthesia practice by Cooper and his colleagues at the Harvard-affiliated hospitals.2 From interviews with staff and resident anesthesiologists, these investigators collected and analyzed 1,089 descriptions of CIs during anesthesia.3 An anesthesia mishap was labeled a CI when it was clearly an occurrence that could have led, if not discovered or corrected in time, or did lead to an undesirable outcome, ranging from increased duration of hospital stay to permanent disability or death. Other CI inclusion criteria were that each incident involved an error made by a member of the anesthesia care team or a failure of the caregiver’s equipment to function properly; the CI occurred during care of a patient; the incident could be clearly described; and the incident was clearly preventable.2 Of the CIs collected by Cooper et al., 70 of 1,089 (6.4%) represented errors or failures that had contributed in some way to a “substantive negative outcome,” which was defined as “death, cardiac arrest, canceled operative procedure, or extended stay in the recovery room, in an intensive care unit, or in the hospital.”3 Although 30% of all CIs were related to equipment failure, including breathing circuit disconnections, misconnections, ventilator malfunctions, and gas flow control errors, only three of 70 (4.3%) of the substantive negative outcome incidents involved equipment failure, suggesting that human error was the dominant problem in the cause of the CIs. In 1993, the Australian Anesthesia Patient Safety Foundation published the results of the Australian Incident Monitoring Study, which collected data on 2,000 CIs.4 Of 65

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these, 177 (9%) were the result of equipment failure in general, and 107 of these (60%) involved the anesthesia delivery system. Failures that were reported included problems resulting from unidirectional valves, ventilator malfunctions, gas or electricity supply, breathing circuit integrity, anesthesia vaporizers, absorbers, and pressure regulators.4 The role of anesthesia equipment problems leading to adverse outcomes and malpractice litigation in the United States has been studied by the American Society of Anesthesiologists Closed Claims Project (American Society of Anesthesiologists–CCP).5 In 1997, Caplan et al. reported an analysis of 3,791 claims arising from events that occurred during the period 1961 to 1994.5 They found that gas delivery equipment problems accounted for 72 of 3,791 (2%) of all claims in the American Society of Anesthesiologists–CCP database. Of these 72 equipment-related claims, 39% were related to the breathing system, 21% to vaporizers, 17% to ventilators, 11% to gas tanks or gas lines, and only 7% to the anesthesia machine itself. Gas delivery equipment accounted for 34 of 1,542 (7%) of all claims in the American Society of Anesthesiologists– CCP database before 1985 but only 18 of 1,495 (1.2%) of claims since 1985.5 Although adverse outcomes from gas delivery equipment are rare and seem to be decreasing, when they do occur, the injuries are usually severe; indeed, death or brain damage was the outcome in 76% of the 72 cases collected.5 Of the 72 gas delivery equipment claims in the 1997 analysis, initiating events were circuit misconnects, disconnects, and delivery system errors.5 Claims involving misuse (that is, they were the result of human fault or error) were three times more common (75% vs. 24%) than “pure” equipment failures (54 vs. 17 cases). Of the cases considered to be the result of human error, 70% were thought to be the direct result of actions of the primary anesthesia provider, whereas in the other 30%, misuse evolved at least in part from the contributory actions of ancillary staff such as technicians, nurses, and respiratory therapists. The predominant mechanisms of injury were hypoxemia, excessive airway pressure, and anesthetic agent overdose. Overall, in 78% of the 72 claims, it was considered that the use or better use of monitoring could have prevented an adverse outcome. As of April 2004, the American Society of Anesthesiologists–CCP database included 6,448 claims of which 95 were related to anesthesia gas delivery equipment (Karen L. Posner, ASA Closed Claims Project, personal communication, March 26, 2004). Claims for events that occurred in the late 1990s are still being processed, and the most recent gas delivery system claims were for events in 2000. Thus far, however, it appears that gas delivery equipment problems are decreasing as a proportion of total claims. Anesthesia gas delivery claims represented 3% of all claims from the 1970s, 2% from the 1980s, and only 1% from the period 1990 through -2000. There were only 19 anesthesia gas delivery system claims from 1990 to 2000. These include four supplemental oxygen line events, seven anesthesia machine problems, three vaporizer problems, one ventilator problem, and four breathing circuit problems. The severity of adverse outcomes in anesthesia gas delivery equipment claims from 1990 to 2000 seems to be less than those of earlier claims. In 1990 to 2000, 31% of anesthesia gas delivery system claims resulted in severe injury or death compared with 80% in 1970 to 1989. Among the 19 claims from 1990 to 2000 were five cases of death, two brain damage, four pneumothorax, four awareness, one cardiac arrest with full recovery, three cancellations of surgery (no actual injury), and one claim with no apparent injury. Payments reflect the lower severity of injury, with a median payment (in 1999 dollars) of $63,250 in 1990 to 2000 compared with $594,750 (adjusted to 1999 dollars) for earlier gas delivery equipment claims. Fifteen of the 19 post1990 claims resulted in payment. All payments from 1990 to 2000 were 80 mL) through the leak site and through the spirometer, thereby satisfying the low tidal volume alarm threshold. Because the spirometry sensor is usually placed by the expiratory unidirectional valve at the carbon dioxide absorber, it does not measure the patient’s actual inspired or expired tidal volume; rather, it measures a volume exhaled by the patient and the gas volume that has been compressed in the circle system tubing during inspiration. Although the spirometer low tidal volume alarm is generally more useful in alerting to a low tidal volume and therefore a possible disconnect condition, a high tidal volume alarm feature is also useful. Anticipated increases in tidal volume have resulted from increasing the gas flow entering the breathing circuit during inspiration, when the breathing circuit is closed (by closing the ventilator pressure relief valve). This increase in tidal volume may be from the anesthesia machine flowmeters, from increasing the inspiratory:expiratory ratio setting on a ventilator12 or through a hole in the bellows in a Draeger AV-E anesthesia ventilator (on Narkomed models 2, 3, and 4) whereby driving gas (air/O2) enters the patient circuit. Thus, any gas that enters the patient circuit during inspiration (when gas cannot escape from the circuit) has the potential to be added to the patient’s inspired tidal volume. Such a situation may be particularly hazardous for the pediatric patient for whom a small tidal volume is intended. Modern electronic workstations incorporate features designed to ensure that the patient will always receive the intended tidal volume. Thus, once the breathing circuit has been connected to the workstation, an automated checkout is performed to ensure that there are no leaks and to measure the compliance of the system. Fresh gas decoupling (FG; used in the Draeger Narkomed Fabius GS and 6400 workstations, and in the Datascope Anestar workstation) ensures that fresh gas flow (FGF) does not contribute to tidal volume by being diverted into the reservoir bag during the inspiratory phase of ventilation. During exhalation, the FG stored in the reservoir bag is drawn into the bellows (Anestar) or piston chamber (Narkomed Fabius GS and Narkomed 6400). If there is inadequate volume of gas stored in the reservoir bag, the system would draw in room air. An O2 concentration or other alarm alerts to this condition. The DatexOhmeda ADU electronically measures FG and vaporizer settings and, through a computer program, subtracts these volumes from the volume of drive gas delivered to the bellows housing of the standing bellows ventilator. Thus, the greater the volume of fresh gas flow (N2O, air, O2, agent) set, the smaller the volume of drive gas needed to displace the ventilator bellows. A spirometer that senses gas flow direction can alert to a situation of reversed gas flow such as may occur with an incompetent expiratory unidirectional valve or with a leak in the breathing system between the expiratory unidirectional valve and the

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spirometer. The Ohmeda (Madison, WI) spirometer used with the GMS absorber system is designed so that it can be used normally in a location on the patient side of the expiratory unidirectional valve or be moved to a location by the patient’s airway when used in conjunction with a Bain circuit. When used near the airway connector, the reverse-flow detection feature of this spirometer must be disabled or the alarm will sound continuously. This occurs because gas flow is normally bidirectional when the flow sensor is in this location. When relocating the spirometry sensor to the position used normally with a circle system (that is, by the expiratory unidirectional valve), the caregiver must remember to reenable the reverse gas flow detection feature. It has been already noted that a spirometer low tidal volume alarm could be “fooled” in the event of a circuit leak or disconnect if a hanging bellows ventilator is used.11 Although less likely, a spirometer alarm that has been set to be satisfied by a low tidal volume might even be “fooled” when a standing bellows ventilator is used. The mechanism is as follows: Consider a standing bellows ventilator in use when there is a disconnect at the patient’s airway. The bellows falls to a resting position (analogous to the functional residual capacity position of the lungs) in the bellows housing during exhalation. With the next inspiration, the bellows is compressed by driving gas and is squeezed down to a residual volume. As exhalation begins, the driving gas no longer compresses the bellows, which then recoil or reexpand to their resting (functional residual capacity) position. This reexpansion of the bellows on exhalation has been reported to result in the drawing of as much as 140 mL air into the circuit through the leak.13 If this entrained volume of air is drawn in through the spirometer, it might satisfy the low-volume alarm if the threshold had been set to a very low limit.

Limitations of Standard Pressure and Volume Monitoring As noted, the basic breathing system pressure and volume monitors are subject to limitations of design, their location in the breathing system, and sometimes their alarmsetting features, particularly the ability to bracket the alarm limits to existing conditions.

Gas Composition in the Breathing System Monitoring of respired gases in the vicinity of the patient’s airway will alert the user to most problems involving gas delivery, composition, and agent dosing (overdose and underdose).

Oxygen All anesthesia delivery systems incorporate a galvanic fuel cell oxygen sensor located near the inspiratory unidirectional valve. The analyzer actually senses the oxygen tension (PO2), although the readout is in volumes-percent. It is calibrated to 21% and, unlike certain other technologies, is not “fooled” by other gases.14 On contemporary machines, the oxygen analyzer is automatically enabled whenever the machine is capable of delivering an anesthetic gas mixture.10 Causes of an inadequate concentration of oxygen in the circuit include a hypoxic gas being delivered through the oxygen pipeline or from the tank, a disconnection of the fresh gas hose between the common gas outlet of the machine and the breathing system during use of a hanging bellows ventilator, the oxygen flow control valve turned off, malfunction of the failsafe system, a nitrous oxide—oxygen proportioning system failure, an oxygen leak in the machine’s

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low-pressure system, and a closed circuit with an inadequate oxygen supply inflow rate. The oxygen analyzer with its low oxygen concentration alarm appropriately set is an essential component of all anesthesia delivery systems to detect the possibility that a hypoxic gas mixture is delivered to the patient.10 In addition, the high oxygen concentration alarm may be valuable in certain situations. Some older anesthesia machines have separate flow meters for oxygen and for helium to deliver a helium–oxygen mixture for use in laser surgery of the airway. Consider the situation in which the flows are 3 L per minute helium and 1 L per minute oxygen to deliver a 75% helium and 25% oxygen mixture. If the helium tank becomes depleted, or if the oxygen flush is used, an oxygen-enriched gas mixture would result that could cause a fire when a laser is used. The high oxygen concentration alarm would alert the clinician to such a condition. These potential problems associated with depletion of a tank of helium can be addressed by adapting the anesthesia machine to receive only tanks of a heliox (that is, premixed 25% oxygen with 75% helium) so that 100% oxygen cannot be delivered during anesthesia. Nevertheless, accidental operation of the oxygen flush valve during laser use remains a hazard that can be prevented only when users are educated. Most modern anesthesia machines are equipped with an auxiliary O2 flow meter. This is used for connection to supplemental oxygen tubing to a nasal cannula or facemask. It must be recognized that there is no O2 analyzer in use with such an arrangement and that one is assuming that this device is a source of O2. A misconnection of gas supply lines to the machine could result in delivery of a hypoxic gas from this flow meter. Although highly unlikely, an O2 flow meter could also be plugged into a “quick connect” wall outlet in the operating room, postanesthesia care unit, intensive care unit, or elsewhere in the facility. Adverse outcomes have resulted from an O2 flow meter that was plugged into a wall outlet for N2O. This “misconnection” was made possible because the O2-specific “quick connect” fitting on the flow meter had been altered.15

Capnography Capnography is the measurement and display of carbon dioxide concentration over time. It is standard of care for all patients receiving general anesthesia. Capnography can provide much information about ventilation of the patient’s lungs as well as about the function of the anesthesia delivery system. Failure to ventilate, which might be the result of a circuit disconnect or misconnect, should result in absence of a capnogram tracing and annunciation of an apnea alarm. An abnormal capnogram may be the result of rebreathing of carbon dioxide (for example, exhausted carbon dioxide absorbent, incompetent inspiratory or expiratory valves, misconfigured circuit, or a Bain circuit with an inner tube disconnect).

Anesthetic Agents and Nitrogen Critical incidents and adverse outcomes have resulted from anesthetic overdosing and underdosing.5 Monitoring concentrations of nitrous oxide and of anesthetic agents using appropriate high- and low-concentration alarm settings will alert the caregiver to anesthetic over- and underdosing problems. Low agent concentration, which may be caused when a vaporizer is empty, leaking, or accidentally turned off, might result in patient awareness. Desflurane vaporizers have an alarm to indicate “low agent.” Excessive concentrations of agent may be the result of vaporizer overfilling, malfunction, tipping, liquid agent in the circuit, or reversal of gas flow through some vaporizers. Modern vaporizers are designed to prevent overfilling, and some even permit tipping without risk of liquid agent entering the bypass.

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Some anesthetic agent analyzers annunciate an alarm in the presence of mixed agents (for example, vaporizer contamination, more than one vaporizer on). An agent analyzer is particularly important if a measured-flow vaporizing system (for example, Copper Kettle or Verni-Trol, neither of which is manufactured now) is used because gas flow setting errors could result in the delivery of potentially lethal concentrations of anesthetic agent. Certain models of anesthetic multigas analyzer, programmed with the MAC values of N2O and the anesthetic agents, are capable of displaying the MAC values of the inspired and end-tidal gas mixtures. With a knowledge of the concept of MAC-AWAKE, the analyzer may be used as a “poor man’s” awareness monitor. Although anesthetic agent analysis is not a standard for basic anesthetic monitoring, it may become a de facto standard as its use becomes more widespread. Monitoring of circuit nitrogen concentration may alert the user to the presence of a leak in the breathing system (such as a hole in the bellows of a North American Drager anesthesia ventilator).

Monitoring Gas Flows and Sidestream Spirometry Sidestream sampling (or diverting) gas analyzers are now widely used to monitor carbon dioxide and other respired gases (including N2O, anesthetic agent, O2, and some N2). In these systems, gas is sampled from an adapter close to the patient’s airway, conducted through a sampling tube to the analyzer and then either returned to the breathing system or dumped into a waste gas scavenging system. The addition of Pitot tube flow sensors to the sidestream sampling airway adapter makes it possible, with only a small increase in the size of the airway adapter (that is, additional apparatus dead space) to monitor pressure, flow, volume, and respired gas composition at the patient’s airway.16 This modality is called sidestream spirometry (used in the Datex-Ohmeda S5/ADU workstation and in other monitors). Monitoring multiple aspects of the breathing system by the patient’s airway offers many potential advantages over the usual pressure and volume monitoring sites that are remote from the patient’s airway. It enables the display of gas analysis results (O2, CO2, anesthetic agent) as well as the patient’s inspired and expired tidal and minute volumes, flow-volume loop, and pressure-volume loop. Comparison of inspired with expired volumes at the airway facilitates detection of a leak distal to the airway adapter. A difference between expired and inspired volumes may be the result of a deflated endotracheal tube cuff or a poorly fitting laryngeal mask airway. With appropriate alarm limits set for all monitored parameters, such a system offers the potential for greater patient safety because it is far less likely to be “fooled” than are monitors whose sensors are remote from the patient’s airway.

Alarms The American Society of Anesthesiologists–CCP database includes occurrences in which monitors or alarms were absent, broken, disabled, ignored, or led to an inadequate response by the anesthesia caregiver.5 The appropriate use of monitors and alarms has been the subject of considerable research effort, but there remains room for improvement both in design and user education.17 Electronic surveillance systems (monitors) should be user-friendly, automatically enabled when needed, have alarm thresholds easily bracketed to prevailing “normal” conditions, be intelligent (“smart”), and the alarm signal annunciated should be appropriate in terms of urgency, specificity, and audibility (volume). Prevention of an adverse outcome may depend on a prompt and focused response to the alarm situation by the caregiver. Some have suggested that verbal alarm messages be used, but these are not popular in the operating


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room because of the possibility of false alarms causing unnecessary concern to the surgeon or even to a patient receiving monitored anesthesia care. Verbal alarm messages may have a place, however, in alerting to conditions that may progress rapidly to injury such as sudden high pressure in the breathing system. Because monitors and alarms may fail or be “fooled” under certain conditions, it has been recommended that critical areas be doubly or triply monitored, preferably by independent and independently energized devices. It is most important that the audibility (volume) of alarms be tested and adjusted for environment in which they are used. An alarm that has been disabled can lead to an otherwise preventable adverse outcome. The Anesthesia Patient Safety Foundation has recently stressed the importance of audible monitor alarms as a safety net.18 The silencing of audible alarms (because “false alarms are annoying”) should be actively discouraged.

Other Potential Problems Monitoring of the anesthesia circuit to assess the function of the anesthesia gas delivery system presumes that almost any problem will be detectable as an abnormality of pressure, volume, flow, or gas composition and that the routinely used monitoring systems will be able to detect such abnormalities. Although this is true for most problems, situations continue to be reported in which what was considered to be state-of-the art monitoring has failed to detect an abnormal situation or potential hazard. Thus, one must always expect the unexpected! Examples of such situations follow.

Carbon Monoxide Since 1990, there have been several reports of patients who developed increased levels of carboxyhemoglobin (COHb) as a result of accumulation of carbon monoxide (CO) in the circle breathing system. The CO is produced when enflurane, isoflurane, sevoflurane, and especially desflurane react with desiccated CO2 absorbent, particularly Baralyme.19,20 Although to date no resulting patient injury from has been reported, CO represents a potential hazard of the anesthesia delivery system.21 Measures that have been recommended to decrease this potential hazard include using only absorbent that has the standard complement of water or adding liquid water to the top of the absorbent.22 Fresh gas flow from the anesthesia machine should be shut off at the end of each case to prevent the absorbent from drying out, and consideration should be given to replacing the absorbent more frequently. This is particularly important if the machine has been left unused for some time but with the oxygen flow accidentally left on such as may happen over a weekend. The respiratory gas monitors in current clinical use (mass spectrometers, Raman spectrometers, infrared analyzers) cannot detect carbon monoxide directly. An awareness of this potential hazard is especially important because it is unlikely that carbon monoxide in the breathing system would be detectable by conventional routine monitoring. It is possible that in the future, use of multiple-wavelength pulse oximetry will facilitate the continuous noninvasive measurement of COHb.

Fires from Interactions of Anesthetics with Desiccated Absorbent In their 2003 study of CO production from sevoflurane breakdown, Holak et al.20 concluded that in extreme cases with completely desiccated absorbents, large quantities of CO may be generated, and flammable gases may be produced and ignited. The

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August 2003 package insert for Ultane (sevoflurane) warned of this potential hazard. In 2004, there appeared disturbing reports of fires and an explosion associated with the clinical use of sevoflurane together with Baralyme.23–25 Laster et al. studied fires from interactions of sevoflurane, isoflurane, and desflurane with desiccated Baralyme in a laboratory situation.26 They concluded that degradation of sevoflurane by desiccated absorbents may lead to temperatures in excess of 200°C and to fire in the anesthetic circuit. With desflurane and isoflurane, degradation may lead to temperatures of approximately 100°C in the circuit that were unlikely to lead to fire. Woehlck, in an editorial, suggested monitoring of the temperature in the absorbent canister, with 50°C as an approximate threshold for intervention.27 In late 2004, the manufacturers of Baralyme (Allied Health Care, St. Louis, MO) withdrew it from the market. Soda lime appears to be less of a hazard because it contains less strong base than Baralyme. Amsorb is a new absorbent that contains no strong base (that is, no sodium, potassium, or barium hydroxides) and is therefore much less likely to react with sevoflurane.28 In addition, this absorbent changes color from white to pink when it becomes exhausted and/or desiccated.

Prevention of Anesthesia Equipment Problems and Adverse Events Patient injury resulting from anesthesia delivery system problems is uncommon, but when it occurs, it is usually a result of user error rather than pure equipment failure. The education of caregivers in the use of the anesthesia gas delivery equipment is essential if it is to be used correctly and safely. Education of ancillary staff (that is, nurses and technicians) is also important because they may unwittingly contribute to the occurrence of a problem. The equipment manufacturers have excellent inservice and educational programs but are concerned that the caregivers devote too little time to learning about new equipment. All equipment should be serviced regularly according to the manufacturer’s recommendations and by authorized personnel, and the equipment should be updated as necessary to conform to existing standards or requirements. In this regard, the equipment manufacturers generally offer to conduct an audit of their own earlier products to determine what aspects, if any, could be upgraded, discuss how the audited machine differs from the state-of-the art, and the implications of such differences. A preuse checkout of the anesthesia delivery system should be developed by each institution to meet local needs. In 1993, the U.S. Food and Drug Administration (FDA) published updated generic anesthesia apparatus checkout recommendations (http:// www.fda.gov/cdrh/humfac/anesckot.html). This checkout, together with the manufacturer’s recommended checkout, can be used to develop the local checkout procedures to be used in a particular institution depending on the equipment in clinical service. New anesthesia workstations commonly have their own unique automated preuse checkout that may appear to have little in common with the 1993 FDA checkout. The American Society of Anesthesiologists Committee on Equipment and Facilities, in conjunction with equipment manufacturers and FDA, is in the process of devising a generic checkout that would have applicability to the new workstations. Meanwhile, item 1 on the FDA 1993 preuse checkout is: “Verify Backup Ventilation Equipment is Available & Functioning.” Thus, if the delivery system should fail for whatever reason, the patient’s lungs can be ventilated using room air (or oxygen if a tank is available) and a self-inflating resuscitation bag. If used as intended by the manufacturers, anesthesia delivery systems are generally very reliable and safe. However, any system that is configured or modified by the caregiver may compromise even the most sophisticated safety features and potentially


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jeopardize patient safety. Adverse outcomes resulting from anesthesia delivery systems are usually complex in origin and involve specific errors, failures, and sequences of events. Eichhorn29 reviewed 70 anesthesia cases reported to the Harvard malpractice insurance carrier for the period 1976 to 1988. Eleven major intraoperative accidents occurred, of which five were related to anesthesia equipment and involved user error. Eichhorn’s report is especially valuable because there is a brief synopsis of each of these major accidents, which provides some insight into how such events can occur and how they may be prevented by safety monitoring.29 A vigilant anesthesia caregiver is the ultimate monitor whose timely and appropriate intervention can often prevent an adverse outcome. A focused response to the various alarms and scenarios is essential, and more and more commonly is being practiced in anesthesia human patient simulators.

References 1. Flanagan JC: The initial incident technique. Psychol Bull 1954; 51:327–58. 2. Cooper JB, Newbower RS, Long CD, McPeek B: Preventable anesthesia mishaps. Anesthesiology 1978; 49:399–406. 3. Cooper JB, Newbower RS, Kitz RJ: An analysis of major errors and equipment failures in anesthesia management. Anesthesiology 1984; 60:34–42. 4. Webb RK, Curine M, Morgan CA, et al.: The Australian Incident Monitoring Study: An analysis of 2000 incident reports. Anaesth Intensive Care 1993; 21:520–8. 5. Caplan RA, Vistica MF, Posner KL, Cheney FW: Adverse anesthetic outcomes arising from gas delivery equipment: A closed claims analysis. Anesthesiology 1997; 87:741–8. 6. Schreiber PJ: Con: There is nothing wrong with old anesthesia machines and equipment. J Clin Monit 1996; 12:39–41. 7. Lee O: PEEP Safety cited. APSF Newsletter 1990; 5:21. 8. Smith CE, Otworth JF, Kaluszyk P: Bilateral tension pneumothorax due to a defective anesthesia breathing circuit filter. J Clin Anesth 1991; 3:229–34. 9. Adams AP: Breathing system disconnections. Br J Anaesth 1994; 73:46–54. 10. Standard Specifications for Minimum Performance and Safety Requirements for Components and Systems of Anesthesia Gas Machines, ASTM F1161-88. Philadelphia: American Society for Testing and Materials; 1989. 11. Schreiber P, Schreiber J: Safety Guidelines for Anesthesia System Risk Analysis and Risk Reduction. Telford, PA: North American Drager; 1987. 12. Scheller MS, Jones BR, Benumof JL: Influence of fresh gas flow and I:E ratio on tidal volume and PaCOs in ventilated patients. J Cardiothorac Anesth 1989; 3:564. 13. Gravenstein JS, Nederstigt JA: Monitoring for disconnection: Ventilators with bellows rising on expiration can deliver tidal volumes after disconnection. J Clin Monit 1990; 6:207–10. 14. Eisenkraft JB, Raemer DB: Monitoring gases in the anesthesia delivery system. In: Ehrenwerth J, Eisenkraft JB, eds. Anesthesia Equipment: Principles and Applications. St. Louis: Mosby-Year Book; 1993:321–49. 15. Surgery mixup causes 2 deaths. New Haven Register, January 20, 2002. 16. Merilainen P, Merilainen P, Hanninen H, Tuomaala L: A novel sensor for routine continuous spirometry of intubated patients. J Clin Monit 1993; 9:374–80. 17. Eisenkraft JB: A commentary on anesthesia gas delivery equipment and adverse outcomes. Anesthesiology 1997; 87:731–3. 18. APSF stresses use of audible monitor alarms. APSF Newsletter 2004; 19:17–28. 19. Fang ZX, Eger EI II, Laster MJ, et al.: Carbon monoxide production from degradation of desflurane, enflurane, isoflurane, halothane and sevoflurane by soda lime and Baralyme. Anesth Analg 1995; 80:1187–93. 20. Holak EJ, Mei DA, Dunning MB, et al.: Carbon monoxide production from sevoflurane breakdown. Anesth Analg 2003; 96:757–64. 21. Woehlck HJ, Dunning M, Connolly CA: Reduction in the incidence of carbon monoxide exposures in humans undergoing general anesthesia. Anesthesiology 1997; 87:228–34.

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22. Baxter PJ, Kharasch ED: Rehydration of desiccated Baralyme prevents carbon monoxide formation from desflurane in an anesthesia machine. Anesthesiology 1997; 86:1061–5. 23. Fatheree RS, Leighton BL: Acute respiratory distress syndrome after an exothermic Baralyme–sevoflurane reaction. Anesthesiology 2004; 101:531–3. 24. Wu J, Previte JP, Adler E, et al.: Spontaneous ignition, explosion, and fire with sevoflurane and barium hydroxide lime. Anesthesiology 2004; 101:534–7. 25. Castro BA, Freedman LA, Craig WL, Lynch C: Explosion within an anesthesia machine: Baralyme, high fresh gas flows and sevoflurane concentration. Anesthesiology 2004; 101:537–9. 26. Laster M, Roth P, Eger EI II: Fires from the interaction of anesthetics with desiccated absorbent. Anesth Analg 2004; 99:769–74. 27. Woehlck HJ: Sleeping with uncertainty [Editorial]. Anesthesiology 2004; 101:276–8. 28. Kharasch ED, Powers KM, Artru AA: Comparison of Amsorb, sodalime, and Baralyme degradation of volatile anesthetics and formation of carbon monoxide and compound a in swine in vivo. Anesthesiology 2002; 96:173–82. 29. Eichhorn JH: Prevention of intraoperative anesthesia accidents and related severe injury through safety monitoring. Anesthesiology 1989; 70:572–7.



CHAPTER 7

V O L U M E


PREOPERATIVE ASSESSMENT OF THE PATIENT WITH CARDIAC DISEASE LEE A. FLEISHER, M.D. ROBERT D. DRIPPS PROFESSOR AND CHAIR DEPARTMENT OF ANESTHESIOLOGY AND CRTICAL CARE PROFESSOR OF MEDICINE UNIVERSITY OF PENNSYLVANIA SCHOOL OF MEDICINE PHILADELPHIA, PENNSYLVANIA



© 2005



Preoperative Assessment of the Patient with Cardiac Disease Lee A. Fleisher, M.D. Robert D. Dripps Professor and Chair Department of Anesthesiology and Critical Care Professor of Medicine University of Pennsylvania School of Medicine Philadelphia, Pennsylvania

Despite the emphasis over the last 2 decades on the role of preoperative cardiac testing before noncardiac surgery, there continues to be a paucity of evidence to demonstrate the benefits of a testing paradigm. Much of the research to date has focused on defining the predictive value of a number of diagnostic tests and the association between coronary revascularization and perioperative cardiac morbidity. More recently, there is increasing emphasis on the value of perioperative pharmacologic management. A basic tenet in preoperative evaluation is that information regarding the extent and stability of disease will affect patient management and lead to improved outcome. In the case of cardiovascular disease, the preoperative evaluation attempts to define the extent of coronary artery disease and the left ventricular function. This Refresher Course uses the American College of Cardiology/American Heart Association (ACC/AHA) Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac Surgery as the basis for discussing the optimal care for the high-risk patient.1 Several authors have suggested that extensive evaluation is no longer necessary in an era of low cardiac morbidity. They argue that improvements in intra- and postoperative care obviate the need for an extensive evaluation, particularly with the use of perioperative pharmacologic therapy. In addition, a recently published randomized trial (CARP) suggests that coronary revascularization is of no benefit before major vascular surgery in patients with coronary disease exclusive of left main disease.2 However, it is important to recognize that these interventions were not studied in those patients with the highest risk, that is, those with extensive symptomatic disease. Therefore, it remains important to identify those with symptomatic and potentially highgrade disease.

Cardiac Risk Indices Since the original manuscript by Goldman and colleagues in 1977 describing a Cardiac Risk Index, multiple investigators have validated various clinical risk indices for their ability to predict perioperative cardiac complications. The Goldman Cardiac Risk Index originally defined nine factors, each of which was given a weight or number of points. The cardiac risk index has been validated in large populations of diverse types of noncardiac surgery but does not appear as robust in selected populations of patients undergoing major vascular surgery. Detsky et al. modified the cardiac risk index, adding Based in part on the ASA Refresher Course Lecture 2004, with permission.

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factors such as major vascular surgery and angina. The most recent index was developed in a study of 4,315 patients aged 50 years or greater undergoing elective major noncardiac procedures in a tertiary-care teaching hospital.3 Six independent predictors of complications were identified and included in a Revised Cardiac Risk Index: high-risk type of surgery, history of ischemic heart disease, history of congestive heart failure, history of cerebrovascular disease, preoperative treatment with insulin, and preoperative serum creatinine >2.0 mg/day, with increasing cardiac complication rates noted with increasing number of risk factors. A primary issue with all of these indices from the anesthesiologist’s perspective is that a simple estimate of risk does not help in refining perioperative management, but may provide information to assess the probability of complications. In contrast, the anesthesiologist is most concerned with defining the cardiovascular risk factors and symptoms or signs of unstable cardiac disease states such as myocardial ischemia, congestive heart failure, valvular heart disease, and significant cardiac arrhythmias. Therefore, the calculation of a simple score does not provide sufficient information for the anesthesiologist to appropriately modify perioperative management. The preoperative evaluation should help define those patients who require perioperative interventions (Table 1).

Clinical Risk Factors A thorough history should focus on cardiovascular risk factors and symptoms or signs of unstable cardiac disease states such as myocardial ischemia with minimal exertion, active congestive heart failure, symptomatic valvular heart disease, and significant cardiac arrhythmias (Table 2). In patients with symptomatic coronary disease, preoperative evaluation may lead to the recognition of a change in the frequency or pattern of anginal symptoms. Symptoms of cardiovascular disease should be carefully determined, especially characteristics of chest pain, if present. The presence of unstable angina has been associated with a high perioperative risk of myocardial infarction (MI).4 The preoperative evaluation can impact on both a patient’s short- and long-term health by instituting treatment of unstable angina. The patient with stable angina represents a continuum from mild angina with extreme exertion to dyspnea with angina after walking up a few stairs. The patient who only manifests angina after strenuous exercise does not demonstrate signs of left ventricular dysfunction and would not be a candidate for changes in management. In contrast, a patient with dyspnea on mild exertion would be at high risk for developing perioperative ventricular dysfunction, myocardial ischemia, and possible MI. These patients TABLE 1.

Perioperative Interventions Based on Preoperative Cardiac Evaluation

Decision to forego surgery Modification of surgical procedure Delay case for treatment of unstable symptoms Modification of intraoperative monitors Modification of perioperative medical therapy Initiation of beta-blockers, statins, alpha-2 agonists Modification of postoperative monitoring (e.g., intensive care unit) Coronary revascularization before noncardiac surgery Modification of location of care

PREOPERATIVE CARDIAC EVALUATION BEFORE NONCARDIAC SURGERY 81 TABLE 2.

Clinical Predictors of Increased Perioperative Cardiovascular Risk (Myocardial Infarction, Congestive Heart Failure, Death)

Major Unstable coronary syndromes Recent myocardial infarction* with evidence of important ischemic risk or clinical symptoms or noninvasive study Unstable or severe† angina (Canadian class III or IV)‡ Decompensated congestive heart failure Significant arrhythmias High-grade atrioventricular block Symptomatic ventricular arrhythmias in the presence of underlying heart disease Supraventricular arrhythmias with uncontrolled ventricular rate Severe valvular disease Intermediate Mild angina pectoris (Canadian class I or II) Prior myocardial infarction by history or pathologic Q waves Compensated or prior congestive heart failure Diabetes mellitus Chronic renal insufficiency Minor Advanced age Abnormal electrocardiogram (left ventricular hypertrophy, left bundle branch block, ST-T abnormalities) Rhythm other than sinus (e.g., atrial fibrillation) Low functional capacity (e.g., inability to climb one flight of stairs with a bag of groceries) History of stroke Uncontrolled systemic hypertension *The American College of Cardiology National Database Library defines recent myocardial infarction as greater than 7 days but less than or equal to 1 month (30 days). † May include “stable” angina in patients who are unusually sedentary. ‡ Campeau L. Grading of angina pectoris. Circulation. 1976; 54:522–3. Reproduced with permission from Eagle KA, Berger PB, Calkins H, et al.: ACC/AHA guideline update for perioperative cardiovascular evaluation for noncardiac surgery—Executive summary: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1996 Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac Surgery). J Am Coll Cardiol 2002; 39:542–53.

have an extremely high probability of having extensive coronary artery disease, and additional monitoring or cardiovascular testing should be contemplated, depending on the surgical procedure and institutional factors. In virtually all studies, the presence of active congestive heart failure preoperatively has been associated with an increased incidence of perioperative cardiac morbidity. Stabilization of ventricular function and treatment for pulmonary congestion is prudent before elective surgery. Also, it is important to determine the etiology of the left heart failure. Congestive symptoms may be the result of nonischemic cardiomyopathy or mitral or aortic valvular insufficiency and/or stenosis. Because the type of perioperative monitoring and treatments would be different, clarifying the cause of cardiac congestion is important. Patients with a prior MI have coronary artery disease, although a small group of patients may sustain an MI from a nonatherosclerotic mechanism. Traditionally, risk assessment for noncardiac surgery was based on the time interval between the MI and surgery. Multiple studies have demonstrated an increased incidence of reinfarction if the MI was within 6 months of surgery. With improvements in perioperative care, this difference has decreased.5

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However, the importance of the intervening time interval may no longer be valid in the current era of thrombolytics, angioplasty, and risk stratification after an acute MI. Although many patients with an MI may continue to have myocardium at risk for subsequent ischemia and infarction, other patients may have their critical coronary stenosis either totally occluded or widely patent. Therefore, patients should be evaluated from the perspective of their risk for ongoing ischemia. The ACC/AHA Guidelines on Perioperative Evaluation of the Cardiac Patient undergoing Noncardiac Surgery has advocated the use of an MI 5%) Emergent major operations, particularly in the elderly Aortic and other major vascular Peripheral vascular Anticipated prolonged surgical procedures associated with large fluid shifts and/or blood loss (Reported cardiac risk generally 0.5 Gy) Streptomycin/kanamycin Tetracycline Thalidomide Trimethadione Valproic acid Vitamin A derivatives

ANESTHESIA FOR THE PREGNANT PATIENT TABLE 2.

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Principles for Anesthetic Management of the Parturient 24 Weeks Gestation

Counsel the patient preoperatively (see text). Discuss use of perioperative tocolytic agents with the obstetrician. Use aspiration prophylaxis of choice. Maintain left uterine displacement perioperatively. Monitor and maintain oxygenation, normocarbia, normotension, and euglycemia. Consider use of fetal monitoring intraoperatively (when feasible) to optimize the intrauterine environment. Monitor for uterine contractions and fetal heart tones postoperatively.

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medical issue. Consider aspiration prophylaxis with some combination of an antacid, metoclopramide, and/or H2-receptor antagonist. Discuss perioperative tocolysis with the patient’s obstetrician. Indomethacin (oral or suppository) and magnesium sulfate (by infusion) are the most commonly used perioperative tocolytics. Indomethacin has few anesthetic implications, but magnesium potentiates nondepolarizing muscle relaxants and attenuates vascular responsiveness, making hypotension difficult to treat during acute blood loss or volume shifts. Intraoperatively, there is no evidence that any anesthetic technique is better than another as long as maternal oxygenation and perfusion are maintained. No one has shown that type of surgery, type of anesthetic, trimester in which surgery occurs, length of surgery, estimated surgical blood loss, or length of anesthesia affects pregnancy outcome. Monitoring should include blood pressure measurement, pulse oximetry, endtidal CO2, and temperature measurement. Remember that pCO2 is decreased by approximately 10 torr during pregnancy resulting from increased minute ventilation. Maternal metabolic requirements are increased so desaturation occurs more quickly. If the procedure is prolonged, blood glucose should be checked to avoid hypoglycemia. If it will not interfere with the surgical field, intermittent or continuous fetal monitoring may be performed after approximately 24 weeks gestation to ensure that the intrauterine environment is optimized. This may be as simple as checking fetal heart tones before and after surgery or as complex as an attempt to do continuous fetal monitoring intraoperatively. Monitoring should be approached as a medical issue, not a medicolegal one! Will this modality change your management? The American College of Obstetricians and Gynecologists (ACOG) has issued a Committee Opinion on “Nonobstetric Surgery in Pregnancy,” which states in part that: “Although there are no data to support specific recommendations regarding nonobstetric surgery and anesthesia in pregnancy, it is important for nonobstetric physicians to obtain obstetric consultation before performing nonobstetric surgery. The decision to use fetal monitoring should be individualized, and each case warrants a team approach for optimal safety of the woman and her baby.”12 At a minimum, an obstetric consult should be obtained before surgery to document the preoperative well-being of the fetus and to introduce the woman to their service in case obstetric intervention is needed perioperatively. If continuous monitoring is performed, loss of beat-to-beat variability is normal after general anesthetic medications or sedatives, but fetal bradycardia is not. Decelerations may indicate the need to increase maternal oxygenation, increase her blood pressure, increase uterine displacement, change the site of surgical retraction, or begin tocolysis. Fetal monitoring can help assess the adequacy of perfusion during induced hypotension, cardiopulmonary bypass, or procedures involving large volume shifts. If the mother is awake during a regional anesthetic, it can be very reassuring for her to hear fetal heart tones during the procedure. However, intraoperative fetal monitoring may be impractical in urgent situations or during abdominal surgery. Monitoring has not been shown to improve fetal outcome. Personnel with labor and delivery (L&D) expertise may not be readily available, and misinterpretation could lead to unsafe interventions such as preterm delivery.13 As stated earlier, ACOG supports preoperative consultation with an obstetrician before any nonobstetric surgery during pregnancy, but states the need for fetal monitoring should be decided on a case-by-case basis. General anesthesia should include full preoxygenation and denitrogenation, rapid sequence induction with cricoid pressure, a high concentration of oxygen, and slow reversal of relaxants to prevent acute increases in acetylcholine that might induce uterine contractions. Keep in mind the pregnant airway is more edematous and vascular, and visualization may be more difficult during laryngoscopy. Propofol has recently been

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shown to reduce oxytocin-induced contractions of uterine smooth muscle in animals, although its value as a tocolytic is unknown. During first trimester, ketamine at doses >2 mg/kg may cause uterine hypertonus so use lower doses. Inhalational agents should be kept less than 2.0 MAC to prevent decreased maternal cardiac output. Nitrous oxide may be used at the anesthesiologist’s discretion. Regional techniques have the advantage of minimizing drug exposure in early pregnancy and changes in fetal heart rate variability later in gestation. Prevent hypotension after neuraxial techniques with adequate volume status and uterine displacement, and treat hypotension aggressively with pressors (phenylephrine or ephedrine) if needed. Decrease the neuraxial dose of local anesthetic by approximately one third from that used in nonpregnant patients. Regional anesthetics provide excellent postoperative pain control, reducing the need for sedation so: 1) the patient can report symptoms of preterm labor, 2) fetal heart rate variability is maintained, and 3) early mobilization can occur, reducing risk of thromboembolic complications. Postoperatively, continue monitoring fetal heart rate and uterine activity. Preterm labor must be treated early and aggressively. Monitoring may require recovery in the L&D unit or provision of L&D nursing expertise in the surgical recovery area or intensive care unit. Remember that parenteral pain medications will decrease fetal heart rate variability, so regional techniques should be used when possible. Pregnant patients are at high risk for thromboembolism and should be mobilized as quickly as possible— another reason for aggressive postoperative pain management. If mobilization is not possible, prophylactic anticoagulation should be considered. Maintain maternal oxygenation and left uterine displacement. Notify the pediatrics service if the fetus is of viable gestational age so they can provide counseling to the parents if preterm labor occurs.

Special Situations Cervical cerclage may be the most common surgical procedure during pregnancy. However, a recent study showed that it may not be beneficial. Two hundred fifty-three women with a short cervix by ultrasound were randomized to cerclage or expectant management. Approximately 22% of women in the cerclage group extended their pregnancies beyond 33 weeks versus 26% in the control group. The conclusion was that cervical cerclage does not substantially reduce the risk of early preterm delivery.14 Trauma is a leading cause of maternal death. Fetal loss in these situations is the result of maternal death or placental abruption. An early ultrasound should be performed in the emergency room to determine fetal viability, and fetal monitoring should be continued. The mother should receive all needed diagnostic tests to optimize her management, with shielding for the fetus when possible. Exposure to less than 5 rad (for example, head computed tomography is 21% in those aged ≥65 years.1 Although operative mortality has decreased in the elderly population in recent decades, perioperative morbidity continues to be more frequent in the elderly, and perioperative mortality rates remain higher than those encountered with younger patients, with steep increases in mortality observed after age 75 years. Although it has been estimated that at least 20,000 gerontologists are currently needed to care for the 35 million Americans over the age of 65, only 9000 of the >650,000 physicians in this country are certified in geriatric medicine. Only three of the 126 accredited medical schools in the United States have a geriatrics department, and only 2% of newly trained physicians select geriatrics as their subspecialty. Thus, it appears that an enlightened approach to this situation is to train all physicians, regardless of their specialty, in the aspects of gerontology related to their field. Clearly, as an ever-increasing proportion of the surgical outpatient population falls into the geriatric category, many anesthesiologists are becoming geriatric subspecialists to a certain extent. Thus, it seems appropriate to summarize our current knowledge about the physiology of aging and to discuss the implications of these concepts for the perioperative anesthetic management of the elderly outpatient.

Physiology and Pathophysiology of Aging Age alters both the pharmacokinetic and pharmacodynamic aspects of anesthetic management. As an individual ages, he or she experiences a loss of reserve and a diminished ability to tolerate stress. The functional capacity of organs declines and coexisting disease further contributes to this decline. Clearly, advanced age is a significant risk factor for increased perioperative morbidity and mortality, and age itself may further amplify the negative prognostic value of impaired physical status.2 The effects of aging at the subcellular level are ubiquitous, and these effects are manifold and manifest when one considers organ function in the elderly. In terms of cardiac function, it is well known that geriatric patients have decreased β-adrenergic responsiveness, and they experience an increased incidence of conduction abnormalities, bradyarrhythmias, and hypertension (Table 1). The progressive decrease in 165

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McGOLDRICK TABLE 1.

Age-related Cardiovascular Changes

↑Incidence of hypertension, conduction abnormalities, and arrhythmias Progressive ventricular hypertrophy →↑ wall stress and myocardial oxygen demand → vulnerability to ischemia ↓Diastolic myocardial function ↓Baroreceptor-mediated heart rate control ↓Beta-adrenergic receptor responsiveness ↓Vascular/ventricular compliance

elasticity of the arterial vasculature produces an increase in systolic blood pressure. The cross-sectional area of the peripheral vascular bed decreases, resulting in higher peripheral vascular resistance. In response to increased afterload, progressive ventricular hypertrophy develops, resulting in deposition of fibrotic tissue. Ventricular hypertrophy increases both wall stress and myocardial oxygen demand, making the ventricle more prone to ischemia. Fibrotic infiltration of cardiac conduction pathways and replacement of myocardial elastic fibers render the elderly individual vulnerable to conduction delay and to atrial and ventricular ectopy. It is well known that postoperative atrial arrhythmias, and atrial fibrillation and flutter specifically, are seen in 6.1% of elderly patients undergoing noncardiothoracic surgery and in 10% to 40% of patients after cardiothoracic operations.3–6 Although it has been firmly established that older age (>60 years) is the strongest predictor of postoperative atrial fibrillation (AF), a recent investigation found that a greater preoperative heart rate (≥74 beats per minute) is also independently associated with postoperative AF.7 This suggests that a lower vagal tone before surgery may be a contributing trigger of this arrhythmia. Interestingly, AF occurred at a median of 69 hours after surgery. Because reliance on atrial “kick” is critically important for older adults, the development of AF has serious implications for the elderly, including the potential for greater risk of stroke, prolonged hospitalization, increased costs, and increased 30-day mortality rates. Elderly patients also have an increased reliance on the Frank Starling mechanism for cardiac output. Although intrinsic contractility and resting cardiac output are typically unaffected by aging per se, the practical effect of ventricular hypertrophy is to limit the ability of the heart to adjust stroke volume. Because ventricular hypertrophy impairs the passive filling phase of diastole, ventricular preload of necessity is more dependent on the contribution of atrial contraction. It is important, therefore, to consider fluid as a drug that the elderly individual may or may not need. In the noncompliant older heart, small changes in venous return will produce large changes in ventricular preload and cardiac output. Owing to significantly reduced diastolic myocardial function, baroreceptor-mediated heart rate control, adrenergic receptor responsiveness, and vascular compliance, the elderly patient compensates poorly for hypovolemia. Similarly, overtransfusion is also poorly tolerated. Clearly, the reduction in ventricular compliance and the attenuated response to catecholamines characteristic of seniors compromise the ability of the heart to buffer changes in circulatory volume. Chronic obstructive pulmonary disease, pneumonia, and sleep apnea are common in the elderly. Closing volume increases with age, and forced expiratory volume in 1 second declines 8% to 10% per decade owing to reduced pulmonary compliance and muscle power.8 Arterial oxygen tension decreases progressively with age-induced V/Q mismatch, diffusion block, and anatomic shunt.9 Owing to these abnormalities in gas exchange, it is recommended that elderly patients be transported to the postanesthesia

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care unit (PACU) with 2 to 4 L/minute of oxygen through a nasal cannula, even after relatively minor ambulatory surgery.10 Given these deleterious changes, it is not surprising that postoperative respiratory complications are common in geriatric patients (Table 2). However, the most significant clinical predictor of adverse pulmonary outcome is the site of surgery, with thoracic and upper abdominal surgery having the highest pulmonary complication rates.11,12 Because the nervous system is the target for virtually every anesthetic drug, age-related alterations in nervous system function have extremely compelling implications for anesthetic management. Indeed, aging universally produces a reduction in total nervous system tissue mass, neuronal density, and concentration of neurotransmitters, as well as norepinephrine and dopamine receptors. The cognitive decline that normally occurs with aging is typically modest and highly variable. Subtle cognitive impairment, however, is detectable in almost two thirds of “normal” seniors. This impairment presents characteristically as a deterioration in fluid intelligence, analytic ability, and short-term memory. In contrast, dementia reflects pathologic brain aging and is characterized by a chronic, progressive, global decline in intellectual function that always involves memory. Conditions producing dementia include, but are not limited to, Alzheimer’s disease, Parkinson’s disease, and stroke. Alzheimer’s disease is the most common form of dementia and is said to affect between 30% and 50% of people ≥85 years of age (Table 3). Drug interactions are a very real concern because the elderly typically undergo physiological changes related to disease as well as normal aging. Although elders represent approximately 13% of the population, they consume one third of all medications and are seven times more likely to experience an adverse drug reaction than their younger counterparts. The elderly account for 50% of all medication-related deaths. Important to an understanding of geriatric pharmacokinetics is an appreciation of the role that reduced drug excretion plays in adverse drug interactions. With advancing age, the number of functioning glomeruli declines, as do glomerular filtration rate and renal blood flow.

Preoperative Evaluation The preoperative assessment of the geriatric patient characteristically is more complex than that of the younger patient owing to the heterogeneity of seniors and the increased frequency and severity of comorbid conditions associated with aging. The process of aging is highly individualized. Different people age at varying rates and often in different ways. Typically, however, virtually all physiological systems decline with advancing chronologic age. Nevertheless, chronologic age is a poor surrogate for capturing information about fitness or frailty. Perioperative functional status can also be difficult to quantitate because many elderly patients have reduced preoperative function

TABLE 2.

Respiratory Changes Associated with Aging

↑Incidence of chronic obstructive pulmonary disease, pneumonia, and sleep apnea ↓Chest wall compliance, elastic recoil, and maximal minute ventilation ↑Work of breathing ↑Closing volume ↓Forced expiratory volume in 1 second ↑V/Q mismatch, diffusion block, and anatomic shunt Progressive decline in arterial oxygen tension Disproportionately high incidence of postoperative respiratory complications

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McGOLDRICK TABLE 3.

Alzheimer’s Disease

Progressive, fatal neurodegenerative disease with characteristic functional and behavioral disturbances Most common cause of dementia >4.5 million Americans afflicted Projected to affect >13 million Americans by 2050, absent effective intervention Third most expensive disease in the United States, outpaced only by heart disease and cancer Data extracted from Cummings JL: Alzheimer’s disease. N Engl J Med 2004; 351:56–67.

related to deconditioning, age-associated disease, or cognitive impairment. Thus, it is challenging to satisfactorily evaluate the patient’s capacity to respond to the specific stresses associated with anesthesia and surgery. How, for example, does one determine cardiopulmonary reserve in a patient severely limited by osteoarthritis and dementia?

Intraoperative Management Because of the pulmonary changes discussed previously, it is imperative to appreciate that desaturation occurs faster in older adults (Table 4). In addition, elderly patients are more vulnerable to desaturation-related cardiac events. Therefore, proper preoxygenation is critical. Benumof points out that maximal preoxygenation is achieved with eight breaths of 100% O2 within 60 seconds with an oxygen flow of 10 L/minute.13 Advanced age is clearly associated with a reduction in median effective dose requirements for all agents that act within the central nervous system regardless of whether these drugs are administered through the oral, parenteral, or inhalational route. Indeed, the ED50 equivalent for inhalation anesthetics falls linearly with age, such that the “typical” 80 year old will require only approximately two thirds of the anesthetic concentration required to produce comparable effects in a young adult. This reduction in anesthetic requirement is agent-independent and probably reflects fundamental neurophysiological changes in the brain such as reduced neuron density or altered concentrations of neurotransmitters. Elderly patients require less propofol (and other agents) for induction. It is also important to appreciate that the concurrent use of midazolam, ketamine, and/or opioids with propofol synergistically increases the depth of anesthesia. Even with an appropriate dose reduction of propofol, hypotension is common. Less hypotension has been reported with appropriately titrated administration of mask sevoflurane for inducTABLE 4.

Geriatric Considerations with General Anesthesia

Aggressively preoxygenate Significantly reduce doses of drugs affecting the central nervous system Anticipate drug synergy Expect drug-induced hypotension Anticipate prolonged duration of action of nondepolarizing drugs that undergo organ-based clearance Select shorter-acting drugs when indicated Meticulously titrate intravenous fluids Maintain normothermia Transport to postanesthesia care unit with supplemental oxygen Provide adequate postoperative analgesia


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tion compared with a propofol infusion.14 Interestingly, gender differences have been described in the pharmacokinetics of propofol given by continuous infusion in elderly patients,15 although in general, the results of investigations exploring putative gender differences have been inconsistent. The time required for clinical recovery from neuromuscular blockade is markedly increased in older adults for nondepolarizing agents that undergo organ-based clearance from plasma, but is minimally different for atracurium, cisatracurium, or mivacurium because they undergo hydrolysis in plasma. The likelihood of postoperative pulmonary complications after long-acting muscle relaxants increases with advanced age, and it is not unusual for patients who meet rigorous extubation criteria in the operating room to deteriorate in the PACU. Therefore, it seems advisable to administer a short or intermediate-acting muscle relaxant to any elderly patient for whom extubation is planned at the end of the surgical procedure. In planning an expeditious emergence, the anesthesiologist should be aware that end-tidal gas monitoring significantly underestimates the brain concentration of the more soluble agents. Failure to appreciate this hysteresis effect leads to prolonged emergence. Moreover, MACawake is more favorable if the vaporizer is turned down gradually rather than turned off abruptly.16 Not surprisingly, it has been reported that use of shorter-acting drugs (propofol, desflurane, sevoflurane), in conjunction with bispectral index (BIS) monitoring, can provide more rapid emergence in geriatric patients and facilitate PACU bypass.17 Whether this approach will have a favorable effect on longerterm outcomes remains to be determined. When one considers selection of anesthetic technique, it is important to appreciate that there are no controlled, randomized studies in elderly patients to show that regional anesthesia is superior to general anesthesia for ambulatory surgery (Table 5). Indeed, neuraxial, plexus, or nerve blocks in the elderly may be associated with an increased risk of persistent numbness, nerve palsies, and other neurologic complications. In addition, it has recently been demonstrated that age is a major determinant of duration of complete motor and sensory blockade with peripheral nerve block, perhaps reflecting increased sensitivity to conduction failure from local anesthetic agents in peripheral nerves in the elderly population.18 That said, peripheral nerve blocks offer some appealing features, especially in terms of postoperative pain control. Clonidine is a valuable adjunct because it enhances both local anesthetic and opioid efficacy, and its addition to the local anesthetic mixture may afford some hemodynamic advantages compared with epinephrine. One should select a dose of clonidine that will not produce postoperative sedation or hypotension. When administering central neuraxial blockade to elderly patients, it is important to remember that a given dose will produce a higher level of block in seniors and is typically accompanied by a greater incidence and degree of hypotension and bradycardia as well as a longer duration of anesthesia.19 Sedation

TABLE 5.

Regional Anesthesia: Concerns with the Geriatric Patient

↑Sensitivity to local anesthetics than younger counterparts Arguably increased risk of persistent numbness, nerve palsies, and other neurologic complications ↑Duration of block Higher level of block and markedly greater incidence and degree of hypotension and bradycardia encountered with given local anesthetic dose for central neuraxial block Dramatic reduction in sedation requirements with central neuraxial block (encountered also with younger patients)

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requirements are dramatically reduced under conditions of central neuraxial block.20 Sensory input to the brain is attenuated and the BIS50 is shifted to a higher index. Although recent data have supported a relaxation of the requirements for voiding before discharge after outpatient neuraxial blockade with short-acting drugs for low-risk surgical procedures in low-risk patients, it is important to appreciate that elderly patients do not meet these criteria.21 It appears currently that elderly patients (≥70 years) who received neuraxial block, regardless of the duration of the block, should be required to demonstrate ability to void before discharge.

Postoperative Management Perioperative hypothermia is prevalent in both young and elderly surgical patients, but it is more frequent, pronounced, and prolonged in the elderly who have compromised ability to regain thermoregulatory control quickly.22 Adverse consequences of postoperative hypothermia include cardiac ischemia, arrhythmias, increased blood loss, wound infection, decreased drug metabolism, and prolonged hospitalization.23 It has been shown that maintaining normothermia decreases cardiac morbidity by 55%.24 Postoperative pain increases the risk of adverse outcome in elderly patients by contributing to tachycardia, hypertension, hypoxemia, and cardiac ischemia. Effective analgesia can decrease the incidence of myocardial ischemia and pulmonary complications, accelerate recovery, promote early mobilization, shorten hospital stay, and reduce the cost of medical care. However, postoperative pain control often is inadequate in the elderly because of concerns about drug overdose, adverse response, and drug interactions. Pain control is further complicated by the fact that the patient’s perception and expression of pain are affected by changes in mental status. Current postoperative analgesic techniques include the use of opioids by various routes, nonsteroidal antiinflammatory drugs, local anesthetic techniques (neuroaxial, intraarticular, and nerve block), and nonpharmacologic (transcutaneous or percutaneous electrical nerve stimulation, acupuncture, and acupressure) methods. Preemptive, multimodal approaches are favored to minimize the risk of opioid-related side effects such as hypoxemia, constipation, and pruritus. A balanced analgesic technique combining opioids, nonopioids, and local anesthetic agents is recommended.

Postoperative Cognitive Impairment Reports of postoperative cognitive deterioration in elderly patients surfaced more than 50 years ago, and anesthesia had often been implicated as a possible cause or contributing factor. Although improvements in surgical techniques and anesthetic agents and methods have led to improved outcomes in the elderly, a troubling proportion of these patients experience postoperative cognitive dysfunction.25–28 The implications of this abrupt cognitive decline are devastating because affected individuals often become dependent and withdraw from society. Postoperative cognitive impairment can be classified as either delirium or postoperative cognitive dysfunction (POCD).29 Although delirium and POCD may have similar predisposing factors, they are not equivalent syndromes. Delirium is defined as an acute change in cognitive function that develops over a brief period of time, often lasting for a few days to a few weeks and frequently having a fluctuating course. Prospective studies have cited an incidence of delirium that ranges from 3% to >50% and is dependent on the type of surgery, the patient’s preoperative physical and cognitive status, and the


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age of the patient.29 The etiology of delirium is probably multifactorial and may include drug intoxication or withdrawal, drug interaction, use of anticholinergic agents, metabolic disturbances, hypoxia, abnormal carbon dioxide levels, sepsis, inadequate analgesia, and organic brain disease.30 Curiously, the incidence of postoperative confusion is similar regardless of whether spinal, epidural, or general anesthesia is used. It has been postulated that postoperative delirium may be associated with failure of CNS cholinergic transmission.31 Recently, the use of melatonin to treat delirium has produced some benefit, presumably by resetting the circadian sleep–awake cycle of older surgical patients.32 Postoperative delirium is common in the elderly and its incidence may be reduced by protocol-driven perioperative treatment. Marcantonio and colleagues recently reported a reduction in postoperative delirium by one third, and of severe delirium by one half, by adherence to multifaceted recommendations that included elimination or minimization of benzodiazepines, anticholinergics, antihistaminics, and meperidine.33 In addition, systolic blood pressure was kept more than two thirds of baseline or >90 mm Hg, oxygen saturation was maintained above 90% (preferably >95%), hematocrit was maintained >30%, early mobilization was encouraged, and appropriate environmental stimuli were provided. POCD is defined as a deterioration of intellectual function that presents as impaired memory or concentration. The clinical features of this disorder range from mild forgetfulness to permanent cognitive impairment resulting in loss of independence. Moller and colleagues25 evaluated cognitive function in patients aged 60 years or older after major abdominal and orthopedic surgery. These investigators found that approximately 25% of the patients had measurable cognitive dysfunction a week after their surgery and 10% had cognitive changes 3 months postoperatively. This finding contrasted with a 3% incidence of cognitive deterioration during a 3-month interval in healthy control subjects in the same age range who did not undergo anesthesia and surgery. Interestingly, hypoxemia and hypotension did not correlate with the occurrence of prolonged cognitive dysfunction. The identified risk factors for early (1 week) postoperative cognitive dysfunction were increasing age and duration of anesthesia, low education level, a need for a second operation, postoperative infection, and respiratory complications. The only risk factor for late (3 months) postoperative cognitive dysfunction was age. Although the incidence of late postoperative cognitive dysfunction was 14% for patients ≥70 years, this rate was only 7% for patients between the ages of 60 and 70 years. An additional large, prospective study conducted by Monk and colleagues evaluated the relationship of age to POCD.28 Using the same methodology as the first multinational study,25 Monk and colleagues reported that cognitive decline occurred in 16% of patients aged 60 years or older at 3 months after major noncardiac surgery but was present in only 3% to 5% of younger patients.28 This study also determined that rates of cognitive decline were higher in those ≥70 years compared with younger elderly patients. There are few prospective studies on long-term cognitive outcomes after outpatient surgery, but an analysis of cognitive recovery after major and minimally invasive surgery exists. Monk classified the type of surgical procedure as minimally invasive (laparoscopic or superficial surgery), major intraabdominal surgery, or orthopedic surgery.28 The incidence of POCD was significantly greater for patients undergoing major or orthopedic procedures compared with minimally invasive surgery. Because outpatient surgery is usually minimally invasive, these results suggest that outpatients may have a better cognitive outcome than patients who require hospitalization. In addition, the International Study of Postoperative Cognitive Dysfunction (ISPOCD) group recently conducted a longitudinal study comparing the incidence of POCD after inpatient versus outpatient

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surgery in patients older than 60 years.34 At 7 days after surgery, the incidence of POCD was significantly lower in the outpatient group, but this difference was not detected 3 months later. These results suggest that elderly outpatients have better cognitive outcomes at discharge than elderly inpatients, but we currently have no explanation for the difference. Possible explanations for the improved early outcome in outpatients include healthier status of patients who qualify for outpatient surgery, briefer surgical and anesthesia times, minimally invasive nature of most outpatient procedures, or avoidance of hospitalization. Similar to studies of delirium, the incidence of POCD does not appear to be associated with the type of anesthesia technique selected.26,35 There is no difference between regional and general anesthesia in the incidence of POCD 3 to 6 months postoperatively, although short-term recovery may be better with regional anesthesia. It is important to understand that full return of cognitive function to preoperative levels may require several days, even after ambulatory surgery in young, healthy patients.30,36 Indeed, Lichtor37 has suggested that even young adults may be sleepy for 8 hours after receiving intravenous sedation with midazolam and fentanyl, and the elderly outpatient experiencing balance disturbances or age-related gait impairment may be at high risk of falling owing to residual drowsiness. Nonetheless, it remains unclear which patient populations are most vulnerable and what the causative factors might be for serious problems of POCD. Although we have much to learn about postoperative delirium and cognitive decline, it is clear that subclinical decrements in functional status may become evident during the perioperative period. Indeed, if a cognitive deficit is noted preoperatively, it may be a harbinger of further postoperative decline. Data on the predictive value of assessment of preoperative cognitive status for the development of delirium38 and the ability of that assessment to result in successful intervention (as may be the case with delirium)33 offer compelling reasons to conduct a simple, brief mental status examination as part of the preoperative interview. Our current understanding of POCD suggests the etiology is multifactorial and may include the preoperative cognitive status of the patient, as well as intraoperative events related to the surgery (for example, microemboli), and anesthetic factors. Recently, investigators reported that increased perioperative levels of stable nitric oxide products (nitrate and nitrite) may be a preoperative predictor for POCD.39 Although we currently have no reliable neuroprotective intervention to offer our patients, a preoperative marker for POCD might influence the decision to have elective procedures such as cosmetic surgery. Hopefully, future studies will lead to a clearer definition of the incidence, mechanisms, and prevention of POCD.

Summary Elderly patients are uniquely vulnerable and particularly sensitive to the stresses of trauma, hospitalization, and surgery/anesthesia in ways that are only partially understood. Accordingly, minimizing perioperative risk in the elderly population requires thoughtful preoperative assessment of organ function and reserve, meticulous intraoperative management of coexisting disorders, and vigilant postoperative monitoring and pain control.

References 1. Ergina P, Gold S, Meakins J: Perioperative care of the elderly patient. World J Surg 1993; 17:192–8.


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2. Forrest JB, Rehder K, Cahalan MK, Goldsmith CH: Multicenter study of general anesthesia III: Predictors of severe adverse outcomes. Anesthesiology 1992; 76:3–15. 3. Polanczyk CA, Goldman L, Marcantonio ER, et al.: Supraventricular arrhythmias in patients having noncardiac surgery: Clinical correlates and effect on length of stay. Ann Intern Med 1998; 129:279–85. 4. Amar D, Roistacher N, Burt M, et al.: Clinical and echocardiographic correlates of symptomatic tachydysrhythmias after noncardiac thoracic surgery. Chest 1995; 108:349–54. 5. Aranki SF, Shaw DP, Adams DH, et al.: Predictors of atrial fibrillation following coronary artery bypass graft surgery: Current trends and impact on hospital resources. Circulation 1996; 94:390–7. 6. Mathew JP, Parks R, Savino JS, et al.: Atrial fibrillation following coronary artery bypass graft surgery: Predictors, outcomes, and resource utilization. JAMA 1996; 276:300–6. 7. Amar D, Zhang H, Leung DHY, et al.: Older age is the strongest predictor of postoperative atrial fibrillation. Anesthesiology 2002; 96:352–6. 8. Knudson RJ, Lebowitz MD, Holberg CJ, Burrows B: Changes in the normal maximal expiratory flow-volume curve with growth and aging. Am Rev Respir Dis 1983; 127:725–34. 9. Sorbini CA, Grassi V, Solinas E, Muiesan G: Arterial oxygen tension in relation to age in healthy subjects. Respiration 1968; 25:3–13. 10. Mathes DD, Conaway MR, Ross WT: Ambulatory surgery: Room air versus nasal cannula oxygen during transport after general anesthesia. Anesth Analg 2001; 93:917–21. 11. Klotz HP, Candinas D, Platz A, et al.: Preoperative risk assessment in elective general surgery. Br J Surg 1996; 83:1788–91. 12. Vodinh J, Touboul C, Lefloch JP, et al.: Risk factors of postoperative pulmonary complications after vascular surgery. Surgery 1988; 105:360–5. 13. Benumof J: Preoxygenation: Best method for both efficacy and efficiency [Editorial]. Anesthesiology 1999; 91:603–5. 14. Kirkbride DA, Parker JL, Williams GD, Buggy DJ: Induction of anesthesia in the elderly ambulatory patient: A double-blind comparison of propofol and sevoflurane. Anesth Analg 2001; 93:1185–7. 15. Vuyk J, Oostwouder CJ, Vletter AA, Burm AGL, Bovill JG: Gender differences in the pharmacokinetics of propofol in elderly patients during and after continuous infusion. Br J Anaesth 2001; 86:183–8. 16. Katoh T, Suguro Y, Kimura T, Ikeda K: Cerebral awakening concentration of sevoflurane and isoflurane predicted during slow and fast alveolar washout. Anesth Analg 1993; 77:1012–7. 17. Fredman B, Sheffer O, Zohar E, et al.: Fast-track eligibility of geriatric patients undergoing short urologic procedures. Anesth Analg 2002; 94:560–4. 18. Pagueron X, Boccara G, Bendahou M, Coriat P, Riou B: Brachial plexus nerve block exhibits prolonged duration in the elderly. Anesthesiology 2002; 97:1245–9. 19. Simon MJG, Veering BT, Stienstra R, van Kleek JW, Burm AGL: The effects of age on neural blockade and hemodynamic changes after epidural anesthesia with ropivacaine. Anesth Analg 2002; 94:1325–30. 20. Pollock JE, Neal JM, Liu SS, et al.: Sedation during spinal anesthesia. Anesthesiology 2000; 93:728–34. 21. Mulroy MF, Salinas FV, Larkin KL, Polissar NL: Ambulatory surgery patients may be discharged before voiding after short-acting spinal and epidural anesthesia. Anesthesiology 2002; 97:315–9. 22. Vaughan MS, Vaughan RW, Cork RC: Postoperative hypothermia in adults: Relationship of age, anesthesia, and shivering to rewarming. Anesth Analg 1981; 60:746–51. 23. Leslie K, Sessler DI, Bjorksten AR, Moayeri A: Mild hypothermia alters propofol pharmacokinetics and increases the duration of action of atracurium. Anesth Analg 1995; 80:1007–14. 24. Frank SM, Higgins MS, Breslow MJ, et al.: The catecholamine, cortisol, and hemodynamic responses to mild perioperative hypothermia: A randomized clinical trial. Anesthesiology 1995; 82:83–93. 25. Moller JT, Cluitmans P, Rasmussen LS, et al.: Long-term postoperative cognitive dysfunction in the elderly: ISPOCD1 study. Lancet 1998; 351:857–61. 26. Williams-Russo P, Sharrock NE, Mattis S, Szatowski TP, Charlson ME: Cognitive effects after epidural vs general anesthesia in older adults. JAMA 1995; 274:44–50. 27. Dodds C, Allison J: Postoperative cognitive deficit in the elderly surgical patient. Br J Anaesth 1998; 81:449–62. 28. Monk TG, Garvin CW, Dede DE, van der Aa MT, Gravenstein JS: Predictors of postoperative cognitive dysfunction following major surgery [Abstract]. Anesthesiology 2001; 95:A50.

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29. Moller JT: Cerebral dysfunction after anaesthesia. Acta Anaesthesiol Scand Suppl 1997; 110:13–6. 30. O’Keefe ST, Chonchubhair AN: Postoperative delirium in the elderly. Br J Anaesth 1994; 73:673–87. 31. Marcantonio ER, Juaraz G, Goldman L, et al.: The relationship of postoperative delirium with psychoactive medication. JAMA 1994; 272:1518–22. 32. Hanania M, Kitain E: Melatonin for the treatment and prevention of postoperative delirium. Anesth Analg 2002; 94:338–9. 33. Marcantonio ER, Flacker JM, Wright RJ, Resnick NM: Reducing delirium after hip fracture: A randomized trial. J Am Geriatr Soc 2001; 49:516–22. 34. Canet J, Raeder J, Rasmussen LS, for the ISPOCD2 Group: Cognitive dysfunction after minor surgery in the elderly. Acta Anaesthesiol Scand 2003; 47:1204–10. 35. Rasmussen LS, Johnson T, Kuipers HM, et al.: Does anaesthesia cause postoperative cognitive dysfunction? A randomized study of regional versus general anaesthesia in 438 elderly patients. Acta Anaesthesiol Scand 2003; 47:260–6. 36. Tzabar Y, Asbury AJ, Millar K: Cognitive failure after general anaesthesia for day-case surgery. Br J Anaesth 1996; 76:194–7. 37. Lichtor JL, Alessi R, Lane BS: Sleep tendency as a measure of recovery after drugs used for ambulatory surgery. Anesthesiology 2002; 96:878–83. 38. Inouye SK: Predisposing and precipitating factors for delirium in hospitalized older patients. Dement Geriatr Cogn Disord 1999; 10:393–400. 39. Iohom C, Szarvas S, Larney V, et al.: Perioperative plasma concentrations of stable nitric oxide products are predictive of cognitive dysfunction after laparoscopic cholecystectomy. Anesth Analg 2004; 99:1245–52.



CHAPTER 15

V O L U M E


PAIN RELIEF WITHOUT SIDE EFFECTS: PERIPHERAL OPIATE ANTAGONISTS JONATHAN MOSS, M.D., PH.D. PROFESSOR AND VICE CHAIRMAN FOR RESEARCH DEPARTMENT OF ANESTHESIA AND CRITICAL CARE THE UNIVERSITY OF CHICAGO CHICAGO, ILLINOIS

JOSEPH FOSS, M.D. DIRECTOR CLINICAL R&D ADOLOR CORPORATION EXTON, PENNSYLVANIA



© 2005



Pain Relief without Side Effects: Peripheral Opiate Antagonists Jonathan Moss, M.D., Ph.D. Professor and Vice Chairman for Research Department of Anesthesia and Critical Care The University of Chicago Chicago, Illinois Joseph Foss, M.D. Director Clinical R&D Adolor Corporation Exton, Pennsylvania

Opiates remain a mainstay in pain management and perioperative care. In the past 2 decades, we have learned much about the molecular pharmacology of opioids and cloned opiate receptors. Opioid receptors are widely distributed in the central nervous system and throughout the gastrointestinal tract.1,2 Of the four classes of opiate receptors (µ, K, δ, nociception), the mu (µ) receptor appears to mediate many adverse effects. Yet understanding the biology of pain has yielded few new approaches to patient care. Despite their widespread use, the adverse effects of opiates are troublesome perioperatively in pain management and palliative care and often can limit their use (Table 1). Pruritus is common, particularly with parenteral and neuraxial opiates. Antitussive effects, which may be therapeutic, also can be problematic in the perioperative setting. Urinary retention, nausea and vomiting, decreased gastric-emptying, and constipation often limit opiate dose or use.3–6 Opiate-induced constipation, however, is often refractory to stool softeners and may limit effective pain control.6,7 A well-recognized clinical problem exists in palliative care in which the escalating doses of opiates that are required to accomplish pain relief are often limited by the constipating effects of the analgesic drugs. Within the central nervous system, opioids alter autonomic output to the gut.8–12 They also act directly on the gut to change gastrointestinal motility and transit. Importantly, patients do not become tolerant to the constipating effects of opiates. Furthermore, the adverse effects of opioids may persist after their analgesic activity has passed. There has also been a growing recognition of the clinically important adverse effects of opiates, which are disadvantageous to postoperative recovery. In the surgical population, ileus can be influenced by endogenous or exogenous opioids. A growing body of evidence suggests that endogenous opioids triggered by pain and bowel manipulation play a role in the pathophysiology of ileus. In a rodent model of postoperative ileus induced by external bowel manipulation, gastrointestinal transit was markedly delayed by the surgery. This delay was reversed by naloxone or alvimopan.13 In equine colic, the major disease of horses associated with gastrointestinal dysmotility, levels of endorphins are elevated 100-fold.14 An elegant series of clinical studies by Kehlet et al.15 over the past This chapter discusses investigational drugs and unapproved uses for approved drugs. The authors are patent holders for methylnaltrexone. Dr. Moss is a consultant for Progenics Pharmaceuticals. Dr. Foss is an employee of Adolor Corp.

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MOSS AND FOSS TABLE 1.

Depression of respiration Pruritus Nausea and vomiting Constipation Urinary retention Chest wall rigidity Cough suppression (antitussive)

Some Side Effects of Opiates Pupillary constriction Gastrointestinal/genitourinary sphincter constriction Dysphoria Depression of stress response Cardiovascular effects (hypotension) Immune suppression

decade suggest that multimodal strategies designed to limit perioperative exogenous opiate use (such as thoracic epidurals) result in faster recovery of intestinal function and decrease length of hospital stay after abdominal operations. Patients received rapid feeding and did not have any nasogastric tubes or parenteral or epidural opiates. These patients generally showed a faster recovery profile than patients who were managed conventionally. However, the ability to maintain this regimen is very time-consuming and potentially costly. Although it can be a benefit in the perioperative period, it does not address some of the issues involved with chronic pain.

Pharmacotherapy for Opiate Adverse Effects Naloxone One approach to manage the side effects of opiates has been the use of low doses of opiate antagonists such as naloxone. Drugs such as naloxone and naltrexone are commonly used to reverse central or peripheral effects of opiates. There have been several attempts to use low doses of these tertiary opiate antagonists to relieve opiate-induced pruritus and constipation. Naloxone seemed a good candidate to reverse opiate-induced constipation because only 2% is absorbed into the circulation as a result of a high first-pass metabolism. In several small trials, naloxone and similar tertiary opiate antagonists successfully reversed the constipating effects of opiates. However, because the tertiary opiate antagonists easily cross the blood–brain barrier, breakthrough pain, which is attributed to variable plasma levels and an inability to titrate an exact dose, has accompanied their use.16–19 One recent study suggested that naloxone can be successfully used in children to reduce opioidinduced side effects.20

Peripheral Opiate Antagonists Although opiates have been used for some 4,000 years and have been the subject of intense study for decades, it is only recently that the development of specific peripheral opiate antagonists has allowed scientists and physicians to differentiate between adverse effects mediated by peripheral opioid receptors and central opioid receptors (that is, located within the blood–brain barrier). Clinicians have debated whether important clinical side effects of opiates, including constipation, nausea and vomiting, pruritus, and urinary retention, are primarily caused by activation of centrally or peripherally located receptors. Peripheral opiate antagonists were developed to antagonize the peripheral adverse effects of opiates while preserving centrally mediated analgesia. Two investigational compounds now in late-stage development may be of interest to anesthesiologists and pain specialists should the drugs be approved by the U.S. Food and Drug Administration.

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The first is methylnaltrexone (Progenics Pharmaceuticals, Tarrytown, NY). The other, alvimopan (ADL 8-2698), is under development by Adolor Pharmaceuticals (Exton, PA). Both drugs target the gastrointestinal side effects of opiates. Among the adverse effects of opiates, the most difficult to treat is opiate-induced bowel dysfunction (OBD), a syndrome whose hallmarks are constipation, bloating, and decreased intestinal motility.21 Constipation occurs in over half of patients receiving opiates for palliative care and can be very difficult to manage with conventional laxatives. OBD is a clinical problem because of its frequency and because patient tolerance for it does not improve over time. Several studies have documented that constipation may be dose-limiting in the management of chronic pain.6,7 Patients preferred pain to the severe constipation induced by opiates.22

Methylnaltrexone Methylnaltrexone is the quaternary derivative of the opioid antagonist naltrexone.23 It was developed by Professor Leon Goldberg for use in patients with opiate-induced constipation. Goldberg reasoned that a charged molecule with opiate antagonist properties would not penetrate the blood–brain barrier, thus preserving central analgesia when given with opiates (Fig. 1). In in vitro studies of human and guinea pig gut, methylnaltrexone had one third the potency of naloxone in reversing morphine-induced inhibition of contraction. In these studies, 97% of morphine’s effect on gastric motility could be reversed by methylnaltrexone.24 In preliminary human studies, administration of small doses of morphine (averaging 3 to 5 mg) to volunteers slowed gastrointestinal transit (as measured by oral–cecal transit time) by 50%. When subjects were treated with small doses of methylnaltrexone (0.45 mg/kg intravenously), this opiate-induced change in motility was almost completely reversed. Importantly, the cold pressor test demonstrated that morphine analgesia was intact with methylnaltrexone. This study represented the first demonstration of separation of the central analgesic and peripheral gastrointestinal motility effects of opiates in humans25 (Fig. 2). To establish whether this effect was systemically or locally mediated, in a subsequent randomized, double-blind, placebo-controlled study in human volunteers, single oral doses of methylnaltrexone (ranging from 0.64 to 19.2 mg/kg) were administered. Oral methylnaltrexone prevented the morphine-induced delay in oral–cecal transit time in a dose-dependent form without affecting analgesia. Pharmacokinetic data revealed the effects appeared to be primarily mediated by receptors in the gut itself, not in response to systemic absorption of the drug.26

FIG. 1. Structural diagrams of naltrexone and methylnaltrexone. The addition of the methyl group confers a charge on the nitrogen.

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FIG. 2. Individual oral–cecal transit time (ordinate) of 12 healthy volunteers according to the injections (abscissa). The heavy dotted line represents the mean. MS, morphine (0.05 mg/kg); MNTX, methylnaltrexone (0.45 mg/kg). Reprinted from Yuan et al.25 © 1996 American Society for Clinical Pharmacology and Therapeutics.

Although the acute effects of opiates on gastrointestinal motility proved to be completely reversible by methylnaltrexone, the efficacy of methylnaltrexone as a therapy in opiate-tolerant individuals was not known. To resolve this problem, a double-blind, placebo-controlled, randomized clinical trial was performed in 22 subjects undergoing chronic methadone maintenance therapy for addiction.27 Normally, patients on methadone maintenance programs laxate only infrequently, sometimes only once or twice per week, and have a marked reduction in oral–cecal transit. Subjects in the study received methylnaltrexone intravenously on an ascending dose schedule. Both oral– cecal transit time and laxation were recorded and signs of withdrawal were monitored. Although oral–cecal transit time was normalized with methylnaltrexone, no subject showed psychologic or physical signs of opiate withdrawal. In the 11 subjects in the placebo-treated group, laxation response was not affected, whereas 10 of the 11 subjects in the methylnaltrexone-treated group evacuated on day 1 and all 11 evacuated on day 2 (Table 2). Laxation occurred within 1 minute of injection of the drug. Importantly, subjects who are tolerant to opioids proved more sensitive to opioid antagonists. Patients on methadone maintenance experienced laxation at a fraction of the dose needed to reverse opiate-induced hypomotility in volunteers. Similar effects were noted with oral methylnaltrexone in 12 methadone maintenance subjects.28 In this study, oral methylnaltrexone reversed hypomotility and bowel movement in 5 hours at the highest dose.

PAIN RELIEF WITHOUT SIDE EFFECTS TABLE 2.

Placebo MNTX

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Methylnaltrexone (MNTX) Effect on Laxation Laxation

No Laxation

0 11

11 0

The route of administration may be significant clinically. Laxation occurred immediately after intravenous administration of methylnaltrexone (MNTX) but several hours after oral administration, which also requires significantly higher doses. After subcutaneous administration, at doses similar to those used intravenously, changes in oral— cecal transit time occurred over a period of approximately 15 minutes.29 Thus, the several routes for administration, oral, intravenous, or subcutaneous, have various onset and duration times. With this dosing knowledge in patients on chronic methadone and knowledge of kinetics of subcutaneous MNTX, a multiinstitutional randomized phase 2b study of subcutaneous MNTX was performed in 33 palliative care patients. Patients were randomized to receive one of four doses of MNTX: 20 mg, 12.5 mg, 5 mg, and a 1-mg dose (which was intended to function as a placebo dose). Patients received a subcutaneous injection and were treated every other day for 1 week. After the 1-week blinded dosing period, they received open-label doses of MNTX for up to 3 additional weeks. MNTX demonstrated significant activity at various doses. Laxation within 4 hours of dosing was reported in approximately 60% of patient doses for the active MNTX dose range versus 10% of the 1-mg dose. Median time to laxation was approximately 1 hour after receiving active doses of MNTX. In contrast, with the 1-mg dose, time to laxation exceeded 48 hours (Fig. 3). Importantly, patients who were treated in the open-label portion of the study experienced drug activity for up to 1 month. MNTX is currently in phase 3 trials for opiate-induced constipation in palliative care patients and in phase 2 trials for prophylaxis and treatment of postoperative bowel dysfunction (Fig. 3). A recently reported phase 3 trial of 154 patients with advanced medical illness demonstrated that MNTX (0.15 mg/kg, 0.3 mg/kg) caused laxation in 58–62% of patients, usually within the first hour of administration (P < 0.0001 vs. placebo).30

Alvimopan (ADL 8-2698) Alvimopan (Adolor Corp., formerly ADL 8-2698) is a peripherally restricted opioid antagonist. Its structure gives it moderately large molecular weight, a zwitterionic form, and a polarity that both prevents penetration of the blood–brain barrier and also limits gastrointestinal absorption31 (Fig. 4). The effect of alvimopan on morphine-induced delays in oral–cecal transit time and lower gastrointestinal transit was confirmed in a series of controlled clinical studies in volunteers. In one such study, intravenous morphine alone prolonged gastrointestinal transit time from 69 minutes to 103 minutes (P = 0.005). Coadministration of oral alvimopan (4 mg) prevented the morphine-induced change in gastrointestinal transit time (P = 0.006), producing transit times similar to baseline. In contrast, coadministration of alvimopan did not antagonize the central effects of morphine as measured by analgesia (cold pressor test) or pupillary constriction. These volunteer studies demonstrated the ability of alvimopan to antagonize opioid-induced effects on gastrointestinal motility while preserving centrally mediated analgesia and led to the initiation of clinical studies in chronic pain patients and in surgical patients at risk for ileus.

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FIG. 3. Percent of patients experiencing laxation at each of three doses of methyltrexone given subcutaneously (n = 33).

The efficacy and safety of alvimopan has been evaluated in a recent study of patients receiving opioid therapy for chronic pain (n = 67) or methadone for opioid addiction (n = 34). All patients were receiving stable doses (1 week to 10 or more years) of a variety of opioids and experiencing symptoms of OBD, with constipation being the primary complaint. Oral alvimopan in doses of 0.5 mg or greater provided significant reversal of constipating effects within 12 hours of administration. No patients showed signs of central nervous system opioid withdrawal or reversal of analgesia.32 A phase II trial demonstrated a role for alvimopan in the prophylaxis and treatment of postoperative ileus.33 In this randomized, double-blind, placebo-controlled trial, 79 patients undergoing abdominal or gynecologic surgery were randomized to receive alvimopan (1 or 6 mg) or a placebo orally 2 hours before surgery and then twice a day until hospital discharge for a maximum of 7 days postoperatively. All patients received

FIG. 4.

Structural diagram of alvimopan.


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morphine or meperidine through patient-controlled analgesia (median dose 70.2 to 71.3 mg morphine equivalent). In treated patients (6 mg twice a day), mean time to first bowel movement was reduced by approximately 2 days, mean time to a solid diet was reduced by 1.3 days, and mean time to discharge was reduced by 1.4 days (Fig. 5). No statistical difference in opioid use or visual analog scale pain scores was reported between the alvimopan and placebo groups. Interestingly, postoperative nausea, vomiting, and the overall incidence of all gastrointestinal side effects were significantly reduced in patients treated with 6 mg alvimopan compared with placebo, suggesting an important role of peripheral opioid receptors in nausea and vomiting. Three randomized, placebo-controlled phase 3 trials of alvimopan in patients undergoing abdominal colectomy or hysterectomy have been subsequently reported. They largely confirm the original observations by Taguchi et al.33 In one phase 3 study, recovery of gastrointestinal function was 14.6 hours faster in patients receiving 6 mg alvimopan orally and 22.0 hours faster in those receiving 12 mg alvimopan orally than those receiving placebo (119.6 hours) (Fig. 6). The time to discharge was also significantly faster (19.5 hours) in the 12-mg group.34 Two additional studies have provided supporting evidence of the effect of alvimopan in postoperative ileus. A statistically significant decrease in time to gastrointestinal recovery was also seen at the 6-mg dose in one trial. Decreased times to hospital discharge of 13.9 to 15.2 hours were demonstrated at the 6- or 12-mg doses.35 Although there has not been a clear dose–response relationship in the return of gastrointestinal function, there appears to be a more consistent response across all subpopulations at the 12-mg dose, with no observed increase in drug-related adverse events with the increased dose, consistent with its role in facilitating gastrointestinal recovery. There is an approximately 50% decrease in prolonged postoperative ileus and the need for nasogastric tube reinsertion reported with alvimopan at both doses (Fig. 7). Importantly, in these clinical trials, as was seen in the volunteers, there has been no observed effect on opioid use or pain scores (Fig. 8).

FIG. 5. Improvement in bowel function time to patient discharge and solid food intake in 79 patients receiving alvimopan.33

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FIG. 6. Cumulative proportion of patients in the modified intent-to-treat population achieving recovery of gastrointestinal function over the 10-day postoperative period. Cox proportional hazard model estimates. Number of patients: placebo (n = 149); 6 mg alvimopan (n = 155); 12 mg alvimopan (n = 165). Reprinted with permission from Wolff BG et al.34

Methylnaltrexone versus Alvimopan There are important differences between methylnaltrexone and alvimopan. Methylnaltrexone can be administered parenterally or orally; alvimopan compound is currently only available orally. Although oral administration has the advantage of ease of use in patients, it also is of slower onset. Furthermore, oral use limits the ability to block the systemic adverse effects of opiates contingent on gastrointestinal absorption. Thus,


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FIG. 7. The incidence of prolonged postoperative ileus after surgery was lower for patients in the alvimopan groups (8.3% and 6.3% in the 6-mg and 12-mg groups, respectively) compared with placebo (15.8%); this difference was statistically significant (*P < 0.05) for both groups. The incidence of nasogastric tube insertion after surgery was also decreased for patients in the alvimopan groups (8.4% and 4.8% in the 6-mg and 12-mg groups, respectively) compared with placebo (14.8%); this difference was statistically significant (**P = 0.004) for the 12-mg group.34

although nausea or constipation can be attenuated with an oral agent, pruritus or urinary retention will not be relieved unless the drug enters the systemic circulation at concentrations sufficient to antagonize the opioids at the receptor.36 The oral route of administration may theoretically be precluded in postoperative or other patients who already have decreased gastrointestinal motility or those receiving gastric suction, although it was well tolerated in subjects undergoing hysterectomy and bowel resection in trials of alvimopan. Use of a parenteral formulation may be preferable in this situation.36 Thus, there are compelling reasons for the development of both a parenteral and oral peripheral opiate antagonist for clinical practice.

Other Uses Although constipation and postoperative gut dysfunction are recognized as the most clinically significant peripheral side effects of opiates, patients taking opioids often con-

FIG. 8. No differences in opioid requirements or analgesia are seen in patients undergoing surgery and receiving alvimopan. With permission from Delaney C.35

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front other side effects. Both pruritus and dysphoria associated with opiate administration have been attenuated by both oral and subcutaneous methylnaltrexone, suggesting an important peripheral component.37 Whether peripheral opiate antagonists can reverse the pruritus associated with parenteral opiates is not known. Decreased gastricemptying, an adverse effect with doses as low as 1 mg of morphine, can be rapidly reversed by methylnaltrexone.36 This may have implications for enteric feeding in the intensive care unit. There is also some intriguing recent evidence that a significant component of urinary retention may be peripheral. In a recent study, 15 volunteers received a remifentanil infusion after placement of urinary and rectal catheters.38 The subjects then received placebo, naloxone, or methylnaltrexone parenterally and bladder pressure was measured. There was no reversal with the placebo, complete relief with naloxone, and partial relief with methylnaltrexone. Pupillary constriction persisted with methylnaltrexone, confirming that the drug does not cross into the central nervous system. Taken as a whole, this study demonstrates that a significant component of urinary retention is peripheral in nature. Because urinary retention often complicates discharge from ambulatory care facilities and also can be a major problem during the recovery period during removal of indwelling urinary catheters, there appears to be significant potential for this drug in these selected populations. The question of opiate-induced emesis is complex. Nausea and vomiting are other well-known adverse effects of opiates that have peripheral and central components. Intraventricularly administered opioids suppress vomiting, even in low doses. However, opioids given intravenously often induce emesis. The explanation for this dichotomy may be that the area of the brain responsible for mediating opioid-induced emesis has a permeable blood–brain barrier. Studies with peripheral opiate antagonists demonstrate a reduction in postoperative nausea and vomiting, perhaps manifest through neural circuits between the enteric nervous system and the brain.39 Initial data obtained in the trials of alvimopan in postoperative patients, a more complex group of patients, demonstrated protection against postoperative vomiting. Volunteer studies with methylnaltrexone demonstrated an antiemetic effect. These postoperative antiemetic effects have been less apparent in the larger phase III trials of postoperative ileus, so the clinical role of this class of drugs as antiemetics remains to be confirmed. Finally, a potentially considerable, but as yet largely unexplored, action of opioids may be their modulation of opiate effects on the immunologic system. Opiate-induced immunosuppression is particularly pertinent for postoperative patients, patients with cancer, and patients with AIDS. It has long been recognized that opiates depress immunologic function and induce apoptosis of lymphocytes.40 Neuraxial opiates reactivate viral entities such as herpes.41,42 Clinically relevant doses of methadone facilitate replication of the CCR5-binding site (the route by which the HIV virus enters cells)43 in monocyte-derived macrophages and glial cells. This observation has been proposed as an explanation for the increased infectivity described in HIV-positive patients receiving opiates. MNTX not only allows us to potentially distinguish between central and peripheral effects of opiates on the immune system, but also attenuate the immunologic dysfunction associated with opiate use.44 We recently demonstrated that clinically relevant doses of MNTX block opiate-induced increases in the CCR5 receptor, as well as viral replication and entry in this model system,45 suggesting a potential therapeutic role in the clinical setting of HIV-positive patients with AIDS pain or addiction.

Summary Peripheral opiate antagonists can be used to discriminate between the central and peripheral effects of opiates. Even more important, it seems likely that if approved


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one or more of the drugs of this class will be important to anesthesiologists and pain physicians.

References 1. Hughes J, Kosterlitz HW, Smith TW: The distribution of methionine–enkephalin and leucine–enkephalin in the brain and peripheral tissues. Br J Pharmacol 1977; 61:639–47. 2. Manara L, Bianchetti A: The central and peripheral influences of opioids on gastrointestinal propulsion. Annu Rev Pharmacol Toxicol 1985; 25:249–73. 3. Walsh TD: Oral morphine in chronic cancer pain. Pain 1984; 18:1–11. 4. McCaffrey M, Beebe A: Managing your patients’ adverse reactions to narcotics. Nursing 1989; 19:166–8. 5. Cameron JC: Constipation related to narcotic therapy: A protocol for nurses and patients. Cancer Nurs 1992; 15:372–7. 6. Glare P, Lickiss JN: Unrecognized constipation in patients with advanced cancer: A recipe for therapeutic disaster. J Pain Symptom Manage 1992; 7:369–71. 7. Fallon MT, Hanks GW: Morphine, constipation, and performance status in advanced cancer patients. Palliat Med 1999; 13:159–60. 8. Parolaro D, Sala M, Gori E: Effect of intracerebroventricular administration of morphine upon intestinal motility in rat and its antagonism with naloxone. Eur J Pharmacol 1977; 46:329–38. 9. Stewart JJ, Weisbrodt NW, Burks TF: Central and peripheral actions of morphine on intestinal transit. J Pharmacol Exp Ther 1978; 205:547–55. 10. Galligan JJ, Burks TF: Centrally mediated inhibition of small intestinal transit and motility by morphine in the rat. J Pharmacol Exp Ther 1983; 226:356–61. 11. Daniel EE, Sutherland WH, Bogoch A: Effects of morphine and other drugs on motility of the terminal ileum. Gastroenterology 1959; 36:510–23. 12. Burks TF: Mediation by 5-hydroxytryptamine of morphine stimulant actions in dog intestine. J Pharmacol Exp Ther 1973; 185:530–9. 13. Fukuda H, Suenaga K, Uemura K, et al.: The selective mu opioid receptor antagonist, alvimopan, accelerates gastrointestinal transit in a rodent model of postoperative ileus. Presented at Digestive Disease Week; May 20, 2004; New Orleans, LA. Abstract No. 100765. 2004 Program & Itinerary Planner. Bethesda, MD: Digestive Disease Week; 2004. 14. McCarthy RN, Jeffcott LB, Clarke IJ: Preliminary studies on the use of plasma β-endorphin in horses as an indicator of stress and pain. J Equine Vet Sci 1993; 13:216–9. 15. Kehlet H, Wilmore DW: Multimodal strategies to improve surgical outcome. Am J Surg 2002; 183:630–41. 16. Sykes NP: An investigation of the ability of oral naloxone to correct opioid-related constipation in patients with advanced cancer. Palliat Med 1996; 10:135–44. 17. Culpepper-Morgan JA, Inturrisi CE, Portenoy RK, et al.: Treatment of opioid-induced constipation with oral naloxone: A pilot study. Clin Pharmacol Ther 1992; 52:90–5. 18. Latasch L, Zimmermann M, Eberhardt B, Jurna I: Treatment of morphine-induced constipation with oral naloxone. Anaesthesist 1997; 46:191–4. 19. Cheskin LJ, Chami TN, Johnson RE, et al.: Assessment of nalmefene glucuronide as a selective gut opioid antagonist. Drug Alcohol Depend 1995; 39:151–4. 20. Maxwell LG, Kaufmann SC, Bitzer S, et al.: The effects of a small-dose naloxone infusion on opioid-induced side effects and analgesia in children and adolescents treated with intravenous patient-controlled analgesia: A double-blind, prospective, randomized, controlled study. Anesth Analg 2005; 100:953–8. 21. Kurz A, Sesslesr DI: Opioid-induced bowel dysfunction: Pathophysiology and potential new therapies. Drugs 2003; 63:649–71. 22. Palmer CS, Ingham M, Schmier J, et al.: Utility assessments of opioid treatment for patients with chronic non-cancer pain [Abstract 790]. Presented at the 20th Annual Scientific Meeting of the American Pain Society; April 19–22, 2001; Phoenix, Arizona. 23. Yuan C-S: Clinical status of methylnaltrexone, a new agent to prevent and manage opioidinduced side effects. J Support Oncol 2004;2:111–22. 24. Yuan CS, Foss J, Moss J: Methylnaltrexone effects on morphine-induced inhibition in isolated guinea-pig ileum and human intestine. Eur J Pharmacol 1995; 276:107–11.

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25. Yuan CS, Foss JF, O’Connor M, et al.: Methylnaltrexone prevents morphine-induced delay in oral-cecal transit time without affecting analgesia: A double-blind randomized placebocontrolled trial. Clin Pharmacol Ther 1996; 59:469–75. 26. Yuan CS, Foss JF, Osinski J, et al.: The safety and efficacy of oral methylnaltrexone in preventing morphine-induced delay in oral-cecal transit time. Clin Pharmacol Ther 1997; 61:467–75. 27. Yuan CS, Foss JF, O’Connor M, et al.: Methylnaltrexone for reversal of constipation due to chronic methadone use: A randomized controlled trial. JAMA 2000; 283:367–72. 28. Yuan CS, Foss JF: Oral methylnaltrexone for opioid-induced constipation [Letter]. JAMA 2000; 284:1383–4. 29. Yuan CS, Foss JF, O’Connor M, et al.: Effects of enteric-coated methylnaltrexone in preventing opioid-induced delay in ora–cecal transit time. Clin Pharmacol Ther 2000; 67:398–404. 30. Thomas J, Lipman AG, Slatkin N, et al.: A phase III double-blind, placebo-controlled trial of methylnaltrexone (MNTX) for opioid-induced constipation (OIC) in advanced medical illness [Abstract]. Presented at the 2005 American Society of Clinical Oncology Annual Meeting, May 13–17. 31. Schmidt WK: Alvimopan (ADL 8-2698) is a novel peripheral opioid antagonist. Am J Surg 2001; 182:27S–38S. 32. Paulson D, Kennedy D, Donovick R, et al.: Alvimopan, a novel, peripherally-acting, mu-opioid receptor antagonist for the management of opioid-induced bowel dysfunction (OBD): Positive results from a phase III randomized, placebo-controlled, 21-day trial. Presented at American Pain Society; May 7, 2004; Vancouver, BC. Abstract No. 796. J Pain 2004; 5:57. 33. Taguchi A, Sharma N, Saleem RM, et al.: Selective postoperative inhibition of gastrointestinal opioid receptors. N Engl J Med 2001; 345:935–40. 34. Wolff BG, Michelassi F, Gerkin TM, et al.: Alvimopan, a novel, peripherally acting µ opioid antagonist: Results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial of major abdominal surgery and postoperative ileus. Ann Surg 2004; 240:728–35. 35. Delaney C: Abstract presented at the 90th Annual Clinical Congress of the American College of Surgeons; New Orleans, LA; October 10-14, 2004. 36. Moss J, Yuan CS: Selective postoperative inhibition of gastrointestinal opioid receptors [Letter]. N Engl J Med 2002; 346:455. 37. Yuan CS, Wei G, Foss JF, et al.: Effects of subcutaneous methylnaltrexone on morphineinduced peripherally mediated side effects: A double-blind randomized placebo-controlled trial. J Pharmacol Exp Ther 2002; 300:118–23. 38. Thomas J, Rosow C, Moss J, et al.: Amelioration of peripheral side effects of opioids: clinical experience with methylnaltrexone (MNTX). Abstract presented at the 13th World Congress of Anesthesiologists; Paris; April 18-23, 2004. 39. Yuan CS, Foss JF: Gastric effects of methylnaltrexone on µ, k, and δ opioid agonists induced brainstem unitary responses. Neuropharmacology 1999; 38:425–32. 40. Yin D, Mufson RA, Wang R, Shi Y: Fas-mediated cell death promoted by opioids. Nature 1999; 397:218. 41. James CF: Recurrence of herpes simplex virus blepharitis after cesarean section and epidural morphine. Anesth Analg 1996; 82:1094–6. 42. Boyle RK: Herpes simplex labialis after epidural or parenteral morphine: A randomized prospective trial in an Australian obstetric population. Anaesth Intensive Care 1995; 23:433–7. 43. Li Y, Wang X, Tian S, et al.: Methadone enhances human immunodeficiency virus infection of human immune cells. J Infect Dis 2002; 185:118–22. 44. Wei G, Moss J, Yuan C-S: Opioid-induced immunosuppression: Is it centrally-mediated or peripherally-mediated? Biochem Pharmacol 2003; 65:1761–6. 45. Ho W-Z, Guo C-J, Yuan C-S, et al.: Methylnaltrexone antagonizes opioid-mediated enhancement of HIV infection of human blood mononuclear phagocytes. J Pharmacol Exp Ther 2003; 307:1158–62.



CHAPTER 16

V O L U M E


PERIOPERATIVE MANAGEMENT OF THE PATIENT UNDERGOING AORTIC VASCULAR SURGERY EDWARD J. NORRIS, M.D., M.B.A., F.A.H.A. ASSOCIATE PROFESSOR DIRECTOR, VASCULAR AND ENDOVASCULAR ANESTHESIA DEPARTMENT OF ANESTHESIOLOGY AND CRITICAL CARE MEDICINE THE JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE BALTIMORE, MARYLAND



© 2005



Perioperative Management of the Patient Undergoing Aortic Vascular Surgery Edward J. Norris, M.D., M.B.A., F.A.H.A. Associate Professor Director, Vascular and Endovascular Anesthesia Department of Anesthesiology and Critical Care Medicine The Johns Hopkins University School of Medicine Baltimore, MarylandT

The perioperative management of the patient undergoing aortic vascular surgery is one of the most challenging and controversial areas in the field of anesthesiology. The goal of this refresher course is to review issues related to the perioperative management of these patients and to address the underlying controversies. Anesthesia for conventional open abdominal aortic vascular surgery requires an understanding of the pathophysiology, knowledge of the surgical procedure, ability to interpret sophisticated hemodynamic data, and skillful pharmacologic control and manipulation of hemodynamics. Perioperative communication with the surgical team is essential. All open procedures on the abdominal aorta and its major branches require large incisions and extensive dissection, clamping and unclamping of the aorta, varying duration of organ ischemia and reperfusion, significant fluid shifts and temperature fluctuations, and activation of neurohumoral and inflammatory pathways. Recently, endovascular aortic surgery has emerged as a less invasive alternative to conventional open surgical repair.1 The endovascular approach to aortic disease is evolving rapidly with new devices, innovations, and indications.

Natural History and Surgical Management Abdominal aortic aneurysms (AAAs) are a very common vascular condition with lifethreatening implications. The prevalence of AAA in elderly males approaches 8%. Age, smoking, family history of AAA, and atherosclerotic disease are risk factors for AAA. The natural history of AAA disease is one of progressive enlargement and ultimate rupture and death. More than 8,000 deaths result from rupture of AAAs each year in the United States.2 To date, surgical intervention has dominated the therapeutic approach to this condition, and approximately 40,000 patients undergo open repair of AAA each year in the United States,3 at a cost likely to exceed $1 billion. The goal of elective surgical intervention is to prevent aneurysm rupture and prolong life.

Pathogenesis of Abdominal Aortic Aneurysms AAA is the end result of a multifactorial process associated with aortic aging and atherosclerosis.4 Although no unified concept of pathogenesis currently exists, there are genetic, biochemical, metabolic, infectious, mechanical, and hemodynamic factors that may contribute to the development and progression of AAA disease. Adventitial elastin degradation, a hallmark of AAA formation, may be the primary event leading to the destruction of aortic wall connective tissue.5 Chronic inflammation is a prominent 187

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feature of AAAs and likely plays a fundamental role in the destruction of connective tissue.6 Approximately 5% of patients undergoing AAA repair have inflammatory aneurysms. Rare causes of AAA include trauma, mycotic infection, syphilis, and Marfan syndrome.

Detection and Screening Ultrasonographic scanning (US) is the most cost-effective method of AAA detection and surveillance. This imaging technique is noninvasive, relatively inexpensive, and can be easily applied in the community setting. US is currently the detection method of choice for AAA screening with a high diagnostic sensitivity (98.9%) and diagnostic specificity (99.9%).7 US screening for AAA in men, and intervention with elective repair, can reduce the incidence of rupture by 53%.8 Although there is no evidence to suggest that the sensitivity of US for the detection of AAA is lower in women, the prevalence of AAA in women is six times lower than in men (1.3% vs. 7.6%) and screening may not be clinically indicated.9 Siblings of patients with AAA have an incidence of aortic enlargement of 30% and likely warrant a targeted screening approach. With more frequent screening of an aging U.S. population, more elderly patients will likely undergo elective repair of their AAAs in the future.

Management Guidelines The Joint Vascular Societies have recently published revised guidelines for the treatment of AAAs.10 The guidelines emphasize that individual decision-making regarding elective repair of AAA requires assessment of factors that influence aneurysm rupture risk, operative mortality risk, and life expectancy. Thus, to be most effective, elective AAA repair should be performed when rupture risk is high compared with operative risk and the patient has a long life expectancy. With the availability of endovascular aortic repair (EVAR), patient participation in the decision-making process has taken on even greater importance. Most management decisions regarding treatment of AAA are based on evaluation of the maximal aneurysm diameter and growth rate. The most accurate method generally available for determination of maximal diameter and growth rate is serial computed tomography (CT) scanning. Randomized trials have concluded that surveillance of AAAs up to a diameter of 5.5 cm is a safe management option.11,12 However, surgical repair is often recommended if such AAAs become symptomatic or expand more than 0.5 cm in a 6-month period. Although some controversy exists regarding elective AAA repair when the diameter is in the 5.5- to 5.9-cm range, it is currently accepted that elective repair should be undertaken in most patients at a diameter of 5.5 cm. The risk of AAA rupture may be higher in women and therefore elective repair has been recommended at the 4.5- to 5.0-cm range. Current guidelines suggest that EVAR is most appropriate for patients at increased risk for conventional open repair.10

Open Aortic Repair: Morbidity and Mortality In population-based studies, operative mortality is approximately 5% and approximately 30% of patients will have one or more major postoperative complication.13 Early mortality rates after open repair are inversely related to hospital volume and experience of individual surgeons with AAA repair.14 Older age is independently associated with an increased risk of major postoperative complications after AAA repair.13 Not surprisingly, cardiac, pulmonary, and renal comorbidities are also associated with an increased risk of postoperative complications. Late survival after elective AAA repair is 92% at 1 year and 67% at 5 years.15 The median length of hospital stay is ∼7 days and each procedure

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costs ∼$25,000. The long-term durability of open AAA repair is excellent and well established. The incidence of late graft complications is very low. As a result of the rapid and widespread acceptance of EVAR, a greater proportion of patients presenting for open repair will have anatomically complex, juxtarenal, or suprarenal AAAs.

Endovascular Aortic Repair The use of endovascular stent-graft devices is one of the most exciting developments in the treatment of aortic disease and has the potential to revolutionize current treatment modalities for aortic aneurysm, aortic dissection, and traumatic aortic injury. The feasibility of the technique for the treatment of AAA was established experimentally in the late 1980s, with the first clinical use reported by Parodi et al. in 1991.16 EVAR is based on the hypothesis that exclusion of the aneurysm sac from arterial pressure will prevent aneurysm rupture. Since Parodi’s initial report, nearly 20 different devices have been developed and tested clinically. To date, only four devices have received U.S. Food and Drug Administration (FDA) approval. It is noteworthy that FDA approval was granted without the usual requirement for a randomized, controlled trial. Instead, the FDA allowed a concurrent “matched” group of patients to serve as a control group. Over the last decade, there has been an explosive increase in the use of EVAR. Selection criteria and indications for EVAR are constantly evolving. Presently, repair of infrarenal AAA is accomplished using EVAR in up to 60% of patients. Although current guidelines suggest that EVAR is most appropriate for patients at increased risk for open AAA repair,10 it is currently used in many patients considered appropriate candidates for open repair. Guidelines suggest that EVAR may be the preferred treatment method for older, high-risk patients and those with clinical circumstances likely to increase the risk of open repair, if anatomic and technical criteria are met. Controlled clinical trials have demonstrated that EVAR is feasible, safe, and may reduce perioperative morbidity compared with open repair. In addition, EVAR is associated with greater hemodynamic stability, reduced stress response, decreased blood loss and transfusion requirements, shorter intensive care and hospital length of stay, improved analgesic control, and more rapid return to baseline activity compared with open repair. To date, controlled clinical trials have not demonstrated a mortality advantage with EVAR and late mortality may actually favor open repair. Of particular note, the long-term durability of EVAR has not been established, with long-term follow up only now beginning to be reported. Several complications are specific to EVAR and include endoleak (inability to obtain or maintain complete exclusion of the aneurysm sac from arterial blood flow), stent-graft migration, stent-graft failure, enlargement of the aneurysm sac, and aneurysm rupture. The annual rate of AAA rupture after EVAR is nearly 1%.1 As a result of reported cases of aneurysm rupture and death, the FDA has increased the surveillance requirement after EVAR to lifelong. Elevated pressure within the aneurysm sac unrelated to endoleak, termed endotension, may play a role in AAA sac expansion and rupture. Adjunctive retroperitoneal procedures may be necessary in up to 20% of patient during EVAR and are associated with increased risk for complications, greater blood loss, and longer hospital length of stay compared with standard femoral access.17 Secondary procedures after EVAR may be required in up to 15% of patients with a cumulative risk of 12% at 1 year, 24% at 2 years, and 35% at 3 years.18 Total inpatient hospital costs for EVAR are higher than for open repair, with the device itself accounting for more than 50% of total EVAR costs.1 Ultimately, randomized, controlled trials will be necessary to evaluate the effectiveness of EVAR compared with open repair. Several such trials are currently underway in the United States and Europe.

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Laparoscopic Management Laparoscopic aortic surgery has been used for occlusive disease for over a decade but has only recently been used for AAA repair. Hand-assisted, robotic-assisted, and totally laparoscopic AAA repair have all been reported, as well as a combined endovascular and laparoscopic approach. At present, the conversion rate to open repair is high and aortic crossclamp times are longer than with open repair. Advances in laparoscopic technique and instrumentation will likely dictate whether this approach becomes a viable minimally invasive alternative to open AAA repair or an alternate to EVAR in high-risk patients with anatomic limitations.

Ruptured Abdominal Aortic Aneurysms The perioperative mortality for ruptured AAA has not changed significantly over the last 4 decades and remains nearly 50%, with few exceptions. If one takes into account patients with rupture who die before reaching a hospital, the overall mortality rate after rupture may exceed 90%.15 In most patients with ruptured AAA, the presence of an aneurysm is previously unknown. To decrease the incidence of rupture, selective screening has been recommended and is under investigation. Endovascular repair of ruptured AAA is an alternative to conventional open repair and may improve clinical outcome.

Preoperative Cardiac Evaluation Patients having vascular surgery are a select group with a high incidence of coexisting disease associated with advanced age, smoking, diabetes, and hypertension, all of which should be assessed and, if possible, optimized before surgery. It is well recognized that coronary artery disease (CAD) is the leading cause of significant morbidity and mortality at the time of vascular surgery, and as a result, numerous evaluation and management strategies have been developed over the last 2 decades.19 Cardiac stress testing, clinical risk factors, and functional assessment have all been used preoperatively to identify patients at increased risk for adverse cardiac outcomes. Most recently, guidelines have been developed to combine both clinical evaluation and stress testing in an effort to identify high-risk patients most efficiently.20 Accurate clinical assessment of the pretest probability of significant CAD is necessary for prudent use and rational interpretation of preoperative stress testing. Importantly, preoperative testing should not be undertaken if it is unlikely to alter patient management. In addition, testing should not be considered as a preliminary step leading to coronary revascularization, because it is rarely necessary to perform revascularization solely for the purpose of getting a patient through the perioperative procedure. Coronary revascularization before vascular surgery is appropriate if indicated independently of the need for vascular surgery.21 Thus, revascularization is largely reserved for those patients with unstable cardiac symptoms or for whom such treatment offers a long-term survival benefit.

Coronary Artery Revascularization Prophylaxis Trial The role of preoperative coronary artery revascularization in patients being evaluated for elective vascular surgery is controversial. Despite consensus guidelines,20 substantial differences of opinion exist among cardiologists regarding the role of preoperative coronary artery revascularization for these high-risk patients.22 The absence of level I recommendations for specific patient management underlies much of this uncertainty. The


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recently reported results of the Coronary Artery Revascularization Prophylaxis (CARP) trial provide the first level I evidence regarding coronary artery revascularization (percutaneous coronary intervention or coronary artery bypass grafting) before elective major vascular surgery.23 Patients (98% male) with clinically significant, stable coronary disease scheduled for elective AAA repair or lower extremity revascularization at 18 Veterans Affairs medical centers were randomly assigned to either coronary revascularization before vascular surgery (258 patients) or no revascularization before vascular surgery (252 patients). Figure 1 summarizes the trial algorithm. Medical therapy (β-blockers, statins, and aspirin) was optimized in both treatment groups. The primary outcome variable was long-term mortality. At a median follow up of 2.7 years, mortality was 22% in the revascularization group and 23% in the no revascularization group (95% confidence interval, 0.70–1.37; P = 0.92). Although the trial was not designed to evaluate the impact of prophylactic

FIG. 1. Algorithm of the Coronary Artery Revascularization Prophylaxis (CARP) trial. AAA, abdominal aortic aneurysm; LV, left ventricular; LVEF, left ventricular ejection fraction. Reprinted from Krupski WC: Update on perioperative evaluation and management of cardiac disease in vascular patients. J Vasc Surg 2002; 36:1292–308. © 2002 Society for Vascular Surgery.

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revascularization on perioperative outcome, there were no differences between the two groups in the incidence of myocardial infarction (MI) or 30-day mortality. These results should help guide the preoperative cardiac therapy for a broad group of male patients presenting for elective major vascular surgery. However, one must keep in mind that the results should not be extrapolated to those patients with unstable coronary disease, left main disease, aortic stenosis, severe left ventricular dysfunction, or those with suboptimal perioperative medical management.

Perioperative Pharmacologic Therapy An expanding list of randomized clinical trials has demonstrated that the perioperative use of β-blockers therapy can reduce cardiac morbidity and mortality after noncardiac surgery.24,25 Although the specific mechanism underlying this improvement in outcome is unknown, blunting of the neurohormonal and hemodynamic effects of sympathetic stimulation likely plays a significant role. Two clinical trials deserve specific mention. Mangano et al.24 found in 200 patients with or at risk for CAD that the 2-year mortality after noncardiac surgery was 10% in patients treated with atenolol perioperatively versus 21% for the control patients. Poldermans et al.25 randomized 112 patients with positive dobutamine stress echocardiography undergoing vascular surgery to perioperative bisoprolol or standard care. The combined 30-day incidence of cardiac death and nonfatal MI was 3.4% in the bisoprolol group and 34% in the standard care group (Fig. 2). At 2 years, the combined incidence of cardiac death and nonfatal MI (in 101 patients who survived surgery) was 12% in the bisoprolol group and 32% in the standard care group (Fig. 3).26 Based on the results of these trials, the American College

FIG. 2. Kaplan-Meier curves of the cumulative percentages of patients who died of cardiac causes or had a nonfatal myocardial infarction during the perioperative period. The differences between groups were significant (P < 0.001). Reprinted from Poldermans D, Boersma E, Bax JJ, et al.: The effect of bisoprolol on perioperative mortality and myocardial infarction in high-risk patient undergoing vascular surgery. DECREASE Study Group. N Engl J Med 1999; 341:1789–94.


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FIG. 3. Kaplan-Meier curves of the cumulative percentage of patients who survived vascular surgery and remained free of cardiac death and nonfatal myocardial infarction during follow up. The difference between groups was significant (P = 0.004). Reprinted with permission of Oxford University Press, from Poldermans D, Boersma E, Bax JJ, et al.: Bisoprolol reduces cardiac death and myocardial infarction in high-risk patients as long as 2-years after successful major vascular surgery. Eur Heart J 2001; 22:1353–8.

of Cardiology/American Heart Association (ACC/AHA) revised guidelines have made the use of β-blockers in vascular surgery patients with a positive stress test a level I recommendation.20 Implementation of these guidelines and administration of β-blockers are associated with improved cardiac outcomes after abdominal aortic surgery.27 In addition, perioperative β-blocker therapy may decrease the number of patients undergoing vascular surgery referred for preoperative cardiac testing. Clinically low-risk patients on β-blocker therapy can safely proceed to vascular surgery without delay.28 Of important note, perioperative β-blocker therapy may not protect patients undergoing vascular surgery at highest risk (multiple clinical markers of risk and widespread ischemia on preoperative dobutamine stress echocardiography) for cardiac complications.28 Coronary revascularization should be considered in this small subgroup of patients. Although no randomized data are available, perioperative statin use is associated with reduced perioperative mortality in patients undergoing vascular surgery.29 Longterm statin use after successful AAA repair is associated with reduced all-cause and cardiovascular mortality.30

Hemodynamic Monitoring The appropriate level of hemodynamic monitoring for a patient undergoing aortic vascular surgery is controversial. Multiple considerations determine the need for monitoring, and it is difficult to generalize for all patients. Given the high frequency of coexisting disease, the potential for significant and rapid blood loss, and the physiological changes associated with aortic crossclamping and unclamping, all patients should be

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monitored with an intraarterial catheter. This allows beat-to-beat blood pressure monitoring, accurate determination of diastolic pressure, and arterial blood sampling for diagnostic purposes. The radial artery is most commonly selected for cannulation because of its superficial location, easy accessibility, and a low complication rate. A noninvasive blood pressure cuff should be placed on the contralateral arm for use in the event of catheter malfunction. The placement of a central venous catheter should be considered routine for all aortic vascular procedures. This allows central venous pressure monitoring and the administration of drugs into the central circulation. The internal jugular vein is most commonly cannulated. In patients with good left ventricular and pulmonary function, central venous pressure correlates well with left ventricular filling pressures. The clinical value of pulmonary artery catheter (PAC) monitoring in high-risk surgical patients has not been established and remains controversial. Existing clinical studies have produced quite conflicting results. Some have reported a decrease in mortality, some no effect, and others have reported an increase in mortality. Randomized, controlled trials (with or without preoperative optimization) in patients undergoing aortic surgery have reported no clinical benefit with PAC monitoring.31 Although the routine, nonselective use of PAC monitoring in patients undergoing aortic vascular surgery is not supported by current evidence,32 the selective use in high-risk patient subgroups and those undergoing complex aortic reconstruction has not been evaluated. PAC monitoring should be considered for patients with significant left ventricular dysfunction (ejection fraction 2.0 mg/dL), cor pulmonale, and those requiring crossclamping above the level of the renal arteries. Clinical studies evaluating the role of anesthetic technique on outcome after aortic vascular surgery suggest that aggressive, goal-directed hemodynamic protocols guided by PAC monitoring may be the most effective intervention to reduce morbidity after vascular surgery.33 Two-dimensional transesophageal echocardiography (TEE) has been used intraoperatively to assess global ventricular function, guide fluid therapy, and monitor for myocardial ischemia. Continuous monitoring of ventricular function is commonly obtained from a single transgastric midleft ventricular short-axis view at the level of the midpapillary muscles. Using this same view, visualization of the left ventricle at end diastole allows rapid assessment of ventricular filling (preload). Ejection fraction can be calculated by using left ventricular end diastolic and end systolic areas. Patients requiring supraceliac aortic crossclamping have significant increases in end diastolic area and significant decreases in ejection fraction by TEE that are not completely normalized with vasodilators and frequently are not detected by PAC monitoring.34 TEE can also reveal abnormalities of left ventricular wall motion and wall thickening. The relationship between these abnormalities and coronary perfusion is well established and they often precede electrocardiographic evidence of myocardial ischemia. The short-axis view at the level of the midpapillary muscles allows assessment of all three major coronary distributions. TEE-detected segmental wall motion abnormalities may occur in more than 90% of patients requiring supraceliac aortic crossclamping.34 Unfortunately, ischemic episodes detected by TEE during noncardiac surgery correlate poorly with postoperative cardiac outcomes. In addition, routine ischemia monitoring with TEE has little incremental value over two-lead electrocardiographic monitoring in identifying patients at high risk for perioperative ischemic outcomes. Ultimately, the clinical usefulness of PAC or TEE monitoring depends on patient selection, accurate interpretation of data, and appropriate therapeutic intervention.


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Hemodynamic Effects of Aortic Crossclamping and Unclamping The pathophysiology of aortic crossclamping (Fig. 4) and unclamping (Fig. 5) is complex and depends on many factors, including level of aortic crossclamping, extent of CAD and myocardial function, degree of periaortic collateralization, blood volume and distribution, activation of the sympathetic nervous system, and anesthetic agents and techniques. Although most open procedures require clamping below the renal arteries, clamping at the suprarenal and supraceliac levels is required for suprarenal aneurysms and renal/visceral reconstructions and is frequently necessary for juxtarenal and inflammatory aneurysms and aortoiliac occlusive disease with proximal extension. As EVAR becomes more common, an increasing proportion of patients for open repair will have anatomically complex aneurysms, many of which will require high aortic crossclamping. These higher levels of crossclamping have a significant impact on the cardiovascular system as well as those vital organs rendered ischemic or hypoperfused.

Crossclamping The systemic cardiovascular consequences of aortic crossclamping depends primarily on the level of aortic occlusion. Arterial hypertension is the most consistent component of the hemodynamic response to crossclamping at any level. The hemodynamic response to infrarenal crossclamping generally consists of increases in arterial pressure

FIG. 4. Systemic hemodynamic response to aortic crossclamping. Preload (asterisk) does not necessarily increase with infrarenal clamping. Depending on splanchnic vascular tone, blood volume can be shifted into the splanchnic circulation, and preload does not increase. Ao, aortic; AoX, aortic crossclamping; R art, arterial resistance. Reprinted from Gelman S: The pathophysiology of aortic cross-clamping and unclamping. Anesthesiology 1995; 82:1026–60. © 1995 American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc.

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FIG. 5. Systemic hemodynamic response to aortic unclamping. AoX, aortic crossclamping; Cven, venous capacitance; R art, arterial resistance; Rpv, pulmonary vascular resistance. Reprinted from Gelman S: The pathophysiology of aortic cross-clamping and unclamping. Anesthesiology 1995; 82:1026–60. © 1995 American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins. Inc.

(7% to 10%) and systemic vascular resistance (20% to 32%) with no significant change in heart rate. Cardiac output is most consistently decreased by 9% to 33%. Changes in ventricular filling pressures are not consistent and factors such as blood volume redistribution, ventricular contractility, and coronary blood flow impact the direction and magnitude of such changes. Ejection fraction, as measured by two-dimensional TEE, is minimally reduced and segmental wall motion abnormalities are common. The hemodynamic consequences of high (supraceliac) aortic crossclamping can be dramatic and require an integrated approach in an attempt to understand the direction and magnitude of the changes.35 In one report, supraceliac aortic crossclamping increased arterial pressure by 54% and left ventricular filling pressure by 38%.34 Ejection fraction was reduced by 38% and wall motion abnormalities were very common. Significant increases in left ventricular end systolic and end diastolic areas persisted despite normalization of systemic and left ventricular filling pressures. Redistribution of blood volume (from tissues below the crossclamp to tissues above the crossclamp) and increased afterload, which occur with aortic crossclamping, helps explain many of the observed hemodynamic changes. Gelman’s comprehensive review of this topic is highly recommended for interested readers.35

Therapeutic Strategies Patients with preexisting impaired ventricular function and reduced coronary reserve are the most vulnerable to the stresses imposed on the cardiovascular system after aortic crossclamping. Such patients requiring supraceliac aortic crossclamping are the most challenging. Rational therapeutic strategies focus primarily on measures to reduce afterload and normalize preload. Controlled (slow clamp application) aortic crossclamping is important to avoid abrupt and extreme stresses on the myocardium. Afterload reduc-


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tion, most commonly accomplished with sodium nitroprusside, “unloads” the heart and reduces ventricular wall tension. Isoflurane and amrinone can provide hemodynamic control similar to that of sodium nitroprusside. Normalization of preload involves careful fluid titration and vasodilator administration. An infusion of nitroglycerine is most commonly used. It is important to keep in mind that vasodilator therapy decreases the pressure-dependent blood flow to vital organs and tissues below the level of the aortic crossclamp.

Unclamping The hemodynamic response to unclamping depends on the level of aortic occlusion, total occlusion time, and intravascular volume. Hypotension is the most consistent hemodynamic response to aortic unclamping and can be profound after removal of a supraceliac crossclamp. Reactive hyperemia distal to the clamp and the resultant relative central hypovolemia are the dominant mechanisms of the hypotension. Washout of vasoactive and cardiodepressant mediators from ischemic tissues, as well as various humoral factors, contribute as well. Avoidance of significant hypotension with aortic unclamping requires close communication with the surgical team and appropriate administration of fluids and vasoactive agents. Gradual release of the aortic clamp and reapplication or digital compression are important measures to prevent severe hypotension. Vasodilators should be discontinued before unclamping. Moderate intravascular volume loading (approximately 500 mL) during the immediate prerelease period is indicated for infrarenal unclamping. More aggressive volume loading is required in the period immediately preceding supraceliac unclamping. Volume loading in an attempt to maintain elevated filling pressures during the crossclamp period is not indicated and may result in overtransfusion of fluids and blood products. Although vasopressors (phenylephrine or norepinephrine) are rarely required after infrarenal unclamping, they are frequently required with release of a supraceliac crossclamp.

Anesthetic Management Open Aortic Surgery A variety of anesthetic techniques, including general anesthesia, epidural anesthesia, and combined techniques, have been used successfully for open aortic vascular surgery. Combined techniques most commonly use a high lumbar or low thoracic epidural catheter in addition to a “light” general anesthetic. Local anesthetics, opioids, or more commonly, a combination of the two may be administered by bolus or continuous epidural infusion. The choice of anesthetic agents for premedication, induction, and maintenance of general anesthesia is not unique to aortic surgery. Current evidence suggests the maintenance of vital organ perfusion and function by the provision of stable perioperative hemodynamics is more important to overall outcome than is the choice of anesthetic agent or technique. Therefore, the specific anesthetic technique and agents for patients undergoing open aortic surgery is important insofar as it allows rapid and precise control of hemodynamic parameters. Given the high incidence of cardiac morbidity in patients undergoing aortic surgery, special emphasis should be placed on factors that influence ventricular work and myocardial perfusion. On arrival to the operating room, small intravenous doses of a benzodiazepine (0.5 mg midazolam) and an opioid (25 µg fentanyl) are appropriate during line placement. Induction of general anesthesia should proceed in a controlled fashion using incremental doses of an intravenous hypnotic agent (propofol or thiopental), usually

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combined with a short-acting, potent opioid such as fentanyl (3 to 5 µg/kg) such that stable hemodynamics are maintained during loss of consciousness, laryngoscopy and intubation, and the postinduction period. Esmolol (10 to 25 mg), sodium nitroprusside (5 to 25 µg), nitroglycerin (50 to 100 µg), and phenylephrine (50 to 100 µg) should be available for bolus administration as needed. Anesthetic maintenance may be accomplished with a balanced technique using a potent opioid (15 to 20 µg/kg fentanyl), 50% nitrous oxide, and a halogenated anesthetic. When epidural local anesthetics are used, the total dose of opioid is reduced approximately 50%. The initial bolus of epidural local anesthetic should be limited to 6 to 8 mL, with additional local anesthetic administered through continuous infusion at 4 to 6 mL per hour and adjusted based on hemodynamics and inhalational anesthetic requirements. Appropriate amounts of fluids for maintenance of euvolemia (deficits, maintenance requirements, and replacement of blood loss) should be administered throughout the intraoperative period. Hemoglobin is maintained ≥9.0 gm/dL with a combination of autologous, scavenged, and allogeneic blood. A forced-air warming blanket over the upper body and fluid warmers are used throughout the intraoperative period in an effort to prevent hypothermia and its associated morbidity.36 Preparation for emergence from anesthesia should begin after restoration of circulation and establishment of adequate organ perfusion. Hemodynamic, metabolic, hemostatic, and temperature homeostasis must be achieved before skin closure if extubation is to be attempted in the operating room. Hypertension and tachycardia should be aggressively controlled during emergence with short-acting agents. Early extubation is generally not attempted in patients with poor baseline pulmonary function, patients with greater than 30 minutes of supraceliac aortic crossclamping, and patients requiring large volumes of blood or crystalloid during surgery. Some centers advocate extubation of all patients in the intensive care unit (ICU) after a period of stability has been established.

Endovascular Aortic Surgery Local, regional, and general anesthesia have all been described for EVAR. Although general anesthesia was commonly used with early-generation devices because procedure times were often long, as centers have gained experience with newer-generation devices, procedure time are significantly shorter and local and regional anesthesia are more often used. The optimal anesthetic technique for EVAR has yet to be determined. Opioid requirements are usually minimal and postoperative pain is easily managed. Although blood loss and fluid requirements are not excessive, the potential for rapid blood loss is real. Active patient warming is often necessary to prevent hypothermia, particularly with longer procedures.

Role of Regional Anesthesia and Analgesia Various regional anesthetic and analgesic techniques have been used effectively during and after open aortic surgery. Because patients undergoing vascular surgery are at increased risk for perioperative morbidity, considerable interest has been focused on the use of regional anesthetic and analgesic techniques to reduce the incidence of adverse postoperative outcomes. Despite numerous randomized clinical trials, the most appropriate regimen of intraoperative anesthesia and postoperative analgesia for patients undergoing open aortic surgery remains controversial, and conflicting results have been reported.33,37,38 The majority of the quality evidence suggests that epidural techniques have no significant impact on mortality, cardiovascular morbidity, myocardial ischemia, pulmonary morbidity, or renal morbidity after aortic surgery (Table 1). In addition, randomized trials have not demonstrated any reduction in length of hospital stay after

Cardiac Outcomes and Length of Hospital Stay in Randomized Studies of Regional versus General Anesthesia in Patients Who Had Undergone Aortic Vascular Surgery Death

Myocardial Ischemia

MI

CHF

LOS (days)

Study

No. of Patients

RA

GA

RA

GA

RA

GA

RA

GA

RA

GA

Baron et al.38 Davies et al.42 Garnett et al.43 Bois et al.44 Boylan et al.45 Norris et al.33* Average

167 50 99 114 40 168

4% 8% 0% 2% 0% 5% 4%

5% 4% 4% 2% 0% 5% 4%

6% 8% 6% 4% 5% 4% 6%

6% 4% 10% 8% 5% 0% 6%

20%

19%

16 16

51% 19% 38% 17% 26%

8% 8% 10% 0% 5% 0% 5%

16 16

58% 18% 32% 16% 24%

6% 12% 6% 5% 11% 1% 5%

16 13 7 11

14 14 7 11

*Any epidural use included in regional anesthesia group. CHF, congestive heart failure; GA, general anesthesia; LOS, length of stay; MI, myocardial infarction; RA, regional anesthesia.


TABLE 1.

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aortic surgery with the use of regional techniques (Table 1).33 A large randomized trial reported no reduction in postoperative complications after aortic surgery with the use of intrathecal opioid.39 Clinical studies have identified several disadvantages with the use of epidural local anesthetics in combination with general anesthesia during aortic surgery, including significant hypotension at the time of aortic unclamping and increased fluid and vasopressor requirements. These disadvantages may be exaggerated with supraceliac aortic crossclamping and many clinicians avoid epidural local anesthetics for such procedures.

Postoperative Management Patients undergoing vascular surgery require close monitoring and special attention during the early postoperative period. Traditionally, this has involved admission to an intensive care unit. Although no randomized studies are available, retrospective studies suggest that a policy of selective intensive care unit utilization is both feasible and safe after infrarenal AAA repair.40 For those patients requiring intensive care unit care, it is important to recognize that organizational characteristics of intensive care units can significantly impact inhospital mortality and morbidity after open aortic surgery.41 For example, not having daily rounds by an intensive care unit physician is associated with a threefold increase in inhospital mortality after aortic surgery.41 Myocardial ischemia and cardiac morbidity occur most frequently in the postoperative period and are the most common complications after aortic surgery. The determinants of myocardial oxygen supply and demand should be optimized and potential triggers of ischemia (pain, anemia, hypothermia, hypovolemia, tachycardia, and ventilatory insufficiency) prevented. β-blocker therapy should be continued throughout the postoperative period. In mechanically ventilated patients, the weaning period can be especially stressful and myocardial ischemia occurs frequently during this time. Other postoperative complications include bleeding from residual heparin, dilutional coagulopathy, significant hypertension, or surgical/technical reasons. Hypovolemia may occur after aortic surgery as a result of bleeding or significant third-space fluid losses. Body temperature should be carefully monitored and controlled in all patients. Residual hypothermia in the early postoperative period is common and is associated with an increased incidence of myocardial ischemia and cardiac morbidity.36

Conclusion Anesthetic management of patients undergoing open aortic surgery remains one of the most significant challenges an anesthesiologist faces in clinical practice. Despite tremendous advances in EVAR, older patients with significant comorbidities will continue to require open repair of increasingly complex aneurysms. EVAR itself presents new and unique challenges to the anesthesiologist. The anesthesiologist must not only keep up to date, but also constantly refine perioperative management of this high-risk patient population.

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2. Gillum RF: Epidemiology of aortic aneurysm in the United States. J Clin Epidemiol 1995; 48:1289–98. 3. Lawrence PF, Gazak C, Bhirangi L, et al.: The epidemiology of surgically repaired aneurysms in the United States. J Vasc Surg 1999; 30:632–40. 4. Anidjar S, Kieffer E: Pathogenesis of acquired aneurysms of the abdominal aorta. Ann Vasc Surg 1992; 6:298–305. 5. White JV, Haas K, Phillips S, Comerota AJ: Adventitial elastolysis is a primary event in aneurysm formation. J Vasc Surg 1993; 17:371–80; discussion 380–1. 6. Shah PK: Inflammation, metalloproteinases, and increased proteolysis: An emerging pathophysiological paradigm in aortic aneurysm. Circulation 1997; 96:2115–7. 7. Lindholt JS, Vammen S, Juul S, Henneberg EW, Fasting H: The validity of ultrasonographic scanning as screening method for abdominal aortic aneurysm. Eur J Vasc Endovasc Surg 1999; 17:472–5. 8. Ashton HA, Buxton MJ, Day NE, et al.: The Multicentre Aneurysm Screening Study (MASS) into the effect of abdominal aortic aneurysm screening on mortality in men: A randomised controlled trial. Lancet 2002; 360:1531–9. 9. Scott RA, Bridgewater SG, Ashton HA: Randomized clinical trial of screening for abdominal aortic aneurysm in women. Br J Surg 2002; 89:283–5. 10. Brewster DC, Cronenwett JL, Hallett JW Jr, et al.: Guidelines for the treatment of abdominal aortic aneurysms. Report of a subcommittee of the Joint Council of the American Association for Vascular Surgery and Society for Vascular Surgery. J Vasc Surg 2003; 37:1106–17. 11. Lederle FA, Wilson SE, Johnson GR, et al.: Immediate repair compared with surveillance of small abdominal aortic aneurysms. N Engl J Med 2002; 346:1437–44. 12. Mortality results for randomised controlled trial of early elective surgery or ultrasonographic surveillance for small abdominal aortic aneurysms. The UK Small Aneurysm Trial Participants. Lancet 1998; 352:1649–55. 13. Vemuri C, Wainess RM, Dimick JB, et al.: Effect of increasing patient age on complication rates following intact abdominal aortic aneurysm repair in the United States. J Surg Res 2004; 118:26–31. 14. Birkmeyer JD, Stukel TA, Siewers AE, et al.: Surgeon volume and operative mortality in the United States. N Engl J Med 2003; 349:2117–27. 15. Ernst CB: Abdominal aortic aneurysm. N Engl J Med 1993; 328:1167–72. 16. Parodi JC, Palmaz JC, Barone HD: Transfemoral intraluminal graft implantation for abdominal aortic aneurysms. Ann Vasc Surg 1991; 5:491–9. 17. Lee WA, Berceli SA, Huber TS, et al.: Morbidity with retroperitoneal procedures during endovascular abdominal aortic aneurysm repair. J Vasc Surg 2003; 38:459–63; discussion 464–5. 18. Sampram ES, Karafa MT, Mascha EJ, et al.: Nature, frequency, and predictors of secondary procedures after endovascular repair of abdominal aortic aneurysm. J Vasc Surg 2003; 37:930–7. 19. Eagle KA, Coley CM, Newell JB, et al.: Combining clinical and thallium data optimizes preoperative assessment of cardiac risk before major vascular surgery. Ann Intern Med 1989; 110:859–66. 20. Eagle KA, Berger PB, Calkins H, et al.: ACC/AHA guideline update for perioperative cardiovascular evaluation for noncardiac surgery–executive summary: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1996 Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac Surgery). J Am Coll Cardiol 2002; 39:542–53. 21. Fleisher LA, Eagle KA: Clinical practice. Lowering cardiac risk in noncardiac surgery. N Engl J Med 2001; 345:1677–82. 22. Pierpont GL, Moritz TE, Goldman S, et al.: Disparate opinions regarding indications for coronary artery revascularization before elective vascular surgery. Am J Cardiol 2004; 94:1124–8. 23. McFalls EO, Ward HB, Moritz TE, et al.: Coronary-artery revascularization before elective major vascular surgery. N Engl J Med 2004; 351:2795–804. 24. Mangano DT, Layug EL, Wallace A, Tateo I: Effect of atenolol on mortality and cardiovascular morbidity after noncardiac surgery. Multicenter Study of Perioperative Ischemia Research Group. N Engl J Med 1996; 335:1713–20. 25. Poldermans D, Boersma E, Bax JJ, et al.: The effect of bisoprolol on perioperative mortality and myocardial infarction in high-risk patients undergoing vascular surgery. Dutch

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26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45.

NORRIS Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography Study Group. N Engl J Med 1999; 341:1789–94. Poldermans D, Boersma E, Bax JJ, et al.: Bisoprolol reduces cardiac death and myocardial infarction in high-risk patients as long as 2 years after successful major vascular surgery. Eur Heart J 2001; 22:1353–8. Licker M, Khatchatourian G, Schweizer A, et al.: The impact of a cardioprotective protocol on the incidence of cardiac complications after aortic abdominal surgery. Anesth Analg 2002; 95:1525–33. Boersma E, Poldermans D, Bax JJ, et al.: Predictors of cardiac events after major vascular surgery: Role of clinical characteristics, dobutamine echocardiography, and beta-blocker therapy. JAMA 2001; 285:1865–73. Poldermans D, Bax JJ, Kertai MD, et al.: Statins are associated with a reduced incidence of perioperative mortality in patients undergoing major noncardiac vascular surgery. Circulation 2003; 107:1848–51. Kertai MD, Boersma E, Westerhout CM, et al.: Association between long-term statin use and mortality after successful abdominal aortic aneurysm surgery. Am J Med 2004; 116:96–103. Valentine RJ, Duke ML, Inman MH, et al.: Effectiveness of pulmonary artery catheters in aortic surgery: A randomized trial. J Vasc Surg 1998; 27:203–11; discussion 211–2. Barone JE, Tucker JB, Rassias D, Corvo PR: Routine perioperative pulmonary artery catheterization has no effect on rate of complications in vascular surgery: A meta-analysis. Am Surg 2001; 67:674–9. Norris EJ, Beattie C, Perler BA, et al.: Double-masked randomized trial comparing alternate combinations of intraoperative anesthesia and postoperative analgesia in abdominal aortic surgery. Anesthesiology 2001; 95:1054–67. Roizen MF, Beaupre PN, Alpert RA, et al.: Monitoring with two-dimensional transesophageal echocardiography. Comparison of myocardial function in patients undergoing supraceliac, suprarenal–infraceliac, or infrarenal aortic occlusion. J Vasc Surg 1984; 1:300–5. Gelman S: The pathophysiology of aortic cross-clamping and unclamping. Anesthesiology 1995; 82:1026–60. Frank SM, Fleisher LA, Breslow MJ, et al.: Perioperative maintenance of normothermia reduces the incidence of morbid cardiac events. A randomized clinical trial. JAMA 1997; 277:1127–34. Park WY, Thompson JS, Lee KK: Effect of epidural anesthesia and analgesia on perioperative outcome: A randomized, controlled Veterans Affairs cooperative study. Ann Surg 2001; 234:560–9; discussion 569–71. Baron JF, Bertrand M, Barre E, et al.: Combined epidural and general anesthesia versus general anesthesia for abdominal aortic surgery. Anesthesiology 1991; 75:611–8. Fleron MH, Weiskopf RB, Bertrand M, et al.: A comparison of intrathecal opioid and intravenous analgesia for the incidence of cardiovascular, respiratory, and renal complications after abdominal aortic surgery. Anesth Analg 2003; 97:2–12. Bastounis E, Filis K, Georgopoulos S, et al.: Selective use of the intensive care unit after elective infrarenal abdominal aortic aneurysm repair. Int Angiol 2003; 22:308–16. Pronovost PJ, Jenckes MW, Dorman T, et al.: Organizational characteristics of intensive care units related to outcomes of abdominal aortic surgery. JAMA 1999; 281:1310–7. Davies MJ, Silbert BS, Mooney PJ, Dysart RH, Meads AC: Combined epidural and general anaesthesia versus general anaesthesia for abdominal aortic surgery: A prospective randomised trial. Anaesth Intensive Care 1993; 21:790–4. Garnett RL, MacIntyre A, Lindsay P, et al.: Perioperative ischaemia in aortic surgery: combined epidural/general anaesthesia and epidural analgesia vs general anaesthesia and IV analgesia. Can J Anaesth 1996; 43:769–77. Bois S, Couture P, Boudreault D, et al.: Epidural analgesia and intravenous patient-controlled analgesia result in similar rates of postoperative myocardial ischemia after aortic surgery. Anesth Analg 1997; 85:1233–9. Boylan JF, Katz J, Kavanagh BP, et al.: Epidural bupivacaine-morphine analgesia versus patient-controlled analgesia following abdominal aortic surgery: Analgesic, respiratory, and myocardial effects. Anesthesiology 1998; 89:585–93.



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MANAGEMENT OF THE PATIENT WITH PULMONARY HYPERTENSION AND RIGHT VENTRICULAR FAILURE GEORGE F. RICH, M.D., PH.D. PROFESSOR OF ANESTHESIOLOGY UNIVERSITY OF VIRGINIA HEALTH SYSTEM DEPARTMENT OF ANESTHESIOLOGY CHARLOTTESVILLE, VIRGINIA



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Management of the Patient with Pulmonary Hypertension and Right Ventricular Failure George F. Rich, M.D., Ph.D. Professor of Anesthesiology University of Virginia Health System Department of Anesthesiology Charlottesville, Virginia

Pulmonary Physiology The pulmonary circulation is normally a low-pressure, low-resistance circuit in comparison to the systemic circulation. The normal systolic, diastolic, and mean pulmonary artery pressures (PAP) are 22 mm Hg, 10 mm Hg, and 15 mm Hg, respectively. The pulmonary vascular resistance (PVR), which is calculated as the mean PAP minus the pulmonary artery occlusion pressure (PAOP) divided by the cardiac output (CO), is normally 0.9 to 1.4 Wood units or approximately 90 to 120 dynes/sec/cm−5. Pulmonary hypertension is generally defined as a mean PAP of greater than 25 mm Hg at rest or greater than 30 mm Hg with exercise, or a PVR greater than 300 dynes/sec/cm−5. A mean PAP greater than 50 mm Hg or a PVR greater than 600 dynes/sec/cm−5 is considered severe pulmonary hypertension. The PVR is important because it represents the afterload of the right ventricle (RV), and, therefore, affects RV function and CO. PVR may also control intracardiac shunting through septal defects and, as such, alter oxygenation. Management of pulmonary hypertension requires an understanding of the anatomy and physiology that is unique to the pulmonary circulation. In contrast to the systemic circulation, the pulmonary vessels have relatively thin walls and the vascular smooth muscle is sparsely distributed in the smaller arterioles.1 The endothelium plays an important role in maintaining low resting pulmonary vascular tone. Normally, endogenous endothelial vasodilators (nitric oxide and prostacyclin) predominate, although vasoconstrictors (endothelin, thromboxane) may also modulate PVR.2 Disruption of the endothelium and the endogenous vasodilators is associated with the development of pulmonary hypertension.2 Cardiac output, airway pressure, and gravity affect the pulmonary circulation more than the systemic circulation because of its lower pressure. Increases in CO distend open pulmonary vessels and recruit previously closed vessels. Therefore, as CO increases, the PVR decreases. Clinically, this means that increasing CO with administration of inotropic agents or increasing blood volume will passively decrease PVR. This relationship becomes less pronounced in disease states of the pulmonary circulation. The PVR is affected by the pressure differences between the vessel lumen and the perivascular space. Intraalveolar vessels are compressed when the transpulmonary pressure is increased during positive pressure inspiration. In contrast, the extraalveolar vessel resistance decreases during inspiration. The contribution of the two vessels accounts for the unique U-shaped relationship between lung volume and PVR, which is minimal at functional residual capacity and increased at high and low lung volumes. Clinically, this may be important because extremes in ventilation that result in hyperinflation or underinflation of the lungs increase PVR. 203

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The distribution of blood flow in the pulmonary circulation is influenced by the relationship among alveolar, pulmonary arterial, and pulmonary venous pressures. Blood flow increases significantly in the dependent areas of the lung. Ventilation is also greater in the dependent lung regions, especially during spontaneous ventilation, although the influence of gravity on ventilation is less than on blood flow. Ventilation and perfusion are normally well-matched; however, in certain diseases, lung units are relatively underor overventilated and result in ventilation/perfusion mismatching. There are many clinical implications that involve these relationships. For example, in patients with lung disease primarily in the dependent zones, the blood flow to the well-ventilated areas in the upper zones may be decreased if the PAP or CO is decreased like when pulmonary hypertension is treated. Also, in patients with unilateral disease, oxygenation may be improved by maintaining patients with the good lung in the dependent position.

Factors Affecting Pulmonary Vascular Resistance Oxygenation has a large influence on PVR with alveolar hypoxia being a potent vasoconstrictor. Small areas of alveolar hypoxia cause diversion of blood flow and minimal changes in PVR. In this situation, hypoxic pulmonary vasoconstriction (HPV) is a protective mechanism that improves ventilation/perfusion matching. This becomes important when treating pulmonary hypertension because all intravenous vasodilators inhibit HPV and may decrease PaO2. Larger areas of hypoxia produce proportionally greater increases in PVR. Acidosis is also a potent vasoconstrictor, whereas alkalosis vasodilates the pulmonary circulation.3 Hypercapnia and hypocapnia most likely alter PVR through their effects on pH, although hypercapnia itself may increase PVR. Atelectasis can increase PVR through stimulation of HPV and mechanical compression; therefore, the lungs should be adequately expanded in patients with pulmonary hypertension. Providing adequate oxygenation and treating acidosis (respiratory or metabolic) represents one of the most important and first-line treatments of pulmonary hypertension. Sympathetic stimulation, cold, and catecholamines are also important factors that increase PVR. α-1 adrenoreceptors and β-2 adrenoreceptors are the most clinically relevant receptors in the pulmonary vasculature. β-2 agonists decrease PVR, whereas α-1 agonists increase PVR. These receptors are less densely distributed compared with the systemic circulation so one would expect the effects of agonists to be decreased.4 Furthermore, the tone of the pulmonary circulation is normally low; therefore, β-2 stimulation normally has little effect; however, in the presence of pulmonary hypertension, β-2 agonists decrease PVR. α-1 agonists increase PVR but not to the same degree as the systemic vascular resistance (SVR) because there is relatively less vascular smooth muscle. β-2 receptors responsible for vasodilation are on the endothelium; therefore, their effect may be decreased in the presence of endothelial dysfunction.

Pulmonary Hypertension Pulmonary hypertension is classified by etiology and pathophysiology.5 Pulmonary hypertension most commonly observed in the perioperative period is caused by cardiac or pulmonary disease. Left ventricular failure, mitral valve disease, and decreased left ventricular compliance result in elevations in left atrial pressure. The increase in left atrial pressure passively increases the pulmonary venous pressure, PAP, and PVR.

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Congenital cardiac diseases that cause left to right shunting result in chronic increased pulmonary blood flow that eventually leads to an elevated PVR. Respiratory disorders such as chronic obstructive airway disease lead to pulmonary hypertension, at least in part, through hypoxia-induced vasoconstriction. Pulmonary hypertension may present as arterial hypertension in which the PAOP is normal (that is, respiratory diseases) or venous hypertension in which both the PAP and PAOP are elevated (that is, mitral valve disease). Pulmonary hypertension is a progressive disease, and the effectiveness of therapy is dependent on its state.6 Pulmonary hypertension may initially consist of vasoconstriction, which is easily reversible with vasodilator therapy. As pulmonary hypertension continues, vasoconstriction results in smooth muscle hypertrophy and narrowing of the vascular lumen. Reversal of smooth muscle hypertrophy is possible over weeks to months with vasodilator therapy. Further progression of the disease involves fibrosis and more fixed disease. Therapy at this point becomes difficult, and attempts to decrease PVR with vasodilators may only result in a decrease in SVR. Endothelial dysfunction may also lead to the loss of important vasodilating factors. The main focus of acute treatment of pulmonary hypertension is reversal of vasoconstriction.

Right Ventricular Anatomy, Physiology, and Failure The RV is a thin-walled crescent-shaped structure that is suited for volume work, in contrast to the thick-walled LV that is suited for pressure work. Thus, the RV is less preload-dependent than the LV and for any given increase in preload, a smaller increase in stroke work would be expected. Although the LV maintains a constant output over a relatively wide range of afterloads, RV function is more sensitive to changes in PAP. An acute increase in mean PAP above 40 mm Hg results in a decrease in RV ejection fraction even in the presence of normal RV contractility. In the presence of decreased RV contractility, the RV is even more sensitive to acute increases in afterload. On the other hand, more gradual changes in PAP may allow time for the RV to hypertrophy and sustain a relatively normal output. Coronary blood flow to the RV occurs throughout systole and diastole because of the continuous pressure gradient (coronary perfusion pressure) between the aorta and the RV. The RV blood/oxygen supply is proportional to the systemic pressure and inversely proportional to the RV pressure. Systemic hypotension (or attempts to treat pulmonary or systemic hypertension) or increased RV pressure may result in decreased RV coronary perfusion pressure. RV oxygen demand is a function of RV pressure, RV volume, and heart rate. Hence, increased RV pressure not only decreases RV oxygen supply, but also increases oxygen demand. Therefore, decreasing PAP with the use of vasodilators to decrease RV pressure is critically important in treating pulmonary hypertension and RV failure. At the same time, it is very important to avoid decreasing systemic pressure and coronary perfusion pressure.

Right Ventricular Failure RV failure may be caused by 1) RV ischemia and infarction, 2) acute or chronic pressure overload, or 3) acute or chronic volume overload from tricuspid regurgitation and atrial septal defects.7 Although angina generally occurs because of LV ischemia, ischemia may also arise from a decrease in RV coronary blood flow or increased RV oxygen

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demand. RV ischemia may also result from inadequate myocardial protection during cardiopulmonary bypass (CPB). Pressure or volume overload of the RV is sometimes well-tolerated for years before symptoms and signs of RV failure, including an elevated central venous pressure (CVP), become evident. In the presence of a chronic buildup of pulmonary hypertension, the RV may hypertrophy and be able to generate systemic pressures. Nevertheless, pulmonary hypertension eventually leads to RV dilation, decreased RV ejection fraction/stroke volume, and decreased global cardiac function. The most common symptoms that occur as a result of pulmonary hypertension and RV failure are dyspnea, fatigue, reduced exercise tolerance, syncope, chest pain, and peripheral edema. Electrocardiographic changes may be consistent with RV enlargement or RV ischemia. Signs of pulmonary hypertension and RV failure may include tachypnea and tachycardia with neck vein distension. RV lifts may be palpated and tricuspid regurgitation auscultated. RV failure may be diagnosed on echocardiography by RV dilation, decreased movement of the RV free wall and/or septum, and tricuspid regurgitation. The CVP, which is normally less than 5 mm Hg, may increase to 20 mm Hg or higher in the presence of RV failure. Pulmonary hypertension and RV failure can alter LV function.8 Interdependence between the ventricles occurs in the presence of increased PVR and RV end-diastolic volume and pressure such that the intraventricular septum shifts toward the LV cavity. Consequently, RV failure may decrease LV filling, increase PAOP, and decrease LV output. In this situation, echocardiography shows a dilated RV and the septal curvature, which is normally to the right, is flattened. RV dilation also may cause an increase in intrapericardial pressure that decreases LV distensibility. RV failure may significantly impair global cardiac performance and CO from either RV failure itself or by impacting LV function.

Therapy for Pulmonary Hypertension and/or Right Ventricle Failure The biggest predictor of outcome in patients with pulmonary hypertension is the presence of RV failure. Therefore, it is important to know if the patient has RV failure, pulmonary hypertension, or both. Treatment of patients with pulmonary hypertension without RV failure consists primarily of the use of vasodilators. In contrast, patients with RV failure without pulmonary hypertension may be treated primarily with inotropic agents and possibly diuretics or vasoconstrictors. Patients with pulmonary hypertension and RV failure may require both vasodilators and inotropic agents. Treatment of pulmonary hypertension and/or RV failure is based on the understanding of the impact of each on the pulmonary and systemic circulation. Pulmonary hypertension increases RV afterload, which may increase RV pressure and volume while decreasing RV ejection fraction and stroke volume. This may cause a shift of the intraventricular septum, increase pericardial pressure and PAOP, and decrease CO. Increased RV volume and pressure may also decrease coronary blood flow and worsen RV ischemia and RV failure, which will further impact on CO. A decrease in CO may cause a metabolic acidosis and worsen pulmonary hypertension. Treatment of pulmonary hypertension may include vasodilators to decrease PVR, inotropic agents to improve RV function, optimizing ventricular volume, and correction of acid base and/or oxygenation status (Table 1). PVR should be decreased based on the understanding of active and passive factors that alter the pulmonary circulation. Patients with chronic pulmonary hypertension

PULMONARY HYPERTENSION AND RV FAILURE TABLE 1.

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Fundamental Treatment Modalities of Pulmonary Hypertension/Right Ventricle Failure

Basic Physiology Volume Vasodilators (intravenous and inhaled) Inotropic agents Inodilators Vasoconstrictors

may already be on therapy that includes an alpha-adrenergic antagonist, calcium channel blockers, and prostacyclin.9 These medications should be continued, whereas it must be recognized that these therapies modify the effects of inotropic agents and vasodilators that may be added in the perioperative period. Anesthetic choices may also be important in patients with pulmonary hypertension. Nitrous oxide and ketamine may increase PVR in patients with preexisting pulmonary hypertension,10,11 although neither of these anesthetics appears to increase PVR in pediatric patients. Clinically, it may be important to avoid these agents in patients with pulmonary hypertension. Volatile anesthetics, which depress myocardial contractility, should be used sparingly in patients with severe RV failure. In patients undergoing extremity procedures, regional or peripheral blocks may be ideal if preload and afterload can be maintained. Volume loading will increase RV output in the absence of pulmonary hypertension if RV contractility is normal. Increasing preload may increase RV ejection fraction and stoke volume, particularly if the CVP is below 10 mm Hg. However, if decreased contractility and pulmonary hypertension accompany RV failure, volume loading may be detrimental. In this situation, volume loading may cause RV dilation and result in a decrease in LV volume and CO. This is particularly true once the CVP reaches approximately 20 mm Hg. The most appropriate action is to assess the effects of volume loading by measuring the CO and evaluating RV and LV function by echocardiography. In the presence of RV volume overload, diuretic therapy may be beneficial in improving RV function. Vasodilator therapy with nitroglycerin or sodium nitroprusside is useful in patients with isolated pulmonary hypertension and in patients with combined pulmonary hypertension and RV failure.12 Nitroglycerin not only decreases PVR, but also has the added advantage over sodium nitroprusside in that it improves coronary blood flow to ischemic myocardium. Prostaglandin E1 and prostacyclin PGI2 are also potent vasodilators, and the ability of these agents to vasodilate the pulmonary vasculature and improve RV function has been demonstrated in cardiac surgical patients.13 All of the intravenous vasodilators used to treat pulmonary hypertension are not selective for the pulmonary circulation and, therefore, may decrease systemic pressure. Decreasing systemic pressure results in decreased coronary perfusion pressure and may worsen RV ischemia. The degree to which intravenous vasodilators may preferentially vasodilate the pulmonary circulation depends on the PVR/SVR ratio, that is, if the PVR is elevated more than the SVR, intravenous agents such as nitroglycerin may produce relatively more pulmonary vasodilation than systemic vasodilation.12 The decrease in systemic pressure secondary to vasodilators may also be minimized if RV afterload reduction results in an increase in RV output and CO. If vasodilators decrease PVR, and the decrease in PVR results in increased RV output, then CO may be increased. This

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may limit the decrease or actually increase systemic pressure. In contrast, if pulmonary vasodilation does not improve RV function, a decrease in systemic pressure may not be avoided. Therefore, in determining the potential benefits of intravenous vasodilators, it is important to evaluate the effects of the vasodilator on RV function and CO (Fig. 1). The phosphodiesterase III (PDE) inhibitors may be useful in the presence of increased PVR and decreased RV contractility because they are vasodilators with a weak positive inotropic effect, hence the term inodilator. Both milrinone and amrinone have been shown to cause pulmonary vasodilation in addition to increasing CO, and hence they may be useful for RV failure and pulmonary hypertension.14 Milrinone, like other vasodilators, is not specific to the pulmonary circulation and may cause systemic hypotension; however, the PVR may be preferentially decreased in the presence of high PVR/SVR ratio.15 PDE inhibitors are also beneficial in patients with severely decreased myocardial contractility because the effects of these drugs potentiate the effects of beta-adrenergic agonists. PDE inhibitors inhibit the breakdown of 3′, 5′ cyclic adenosine monophosphate (cAMP). In contrast, beta-agonists used for inotropic support stimulate adenylate cyclase to increase cAMP; hence, prevention of breakdown of cAMP by PDE inhibitors enhances the effects of inotropic agents. Milrinone not only enhances the inotropic effects of epinephrine and norepinephrine, but causes vasodilation of the pulmonary circulation. In the presence of decreased RV contractility, inotropic agents and/or vasodilators will be needed. If the primary etiology for the RV failure is decreased contractility, virtually all β-1-adrenergic agonists will be effective. Many studies have demonstrated that epinephrine, norepinephrine, dobutamine, isoproterenol, and dopamine may be beneficial in managing RV failure secondary to decreased contractility.16 The particular agent of choice may depend on the severity of myocardial dysfunction. In the presence of mildly decreased RV contractility, dopamine or dobutamine may be appropriate. Of the two, dobutamine may be better than dopamine in treating patients with pulmonary hypertension and RV failure because it lacks α-1-adrenergic agonist effects and the subsequent increase in PVR.16 Isoproterenol may also be used because it has positive inotropic effects and it vasodilates the pulmonary circulation; however, its usefulness is limited by its profound tachycardic effect. More severely decreased RV contractility may require treatment with more potent adrenergic agonists such as epinephrine or

FIG. 1. Effect of intravenous vasodilators on right ventricular function and cardiac output. AoP = aortic pressure; PAP = pulmonary artery pressure; CO = cardiac output; PVR = pulmonary vascular resistance.


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norepinephrine. In the presence of systemic hypotension, norepinephrine may be an appropriate choice because it not only provides inotropic support, but it may also increase RV coronary perfusion pressure through its relatively potent α-1-adrenergic effects in comparison to its β-2-vasodilating effects. Pure alpha-adrenergic agonists may also be useful in RV failure, because they increase coronary perfusion pressure, and thus may reverse RV ischemia and improve contractility.17 However, it is important to realize that all α-1 agonists may increase PVR. In an attempt to decrease PVR and increase CO, all inotropic agents can be used in combination with vasodilators. The precise combination will depend on the degree of inotropic support and vasodilation required. Pulmonary hypertension with mild RV dysfunction may be treated with dobutamine, or combinations of dopamine or dobutamine plus nitroglycerin. Milrinone alone may be useful, but the primary use of milrinone may be to potentiate the inotropic effects epinephrine or norepinephrine while adding pulmonary vasodilation (Table 2). An intraaortic balloon pump may augment CO and subsequently decrease PVR. Right ventricular assist devices that use a mechanical pump to withdraw blood from the right atrium and return blood to the pulmonary artery have been demonstrated to reverse RV failure.

Inhaled Pulmonary Vasodilator Therapy The primary inhaled pulmonary vasodilators used clinically are nitric oxide (NO) and prostacyclin (PGI2). Inhaled vasodilators are selective to the pulmonary circulation, that is, they cause pulmonary vasodilation but not systemic vasodilation. Inhaled NO acts by diffusing from the alveoli into the pulmonary vascular smooth muscle to stimulate the production of cGMP and subsequently result in vasodilation. NO is prevented from producing downstream systemic vasodilation because it rapidly combines with hemoglobin. Inhaled PGI2 increases cAMP to cause vascular smooth muscle vasodilation but is hydrolyzed before producing systemic effects. Inhaled vasodilators also have the potential to increase PaO2 in patients with ventilation/perfusion abnormalities. Because these drugs are inhaled, vasodilation is limited to areas that are ventilated and hence, ventilation/perfusion abnormalities and shunt are potentially decreased. This effect of inhaled vasodilators on oxygenation is in sharp contrast to intravenous vasodilators, which vasodilate all lung areas and potentially worsen oxygenation. Inhaled NO and PGI2 have been demonstrated to selectively vasodilate the pulmonary circulation and/or improve RV function in pediatric and adult cardiac surgical patients, patients with acute respiratory distress syndrome, and in patients with persistent pulmonary hypertension of the newborn.18,19 Furthermore, numerous case reports have demonstrated that inhaled NO may be lifesaving in weaning patients from CPB who have pulmonary hypertension and RV failure. The primary advantage of inhaled vasodilators over intravenous vasodilators is that pulmonary vasodilation is not accompanied by systemic vasodilation and the resulting TABLE 2.

Combination Therapy: Pulmonary Hypertension/Right Ventricle Failure

Dobutamine/dopamine + nitroglycerin Milrinone NE/EPI + nitroglycerin NE/EPI/dobutamine + milrinone EPI = epinephrine; NE = norepinephrine.

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decrease in coronary perfusion pressure. Therefore, perhaps the greatest use of inhaled vasodilators is in patients with pulmonary hypertension and systemic hypotension or in patients in whom a decrease in systemic pressure would critically decrease coronary perfusion pressure. Inhaled NO and prostacyclin may also be useful in treating patients with pulmonary hypertension who are hypoxemic secondary to ventilation/ perfusion abnormalities. A number of inhaled agents in addition to NO and PGI2 have been demonstrated to be selective vasodilators.20 These include PGE1, NO donors, sodium nitroprusside, nitroglycerin, PDE inhibitors specific to cAMP or cGMP, and combinations of these. All have been shown to be effective and comparable to NO and PGI2. Although inhaled NO is delivered as a gas through a specialized delivery system, PGI2 and the other agents are delivered as nebulized drugs. Most studies indicate that NO and PGI2 are equally effective in terms of decreasing PAP and PVR. Both potentially can cause rebound pulmonary hypertension because their prolonged use may downregulate endogenous vasodilators. NO can result in methemoglobinemia, although this effect is minimal with low-dose NO. NO2 formation in the airway is also a potential for toxicity but unlikely at low clinical, inhaled NO concentrations. Inhaled PGI2 may have toxic effects on the airway, but it has not been studied to the extent of NO. Both NO and PGI2 can increase bleeding because of platelet inhibition, although this is usually not clinically significant. The biggest difference between NO and PGI2 is the cost of NO is far greater (Fig. 2). There are important differences between the effects of intravenous and inhaled vasodilators. Intravenous vasodilators decrease PAP, CVP, PAOP, and systemic pressure. In contrast, inhaled vasodilators decrease PAP but have minimal effect on preload and systemic pressure (Fig. 3). If the desired effect is to decrease preload or systemic pressure, then intravenous agents may be a more appropriate choice. If a decrease in PAP without a decrease in systemic pressure is critically important in the treatment of pulmonary hypertension and RV failure, then inhaled agents are a more appropriate choice.

FIG. 2.

Inhaled NO compared with inhaled PGI2. NO = nitric oxide.


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FIG. 3. The effects of intravenous compared with inhaled vasodilators on right ventricular function. PAP = pulmonary artery pressure; PAOP = pulmonary artery occluded pressure; AoP = aortic pressure; CVP = central venous pressure.

References 1. Reeves JT, Rubin LJ: The pulmonary circulation: Snapshots and progress. Am J Respir Crit Care Med 1998; 157:S101–8. 2. Tuan Dinh-Xuan A, Higenbottam TW, Clelland CA, et al.: Impairment of endotheliumdependent pulmonary-artery relaxation in chronic obstructive lung disease. N Engl J Med 1991; 324:1539–47. 3. Marshall C, Lindgren L, Marshall BE: Metabolic and respiratory hydrogen ion effects on hypoxic pulmonary vasoconstriction. J Appl Physiol 1984; 57:545–50. 4. Hyman AL, Dempsey CW, Richardson DE, Lippton HL: Neural control. In: Crystal RG, West JB, Barnes PJ, Cherniack NS, Weibel ER, eds. The Lung: Scientific Foundations. New York: Raven Press; 1991:1087–102. 5. Blaise G, Langleben D, Hubert B: Pulmonary arterial hypertension: Pathophysiology and anesthetic approach. Anesthesiology 2003; 99:1415–32. 6. Voelkel NF, Tuder FM, Weir EK: Pathophysiology of primary pulmonary hypertension: From physiology to molecular mechanisms. In: Rubin LJ, Rich S, eds. Primary Pulmonary Hypertension. New York: Marcel Dekker; 1997:83–129. 7. Calvin JE Jr: Acute right-sided heart failure: Pathophysiology, recognition, and pharmacological management. Cardiothoracic and Vascular Anesthesia Update 1991; 2:1–13. 8. Bristow MR, Zisman LS, Lowest BD, et al.: The pressure-overloaded right ventricle in pulmonary hypertension. Chest 1998; 114:101S–6S. 9. Palevsky HI, Fishman AP: Chronic cor pulmonale: Etiology and management. JAMA 1990; 263:2347–53. 10. Schulte-Sasse U, Hess W, Tarnow J: Pulmonary vascular responses to nitrous oxide in patients with normal and high pulmonary vascular resistance. Anesthesiology 1982; 57:9–13.

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11. Gooding JM, Dimick AR, Tavakoli M, Corssen G: A physiologic analysis of cardiopulmonary responses to ketamine anesthesia in noncardiac patients. Anesth Analg 1977; 56:813–6. 12. Ziskind Z, Pohoryles L, Mohr R, et al.: The effect of low-dose intravenous nitroglycerin on pulmonary hypertension immediately after replacement of a stenotic mitral valve. Circulation 1985; 72:164–9. 13. D’Ambra MN, LaRaia PJ, Philbin DM, et al.: Prostaglandin E1—A new therapy for refractory right heart failure and pulmonary hypertension after mitral valve replacement. J Thorac Cardiovasc Surg 1985; 89:567–72. 14. Goldstein RA: Clinical effects of intravenous amrinone in patients with congestive heart failure. Am J Cardiol 1985; 56:B16–8. 15. Feneck RO and the European Milrinone Multicentre Trial Group: Intravenous milrinone following cardiac surgery; I. Effects of bolus infusion followed by variable dose maintenance infusion. J Cardiothoracic Vasc Anesth 1992; 6:554–62. 16. Calvin JE Jr: Inotropic therapy for the failed heart: Picking the right drug for the job. Cardiothoracic and Vascular Anesthesia Update 1991; 2:1–13. 17. Ferlinz J, Gorlin R, Cohn PF, et al.: Right ventricular performance in patients with coronary artery disease. Circulation 1975; 52:608–15. 18. Steudel W, Hurford WE, Zapol WM: Inhaled nitric oxide: Basic biology and clinical applications. Anesthesiology 1999; 91:1090–121. 19. Walmrath D, Schneider T, Schermuly R, et al.: Direct comparison of inhaled nitric oxide and aerosolized prostacyclin in acute respiratory distress syndrome. Am J Respir Crit Care Med 1996; 153:991–6. 20. Lowson SM: Inhaled alternatives to nitric oxide. Anesthesiology 2002; 96:1504–13.



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HEMATOLOGIC ASPECTS OF CARDIAC SURGERY LINDA SHORE-LESSERSON, M.D. ASSOCIATE PROFESSOR OF ANESTHESIOLOGY DIRECTOR, DIVISION OF CARDIOTHORACIC ANESTHESIOLOGY MT. SINAI MEDICAL CENTER NEW YORK, NEW YORK



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Hematologic Aspects of Cardiac Surgery Linda Shore-Lesserson, M.D. Associate Professor of Anesthesiology Director, Division of Cardiothoracic Anesthesiology Mt. Sinai Medical Center New York, New York

The hematologic management of the cardiac surgical patient entails a complex balance between extreme degrees of anticoagulation and the restoration of normal hemostasis after the procedure. These two opposing processes must be managed carefully and modified with respect to preoperative disease state, duration of cardiac surgery, use of extracorporeal circulation, and the desired hemostatic outcome. During cardiopulmonary bypass (CPB), optimal anticoagulation dictates that coagulation is minimized and platelets are kept quiescent so that microvascular clots do not form on the extracorporeal circuit. The frequent preoperative use of heparin has created a population of patients who are heparin-resistant. There is also a perceived increase in the incidence of heparin-induced thrombocytopenia (HIT). The management of this syndrome requires the use of alternative anticoagulant agents. After CPB, coagulation abnormalities, platelet dysfunction, and fibrinolysis occur and render the patient hemostatically impaired. Bleeding should be managed using careful hemostasis monitoring. Fibrinolysis can be prevented and transfusions minimized by the use of antifibrinolytic therapy. Uncontrolled hemorrhage has been anecdotally treated with success using activated factor VII, and this therapy has thus gained increasing popularity in postoperative hemorrhage. In off-pump cardiac surgery, activation of coagulation and inflammation occur early in the postoperative period, and the potential for hypercoagulation must be minimized. This complex hemostatic picture is coupled with the concurrent use of antithrombotic medication in the cardiovascular patient in both the preoperative and the postoperative periods. The frequent and prevalent use of antiplatelet medication is of great concern to the cardiovascular anesthesiologist because this therapy may cause increased bleeding after surgery and bleeding-related complications.

Extracorporeal Circulation It is well-accepted that bioincompatibility of the CPB circuit and blood trauma incurred as a result of the pump and cardiotomy suction are responsible for the disruption of homeostatic systems. The major three homeostatic systems affected are the coagulation, fibrinolytic, and inflammatory cascades. Efforts to reduce the activation of these systems can reduce morbidity and improve outcome. Coated circuits, either with heparin or other substances, have been demonstrated to reduce the inflammatory response to CPB.1,2 Markers of leukocyte activation and complement activation are lower when heparin-coated circuitry is used. Overt improvements in outcome are difficult to correlate with these plasma markers. There does seem to be a lower inci213

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dence of atrial fibrillation when heparin-coated circuits are used. Although Aldea et al. have been able to reduce bleeding using lower heparin doses and heparin-coated circuits, the potential risks of giving lower heparin doses have probably frightened most clinicians from adopting this practice.3–5 The use of cardiotomy suction is traumatic to blood cells, yet it is an integral part of most cardiac surgical procedures. Data support that when cardiotomy suction is avoided, platelet function is better protected and inflammatory markers are reduced. Neurologic outcomes have not been definitively shown to improve despite a reduction in cerebral embolic phenomenon.6 Activation of thrombin occurs during CPB. When thrombin is activated, anticoagulant proteases are released, and fibrin crosslinkage, fibrinolysis, and platelet activation occur. It should be evident then that prevention of thrombin activation should be a major goal of the management of CPB.7 Heparin alone is an inadequate method for deactivating thrombin. The following section describes the thrombin-inhibitor drugs and their use in cardiac surgery.

Heparin Resistance Patients on preoperative heparin therapy traditionally require larger heparin doses to achieve a given level of anticoagulation when that anticoagulation is measured by the activated clotting time (ACT). Presumably, this “heparin resistance” is the result of deficiencies in the level or activity of antithrombin III (ATIII).8 Other possible etiologies include enhanced factor VIII activity and platelet dysfunction causing a decrease in ACT response to heparin.9 Montes and Levy have shown that the in vitro addition of ATIII enhances the ACT response to heparin.10 Lemmer demonstrated that this heparin resistance, as measured by the ACT, does not correlate with preoperative ATIII levels.11 It is unclear that these patients have increased heparin requirements during CPB because the ideal ACT and monitoring techniques have yet to be elucidated.12 ATIII concentrate is now available and represents a reasonable method of treating patients with documented ATIII deficiency.

Heparin-Induced Thrombocytopenia The syndrome known as HIT develops in anywhere from 5% to 28% of patients receiving heparin. HIT is commonly categorized into two subtypes. HIT type I is characterized by a mild decrease in platelet count and is the result of the proaggregatory effects of heparin on platelets. HIT type II is considerably more severe, most often occurs after more than 5 days of heparin administration (average onset time, 9 days), and it is mediated by antibody binding to the complex formed between heparin and platelet factor 4 (PF4). Associated immune-mediated endothelial injury and complement activation cause platelets to adhere, aggregate, and form platelet clots, or “white clots.” Among patients developing HIT II, the incidence of thrombotic complications approximates 20%, which in turn may carry a mortality rate as high as 40%. Demonstration of heparin-induced proaggregation of platelets confirms the diagnosis of HIT type II. This can be accomplished with a heparin-induced serotonin release assay or a specific heparininduced platelet activation assay. A highly specific enzyme-linked immunosorbent assay for the heparin/PF4 complex has been developed and has been used to delineate the course of IgG and IgM antibody responses in patients exposed to unfractionated

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heparin during cardiac surgery. Bedside antibody tests are being developed that may speed the diagnosis of this condition. The risks and appropriate courses of action in patients with HIT II are unclear because the antibodies associated with HIT often become undetectable several weeks after discontinuing heparin. Also, the clinical syndrome does not always recur on reexposure to the drug and sometimes resolves despite continued drug therapy. Many patients never develop thrombosis and disseminated intravascular coagulation despite positive laboratory testing. Heparin-induced thrombocytopenia should be considered in the differential diagnosis of intraoperative heparin resistance in patients receiving preoperative heparin therapy. The options for treating these patients are few. If one has the luxury of being able to discontinue the heparin for a few weeks, the antibody will often disappear and allow a brief period of heparinization for CPB without complications.13,14 Changing the tissue source of heparin is no longer an option because most heparin is porcine. Some types of low-molecular-weight heparin (LMWH) have been given in HIT, but crossreactivity of the particular LMWH with the patient’s platelets should be confirmed in vitro. Supplementing heparin administration with pharmacologic platelet inhibition using prostacyclin, iloprost, aspirin, or aspirin and dipyridamole have been reported, all with favorable outcomes. Plasmapheresis may be used to reduce antibody levels. The use of heparin could be avoided altogether by anticoagulating with hirudin or bivalirudin.

Bivalirudin Bivalirudin is a small 20-amino acid molecule with a plasma half-life of 24 minutes. It is a synthetic derivative of hirudin and thus acts as a direct thrombin inhibitor. Bivalirudin binds to both the catalytic-binding site and the anion-binding exosite on fluid phase and clot-bound thrombin (Fig. 1). The part of the molecule that binds to thrombin is actually cleaved by thrombin itself, so the elimination of bivalirudin and cessation of its activity is independent of specific organ metabolism. Bivalirudin has been used successfully as an anticoagulant replacement for heparin therapy in interventional cardiology procedures. In fact, in interventional cardiology, bivalirudin has been associated with less bleeding and equivalent ischemic outcomes when compared with heparin plus a platelet inhibitor.15 This may be the result of bivalirudin being both an antithrombin anticoagulant and an antithrombin at the level of the platelet. Merry et al. showed equivalence with regard to bleeding outcomes and an improvement in graft flow after

FIG. 1. Structure and binding sites of bivalirudin. Note the molecule binds to thrombin at two binding sites: the catalytic site and the anion-binding exosite. (Figure courtesy of The Medicines Company, Parsipanny, NJ.)

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off-pump cardiac surgery when bivalirudin was used (0.75-mg/kg bolus, 1.75-mg/kg/hour infusion).16 Case reports confirm the safety of bivalirudin use during CPB,17 and current trials are underway. Monitoring of anticoagulant activity can be performed using the ecarin clotting time18 but this assay is not clinically available at present, and ACT levels 2.5 times baseline levels are recommended as safe. The ecarin clotting time has a closer correlation with anti-IIa activity and plasma drug levels than does the ACT. For this reason, standard ACT monitoring during antithrombin therapy is not yet recommended.

Antifibrinolytic Therapy Efficacy of Antifibrinolytic Activity When administered in the full Hammersmith regimen, aprotinin has been shown to reduce perioperative blood loss and transfusion requirements in patients undergoing primary and repeat cardiac surgery, in patients with endocarditis, and in those with aspirin pretreatment.19,20 “High dose” is 2 million kallikrein-inhibiting units (KIU) as a loading dose, 2 million KIU added to the pump-priming solution, and 500,000 KIU/hour as an infusion. Beneficial hemostatic effects have also been documented using “low-dose” aprotinin (half and quarter Hammersmith doses) and a single pump-prime dose. The use of aprotinin in “high” or “low” dose has been shown to be superior to placebo in reducing chest tube drainage, limiting transfusion requirements, and in creating a dry surgical field. The cost of “high-dose” aprotinin (approximately $1,000 per patient) has stimulated interest in the use of lower dose regimens and in the use of synthetic antifibrinolytic agents, which are considerably less expensive and potentially adequately efficacious in reducing transfusions. These agents are epsilon aminocaproic acid (EACA) and tranexamic acid (TA), which act as lysine analogs and attach to the lysine-binding sites of plasmin and plasminogen thereby preventing their activity. Plasmin and fibrin degradation products have adverse effects on platelet function and are associated with hydrolysis of the platelet GPIb receptor. Plasmin inhibition may therefore contribute to some form of indirect platelet protection; however, the major mechanism whereby these agents reduce bleeding in cardiac surgery is through direct inhibition of fibrinolysis. Standard dose regimens include 150 mg/kg EACA followed by 15 mg/kg per hour, although other dose schedules have been used successfully (10 g × three doses). TA has a wide variation in dosing applications. Some investigators have administered large doses of 5 to 10 g and have shown efficacy without adverse sequelae.21 Horrow studied the dose response of TA and found 10 mg/kg followed by 1 mg/kg per hour to be the minimum effective dose.22 Comparison of the synthetic antifibrinolytic agents with placebo indicate that they effectively attenuate markers of fibrinolysis and have blood-sparing properties that are most apparent during higher risk surgical procedures. When the synthetic agents are compared, aprotinin reduces blood loss to a greater degree; however, differences in transfusion requirements are much more difficult to elicit. Multiple metaanalyses have been published that confirm the overall statement that each class of drug reduces chest tube drainage.23–25 Aprotinin has been shown to reduce reoperations for bleeding, specifically in high-risk patients.

Antiinflammatory Activity of Antifibrinolytic Therapy The “whole-body inflammatory response” to CPB is a constellation of cascades that become activated as a result of contact of blood with the nonendothelial surfaces of the extracorporeal circuit. The activated cascades include the coagulation system, the fibrinolytic system, and the complement cascade. This is marked by an increase in


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cytokine levels and leukocyte activation markers. Cytokines that increase during the systemic inflammatory response include tumor necrosis factor alpha, interleukin (IL)-1, IL-6, IL-8, and others. Antiinflammatory cytokines decrease during CPB. Leukocyte activation markers and cytokine levels are increased after CPB and remain so for up to 24 hours postoperatively. Many technologic and pharmacologic interventions have been investigated for their abilities to reduce the inflammatory response to CPB. Pharmacologic interventions are also widely used as antiinflammatory measures. Steroids are well-known for their antiinflammatory effects. Concerns of increased risk of infection caused a reduction in the use of steroids in the last decade, but recent interest in attenuating the inflammatory response has caused a renewed interest in their use. As a result of aprotinin’s antikallikrein activity, the use of high-dose aprotinin attenuates the inflammatory response to CPB, and minimizes elevations of IL-6 and leukocyte elastase. In a randomized, prospective study in 20 patients, aprotinin therapy reduced airway NO production and reduced the in vitro expression of mRNA for NO synthesis.26 Aprotinin has also been shown to increase the concentration of the antiinflammatory cytokine IL-10. Hill et al. elegantly demonstrated that these antiinflammatory effects are not achieved with the synthetic antifibrinolytic agents. Antiinflammatory effects of aprotinin are achieved at concentrations greater than 200 to 400 KIU/mL. These plasma levels are reliably obtained after treatment with the high-dose regimen. Clinical studies comparing the antiinflammatory potency of highdose aprotinin with that of methylprednisolone reveal comparable degrees of attenuated inflammatory markers.27 In dogs, a randomized comparison of aprotinin versus placebo was undertaken in a coronary occlusion and reperfusion model. Animals who received high-dose aprotinin demonstrated preserved regional myocardial contractility and systolic shortening compared with placebo. The mechanism of this protection was not studied but was postulated as an antiinflammatory effect.28 Outcome has been shown to be significantly improved by aprotinin therapy in the pediatric population.29 Whether this is a result of an attenuation of the inflammatory response or just a result of reduced transfusions has yet to be determined. A study in cardiac reoperations revealed a reduced incidence of stroke in patients receiving highdose aprotinin.30 The reduction in stroke has been documented in other observational studies and may represent a long-term cost savings.31 There is currently no large-scale randomized study powered to look at stroke outcomes using aprotinin.

Thrombotic Complications of Antifibrinolytic Therapy Agents that promote hemostasis impose the theoretical risk of thrombotic complications. Although reports and case studies exist that document thrombotic complications of these agents, the documentation is largely anecdotal and fails to account for other preexisting thrombosis risks such as factor V Leiden.32 The incidence of stroke after cardiac surgery does not appear to have increased since the widespread pervasive use of EACA at a single large institution.33 Thrombosis is less likely to occur using high-dose aprotinin therapy because plasma levels are achieved that cause kallikrein inhibition, which induces a mild anticoagulant effect. Nevertheless, an increased incidence of myocardial infarction (MI), which was corroborated by intracoronary thromboses seen on autopsy evaluation, was found in patients undergoing cardiac reoperation.34 However, these study patients were likely to have received subtherapeutic heparin doses as a result of prolongation of the celite–ACT measurements when aprotinin is used. Because the celite ACT is synergistically prolonged in the presence of aprotinin and heparin, it is necessary to maintain celite ACT >800 seconds or to use another method of anticoagulation monitoring (kaolin

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ACT, heparin concentration, high-dose thrombin time). In a prospective multinational study, graft patency and MI rates were compared in placebo and aprotinin therapy groups. There was no difference in the incidence of MI between groups; however, there was a slight increased risk of graft nonpatency in the aprotinin group, which disappeared when the data were adjusted for surgical risk factors.35 Evidence is strong that antifibrinolytic agents decrease bleeding and even transfusions associated with cardiac surgery. A careful risk–benefit analysis looking for causes of hypercoagulability and a careful cost–benefit analysis should be performed before choosing one of these agents for cardiac surgery.

Activated Factor VII Recombinant factor VIIa (NovoSeven, Novo Nordisk, Denmark) has been reported to be effective in restoring hemostasis that results from severe hemorrhagic complications after CPB. Originally, this drug was prescribed for patients with specific factor deficiencies such as hemophilia A with and without inhibitors. The principle on which recombinant factor VIIa induces hemostasis is that it acts directly at the site of bleeding by binding to locally expressed tissue factor. This activated factor VII then activates factor X of the common coagulation pathway and factor IX of the intrinsic coagulation pathway. Thrombin generation is enhanced but without systemic activation of coagulation. This is the reason that hypercoagulability and thrombotic occurrences are rare.36 Another potential mechanism of activity is that recombinant factor VIIa acts independently of tissue factor and enhances platelet function through a different mechanism. Occasional case reports indicate that in severe uncontrolled hemorrhage, after other possible therapeutic modalities were exhausted, recombinant factor VIIa was effective in attenuating bleeding after CPB and in other surgical settings.37,38

Off-pump Cardiac Surgery The ability to perform coronary artery bypass grafting (CABG) without the use of CPB holds many potential hemostatic advantages. Lack of exposure to extracorporeal circulation minimizes the systemic inflammatory response, hemostatic defects, and thromboembolic risks that result from conventional CABG using CPB. Additional benefits include the potential for lowered costs as a result of decreased perioperative bleeding, reduced need for transfusion, rapid patient recovery, and early extubation.39 A survey sent to 800 cardiac surgeons in Canada and the United States demonstrates that there is still considerable variability in heparin management, protamine reversal, and the use of antiplatelet therapy in off-pump coronary artery surgery.40 The coagulation changes that occur after off-pump cardiac surgery are similar to those that occur after surgery performed using CPB. They include platelet hyperactivity, increased microvascular coagulation, and increased fibrinolysis.41 These alterations in coagulation indices occur immediately postoperatively in patients exposed to CPB and occur on the fourth postoperative day in off-pump patients.42

Antiplatelet Medication Aspirin remains the most commonly used antiplatelet agent. It acts by inhibiting cyclooxygenase, which inhibits formation of thromboxane A2 (TXA2)—a potent platelet agonist. Although calcium entry and the resultant aggregation are prevented,


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platelets can still respond to exogenous thromboxane analogs or an aggregatory stimulus that uses another pathway. The glycoprotein IIb/IIIa (GPIIb/IIIa) receptor is responsible for mediating platelet– platelet aggregation through fibrinogen bridging. Abciximab (Reopro; Eli Lilly, Indianapolis, IN), eptifibatide (Integrelin; Millenium and Schering Corporation, Kenilworth, NJ), and tirofiban (Aggrastat; Merck, Whitehouse Station, NJ) inhibit this receptor in a reversible or an irreversible fashion and are potent inhibitors of platelet aggregation. Clinically, they are infused to prevent thrombus formation in patients who have undergone a high-risk coronary interventional procedure. The results of large-scale multicenter studies show that rethrombosis and infarction rates after percutaneous angioplasty and stent procedures are reduced with the use of these drugs.43 Reduced mortality and reinfarction rates have been shown in diabetic patients and those with prior cardiac surgery, respectively.44,45 Antiplatelet therapy has advanced rapidly as a result of the introduction of the thienopyridine derivatives ticlopidine (Ticlid; Roche, Nutley, NJ) and clopidogrel (Plavix; Sanofi-Aventis, Bridgewater, NJ). These drugs act by noncompetitive antagonism at one of the platelet adenosine diphosphate (ADP) receptors—the P2Y12 receptor. Stimulation of this receptor by ADP or its analogs causes inhibition of adenylyl cyclase production, which potentiates platelet aggregation. Blockade of this receptor by ticlopidine or clopidogrel causes increased levels of adenylyl cyclase, elevated cyclic adenosine monophosphate levels, and hence a profound and rapid disaggregation (Fig. 2).46 The use of ticlopidine has generally been replaced by clopidogrel as a result of the lesser occurrence of side effects with the latter drug. Clopidogrel is an inactive drug

FIG. 2. The platelet adenosine diphosphate (ADP)–receptor subtypes. P2X1, a calcium ion channel, is the major ADP receptor by which shape change, calcium influx, and platelet aggregation occur. Stimulation of the P2Y12 receptor causes reduced levels of cyclic adenosine monophosphate, which potentiates aggregation. Both P2Y receptors are G-protein linked receptors. The thienopyridine drugs, clopidogrel and ticlopidine, inhibit the P2Y12 receptor in a noncompetitive fashion and cause rapid deaggregation.

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that is metabolized in the liver to its active metabolite. The duration of antiplatelet activity is the lifespan of the platelet, because the P2Y12 receptor is permanently altered. The effects of clopidogrel plus aspirin are synergistic, and this might explain why cardiac surgical patients having received this combination of drugs seem to have excessive postoperative bleeding.47 Patients on these medications who then present for cardiac surgery are at increased risk for bleeding complications and have a documented increase in transfusions and reoperations for bleeding.48,49 Resistance to thienopyridine agents has been documented and can be predicted in patients with a high resting level of platelet reactivity.50 For this reason, specific platelet function monitoring could guide platelet transfusion therapy so that platelet transfusions are not given indiscriminately.51

Platelet Function Monitoring The following platelet function monitors have been studied in cardiac surgical patients for their ability to predict excessive bleeding. Thromboelastography52 and HemoStatus (Medtronic Inc., Minneapolis, MN)53 have been successfully used in transfusion algorithms. The Platelet Function Analyzer (PFA-100; Dade Behring, Dade, FL), Ultegra (Accumetrics, San Diego, CA), and the Clot Signature Analyzer (Xylum, Scarsdale, NY) have a high negative predictive value, but are not specific when positive for platelet dysfunction. Ultegra54 has been shown to be accurate and specific for measuring the effects of GPIIb/IIIa inhibitors. PlateletWorks (Helena Labs, Beaumont, TX) and the Ultegra55 have specific diagnostic abilities but have not been extensively evaluated after CPB. Modifications of thromboelastrography, Ultegra, and PlateletWorks are currently being evaluated for their ability to detect thienopyridine-induced platelet dysfunction.56 See Table 1 for a complete list of point-of-care platelet function monitors and their mechanisms of measurement.

TABLE 1.

Point-of-Care Platelet Function Tests

Instrument

Mechanism/Agonist

Clinical Use

Thromboelastograph (Haemoscope Inc., Skokie, IL) Sonoclot (Sienco Inc., Arvada, CO) Hemostatus

Viscoelastic/thrombin (native), ADP, aracidonic acid

Post-CPB, liver transplant, pediatric, obstetrics, drug efficacy

Viscoelastic/thrombin

Post-CPB, liver transplant

ACT reduction/PAF

PlateletWorks

Platelet count ratio/ADP, collagen In vitro bleeding time/ADP, epinephrine Agglutination/TRAP

Post-CPB, DDAVP, transfusion algorithm Post-CPB, drug therapy

PFA-100 Ultegra Clot Signature Analyzer Whole blood aggregometry

Shear-induced in vitro bleeding time/collagen Electrical impedance/many

VWD, congenital disorder, aspirin therapy, post-CPB GPIIbIIIa receptor blockade therapy Post-CPB, drug effects Post-CPB

ADP = adenosine diphosphate; CPB = cardiopulmonary bypass; ACT = activated clotting time; PAF = platelet activating factor; DDAVP = desmopressin; VWD = von Willebrand’s disease; TRAP = thrombin receptor agonist peptide; GP = glycoprotein.


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24. Levi M, Cromheecke ME, de Jonge E, et al.: Pharmacological strategies to decrease excessive blood loss in cardiac surgery: A meta-analysis of clinically relevant endpoints. Lancet 1999; 354:1940–7. 25. Munoz JJ, Birkmeyer NJ, Birkmeyer JD, O’Connor GT, Dacey LJ: Is epsilon–aminocaproic acid as effective as aprotinin in reducing bleeding with cardiac surgery?: a meta-analysis. Circulation 1999; 99:81–9. 26. Hill GE, Robbins RA: Aprotinin but not tranexamic acid inhibits cytokine-induced inducible nitric oxide synthase expression. Anesth Analg 1997; 84:1198–202. 27. Hill GE, Alonso A, Spurzem JR, Stammers AH, Robbins RA: Aprotinin and methylprednisolone equally blunt cardiopulmonary bypass-induced inflammation in humans. J Thorac Cardiovasc Surg 1995; 110:1658–62. 28. McCarthy RJ, Tuman KJ, O’Connor C, Ivankovich AD: Aprotinin pretreatment diminishes postischemic myocardial contractile dysfunction in dogs. Anesth Analg 1999; 89:1096–100. 29. D’Errico CC, Shayevitz JR, Martindale SJ, Mosca RS, Bove EL: The efficacy and cost of aprotinin in children undergoing reoperative open heart surgery. Anesth Analg 1996; 83:1193–9. 30. Levy JH, Pifarre R, Schaff HV, et al.: A multicenter, double-blind, placebo-controlled trial of aprotinin for reducing blood loss and the requirement for donor-blood transfusion in patients undergoing repeat coronary artery bypass grafting. Circulation 1995; 92:2236–44. 31. Smith PK, Datta SK, Muhlbaier LH, et al.: Cost analysis of aprotinin for coronary artery bypass patients: Analysis of the randomized trials. Ann Thorac Surg 2004; 77:635–42. 32. Fanashawe MP, Shore-Lesserson L, Reich DL: Two cases of fatal thrombosis after aminocaproic acid therapy and deep hypothermic circulatory arrest. Anesthesiology 2001; 95:1525–7. 33. Bennett-Guerrero E, Spillane WF, White WD, et al.: Epsilon-aminocaproic acid administration and stroke following coronary artery bypass graft surgery. Ann Thorac Surg 1999; 67:1283–7. 34. Cosgrove DMd, Heric B, Lytle BW, et al.: Aprotinin therapy for reoperative myocardial revascularization: A placebo-controlled study. Ann Thorac Surg 1992; 54:1031–6; discussion 1036–8. 35. Alderman EL, Levy JH, Rich JB, et al.: Analyses of coronary graft patency after aprotinin use: Results from the International Multicenter Aprotinin Graft Patency Experience (IMAGE) trial. J Thorac Cardiovasc Surg 1998; 116:716–30. 36. Dietrich W, Spannagl M: Caveat against the use of activated recombinant factor VII for intractable bleeding in cardiac surgery. Anesth Analg 2002; 94:1369–70. 37. Kovesi T, Royston D: Pharmacological approaches to reducing allogeneic blood exposure. Vox Sang 2003; 84:2–10. 38. Al Douri M, Shafi T, Al Khudairi D, et al.: Effect of the administration of recombinant activated factor VII (rFVIIa; NovoSeven) in the management of severe uncontrolled bleeding in patients undergoing heart valve replacement surgery. Blood Coagul Fibrinolysis 2000; 11(suppl 1):S121–7. 39. Puskas JD, Wright CE, Ronson RS, et al.: Clinical outcomes and angiographic patency in 125 consecutive off-pump coronary bypass patients. Heart Surg Forum 1999; 2:216–21. 40. D’Ancona G, Donias HW, Karamanoukian RL, Bergsland J, Karamanoukian HL: OPCAB therapy survey: Off-pump clopidogrel, aspirin or both therapy survey. Heart Surg Forum 2001; 4:354–8. 41. Mariani MA, Gu YJ, Boonstra PW, et al.: Procoagulant activity after off-pump coronary operation: Is the current anticoagulation adequate? Ann Thorac Surg 1999; 67:1370–5. 42. Lo B, Fijnheer R, Castigliego D, et al.: Activation of hemostasis after coronary artery bypass grafting with or without cardiopulmonary bypass. Anesth Analg 2004; 99:634–40. 43. Azar RR, McKay RG, Thompson PD, et al.: Abciximab in primary coronary angioplasty for acute myocardial infarction improves short- and medium-term outcomes. J Am Coll Cardiol 1998; 32:1996–2002. 44. Bhatt DL, Chew DP, Hirsch AT, et al.: Superiority of clopidogrel versus aspirin in patients with prior cardiac surgery. Circulation 2001; 103:363–8. 45. Bhatt DL, Topol EJ: Antiplatelet and anticoagulant therapy in the secondary prevention of ischemic heart disease. Med Clin North Am 2000; 84:163–79, ix. 46. Savi P, Pereillo JM, Uzabiaga MF, et al.: Identification and biological activity of the active metabolite of clopidogrel. Thromb Haemost 2000; 84:891–6. 47. Herbert JM, Dol F, Bernat A, et al.: The antiaggregating and antithrombotic activity of clopidogrel is potentiated by aspirin in several experimental models in the rabbit. Thromb Haemost 1998; 80:512–8.


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48. Yende S, Wunderink RG: Effect of clopidogrel on bleeding after coronary artery bypass surgery. Crit Care Med 2001; 29:2271–5. 49. Hongo RH, Ley J, Dick SE, Yee RR: The effect of clopidogrel in combination with aspirin when given before coronary artery bypass grafting. J Am Coll Cardiol 2002; 40:231–7. 50. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, et al.: Identification of low responders to 300-mg clopidogrel loading dose in patients undergoing coronary stenting. Thrombosis Res 2005; 115:101–8. 51. Merritt JC, Bhatt DL: The efficacy and safety of perioperative antiplatelet therapy. J Thromb Thrombolysis 2002; 13:97–103. 52. Shore-Lesserson L, Manspeizer HE, DePerio M, et al.: Thromboelastography-guided transfusion algorithm reduces transfusions in complex cardiac surgery. Anesth Analg 1999; 88:312–9. 53. Despotis GJ, Levine V, Saleem R, Spitznagel E, Joist JH: Use of point-of-care test in identification of patients who can benefit from desmopressin during cardiac surgery: a randomised controlled trial. Lancet 1999; 354:106–10. 54. Steinhubl SR, Talley JD, Braden GA, et al.: Point-of-care measured platelet inhibition correlates with a reduced risk of an adverse cardiac event after percutaneous coronary intervention: results of the GOLD (AU-Assessing Ultegra) multicenter study. Circulation 2001; 103:2572–8. 55. Smith JW, Steinhubl SR, Lincoff AM, et al.: Rapid platelet-function assay: An automated and quantitative cartridge-based method. Circulation 1999; 99:620–5. 56. Shore-Lesserson L, Fischer G, Sanders J, Mitchell-Bligen M, Stone M: Clopidogrel induces a platelet aggregation defect that is partially mitigated by ex-vivo addition of aprotinin. Anesthesiology 2004; 101:A–268.



CHAPTER 19

V O L U M E


CLINICAL MONITORING OF THE BRAIN AND SPINAL CORD TOD SLOAN, M.B.A., M.D., PH.D. DEPARTMENT OF ANESTHESIOLOGY UNIVERSITY OF COLORADO HEALTH SCIENCES CENTER DENVER, COLORADO



© 2005



Clinical Monitoring of the Brain and Spinal Cord Tod Sloan, M.B.A., M.D., Ph.D. Department of Anesthesiology University of Colorado Health Sciences Center Denver, Colorado

Electrophysiological monitoring of the central nervous system (CNS) has become a valuable adjunct, and in selected circumstances, a standard of care for surgical procedures in which neural injury can be reduced. Made possible by the inherent electrical properties of the human nervous system, electrophysiological monitoring can assess both structural and functional aspects of the neural pathways tested. These methods can be used when the patient is unable to cooperate (for example, traumatic coma) or is rendered unconscious (for example, anesthesia). Although limited to specific neural pathways of central and peripheral nervous system, these techniques have become an integral component of some surgeries in which their use provides a unique contribution to operative decision-making. This Refresher Course reviews the methods and applications of the electroencephalogram (EEG) and of sensory and motor-evoked potentials (SEP, MEP), and the anesthetic implications when these techniques are used.

Awake Testing Because electrophysiological methods are limited to specific neural pathways, they cannot assess the wide variety of neural function tested by awake examination. A good example is awake monitoring during cerebral surgery for resection of a seizure focus in which the “eloquent” areas of cortical function can be defined before seizure focus resection. Another good example is carotid endarterectomy conducted under regional block. In this situation, awake testing is more sensitive to blood flow reductions (25 mL per minute per 100 g) than when the EEG and SEP are affected (15 to 20 mL per minute per 100 g). With respect to the “wakeup” test in spinal surgery, advances in surgical methods (notably hardware techniques) have changed the period of neural risk in scoliosis surgery from one identifiable event (distraction) to multiple, potentially deleterious events (for example, sublaminar wires, multiple hooks, pedicle screws) such that a more continuous method of assessment is now desirable. There is currently controversy about whether a wakeup test alone is sufficient for monitoring these surgeries.1

The Electroencephalogram The EEG is the measurement of the spontaneous electrical activity of the brain as produced by inhibitory and excitatory postsynaptic potentials in the pyramidal layer of the cortex.2 The EEG is measured from electrode pairs on the scalp and represents comparative activity in the two cerebral regions immediately below the electrodes. A 225

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variety of methods have been used for monitoring, including raw and processed EEG. In general, a reduction in amplitude and frequency or asymmetric distribution of activity of the EEG over the head is consistent with ischemia. A large number of factors (including deepening anesthesia) can cause symmetric reduction in EEG activity as they alter synaptic function. EEG monitoring is particularly useful for the detection of electrical seizure activity and for detection of cortical ischemia. The EEG has therefore become indispensable for intraoperative mapping of seizure foci in preparation for cortical resection. Because the EEG changes during ischemia precede cell death, use of this monitor has been advocated during procedures interfering with the vascular supply of the brain (intracranial aneurysm clipping, arteriovenous malformation management, and carotid endarterectomy). In general, the EEG has decreased frequency and decreased amplitude with ischemia, and a variety of raw and processed EEG methods have been developed to detect these changes. Several excellent studies have indicated the value of the EEG in reducing cortical morbidity in carotid endarterectomy (CEA). Operative vascular shunting has associated risks, yet stroke risk can be reduced tenfold using selective shunting in CEA based on EEG monitoring.3 Advocates of monitoring in CEA suggest that EEG monitoring may be able to assist by the detection of major ischemia related to crossclamping, prompt the selective use of a shunt, detect an occluded shunt after it has been placed, assess cerebral tolerance to ischemia (that is, judge adequacy of collateral blood flow), and detect unexpected ischemia in other cerebral regions as a consequence of vertebral— basilar insufficiency from positioning or inadequacies in collateral flow through the Circle of Willis. However, the EEG’s value in reducing overall morbidity remains controversial because of studies in which it was not associated with a reduction in cortical injury. This latter failing may be related to the fact that many strokes are the result of postoperative occlusion by clot formation in the denuded carotid or the result of emboli of air or particulate matter during the case. Furthermore, the development of a stroke is dependent on the interaction of the degree of reduced cerebral blood flow and the time of the reduction; when blood flow is below the ischemic threshold the time to stroke is inversely related to the residual blood flow. Thus, patients with short crossclamp times (10 to 15 minutes), despite poor cerebral perfusion, have low ischemic stroke risk.

Electroencephalography and Anesthesia Although changes in the EEG have long been recognized as consequences of deepening anesthesia, the raw EEG patterns associated with anesthesia vary between drugs (Fig. 1).4,5 In the awake state, the EEG has high-frequency activity with substantial variability at and between locations on the brain. When deeply asleep, the EEG is flat in burst suppression or is predominantly low-frequency activity. In general, deepening the anesthetic is associated with 1) a reduction in the variability of the EEG; 2) a decrease in frequency content with the formation of a rhythmic activity in the 8- to 10-Hertz range that becomes progressively slower into burst suppression and finally a flat EEG; 3) an initial increase in amplitude as the rhythmic activity occurs and then a reduction in amplitude; and 4) a shift of the rhythmic activity from an occipital predominance to a frontal predominance. The degree of EEG suppression and the transition between these states varies between anesthetic agents.

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FIG. 1. Typical changes in the electroencephalogram (EEG) with anesthesia. With increasing depth of anesthesia, the EEG organizes into rhythmic waves in the 8- to 10-Hertz range. Increasing depth causes a reduction of amplitude and frequency until burst suppression and a flat EEG is produced. Reprinted with permission from Martin JT, et al.4

These patterns and the differences between drugs have challenged the development of methods of EEG processing for measuring the adequacy of sedation during general anesthesia. A variety of EEG processing techniques have identified some parameters that appear to correlate with sedation and are relatively drug-independent, showing promise of having a measure of our anesthetic drugs on the CNS for improved patient management.6 Presently, the full impact of these techniques on anesthetic management is evolving.

Evoked Potentials Evoked potentials are a measurement of the electrical potentials “evoked” by a stimulus and allow assessment of an otherwise silent neural tract by observing its reaction to the stimulus.7–9 Because the majority of these evoked electrical potentials are exceptionally small, digital signal averaging is used to resolve them from the much larger EEG and the electrocardiogram (ECG) activity. This method involves repeatedly stimulating the nervous system and measuring the response for a set window of time. The evoked response becomes apparent because the unwanted background activity is unrelated to the stimulus and averaged out. The peaks (and valleys) of the evoked response are thought to arise from specific neural generators (often more than one neural structure per peak) and therefore can be used to follow the response at various points along the stimulated tract. Like the EEG, anesthetic effect appears to be primarily related to the inhibition of synaptic transmission along the stimulated pathway. Selective application to surgical procedures has been successful with operative decision-making so as to reduce, but not eliminate, the risk of neural complications. The most commonly used evoked potentials are those produced by stimulation of the sensory system: sensory-evoked potentials (SSEP). Some practitioners feel that in many cases, the reduction in neural risk associated with monitoring offsets the added cost.

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Somatosensory-evoked Responses The electrophysiological sensory technique with the widest possible application is the SSEP. In this technique, a peripheral nerve (typically posterior tibial, common peroneal, ulnar, or median) is stimulated and the neural response measured. It is currently thought that the incoming volley of neural activity represents primarily the activity in the spinal pathway of proprioception and vibration (posterior columns) (Fig. 2).10 After ascending in the ipsilateral dorsal column, it has its first synapse at the cervicomedullary junction and ascends in lemniscal pathways to a second synapse in the thalamus. From there, it terminates in the cortex in multiple synapses in the gyrus between the sensory and motor strip. Perhaps the most common application of the SSEP is for monitoring during spinal corrective surgery. Several studies in spine surgery have shown that monitoring is predictive of neural outcome and can reduce neural morbidity in patients undergoing stabilization for spinal instability (trauma) or other pathology.11 The Scoliosis Research Society and the European Spinal Deformities Society reviewed the effectiveness of monitoring in more than 51,000 scoliosis cases.12 In their review, the incidence of neural injury was markedly reduced from similar procedures without monitoring. SSEP changes were observed in almost all patients who experienced a neural deficit; the occurrence of a neurologic deficit without SSEP warning (“false-negative”) was 0.63%. These societies concluded that “these results confirm the clinical efficacy of experienced SSEP spinal cord monitoring.” The Scoliosis Research Society developed a position statement that concludes that “neurophysiological monitoring can assist in the early detection of complications and possibly prevent postoperative morbidity in patients undergoing operations on the spine.” This made electrophysiological monitoring during scoliosis correction a standard of care. The SSEP can also be used for monitoring the viability of the pathways as they travel through the brainstem (for example, posterior fossa surgery) and cerebral cortex. A good example of SSEP use is the detection of cerebral ischemia in subarachnoid hemorrhage associated with intracranial aneurysm rupture, detection of the adequacy of collateral

FIG. 2. The trace shows a typical somatosensory evoked potential after stimulation of the median nerve at the wrist. This is coupled on the diagram with the anatomy of the somatosensory pathway thought to correspond to the peaks in the response. Reprinted with permission from Weiderholt WC, et al.10


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blood flow during temporary vessel clipping (that is, assess the cerebral tolerance to temporary occlusion), inadvertent vessel occlusion (improper clip application), safety of vessel sacrifice in arteriovenous malformations, tolerance to deliberate hypotension, and the detection of vasospasm. Evoked responses have also been used during neuroradiologic procedures such as intentional embolism of vessels (for example, arteriovenous malformation) or during streptokinase dissolution of occluding blood clots. Some individuals believe that the SSEP may be less useful than the EEG for the detection of cerebral ischemia because the SSEP can only assess the specific neural tract being stimulated. However, as opposed to the EEG, the SSEP can detect ischemia in subcortical regions of the neural tracts monitored. Evoked potentials have also been termed “indispensable” during craniotomy for localization of the sensory–motor strip where the primary cortical response is generated.13 One important limitation of the SSEP is the sensitivity of cortical responses to anesthesia. Because the major synaptic components of the pathway are in the cerebral cortex, depressant agents such as inhalational anesthetics may need to be limited for recording of cortical responses, whereas subcortical and peripheral responses are less affected. Fortunately, intravenous anesthetic agents have less effect such that responses can usually be recorded. Alternatively, monitoring techniques have been developed for stimulation or recording from the spinal cord, which are less susceptible to anesthetic effects. Epidural electrodes have become widely used, particularly in Japan and the United Kingdom where they can also be used for stimulation as well as recording.

Monitoring of the Peripheral Nervous System The SEP technique has also been considered “indispensable” for intraoperative evaluation and monitoring during surgical procedures of peripheral nerves and plexus regions.14 For example, the identity of residual function in damaged nerves (“neuroma in continuity”) and identification of a preganglionic or postganglionic injury of a plexus allows selective and focused repair. Evoked responses have also been used to detect sciatic nerve injury with hip procedures and positioning related nerve compromise. Another area of interest has been monitoring spinal roots during spinal disc surgery or vertebral pedicle screw placement. Monitoring of muscle activity from intentional or inadvertent mechanical stimulation of the nerve root has been advocated.15 This latter technique has also allowed monitoring of bladder and rectal sphincter innervation during cauda equina procedures. Finally, assessment of the peripheral nerve and spinal cord can be done using “reflex testing” in which the H and F reflex is assessed by peripheral nerve stimulation.16 Similar techniques can also be used for selective dorsal rhizotomy conducted to relieve leg spasticity in cerebral palsy in which troublesome dorsal rootlets are sectioned. These advantages of muscle recording have made continuous EMG commonplace during spinal surgery. Not surprising, neuromuscularblocking agents can obscure the responses as can anesthetic effects on synapses in the reflex pathways within the spinal cord. Controversy exists whether partial paralysis allows adequate motor function during some monitoring techniques in which muscle recordings are used to detect inadvertent nerve irritation.

Motor Tract Monitoring Techniques that include monitoring of spinal motor tracts have become popular because occasional unpredicted motor deficits occur with SSEP spine evaluation. Early techniques included stimulation of the spinal cord and recording from peripheral

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nerves or muscles. It is now thought that these techniques, although useful, stimulate both sensory and motor tracts such that the monitoring does not focus solely on the motor pathways. Pure motor tract monitoring is best accomplished using transcranial electrical or magnetic stimulation.17,18 The responses can be recorded in the spinal cord or as compound muscle action potentials (CMAPs). Because of U.S. Food and Drug Administration approval and studies showing safety,19 transcranial multipulse electrical motorevoked potential monitoring is becoming commonplace. Anesthetic effect at synapses in the motor cortex, and the spinal cord have made anesthesia a challenge with this technique and intravenous techniques have become commonplace.20,21 Limited, controlled muscle relaxation has been considered acceptable in some circumstances.21

Cranial Nerve Monitoring The most common monitoring application for posterior fossa surgery is to preserve facial nerve function and hearing because many of the procedures in the posterior fossa are for benign tumors, which may grow to large size (4 cm) that obscure or are intertwined with these cranial nerves. Because of the importance of facial nerve function, extensive experience is available with facial nerve monitoring (FNM).22 FNM is usually accomplished by recording muscle (EMG) responses in the orbicularis oris and orbicularis oculi (Fig. 3).7 Brief phasic “bursts” of EMG activity in these muscles are usually caused by mechanical stimulation of the facial nerve indicating to the surgeon that the nerve is in the immediate vicinity of the surgical field. More injurious stimuli can cause tonic or “train” activity (continuous, synchronous motor unit discharges in trains of neurotonic activity lasting up to several minutes), which are associated with nerve compression, traction, or ischemia suggesting nerve injury. The surgeon can also directly stimulate to locate the facial nerve or identify regions of nerve injury. Experience suggests that if the anatomic integrity of the nerve can be maintained by monitoring, eventual neural function is highly likely postoperatively. Several studies using FNM have demonstrated an improvement in facial nerve outcome in posterior fossa surgery.23,24 The case is sufficiently strong for maintenance of facial nerve integrity that a National Institutes of Health consensus panel has concluded, “the benefits of routine intraoperative monitoring of the facial nerve have been clearly established. This technique should be included in surgical therapy.”25 This has established FNM as a standard of care during surgery on vestibular schwannoma (acoustic neuroma). Monitoring frequently also includes recording EMG activity in the temporalis and masseter muscles to differentiate stimulation of the trigeminal nerve. Fortunately, the anesthetic implications for FNM are isolated to the restriction of neuromuscular-blocking agents.

Auditory Brainstem Responses A second widely used sensory evoked response is the auditory brainstem response (ABR; also referred to as brainstem auditory evoked response [BAER]). The ABR is produced by auditory stimulation and measured as a series of peaks produced by the brainstem pathways of hearing (Fig. 4).26 Cortical responses to auditory stimulation recorded over the auditory cortex (midlatency cortical AEP) can also be recorded. The brainstem responses are rather tolerant of anesthetics, including inhalational agents.


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FIG. 3. Location of electrodes for recording of facial nerve monitoring. Electrodes are usually placed in the orbicularis oculi and orbicularis oris. Additional electrodes are often also placed in other muscles on the face to monitor other cranial nerves. Reproduced with permission from Moller AR.7

The ABR is most frequently used for hearing preservation. The cochlear nerve has been termed one of the most fragile cranial nerves and is frequently involved in tumors of the posterior fossa. Many studies have shown an improvement in hearing outcome using ABR in vestibular schwannoma surgery.27–29 With large tumors, or some other tumor types or locations, the involvement of the cochlear nerve in the tumor makes hearing preservation more difficult. A variety of elegant variations of the ABR include stimulation and recording from the cochlear nerve or nucleus within the brainstem to assess components of the pathway. The ABR can also be used for monitoring brainstem viability during procedures for microvascular decompression for relief of hemifacial spasm and trigeminal neuralgia or glossopharyngeal neuralgia. It is also used in conjunction with procedures to relieve tinnitus and disabling positional vertigo, during decompression of space-occupying defects in the cerebellum, and for removal of cerebellar vascular malformations.

Other Cranial Nerves Monitoring of the sensory or motor component of other cranial nerves has been used extensively in surgery on the base of the skull, cavernous sinus, and surgery in

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FIG. 4. Anatomic correlation of the peaks of the auditory evoked response: I (extracranial c.n. VIII), II (DCN, dorsal cochlear nucleus), III (VCN, ventral cochlear nucleus), intravenous (SO, superior olivary complex), V (LL, lateral lemniscus), VI–VII (IC, inferior colliculus). Reprinted with permission from Moller AR and Jannetta PJ.26

the posterior fossa.7,23 Cranial nerves III–VII and IX–XII can be monitored by recording the muscle activity of innervated muscle similar to FNM (see Table 1). The anesthetic implications are similar to the other sensory monitoring techniques (that is, limited inhalational agents for cortical responses with less effect on subcortical responses and restrictions on neuromuscular-blocking agents when muscle EMG is recorded). Monitoring of the caudal cranial nerves (c.n. IX, X, XI, and XII) is important during resection of large brainstem lesions because injury may cause airway collapse and inadequate protection from aspiration of gastric contents. Of particular recent interest has been monitoring of the vagal innervation of the larynx through EMG recording of the vocalis muscle. This can be done using electrodes placed in the false vocal cords and has been advocated in resection of tumors of the lower brainstem, thyroidectomy, parathyroidectomy, and anterior cervical spine surgery.

Visual Evoked Responses Visual evoked potentials (VEPs) are monitored by flash stimulation of closed eyes with recording electrodes positioned over the occipital cortex. The classic monitoring

CLINICAL MONITORING OF THE BRAIN AND SPINAL CORD TABLE 1. II III IV V VI VII VIII IX X XI XII

Optic Oculomotor Trochlear Trigeminal Abducens Facial Auditory Glossopharyngeal Vagus Spinal accessory Hypoglossal

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Visual evoked potentials Inferior rectus (motor) Superior oblique (motor) Masseter, temporalis (motor) Lateral rectus (motor) FNM; orbicularis oculi, orbicularis oris (motor) ABR, BAER Posterior soft palate (stylopharyngeus) (motor) Vocal folds, special ETT, cricothyroid m. (motor) Sternocleidomastoid, trapezius (motor) Tongue, genioglossus (motor)

application is in procedures near the anterior visual pathways (such as transphenoidal pituitary tumor removal) or other procedures in which monitoring may allow identification of surgical encroachment on the optic pathways (such as during lesioning of the globus pallidus for Parkinson’s disease). Flash VEP is also hampered by poor correlation with useful vision and substantial anesthetic depression necessitating intravenous techniques with limited inhalational concentrations.30 Some authors have had better success using smaller stimulators made with contact lenses or scleral caps.

Other Techniques Similar recording techniques can be used from neural structures to identify the location of depth probes in preparation for lesioning. For example, placement of lesions in the thalamus or globus pallidus for Parkinson’s disease and other movement disorders can be assisted by recordings of spontaneous electrical activity from the tip of the lesion probe. Similarly, depth recordings have been used during lesioning for pain syndromes and dorsal root entry.

Conclusion Electrophysiological monitoring has become a valuable adjunct to the clinical neurologic examination, especially in circumstances in which the clinical examination is hampered by injury or medications that interfere with patient participation such as during surgery. Newer innovative techniques have allowed better operative decisionmaking during certain procedures in which neural morbidity may be reduced.

References 1. Sloan TB: Scoliosis surgery: Appropriate monitoring. Anesthesiol Clin North America 1997; 15:573–92. 2. Cooper R, Osselton JW, Shaw JC: EEG Technology. Boston: Butterworths; 1980. 3. Nuwer MR: Intraoperative electroencephalography. J Clin Neurophysiol 1993; 10:437–44. 4. Martin JT, Faulconer A Jr, Bickford RG, et al.: Electroencephalography in anesthesiology. Anesthesiology 1959; 20:360. 5. Sloan T: Anesthetic effects on electrophysiologic recordings. J Clin Neurophysiol 1998; 15:217–26.

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6. Rampil IJ: A primer for EEG signal processing in anesthesia. Anesthesiology 1998; 89: 980–1002. 7. Moller AR: Evoked Potentials in Intraoperative Monitoring. Baltimore: Williams & Wilkins; 1988. 8. Nuwer MR: Evoked Potential Monitoring in the Operating Room. New York: Raven Press; 1986. 9. Sloan T: Evoked potentials. In: Albin MS, ed. A Textbook of Neuroanesthesia With Neurosurgical and Neuroscience Perspectives. New York: McGraw-Hill; 1996:221–76. 10. Wiederholt WC, Meyer-Hardting E, Budnick B, McKeown KL: Stimulating and recording methods used in obtaining short latency somatosensory evoked potentials (SSEPs) in patients with central and peripheral neurologic disorders. Ann NY Acad Sci 1982; 388:349–58. 11. Meyer PR, Cotler HB, Gireesan GT: Operative neurological complications resulting from thoracic and lumbar spine internal fixation. J Clin Orthop 1988; 237:125–31. 12. Nuwer MR, Dawson EG, Carlson LG, et al.: Somatosensory evoked potential spinal cord monitoring reduces neurologic deficits after scoliosis surgery: Results of a large multicenter survey. Electroencephalogr Clin Neurophysiol 1995; 96:6–11. 13. Friedman WA: Somatosensory evoked potentials in neurosurgery. Clin Neurosurg 1988; 34:187–238. 14. Friedman WA, Grundy BL: Monitoring of sensory evoked potentials is highly reliable and helpful in the operating room. J Clin Monit 1987; 3:38–44. 15. Owen JH, Kostuik JP, Gornet M, et al.: The use of mechanically elicited electromyograms to protect nerve roots during surgery for spinal degeneration. Spine 1994; 19:1704–10. 16. Leppanen R, Maquire J, Wallace S, et al.: Intraoperative lower extremity reflex muscle activity as an adjunct to conventional somatosensory-evoked potentials and descending neurogenic monitoring in idiopathic scoliosis. Spine 1995; 20:1872–7. 17. Owen JH: Intraoperative stimulation of the spinal cord for prevention of spinal cord injury. Adv Neurol 1993; 63:271–88. 18. Day BL, Dressler D, et al.: Electric and magnetic stimulation of human motor cortex: Surface EMG and single motor unit responses. J Physiol 1990; 412:449–73. 19. MacDonald DB: Safety of intraoperative transcranial electrical stimulation motor evoked potential monitoring. J Clin Neurophysiol 2002; 19:416–29. 20. Taniguchi M, Cedzich C, Schramm J: Modification of cortical stimulation for motor evoked potentials under general anesthesia: Technical description. Neurosurgery 1993; 32:219–26. 21. Sloan T, Heyer E: Anesthesia for intraoperative neurophysiologic monitoring of the spinal cord. J Clin Neurophysiol 2002; 19:430–43. 22. Cheek JC: Posterior fossa intraoperative monitoring. J Clin Neurophysiol 1993; 10:412–24. 23. Yingling CD: Intraoperative monitoring of cranial nerves in skull base surgery. In: Jackler RK, Brackmann DE, eds. Neurotology. St. Louis: Mosby; 1994:967, 1002. 24. Apel DM, Marrero G, King J, Tolo VT, Bassett GS: Avoiding paraplegia during anterior spinal surgery. The role of somatosensory evoked potential monitoring with temporary occlusion of segmental spinal arteries. Spine 1991; 16(suppl):S365–70. 25. National Institutes of Health (NIH) Consensus Development Conference (held December 11–13, 1991). Consensus Statement 9, 1991. 26. Moller AR, Jannetta PJ: Neural generators of the brainstem auditory evoked potentials. In: Nodar RH, Barber C, eds. Evoked Potentials II: The Second International Evoked Potentials Symposium. Boston: Butterworth; 1984:137–44. 27. Harper CM, Harner SG, Slavit DH, et al.: Effect of BAEP monitoring on hearing preservation during acoustic neuroma resection. Neurology 1992; 42:1551–3. 28. Nadol JB Jr, Chiong CM, Ojemann RG, et al.: Preservation of hearing and facial nerve function in resection of acoustic neuroma. Laryngoscope 1992; 102:1153–8. 29. Fischer G, Fischer C, Remond J: Hearing preservation in acoustic neurinoma surgery. J Neurosurg 1992; 76:910–7. 30. Cedzich C, Schramm J: Monitoring of flash visual evoked potentials during neurosurgical operations. Int Anesthesiol Clin 1990; 28:165–9.



CHAPTER 20

V O L U M E


ANESTHESIA FOR CESAREAN DELIVERY LAWRENCE C. TSEN, M.D. ASSOCIATE PROFESSOR IN ANAESTHESIA HARVARD MEDICAL SCHOOL DEPARTMENT OF ANESTHESIOLOGY PERIOPERATIVE AND PAIN MEDICINE BRIGHAM & WOMEN’S HOSPITAL BOSTON, MASSACHUSETTS



© 2005



Anesthesia for Cesarean Delivery Lawrence C. Tsen, M.D. Associate Professor in Anaesthesia Harvard Medical School Department of Anesthesiology Perioperative and Pain Medicine Brigham & Women’s Hospital Boston, Massachusetts

BOSTON, MASSACHUSETTS Despair thy charm; And let the angel whom thou still hast serv’d Tell thee Macduff was from his mother’s womb Untimely ripp’d. — Shakespeare, MacBeth Act V: Scene 8 The origin of the procedure termed cesarean section predates the Roman Emperor Julius Cesar (100 BC), whose namesake is often invoked but who was most likely not born in this manner. Jacques Guillimeanu, in his book of midwifery in 1589, was the first person of record to use the word “cesarean” in connection with “section”; however, because their Latin equivalents (caesaru and seco) both imply cutting, cesarean “birth” or “delivery” may be the most appropriate description. Cesarean delivery is generally defined as a laparotomy (opening of the abdominal cavity through an anterior incision) plus a hysterotomy (an incision into the uterus) to remove a fetus. The high mortality rate associated with the procedure, mostly from hemorrhage and infection, continued into the 19th century and dissuaded most obstetricians from this mode of delivery. With improvements in obstetric, surgical, and anesthetic techniques, the safety and incidence of the procedure increased; over the past 2 decades, with the advent of fetal heart rate and tocodynameter monitoring, a reduction in breech and forceps-assisted deliveries, and a changing social and mediocolegal environment, cesarean deliveries now account for 25% to 30% of deliveries nationally and internationally (Fig. 1).1 Anesthesia-related maternal mortality, although declining during the last few decades, still accounts for 3% to 12% of maternal deaths with the majority associated with intubation, ventilation, and oxygenation failures during the provision or attempted provision of general anesthesia.

Prevention of Cesarean Delivery Anesthesiologists, and the techniques used for obstetric anesthesia and analgesia, can play a role in the prevention of cesarean delivery. Although the association between regional analgesia and the progress and outcome of labor is often the first relationship cited, the research and results generated have a number of confounders, are controversial, and deserve a completely separate discussion. A significant impact on reducing cesarean deliveries, however, can be made by providing adequate analgesia for 235

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FIG. 1. Incidence of cesarean deliveries, as a percentage of total deliveries, in the United States, 1945 to 2003.

forceps/vacuum deliveries, using nitroglycerin in cases of fetal entrapment (50 µg intravenous, waiting 40 to 50 seconds before delivery attempt), promoting the use of labor neuraxial techniques for multiple gestation births, and most dramatically, by encouraging the use of central neuraxial techniques for external cephalic version.

External Cephalic Version Occurring in approximately 3% to 5% of term pregnancies, breech fetal presentations can significantly alter obstetric and anesthetic management. External cephalic version (ECV) is a method by which manual external pressure is applied to the maternal abdomen to change the position of a fetus from a breech to cephalic presentation. The use of ECV has been associated with decreases in fetal and maternal morbidity and costs associated with a breech or operative delivery. Despite these advantages, ECVs represent an underused option, in part as a result of limited success rates; these success rates can be improved significantly by three variables that anesthesiologists can influence: the timing of anesthetic interventions, the coadministration of tocolytics, and the anesthetic techniques used. Timing. ECVs are usually performed around the 36th week of gestation to balance fetal movability versus viability should an immediate cesarean delivery be necessary. Because ECVs become increasingly difficult in later gestation as a result of the growth of the fetus and a decreasing ratio of amniotic fluid volume to fetal size, the importance of timing becomes apparent.

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Neuraxial analgesia is frequently requested for an ECV reattempt only after prior attempts have failed. The timing of this reattempt, often scheduled for a week or 2 later, could independently be responsible for lower success rates; the available literature appears to corroborate this hypothesis. When ECVs were reattempted with the addition of epidural anesthesia 1 to 3 weeks after the initial attempt (that is, at the 38th or 39th gestational week), lower success rates, that is, 39.7% (27 of 68)2 and 56% (nine of 16)3 have been observed. By contrast, when ECVs were reattempted with the addition of epidural analgesia immediately after an initial attempt at the 37th gestational week, success rates have been very high (89%).4 Encouraging an immediate ECV reattempt with the addition of a central neuraxial blockade is of value. Tocolytic Use Beta Agonists. Although the effect of uterine tocolytics such as the b-agonists terbutaline, salbutamol, and ritodrine on the success of ECV remains controversial, the current ECV practice bulletin published by the American College of Obstetricians and Gynecologists (ACOG)5 and a recent review of randomized and quasirandomized trials of ECV support their use.6 As an example, Fernandez et al.7 demonstrated a doubling of the success rate (52% versus 27%) with the use of a tocolytic agent versus a placebo. Of interest, ECV reattempts with anesthesia are often conducted without these potentially beneficial adjuvants.3,4 The use of tocolytic agents, even in the presence of neuraxial techniques, should be supported. Nitroglycerin. The recent use of nitroglycerin as a uterine relaxant has allowed for its consideration and demonstration as a successful adjuvant during ECV.8 In a recent study,4 uterine relaxation with terbutaline was augmented by nitroglycerin for ECV attempts conducted under neuraxial blockade; six of eight patients who received nitroglycerin in this setting had successful ECV attempts. No adverse effects were observed as a result of the nitroglycerin. Although the independent effect of nitroglycerin for uterine tocolysis in the setting of ECV deserves further investigation, as an adjuvant that anesthesiologists are familiar with, it appears to improve ECV success. Tocolytics with Neuraxial Anesthesia Techniques. The success of ECVs performed with tocolytics appears to be improved with the use of regional anesthesia. With all patients receiving tocolytics, Schorr et al.9 randomized patients to undergo attempted external version with or without an epidural (2% lidocaine with 1:200,000 epinephrine to a T6 sensory level). In 69 demographically and obstetrically similar parturients, the overall success rate of external version was higher in the epidural group (69% versus 32%), with more successful versions occurring on the first attempt. There were no cases of fetal distress or abruptio placentae in either group. Abdominal delivery was ultimately noted in 79% of the control group versus 34% in the epidural group. There are no completed reports comparing the success of ECV attempts with the independent use of a tocolytic agent versus an epidural or spinal anesthetic. Technique. Central neuraxial analgesic and anesthetic techniques most likely improve ECV success by relaxing the abdominal wall muscles, improving patient comfort during the ECV attempt, and allowing the obstetrician to provide a more concerted attempt. The relative safety and benefit of performing ECV attempts and reattempts with anesthetic techniques, in terms of fetal outcome, limited need for emergent operative deliveries, and cost–benefit analyses has been favorably recorded in studies using these techniques to date.7 Epidural Technique. The evidence cited above demonstrates the value of epidural anesthesia techniques for primary and repeat ECV attempts.

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Spinal Technique. The use of the spinal technique has been reported for ECV attempts and recently for reattempts. With primary attempts, analgesic doses were used with contrasting results. Dugoff et al.10 noted no improvement with the intrathecal administration of 2.5 mg bupivacaine with 10 µg sufentanil (44% and 42%), whereas Birnbach et al.11 noted a significant improvement (80% versus 33%) with the use of 10 µg sufentanil alone. Reasons for these contrasting outcomes may ultimately reflect differences in obstetric practice such as how much force is applied and/or how much maternal discomfort is tolerated for a given level of analgesia or anesthesia. As a consequence, whether ECV version success can be predictably produced with analgesic doses using spinal techniques or whether the results of such studies can be extrapolated to other practices will require further investigation. The findings of Birnbach11 validate the potential value of spinal techniques in both primary and reattempted ECVs. In a small retrospective analysis of spinal anesthesia (45 mg lidocaine with 10 µg fentanyl) a high success rate (83%) was noted with the use of spinal anesthesia in the setting of previously failed ECV attempts.4 Combined Spinal Technique. Whether used for primary or failed ECV attempts, a combined spinal epidural technique with a short-duration intrathecal local anesthetic may represent an optimal technique. The short anesthetic duration would allow for a timely discharge in the event of a successful version and should success or failure mandate a trial of labor or an operative delivery, particularly in the setting of an emergent cesarean delivery, the epidural catheter would allow additional analgesia or anesthesia to be administered potentially without the need for general anesthesia. ECVs done under neuraxial anesthesia can potentially increase maternal safety, reduce morbidity, decrease cesarean sections, and produce cost savings. Central neuraxial anesthetic techniques have been associated with increased success rates of primary and previously failed ECVs. Immediately reattempting ECVs with the addition of these techniques (or performing primary attempts with these techniques), providing uterine tocolysis including nitroglycerin, and using catheter-based neuraxial techniques are considerations that add value and success to ECV attempts.

Anesthesia for Cesarean Delivery The Practical Guidelines for Obstetrical Anesthesia12 from the American Society of Anesthesiologists Task Force on Obstetrical Anesthesia observe that cesarean delivery can be successfully managed with all conduction techniques (spinal, epidural, combined spinal/epidural [CSE]). The report also notes that general anesthesia may be associated with increased maternal mortality/morbidity as well as lower neonatal Apgar scores; these differences, however, in maternal and fetal outcomes after general versus regional anesthesia may be related in part to an observation bias. Thus, the use of any technique should consider specific case-by-case assessments of clinical, laboratory, anesthetic, and obstetric issues.

Is Regional Anesthesia the Preferred Technique? Complications related to anesthesia represent the sixth leading cause of peripartum maternal being mortality in the United States and abroad,13 with the risk of a maternal death being 16.7 times greater with general versus regional anesthesia.14 Almost all deaths associated with general anesthesia are related to problems with intubation and ventilation, which can be explained in part by the airway changes that occur over the course of pregnancy and labor. As such, a risk/benefit analysis for the use of general anesthesia


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should be strongly considered before its use. In an acknowledgment of the risks associated with general anesthesia, ACOG has accepted that “cesarean deliveries for a nonreassuring fetal heart rate pattern do not necessarily preclude the use of regional anesthesia.”15 Anesthesiologists, however, should be comfortable with their skills and treatment algorithms for the administration of general anesthesia to the parturient, because even when the philosophy and practice of a group aggressively favors regional anesthetic use, the need for general anesthesia arises. In a review of anesthetic techniques used for all cesarean sections at Brigham & Women’s hospital from 1990 to 1995, the use of general anesthesia was between 3.5% and 7.2% per year.16 A perceived lack of time or contraindications to regional anesthesia were responsible for 70% to 90% of the general anesthesia cases per year, an additional 6% to 24% were the result of failed regional techniques, and the remaining cases were the result of patient refusal. In parturients at high risk for cesarean delivery, and especially in those who have critically increased airway risks or contraindications to neuraxial techniques, advanced planning and communication with patients and obstetric colleagues can potentially limit the use of general anesthesia. The early placement and confirmation of an epidural catheter allows for its rapid extension for surgical anesthesia, even if not used for labor analgesia.

Should Newer Local Anesthetics Be Used? Potentially reduced recovery times and toxicity profiles have fostered a growing interest in the newer local anesthetics, ropivacaine and levobupivacaine. However, when compared with racemic bupivacaine, distinct advantages of the newer and more expensive solutions remain clinically unclear. Although the safety of ropivacaine for elective cesarean deliveries has been established,17 the conclusion that ropivacaine is less cardiotoxic than bupivacaine is based in part on an assumption of equipotency. However, ropivacaine has been consistently noted to be 40% less potent than bupivacaine when compared epidurally for labor analgesia,18 as well as intrathecally for surgical anesthesia.19 Because ropivacaine and bupivacaine toxicity may not be enhanced in pregnancy,20 cardiac toxicity should only occur when an unintentionally large intravascular dose of either drug is administered. Proper epidural administration of either drug, including attention to incremental dosing practices, total dose guidelines, and toxicity symptoms, should not result in toxic blood levels. In addition, although more rapid motor recovery after cesarean delivery has been reported with epidural ropivacaine (versus racemic bupivacaine at an equivalent concentration), this also may be the result of the differences in potency.21 Whereas ropivacaine represents a new chemical entity, levo (L) bupivacaine represents a single enantiomer of the racemic bupivacaine currently in use. Although a margin of safety has been demonstrated in terms of central nervous system and cardiac toxicity in animal studies,22 further study is needed to determine the magnitude of the difference. Clinical investigations appear to demonstrate that levobupivacaine offers similar blocking characteristics and complication profiles. Bader et al.,23 using 30 mL epidural L-bupivacaine 0.5% versus racemic bupivacaine 0.5% for elective cesarean deliveries, noted no differences in the block onset or resolution, and no significant differences in signal averaged electrocardiograms, complications, or maternal and/or fetal plasma pharmacokinetics. The equivocal advantage and the increased cost of L-bupivacaine have already appeared to determine its overall use. At this time, there appears to be no compelling advantage heralding the use of newer local anesthetics for cesarean delivery. The safety of the lower concentrations (0.5%) of bupivacaine currently in epidural use for cesarean deliveries, the availability and more common use of other epidural local anesthetics (chloroprocaine and lidocaine),

240

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and the greater attention to safe practices such as incremental dosing will most likely limit the use of ropivacaine and L-bupivacaine.

Should Lower Doses of Bupivacaine Be Used? In an attempt to obtain faster motor recovery and discharge times, increase maternal satisfaction, and potentially lower costs, the amount of local anesthetics has been reduced through dose reductions and/or the use of adjuvant medications. One method of overall dose reduction is the use of spinal versus epidural anesthesia. Riley et al.,24 in a retrospective study, demonstrated the advantage of spinal versus epidural anesthesia for elective cesarean deliveries in terms of time management, costs, charges, and complications (defined as failed blocks, intravascular injections, inadvertent dural punctures, postdural puncture headache [PDPH]). A second method of dose reduction is the use of lower total amounts of bupivacaine. In addition to the reduction in the concentration of epidural bupivacaine (from 0.75% to 0.5%) used for cesarean delivery, a reduction in the total dose of spinal bupivacaine has been proposed (Table 1). Although these data suggest that very low doses of spinal bupivacaine can be used for cesarean delivery, dosing within this range should consider the use of a CSE technique, because supplementation can be provided through the epidural catheter. Although the epidural catheter of a CSE is often “untested” (despite some clinicians using a small test dose of lidocaine 1.5% with epinephrine on placement), most studies indicate that the catheter is reliable should supplementation be necessary. Norris et al.,29 in a patient database review, noted lower failures rates (4% and 6%, respectively) with CSE (n = 183) versus epidural (n = 133) catheters initially placed for labor and later used for surgery. Albright et al.,30 in a clinical series, noted a significantly lower overall failure rate for CSE, versus epidural or spinal anesthesia alone, and Davies et al.31 prospectively observed lower anxiety and pain scores and higher maternal satisfaction with a CSE versus an epidural for cesarean delivery. Taken together, these reports suggest that CSE techniques are as reliable, and offer greater flexibility, than other central neuraxial alternatives for cesarean delivery.

Can Hypotension Be Prevented? The use of central neuraxial techniques for cesarean delivery has grown in large measure as a result of the overall maternal and fetal safety profiles. Maternal hypotension, however, frequently follows such techniques and, when severe and sustained, can lead to impairment of the uterine and intervillous blood flow, and result in fetal hypoxia, acidosis, and neonatal depression.32 Three interventions, including left uterine displacement,33 intravascular volume expansion,34,35 and vasopressor prophylaxis and treatment,36 have attempted to reduce the incidence of hypotension with variable success. Although the use of smaller spinal doses of local anesthetic is an intriguing hypothesis

TABLE 1.

Doses of Spinal Bupivacaine for Cesarean Delivery

Hyperbaric Bupivacaine Dose

Motor Recovery to T10 (minutes)

Notes

15 mg25 12 mg26 7.5–8.0 mg + 25 mg epidurally27 6.6 mg + 3.3 µg sufenta28

162.1 ± 33.8 140 ± 16.5 146 ± 43.9 110 ± 27 I; 92 ± 24 H

7/12 c-level 3/16 c-level CSE CSE

c-level = cervical vertebral level; CSE = combined spinal epidural technique; H = hyperbaric; I = isobaric.


241

for controlling hypotension, when comparisons are made, recognition must be given to the potential effects of fluid types and volumes and the vasopressors used; studies that more robustly assess individual variables will need to be conducted (Table 2).

Are There Valuable Adjuvant Medications? Adjuvant medications are used to express their own benefits and reduce the dose and side effects of local anesthetics. For cesarean delivery, a prolongation of postoperative analgesia and a reduction in motor blockade are pharmacologic goals. Aside from epinephrine and narcotics, neostigmine and clonidine are two agents undergoing clinical investigation. Interest in neostigmine followed animal studies demonstrating increased analgesia duration and a reduced incidence of hypotension when added intrathecally.38 When evaluated for elective cesarean delivery, the addition of neostigmine in spinal doses up to 100 µg significantly reduced postoperative pain with no effect on fetal heart rate tracings or Apgar scores,39 and equivocal alterations on the incidence of bradycardia and hypotension.40 Unfortunately, a high incidence of side effects, including prolonged motor blockade, nausea, and vomiting, has been observed with spinal doses as little as 6.25 µg41 and will most likely limit the clinical use of this medication. Currently, only a limited number of clinical studies exist that examine the use of clonidine for labor and postcesarean analgesia.42 With doses varying from 15 to 50 µg and 50 to 120 µg in spinal and epidural techniques, respectively, clonidine has demonstrated the ability to prolong analgesia and decrease shivering; however, mild hypotension and sedation have been witnessed as frequent side effects.43 Currently, clonidine has only one specific neuraxial indication (intractable cancer pain) and a “black box” U.S. Food and Drug Administration (FDA) warning that “epidural clonidine is not recommended for obstetrical, postpartum, and perioperative pain management.” The FDA warning mentions the unacceptability of hemodynamic instability risks. With a cost of approximately $50 for a 10 mL vial of clonidine, additional studies will need to more fully examine the clinical use and cost–benefit of this medication. Preservative-free morphine sulfate is perhaps the most popular adjuvant as a result of a postcesarean analgesia duration of 17 to 27 hours. Palmer et al. studied the dose response to the intrathecal44 and epidural45 use of morphine after cesarean delivery. Intrathecally, by comparing 0.0-, 0.025-, 0.05-, 0.1-, 0.2-, 0.3-, 0.4-, and 0.5-mg doses, a

TABLE 2.

Spinal Bupivacaine Dose and the Incidence of Hypotension in Patients Undergoing Cesarean Delivery

Study

Bupivacaine

Hypotension

Fluids

Vasopressors

LR 1000 mL preload LR 1000 mL preload; LR 500 mL postspinal LR 1000 mL preload; 6% starch 500 mL preload

10-mg ephedrine prophylaxis 15-mg ephedrine prophylaxis

Tsen et al.26

12 mg

70%

Sarvela et al.37

9 mg

58%

Vercauteren et al.28

6.6 mg + 3.3 µg sufenta

33%

LR = Lactated Ringers.

5-mg ephedrine prophylaxis

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dose of 0.1 mg was found to produce analgesia comparable to doses as high as 0.5 mg. Given free access to additional analgesics through patient-controlled analgesia, parturients were noted to self-administer low but constant amounts in all dose ranges above 0.075 mg morphine. In addition, the incidence of pruritus appeared doserelated, although this relationship was not found with nausea and vomiting. When given in the epidural space, a comparison of 1.25-, 2.5-, 3.75-, and 5-mg doses observed that the quality of postcesarean analgesia did not improve beyond 3.75 mg. In comparison to the intrathecal study, neither nausea and vomiting nor pruritus (beyond 1.25 mg) appeared dose-related.

Is There a Perfect Cocktail? An infinite number of medication combinations exist. However, based on the most recent evidence, there appears to be advantages in using the combinations noted in Table 3. Smaller doses of spinal bupivacaine may be used if the expected cesarean delivery duration is short or a CSE is administered. In the epidural space, lidocaine 2% offers a rapid-onset, dense block; both of these factors are enhanced with the use of 8.4% bicarbonate 1 mL per 10 mL of lidocaine.

Postoperative Bliss Pain, pruritus, nausea/vomiting, and postoperative shivering are four issues that complicate postoperative recovery. Pain is optimally handled with prophylaxis; neuraxial morphine administered intraoperatively provides very good analgesia of long duration. Should breakthrough pain occur, analgesia can be augmented with a nonsteroidal agent; Wilder-Smith et al. observed that the combination of an opioid and a nonsteroidal antiinflammatory drug was more effective for the provision of postoperative cesarean delivery analgesia and the prevention of pain sensitization than the two drugs given individually.47 Torodol has been listed as being compatible with breast feeding by the American Academy of Pediatrics and has been demonstrated to be effective for postcesarean delivery analgesia.48 Although pruritus after neuraxial blockade has a number of postulated mechanisms and treatments,49 a direct antagonist or partial antagonist such as 4 mg nalbuphine administered intravenously appears to have a greater effect than some other modalities.50 Nausea and emesis after cesarean delivery can be difficult to treat; recently, 50 mg cyclizine administered intravenously has been observed to be superior to 8 mg dexamethasone administered intravenous after intrathecal morphine for cesarean delivery.51 Finally, postoperative shivering can have a number of causes and treatments. Intravenous meperidine at a dose of 25 mg, 150 µg clonidine, 100 mg doxapram, 10 mg ketanserin, or 250 µg alfentanil have all been demonstrated to be effective, although meperidine appears to be the most consistently effective.52,53

TABLE 3. Medication Local anesthetic Fentanyl Morphine

Suggested Spinal and Epidural Medications for Cesarean Delivery Spinal Bupivacaine 9–12 mg (depending on technique) 15–35 µg46 0.1 mg

Epidural Lidocaine 2% + bicarbonate 50–100 µg 3.75 mg


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Conclusion The rapidly changing field of obstetric anesthesia has placed more emphasis on certain techniques and dosing regimens. By reflecting on and adopting many of these advances, fewer parturients undergoing cesarean delivery will hopefully comment: This was the most unkindest cut of all. —Shakespeare, Julius Caesar, Act III, v 2

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