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 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

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Anticoagulation and R egional Anes thes ia Lynn M. Broadman

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

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

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

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

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

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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

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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

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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

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

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

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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.

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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

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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

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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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CHAPTER 2

V O L U M E

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

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

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.

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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

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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CHAPTER 3

V O L U M E

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

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

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.

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-

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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.

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CHAPTER 4

V O L U M E

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

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

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.

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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 <1.5.

Nonsteroidal Antiinflammatory Drugs, Antiplatelet Medications, and Spinal Anesthesia Many individuals use cyclooxygenase-1 and -2 inhibitory drugs (COX-1 and COX-2) nonsteroidal antiinflammatory drugs (NSAIDs) on a regular basis. This is particularly true of the elderly who are more prone to having osteoarthritis and rheumatoid diseases. The elderly are also more likely to have had cardiac stent placements or coronary angioplasties performed, and may be taking antiplatelet medications such as the thienopyridines (ticlopidine and clopidogrel) or the newer platelet antagonists, platelet glycoprotein (GP) IIb/IIIa agents such as (abciximab, eptifibatide, and tirofiban). All of these agents alter platelet function and may increase the risk of spinal/epidural hematoma formation if spinal axis anesthesia is used without following proper precautions.

What Are the Risks of Developing a Spinal Hematoma by Performing a Spinal Anesthetic in a Patient Who Is Receiving Aspirin or a COX-1 Nonsteroidal Antiinflammatory Drug? There is little evidence in the literature to suggest that it is necessary to stop COX-1 NSAIDs before surgery or to avoid spinal or epidural anesthesia in patients who have been using these medications in the preoperative period. Vandermeulen et al., in their review of the literature from 1906 until 1994, were only able to find three cases in which an NSAID was associated with the formation of a postspinal/ epidural hematoma.4 One of the cases involved indomethacin and in the two other cases, aspirin was implicated. One of these latter two cases also involved the concurrent use of heparin. However, a recent report by Litz and colleagues37 implicates the perioperative administration of ibuprofen as the offending agent that led to the formation of a spinal–epidural hematoma after epidural catheter removal on the second postoperative day in a patient who had undergone a TKR. However, the patient was also receiving LMWH.

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The most alarming report is by Gerancher et al.38 Their patient was not anticoagulated and only received a single dose of ketorolac during surgery (30 mg intravenously) and then three doses in the postoperative period (15 mg, intramuscularly, every 6 hours). The patient’s lumbar hematoma developed during the afternoon of the first postoperative day and its presence was confirmed by a magnetic resonance imaging study. Even more alarming was the fact that it occurred as the result of a lumbar puncture with a small-gauge spinal needle. She had required three needle passes to place her block. The first two were performed with a 27-gauge Quincke needle and bone was encountered each time. The final pass was undertaken with a 25-gauge Quincke needle. No blood was aspirated or detected during any of the needle placements.38 Fortunately, the woman regained a full recovery from her paraparesis without surgical decompression. The concurrent use of ketorolac and LMWH has also been implicated in three recent reports of spinal–epidural hematoma formation in conjunction with an axis anesthetic.39 Two of these hematomas occurred immediately after the removal of an epidural catheter. Litz et al.37 also warn that epidural catheter removal may be just as risky as catheter placement in regard to epidural hematoma formation in patients receiving anticoagulation or antiplatelet therapy.

Is There Any Value in Obtaining a Bleeding Time before Block Placement or Catheter Removal? Measurement of the Ivy bleeding time before placement of a spinal or epidural anesthetic is not indicated and it will not provide one with any useful information.40

Abridged Guidelines for Performing Neuraxial Blockade in Patients Who Are Receiving Aspirin or a Nonsteroidal Antiinflammatory Drug The ASRA Guidelines COX-1 NSAIDs appear to represent no added risk for the development of spinal hematoma in patients having epidural or spinal anesthesia. The use of COX-1 NSAIDs alone does not create a level of risk that will interfere with the performance of neuraxial blocks. COX-2 inhibitors have minimal effect on platelet function, and it is quite safe to perform a neuraxial block or remove an epidural catheter in an individual who is receiving a COX-2 agent.

German and Spanish Guidelines The guidelines promulgated by both the German Society of Anesthesiology and Intensive Care Medicine and the Spanish Consensus Forum are much more rigid than those set forth by ASRA.18 Both of these societies believe that there is a risk of hematoma formation when these agents are used in the perioperative period, and they mandate at least a 3-day interval without aspirin or aspirin-containing medications before neuraxial blocks are performed or epidural catheters are removed. In addition, they mandate a 1- to 2-day drug-free interval for all other COX-1 NSAIDs.19,41

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Antiplatelet Drugs Ticlopidine Ticlopidine (Ticlid) is the first agent in this new class of drugs. It is a longlasting inhibitor of both primary and secondary phases of platelet aggregation induced by ADP, collagen, thrombin, arachidonic acid, prostaglandin endoperoxidase, and thromboxane A2-like substances.42 The effect on platelet function is irreversible and the drug’s action lasts for the lifetime of the platelet.43 The half-life of ticlopidine after a single 250-mg dose is 12.6 hours, but with repeated dosing at 250 mg twice a day, the elimination half-life rises to 4 to 5 days.43 Prolonged bleeding time is normalized within 2 hours after the intravenous administration of 20 mg methylprednisolone or the transfusion of platelets.43 The drug is indicated for reducing the risk of thrombotic events in patients who have experienced stroke precursors and who are also intolerant to aspirin.43

Clopidogrel Clopidogrel (Plavix) irreversibly inhibits platelet aggregation by selectively binding to adenylate cyclase-coupled ADP receptors on the platelet surface and also inhibits the binding of fibrinogen to the glycoprotein GP IIb/IIIa receptor.44 The elimination halflife of clopidogrel is only 7.7 hours after a single 75-mg dose, but platelet inhibition persists for several days after withdrawal of the drug and diminishes in proportion to platelet renewal.45 Clopidogrel is 40 to 100 times more potent than ticlopidine and bleeding times are significantly prolonged after a single loading dose of 375 mg. There are no case reports in the literature that implicate clopidogrel alone as the causative agent in the production of a postneuraxial block spinal hematoma.

ASRA Guidelines for Performing a Spinal Anesthetic in Patients Who Are Receiving Either Ticlopidine or Clopidogrel Ticlopidine should be discontinued 14 days before surgery. It is recommended that clopidogrel be stopped 7 days before surgery.

Platelet Glycoprotein IIb/IIIa Antagonists The identification of the platelet glycoprotein IIb/IIIa receptor, a fibrinogen receptor important for platelet aggregation, has led to the development of platelet receptor antagonists.46 Activated glycoprotein IIb/IIIa receptors become receptive to fibrinogen, and when fibrinogen binds to the glycoprotein IIb/IIIa receptors located on two different platelets, it builds the crosslinks for platelet-to-platelet aggregation. The glycoprotein IIb/IIIa also mediates platelet adhesion and spreading.46

Abciximab Abciximab is a monoclonal antibody that binds nonspecifically to the glycoprotein IIb/IIIa receptor.46 The biologic half-life of abciximab is approximately 12 to 24 hours, but 24 hours after administration, 50% to 60% of the platelet receptors are still blocked.47

ANTICOAGULATION AND REGIONAL ANESTHESIA

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Abciximab can be detected on circulating platelets for more than 15 days, indicating platelet-to-platelet transfer.46 Abciximab cannot be effectively reversed with the transfusion of platelets because the free circulating monoclonal antibody or platelet-toplatelet transfer of the drug inactivates the new platelets. Platelet function recovers over the course of 48 hours as a result of platelet turnover.46

Eptifibatide Eptifibatide occupies the binding site between the IIb and IIIa arms of glycoprotein IIb/IIIa preventing the binding of fibrinogen and thrombus formation.48 Eptifibatide has a plasma half-life of 2.5 hours, with a rapid onset of action and a rapid reversibility of platelet inhibition.46 Four hours after the termination of an eptifibatide infusion, platelet aggregation recovers to approximately 70% of normal and there is normal hemostasis.49

Tirofiban Tirofiban occupies the binding site on the glycoprotein IIb/IIIa receptor and competitively inhibits platelet aggregation mediated by fibrinogen and von Willebrand factor.49 It is given through an intravenous infusion and the half-life is approximately 1.5 to 2.5 hours.46

What Is the Evidence That It Is Not Safe to Perform a Spinal Anesthetic in a Patient Who Is Receiving a Glycoprotein IIb/IIIa Antagonist? There are no know case reports of a spinal–epidural hematoma being formed as the result of spinal blockade being performed in a patient who was simultaneously being treated with a glycoprotein IIb/IIIa antagonist. However, a recent study by Gammie et al.50 shows that patients who were using glycoprotein the IIb/IIIa medication abciximab and who subsequently required emergency cardiac surgery were at increased risk of having major bleeding when they required immediate surgery as compared with patients who could delay their surgery 12 or more hours after stopping their abciximab (Table 3). In the Gammie study, 11 consecutive patients who were taking abciximab and who also required emergency cardiac surgery after failed angioplasty or stent placement were randomized into two groups.50 Patients in group 1 (n = 6) had taken the last dose of abciximab 12 or less hours before surgery and group 2 (n = 5) had taken TABLE 3.

Abciximab and Emergency Cardiac Surgery

Group 1: last dose abciximab <12 hours before surgery *(P < 0.02 group 1 vs group 2) Group 2: last dose abciximab >12 hours before surgery

No.

No. of Packs of Platelets

No. of Packs of Packed Cells

6

20*

6*

5

0

0

Table derived from the work of Gammie et al.50 and shows the relationship between the time in hours from the last dose of abciximab until surgery and the need for platelet administration to control bleeding.

44

BROADMAN

it more than 12 hours before their surgery. Patients in group 1 required 20 packs of platelets to control bleeding and group 2 did not require any platelets (P < 0.02). Patients in group 1 also required more packed erythrocyte transfusions (6 vs. 0) (P < 0.02).

ASRA Guidelines for Performing a Spinal Anesthetic in Patients Who Are Receiving a Glycoprotein IIb/IIIa Antagonist Abciximab should be discontinued 48 hours before surgery. It is recommended that eptifibatide and tirofiban be stopped 8 hours before surgery.

What Are the Presenting Signs and Symptoms of a Spinal–Epidural Hematoma and How Does One Manage This Potentially Catastrophic Event? Vandermeulen and colleagues4 indicate that patients who are developing a neuraxial hematoma initially complain of new onset of numbness, weakness, or radicular back pain, and they ascertained that muscle weakness was the first neurologic symptom in 46% of patients with spinal hematoma and that sensory deficit was the presenting symptom in 14% of the patients. Prompt recognition and treatment of this condition is essential to optimize recovery of neurologic function in these patients (Table 4). An immediate magnetic resonance image should be obtained in every patient who develops new-onset neurologic deficits after the placement of a neuraxial block or removal of an epidural catheter. If the magnetic resonance image identifies the presence of a neuraxial hematoma, immediate surgical decompression is the treatment of choice. Vandermeulen et al.4 reported the results of 13 patients who had a decompressive laminectomy to evacuate their spinal hematoma within 8 hours of the development of paraplegia. Good or partial recovery of neurologic function was obtained in 77% of these patients (10 of 13). However, if the surgery was delayed for more than 24 hours, only 15% (two of 12) obtained good recovery, and the majority of these unfortunate patients never regained any neurologic function. TABLE 4. Neurologic Outcome in Patients with Spinal Hematoma after Neuraxial Blockade Interval from Onset Paraplegia to Surgery

Good Recovery (n = 15)

Partial Recovery (n = 11)

Poor Recovery (n = 29)

<8 hrs (n = 13) 8–24 hrs (n = 8) >24 hrs (n = 11) No surgical intervention (n = 13) Unknown (n = 10)

6 2 1 4 2

4 2 0 1 4

3 4 10 8 4

Table derived from the work of Vandermeulen and colleagues4 and shows the need to rapidly determine the cause of new onset neurologic symptoms in patients receiving both anticoagulation therapy and a neuraxial block. It is imperative to surgically decompress all magnetic resonance imaging–diagnosed neuraxial hematomas in less than 8 hours time from the onset of symptoms if the patient is going to obtain optimal neurologic recovery.

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Suggested Readings for Those Who Want to Attain a More In-depth Knowledge of This Subject 1. Broadman LM: Fondaparinux: What is its efficacy and safety in surgical patients? In: Fleischer LA, ed. Evidenced-Based Practice of Anesthesiology. Philadelphia: WB Saunders; 2004:218–22. 2. Hawkinberry DW, Broadman LM: The best approaches to prophylaxis against DVT formation when using a combination of neuraxial anesthesia and the heparins. In: Evidenced-Based Practice of Anesthesiology. Philadelphia: WB Saunders; 2003:292–304. 3. Broadman LM: Vitamin K antagonists and spinal axis anesthesia. In: Fleisher LA, ed. Evidenced-Based Practice of Anesthesiology. Philadelphia: WB Saunders; 2004:305–11. 4. Broadman LM: Herbal medications and spinal axis anesthesia. In: Fleisher LA, ed. Evidenced-Based Practice of Anesthesiology. Philadelphia: WB Saunders; 2004:312–13. 5. Broadman LM: Nonsteroidal antiinflammatory drugs, antiplatelet medications and spinal axis anesthesia. Best Practice & Research Clinical Anesthesiology 2005; 19:47–58.

References 1. Rodgers A, Walker N, Schug S, et al.: Reduction of post-operative mortality and morbidity with epidural and spinal anesthesia: Results from overview of randomized trials. BMJ 2000; 321:1–12. 2. Modig J, Borg T, Karlstrom G, et al.: Thromboembolism after total hip replacement: Role of epidural and general anesthesia. Anesth Analg 1983; 62:174–80. 3. Geerts WH, Heit JA, Clagett GP, et al.: Prevention of venous thromboembolism. Chest 2001; 119(suppl):132S–75S. 4. Vandermeulen EP, Van Aken H, Vermylen J: Anticoagulants and spinal–epidural anesthesia. Anesth Analg 1994; 79:1165–77. 5. Brummel KE, Paradis SG, Butenas S, Mann KG: Thrombin functions during tissue factorinduced blood coagulation. Blood 2002; 100:148–52. 6. Mann KG, Butenas S, Brummel K: The dynamics of thrombin formation. Arterioscler Thromb Vasc Biol 2003; 23:17–25. 7. Baja SP, Joist JH: New insights into how blood clots: Implications for the use of APTT and PT as coagulation screening tests and in monitoring of anticoagulation therapy. Semin Thromb Hemost 1999; 25:407–18. 8. Rosenberg RD, Damus PS: The purification and mechanism of action of human antithrombin– heparin cofactor. J Biol Chem 1973; 248:6490–505. 9. Olson ST, Bjork I, Sheffer R, et al.: Role of antithrombin-binding pentassacharide in heparin acceleration on antithrombin—protease reactions: Resolution of the antithrombin conformational change contribution to heparin rate enhancement. J Biol Chem 1992; 267:12538. 10. Hirsh J Levine MN: Low molecular weight heparin. Blood 1992; 79:1–17. 11. Weitz JI: Low-molecular weight heparins. N Engl J Med 1997; 337:688–98. 12. Hirsh J, Warkentin TE, Raschke R, et al.: Heparin and low-molecular-weight heparin: Mechanisms of action, pharmacokinetics, dosing considerations, monitoring efficacy and safety. Chest 1998; 114:498S–510S. 13. Fondaparinux sodium (Arixtra). Physicians’ Desk Reference (Edition 58). Montvale, NJ: Thompson PDR; 2004:2399–403. 14. Van der Velde EA, Poller L: The APTT monitoring of heparin–The ISTH/ICSH collaborative study. Thromb Haemost 1995; 73:73–81.

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15. Bratt G, Thornebohm E, Granqvist S, et al.: A comparison between low molecular weight heparin (KABI 2165) and standard heparin in the intravenous treatment of deep vein thrombosis. Thromb Haemost 1985; 54:813–7. 16. Rosenbloom DGJ: Argument against monitoring levels of anti-factor Xa in conjunction with low molecular-weight heparin therapy. Can J Hosp Pharm 2002:15–9. 17. Warkentin TE, Levine MN, Hirsh J, et al.: Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. N Engl J Med 1995; 332:1330–5. 18. Horlocker TT, Wedel DJ, Benzon H, et al.: Regional anesthesia in the anticoagulated patient: Defining the risks (The Second ASRA Consensus Conference on Neuraxial Anesthesia and Anticoagulation). Reg Anesth Pain Med 2003; 28:172–97. 19. Gogarten W, Van Aken H, Wulf H, et al.: Regional anaesthesia and thromboembolism prophylaxis/anticoagulation: Guidelines of the German Society of Anaesthesiology and Intensive Care medicine (DGAI). Anaesthesiol Intensivmed 1997; 38:623–8. 20. Sanchez R, Nygard E: Epidural anesthesia in cardiac surgery: Is there an increased risk? Cardiothoracic Vasc Anesth 1998; 12:170–3. 21. Planes A, Vochelle N, Fagola M, et al.: Once-daily dosing off enoxaparin (a low molecular weight heparin) in prevention of deep vein thrombosis after total hip replacement. Acta Chir Scand Suppl 1990; 556:108–15. 22. Lassen MR, Bauer KA, Eriksson BI, Turpie AGG, for the European Pentasaccharide Hip Elective Surgery Study (EPHESUS) Steering Committee: Postoperative fondaparinux versus preoperative enoxaparin for prevention of venous thromboembolism in elective hip-replacement surgery: A randomized double-blind comparison. Lancet 2002; 359:1715–20. 23. Turpie AGG, Bauer KA, Eriksson BI, Lassen MR, for the PENTATHLON 2000 Study Steering Committee: Postoperative fondaparinux versus postoperative enoxaparin for prevention of venous thromboembolism in elective hip-replacement surgery: A randomized doubleblind comparison. Lancet 2002; 359:1721–6. 24. Turpie AGG, Gallus AS, Hoek JA, for the Pentassacharide Investigators: A synthetic pentassacharide for the prevention of deep-vein thrombosis after total hip replacement. N Engl J Med 2001; 344:619–25. 25. Eriksson BI, Bauer KA, Lassen MR, Turpie AGG, for the Steering Committee of the Pentassacharide in Hip-Fracture Surgery Study: Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after hip-fracture surgery. N Engl J Med 2001; 345:1298–304. 26. Bauer KA, Eriksson BI, Lassen MR, Turpie AGG, for the Steering Committee of the Pentassacharide in Major Knee Surgery Study: Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after elective major knee surgery. N Engl J Med 2001; 345:1305–310. 27. Hull R, Pineo G: A synthetic pentasaccharide for the prevention of deep-vein thrombosis. N Engl J Med 2001; 345:291–2. 28. Schroeder DR: Statistics: Detecting a rare adverse drug reaction using spontaneous reports. Reg Anesth Pain Med 1998; 23:183–9. 29. Hirsh J: Oral anticoagulant drugs. N Engl J Med 1991; 324:1865–75. 30. Whitlon DS, Sadowski JA, Suttie JW: Mechanisms of coumarin action: Significance of vitamin K epoxide reductase inhibition. Biochemistry 1978; 17:1371–7. 31. O’Reilly RA, Aggeler PM: Determinants of the response to oral anticoagulant drugs in man. Pharmacol Rev 1970; 22:35–96. 32. Hellemans J, Vorlat M, Verstraete M: Survival time of prothrombin and factors VII, IX, and X after completely synthesis blocking doses of coumarin derivatives. Br J Haematol 1963; 9:506–12. 33. Vigano S, Mannucci PM, Solinas S, et al.: Decrease in protein C antigen and formation of an abnormal protein soon after starting oral anticoagulation therapy. Br J Haematol 1984; 57:213–20. 34. Wille-Jorgensen P, Jorgensen LN, Rasmussen LS: Lumbar regional anaesthesia and prophylactic anticoagulation therapy. Anaesthesia 1991; 46:623–7. 35. Hass T, Innerhofer P, Kuhbacher G, Fries D: Successful reversal of deleterious coagulopathy by recombinant factor VIIa. Anesth Analg 2005; 100:54–8. 36. Kearon C, Hirsh J: Management of the anticoagulation before and after elective surgery. N Engl J Med 1997; 336:1506–11. 37. Litz RJ, Hubler M, Koch T, Albrecht M: Spinal–epidural hematoma following epidural anesthesia in the presence of antiplatelet and heparin therapy. Anesthesiology 2001; 95:1031–3.

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38. Gerancher JC, Waterer R, Middleton J: Transient paraparesis after postdural puncture spinal hematoma in a patient receiving ketorolac. Anesthesiology 1997; 86:490–4. 39. Urmey WF, Rowlingson J: Do antiplatelet agents contribute to the development of perioperative spinal hematoma? Reg Anesth Pain Med 1998; 23:146–51. 40. Horlocker TT, Wedel DJ, Schroeder DR, et al.: Preoperative antiplatelet therapy does not increase the risk of spinal hematoma associated with regional anesthesia. Anesth Analg 1995; 80:303–9. 41. Llau JV, de Andres J, Gomar C, et al.: Drugs that alter hemostasis and regional anesthetic techniques: Safety guidelines. (Consensus Conference) [Spanish]. Rev Esp Anesthesiol Reanim 2001; 48:270–8. 42. Ashida S, Abiko Y: Inhibition of platelet aggregation by a new agent, ticlopidine. Thromb Haemost 1978; 40:542–50. 43. Ticlopidine hydrochloride (Ticlid). Physicians’ Desk Reference (Edition 58). Montvale, NJ: Thompson PDR; 2004:2963–6. 44. Coukell AJ, Markham A: Clopidogrel. Drugs 1997; 54:745–50. 45. Savi P, Herbert JM, Pflieger AM, et al.: Importance of hepatic metabolism in the antiaggregating activity of the theinopyridine clopidogrel. Biochem Pharmacol 1992; 44:527–32. 46. Kam PCA, Egan MK: Platelet glycoprotein IIb/IIIa antagonists. Anesthesiology 2002; 96: 1237–49. 47. Tcheng JE, Ellis SG, George BS, et al.: Pharmacodynamics of chimeric glycoprotein IIb/IIIa integrin antiplatelet antibody fab 7E3 in high-risk coronary angioplasty. Circulation 1994; 90:1757–64. 48. Phillips DR, Scarborough RM: Clinical pharmacology of eptifibatide. Am J Cardiol 1997; 80:11B–20B. 49. Tcheng JE: Clinical challenges of platelet glycoprotein IIb/IIIa receptor inhibitor therapy: Bleeding, reversal, thrombocytopenia, and retreatment. Am Heart J 2000; 139:S38–45. 50. Gammie JS, Zenati M, Kormos RL, et al.: Abciximab and excessive bleeding in patients undergoing emergency cardiac operations. Ann Thorac Surg 1998; 65:465–9.

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CHAPTER 5

V O L U M E

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

ANESTHESIA FOR BARIATRIC SURGERY JAY B. BRODSKY, M.D. PROFESSOR, DEPARTMENT OF ANESTHESIA STANFORD UNIVERSITY SCHOOL OF MEDICINE STANFORD, CALIFORNIA

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.

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Anesthesia for Bariatric Surgery Jay B. Brodsky, M.D. Professor, Department of Anesthesia Stanford University School of Medicine Stanford, California

More than 60% of Americans are overweight, and more than 30% of adults can be classified as obese. In fact, one in every 16 American women meets the criteria for “morbid obesity.” It is estimated that by the year 2025, more than 40% of the adult population will be obese. Obesity has become a worldwide problem of epidemic proportions. Therefore, it is not uncommon for anesthesiologists everywhere to be expected to manage obese patients, not only for weight reduction procedures, but for all other types of surgery as well. Because the risks of anesthesia and surgery are thought to be higher for the obese population, it is important that every anesthesiologist be familiar with their clinical management. In industrialized countries, obesity is usually associated with poverty, whereas in developing countries, it is more often associated with affluence. The many precursors to obesity include gender, genetic and environmental effects, ethnicity, education, and socioeconomic status. Obesity affects every organ system and is associated with many chronic medical problems. Obese patients have more annual admissions to the hospital, more outpatient visits, and higher prescription drug costs than nonobese adults. In addition, obese patients have “quality-of-life” issues, including depression and a feeling of social incompetence. In 1991, the National Institutes of Health Consensus Development Conference Panel recommended weight reduction surgery as the best alternative for extreme obesity for patients who are unable to lose weight by diet and exercise. Most of the medical conditions associated with extreme obesity are reversible after sustained surgical weight loss.1 In July 2004, the Medicare administration recognized obesity as a disease, thus opening the door for financial coverage of bariatric operations for Medicare patients.

Definitions There is no precise definition of when obesity actually begins. A person is considered obese when the amount of body fat increases beyond the point at which health deteriorates and life expectancy is shortened. Total body weight (TBW) has two components, lean body weight (LBW) and fat weight (FW). LBW includes the weight of the muscles, bones, tendons, ligaments, and body water, whereas FW includes adipose tissue. LBW should be approximately 80% of TBW for males and 75% of TBW for females. An individual is considered obese when FW exceeds 30% of TBW. Ideal body weight (IBW) is a measure that was initially derived from life insurance studies to describe the weight that is statistically associated with maximum life 49

50

BRODSKY

expectancy. IBW is calculated based on height, gender, and age. Formulas for estimating IBW in either kilograms or pounds are given in Table 1. Normal weight ranges between 10% above and below IBW. Two general types of obesity are described. In “central–android” obesity, more often found in men, adipose tissue is located predominantly in the abdomen and upper body. In “peripheral–gynecoid” obesity, more common in women, fat is located primarily in the hips, buttocks, and thighs. Central–android obesity is associated with the “metabolic” syndrome with an increased risk of cardiovascular disease, dyslipidemia, glucose intolerance, and diabetes mellitus. Although the reasons are unknown, it is believed that the breakdown products of the visceral “central” fat are delivered directly into the portal circulation where they produce a metabolic imbalance. Criteria for a diagnosis of metabolic syndrome are given in Table 2. Body mass index (BMI) is an indirect measure of obesity widely used in clinical and epidemiologic studies. A patient’s BMI is calculated by dividing their weight in kilograms (kg) by the square of their height in meters (m2). Definitions of obesity, which are based solely on BMI, do not consider the patient’s gender or other contributing factors (water, muscle) as potential causes of increased TBW. A patient with a BMI of 20 to 25 kg/m2 is by definition normal weight, whereas a patient with a BMI of 26 to 29 kg/m2 is “overweight.” Patients with a BMI <30 kg/m2 have lower risks of obesity-associated health problems. An individual with a BMI >30 kg/m2 is “obese” and often experiences at least one of the many chronic medical conditions that are associated with obesity. “Morbid obesity” describes obesity that, if untreated, will significantly shorten the patient’s life expectancy. A variety of definitions exist, but a BMI >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.

51

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 <40 mg/dL (men), <50 mg/dL (women) Systolic blood pressure ≥130 mmHg and/or diastolic ≥85 mmHg or on treatment for hypertension Fasting serum glucose ≥110 mg/dL or on treatment for diabetes

Preoperative Evaluation General Considerations A patient who is moderately overweight probably carries no increased health risks, particularly when young. However, morbidity and mortality rise sharply with increasing age and BMI. The risk of premature death doubles for an individual with a BMI >35 kg/m2 and rises exponentially for patients with morbid obesity. The preoperative history and physical examination are extremely important because obesity is associated with so many chronic medical conditions. Comorbidities must be recognized, and when possible optimized, before elective bariatric surgery (Table 3). Endocrine conditions such as Cushing’s disease, hypothyroidism, and polycystic ovary syndrome are also associated with obesity, but these disorders are usually identified and treated before elective bariatric surgery. A patient scheduled for any surgical procedure after a previous bariatric operation should also be evaluated for metabolic changes, which can include protein, vitamin, iron, and calcium deficiencies.

Medications It is important that all current medications, including nonprescription appetite suppressors and diet drugs, be listed during the preoperative visit because they may have important implications for anesthetic management (Table 4). The once popular combination of phentermine and fenfluramine (“Phen-Fen”) is no longer prescribed. However, phentermine is still in use. An association between Phen-Fen and heart and lung problems is clearly established, whereas a similar link between phentermine alone has TABLE 3.

Medical Conditions Associated with Obesity

System

Associated Medical Comorbidity

Respiratory

Restrictive lung disease, “asthma,” obstructive sleep apnea (OSA) syndrome, obesity hypoventilation syndrome, Pickwickian syndrome

Cardiovascular

Hypertension, cardiomegaly, congestive heart failure, coronary artery disease, peripheral vascular disease, pulmonary hypertension, thromboembolism, sudden death

Endocrine/metabolic

Diabetes mellitus, Cushing’s syndrome, hypothyroidism, hyperlipidemia, vitamin deficiencies

Gastrointestinal

Hiatal, inguinal, and ventral hernia, fatty liver (NASH*), gallstones

Musculoskeletal

Osteoarthritis on weight-bearing joints, low back pain

Malignancy

Breast, prostate, cervix, uterine, colorectal

*NASH = nonalcoholic steatohepatitis.

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Pharmacologic Interventions for the Treatment of Obesity

Prescription Drug

Implications for Anesthesia

Diethylproprion

Pulmonary hypertension and psychosis

Dexfenfluramine

Associated with valvular heart disease, pulmonary hypertension (no longer prescribed in United States)

Fenfluramine

Associated with valvular heart disease, pulmonary hypertension (no longer prescribed in United States)

Fluoxetine

Seritonin reuptake inhibitor associated with diarrhea, nausea, headache, and dry mouth; bradycardia, bleeding, seizures, hyponatremia, hepatotoxicity, and extrapyramidal effects have been reported

Mazindol

Reports of pulmonary hypertension, atrial fibrillation, and syncope

Metformin

No side effects reported

Orlistat

Diarrhea, low levels of fat-soluble vitamins (including vitamin K which can affect coumadin dosing)

Phentermine

Association with cardiopulmonary problems has not been excluded

Phenylpropanolamine

Increased risk of hemorrhagic stroke (no longer prescribed in United States)

Sibutramine

Small increases in blood pressure and heart rate; reports of associated arrhythmias, hypertension, and possibly cardiac arrest

Dietary Supplement/ Herbal Product

Implications for Anesthesia

Chitosan

No adverse effects reported

Chromium

No adverse effects reported

Ephedra (Ephredrine, Ma Huang)

Hypertension, psychiatric symptoms, autonomic dysfunction, gastrointestinal symptoms

Hydroxycitric acid (Garcinia cambogia)

No adverse effects reported

Pyruvate

Case report of a death in a patient with restrictive cardiomyopathy

not been excluded. These medications must be stopped at least 2 weeks before surgery, and a complete cardiac evaluation should be obtained. Sibutramine works in the brain by inhibiting the reuptake of norepinephrine, serotonin, and dopamine. Sibutramine produces a feeling of “anorexia,” which limits food intake. Although sibutramine is claimed to have no significant systemic effects or interaction with anesthetic agents, it has been implicated as a cause of arrhythmias and hypertension. Orlistat blocks digestion and absorption of dietary fat by binding lipases in the gastrointestinal tract and can cause deficiencies in fat-soluble vitamins (A, D, E, and K). A reduction in vitamin K level can increase the anticoagulation effects of coumadin.

Physical Examination During the preoperative physical examination, attention is directed to the cardiac and pulmonary systems, and to the head and neck in anticipation of difficult tracheal intubation.

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Cardiovascular System Cardiac output rises about 0.1 L/min for each 1-kg addition in weight. Stroke volume is elevated because total blood volume increases to perfuse the added body fat. The increased cardiac output combined with normal peripheral vascular resistance leads to systemic hypertension. Mild to moderate hypertension is seen in most morbidly obese patients. A 3 to 4 mm Hg increase in systolic pressure and a 2 mm Hg increase in diastolic arterial pressure can be expected for every 10 kg of weight gained. The increases in blood volume and cardiac output eventually produces dilational cardiac hypertrophy.2 Left ventricular dysfunction is often present in young, asymptomatic patients. The degree of cardiac abnormality is correlated with the degree of obesity. Even normotensive patients have increased preload and afterload, increased mean pulmonary artery pressure (PAP), and an elevation in right and left ventricular stroke work. Because obese patients are often not physically active, they may appear to be asymptomatic even when they have significant cardiovascular disease. Signs of pulmonary hypertension (exertional dyspnea, fatigue, syncope) should be sought and transesophageal echocardiography (TEE) obtained in symptomatic patients. Right heart failure is common in older patients. The electrocardiogram (ECG) may show increased rate, changes in QRS voltage, left QRS axis shift, slowed conduction, and evidence of ischemia or previous myocardial infarction. Even in normotensive morbidly obese patients, the ECG often demonstrates left ventricular hypertrophy, cardiac chamber enlargement, ventricular ectopy, and other arrhythmias. Cardiac dysrhythmias are precipitated by chronic hypoxia, hypercapnia, and ischemic heart disease. Polycythemia suggests chronic hypoxemia. Further investigation and a formal cardiology consult may be needed for medical optimization of the patient before elective bariatric surgery.

Pulmonary System Adipose tissue is metabolically active. O2 consumption and CO2 production rise with increasing weight as a result of increased metabolic demands. The work of breathing is increased because more energy must be expended to carry the additional body mass, whereas respiratory muscle performance is impaired. The fatty chest and abdominal walls reduce chest wall compliance. Mass loading of the thoracic and abdominal chest walls causes abnormalities in both lung volumes and gas exchange, especially when the patient is supine. Functional residual capacity (FRC) is significantly reduced as a result of a decrease in expiratory reserve volume (ERV), so total lung capacity (TLC) may be reduced. Inspiratory reserve volume (IRV) may actually be increased leading to a normal TLC. Airways close during normal ventilation. Continued perfusion of nonventilated alveoli alone results in an arterial oxygen tension (PaO2) that is lower than predicted for similarly aged nonobese patients. These changes are directly proportional to increasing BMI.3 General anesthesia compounds these problems by causing a further reduction in FRC. Younger obese patients have an increased ventilatory response to hypoxia. An arterial blood sample usually shows alveolar hyperventilation (PaCO2 30 to 35 mm Hg) and relative hypoxemia (PaO2 70 to 90 mm Hg) while the patient breathes air. With increasing age, sensitivity to CO2 decreases so PaCO2 rises and PaO2 falls further. Many obese patients maintain a normal PaCO2 during the day but have CO2 retention, sleep disturbances, intermittent airway obstruction with hypoxemia, pulmonary hypertension, and cardiac arrhythmias at night. Obstructive sleep apnea (OSA) syndrome is characterized by frequent episodes of apnea (>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.

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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.

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CHAPTER 6

V O L U M E

T H I R T Y - T H R E 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

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.

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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 <$500,000 (Karen L. Posner, ASA Closed Claims Project, personal communication, March 26, 2004).

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With the recognition of how CIs and adverse outcomes can arise, the anesthesia delivery system has evolved considerably to the contemporary machines now available. This evolution continues to apply the principles of risk reduction so that delivery systems should be designed to be safer. New systems, new agents, and new technology may bring with them new problems. A vigilant, educated anesthesia caregiver is therefore essential to ensuring the safety of both patients and the operating room staff. Modern anesthesia delivery systems contain pneumatic, mechanical, and electronic components that are extremely reliable so that unexpected “pure” failure of equipment is rare in a system that has been well maintained and properly checked before use. Recognition of the importance of human error in CIs and of the limitations of human vigilance has led to a three-tier approach in the design of new delivery systems in the quest for increased safety.6 Thus: 1. When possible, design is such that human error cannot occur. The introduction of keyed connections for gas tanks, gas lines, and vaporizers and of fail-safe systems are examples. It should be virtually impossible to connect anything but an oxygen tank or line to the oxygen inlet of the machine. 2. If human error cannot be prevented, then the system is designed to prevent such errors from causing injury. Examples of this are gas flow proportioning systems for nitrous oxide and oxygen such that a mixture containing <25% oxygen cannot be accidentally set if nitrous oxide and oxygen are the only gases used. With modern electronics, the anesthesia workstation (for example, DatexOhmeda ADU) can also adjust the flow of N2O to maintain at least 25% O2 during use of high concentrations of desflurane. To prevent barotrauma use of a high-pressure limit device affords protection if an excessive tidal volume or pressure is set on the ventilator. 3. Recognizing that it is not always possible to prevent or correct for user error, the delivery system should be equipped with monitors and alarms to alert the user to an operator error or to an adverse condition that might be caused by an equipment failure or a change in the patient’s condition.6

The Anesthesia Breathing System In Caplan et al.’s American Society of Anesthesiologists–CCP analysis, the single largest source of gas delivery equipment-related claims was perhaps the simplest of all of the delivery system components, the anesthesia breathing system.5 This has undergone many design changes to promote improved safety. Thus, the manufacturers, by limiting the opportunities for the user to configure the circuit, have decreased the opportunities for human error. Consider an older design of a delivery system in which the user can switch from bag/manual mode to ventilator/automatic mode. Five user steps are needed: 1) The reservoir bag would be removed from the bag mount; 2) the ventilator hose connected to the bag mount; 3) the adjustable pressure limit (APL or “popoff”) valve closed; 4) the ventilator turned on; and 5) the breathing system low-pressure alarm enabled. Each step provided an opportunity for user error during the change from bag to ventilator mode, and again on changing back to bag mode. The bag–ventilator selector switch used on contemporary systems decreases the need for user-made connections and reconnections. Switching to the ventilator mode also turns on the ventilator and automatically enables the breathing system low-pressure alarm. Thus, one simple maneuver with a bag–ventilator switch replaces five potentially complex ones. Another opportunity for user error exists when freestanding positive end-expiratory pressure (PEEP) valves are available. If the caregiver mistakenly places such a valve

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into the inspiratory, rather than correctly into the expiratory, side of a circle breathing system, ventilation of the patient’s lungs can be completely obstructed. Fortunately, the availability and therefore use of such devices is uncommon. On contemporary anesthesia delivery systems, the PEEP valves are designed (by the machine manufacturer) as an integral component of the breathing circuit or are built into the ventilator. This avoids the potentially catastrophic use error that has been associated with these freestanding valves. The correct installation of a freestanding PEEP valve into the circuit is the user’s responsibility. If a freestanding PEEP valve must be used, some have recommended that it be of bidirectional design so that in the event of incorrect placement, the circuit would not be completely obstructed.7 The American Society of Anesthesiologists–CCP database includes several such cases of incorrect placement of a PEEP valve.5 User placement of other devices into the breathing system such as filters and humidifiers that can become blocked can cause other problems that may not be preventable by design efforts made by the delivery system manufacturer.8 The breathing circuits of many anesthesia delivery systems have numerous hoses and connections, each an opportunity for error. Some contemporary designs have sought to streamline the breathing system by minimizing the number of hoses and connections (for example, Datex-Ohmeda Aestiva). Even with modern anesthesia breathing systems, the anesthesia caregiver remains responsible for making a limited number of connections, the correctness and integrity of which remain the caregiver’s responsibility. Failure to completely remove the plastic wrapping from a facemask and/or breathing circuit before use has led to circuit obstruction and adverse outcomes. Devices designed to prevent disconnections in the breathing circuit have been proposed but none have been adopted.9 Contemporary machines are now, by standard, equipped with retaining devices to prevent disconnection of the fresh gas hose from the common gas outlet.10

Monitoring the Breathing System The anesthesia breathing system (patient circuit) is the interface between the patient and the anesthesia machine. Although not all equipment failures can be prevented, appropriate preuse checkout and subsequent monitoring of the breathing system should lead to the early detection of failures and permit prompt human intervention before an adverse outcome occurs. Perhaps the greatest advance in the design of modern anesthesia gas delivery systems has been the incorporation of integrated monitoring and prioritized alarm systems such that certain basic monitors and alarms are automatically enabled whenever the system is capable of delivering an anesthetic gas mixture or mechanical ventilation.10 Aspects of the patient breathing system that can be monitored routinely include pressure, volume, capnography, respiratory gas composition, and gas flows. Applied correctly (that is, with appropriate monitors, alarm threshold limits, and alarms enabled and functioning), such monitoring should detect most, but not all, delivery system problems.

Pressure Monitoring Most anesthesia workstations incorporate an analog pressure gauge and an electronic pressure monitoring and alarm system. The analog pressure gauge is a simple device that is normally mounted on the carbon dioxide absorber to measure the pres-

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sure at that point in the circuit. In other systems (for example, Ohmeda GMS), absorber system pressure is sensed downstream (that is, on the patient side) of the inspiratory unidirectional valve and is “piloted” through plastic tubing to the pressure gauge and pressure monitoring system. The analog pressure gauge is valuable because of its simplicity. When the circuit is open to the atmosphere, the gauge should indicate zero pressure. The ability to perform such immediate zero calibration can be helpful. Provided that the pressure gauge is used with the circuit as intended by the manufacturer, the gauge readings will reflect pressure at the patient’s airway. If, however, the user has altered the manufacturer’s original circuit configuration, the breathing system pressure gauge and monitoring system may fail to detect certain cases of abnormal pressure at the airway. Thus, sensing pressure at the absorber will not detect application of PEEP resulting from a freestanding PEEP valve that has been placed (albeit correctly) between the expiratory limb of the circle system and the expiratory unidirectional valve. Some contemporary workstations do not incorporate a freestanding analog pressure gauge in the breathing system, but use electronic measurement and a screen display of pressure parameters. Because circuit disconnects and misconnects are not uncommon occurrences, monitoring of circuit integrity and correct configuration is essential. How can various pressure monitoring and alarm modalities be used to monitor for these conditions?

Low-pressure Alarm Breathing system low-pressure monitors sometimes have been called “disconnect monitors” or alarms. This is a misnomer because they monitor pressure, enabling the user to infer circuit integrity if the pressure monitor is being used appropriately. These monitors annunciate an audible and visual alarm within 15 seconds when a minimum pressure threshold is not exceeded within the circuit. This minimum pressure threshold therefore should be adjusted by the user to be just below the normal peak inspiratory pressure so that any slight decrease will trigger the alarm. If the low-pressure alarm threshold is not bracketed to be close to the peak inspiratory pressure, a circuit leak or disconnect may be undetected if an inappropriately set low-pressure threshold is crossed.11 Thus, a small-diameter endotracheal tube (for example, 3-mm internal diameter) connected to a circle breathing system might be pulled completely out of the trachea, leaving the lungs unventilated. Because the tube has a high resistance to gas flow (and pressure is the product of resistance and flow), the pressure increase in the circuit with each positive-pressure inspiration may satisfy the low-pressure alarm threshold, and the disconnect between the endotracheal tube and the patient’s trachea may go undetected by pressure monitoring. On contemporary anesthesia delivery systems, the circuit pressure waveform is displayed on a screen, as are the low- and high- pressure alarm thresholds, so that the caregiver can suitably adjust the latter. On contemporary workstations, the low-pressure alarm threshold can be bracketed automatically to the existing peak inspiratory pressure by merely pressing one button (thereby setting “autolimits”); in older designs, the user must adjust it. Although contemporary pressure monitors and alarms have an infinitely variable lowpressure alarm threshold, some older models may provide only a limited choice of settings (for example, 8, 12, or 26 cm H2O), which may limit the monitor’s sensitivity to detect small decreases in peak pressure. If such “manual-set” monitors are used, it may be advisable to readjust the ventilator settings such that the peak pressure achieved

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just exceeds the available low-pressure alarm limit. Thus, if the low-pressure alarm limit cannot be adequately adjusted to the desired ventilator settings, the caregiver should consider adjusting the ventilator settings to the alarm limits that are available. Contemporary anesthesia delivery systems incorporate low-pressure alarms that are automatically enabled whenever the ventilator is turned on. Cost considerations may lead to purchase of older delivery systems for use in offices, ambulatory facilities, and even in little used remote locations within a hospital. Some older-model alarm systems that must be enabled by the user may therefore still be in clinical use. Because the circuit low-pressure alarm is critical during positive-pressure ventilation, the caregiver must be aware of the features of the monitoring system on the individual machine being used. If there is any question as to whether a monitor or alarm is working or is interfaced with the ventilator on/off switch, the alarm can be tested during the before-use machine checkout by deliberately creating a disconnect in the circuit. Some low-pressure monitoring alarm systems offer an optional 60-second alarm delay in the event that a slow ventilatory rate (for example, four breaths per minute) has been set. Whereas the breathing system low-pressure alarm must be enabled (either automatically or manually) in association with the use of positive-pressure ventilation, the following pressure monitoring modalities are always enabled.

Continuing Pressure Alarm The continuing pressure alarm is annunciated when the breathing circuit pressure exceeds 10 cm H2O for >15 seconds. This alerts the caregiver to more gradual increases in circuit pressure such as those caused by malfunction of a ventilator pressure-relief valve (that is, the valve is stuck closed) or a waste gas scavenging system occlusion. In such cases, gas is flowing continuously from the anesthesia machine into the breathing circuit but cannot get out. In this situation, the rate of pressure increase will depend on the fresh gas flow rate set on the machine’s gas flowmeters.

High-pressure Alarm The breathing system high-pressure alarm is annunciated immediately whenever the high-pressure threshold is exceeded. On contemporary machines, this threshold can be adjusted by the user, with a default setting generally of 50 cm H2O. Some older models of pressure monitors are not user-adjustable and have a threshold of 65 cm H2O. The latter pressure threshold might be too high to detect an otherwise harmful high-pressure condition such as total obstruction of the endotracheal tube in which the breathing circuit pressure does not exceed +65 cm H2O. The high pressure alarm together with a breathing system/ventilator high-pressure limit facilitates ventilation of lungs with low compliance.

Subatmospheric Pressure Alarm This alarm is annunciated immediately when the pressure in the breathing system falls below −10 cm H2O. Therefore, it should alert clinicians to situations that could potentially lead to negative-pressure barotrauma, negative-pressure pulmonary edema caused when suction is applied to the breathing system, or both. Such negative pressures in the breathing system may be the result of spontaneous respiratory efforts by a patient whose lungs are being mechanically ventilated, a malfunctioning waste gas scavenging system, a sidestream sampling respiratory gas analyzer or capnograph when fresh gas flow into the circuit is inadequate, a suction catheter passed into the airway, or suction applied through the working channel of a fiberscope passed into the airway.

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Volume Monitoring Routine monitoring of expired tidal and minute volumes is usually accomplished using a spirometer that is located near the expiratory unidirectional valve in the circle system. Spirometry is used to monitor ventilation as well as circuit integrity. In the event of a circuit disconnect, the spirometer alarm should annunciate a low tidal volume warning if appropriate limits for the low tidal volume alarm have been set. A limitation of some older spirometry units is that the low-volume alarm limit threshold may not be user-adjustable. Thus, one older-model machine incorporates a spirometer with a “low-volume” alarm threshold fixed at 80 mL. When a hanging bellows design of ventilator is used, a circle system disconnection may fail to trigger a low tidal volume condition. This is because as the bellows descends during exhalation, it may draw in a normal adult tidal volume (that is, >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.

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CHAPTER 7

V O L U M E

T H I R T Y - T H R E 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

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.

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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 <30 days before surgery as the group at highest risk, whereas after that period, risk stratification is based on the presentation of disease and exercise tolerance.

Patients at Risk for Coronary Artery Disease For those patients without overt symptoms or history, the probability of coronary artery disease (CAD) varies with the type and number of atherosclerotic risk factors present. Peripheral arterial disease has been shown to be associated with CAD in multiple studies. Hertzer and colleagues studied 1,000 consecutive patients scheduled for major vascular surgery and found that approximately 60% of patients had at least one coronary artery with a critical stenosis.6 Diabetes mellitus is common in the elderly and represents a disease that impacts multiple organ systems. Complications of diabetes mellitus are frequently the cause of urgent or emergent surgery, especially in the elderly. Diabetes accelerates the progression of atherosclerosis, which can frequently be silent in nature. Diabetics have a high incidence of both silent MI and myocardial ischemia. Diabetes is an independent risk factor for perioperative cardiac morbidity.3 In attempting to determine the degree of this increased probability, the length of the disease and other associated end-organ dysfunction should be taken into account, including autonomic neuropathy. Hypertension has also been associated with an increased incidence of silent myocardial ischemia and infarction. Those hypertensive patients with left ventricular hypertrophy and who are undergoing noncardiac surgery are at a higher perioperative risk than nonhypertensive patients. There is a great deal of debate regarding a trigger to delay or cancel a surgical procedure in a patient with poorly or untreated hypertension. Although Goldman and Caldera suggested that a case should be delayed if the diastolic pressure is greater than 110 mm Hg, they demonstrated no major morbidity in this small cohort of individuals in their study.7 In the absence of end-organ changes such as renal insufficiency or left ventricular hypertrophy with strain, it would seem appropriate to proceed with surgery. A recent randomized trial of treated hypertensive patients without known CAD who presented the morning of surgery with an elevated diastolic blood pressure was unable to demonstrate any difference in outcome between those who were actively treated versus those in whom surgery was delayed.8 In contrast, a patient with a markedly elevated blood pressure and the new onset of a headache should have surgery delayed for further evaluation and potential treatment. Several other risk factors have been used to suggest an increased probability of CAD. These include the atherosclerotic processes associated with tobacco use and hypercholesterolemia. Based on work by Lee et al., chronic renal insufficiency is also a risk factor for perioperative cardiac morbidity.3 Although these risk factors increase the probability of developing CAD, they have not been shown to increase perioperative risk. When attempting to determine the overall probability of disease, the number and severity of the risk factors are important.

PREOPERATIVE CARDIAC EVALUATION BEFORE NONCARDIAC SURGERY 83

Importance of Surgical Procedure The surgical procedure influences the extent of the preoperative evaluation required by determining the potential range of changes in perioperative management. For example, coronary revascularization may be beneficial for procedures associated with a high incidence of morbidity and mortality, but not those associated with a low incidence, as described subsequently. There is little hard data to define the surgery-specific incidence of complications. It is known that peripheral procedures such as those included in a study of ambulatory surgery completed at the Mayo Clinic are associated with an extremely low incidence of morbidity and mortality.9 Similarly, major vascular procedures are among those with the highest incidence of complications, with a similar incidence documented for infrainguinal and aortic surgery. Eagle et al. published data on the incidence of perioperative MI and mortality by procedure for patients enrolled in the Coronary Artery Surgery Study (CASS).10 They determined the overall risk of perioperative morbidity in patients with known CAD on medical treatment, and the potential reduced rate of perioperative morbidity in those patients who had prior coronary artery bypass grafting (CABG). High-risk procedures for which CABG reduced the risk of noncardiac surgery compared with medical therapy include major vascular, abdominal, thoracic, and orthopedic surgery. The ACC/AHA Guidelines defined three tiers of surgical stress based on composite cardiac events rates, which are shown in Table 3.

Importance of Exercise Tolerance Exercise tolerance is one of the most important determinants of perioperative risk and the need for invasive monitoring. Excellent exercise tolerance, even in patients TABLE 3. High

Intermediate

Low†

Cardiac Risk* Stratification for Noncardiac Surgical Procedures (Reported cardiac risk often >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 <5%) Carotid endarterectomy Head and neck Intraperitoneal and intrathoracic Orthopedic Prostate (Reported cardiac risk generally <1%) Endoscopic procedures Superficial procedure Cataract Breast

*Combined incidence of cardiac death and nonfatal myocardial infarction. †Do not generally require further preoperative cardiac testing. 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.

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with stable angina, suggests that the myocardium can be stressed without becoming dysfunctional. If a patient can walk a mile without becoming short of breath, then the probability of extensive CAD is small. Alternatively, if patients become dyspneic associated with chest pain during minimal exertion, then the probability of extensive CAD is high. Reilly and colleagues demonstrated that the likelihood of a serious complication occurring was inversely related to the number of blocks that could be walked or flights of stairs that could be climbed.11 Exercise tolerance can be assessed with formal treadmill testing or with a questionnaire that assesses activities of daily living (Table 4).

Approach to the Patient The algorithm to determine the need for testing proposed by the ACC/AHA Task Force is based on available evidence and expert opinion, and integrates clinical history, surgery specific risk, and exercise tolerance (Fig. 1).1 First, the clinician must evaluate the urgency of the surgery and the appropriateness of a formal preoperative assessment. Next, determine if the patient has undergone a previous revascularization procedure or coronary evaluation. Those patients with unstable coronary syndromes should be identified and appropriate treatment instituted. Finally, the decision to undergo further testing depends on the interaction of the clinical risk factors, surgeryspecific risk, and functional capacity. For patients at intermediate clinical risk, both exercise tolerance and the extent of the surgery are taken into account with regard to the need for further testing. No preoperative cardiovascular testing should be performed if the results will not change perioperative management. Therefore, although the algorithm may suggest testing, the recommendation is not for mandatory testing, but simply identification of a group that may benefit. Given the results of the CARP trial, these guidelines may soon be revised to suggest testing in an even smaller subset of patients.

TABLE 4. 1 MET

Estimated Energy Requirement for Various Activities*

Can you take care of yourself? Eat, dress, or use the toilet? Walk indoors around the house? Walk a block or two on level ground at 2 to 3 mph or 3.2 to 4.8 km/h? Do light work around the house like dusting or washing dishes?

4 METs

Climb a flight of stairs or walk up a hill? Walk on level ground at 4 mph or 6.4 km/h? Run a short distance Do heavy work around the house like scrubbing floors or lifting or moving heavy furniture? Participate in moderate recreational activities like golf, bowling, dancing, doubles tennis, or throwing a baseball or football?

>10 METs

Participate in strenuous sports like swimming, singles tennis, football, basketball, or skiing?

MET = metabolic equivalent. *Adapted from the Duke Activity Status Index and AHA Exercise Standards. 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.

PREOPERATIVE CARDIAC EVALUATION BEFORE NONCARDIAC SURGERY 85

FIG. 1. The American Heart Association/American College of Cardiology Task Force on Perioperative Evaluation of Cardiac Patients undergoing Noncardiac Surgery has proposed an algorithm for decisions regarding the need for further evaluation. This represents one of multiple algorithms proposed in the literature. It is based on expert opinion and incorporates six steps. First, the clinician must evaluate the urgency of the surgery and the appropriateness of a formal preoperative assessment. Next, he or she must determine whether the patient has had a previous revascularization procedure or coronary evaluation. Those patients with unstable coronary syndromes should be identified, and appropriate treatment should be instituted. The decision to have further testing depends on the interaction of the clinical risk factors, surgery-specific risk, and functional capacity. Adapted 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.

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Choice of Diagnostic Test There are multiple noninvasive diagnostic tests that have been proposed to evaluate the extent of CAD before noncardiac surgery. The exercise electrocardiogram has been the traditional method of evaluating individuals for the presence of CAD. It represents the least invasive and most cost-effective method of detecting ischemia, with a reasonable sensitivity (68% to 81%) and specificity (66% to 77%) for identifying CAD. Electrocardiographic signs of MI and clinical signs of left ventricular dysfunction are considered positive. However, as outlined here, patients with a good exercise tolerance will rarely benefit from further testing. A significant number of high-risk patients are either unable to exercise or have contraindications to exercise. Therefore, pharmacologic stress testing has become popular, particularly as a preoperative test in patients undergoing vascular surgery. Pharmacologic stress for the detection of CAD can be divided into two categories: 1) those that result in coronary artery vasodilation such as dipyridamole, and 2) those that increase myocardial oxygen demand such as dobutamine. The coronary artery vasodilators work by producing differential flows in normal coronary arteries when compared with those with a stenosis. Several authors have shown that the presence of a redistribution defect on dipyridamole thallium imaging in patients undergoing peripheral vascular surgery is predictive of postoperative cardiac events. To increase the predictive value of the test, several strategies have been suggested. Lung uptake, left ventricular cavity dilation, and redistribution defect size have all been shown to be predictive of subsequent morbidity. Dobutamine stress echocardiography has been suggested as the best preoperative test in several recent metaanalyses. The appearance of new or worsened regional wall motion abnormalities is considered a positive test. These represent areas at risk for myocardial ischemia. The advantage of this test is that it is a dynamic assessment of ventricular function. Dobutamine echocardiography has also been studied and was found to have among the best positive and negative predictive values. Poldermans et al. demonstrated that the group at greatest risk was those who demonstrated regional wall motion abnormalities at low heart rates.12

Interventions for Patients with Documented Coronary Artery Disease Strategies to reduce the perioperative risk of noncardiac surgery have recently been reviewed. Eagle et al. studied more than 3,000 noncardiac surgeries in patients who were originally enrolled in CASS and compared the rate of perioperative cardiac morbidity and mortality in those patients in the surgical versus medical treatment arms. In those patients who survived CABG, the rate of perioperative MI was lower for intermediate- or high-risk surgeries but not low-risk surgeries. The current evidence does not support the use of percutaneous transluminal coronary angioplasty (PTCA) beyond established indications for nonoperative patients, because the incidence of perioperative complications does not appear to be reduced in those patients in whom PTCA was performed less than 90 days before surgery.13 The results of a multicenter Veterans Administration Cooperative Study (CARP) addressing the value of prophylactic coronary revascularization before major vascular surgery have recently been reported.14 Patients with risk factors underwent coronary angiography and

PREOPERATIVE CARDIAC EVALUATION BEFORE NONCARDIAC SURGERY 87 TABLE 5.

Risks/Benefits Associated with Preoperative Testing and Coronary Revascularization

Morbidity/mortality association with: Preoperative testing Coronary angiography Coronary revascularization Benefits of preoperative coronary revascularization Reduced complications after noncardiac surgery Long-term improvement

were then randomized to coronary revascularization (CABG or PTCA) versus medical therapy, excluding those with left main disease. No difference in either perioperative or long-term (average 2.7 years) outcome was observed. Based on the prevailing evidence, the indications for CABG and PTCA are identical to those in the nonoperative setting, and simply performing coronary revascularization to “get the patient through surgery” is not indicated. Coronary stent placement may be a unique issue in that two studies suggest that a minimum of 2 weeks, but preferably 6 weeks, is required before the rate of perioperative complications is low (Table 5).15 Drug-eluting stents may represent an additional risk over a prolonged period (up to 6 months) based on case reports. There is now a great deal of evidence to suggest that perioperative medical therapy can be optimized in those patients with CAD as a means of reducing perioperative cardiovascular complications.16 Multiple studies have demonstrated improved outcome in patients given perioperative β-blockers, especially if heart rate is controlled.17 The current ACC/AHA Guidelines advocate these agents based on level I data in patients previously on β-blockers and those with a positive stress test undergoing major vascular surgery.1 The use of these agents in those without active CAD or undergoing less-invasive procedures is advocated as a level IIa recommendation. Based on these newer studies, β-blockers may not be effective if heart rate is not well controlled or in lower-risk patients. A study of 497 patients undergoing vascular surgery randomized to a fixed dose of metoprolol versus placebo demonstrated no difference in perioperative outcome.18 A trial of metoprolol in diabetic patients undergoing a diverse group of surgical procedures was unable to demonstrate any difference in perioperative outcomes. Other pharmacologic agents have also been shown to improve perioperative cardiac outcome. α-2 agonists have been shown to improve both perioperative mortality and 6-month event-free survival.19 Most recently, perioperative statins have been shown to improve cardiac outcome.20 A multimodal approach to medical management should be taken in high-risk patients.

Summary Preoperative evaluation should focus on identifying patients with symptomatic and asymptomatic CAD and the exercise capacity of the patient. The decision to perform further diagnostic evaluation depends on the interactions of patients and surgeryspecific factors, as well as exercise capacity, and should be reserved for those at moderate risk undergoing major or intermediate surgery with poor exercise capacity. The indications for coronary interventions are the same in the perioperative period as for the nonoperative setting.

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References 1. 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. 2. McFalls EO, Ward HB, Moritz TE, et al.: Coronary artery revascularization prior to major elective vascular surgery and long-term outcome: the Coronary Artery Revascularization Prophylaxis (CARP) trial. N Engl J Med 2004; 351:2795–804. 3. Lee TH, Marcantonio ER, Mangione CM, et al.: Derivation and prospective validation of a simple index for prediction of cardiac risk of major noncardiac surgery. Circulation 1999; 100:1043–9. 4. Shah KB, Kleinman BS, Rao T, et al.: Angina and other risk factors in patients with cardiac diseases undergoing noncardiac operations. Anesth Analg 1990; 70:240–7. 5. Rivers SP, Scher LA, Gupta SK, Veith FJ: Safety of peripheral vascular surgery after recent acute myocardial infarction. J Vasc Surg 1990; 11:70–5; discussion 76. 6. Hertzer NR, Bevan EG, Young JR, et al.: Coronary artery disease in peripheral vascular patients: A classification of 1000 coronary angiograms and results of surgical management. Ann Surg 1984; 199:223–33. 7. Goldman L, Caldera DL: Risks of general anesthesia and elective operation in the hypertensive patient. Anesthesiology 1979; 50:285–92. 8. Weksler N, Klein M, Szendro G, et al.: The dilemma of immediate preoperative hypertension: To treat and operate, or to postpone surgery? J Clin Anesth 2003; 15:179–83. 9. Warner MA, Shields SE, Chute CG: Major morbidity and mortality within 1 month of ambulatory surgery and anesthesia. JAMA 1993; 270:1437–41. 10. Eagle KA, Rihal CS, Mickel MC, et al.: Cardiac risk of noncardiac surgery: Influence of coronary disease and type of surgery in 3368 operations. CASS Investigators and University of Michigan Heart Care Program. Coronary Artery Surgery Study. Circulation 1997; 96:1882–7. 11. Reilly DF, McNeely MJ, Doerner D, et al.: Self-reported exercise tolerance and the risk of serious perioperative complications. Arch Intern Med 1999; 159:2185–92. 12. Poldermans D, Arnese M, Fioretti PM, et al.: Improved cardiac risk stratification in major vascular surgery with dobutamine–atropine stress echocardiography. J Am Coll Cardiol 1995; 26:648–53. 13. Posner KL, Van Norman GA, Chan V: Adverse cardiac outcomes after noncardiac surgery in patients with prior percutaneous transluminal coronary angioplasty. Anesth Analg 1999; 89:553–60. 14. McFalls EO, Ward HB, Krupski WC, et al.: Prophylactic coronary artery revascularization for elective vascular surgery: Study design. Veterans Affairs Cooperative Study Group on Coronary Artery Revascularization Prophylaxis for Elective Vascular Surgery. Control Clin Trials 1999; 20:297–308. 15. Wilson SH, Fasseas P, Orford JL, et al.: Clinical outcome of patients undergoing non-cardiac surgery in the two months following coronary stenting. J Am Coll Cardiol 2003; 42:234–40. 16. Fleisher LA, Eagle KA: Clinical practice. Lowering cardiac risk in noncardiac surgery. N Engl J Med 2001; 345:1677–82. 17. Auerbach AD, Goldman L: Beta-blockers and reduction of cardiac events in noncardiac surgery: Scientific review. JAMA 2002; 287:1435–44. 18. Yang H, Raymer K, Butler R, et al.: Metoprolol after vascular surgery (MaVS) [Abstract]. Can J Anaesth 2004. 19. Wallace AW, Galindez D, Salahieh A, et al.: Effect of clonidine on cardiovascular morbidity and mortality after noncardiac surgery. Anesthesiology 2004; 101:284–93. 20. Durazzo AE, Machado FS, Ikeoka DT, et al.: Reduction in cardiovascular events after vascular surgery with atorvastatin: A randomized trial. J Vasc Surg 2004; 39:967–75.

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CHAPTER 8

V O L U M E

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

POSTDURAL PUNCTURE HEADACHE: WHOSE HEADACHE IS IT? ROBERT R. GAISER, M.D. ASSOCIATE PROFESSOR OF ANESTHESIA UNIVERSITY OF PENNSYLVANIA PHILADELPHIA, PENNSYLVANIA

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.

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Postdural Puncture Headache: Whose Headache Is It? Robert R. Gaiser, M.D. Associate Professor of Anesthesia University of Pennsylvania Philadelphia, Pennsylvania

A 24-year-old primigravida (162 cm, 65 kg) requests labor analgesia. Her cervix is dilated 4 cm, and she is experiencing severe pain. The L3 to L4 epidural space is entered using a loss of resistance to air technique. A combined spinal–epidural is planned. After removal of the spinal needle, free-flowing cerebrospinal fluid (CSF) is noted from the epidural needle. At this point, the anesthesia practitioner is confronted with several questions and decisions. Will this patient develop a headache? What is the expected course of this headache? Should the epidural needle be removed and resited or should an intrathecal catheter be placed? Should the patient receive a prophylactic epidural blood patch? What should be done if the patient develops a headache?

History Postdural puncture headache (PDPHA) is the most frequent adverse complication of dural puncture. It is not unique to the specialty of anesthesia and is seen by radiologists after lumbar myelograms and by neurologists after diagnostic dural puncture. PDPHA was first described by August Bier in 1898 when he was investigating spinal anesthesia by injecting cocaine into the subarachnoid space. Bier reportedly felt fine until the next morning when he noted a headache when arising that was relieved by lying down.1 He postulated the headache to be a result of CSF loss. How does a PDPHA become a headache for the anesthesiologist? An obstetric anesthesia closed claims update was published in the American Society of Anesthesiologists newsletter in 1999.2 For obstetric anesthesia, there were 434 claims; 71% involved anesthesia for cesarean section and 29% for vaginal delivery. Although maternal death was the most common injury in this series, the third most common complication was headache (15%) (Fig. 1). Given this high incidence for a relatively minor complication (as compared with brain injury or death), it is easy to see how a PDPHA may become the anesthesiologist’s headache. PDPHA is distressing to the patient. Costigan surveyed 63 patients who experienced accidental dural puncture.3 PDPHA occurred in 86% of the group. After PDPHA, bedrest was the second major complaint. These patients could only get relief from their PDPHA when assuming the supine position. As such, nursing and feeding the baby were extremely difficult. These difficulties increase the patient’s dissatisfaction. In fact, 86% of the group would not choose an epidural again, 72% of the group would not recommend it to family or friends, and 77% denied that the risk of PDPHA had been explained to them beforehand. In another survey of patients who received diagnostic lumbar puncture with a 22-gauge Quincke needle, 39% of the 218 patients had impairment of their daily activities for greater than 7 days.4 89

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FIG. 1. Headache is the third most common reason a lawsuit is filed against the obstetric anesthesiologist. The majority of headaches tend to occur in patients undergoing vaginal delivery. Mat = maternal; Inj = injury; Anesth = anesthesia.

Symptoms The International Headache Society has defined a PDPHA as a bilateral headache that develops within 7 days after lumbar puncture and disappears within 14 days after the lumbar puncture (Table 1). The headache occurs or worsens within 15 minutes of assuming the upright position and disappears or improves within 30 minutes of resuming the recumbent position.5 It usually occurs in the frontal, occipital, or both areas, but also may involve the neck and upper shoulders.6 Although it generally occurs within 48 hours of the dural puncture, it may occur later than 3 days after dural puncture in 25% of the cases. In regard to duration, the largest study was by Vandam and Dripps.7 They followed 8460 patients who received 10,098 spinal anesthetics. The patients were evaluated daily for 1 week and then 6 months later by survey. The needles used were

POSTDURAL PUNCTURE HEADACHE TABLE 1.

91

Symptoms of a Postdural Puncture Headache

Headache (usually frontal or occipital areas) Usually occurs within 3 days of dural puncture Postural component Nausea Neck stiffness Visual disturbance Hearing loss at low-frequency range

of the Quincke type and the gauges ranged from 16 to 24. They reported that 72% of the headaches resolved within 7 days and 87% by 6 months. The persistence of headache beyond 6 months has been documented in a case report in which an epidural blood patch was used to treat a headache 1 year after accidental dural puncture.8 The epidural blood patch was successful. Duration of headache is related to gauge of the needle used. Seven hundred thirty patients received spinal anesthesia with a 26- or 27-gauge Quincke needle.9 Of the patients 40 years or younger, the duration of PDPHA was 4.9 days in the 26-gauge group and 3.8 days in the 27-gauge group. Other symptoms accompanying PDPHA include nausea, vomiting, visual disturbances, and hearing alteration. The visual disturbance was noted by Vandam and Dripps and was attributed to abducens nerve palsy. Subsequent studies reveal that cranial nerves III, IV, and VI are involved with the majority of cases (95%) involving cranial nerve VI. The incidence of visual disturbance is one in 8000. Lybecker studied 75 consecutive patients with PDPHA.10 Visual disturbances occurred in 14% of the patients and was attributed to dysfunction of the extraocular muscles. Unlike visual disturbances, alterations in hearing have been well studied. Fog performed audiograms preoperatively and 2 days postoperatively in 28 patients given spinal anesthesia.11 In 14 patients, a 22-gauge spinal needle was used and a 26-gauge needle in the remainder. Hearing loss of 10 decibels or more was observed in 13 of 14 patients in the 22-gauge group and four of 14 patients in the 26-gauge group. The loss tended to occur in the low-frequency range. The etiology of the hearing deficit is the loss of CSF causing a decrease in CSF pressure, disrupting the balance in the endolymph and perilymph of the inner ear. Not all anesthesiologists agree whether there is an alteration in hearing. Ok studied 30 patients undergoing spinal anesthesia with a 22-gauge Quincke needle. There was no alteration in hearing as compared with before the spinal anesthetic.12 Of note, in this group of patients with an age ranging from 20 to 40 years, only two patients had PDPHA that did not require further intervention.

Incidence The incidence of PDPHA has been extensively studied using different needles and designs and is presented in Table 2.

Etiology In the central nervous system, the choroid plexus makes the majority of CSF. The ventricles and subarachnoid space contains 70 to 180 mL of CSF (80% in the ventricles). The production of CSF is approximately 20 mL per hour. It is generally believed that PDPHA is the result of leakage of CSF through the dural tear. Kunkle showed that in volunteers, removal of 10% of CSF through a lumbar needle reliably produced a headache

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GAISER TABLE 2.

Incidence of Postdural Puncture Headache

Needle Type

Gauge

Incidence

Quincke Quincke Quincke Quincke Quincke Quincke Quincke Quincke Pencil point Pencil point Pencil point Tuohey

16 19 20 22 24 25 26 27 22 24 25 18

18% 10% 16% 10% 6% 6% 6% 1.5% 1.6% 2% 1.1% 52.5%

Data is extrapolated from various studies but primarily from the metaanalysis done by Choi et al.59

that was relieved by the replacement of CSF with an equal amount of sterile saline.13 Actual leakage of fluid into the epidural space has been visualized by epidurography, and an extradural collection of CSF has been demonstrated by magnetic resonance imaging (MRI).14 If the rate of leakage exceeds production, it has been postulated that there is traction on pain-sensitive structures within the cranial cavity as a result of movement of the intracranial structures from decreased CSF volume. There is no evidence to support the hypothesis as MRIs of patients with PDPHA show no measurable sag.15 Another hypothesis for the etiology of PDPHA is cerebral venous dilation. Loss of CSF causes a decrease in CSF pressure without a decrease in intravenous pressure. This pressure difference causes the veins to dilate. In the animal model, removing 10 mL of CSF from anesthetized pigs in 1-mL increments revealed that cerebral blood flow doubled when 7 mL had been removed.16 There is another component to PDPHA if accidental dural puncture occurs and if loss of resistance to air is used to locate the epidural space. A total of 3730 epidural blocks were performed in 2955 patients.17 The identification of the epidural space was either by loss of resistance to air or saline using a total of 1 to 5 mL of either substance. After loss of resistance, 10 mL 0.5% lidocaine was injected. Dural puncture was identified either if backflow of CSF was recognized or if evidence of spinal block occurred. In all patients with evident or suspected dural puncture, a computed tomography scan was immediately obtained. Although dural puncture occurred to a similar extent in both groups (2.6% for air and 2.7% for saline), the incidence of headache was markedly different, 66.7% for air and 9.8% for saline. In the air group, supraspinal intrathecal air bubbles were found on computed tomography examination in 78% of those with a PDPHA. Air was spread widely throughout the lateral, third, and fourth ventricles, Sylvian fissures, and over the convexity of the brain. The headache from intrathecal air is more rapid in onset and has a shorter duration. When a headache occurs after dural puncture if the loss of resistance to air technique is used, there are two components to the PDPHA, CSF loss and intrathecal air.

Risk Factors Not all patients who have dural puncture develop a PDPHA. There are certain patient characteristics that place a patient at a higher risk (Table 3). Lybecker investigated 873 consecutive patients undergoing a total of 1021 spinal anesthetics using a

POSTDURAL PUNCTURE HEADACHE TABLE 3.

93

Risk Factors for Postdural Puncture Headache

Young age Women (debatable) Quincke needle (especially if inserted perpendicular to the longitudinal axis of the spine) Larger-bore needles Pushing during second stage Luck

22-, 25-, or 26-gauge Quincke needles. Seventy-five patients developed a PDPHA. The frequency of PDPHA was inversely associated with age.18 It is important to note that PDPHA virtually never occurs in those <10 years of age. According to Lybecker, there was no difference in the incidence of PDPHA between men and women. Vandam and Dripps noted a higher incidence in women (15% vs. 9%). Because migraines occur more frequently in women and tend to occur during menses, Echevarria studied the influence of the menstrual cycle in PDPHA.19 Hormonal studies were performed when a patient developed PDPHA. The menstrual cycle and hormonal levels had no influence on the incidence or severity of PDPHA in women. The greatest influences on risk of developing a PDPHA are choice of needle and technique. Technique is important for the Quincke needle, ensuring that the direction of the bevel is parallel to the longitudinal axis of the spine. Flaaten studied 212 patients aged 18 to 50 years scheduled for minor nonobstetric surgery during spinal anesthesia using a 27-gauge Quincke needle.20 Half had the bevel of the needle oriented parallel to the dural cylinder and half had the bevel of the needle oriented transverse to the dural cylinder. Headache occurred in 28 patients, four of 106 in the parallel group and 24 of 106 in the transverse group. To understand these results, it is important to consider the histology of the dura mater. The dura mater has an extracellular matrix mainly composed of a ground substance embedding collagen and elastic fibers. The dura mater is a laminated structure built up from well-defined layers oriented concentrically with no predominant direction of the fibers.21 Dittman examined fresh preparations of lumbar dura from five cadavers, puncturing it with 20-to 29-gauge Quincke needles.22 A “tin-lid” phenomenon was evident with parallel puncture: a parallel perforation resembled the top of a tin that had been almost completely opened but with the lid hinged at one point. When turned to enter transversely, the holes were somewhat rounded and the “tin-lid” was not seen. It is postulated that the “tin-lid” is capable of closing the hole and may explain why direction of the bevel of a Quincke needle is important. Parallel in contrast to transverse dural puncture has the greater chance of developing this “tin-lid.” For epidural needles, bevel orientation is not as important if dural puncture occurs. Angle has shown that with an 18-gauge Tuohy needle, perpendicular orientation produced similar rates of CSF leakage as compared with parallel orientation.23 Angle also showed that the thickness of the lumbar dura mater varies. When penetrating the dura mater at a thinner part, the puncture causes a greater hole than when penetrating the thicker part. When translucent specimens of dura are punctured, there is a markedly greater leakage. It appears that there is some component of luck to accidental dural puncture and to accidental intrathecal catheters. In regard to needle type, needle size and design are important. Smaller needles have a lower incidence of PDPHA, especially with the Quincke needle. Vandam and Dripps reported a 16% incidence of PDPHA when using a 20-gauge needle versus a 6% incidence with a 24-gauge Quincke needle. Gauge is not as important for the pencil point needle. A study comparing the 24-gauge (n = 186) and the 22-gauge Sprotte needle (n = 189)

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showed a similar incidence of PDPHA, 1.6%.24 One patient from the 22-gauge needle group required an epidural blood patch. When a blood patch is required in a patient who has a PDPHA from a pencil point needle, consideration should be given to how far the local infiltration needle was inserted. Absalom described a case of spinal cord injury when the local infiltration needle was inserted to the hub.25 It is my opinion that many of these headaches that require epidural blood patch when a pencil point spinal needle is used result from the local infiltration needle being inserted too far and puncturing the dura. With regard to needle design, the pencil point needles (Sprotte, Whitacre, European, Gertie Marx) have a low incidence of PDPHA. When comparing a 27-gauge Quincke needle with a 25-gauge Whitacre needle, the pencil point needle had the lowest incidence.26 However, not all authors have found a difference in incidence between a 24-gauge pencil point needle and a 27-gauge Quincke needle.27 Another factor affecting the incidence of PDPHA from accidental dural puncture during epidural placement is the management of the second stage. In 33 patients with welldocumented puncture with a 17-gauge Tuohy needle, 23 engaged in pushing during the second stage of labor, whereas 10 had cesarean sections before pushing.28 Seventeen of the 23 patients in the pushing group developed a PDPHA versus one of 10 patients in the nonpushing group. Active bearing down during the second stage causes a marked increase in CSF pressure and possibly greater CSF loss. This also may explain whey parturients tend to have a higher incidence of PDPHA from accidental dural puncture than the general population.

Prevention Several maneuvers have been suggested to prevent or treat a PDPHA. Choi reviewed the literature in regard to the obstetric population. They identified 196 relevant citations from 1949 to 1999 with the majority of the studies published in the 1990s.29 Prevention was the focus of over half of the citations. The authors noted that the literature, in regard to prevention and treatment, used suboptimal study design and were nonrandomized. This point deserves consideration as prevention and treatment are considered. Many recommend bedrest after dural puncture to prevent a PDPHA. The first systematic examination of recumbency after dural puncture with a 22-gauge Quincke needle randomized patients to 4 hours or 24 hours of recumbency.30 There was no difference in the incidence of PDPHA (11.6% in the 4-hour group vs. 11.9% in the 24-hour group). Another study examined 80 obstetric patients after dural puncture with a 25-gauge or 26-gague Quincke needle.31 Patients were randomized to 6 hours or 24 hours bedrest. The group who rested 24 hours had a higher incidence (22 of 39 patients) versus those who walked after 6 hours (10 of 41). There appears to be no benefit to recumbency after dural puncture. If dural puncture occurs during attempted epidural analgesia, the anesthesiologist has the option of passing a subarachnoid catheter. It is postulated that leaving a catheter in the dural tear will act as a barrier to CSF leakage during the second stage of labor and also incite an inflammatory reaction that could seal the hole. Norris and Leighton were the first to study intrathecal catheters after accidental dural puncture in the obstetric population.32 Thirty-five women with accidental dural puncture received a subarachnoid catheter that was pulled after delivery. These women were compared with 21 women who had dural puncture and no subarachnoid catheter. There was no difference in the incidence or severity of headache or in the need for epidural blood patch. Liu altered the study design by leaving the catheter in place for 12 to 24 hours after surgery.33

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Eighty-seven patients with an average age of 70 years were studied undergoing orthopedic surgery. Clearly, these patients were already at low risk of developing a PDPHA because only eight developed PDPHA (five in the immediate removal group and three in the delayed removal group). The authors concluded that an intrathecal catheter with delayed removal was no better than an intrathecal catheter with immediate removal. I feel that this study chose the wrong group by selecting a low-risk population. Ayad corrected this problem by studying 115 parturients who had accidental dural puncture.34 The patients were randomized into one of three groups: resite the epidural catheter, intrathecal catheter that was removed after delivery, and intrathecal catheter that was left in place for 24 hours after delivery. The incidence of PDPHA was 91.1% in the resite group, 51.4% in the immediate group, and 6.2% in the delayed group. This data supports the placement of a subarachnoid catheter after the occurrence of a dural puncture with an epidural needle and leaving intrathecal in place for 24 hours. It also helps to explain why the results of Norris and Leighton were less promising. They apparently pulled the catheter too soon. Another maneuver that has been suggested is the injection of intrathecal normal saline. Charsley and Abram studied 28 obstetric patients who received 10 mL of normal saline intrathecally after an accidental dural puncture.35 Of these 28 patients, six received an intrathecal catheter in addition. They compared these patients with 26 patients who did not receive intrathecal saline (five did get an intrathecal catheter). Excluding patients who received intrathecal catheters, 31% of patients in the saline group had a headache versus 62% (although appearing impressive, this did not achieve a statistical difference). The larger difference was in the need for epidural blood patch: one of 22 in the saline group versus nine of 21 patients in the no saline group. Intrathecal injection of 10 mL saline before removal of the epidural needle might prevent the need for an epidural blood patch. I am concerned by this study because the numbers were small and patients were not randomized to isolated therapies (at times combining therapies). I would await a larger study before advocating this therapy. Increasing the complexity of a procedure increases the opportunity for error. Many anesthesiologists recommend placing a prophylactic epidural blood patch through a resited epidural catheter to prevent PDPHA. This practice will be addressed in the epidural blood patch section.

Treatment The treatment of PDPHA ranges from conservative to invasive. Conservative measures include analgesics, bedrest, and intravenous hydration. Other medications have been advocated in the treatment. Caffeine is commonly recommended for the treatment of PDPHA because of its ability to increase cerebral vascular resistance, decrease cerebral blood flow, and decrease cerebral blood volume. The only study examining intravenous caffeine was published in 1978.36 The authors studied 1932 patients undergoing spinal anesthesia with a 22-gauge Quincke needle. Of the 104 patients with PDPHA, 63 cases improved without any therapy. The remaining 41 cases requested therapy and were enrolled in this study. If patients were randomized to caffeine, they received 500 mg caffeine benzoate while the control group received saline. Treatments were effective in 15 of 20 patients in the caffeine group (75%) with one dose and in two patients who received a second dose (thus rendering the overall effectiveness of 85% quoted in the literature). Since this study, there has been no formalized study examining intravenous caffeine.

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Camann investigated 300 mg oral caffeine.37 In this study, the investigators included patients who had PDPHA from dural puncture with either a 17-gauge Tuohy needle or a 26-gauge Quincke needle. Although a difference in severity of symptoms was seen at 4 hours, there was no difference in the severity of headache at 24 hours and no difference in the need for an epidural blood patch. Examining this literature, it is surprising that caffeine is advocated, especially because caffeine is not without risk. Cohen reported a parturient who developed a grand mal seizure from intravenous caffeine.38 Sumatriptan is another potent cerebral vasoconstrictor that is effective for migraines. It acts by binding to serotonin receptors that are responsible for cerebral vasoconstriction. Carp described six cases of PDPHA treated with sumatriptan.39 The PDPHA resolved within 30 minutes after a single subcutaneous injection of 6 mg in all patients. The PDPHA returned in two patients and resolved in one patient after a second subcutaneous injection. Connelly studied 10 patients with PDPHA after accidental dural puncture with an epidural needle.40 Patients were randomized to receive either 6 mg sumatriptan or saline subcutaneously. There was no difference in the relief of symptoms between the two groups. Sumatriptan is probably not effective for PDPHA from accidental dural puncture with an epidural needle, although there have been no adequate studies to fully test this hypothesis. It would be interesting to study whether it is effective for PDPHA accompanying spinal anesthesia using a smaller gauge needle. The pharmacologic interventions mentioned thus far have been given intravenously, orally, and subcutaneously. Additional treatments may be administered through the epidural route. Epidural saline has been used to treat PDPHA. It is thought that epidural saline increases pressure in the epidural space and decreases the outflow of CSF. In 15 patients who had a PDPHA after a 25-gauge dural puncture, 30 mL of saline provided relief in nine of 15 patients 24 hours later.41 No patients (n = 6) who had a PDPHA after a 17-gauge dural puncture had relief at 24 hours. Stevens reported a case of PDPHA that required a 24-hour infusion to obtain relief.42 Epidural saline provides temporary relief that disappears once the saline is absorbed. Case reports suggest that greater success may be achieved if a continuous infusion is administered. Other substances such as dextran have been described. Dextran has slower absorption from the epidural space as compared with saline. Fifty-six adults, who failed various therapeutics, had success after an average of 20 mL dextran was injected epidurally.43 Burning sensation at the injection site and dysesthesia were noted in 3.5% and 7.1% of the patients, respectively. In 1960, Gormley reasoned that blood could serve as the sealing material.44 In his report of seven cases of PDPHA (one of which was himself), the injection of 2 to 3 mL of blood at the site of dural puncture was effective in relieving the headache. Others had difficulty repeating his results, most likely as a result of the volume injected. Taivainen reported an initial success of 91% (30% had return of the headache) when 10 mL of blood was used.45 Crawford recommended up to 20 mL of blood, stopping if the patient reports back or leg pain.46 Using this method, he reported 97% had complete success, whereas the others had a mild headache the next day. The postulated mechanism for its effectiveness is compression of the thecal space increasing the subarachnoid pressure. Sustained therapeutic effect is attributed to clot preventing further CSF leakage.47 Blood injected into the space has been studied both by radioactive studies and by MRI. It has been shown that blood will spread between seven and 14 spinal segments.48 The mean spread of blood is six segments upward and three segments downward. Blood travels to a greater extent cephalad than caudad. MRI shows the blood patch as a large extradural collection, mainly in the posterior space, with spread to the anterior epidural space as well as out the intervertebral foramina into the paravertebral space.49 Complications of the epidural blood patch include back pain (occurs during the first 48 hours

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in 35% of patients and persists in 16% of patients for a mean duration of 27 days) and bradycardia.50,51 Prior dural puncture with or without an epidural blood patch does not affect the success rate of subsequent epidural anesthesia.52 Epidural blood patch has been done in HIV-positive patients without adverse consequences.53 The timing of a blood patch has also been examined. Loesner noted a 71% failure rate if the epidural blood patch was done within 24 hours of the dural puncture as compared with a 4% failure rate if done 24 hours later.54 Subsequent studies have also noted this finding. In an audit of 62 blood patches, only 33% of patients achieved complete relief after epidural blood patch, whereas 50% of the study group achieved partial relief.55 The majority of patches were done less than 24 hours after dural puncture. Another group noted that recurrent headache was significantly higher if the blood patch was performed within 48 hours.56 Finally, the largest series consists of 504 patients.57 Seventy-five percent of patients achieved complete relief, 18% incomplete relief, and 7% no relief. Performing the blood patch within 3 days was a risk factor for failure (odds ratio = 2.63). Thus, depending on definition of relief, it could range from 75% to 93% based on the data from this large series. The diminished effectiveness of epidural blood patch is more likely related to severity of initial headache because those who received the epidural blood patch earlier probably had a worse headache from greater CSF leak. If delay improves the success, one would have to question the feasibility of a prophylactic epidural blood patch. A prophylactic blood patch involves the injection of blood through the epidural catheter before the development of a headache. There are 34 cases of success reported in the literature. Audits of epidural blood patching fail to prove a difference compared with those without a prophylactic blood patch. Furthermore, as all these studies demonstrate, not all patients develop a PDPHA and of those who develop a PDPHA, not all require an epidural blood patch. By doing a prophylactic epidural blood patch, some patients are subjected needlessly to the risks of an epidural blood patch. In a survey of academic institutions in Canada and the United States, prophylactic blood patch was routinely recommended in 37% of centers.58 Of these centers, 80% expressed limited expectations for efficacy, stating it works some of the time.

Case Outcome After accidental dural puncture, a subarachnoid catheter was placed. The patient was begun on an infusion of ropivacaine 0.1% with fentanyl 2 µg/mL at 2 mL/hour. After delivery, the catheter was left in place for 24 hours. She did not develop a PDPHA. If she had, I would not have used caffeine benzoate or sumatriptan. If the PDPHA limited her activities, I would encourage an epidural blood patch. Of note, because the subarachnoid catheter was left in place for 24 hours, it had already been 24 hours since dural puncture. I would use 20 mL autologous blood or less if she developed back pain or leg pain. I would advise the patient that she is at risk for development of a backache and that the headache most likely will return but to a lesser extent. I do monitor the heart rate during placement of an epidural blood patch with pulse oximetry given the risk of bradycardia.

References 1. Turnbull DK, Shepherd DB: Post-dural puncture headache: Pathogenesis, prevention, and treatment. Br J Anaesth 2003; 91:718–29. 2. Chadwick HS: Obstetric anesthesia closed claims update II. ASA Newsletter 1999; 63:6.

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3. Costigan SN, Sprigge JS: Dural puncture: The patients’ perspective. A patient survey of cases at a DGH maternity unit 1983–1993. Acta Anaesthesiol Scand 1996; 40:710–4. 4. Tohmo H, Vuorinen E, Muuronen A: Prolonged impairment in activities of daily living due to postdural punctured headache after diagnostic lumbar puncture. Anaesthesia 1998; 53:296–307. 5. Evans RW, Armon C, Frohman EM, et al.: Assessment/prevention of post-lumbar puncture headaches. Report of the Therapeutics and Technology Assessment Subcommittee of the Academy of Neurology. Neurology 2000; 55:909–14. 6. Wang LP, Schmidt JF: Central nervous side effects after lumbar puncture. Dan Med Bull 1997; 44:79–81. 7. Vandam LD, Dripps RD: Long-term follow-up of patients who received 10,098 spinal anesthetics. Failure to discover major neurological sequelae. JAMA 1954; 156:1486–91. 8. Klepstad P: Relief of postural post dural puncture headache by an epidural blood patch 12 months after dural puncture. 1999; 43:964–6. 9. Kang SB, Goodnough DE, Lee YK, et al.: Comparison of 26- and 27-G needles for spinal anesthesia for ambulatory surgery patients. Anesthesiology 1992; 76:734–8. 10. Lybecker H, Djernes M, Schmidt JF: Postdural puncture headache (PDPH): Onset, duration, severity, and associated symptoms. An analysis of 75 consecutive patients with PDPH. Acta Anaesthiol Scand 1995; 39:605–12. 11. Fog J, Wang LP, Sundberg A, Mucchiano C: Hearing loss after spinal anesthesia is related to needle size. Anesth Analg 1990; 70:517–22. 12. Ok G, Tok D, Erbuyun K, Aslan A, Tekin I: Hearing loss does not occur in young patients undergoing spinal anesthesia. Reg Anesth Pain Med 2004; 29:430–3. 13. Kunkle EC, Ray BS, Wolff HG: Experimental studies on headache: Analysis of the headache associated with changes in intracranial pressure. Arch Neurol Psychiatry 1943; 49:323–58. 14. Vakharia SB, Thomas PS, Rosenbaum AE, et al.: Magnetic resonance imaging of cerebrospinal fluid leak and tamponade effect of blood patch in postdural puncture headache. Anesth Analg 1997; 84:585–90. 15. Grant R, Condon B, Hart I, et al.: Changes in intracranial CSF volume after lumbar puncture and their relationship to post-LP headache. J Neurol Neurosurg Psychiatry 1991; 54:440–2. 16. Boezaart AP: Effects of cerebrospinal fluid loss and epidural blood patch on cerebral blood flow in swine. Reg Anesth Pain Med 2001; 26:401–6. 17. Aida S, Taga K, Yamakura T, et al.: Headache after attempted epidural block. The role of intrathecal air. Anesthesiology 1998; 88:76–81. 18. Lybecker H, Moeller JT, May O, et al.: Incidence and prediction of postdural puncture headache. A prospective study of 1021 spinal anesthesias. Anesth Analg 1990; 70:389–94. 19. Echevarria M, Caba F, Rodriguez R: The influence of the menstrual cycle in postdural puncture headache. Reg Anesth Pain Med 1998; 23:485–90. 20. Flaatten H, Thorsen T, Askeland B, et al.: Puncture technique and postural postdural puncture headache. A randomized, double-blind study comparing transverse and parallel puncture. Acta Anaesthsiol Scand 1998; 42:1209–14. 21. Runza M, Pietrabissa R, Mantero S, et al.: Lumbar dura mater biomechanics: Experimental characterization and scanning electron microscopy observations. Anesth Analg 1999; 88:1317–21. 22. Dittman M, Schaefer HG, Ulrich J, et al.: Anatomical re-evaluation of lumbar dura mater with regard to postspinal headache. Effect of dural puncture. Anaesthesia 1988; 43:635–7. 23. Angle PJ, Kronberg JE, Thompson DE, et al.: Dural tissue trauma and cerebrospinal fluid leak after epidural needle puncture: Effect of needle design, angle, and bevel orientation. Anesthesiology 2003; 99:1376–82. 24. Sears DH, Leeman MI, Jassy LJ, et al.: The frequency of postdural puncture headache in obstetric patients: A prospective study comparing the 24-gauge versus the 22-gauge Sprotte needle. J Clin Anesth 1994; 6:42–6. 25. Absalom AR, Martinelli G, Scott NB: Spinal cord injury caused by direct damage by local anaesthetic infiltration needle. Br J Anaesth 2001; 87:512–5. 26. Lambert DH, Hurley RJ, Hertwig L, et al.: Role of needle gauge and tip configuration in the production of lumbar puncture headache. Reg Anesth 1997; 22:66–72.

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27. Brattebo G, Wisborg T, Rodt SA, et al.: Is the pencil point spinal needle a better choice in younger patients? A comparison of 24G Sprotte with 27G Quincke needles in an unselected group of general surgical patients below 46 years of age. Acta Anaesthesiol Scand 1995; 39:535–8. 28. Angle P, Thompson D, Halpern S, et al.: Second stage pushing correlates with headache after unintentional dural puncture in parturients. Can J Anesth 1999; 46:861–6. 29. Choi PTL, Galinski SE, Lucas S, et al.: Examining the evidence in anesthesia literature: A survey and evaluation of obstetrical postdural puncture headache reports. Can J Anesth 2002; 49:49–56. 30. Thornberry EA, Thomas TA: Posture and post-spinal headache. A controlled trial in 80 obstetric patients. Br J Anaesth 1988; 60:195–7. 31. Cook PT, Davies MJ, Beavis RE: Bed rest and postlumbar puncture headache. The effectiveness of 24 hours’ recumbency in reducing the incidence of postlumbar puncture headache. Anaesthesia 1989; 44:389–91. 32. Norris MC, Leighton BL: Continuous spinal anesthesia after unintentional dural puncture in parturients. Reg Anesth 1990; 15:285–7. 33. Liu N, Montefiore A, Kermarec N, et al.: Prolonged placement of spinal catheters does not prevent postdural puncture headache. Reg Anesth 1993; 18:110–3. 34. Ayad S, Demian Y, Narouze SN, et al.: Subarachnoid catheter placement after wet tap for analgesia in labor: Influence on the risk of headache in obstetric patients. Reg Anesth Pain Med 2003; 28:512–5. 35. Charsley MM, Abram SE: The injection of intrathecal normal saline reduces the severity of postdural puncture headache. Reg Anesth Pain Med 2001; 26:301–5. 36. Sechzer PH, Abel L: Post-spinal anesthesia headache treated with caffeine. Evaluation with demand method. Part 1. Current Therapeutic Research 1978; 24:307–12. 37. Camann WR, Murray RS, Mushlin PS, et al.: Effects of oral caffeine on postdural puncture headache: A double-blind, placebo-controlled trial. Anesth Analg 1990; 70:181–4. 38. Cohen SM, Laurito CE, Curran MJ: Grand mal seizure in a postpartum patient following intravenous infusion of caffeine sodium benzoate to treat persistent headache. J Clin Anesth 1992; 4:48–51. 39. Carp H, Singh PJ, Vadhera R, et al.: Effects of the serotonin-receptor agonist sumatriptan on postdural puncture headache: Report of six cases. Anesth Analg 1994; 79:180–2. 40. Connelly NR, Parker RK, Rahimi A, et al.: Sumatriptan in patients with postdural puncture headache. Headache 2000; 40:316–9. 41. Bart AJ, Wheeler AS: Comparison of epidural saline placement and epidural blood placement in the treatment of post-lumbar puncture headache. Anesthesiology 1978; 48:221–3. 42. Stevens RA, Jorgensen N: Successful treatment of dural puncture headache with epidural saline infusion after failure of epidural blood patch. Case Report. Acta Anaesthesiol Scand 1988; 32:429–31. 43. Barrios-Alarcon J, Aldrete JA, Paragas-Tapia D: Relief of post-lumbar puncture headache with epidural dextran 40: A preliminary report. Reg Anesth 1989; 14:78–80. 44. Gormley JB: Treatment of postspinal headache. Anesthesiology 1960; 21:565–6. 45. Taivainen T, Pitkaenen M, Tuominen M, et al.: Efficacy of epidural blood patch for postdural puncture headache. Acta Anaesthesiol Scand 1993; 37:702–5. 46. Crawford JS: Experiences with epidural blood patch. Anaesthesia 1980; 35:513–5. 47. Rosenberg PH, Heavner JE: In vitro study of the effect of epidural blood patch on leakage through a dural puncture. Anesth Analg 1985; 64:501–4. 48. Szeinfeld M, Ihmeidan IH, Moser MM, et al.: Epidural blood patch: Evaluation of the volume and spread of blood injected into the epidural space. Anesthesiology 1986; 64:820–2. 49. Beards SC, Jackson A, Griffiths AG, et al.: Magnetic resonance imaging of extradural blood patches: Appearances from 30 min to 18 h. Br J Anaesth 1993; 71:182–8. 50. Abouleish E, Vega S, Blendinger I, et al.: Long-term follow-up of epidural blood patch. Anesth Analg 1975; 54:459–63. 51. Andrews PJD, Ackerman WE, Juneja M, et al.: Transient bradycardia associated with extradural blood patch after inadvertent dural puncture in parturients. Br J Anaesth 1992; 69:401–3. 52. Hebl JR, Horlocker TT, Chantigian RC: Epidural anesthesia and analgesia are not impaired after dural puncture with or without epidural blood patch. Anesth Analg 1999; 89:390–4.

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53. Tom DJ, Gulevich SJ, Shapiro HM, et al.: Epidural blood patch in the HIV-positive patient. Anesthesiology 1992; 76:943–7. 54. Loeser EA, Hill GE, Bennett GM, et al.: Time vs success rate for epidural blood patch. Anesthesiology 1978l; 49:147–8. 55. Banks S, Paech M, Gurrin L: An audit of epidural blood patch after accidental dural puncture with a Tuohy needle in obstetric patients. Int J Obstet Anesth 2001; 10:172–6. 56. Williams EJ, Beaulieu P, Fawcett WJ, Jenkins JG: Efficacy of epidural blood patch in the obstetric population. Int J Obstet Anesth 1999; 8:105–9. 57. Safa-Tisseront V, Thormann F, Malassine P, et al.: Effectiveness of epidural blood patch in the management of post-dural puncture headache. Anesthesiology 2001; 95:334–9. 58. Berger CW, Crosby ET, Grodecki W: North American survey of the management of dural puncture occurring during labour epidural analgesia. Can J Anaesth 1998; 45:110–4. 59. Choi PT, Galinski SE, Takeuchi L, et al.: PDPH is a common complication of neuraxial blockade in parturients: A meta-analysis of obstetrical studies. Can J Anesth 2003; 50:460–9.

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CHAPTER 9

V O L U M E

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

LESS JOLTS FROM YOUR VOLTS: ELECTRICAL SAFETY IN THE OPERATING ROOM JEFFREY B. GROSS, M.D., B.S.E.E. PROFESSOR OF ANESTHESIOLOGY AND PHARMACOLOGY UNIVERSITY OF CONNECTICUT SCHOOL OF MEDICINE FARMINGTON, CONNECTICUT

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.

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Less Jolts from Your Volts: Electrical Safety in the Operating Room Jeffrey B. Gross, M.D., B.S.E.E. Professor of Anesthesiology and Pharmacology University of Connecticut School of Medicine Farmington, Connecticut

The electrical nature of matter has been known since antiquity. In fact, the term “electricity” itself derives from the Greek word “elektron,” which means “amber”; approximately 600 years BCE, the Greek philosopher Thales found that when rubbed with fur or wool, amber would attract small objects or give off an eerie bluish glow in the dark. In the 1780s, Luigi Galvani discovered that when a metal scalpel touched the sciatic nerve of a frog, its legs would twitch. A few years later, his colleague, Alessandro Volta, found the reason: When bathed in a conducting medium (like interstitial fluid), two dissimilar metals generate an electrical current; his voltaic “pile” is the precursor of modern batteries. Throughout the 19th century, scientists such as Faraday, Henry, Ohm, and Maxwell discovered the basic principles of electricity, magnetism, and their interactions. Practical application of their findings culminated with the development of the electric light and power distribution system by Edison, Westinghouse, Tesla, and Steinmetz. The perioperative environment poses unique electrical risks to our patients. Electricity is everywhere; operating room tables, lamps, blood warmers, monitors, and cautery devices all pose potential risks. In addition, an abundance of electrically conductive liquids (for example, intravenous and irrigating solutions, interstitial fluids) increases the likelihood of electrical shock. Finally, anesthetized patients are unable to report or withdraw from a painful electrical current, further increasing the risk of burns or cardiac arrest. In this Refresher Course, we first discuss some basic electrical principles. Building on these, we learn how electricity is transmitted from the generating station to our homes or hospitals, and the safety measures that have been developed to reduce the risk of electrical shock in routine applications. Because some of these measures may actually increase the risk of injury in “wet locations” such as the operating room (or your kitchen), additional precautions must be taken to ensure safety in these circumstances. Finally, we discuss the electrocautery—how it works, why it does not cause electrocution, and what problems may result if it is used improperly.

Basic Principles Remember from physics that the atoms of which all matter is composed consist of a positively charged nucleus surrounded by a “cloud” of negatively charged electrons. In some materials (typically metals), the outermost electrons are loosely bound to the corresponding nucleus and thus can move freely; these materials are said to “conduct” electricity. Solutions of ions such as salt water can also conduct electricity; in this case, the ions themselves are free to move within the solution. In either case, however, the number of available current-carrying charged particles (be they electrons or ions) in a given 101

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system is fixed. Thus, the situation is similar to that seen in an ornamental fountain, in which water is pumped from a reservoir in the base to the top of the fountain, at which point it washes over the ornamental decorations, ultimately returning to the reservoir below. Just as interrupting the flow of water at any point in its “circuit” around the fountain will quickly cause the flow of water to cease throughout the fountain, interrupting the flow of electricity at any point in an electrical circuit will cause the electrical current to cease throughout the electrical circuit. Figure 1 is an example of just such an ornamental fountain. The flow of water in the fountain “circuit” is limited by the flow through the orifice at the bottom of the reservoir tank. As the orifice gets smaller, the resistance to flow of water increases and the flow decreases. Conversely, as the height of the water in the reservoir increases, the amount of pressure pushing water through the orifice increases and the flow increases. In this hydraulic analog, the flow is measured in units of liters per second, whereas the pressure corresponds to the energy imparted by the pump to each liter of water (joules/L). The relationship among flow, pressure, and resistance is given by: flow = pressure/resistance, which is the mechanical analog of Ohm’s law. Now consider the diagram of Figure 2. In this case, the electric battery serves the role of the pump, pushing electrical charge around the circuit. Electrical charge is measured in Coulombs (1 Coul = 6.2 × 1018 electrons), and the flow of electrical charge (denoted by the symbol “I”) is measured in amperes (1 A = 1 Coul/sec). Electrical pressure (the amount of energy imparted to each Coul of charge by the battery) is denoted by the symbol “E” measured in volts (1 V = 1 J/Coul). The amount of current that will flow at any

FIG. 1. Hydraulic analog of electric circuit. The pump imparts potential energy to the water. This energy is dissipated as the water flows “downhill” through the reservoir and out the orifice. The flow is directly proportional to the pressure (height) of the water and inversely proportional to the resistance imposed by the orifice. Interruption of flow at any point in the “circuit” will quickly cause all flow to cease.

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FIG. 2. Simple electric circuit. The battery imparts a potential energy (E) of 6 J to each Coul of charge (6 V = 6 J/Coul). The current flow (I) in the circuit is 2 A (2 Coul/sec) according to Ohm’s law (I = E/R). The power dissipated in the resistor is 12 W (P = I × E: 6 J/Coul × 2 Coul/sec = 12 J/sec = 12 W).

given voltage depends on the resistance “R” according to Ohm’s law: I = E/R. The product of current (I) and voltage (E) is the power delivered by the battery to the circuit: P = I × E (J/Coul × Coul/sec = J/sec = W). By algebraic substitution, we can also show that P = I2 × R. The effect of electricity on the body depends on the magnitude of the current as well as the composition of the tissues through which the current passes (Table 1). Note that currents of less than 1 mA are below the threshold of sensation. If brought into proximity of the cardiac conducting system (by an intracardiac catheter or electrode), the cardiac rhythm may be disrupted as a result of “microshock.” Because the currents involved are so small, special precautions must be used when intracardiac electrodes are in place (see subsequently). Currents in the 1- to 10-mA range cause a tingling sensation by activating sensory nerves; for example, a 9-V battery may be tested by placing its contacts on the tongue; the resulting current will cause a tingling sensation. Currents in the 10- to 100-mA range cause muscular contractions; anesthesiologists use this phenomenon daily with our neuromuscular “twitch” monitors. Currents between 100 mA and 5 A are likely to cause ventricular fibrillation if they pass through the chest. In contrast, currents in excess of 5 A passing through the chest cause complete ventricular standstill, allowing the heart to resume a normal rhythm when the current is removed; this is the principle of cardiac defibrillation. Note that electrical current can cause damage without flowing through the chest; currents on the order of 100 mA passing through the brain cause seizures (electroconvulsive therapy), whereas currents in the 1-A range passing through TABLE 1.

Effect of Electrical Current on the Human Body

Current

Effect

10–100 µA 1–10 mA 10–100 mA 100 mA–5A >5A

V-Fib if applied directly to cardiac conducting system (microshock) Minimal sensation Muscle contractions V-Fib if current passes through chest Cardiac standstill/defibrillation

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extremities can cause severe burns. Because electrical burns involve not only the skin, but also the underlying muscle, they can be very difficult to treat and slow to heal.

Early Electrical Power Systems The skin is the body’s primary barrier to electrical current. Dry skin has a resistance of 1,000 to 10,000 ohms. In designing his original electrical distribution system, Edison limited the voltage to 100 V so that an individual accidentally touching the wires would be subjected to a current of no more than 0.1 A (100 V/1,000 ohms), just below the limit of cardiac arrhythmia production. Unfortunately, limiting the voltage to 100 V caused significant problems in power distribution. Remember that power lines, themselves, have some resistance to the flow of electricity (Edison attempted to minimize this by using thick copper conduits buried under the sidewalks.). Nonetheless, some of the power delivered to the system was dissipated in the power line before getting to the customer. In the example of Figure 3, with a single customer using 100 W of power at 100 V, the current is 1 A. According to the I2R law (see previously), 1 W is lost in the power line, so the system is 99% efficient. However, when a second customer signs on, using an additional 100 W, the current increases to 2 A, and the power dissipated in the power line increases to 4 W. When a third customer turns on their 100-W lamp, the losses in the power line increase to 9 W; thus, the losses in the power line increase in proportion to the square of the power delivered to the customers. With Edison’s system, it was imperative that the power lines be kept as short as possible (minimizing their resistance); therefore, power stations were necessarily located at intervals of 1 mile or less! As customers found more and more uses for electricity (fans, toasters, space heaters, and so on), engineers sought more efficient ways of generating electricity. Near Buffalo, there was an apparently limitless source of power—Niagara Falls. The only problem was how to transmit the power from the falls to where it was needed. It became apparent that higher voltages could overcome the problem of energy losses in the power line: If, in the example cited here, the voltage were 1,000 V rather than 100 V, the current required by a 100-W light bulb would be 0.1 A, and the power line loss would be 0.01 W. Even with three customers (each using 100 W), the power line dissipation would be only 0.09 W—a 100-fold saving. The problem was that 1,000 V was too dangerous for household use, and there was no practical way of changing the voltage of the one-way or “direct current” used by Edison’s system.

The Rise of Alternating Current Fortunately, some 40 years earlier, Faraday had demonstrated the interrelationship between electricity and magnetism: When a changing magnetic field passes through a coil of wire, an electrical current is generated; furthermore, when a changing electrical current passes through a coil of wire, a changing magnetic field is produced. Using these two observations in tandem led to the invention of the electrical “transformer.” This ubiquitous device allows electrical voltage to be changed, because the ratio of input:output voltage is the same as the ratio of turns in the primary:secondary coils (Fig. 4). The only proviso is that the electrical current fed to the device must be constantly changing. By using current that flows in a sinusoidal pattern (first one way, then the other), Tesla and Westinghouse devised a practical “alternating current” or “AC” power delivery system, whereby power is transmitted over long distances at high voltages and then

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FIG. 3. (A) Early electric delivery system delivering 100 W of power to a single customer. In this case, the power lost in the “power line” on the way to the customer is given by P = I2R = 1 W. (B) When a second customer, also using 100 W of power, signs up, the total current rises to 2 A, and by the I2R law, the loss in the power line rises to 4 W. Before long, more power is lost in the power line than is delivered to the customers.

“stepped down” to a safe voltage by a transformer near the consumer. Note that although the primary and secondary coils are magnetically coupled, they are electrically insulated from each other. Early AC power delivery systems presented significant hazards to their users. Power was transmitted from the power station to the user at the relatively high (then) voltage of 2,400 V and “stepped down” to 120 V by a 20:1 transformer on the power pole near the customer (Fig. 5). To save money (copper), engineers used the earth as one of the conductors. Because normally functioning transformers do not provide an electrical connection between the primary and secondary circuits, the 120 V delivered to the user was perfectly safe. That is, unless moisture got into the power pole transformer and

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FIG. 4. Schematic of an electrical transformer. The primary and secondary coils are electrically insulated from each other but are wound around a common iron core, providing a common magnetic field. The ratio of voltages in the primary and secondary coils is equal to the ratio of turns in the coils. Note that the amount of power remains unchanged: if the voltage in the secondary is three times that of the primary, the current in the secondary circuit is one third that in the primary circuit.

FIG. 5. Early alternating current electrical power system. In normal operation, the secondary conductors leading into the house have 120 V between them and they are isolated from ground by the insulation in the power transformer. However, if the transformer’s insulation becomes conductive (like in a rainstorm), high voltage from the primary side (2,400 V referenced to ground) can “leak” to the secondary side. Although there will still be 120 V between the two conductors, they are at 2,280 and 2,400 V above ground potential. Because the insulation in switches and fixtures generally breaks down at approximately 600 V, great-grandma is likely to get “Westinghoused” if she touches the light switch. In modern wiring systems, one side of the power line is directly connected to ground (usually a water pipe) at the place where the electrical services enters the building.

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allowed some of the 2,400 V power to “leak” into the secondary side of the circuit. Then, although there would still be 120 V between the two wires leading to the house, 2,400 V would exist between these wires and ground, creating risk of a lethal electrical shock. After several unfortunate people were killed in this manner, Edison (whose patents covered DC but not AC power) lobbied to have AC power banned, because people were likely to be “Westinghoused” by this dangerous system. However, engineers soon discovered how to make AC systems safe: One side of the 120-V power line entering the house was directly connected to a ground; even today, the fuse box where power enters your house is directly connected to a cold water pipe or grounding rod— take a look! Although this innovation prevented high voltages from entering the house, having one side of the power line attached to a ground created other hazards. Consider great-grandma’s refrigerator (or Frigidaire) in the 1920s. When manufactured, the electrical wiring was completely insulated from the steel cabinet; however, with time, the insulation on the internal wiring was likely to deteriorate. If the nongrounded or “hot” power conductor came into contact with the case, a dangerous situation would be created. An individual touching both the refrigerator case and any grounded object in the kitchen (like the proverbial kitchen sink) would complete a circuit and be subject to electrocution. What’s more, the refrigerator would appear to be functioning normally, because household fuses are designed to “blow” when current exceeds the safe capacity of the wiring (15 to 30 A) rather than the 0.1 A extra current needed to cause ventricular fibrillation. A dangerous situation could exist even if the refrigerator wiring were not in direct contact with the case. Moisture (in the form of spilled liquids or condensation) could easily conduct sufficient current to the case to create an electrical hazard. The risk that the case of an appliance might be electrically “hot” led to the frequent parental admonition of never touching an electrical appliance while your hands/feet are wet (and potentially grounded).

Safety Ground—Three-Wire Receptacles By the 1950s, this risk was recognized, and a solution was adopted: appliances whose cases were likely to become electrically “live” were fitted with three-wire electrical plugs (Fig. 6). The third prong, slightly longer than those used to power the device, served to connect the case of the appliance directly to a ground; in this manner, any stray voltage which found its way to the case would be diverted to a ground rather than posing a risk to the user. If the “hot” power conductor were shorted directly to the appliance case, a high current would flow, blowing the main fuse; if the problem were “leakage” through moisture or an indirect connection, the fuse would not blow, but the user would still be safe because current would be shunted safely to ground through the third wire. Although the three-wire system is still widely used “around the house,” it is not safe enough for use in “wet locations” such as the kitchen, bathroom, or operating room. The reason is twofold: First, if the ground wire breaks or becomes disconnected, users are at immediate risk; although grounding continuity is checked on an annual basis by most hospital biomedical departments, rolling an operating table or anesthesia machine over an electrical wire could easily disrupt the connection. Second, if an individual should accidentally touch the “hot” conductor (for example, by letting the hair dryer drop into the sink), grounding the case offers no protection (in fact, it may actually increase the risk by increasing the likelihood of touching the “hot” conductor and grounded case simultaneously). Finally, anesthetized patients are at additional risk because they cannot “feel” potentially hazardous leakage currents and pull away appro-

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FIG. 6. Typical three-wire electrical system introduced in the 1950s. Note that the “safety ground” connection will preferentially carry any current that leaks to the case of the refrigerator directly to a ground, preventing it from harming an individual who simultaneously touches the refrigerator and the ground. If the hot conductor is directly touching the case of the refrigerator, the current flowing through the safety ground will be sufficient to “blow” the fuse or “trip” the circuit breaker, removing power and indicating a problem. However, if there is an incomplete connection (through moisture, and so on) from the hot conductor to the case, the refrigerator will continue to function normally. Under these circumstances, if the ground wire were damaged, the user would be at risk.

priately. For these reasons, operating rooms (and other wet locations) are required to have additional safety devices.

Isolated Electrical Power The older (and still more common) system used in operating rooms is “isolated electrical power.” In this system, a second 1:1 transformer is interposed between the standard hospital power (having “hot” and “neutral”) conductors and the electrical receptacles in the operating room (Fig. 7). In this system, neither of the power conductors is grounded; therefore, you could safely touch either of the power conductors and ground simultaneously without any risk (Fig. 7). This alleviates both of the problems alluded to here: Even if the ground wire is defective, a short circuit (or leakage) between one of the power conductors and the case of the monitor poses no risk, because the other power conductor is not connected to a ground. Thus, touching an electrically “live” case and ground simultaneously does not complete a circuit. However, if one of the power

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FIG. 7. Isolated electrical power system as used in operating rooms. Note that output voltage of the 1:1 isolation transformer is the same as its input voltage (120 V) but that neither of the output conductors is grounded. Thus, like the proverbial “bird sitting on the power line,” you can safely touch either of the isolated power conductors and ground simultaneously without risk. However, if one side of the isolated system was to become grounded (either through a direct connection or an electrical “leak” through a moist surface), then touching the other side and ground simultaneously would create a risk. The line isolation monitor (LIM) tells the maximum amount of current that could flow through a second fault if one side of the power line becomes indirectly or directly grounded.

conductors should touch the case of the monitor, that conductor is now grounded, and the power in the operating room is no longer electrically isolated. Because it is important to know that the isolation is no longer in effect, isolated electrical power systems are equipped with “line isolation monitors” (LIMs). These continuously monitor the power system to determine if there is a potential leakage of current from either side of the power line to a ground (note that leakage does not actually occur unless the other side of the power line was attached to a ground as well). Thus, the LIM monitors the maximum current that could flow to a ground if the other side of the power line were attached directly to a ground. The LIM reading is an indication of the risk to which a patient (or anesthesiologist) would be exposed if there were a second defective piece of equipment wherein the other side of the power line was connected directly to the case. Note that the third “grounding” wire plays an important role in isolated power systems; it is current flow through this conductor that causes the LIM to register. Note

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that if the LIM registers leakage current only when the operator (or patient) touches the defective device, a much more serious condition exists: Not only is there a connection between one of the power conductors and the case of the equipment, but the case is not effectively grounded. LIMs are designed to audibly alarm if the potential leakage current from either side of the isolated power system to ground exceeds 5 mA. Hazard currents below this level are readily achievable, yet currents in this range do not pose a risk when applied externally. Note that isolated power systems do not protect against microshock, which may occur with currents two orders of magnitude smaller. If the LIM alarms, it is incumbent on the operating room personnel to locate and remove the offending equipment from the electrical circuits. This may be accomplished by unplugging devices one at a time (starting with the most recently plugged in or with any devices that may have been accidentally exposed to liquids) until the offending device is located. Note that hazard currents are cumulative. That is, the electrical leakage from several devices, each of which is individually below the 5-mA threshold, may combine to cause a potentially hazardous situation. If, after all portable equipment has been unplugged, the LIM continues to indicate a potentially hazardous condition, the problem most likely lies in the room wiring or fixed devices such as the operating lamps. Note that life-sustaining equipment that does not have battery backup should not be unplugged during a procedure in an effort to determine the cause of an LIM alarm condition. (Do not unplug the cardiopulmonary bypass machine!) Remember, although the LIM is telling you that the electrical power is no longer isolated (that is, you have the same situation that existed in laundry rooms, kitchens, and bathrooms until the 1980s), it is still necessary to have a second electrical defect to put you or your patient at immediate risk.

Ground Fault Circuit Interrupters With the advent of microelectronics in the 1970s and 1980s, a new option has become available for preventing electric shock in wet locations: the ground fault circuit interrupter (GFCI). These devices (which cost less the $10 each) work in a different way than the isolated power systems described here. They continuously monitor the current flowing in the “hot” and “neutral” power conductors of an ordinary (one side grounded) power system. If the device senses that the current in the “hot” and the “neutral” conductors differs by more than 5 mA, it immediately (<25 ms) disconnects the power from the receptacle. Under what conditions would the current between the two power conductors differ? First, if there is a direct connection (or leakage) between the “hot” conductor and the case of the monitor, some of the current flowing in the “hot” conductor would return to ground through the safety ground connection rather than the “neutral” conductor. Thus, the current in the “hot” conductor would exceed that in the “neutral” and the current would be interrupted. If the safety ground connection is defective, the equipment will continue to operate even if the case is electrically “hot.” However, if the user (or patient) completes a circuit between the case and the ground, a current imbalance will once again occur. A portion of the current will return to ground through an alternate route (the user) rather than through the “neutral” conductor, and the GFCI will disconnect the circuit. This occurs so quickly that cardiac arrhythmias are unlikely. If a GFCI “trips” in the operating room, the first step is to press the reset button to see if the tripping was caused by a current surge; some motors may cause a transient current imbalance that does not indicate a hazardous condition. If the GFCI trips again, it is

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necessary to unplug equipment sequentially, resetting the GFCI after each until the defective equipment is located. A disadvantage of the GFCI is that it protects by turning the power off. Hence, if the defect lies in a piece of life-sustaining equipment, there is no way to continue using that equipment until it is repaired. Resist the temptation to use a “cheater” that ungrounds the case of the defective equipment. Although the GFCI will not trip if the case is not grounded, the case is electrically live and poses a hazard to the operator or patient. Note that if the GFCI only trips when the equipment is touched by the operator or attached to the patient, a more hazardous situation exists: Not only is there electrical leakage from the “hot” side of the power line to the case, but the safety ground of the equipment is not functional.

Microshock None of the safety measures discussed so far has any influence on the risk of microshock, which results when currents on the order of 10 to 100 µA are applied directly to the conducting system of the heart through intracardiac catheters or pacing wires. Because such wires bypass the skin resistance, relatively small voltages may suffice to produce microshock; isolated power systems, GFCIs, and equipment safety grounding cannot prevent it. Rather, special precautions must be taken when the possibility of microshock exists. All monitoring equipment attached to intracardiac catheters or electrodes must be electrically isolated. This means that there is no direct electrical connection between the wiring attached to the patient (for example, electrocardiogram, pressure transducers) and the internal wiring of the monitoring equipment. How can this be accomplished? The monitoring modules are typically powered through special isolation transformers, which effectively isolate the power within the modules from the power system of the remainder of the monitoring unit as well as from a ground (see subsequently). The monitored signals are transmitted from the module to the main chassis of the monitor through “opto-isolators.” These devices convert the electrical signals corresponding to the electrocardiogram or pressure trace to a beam of light (whose intensity is related to the strength of the signal); the light beam impinges on a photodetector that converts the light intensity back to an electrical signal, which is ultimately displayed on the monitor screen. In this way, a maximum current of 50 µA can flow through an intracardiac electrode, even if the patient is attached directly to the “hot” side of a standard, grounded power system. Temporary external pacemakers are typically battery-powered and hence intrinsically electrically isolated unless one of the pacing wires or an internal component comes into contact with a conductor. Therefore, such devices should not be powered by “battery eliminators” unless such devices are specifically designed to provide adequate patient isolation. An important consideration is that “grounding” an intracardiac catheter or electrode does not provide an increased margin of safety; rather, this would tend to increase the risk of microshock. The reason for this is that other devices with which the patient may be in contact may not be electrically grounded. For example, suppose that a patient’s skin is electrically in contact with the operating table through moisture in the sheets. If the operating table is not properly grounded (frayed or loose grounding conductor), a leakage current of several mA could be present with no indication on the LIM. However, passage of this current to ground through the intracardiac catheter could suffice to cause ventricular fibrillation (Fig. 8). The same scenario may occur if cardiac pacing wires accidentally touch the operating table even though the table is, theoretically, grounded.

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FIG. 8. Microshock risk associated with a grounded intracardiac electrode. In this case, the safety ground of the operating table has become frayed, and a small hazard current (perhaps 1 mA) could potentially flow from the operating room table to a grounded conductor. This current is too low to trigger the line isolation alarm, but, by returning to ground through the grounded intracardiac catheter, may allow enough current to flow through the cardiac conducting system to cause ventricular fibrillation. For this reason, intracardiac electrodes should be electrically isolated so that no current can flow through them even if the patient comes in contact with a live electrical conductor.

Electrocautery The electrosurgical unit (ESU) is designed to create a localized, high-temperature electrical discharge at the site of surgical bleeding, causing coagulation of tissues and cessation of bleeding. This is accomplished by creating a high-density electrical current: When a large amount of current is concentrated in a small area, heating is inevitable. In addition, the voltages produced by the electrosurgical unit are sufficient to ionize the adjacent air, with the resulting “sparks” contributing to the heating and coagulation process. There are two reasons that those parts of the patient not directly under the cauterizing electrode are unaffected by the process. First, immediately after entering the tissues, the current spreads out to be conducted over a much wider area of the patient’s body. As a result, the current density (and heating) is minimized. Of course, the patient forms part of the electrical circuit of the electrosurgical system and therefore some means must be provided to complete the circuit from the patient back to the unit (Fig. 9). This is accomplished through the return electrode or “grounding pad.” This pad is designed to dissipate the current over a wide enough area to prevent accidental heating or burning of the region under the pad. Note that in modern electrosurgical units, the pad is not “grounded” per se; this prevents it from serving as an inadvertent means of conducting macro- or microshock currents into the patient. If the return pad is not attached to the patient, current from the active electrode will seek an alternative route to return to the generator. Because the electrocautery produces alternating current of high frequency

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FIG. 9. The electrocautery unit functions at “radio” frequencies of several hundred kilohertz (hundreds of thousands of cycles per second). These frequencies are chosen because they tend to flow on the surface rather than through the center of a conductor, minimizing the risk of interacting with the cardiac conducting system. However, because of “capacitative coupling,” the cautery current can easily pass through “electrically isolated” electrocardiogram electrodes and other patient connections. Normally, the current enters the patient through the small active electrode used by the surgeon (high current density results in cauterizing of tissue) and returns to the generator through the large grounding electrode (low current density keeps underlying tissue safe). If the return electrode is not properly connected, current will find its way back through the path of least resistance, which may include the electrocardiogram pads, a place where the patient is touching the metal operating room table, or the anesthesiologist’s hand. If the contact area is small, the current density will be high and a “Bovie burn” may result.

(typically 100 KHz or more), the current can actually be conducted between two adjacent conductors even if they are not in electrical contact (capacitative coupling). Furthermore, the electrical isolation of monitoring equipment and power systems is ineffective at these frequencies. Therefore, if the return electrode is not attached to the patient, the current may return to the generator through electrocardiogram electrodes or other metallic objects (for example, the operating table) that may be in contact with the patient. Because these provide a smaller contact area with the patient, the current will be more concentrated, and the patient may be burned at the site of these inadvertent return paths. Modern electrocautery machines are equipped with “split pads”; the unit will not function unless both halves of the pad are in contact with the patient. Because it delivers currents in excess of those required to cause ventricular arrhythmias, why do we not see such arrhythmias when the cautery is used? As mentioned previously, the cautery uses high-frequency alternating current. Tesla demonstrated more than 100 years ago that such currents are carried on the surface of a conductor rather than penetrating it; this is the “skin effect.” Accordingly, almost all of the electrosurgical current is carried by the skin and subcutaneous tissues rather than penetrating to the cardiac conduction system. In fact, it is possible to use the electrosurgical unit on the epicardial surface of the heart without affecting the internally located conducting system.

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References Gross JB, Seifert HA: Electrical, Fire and Compressed Gas Safety for the Patient and Anaesthetist. In: Healy TEJ, Cohen PJ, eds. Wylie and Churchill-Davidson’s A Practice of Anaesthesia, 6th ed. London: Edward Arnold; 1995. Jonnes J: Empires of Light. Edison, Tesla, Westinghose and the Race to Electrify the World. New York: Random House; 2003. Cheney M, Uth R: Tesla: Master of Lightning. New York: Barnes and Noble Books; 1999. NFPA 70: National Electrical Code. New York: American National Standards Institute; 1999.

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CHAPTER 10

V O L U M E

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

LOWER EXTREMITY PERIPHERAL NERVE BLOCKS ADMIR HADZIC, M.D., PH.D. DIRECTOR OF REGIONAL ANESTHESIA DEPARTMENT OF ANESTHESIOLOGY ST. LUKE’S–ROOSEVELT HOSPITAL CENTER COLLEGE OF PHYSICIANS AND SURGEONS COLUMBIA UNIVERSITY NEW YORK, NEW YORK TONY TSAI, M.D. REGIONAL ANESTHESIA FELLOW DEPARTMENT OF ANESTHESIOLOGY ST. LUKE’S–ROOSEVELT HOSPITAL CENTER NEW YORK, NEW YORK TAKASHIGE IWATA, M.D. RESEARCH FELLOW IN REGIONAL ANESTHESIA DEPARTMENT OF ANESTHESIOLOGY (REGIONAL ANESTHESIA) ST. LUKE’S HOSPITAL NEW YORK, NEW YORK KAYSER ENNEKING, M.D. ASSOCIATE PROFESSOR OF ANESTHESIOLOGY UNIVERSITY OF FLORIDA AMBULATORY SURGERY CENTER GAINESVILLE, FLORIDA

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.

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Lower Extremity Peripheral Nerve Blocks Admir Hadzic, M.D., Ph.D. Director of Regional Anesthesia Department of Anesthesiology St. Luke’s–Roosevelt Hospital Center College of Physicians and Surgeons Columbia University New York, New York Tony Tsai, M.D. Regional Anesthesia Fellow Department of Anesthesiology St. Luke’s–Roosevelt Hospital Center New York, New York Takashige Iwata, M.D. Research Fellow in Regional Anesthesia Department of Anesthesiology (Regional Anesthesia) St. Luke’s Hospital New York, New York Kayser Enneking, M.D. Associate Professor of Anesthesiology University of Florida Ambulatory Surgery Center Gainesville, Florida

Lower extremity peripheral nerve blocks (PNBs) have not been as widely taught or used as other forms of regional anesthesia. Unlike the upper extremity, the entire lower extremity cannot be anesthetized with a single injection, and injections are generally deeper than those required for upper extremity blocks. Over the past decade, several developments have led to an increased interest in lower extremity PNBs, including transient neurologic symptoms associated with spinal anesthesia, increased risk of epidural hematoma with the introduction of new antithromboembolic prophylaxis regimens, and evidence of improved rehabilitation outcome with continuous lower extremity PNBs. This refresher course focuses on techniques and applications of lower extremity nerve blocks, as well as potential complications and means to avoid them.

Lower Extremity Nerve Block Techniques Psoas Compartment Block (Lumbar Plexus Block) The psoas compartment block (PCB) is a deep block of the lumbar plexus approached posteriorly and can be performed either as a single injection or as a continuous technique This research was supported by the Department of Anesthesiology at St. Luke’s–Roosevelt Hospital Center, New York, NY

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with catheter placement for prolonged analgesia. The PCB block provides anesthesia for thigh surgery and hip fracture repair in combination with a parasacral nerve block.1 The PCB is successfully used for analgesia after total hip arthroplasty (THA),2–4 total knee arthroplasty (TKA),5 and in the treatment of chronic hip pain.2 At the level of L4 to L5, the following anatomic structures would be encountered from posterior to anterior: posterior lumbar fascia, paraspinous muscles, anterior lumbar fascia, quadratus lumborum, and the psoas muscle. The common iliac artery and vein lay anterior to the psoas muscle, which is located inside a fascial sheath, the psoas compartment. The most consistent approach to block the entire lumbar plexus with a single injection is through the posterior approach, because the lumbar plexus travels through the body of the psoas muscle. The PCB provides consistent anesthesia in the distributions of the femoral, lateral cutaneous nerve of the thigh, and the obturator nerves. Several descriptions of the needle entry site for PCB have been described.1–3,6,7 (Fig. 1) Most descriptions rely on bony contact with the transverse process as a guide to depth of needle placement. The distance from the skin to the lumbar plexus ranges from 6.1 to 10.1 cm in men and 5.7 to 9.3 cm in women, and this distance correlates with gender and body mass index (BMI). The distance from the transverse process to the lumbar plexus is typically less than 2 cm, and this is independent of BMI or gender. Contact with the transverse process provides a consistent landmark to avoid excessive needle penetration during PCB.8 The depth of needle insertion is emphasized because of the complications associated with deep needle penetration, including renal hematoma, pneumocele, total spinal anesthesia, and unintended intraabdominal and intervertebral disk catheter placement.8–11 Epidural spread of local anesthetic is a common side effect of PCB occurring in 9% to 16% of adult patients.12,13 In children, Dalens reported a greater than 90% incidence of epidural spread when using the original landmarks of Chayen compared with no epidural spread when using the landmarks as modified by Winnie.14

FIG. 1. Lumbar plexus block: A 10-cm long needle is inserted at the L3/4 level and 3 to 4 cm lateral to the midline. Reproduced with permission from: Hadzic A, Vloka J: Peripheral Nerve Blocks: Principles and Practice. New York, McGraw Hill, 2003.

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The epidural spread is attributed to diffusion of the local anesthetic into the epidural space when large volumes of local anesthetic (greater than 20 mL) are used. In most cases of epidural spread, residual lumbar plexus blockade is apparent after resolution of the contralateral block. However, there are case reports of total spinal anesthesia occurring during PCB, and vigilance must be maintained during the management of this block.10,15

Continuous Psoas Compartment Blocks Continuous PCB techniques have been described to provide analgesia after a variety of operations, including THA, TKA, open reduction and internal fixation (ORIF) of acetabular fractures, ORIF of femur fractures, and anterior cruciate ligament (ACL) reconstruction.4,8,16–20 Interest in this block developed as practitioners sought alternatives to central neuraxial techniques that could provide consistent analgesia after hip, femur, and knee surgery. One advantage of PCB over other continuous approaches to the lumbar plexus is the decreased likelihood of catheter dislodgement because of the large muscle mass that must be traversed to reach the lumbar plexus. Continuous infusion of local anesthetic should be started after an initial bolus is given through the catheter. Care must be taken to watch for local anesthetic toxicity, intravascular injection, and the unilateral sympathetic blockade that accompanies a PCB.

Femoral Nerve Block Indications for single injection femoral nerve block (FNB) include anesthesia for knee arthroscopy in combination with intraarticular local anesthesia and analgesia for femoral shaft fractures, ACL reconstruction, and TKA in multimodal regimens.21–27 The femoral nerve divides into the posterior and anterior divisions shortly after it emerges from under the inguinal ligament and undergoes extensive arborization. Commonly, the anterior branch of the femoral nerve, which innervates the sartorius muscle, will be identified first. Vloka and Hadzic reported this to be a common first motor response.28 Stimulation of this branch leads to contraction of the sartorius muscle on the medial aspect of the thigh and should not be accepted, because the articular and muscular branches arise from the posterior part of the femoral nerve. The needle should be redirected slightly laterally and deeper to encounter the posterior branch of the femoral nerve. Stimulation of this branch is identified by patellar ascension as the quadriceps contract (Fig. 2).

A Three-in-One Block During FNB, it has been advocated to use a higher volume of local anesthetic and apply firm pressure just distal to the needle during and a few minutes after injection to block the femoral, lateral femoral cutaneous (LFC), and obturator nerves, the socalled 3-in-1 block.29 Despite many efforts to consistently produce a 3-in-1 block, the efficiency of these maneuvers has not been demonstrated. In most reports, the femoral nerve is the only nerve consistently blocked with this approach.30–32 Occasional blockade of the LFC nerve occurs through lateral diffusion of local anesthetic and not through proximal spread to the lumbar plexus.31 The obturator nerve is less frequently anesthetized during 3-in-1 block than the LFC nerve, which is not surprising given the number of fascial barriers between these structures at the level of the inguinal ligament.

Continuous Femoral Nerve Block Continuous FNB has been shown to improve surgical outcome after major knee and vascular surgery of the lower extremity compared with intravenous opioid therapy or

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FIG. 2. Femoral nerve block: A 5-cm needle is inserted at the femoral crease and immediately laterally to the pulse of the femoral artery. The nerve is typically stimulated at a depth of 1 to 3 cm. Reproduced with permission from: Hadzic A, Vloka J: Peripheral Nerve Blocks: Principles and Practice. New York, McGraw Hill, 2003.

continuous intraarticular infusion of analgesics.33–36 Two prospective, randomized studies examined three different modes of analgesia: continuous FNB, epidural analgesia, and intravenous opioid therapy after TKA.33,34 These studies demonstrated improvement in perioperative rehabilitation scores and a decreased duration of stay in a rehabilitation center for patients receiving the regional anesthesia techniques. Continuous FNB was shown to have equivalent analgesia with fewer side effects than epidural analgesia in both of these studies.33,34 However, not all investigators have been able to demonstrate these improvements in outcome with continuous FNBs. Lang found no difference between patients receiving a single-injection FNB and patients receiving a continuous FNB after TKA.32 The accuracy of catheter placement may play a role in

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these conflicting findings. In a prospective study, Capdevila showed that continuous FNB using a standard approach led to unpredictable catheter placement. In the Capdevila study, a vastus intermedius muscle response was elicited at 0.5 mA, the sheath was distended with 5 mL of saline, a catheter was inserted 16 to 20 cm, and then a bolus of local anesthetic was given through the catheter.37 Most of the catheters tended to course medially in the direction of the psoas muscle or laterally in the direction of the iliacus muscle. The accuracy of final catheter placement correlated well with the quality of analgesia after proximal lower limb surgery, although visual analog scale values were generally low in all groups.37

Lateral Femoral Cutaneous Nerve Block The LFC nerve of the thigh is a sensory nerve that supplies the cutaneous sensation to a large but variable area from the inguinal ligament to the knee on the lateral aspect of the thigh.38 LFC nerve block is most commonly used as the sole anesthetic during diagnostic muscle biopsy and harvesting of split-thickness skin grafts.39,40 It has also been used to provide analgesia in elderly patients undergoing hip fracture repair.41 However, in a study comparing LFC nerve block, FNB, and patients receiving no block after femoral neck repair, LFC nerve block was not as effective at controlling postoperative pain as FNB.42 Typically, LFC nerve block is done as a blind, “fan” technique with a variable success rate. This may be the result of variability in the innervation of the nerve or imprecise localization of the nerve. Shannon compared the traditional fan technique for LFC nerve block with the use of a nerve stimulator technique seeking tingling in the distribution of the nerve.43 A 40% success rate with the “fanning” technique was reported compared with 100% with the nerve-stimulating technique. There was no difference in the extent of the blockade in successful blocks. FNB has been reported after LFC block,44 which is not surprising given the fact that most FNB literature reports that FNB results in anesthetic spread to the LFC nerve.

Saphenous Nerve Block The saphenous nerve (SN) follows the saphenous vein to the medial malleolus and supplies the cutaneous area of the medial aspect of the calf and foot to the level of the midfoot. The SN block is often combined with a sciatic block to provide anesthesia and analgesia for surgery involving the medial aspect of the lower leg and foot. The SN is a sensory nerve and does not contribute to the bony innervation of the foot. Approaches to the SN along its entire course, from the adductor canal to the ankle, have been described. Success rates vary widely between techniques. For example, successful block is reported in 33% to 65% of cases with a field infiltration performed medially at the level of the tibial plateau,45,46 70% to 80% of cases with the transarterial approach,45,47 95% to 100% of cases with femoral paracondylar approach,47 and nearly 100% of cases with the paravenous approach.46 The SN has been reported to be selectively blocked, sparing the quadriceps musculature in the adductor canal.48 However, this finding has not been confirmed in a large series of patients receiving this approach for a SN block.

Psoas Compartment Block versus Femoral Nerve Block Parkinson compared the extent of blockade after FNB and the posterior approach with the lumbar plexus.13 They compared the extent of blockade of the lumbar plexus with four different methods: posterior approach at L3 (posterior approach of Dekrey) and L4 to L5 (Chayen’s approach) with a nerve stimulator using noninsulated needles, and anterior FNB (approach of Winnie) with paresthesia and nerve stimulation techniques.13 The

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FNB had a 100% success rate, whereas the LFC nerve block success rate was 85% to 95%. The obturator nerve, as assessed by thigh adduction, was blocked 100% of the time with posterior approaches and never with anterior approaches. Limitations of this report include lack of details regarding the type of nerve stimulation, the small sample size, and exclusion of patients in whom FNB failed to develop. A more recent comparison has been made between PCB and FNB.49 In this study, patients receiving a PCB developed a sensory block of the femoral, LFC, and obturator nerves in 100%, 97%, and 77% of patients versus 93%, 63%, and 47% of the patients receiving an FNB.

Continuous Psoas Compartment Blocks versus Epidural Analgesia Advantages of continuous PCB compared with epidural block include unilateral analgesia and motor block, lack of impairment of bladder function, and improved risk/benefit ratio in patients receiving anticoagulation medications after surgery. These advantages must be weighed against the disadvantages of incomplete blockade for anesthesia and the need for supplementation in a balanced regimen for effective analgesia. Türker recently compared continuous PCB with epidural block for analgesia after THA under combined general/regional technique and demonstrated that continuous PCB provided excellent intra- and postoperative analgesia with a low incidence of complications.4 Epidural block took longer to perform and had a significantly higher incidence of hypotension, whereas the analgesia and patient satisfaction provided by the two blocks were similar. Epidural block also provided more motor blockade, longer time to ambulation, and significantly more complications.

Continuous Psoas Compartment Blocks versus Continuous Femoral Blocks After TKA, continuous FNB and continuous PCB reduce opioid consumption and pain scores compared with intravenous morphine usage alone.34 However, no differences in outcome were observed between the two peripheral nerve block groups despite a more consistent presence of obturator nerve block in the psoas compartment group. Both continuous FNB and continuous PCB can be effective for pain control after a TKA, and the decision of which continuous nerve block to choose should be based on patient profile and preference, comfort of the anesthesiologist in placing the block and catheter, and preference of the surgeon.

Parasacral Block The parasacral nerve block (PSNB) has been described by Mansour in 1993 as more than an isolated sciatic nerve block.50,51 It has been used to provide analgesia after major foot and ankle reconstruction. PSNB will consistently block both components of the sciatic nerve and the posterior cutaneous nerve of the thigh. Spread of local anesthetic may also anesthetize other branches of the sacral plexus, including the superior and inferior gluteal, and pudendal nerves. The pelvic splanchnic nerves, the terminal portion of the sympathetic trunk, the inferior hypogastric plexus, and the obturator nerve all lie in close proximity to the elements of the sacral plexus and may all be anesthetized with this approach. For procedures around the knee, this may be advantageous over more distal approaches to the sciatic nerve.51,52 For procedures below the knee, adductor weakness from the obturator and superior gluteal nerve block may actually be disadvantageous for mobilization of the patient after blockade. The sympathetic nerve supply to the bladder is in close proximity to the sacral plexus, but problems with voiding and the need for bladder catheterization after PSNB have not been reported.52 A notable difference from other approaches to the sciatic nerve is the type of muscle

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response deemed acceptable as an end point for injection. Mansour described contraction of the hamstring muscles (biceps femoris, semitendinous) above the knee as the end point for PSNB with consistent success.50

Continuous Parasacral Blocks Continuous PSNBs have been used in combination with PCBs to provide lower extremity anesthesia for TKA, above-the-knee amputation, ACL repair, and a variety of other lower extremity procedures.53 Gaertner reported successful catheter placement, as confirmed by radiographic contrast dye, in 86 of 87 consecutive patients undergoing lower extremity surgery.53 All patients developed analgesia in the distribution of the tibial, peroneal, and cutaneous nerve of thigh.

Sciatic Nerve Block: At the Level of the Gluteus Maximus The sciatic nerve, the largest nerve derived from the sacral plexus, innervates the posterior thigh and almost the entire leg below the knee. The most common indications for sciatic nerve block (SNB) are anesthesia and analgesia for foot and ankle surgery. Gaston Labat first described the approach to the SNB, now referred to as the Classic Approach of Labat, at the beginning of the 20th century. This approach is based on the bony relationship of the posterior superior iliac spine (PSIS) and the greater trochanter with the patient positioned in a modified Sims position (Fig. 3). Winnie was the first to modify the original description by adding another landmark, the sacral hiatus, to more precisely account for varying body habitus.54 The reported success rate of this approach ranges from 33% to 95%.54–57 More recently, Franco described a simplified approach to the SNB in the prone position. The needle entry site is perpendicular

FIG. 3. Sciatic nerve block: Anatomic relationships of importance to the technique. Reproduced with permission from: Hadzic A, Vloka J: Peripheral Nerve Blocks: Principles and Practice. New York, McGraw Hill, 2003.

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to the floor 10 cm lateral from the middle of the intragluteal sulcus regardless of the patient’s gender or BMI.58 The sciatic nerve was found by trainees in three passes or less in 85% of the cases reported. Whether the success of this simple approach will be replicated in a larger sample size remains to be seen.

Subgluteal Approaches to the Sciatic Nerve Raj described a supine approach to the sciatic nerve in the flexed hip position initiating the block at the midpoint between the greater trochanter of the femur and the ischial tuberosity.55 This positioning of the patient is thought to be advantageous compared with the classic approach of Labat by “thinning the gluteus maximus muscles, making the sciatic nerve more superficial.” However, identifying these bony landmarks in very obese patients is sometimes difficult, and maintaining this position requires additional personnel to assist the patient. A lateral subgluteal approach to the sciatic nerve using the greater trochanter of the femur as a landmark was first described by Ichniyanagi in 1959. Other investigators have described a high success rate using this high lateral approach with a slightly more caudal entry point.57 When using this approach, the success rate of the blockade of the posterior cutaneous nerve of the thigh was 83%. Although theoretically, this nerve should reliably be blocked in most proximal approaches to the sciatic nerve, the success rate of blockade of the posterior cutaneous nerve of the thigh is not usually reported. The anterior approach to the sciatic nerve has the appeal of supine positioning and one skin prep when performing a combined femoral and sciatic nerve block. However, its clinical use has been limited by its complexity, patient discomfort, and low success rate.59,60 Numerous variations of the original Beck’s technique description have been described.61,62 In separate studies, Vloka and Hadzic, and Moore described the importance of internal rotation of the leg if the path to the sciatic nerve is obstructed by the lesser trochanter.63,64 A magnetic resonance imaging study of the anatomy of this area found that in 65% of patients, the sciatic nerve is inaccessible from the anterior approach at the level of the lesser trochanter.65 These authors suggested needle placement 4 cm lower, where obstruction to the sciatic nerve occurred in only 5% of the patients. Dalens compared the success rate of the posterior, lateral, and anterior approaches with the sciatic nerve in children.66 Although a success rate of 90% with all approaches was reported, fewer manipulations were required to perform either a lateral or posterior approach compared with the anterior approach. Recently, a medial approach to the sciatic nerve at the level of the lesser trochanter was reported in a series of 10 children.67 Advantages of this approach are the lack of obstruction from the femur and no muscle mass to transverse. The authors reported a 70% rate of blockade of the posterior cutaneous nerve of the thigh with this medial approach. di Bendetto recently described results from 135 consecutive patients using a posterior subgluteal approach to the sciatic nerve.68 The time to perform the block was 41 ± 25 seconds (mean ± standard deviation), with an average of two needle redirections. The degree of discomfort reported was very low and only 16 patients (12%) reported severe pain during placement of the block. In contrast to this, Fanelli reported patient discomfort in 88% of patients receiving a classic Labat approach to the sciatic nerve.69

Sciatic Nerve Block at the Level of the Popliteal Fossa Popliteal block is typically used for foot and ankle surgery.70–72 This technique offers advantages over spinal anesthesia in patients having short saphenous vein stripping.73 The block has also been successfully used in the pediatric population.74 As opposed to an ankle block, popliteal block anesthetizes the musculature of the lower leg, which

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likely improves tolerance for a calf tourniquet and provides an immobile foot for surgery. Performance of popliteal fossa block in patients with previous TKA or vascular bypass (femoral–popliteal) should be done with care although there are no reported cases of joint infections or graft disruption relating to needle placement in these patients. The components of the sciatic nerve may be blocked at the level of the popliteal fossa through a posterior or lateral approach. Access to the sciatic nerve may also occur with the patient in the lithotomy position.75 Continuous techniques have been described using both the posterior76–78 and lateral79 approaches. The posterior approach to the popliteal fossa is accomplished with a patient in the prone position.64 To block the sciatic nerve before it divides, injection of local anesthetic is given 7 to 10 cm above the popliteal crease (Fig. 4).58,71,72,80–82 With a single injection technique, inversion may be the best predictor of complete neural block of the foot.83 A lateral approach to blockade of the sciatic nerve in the popliteal fossa has recently been described.83–86 Success rate with all approaches to the popliteal sciatic nerve block is typically 90% to 95%, with approximately 5% of patients requiring supplemental general anesthesia. It is believed that incomplete block is the result of poor diffusion (as a result of the size of the sciatic nerve), separate fascial coverings of the tibial and peroneal nerves, or blockade of only a single component of the sciatic nerve. This has led some practitioners to endorse the practice of dual stimulation to improve the success rate.85

Continuous Sciatic Nerve Blocks Continuous SNBs can theoretically be achieved at any place along the course of the sciatic nerve. Continuous SNBs have been used for analgesia after major foot and ankle

FIG. 4. Popliteal sciatic block through the lateral approach: surface landmarks. Reproduced with permission from: Hadzic A, Vloka J: Peripheral Nerve Blocks: Principles and Practice. New York, McGraw Hill, 2003.

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reconstruction, ankle fracture fixation, and below-the-knee amputation.52,77,81,87,88 Three studies have been published on the use of continuous popliteal blocks for analgesia after extensive foot and ankle surgery.76,77,79 All three studies reported excellent analgesia with few side effects. Compared with intravenous analgesia or placebo infusion, a continuous infusion of local anesthetic through a popliteal catheter reduces pain scores, opioid consumption, and sleep disturbances.76,77 Successful catheter placement has been reported with both the lateral and posterior approach. The only consistent problem reported with popliteal catheters is a high incidence, 15% to 25%, of kinking or dislodgment.76,77 di Benedetto compared the subgluteal approach with the posterior popliteal approach for continuous infusions in a prospective study.87 In the 24-hour observation period after surgery, 13.3% of the catheters in the popliteal group were either occluded or dislodged compared with 6.6% of the catheters in the subgluteal group. This difference did not reach statistical difference.

Ankle and Foot Block The main indication for blockade of the lumbosacral plexus distally, at the ankle and midtarsal levels, is anesthesia for surgery to the foot.89,90 A diagnostic ankle block for sympathetically mediated ankle pain has also been described.91 The peripheral nerves blocked at the ankle are the terminal branches of both the sciatic (posterior tibial, superficial peroneal, deep peroneal, and sural) and femoral (saphenous) nerves. The five peripheral nerves that supply the foot are relatively easy to block at the ankle. There are no important variants in the innervation of the distal musculature. However, there is considerable variation in the branching and distribution of the sensory nerves of the foot. For this reason, blockade of all five nerves has been advocated.92 Neural blockade of the posterior tibial nerve has been described at the supramalleolar,92–94 midmalleolar,89 subcalcaneal,95,96 and midtarsal97 levels with no evidence of superiority of one technique. The three superficial nerves are consistently blocked with simple field infiltration. Few studies evaluating perioperative outcomes with ankle block exist,98 although the technique has been in clinical practice for decades. Many publications describe variations to improve success rate. Peak blood levels of local anesthetic occur approximately 90 minutes after blockade and are very low even after bilateral ankle block.99

Pharmacologic Considerations Complete unilateral lower extremity blockade involves multiple nerve blocks using a large volume of local anesthetics. Attention must be given to total local anesthetic dose; the concentration should be adjusted to accommodate the volume required for initial blockade as well as the ongoing local anesthetic administered as part of a continuous postoperative infusion. The concentration must also take into account the degree of sensory and/or motor block desired. Residual blockade may impede the ability of the patient to ambulate or actively participate in physical therapy. It is critical for the anesthesiologist to be aware of the planned postoperative rehabilitation program. The efficacy of adjuvants such as clonidine, opioids, and ketorolac in improving the quality or duration of blockade has not been consistently demonstrated. Relatively few randomized studies have compared local anesthetics for lower extremity block. Casati evaluated the onset and duration of combined femoral–sciatic block performed with 0.5%, 0.75%, or 1% ropivacaine versus 2% mepivacaine.100 Dosages of 0.75% and 1% ropivacaine had an onset similar to that of mepivacaine but with a dura-

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tion of analgesia longer than mepivacaine. These results are similar to those involving upper extremity blocks, which suggest that 0.75% ropivacaine and 0.5% bupivacaine produce similar block quality and duration. In a single comparative study of SNB, levobupivacaine has block characteristics similar to ropivacaine. Although 0.5% ropivacaine took a longer time to onset than 2% mepivacaine, the duration of analgesia with 0.5% ropivacaine was much longer (mean of 12 hours vs. 5 hours).

Epinephrine Epinephrine prolongs the duration and quality of most local anesthetics used for lower extremity peripheral nerve blocks. The effects are the result of vasoconstriction of the perineural vessels, which decreases uptake and increases the neural exposure time to the local anesthetic. The difference in effect is only somewhat dose-dependent. For example, the addition of 5 µg/mL epinephrine (1:200,000 dilution) significantly increases the duration of lidocaine from 186 minutes to 264 minutes. Epinephrine at a dosage of 2.5 µg/mL (1:400,000 dilution) prolongs the block to nearly the same extent (240 minutes) without any effect on nerve blood flow.101,102 The addition of epinephrine to local anesthetics with vasoconstrictive properties such as ropivacaine may not significantly increase block duration, but may facilitate detection of intravascular injection.103 The decision to add epinephrine and the dose selected is based on the concerns related to cardiac or neural ischemia versus the ability to discern an intravascular injection. In general, because seizures related to intravascular injection are highest in patients undergoing PNB,104 the benefits of adding epinephrine may outweigh the risks. However, the nearly equivalent effects on block quality and duration reported with 2.5 µg/mL epinephrine when compared with 5 µg/mL suggest that the lower concentration is sufficient. It is a personal bias of this author that epinephrine should not be used for sciatic blocks, in particular the anterior SNB, as a result of the long duration of sciatic blockade and risks of nerve ischemia compounded by vasoconstriction, the possibility of arterial puncture, pressure on the anesthetized sciatic nerve, and application of the tourniquet over the upper thigh.

Bicarbonate The addition of bicarbonate has been recommended to increase the speed of onset of peripheral and plexus blockade. However, most studies that have demonstrated a statistically significant difference used commercially prepared epinephrine-containing solutions of local anesthetics (which have a much lower pH as a result of the addition of antioxidants) compared with plain local anesthetic solutions. A recent review of the literature involving brachial plexus block concluded that there was little reason to add sodium bicarbonate with plain local anesthetics or those with freshly added epinephrine.105 These results were substantiated in a study by Candido106 that reported no difference in the onset or duration of combined lumbar plexus–sciatic block in patients that received 0.5% bupivacaine with bicarbonate compared with those who received a nonalkalinized solution.

Complications of Lower Extremity Peripheral Nerve Blocks Auroy prospectively evaluated serious complications after 21,278 PNBs in a 5-month period in France.104 Using a 95% confidence interval, the potential for serious complications was estimated to be 0 to 2.6 deaths, 0.3 to 4.1 cardiac arrests, 0.5 to 4.8 neurologic injuries, and 3.9 to 11.2 seizures per 10,000 PNBs. There is a paucity of reports of

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complications specifically associated with lower extremity PNBs as compared with upper extremity PNBs. This is most likely related to decreased use rather than inherent safety of the techniques. Complications can occur with lower extremity PNBs and it is up to the anesthesiologist performing the block to be aware of these complications and be vigilant in preventing them.

Local Anesthetic Systemic Toxicity The potential for systemic local anesthetic toxicity would seem to be very high for lower extremity PNBs. Relatively large doses of local anesthetic are used for combined femoral and sciatic nerve blocks to anesthetize the entire lower extremity, but there are only a few case reports of local anesthetic toxicity associated with lower extremity PNBs. For instance, Fanelli reported a series of 2175 patients undergoing femoral sciatic combined blocks in which there were no systemic adverse local anesthetic reactions reported.69 The apparent margin of safety seems to vary with individual block techniques. For instance, there are no case reports of toxicity after popliteal sciatic blockade, whereas there are several case reports of severe toxicity after lumbar plexus and sciatic nerve blocks.107–110 Differences in anatomy, primarily in the vasculature and presence of deep muscle beds in the area blocked, are the most likely explanation for this discrepancy. Interestingly, severe toxic reactions typically occur during or immediately after the injection. This suggests that the mechanism of these events is most commonly an unintentional intravascular injection of local anesthetic rather than absorption.12,111–115 A forceful, rapid injection of local anesthetic carries a much higher risk of local anesthetic toxicity than a slow, gentle injection.116 This is because the mean dose of local anesthetic that elicits the signs of central nervous system toxicity is much less during rapid intravascular injection as compared with that associated with slower absorption after appropriate deposition of the local anesthetic. With lower extremity PNB, local anesthetic levels peak at approximately 60 minutes after injection. Perhaps this slow time-to-peak level in the bloodstream offers an explanation for the low incidence of toxic complications associated with absorption of local anesthetics after PNB. Important measures to decrease the risk of severe toxicity include the use of epinephrine as an intravascular marker, slow and methodical injection while avoiding high-injection pressures, frequent aspiration, constant assessment of the patient and vital signs, and prudent selection of local anesthetic concentration and volume.

Proximal Spread (Neuraxial Block) Another potential needle misadventure is intrafascicular spread of the local anesthetic proximally toward the spinal cord, resulting in central neuraxial blockade.10,117 This is of particular concern with block techniques that involve needle placement at the level of the nerve roots or spinal nerves such as paravertebral and PCBs. Forceful, fast injections under high pressures into dural cuffs or perineurium can result in unintentional spinal or epidural anesthesia.15,118,119 In a large series of severe complications associated with regional anesthesia, Auroy found that the posterior approach to the lumbar plexus has the highest incidence of complications of the lower extremity PNBs.120 Of the 394 posterior lumbar plexus blocks reported, there were five serious complications reported. Three of these complications, one cardiac arrest and two respiratory arrests, were directly attributed to cephalad diffusion of the local anesthetic to the epidural or intrathecal space. Managing this block with the same degree of vigilance as a neuraxial block is essential to detect and treat these complications early if they should occur.

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Hemorrhagic Complications Several approaches for PNBs of the lower extremity involve deep needle insertion, including the PCB, the obturator nerve block, and the parasacral and classical approaches to the sciatic nerve. Despite the proximity of these deep nerves to vascular and hollow viscous structures, there are relatively few published reports of needle misadventures. Retroperitoneal hematoma formation after PCB has been reported.9 To reach the lumbar plexus, the needle must transverse multiple muscle and other tissue layers. The combination of deep location and inability to apply direct pressure after an inadvertent puncture of deep blood vessels makes this block less suitable in the setting of anticoagulation as compared with other, more superficial lower extremity PNBs.

Infectious Complications There are no case reports of infection after single-injection, lower extremity PNBs. However, Cuvillon reported bacterial complications associated with the use of continuous FNBs.121 In a cohort of 208 patients, 57% had positive bacterial colonization of the catheter at 48 hours postoperatively. Three patients had transitory symptoms of bacteremia that resolved after removal of the catheter. There were no long-term sequelae related to these positive catheter cultures. Two case reports of psoas abscess requiring drainage and intravenous antibiotic therapy have been reported in patients who received a continuous FNB. This stresses the importance of keeping a sterile field when performing a continuous catheter placement.

Neurologic Complications Neurologic injury is an infrequent but often feared complication of PNBs and may be present in 0.4% to 18% of all nerve block procedures.69,104,120 Most reports of neurologic complications after PNBs are related to upper extremity nerve blocks, a fact that more likely reflects the higher use of upper extremity blocks rather than a unique sensitivity to nerve injury in the upper extremity. The symptoms of nerve injury after PNB usually manifest shortly after block resolution. The perception and presentation of symptoms are typically influenced by the origin of the nerve lesion and other confounding factors such as postoperative pain, immobility, effects of surgery, operative position, and the application of casts, dressings, and bandages. Intensity and duration of symptoms also vary with the severity of the injury and range from light, intermittent tingling and numbness lasting a few weeks to persistent and painful paresthesias, neuropathic pain, and sensory and/or motor deficits that can last for several months or years.122,123 Some nerve injuries result in permanent neurologic deficit or evolve into severe reflex sympathetic dystrophies.124 Unfortunately, current understanding of the factors that lead to neurologic complications after PNBs is limited. This is partly the result of our inability to conduct meaningful retrospective studies owing to a lack of standard and objective documentation procedures for PNBs. In the absence of objective data, published discussions of the factors that lead to nerve injury, as well as medicolegal reviews, are often speculative at best. Intraneural injection is a well-known mechanism of neurologic injury associated with PNBs.125–138 However, in current clinical practice, there is no consensus on the techniques or methods that can reduce the risk of intraneural injection. Much of the debate has focused on methods of nerve localization (i.e., paresthesia vs. nerve stimulation). However, there is still no evidence that one method is safer than the other, and neurologic injury can occur even with experienced practitioners using either technique.139 Recent reports have also suggested that nerve stimulator-assisted nerve localization may not eliminate the risk of intraneural needle placement. These reports document that

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paresthesia (presumably caused by needle–nerve contact or intraneural placement of the needle) may be present without a motor response to nerve stimulation even with current intensity as high as 1.5 mA.140,141 In addition, there are currently no manufacturing standards for nerve stimulators, and older models may be inaccurate.142 Use of short-bevel needles and a nerve stimulator is generally believed to result in a lower risk of nerve trauma.143 The advantages of short-bevel over sharper, long-bevel needles remain controversial.144 Educational material in regional anesthesia suggests that lancinating pain and high injection pressure may portend intraneural injection of local anesthetic, thus increasing the potential for nerve injury.145–148 However, a number of case reports suggests that pain is not a reliable warning sign of impending nerve injury.146,149–151 Because greater force required to perform an injection may be associated with intraneural injection, anesthesiologists often rely on a subjective evaluation of injection pressure during PNB to detect abnormal resistance to injection and prevent intraneural injection.108,116,117,152,153 Indeed, an earlier study performed in rabbits suggested that intraneural injections result in higher injection pressures than perineural (“normal”) injections.149 More recently, studies in large animal models documented that high injection pressures (>20 psi) with intraneural needle placement lead to nerve injury.154 Unfortunately, clinical perception of an abnormally high resistance and pressure required to inject is impossible to verify because clinicians vary widely in what they perceive as appropriate force and rate of injection during PNB.153 Because current clinical practice does not allow for meaningful assessment, monitoring, and documentation of the injection technique, objective monitoring of injection pressures may prove beneficial to avoid pressures known to be capable of injuring the nerve fascicles.153 Neuronal ischemia can occur from a variety of sources, including disruption of the neuronal microvasculature, high endoneurial pressures, addition of vasoconstricting agents, and exogenous compression from tourniquets,155 although a combination of these events is most likely required for development of nerve injury. The perineurium is a tough and resistant tissue layer. An injection into this compartment or into a fascicle can cause a prolonged increase in endoneurial pressure, exceeding the capillary perfusion pressure, which can result in endoneural ischemia.150 Addition of vasoconstricting agents theoretically can enhance ischemia because of the resultant reduction in blood flow. Addition of epinephrine has been shown in vitro to decrease blood supply to intact nerves; however, this has not been shown to be a risk factor for development of postblock nerve dysfunction in patients having lower extremity PNBs.69,149 An additional source of ischemia may be the application of a tourniquet, particularly over the site of a nerve block. Posttourniquet palsy (“tourniquet paralysis”) has been reported to occur in one in 8000 operations.155 However, the paucity of reported severe complications, despite the widespread use of tourniquets, suggests that peripheral nerves are relatively resistant to ischemia of limited duration and magnitude.156 The potential for neurotoxicity with a local anesthetic is a function of its potency, concentration, and the length of exposure of the neuronal tissue to the agent. Local anesthetics are used in concentrations that, under normal clinical conditions, do not cause irreversible nerve damage. Under normal circumstances, the concentration of local anesthetic at the injection site decreases quickly because of dilution by interstitial fluids and absorption in the blood. For this reason, local anesthetic solutions used in vivo are of a higher concentration than what is needed for nerve block in vitro. Nonetheless, exposure of the endoneurium (like may occur during intraneuronal injection) to a very high concentration of local anesthetic, particularly when coupled with intraneural pressure and ischemia, may contribute to the increased vulnerability of the nerve to neurologic

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TABLE 1. Choice of Peripheral Nerve Block Technique for Common Surgical Procedures of the Lower Extremity Lower Extremity Surgery Knee arthroscopy Patella tendon and anterior cruciate ligament repair Saphenous vein stripping Open reduction internal fixation of patella fracture Pain management after hip and knee surgery

Above and below knee amputations Any surgery on the tibia or fibula Achilles tendon repair Foot surgery Pain management after surgery on the lower extremity

Ankle surgery Foot surgery Achilles tendon repair Short saphenous vein stripping

Nerve Block

Lumbar plexus block Femoral nerve block

Sciatic nerve block

Popliteal nerve block or ankle block

Comments Groin, portion of the hip and knee, anterolateral and medial thigh, and medial skin below knee are anesthetized Femoral nerve block combined with a genitofemoral nerve block is an excellent choice for saphenous vein stripping For complete anesthesia of the leg, femoral or lumbar plexus blocks must be combined with sciatic block When choosing femoral vs. lumbar plexus block, a lumbar plexus block should be chosen when anesthesia of the lumber plexus (lateral femoral cutaneous nerve, obturator nerve) is sought Femoral nerve block with large dose of local anesthetic will not result in lumbar plexus blockade regardless of volume used Combined with a lumbar plexus or femoral block results in complete anesthesia of the lower extremity Can be combined with a saphenous block or “low-volume” femoral block to achieve complete anesthesia of the leg below the knee Femoral nerve block is not an adequate supplement for above-theknee surgery because the obturator nerve and lateral femoral cutaneous nerve of the thigh are not anesthetized and may be important for complete anesthesia; a lumbar plexus block is a better choice When surgery involves the medial aspect of the lower leg, a saphenous nerve block is needed Success rate is volume dependent Popliteal block is chosen over ankle block for more proximal, more extensive surgery and surgery requiring the use of tourniquet

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injury.114,157 Although neurologic complications of PNBs are uncommon, they can and do occur even in the hands of experienced practitioners139 and may result in significant patient suffering, distress to the practitioner, and medicolegal consequences. In summary, recent developments in the field of regional anesthesia have led to an increased interest in lower extremity PNBs. These include reports of transient neurologic symptoms associated with spinal anesthesia, increased risk of epidural hematoma with the introduction of new antithromboembolic prophylaxis regimens, and evidence of improved rehabilitation outcome with continuous lower extremity PNBs. Research and focus on functional regional anesthesia anatomy have significantly contributed to the ease and success rate of lower extremity nerve blocks. More widespread acceptance of nerve blocks in clinical practice will depend on our ability to complete the transformation of this subspecialty field of anesthesiology to a more objective, standardized, and reproducible practice with more clearly defined indications (Table 1) both to improve their clinical use and to reduce the risk of complications.

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96. Wassef M: Posterior tibial nerve block. A new approach using the bony landmark of the sustentaculum tali. Anaesthesia 1991; 46:841–4. 97. Sharrock N, Waller J, Fierro L: Midtarsal block for surgery of the forefoot. Br J Anaesth 1986; 58:37–40. 98. Needoff M, Radford P, Costigan P: Local anesthesia for postoperative pain relief after foot surgery: A prospective clinical trial. Foot Ankle Int 1995; 16:11–3. 99. Mineo R, Sharrock N: Venous levels of lidocaine and bupivacaine after midtarsal ankle block. Reg Anesth Pain Med 1992; 17:47–9. 100. Casati A, Fanelli G, Borghi B, Torri G: Ropivacaine of 2% mepivacaine for lower limb peripheral nerve blocks. Anesthesiology 1999; 90:1047–52. 101. Kennedy W Jr, Bonica J, Ward R, et al.: Cardiorespiratory effects of epinephrine when used in regional anesthesia. Acta Anaesthesiol Scand Suppl 1966; 23:320–33. 102. DiFazio C, Rowlingson J: Additive to local anesthetic solutions. In: Brown D, ed.: Regional Anesthesia and Analgesia, 1st ed. Philadelphia: WB Saunders, 1996, pp 232–9. 103. Weber A, Fournier R, Van Gessel E, et al.: Epinephrine does not prolong the analgesia of 20 mL ropivacaine 0.5% or 0.2% in a femoral three-in-one block. Anesth Analg 2001; 93:1327–31. 104. Auroy Y, Narchi P, Messiah A, et al.: Serious complications related to regional anesthesia: Results of a prospective survey in France. Anesthesiology 1997; 87:479–86. 105. Neal J, Hebl J, Gerancher J, Hogan Q: Brachial plexus anesthesia: Essentials of our current understanding. Reg Anesth Pain Med 2002; 27:402–28. 106. Candido K, Winnie A, Covino B, et al.: Addition of bicarbonate to plain bupivacaine does not significantly alter the onset or duration of plexus anesthesia. Reg Anesth Pain Med 1995; 20:133–8. 107. Pham-Dang C, Beaumont S, Floch H, et al.: Acute toxic accident following lumbar plexus block with bupivacaine. Ann Fr Anesth Reanim 2000; 19:356–9. 108. Breslin D, Martin G, Macleod D, et al.: Central nervous system toxicity following the administration of levobupivacaine for lumbar plexus block: A report of two cases. Reg Anesth Pain Med 2003; 28:144–7. 109. Mullanu C, Gaillat F, Scemama F, et al.: Acute toxicity of local anesthetic ropivacaine and mepivacaine during a combined lumbar plexus and sciatic block for hip surgery. Acta Anaesthesiol Belg 2002; 53:221–3. 110. Petitjeans F, Mion G, Puidupin M, et al.: Tachycardia and convulsions induced by accidental intravascular ropivacaine injection during sciatic block. Acta Anaesthesiol Scand 2002; 46:616–7. 111. Odoom J, Zuurmond W, Sih I, et al.: Plasma bupivacaine concentrations following psoas compartment block. Anaesthesia 1986; 41:155–8. 112. Elmas C, Atanassoff P: Combined inguinal paravascular (3-in-1) and sciatic nerve blocks for lower limb surgery. Reg Anesth Pain Med 1993; 18:88–92. 113. Misra U, Pridie A, McClymont C, Bower S: Plasma concentrations of bupivacaine following combined sciatic and femoral 3 in 1 nerve blocks in open knee surgery. Br J Anaesth 1991; 66:310–3. 114. Simon M, Gielen M, Lagerwerf A, Vree T: Plasma concentrations after high doses of mepivacaine with epinephrine in the combined psoas compartment/sciatic nerve block. Reg Anesth Pain Med 1990; 15:256–60. 115. Edkin B, Spindler K, Flanagan J: Femoral nerve block as an alternative to parenteral narcotics for pain control after anterior cruciate ligament reconstruction. Arthroscopy 1995; 11:404–9. 116. Liu P, Feldman H, Giasi R, et al.: Comparative CNS toxicity of lidocaine, etidocaine, bupivacaine, and tetracaine in awake dogs following rapid intravenous administration. Anesth Analg 1983; 62:375–9. 117. Selander D, Sjostrand J: Longitudinal spread of intraneurally injected local anesthetics. An experimental study of the initial distribution following intraneural injections. Acta Anaesthesiol Scand 1978; 22:622–34. 118. Singelyn F, Contreras V, Gouverneur J: Epidural anesthesia complicating continuous 3in-1 lumbar plexus blockade. Anesthesiology 1995; 83:217–20. 119. Gentili M, Aveline C, Bonnet F: Total spinal anesthesia after posterior lumbar plexus block. Ann Fr Anesth Reanim 1998; 17:740–2. 120. Auroy Y, Benhamou D, Bargues L, et al.: Major complications of regional anesthesia in France: The SOS regional anesthesia hotline service. Anesthesiology 2002; 97:1274–80.

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121. Cuvillon P, Ripart J, Lalourcey L, et al.: The continuous femoral nerve block catheter for postoperative analgesia: Bacterial colonization, infectious rate and adverse effects. Anesth Analg 2001; 93:1045–9. 122. Lim E, Pereira R: Brachial plexus injury following brachial plexus block. Anaesthesia 1984; 39:691–4. 123. Bashein G, Robertson H, Kennedy WJ: Persistent phrenic nerve paresis following interscalene brachial plexus block. Anesthesiology 1985; 63:102–4. 124. Gillespie J, Menk E, Middaugh R: Reflex sympathetic dystrophy: A complication of interscalene block. Anesth Analg 1987; 66:1316–7. 125. Fremling M, Mackinnon S: Injection injury to the median nerve. Ann Plast Surg 1996; 37:561–7. 126. Curtiss PJ, Tucker H: Sciatic palsy in premature infants: A report and follow-up study of ten cases. JAMA 1960; 174:1586–8. 127. Gilles F, French J: Postinjection sciatic nerve palsies in infants and children. J Pediatr Orthop 1961; 58:195–204. 128. Ling C, Loong S: Injection injury of the radial nerve. Injury 1976; 8:60–2. 129. Hudson A, Kline D, Gentili F: Management of Peripheral Nerve Problems, 1st ed. Philadelphia, WB Saunders, 1980. 130. Burkel W, McPhee M: Effect of phenol injection into peripheral nerve of rat: Electron microscope studies. Arch Phys Med Rehabil 1970; 51:391–7. 131. Holbrook T, Pilsher C: The effects of injection of penicillin; peanut oil and beeswax, separately and in combination, upon nerve and muscle; an experimental study. Surg Gynecol Obstet 1950; 90:39–44. 132. Shapiro S, Norman D: Neurological complications following the use of efocaine; report of three cases. JAMA 1953; 152:608–9. 133. Gentili F, Hudson A, Kline D, Hunter D: Peripheral nerve injection injury: An experimental study. Neurosurgery 1979; 4:244–53. 134. Gentili F, Hudson A, Hunter D, Kline D: Nerve injury with local anesthetic agents: A light and electron microscopic, fluorescent microscopic, and horseradish peroxidase study. Neurosurgery 1980; 6:263–72. 135. Gentili F, Hudson A, Kline D, Hunter D: Early changes following injection injury of peripheral nerves. Can J Surg 1980; 23:177–82. 136. Allensworth M, Scheinberg L: Sciatic neuropathy in infants related to antibiotic injections. Pediatrics 1957; 19:261–5. 137. Selander D, Dhuner K, Lundborg G: Peripheral nerve injury due to injection needles used for regional anesthesia. An experimental study of the acute effects of needle point trauma. Acta Anaesthesiol Scand 1977; 21:182–8. 138. Selander D, Brattsand R, Lundborg G, et al.: Local anesthetics: Importance of mode of application, concentration and adrenaline for the appearance of nerve lesions. An experimental study of axonal degeneration and barrier damage after intrafascicular injection or topical application of bupivacaine (Marcaine). Acta Anaesthesiol Scand 1979; 23:127–36. 139. Kent K, Moscucci M, Mansour K, et al.: Retroperitoneal hematoma after cardiac catheterization: Prevalence, risk factors, and optimal management. J Vasc Surg 1994; 20:905–10. 140. Mulroy M, Mitchell B: Unsolicited paresthesias with nerve stimulator: Case reports of four patients. Anesth Analg 2002; 95:762–3. 141. Urmey W, Stanton J: Inability to consistently elicit a motor response following sensory paresthesia during interscalene block administration. Anesthesiology 2002; 96:552–4. 142. Hadzic A, Vloka J, Hadzic N, et al.: Nerve stimulators used for peripheral nerve blocks vary in their electrical characteristics. Anesthesiology 2003; 98:969–74. 143. Barber F, Click J, Britt B: Complications of ankle arthroscopy. Foot Ankle Int 1990; 10:263–6. 144. Rice A, McMahon S: Peripheral nerve injury caused by injection needles used in regional anaesthesia: Influence of bevel configuration, studied in a rat model. Br J Anaesth 1992; 69:433–8. 145. Weaver M, Tandatnick C, Hahn M: Peripheral nerve blockade. In: Raj P, ed.: Textbook of Regional Anesthesia, 3rd ed. Philadelphia, Churchill Livingstone, 2002, pp 857–70. 146. Selander D: Peripheral nerve injury after regional anesthesia. IN: Fnucane B, Ross A, eds.: Complications of Regional Anesthesia, 1st ed. Philadelphia, Churchill Livingstone, 1999, pp 105–15. 147. Jankovic D, Wells C: Brachial plexus. In: Jankovic D, Wells C, eds.: Regional Nerve Blocks: Textbook and Color Atlas, 2nd ed. Berlin, Blackwell, 2000, pp 76–7.

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148. Adriani J: Labat’s Regional Anesthesia: Techniques and Clinical Applications, 4th ed. St. Louis, Warren H. Green, 1985. 149. Selander D, Mansson L, Karlsson L, Svanvik J: Adrenergic vasoconstriction in peripheral nerves of the rabbit. Anesthesiology 1985; 62:6–10. 150. Myers R, Kalichman M, Reisner L, Powell C: Neurotoxicity of local anesthetics: Altered perineurial permeability, edema, and nerve fiber injury. Anesthesiology 1986; 64:29–35. 151. Bonner S, Pridie A: Sciatic nerve palsy following uneventful sciatic nerve block. Anaesthesia 1997; 52:1205–7. 152. Kent K, Moscucci M, Gallagher S, et al.: Neuropathy after cardiac catheterization: Incidence, clinical patterns, and long-term outcome. J Vasc Surg 1994; 19:1008–13. 153. Claudio R, Hadzic A, Shih H, et al.: Injection pressures by anesthesiologists during simulated peripheral nerve block. Reg Anesth Pain Med 2004; 29:201–5. 154. Hadzic A, Dilberovic F, Shah S, et al.: Combination of intraneural injection and high injection pressure leads to severe fascicular injury and neurologic deficits in dogs. Reg Anesth Pain Med 2004; 29:417–23. 155. Middleton R, Varian J: Tourniquet paralysis. Aust N Z J Surg 1974; 44:124–8. 156. Shrarock N, Savarese J: Anesthesia for orthopedic surgery. In: RD M, ed.: Anesthesia, 5th ed. Philadelphia, Churchill Livingstone, 1998, pp 2118–39. 157. Selander D: Nerve toxicity of local anesthetics. In: Lofstrom J, Sjostrand U, eds.: Local Anesthesia and Regional Blockade. Amsterdam, Elsevier Science Publisher B.V, 1988, p 77.

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CHAPTER 11

V O L U M E

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

ANESTHESIA FOR THE PREGNANT PATIENT UNDERGOING NONOBSTETRIC SURGERY JOY L. HAWKINS, M.D. PROFESSOR OF ANESTHESIOLOGY UNIVERSITY OF COLORADO SCHOOL OF MEDICINE DENVER, COLORADO

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.

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Anesthesia for the Pregnant Patient Undergoing Nonobstetric Surgery Joy L. Hawkins, M.D. Professor of Anesthesiology University of Colorado School of Medicine Denver, Colorado

Discovering that our “routine” surgical patient happens to be pregnant adds a new level of anxiety for most of us. Yet approximately 2% of parturients will have surgery during their pregnancy, involving more than 80,000 anesthetics per year. This number is increasing, largely as a result of laparoscopic procedures. Most surgeries are performed to treat conditions common to this age group: traumatic injuries, ovarian cysts, appendicitis, cholelithiasis, breast biopsy, and cervical incompetence. However, major procedures such as craniotomy, cardiopulmonary bypass, and liver transplantation may also be necessary in the pregnant patient, and usually result in good outcomes for mother and fetus. Despite favorable results overall, both medically trained and nonmedical individuals have a strong aversion to drugs being used or procedures being performed during pregnancy. For example, during Congressional testimony on late-term abortions in 1995, the erroneous statement was made that “The fetus usually dies from the anesthesia administered to the mother before the procedure begins.” Naturally, with the availability of such misinformation, a pregnant patient requiring surgery is likely to present with extreme anxiety. When women exposed to nonteratogenic drugs discovered they were pregnant, they estimated they had a 25% risk of major congenital malformations resulting from that exposure!1 How do we counsel a pregnant patient having surgery and anesthesia? What can you tell her about the risks to her pregnancy associated with anesthesia?

Physiology and Risk Assessment Anesthetic management now involves two patients and physiology specific to pregnancy. Thus, several unique concerns should be addressed when creating an anesthetic plan. Alterations in maternal physiology involve many organ systems, but those most important to anesthetic management include the following: 1. Respiratory: The pregnant woman will have increased oxygen consumption, decreased functional residual capacity, lower pCO2 resulting from increased minute ventilation, greater likelihood of difficult intubation, and increased mucosal vascularity with potential bleeding. 2. Cardiovascular: Changes include increased blood volume and cardiac output, dilutional anemia, aortocaval compression when supine, and decreased vascular responsiveness despite increased baroreceptor responsiveness. 3. Gastrointestinal: It is unclear whether gastric volume, pH, and emptying are altered during pregnancy, but gastroesophageal sphincter tone is usually reduced, and women often describe reflux symptoms. 137

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4. Central nervous system: Local anesthetic requirements and minimum alveolar concentration (MAC) for inhalational agents are both decreased during pregnancy. Maintenance of uterine perfusion with adequate maternal oxygenation is the variable that preserves fetal oxygenation. These are of utmost importance to any anesthetic during pregnancy. Be aware of effects your interventions may have on maternal cardiac output, oxygen delivery, and uterine blood flow. Above all, avoid maternal hypoxia and hypotension! Prevention and treatment of preterm labor is the most difficult problem to overcome perioperatively, and preterm delivery is the most common cause of fetal loss. It is probably not related to anesthetic management, but to the underlying disease and the surgery itself. Unfortunately, there are no reliable therapies to prevent or treat preterm labor in the perioperative period. Most outcome studies have shown that women who require surgery while pregnant will deliver earlier in gestation than those who have not, even if delivery is remote from surgery, and that their babies will be smaller. Teratogenic effects of anesthetics are probably minimal and have never been conclusively demonstrated in humans (Table 1). A problem for physicians and patients is that drugs are rarely tested for safety in pregnancy before or after they are marketed.2 Inadequate information is available for women and their physicians to determine risks of most drugs. The anesthetic drugs that usually generate the most concern are nitrous oxide and the benzodiazepines. In animal studies, nitrous oxide increases adrenergic tone and may vasoconstrict uterine vessels and reduce uterine blood flow if not combined with a halogenated (sympatholytic) agent.3 This leads to abortions and congenital anomalies in Sprague-Dawley rats. No adverse effects of nitrous oxide have been demonstrated in human pregnancy, however, despite extensive use. An association between benzodiazepine use and oral cleft anomalies was reported, but later case–control and prospective studies failed to demonstrate any relationship to benzodiazepine use during pregnancy.4,5 Opioids, intravenous induction agents, and local anesthetics have a long history of safety when used during pregnancy. A recent metaanalysis of studies on anesthetic exposure in the workplace concluded that a slight increased risk of miscarriage is the only potential obstetric problem for operating room (OR) personnel.6 The risk of smoking during pregnancy or ionizing radiation risks for pregnant personnel working in radiology are much higher than the potential risk for OR staff. Of concern, however, is recent animal work on NMDA receptor blockers (for example, ketamine, nitrous oxide) and GABAA receptor enhancers (for example, benzodiazepines, intravenous induction agents, volatile agents).7,8 All currently used anesthetics act by one of these mechanisms. In animal studies, fetal or newborn exposure TABLE 1.

Documented Teratogens

Angiotensin-converting enzyme inhibitors Alcohol Androgens Antithyroid drugs Carbamazepine Chemotherapy agents Cocaine Coumadin Diethylstilbestrol Lead Adapted from ACOG Educational Bulletin #236, 1997.

Lithium Mercury Phenytoin Radiation (>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

Postpone surgery until second trimester or postpartum, if possible. Request preoperative assessment by an obstetrician. Counsel the patient preoperatively (see text). Use (at least) a nonparticulate antacid as aspiration prophylaxis. Monitor and maintain oxygenation, normocarbia, normotension, and euglycemia. Use regional analgesia for postoperative pain management when appropriate. Document fetal heart tones before and after the procedure.

to these agents results in widespread apoptotic neurodegeneration and persistent memory/learning impairments. For example, 7-day-old rats (the equivalent of 0 to 6 months of age in humans) received 6 hours of general anesthesia using midazolam, nitrous oxide, and isoflurane. They had memory and learning impairments, apoptotic neurodegeneration, and hippocampal synaptic function deficits.9 The relevance to human exposure is unclear; however, isoflurane has also been associated with postoperative cognitive deficits in human adults. Are these results in animals attributable to the direct effects of anesthetics, or are they the result of factors we would not see clinically, for example, high anesthetic doses over long periods of time, hypoxia, respiratory acidosis, or starvation? At present, there is not enough information to change our clinical practice, and alleviation of pain and stress during surgery is obviously an essentially clinical goal.10,11

Anesthetic Management Preoperative assessment should include: pregnancy testing if pregnancy status is unsure or if the patient requests it, possible delay to the second trimester or postpartum period, counseling the patient on anesthetic risks (or lack thereof) to the fetus and pregnancy, and educating her about symptoms of preterm labor and the need for left uterine displacement (Tables 2 and 3). Mandatory pregnancy testing is a controversial issue, raising both medical and ethical issues. Any female patient should have the date of her last menstrual period documented on the anesthetic record if she is between the ages of 12 and 50. Pregnancy testing should be offered if more than 3 weeks has elapsed. If surgery can be delayed until the second trimester, risk of teratogenicity and spontaneous miscarriage are less. Preterm labor is not as common during second as in the third trimester. Administration of preoperative medications to allay anxiety or pain is appropriate, because elevated maternal catecholamines may decrease uterine blood flow. Whether you choose to use benzodiazepines such as midazolam is more of a medicolegal than TABLE 3.

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 <1 rad) does not increase risk to the fetus.15 Ultrasound and magnetic resonance imaging are alternatives that do not use ionizing radiation. There are few indications for an emergent cesarean delivery, but these would include: 1) a stable mother with a viable fetus in distress, 2) traumatic uterine rupture, 3) a gravid uterus interfering with intraabdominal repairs in the mother, and 4) a mother who cannot be saved with a fetus that is viable. If the fetus is previable or dead, optimize the mother’s condition. She will tolerate vaginal delivery at a later time better than emergent laparotomy for cesarean delivery. Neurosurgical procedures such as aneurysm clipping or arteriovenous malformation (AVM) repair may be required in women of this age group. A variety of anesthetic agents

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have been administered successfully for neurosurgical procedures during pregnancy. Fetal monitoring may be helpful when controlled hypotension is planned, or if large volume shifts or blood loss are anticipated. Aggressive diuresis may reduce uterine perfusion if the mother’s cardiac output is impaired. In animal studies, very high doses of mannitol cause fetal dehydration, but this is probably not clinically relevant. Hyperventilation reduces maternal cardiac output and decreases oxygen release to the fetus by shifting the maternal oxyhemoglobin dissociation curve to the left. Endovascular treatment of acutely ruptured intracranial aneurysms has been done successfully during pregnancy, thus avoiding craniotomy.16 Fetal shielding should be used whenever possible during radiology procedures. Cardiac surgery requiring bypass has also been successfully performed during pregnancy. During pregnancy, the physiological increase in blood volume and cardiac output is maximal at 28 to 30 weeks, and this is a common time for cardiac decompensation in parturients with stenotic valvular lesions or pulmonary hypertension. Another high-risk period occurs immediately postpartum. After delivery, the release of aortocaval compression and autotransfusion of uteroplacental blood increases cardiac output to a maximum. Women who have severe cardiac symptoms during pregnancy, unresponsive to medical management, may benefit from surgery. If possible, surgery should be delayed until the second trimester when the major risk of teratogenicity (from cardiac drugs, x-rays, low-flow or hypoxic states) is past and preterm labor is less likely. If close to term, combined cesarean delivery and valve replacement has been done successfully. Do not withhold surgery if it is indicated for maternal reasons; maternal mortality during pregnancy is comparable to nonpregnant rates, although fetal morbidity may be high.17 After 24 weeks gestation, monitor the fetus and maintain left uterine displacement to optimize uterine perfusion. Optimal pressures and flows on bypass are unknown and controversial, but animal studies indicate higher flows and pressures may be beneficial to maintain uterine blood flow and fetal oxygenation. Fetal monitoring is a very sensitive measure of perfusion and can be used to optimize these values. Fetal bradycardia commonly occurs at the onset of cardiopulmonary bypass and slowly returns to a low normal rate with little or no beat-to-beat variability. Hypothermia has been used successfully, although some authors advocate warm bypass. Optimizing the mother’s intraoperative and postoperative condition is the best way to ensure good fetal outcome.18 EXIT procedures (EX utero Intrapartum Treatment) are done for oropharyngeal or neck masses or other problems that could compromise the airway of the newborn.19 At cesarean delivery under general anesthesia, the fetal head is delivered but placental circulation is kept intact until the airway is secured by intubation or surgical means. With excellent prenatal diagnosis available using ultrasound and magnetic resonance imaging, the EXIT procedure will likely become more common in labor and delivery suites. In contrast, fetal surgery is only being performed at a few centers and for limited indications (for example, closure of a myelomeningocele). There are major problems to overcome, including postoperative preterm labor and maternal morbidity resulting from pulmonary edema. Patients often receive perioperative indomethacin or magnesium sulfate for tocolysis. High concentrations of an inhalation agent are used for maternal and fetal anesthesia and for uterine relaxation. Laparoscopic techniques avoid unnecessary laparotomy when abdominal pain presents a diagnostic challenge during pregnancy and may also allow management of some surgical procedures such as cholecystectomy. Interestingly, fetal outcomes are similar with either laparotomy or laparoscopy, although maternal benefits of minimally invasive surgery are similar to nonpregnant patients.20 Animal investigations have shown that CO2 pneumoperitoneum does not cause hypoxia or significant fetal hemodynamic changes

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but does induce fetal respiratory acidosis. Normalizing maternal end-tidal CO2 produces late and incomplete correction in the fetus.21 Whether this is biologically significant to the developing brain is unknown. Intraabdominal pressure should be maintained as low as possible and operative time (that is, insufflation time) kept to a minimum. Other technical considerations should include fetal shielding during cholangiograms, pneumatic stockings, left lateral table rotation, and open trocar placement.22

Conclusions Surgery may be necessary during pregnancy. Anesthesiologists should reassure the mother that anesthetic drugs and techniques by themselves will not put her fetus or the pregnancy at risk. Prevention of preterm labor is the greatest concern and may require perioperative monitoring and tocolysis. Effective postoperative pain management without sedation will aid in early diagnosis and treatment of preterm labor and assist with early mobilization to prevent thrombotic complications.

References 1. Koren G, Bologa M, Long D, Feldman Y, Shear NH: Perception of teratogenic risk by pregnant women exposed to drugs and chemicals during the first trimester. Am J Obstet Gynecol 1989; 160:1190–4. 2. Lo WY, Friedman JM: Teratogenicity of recently introduced medications in human pregnancy. Obstet Gynecol 2002; 100:465–73. 3. Mazze RI, Fujinaga M, Baden JM: Halothane prevents nitrous oxide teratogenicity in SpragueDawley rats; folinic acid does not. Teratology 1988; 38:121–7. 4. Rosenberg L, Mitchell AA, Parsells JL, et al.: Lack of relation of oral clefts to diazepam use during pregnancy. N Engl J Med 1983; 309:1282–5. 5. Shiono PH, Mills JL: Oral clefts and diazepam use during pregnancy [Letter]. N Engl J Med 1984; 311:919–20. 6. Boiven JF: Risk of spontaneous abortion in women occupationally exposed to anesthetic gases: A meta-analysis. Occup Environ Med 1997; 54:541–8. 7. Ikonomidou C, Bosch F, Miksa M, et al.: Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain. Science 1999; 283:70–4. 8. Ikonomidou C, Bittigau P, Ishimaru MJ, et al.: Ethanol-induced apoptotic neurodegeneration and fetal alcohol syndrome. Science 2000; 287:1056–60. 9. Jevtovic-Todorovic V, Hartman RE, Izumi Y, et al.: Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits. J Neurosci 2003; 23:876–82. 10. Anand KJS, Soriano SG: Anesthetic agents and the immature brain: Are these toxic or therapeutic? Anesthesiology 2004; 101:527–30. 11. Olney JW, Young C, Wozniak DF, Ikonomidou C, Jevtovic-Todorovic V: Anesthesia-induced developmental neuroapoptosis, does it happen in humans? Anesthesiology 2004; 101:273–5. 12. ACOG Committee on Obstetric Practice: Nonobstetric surgery in pregnancy. Obstet Gynecol 2003; 102:431. 13. Immer-Bansi A, Immer FF, Henle S, Sporri S, Petersen-Felix S: Unnecessary emergency caesarean section due to silent CTG during anaesthesia? Br J Anaesth 2001; 87:791–3. 14. To MS, Alfrivecic Z, Heath VCF, et al.: Cervical cerclage for prevention of preterm delivery in women with short cervix: Randomized controlled trial. Lancet 2004; 363:1849–53. 15. ACOG Committee on Obstetric Practice: Guidelines for diagnostic imaging during pregnancy. Obstet Gynecol 2004; 104:647–51. 16. Piotin M, de Souza Filho CBA, Kothimbakam R, Moret J: Endovascular treatment of acutely ruptured intracranial aneurysms in pregnancy. Am J Obstet Gynecol 2001; 185:1261–2. 17. Khandelwal M, Rasanen J, Ludormirski A, Addonizio P, Reece EA: Evaluation of fetal and uterine hemodynamics during maternal cardiopulmonary bypass. Obstet Gynecol 1996; 88:667–71.

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18. Strickland RA, Oliver WE Jr, Chantigian RC, Ney JA, Danielson GK: Anesthesia, cardiopulmonary bypass and the pregnant patient. Mayo Clin Proc 1991; 66:411–29. 19. Bouchard S, Johnson MP, Flake AW, et al.: The EXIT procedure: Experience and outcome in 31 cases. J Pediatr Surg 2002; 37:418–26. 20. Reedy MB, Kallen B, Kuehl TJ: Laparoscopy during pregnancy: A study of five fetal outcome parameters with use of the Swedish Health Registry. Am J Obstet Gynecol 1997; 177:673–9. 21. Reynolds JD, Booth JV, de la Fuente S, et al.: A review of laparoscopy for non-obstetricrelated surgery during pregnancy. Curr Surg 2003; 60:164–73. 22. Guidelines for laparoscopic surgery during pregnancy [Editorial]. Surg Endosc 1998; 12:189–90.

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CHAPTER 12

V O L U M E

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

ANESTHETIC CONSIDERATIONS FOR INTERVENTIONAL NEURORADIOLOGY CHANHUNG Z. LEE, M.D., PH.D. ASSISTANT PROFESSOR OF ANESTHESIOLOGY DEPARTMENT OF ANESTHESIA AND PERIOPERATIVE CARE UNIVERSITY OF CALIFORNIA SAN FRANCISCO, CALIFORNIA

WILLIAM L. YOUNG, M.D. JAMES P. LIVINGSTON PROFESSOR AND VICE-CHAIR DEPARTMENT OF ANESTHESIA AND PERIOPERATIVE CARE PROFESSOR OF NEUROLOGICAL SURGERY AND NEUROLOGY UNIVERSITY OF CALIFORNIA SAN FRANCISCO, CALIFORNIA

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.

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Anesthetic Considerations for Interventional Neuroradiology Chanhung Z. Lee, M.D., Ph.D. Assistant Professor of Anesthesiology Department of Anesthesia and Perioperative Care University of California San Francisco, California William L. Young, M.D. James P. Livingston Professor and Vice-Chair Department of Anesthesia and Perioperative Care Professor of Neurological Surgery and Neurology University of California San Francisco, California

Interventional neuroradiology (INR), or endovascular neurosurgery, may be broadly defined as treatment of central nervous system (CNS) disease by endovascular access for the purpose of delivering therapeutic agents, including both drugs and devices. This specialty is a hybrid of traditional neurosurgery and neuroradiology; practitioners may use both training pathways. Because of a rapid advancement in INR, anesthesiologists are increasingly involved in this arena.

Primary Functions of the Anesthesiologist Main anesthetic concerns for INR procedures, in addition to routine responsibilities of anesthetized patients, include: 1) maintaining immobility during the procedure to facilitate imaging; 2) rapid recovery from anesthesia at the end of the case to facilitate neurologic examination and monitoring or provide for intermittent evaluation of neurologic function during the procedure; 3) managing anticoagulation; 4) treating and managing sudden unexpected procedure-specific complications during the procedure, that is, hemorrhage or vascular occlusion, which may involve manipulating systemic or regional blood pressures; 5) guiding the medical management of critical care patients during transport to and from the radiology suites; and 6) self-protection issues related to radiation safety.1,2

Preanesthetic Considerations Baseline blood pressure and cardiovascular reserve should be assessed carefully, especially when blood pressure manipulation and perturbations are anticipated. For intravenous sedation cases, careful padding of pressure points and working with the patient to obtain final safe and comfortable positioning may assist in the patient’s ability to tolerate a long period of lying supine and motionless, decreasing the requirement for sedation, anxiolysis, and analgesia. The possibility of pregnancy in female patients and a history of adverse reactions to radiographic contrast agents should be explored. For cases managed with an unsecured airway, routine evaluation of the potential ease of laryngoscopy in an emergent situation should take into account that direct 145

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access to the airway may be limited by imaging table or room logistics. Furthermore, this patient population often includes patients with head and neck tumors with their associated airway abnormalities. Preoperative calcium channel blockers for prophylaxis for cerebral ischemia may be used and can affect hemodynamic management in the perianesthetic period. These agents or transdermal nitroglycerine are sometimes used to reduce the incidence of catheter-induced vasospasm.

Monitoring and Vascular Access Secure intravenous access should be available with adequate extension tubing to allow drug and fluid administration at maximal distance from the image intensifier during fluoroscopy. Access to the intravenous or arterial catheter can be difficult when the patient is draped and the arms are restrained at the sides; connections should be secure and Luer-locked if possible. Infusions of anticoagulant, primary anesthetics, or vasoactive agents should be through proximal ports, minimizing dead space. In addition to standard monitors, capnography through the sampling port of a nasal cannula is useful for intravenous sedation cases. A pulse oximeter probe can be placed on the great toe of the leg that will receive the femoral introducer sheath to provide an early warning of femoral artery obstruction or distal thromboembolism. For intracranial procedures and postoperative care, beat-to-beat arterial pressure monitoring and blood sampling can be facilitated by an arterial line. A side port of the femoral artery introducer sheath can be used, but the sheath may be removed immediately after the procedure. Using a coaxial or triaxial catheter system, arterial pressure at the carotid artery, vertebral artery, and the distal cerebral circulation can be measured. The presence of a coaxial catheter can underestimate systolic and overestimate diastolic pressure; however, mean pressures are reliable and may be used to monitor the occurrence or intentional induction of either hyper- or hypotension. For a patient who requires continuous blood pressure monitoring postoperatively, it is convenient to have a separate radial artery blood pressure catheter. Bladder catheters assist in fluid management as well as patient comfort. A significant volume of heparinized flush solution and radiographic contrast is often used.

Radiation Safety There are three sources of radiation in the INR suite: direct radiation from the x-ray tube, leakage (through the collimators’ protective shielding), and scattered (reflected from the patient and the area surrounding the body part to be imaged). A fundamental knowledge of radiation safety is essential for all staff members working in an INR suite. It must be realized that the amount of exposure decreases proportionally to the square of the distance from the source of radiation (inverse square law). It should also be realized that digital subtraction angiography (DSA) delivers considerably more radiation than fluoroscopy. Optimal protection dictates that all personnel wear lead aprons, thyroid shields, and radiation exposure-monitoring badges. The lead aprons should be periodically evaluated for any cracks in the lead lining that may allow accidental radiation exposure. Movable lead glass screens may provide additional protection for the anesthesia team. Clear communication between the INR and anesthesia teams is crucial for limiting radiation exposure. With proper precautions, the anesthesia team should be exposed to far less than the annual recommended limit for healthcare workers (see URL http://pdg.lbl.gov/).

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Anesthetic Technique Choice of Anesthetic Technique. Choice of anesthetic technique varies between centers with no clearly superior method. There is an increasing trend to use general endotracheal anesthesia, which is particularly attractive for control of motion that may be required during imaging and temporary periods of apnea. Intravenous Sedation. Primary goals of anesthetic choice for intravenous sedation are to alleviate pain, anxiety, and discomfort, and to provide patient immobility. A rapid recovery from sedation is often required for neurologic testing. Many neuroangiographic procedures, although not painful per se, can be psychologically stressful. There may be a discomfort associated with injection of contrast into the cerebral arteries (burning) and distention or traction on these vessels (headache). A long period of lying still can cause significant pain and discomfort. A variety of sedation regimens are available, and specific choices are based on the experience of the practitioner and the goals of anesthetic management. Common to all intravenous sedation techniques is the potential for upper airway obstruction. Placement of nasopharyngeal airways may cause troublesome bleeding in anticoagulated patients and is generally avoided. Dexmedetomidine is a new agent that may have applicability in the setting of INR. It is a potent, selective α2-agonist with sedative, anxiolytic, and analgesic properties with recent regulatory approval for sedation. Dexmedetomidine is especially noteworthy for its ability to produce a state of patient tranquility without depressing respiration. However, there are two caveats to consider. First, effects on cerebral perfusion are still unclear.3 More importantly, there is a tendency for patients managed with dexmedetomidine to have relatively low blood pressure in the postanesthesia recovery period.4 Because many INR patients are critically dependent on adequate collateral perfusion pressure, use of regimens that may result in decreased blood pressure should be used with great caution. General Anesthesia. The primary reason for using general anesthesia is to minimize motion artifacts and to improve the quality of images, especially in small children and uncooperative adult patients. This is especially pertinent to INR treatment of spinal pathology in which extensive multilevel angiography may be performed. The specific choice of anesthesia may be guided primarily by other cardio- and cerebrovascular considerations. Total intravenous anesthetic (TIVA) techniques, or combinations of inhalational and intravenous methods, may optimize rapid emergence. To date, pharmacologic protection against ischemic injury during neurosurgical procedures has not been proven. A theoretical argument could be made for eschewing the use of N2O because of the possibility of introducing air emboli into the cerebral circulation, but there are no data to support this.

Anticoagulation Careful management of coagulation is required to prevent thromboembolic complications during and after the procedure. Heparin. Generally, after a baseline activated clotting time (ACT) is obtained, intravenous heparin (70 units/kg) is given to achieve a target prolongation of two to three times baseline. Heparin can then be given continuously or as an intermittent bolus with hourly monitoring of ACT. Occasionally, a patient may be refractory to attempts to obtain adequate anticoagulation. Switching from bovine to porcine heparin or vice versa should be considered. If antithrombin III deficiency is suspected, administration of fresh-frozen plasma may be necessary.

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Direct Thrombin Inhibitor. Heparin-induced thrombocytopenia (HIT) is a potentially devastating prothrombotic disease caused by heparin-dependent antibodies that develop after heparin exposure. Direct thrombin inhibitors are indicated in patients with or at risk of HIT, although a small chance of anaphylactic reactions has been reported. They inhibit thrombin both in the free form or bound to the clot. Monitoring is accomplished by measuring the aPTT or ACT. Lepirudin is U.S. Food and Drug Administration-approved for anticoagulation in patients with HIT. The half-life of lepirudin is 40 to 120 minutes, and it undergoes renal elimination. For HIT patients with renal impairment, Argatroban, predominantly metabolized in the liver, would be preferred. Bivalirudin, a synthetic derivative of lepirudin, has a short half-life of approximately 25 minutes. Because bivalirudin is partially renally eliminated, dose adjustments may be needed in patients with renal dysfunction. Bivalirudin has been used in the cardiac catheterization lab for patients who have contraindications to heparin. There is a recent report suggesting that bivalirudin may be a potential alternative to intravenously administered heparin for neuroendovascular procedures based on its thrombolytic property.5 Antiplatelets. Antiplatelet agents (aspirin, the glycoprotein IIb/IIIa receptor antagonists, and the thienopyridine derivatives) are increasingly being used for cerebrovascular disease management as well as rescue from thromboembolic complications.6,7 Activation of the platelet membrane glycoprotein (GP) IIb/IIIa leads to fibrinogen binding and is a final common pathway for platelet aggregation. Abciximab, eptifibatide, and tirofiban are glycoprotein IIb/IIIa receptor antagonists. The long duration and potent effect of Abciximab also increase the likelihood of major bleeding. The smaller molecule agents, eptifibatide and tirofiban, are competitive blockers and have a shorter half-life of approximately 2 hours, which make them preferable for less risk of postoperative bleeding. Thienopyridine derivatives (ticlopidine and clopidogrel) bind to the platelet’s ADP receptors and permanently alter the receptor; therefore, the duration of action is the lifespan of the platelet. The addition of clopidogrel to the antiplatelet regimen is recommended when stent-assisted coiling is anticipated. Reversal of Anticoagulation. At the end of the procedure or at an occurrence of a hemorrhagic complication, heparin may be reversed with protamine. Because there is no specific antidote for the direct thrombin inhibitors or the antiplatelet agents, the biologic half-life is one of the major considerations in drug choice. Although aspirin and the glycoprotein IIb/IIIa inhibitors may be reversed by platelet transfusion, the antiplatelet activity of thienopyridine metabolites can last for 48 hours. Moreover, there is no accurate test to measure platelet function in patients taking the newer antiplatelet drugs. Desmopressin (DDAVP) has been reported to shorten the prolonged bleeding time of individuals taking antiplatelet agents such as aspirin and ticlopidine. There are also increasing recent reports on using specific clotting factors, including recombinant factor VIIa and factor IX complex, to rescue severe life-threatening bleeding, including intracranial hemorrhage uncontrolled by standard transfusion therapy. The safety and efficacy of these coagulation factors have yet to be investigated.

Superselective Anesthesia Functional Examination Superselective anesthesia functional examination (SAFE) is carried out to determine, before therapeutic embolization, if the tip of the catheter has been inadvertently placed proximal to the origin of nutritive vessels to eloquent regions either in the brain or spinal cord.8 Such testing is an extension of the Wada and Rasmussen test in which amobarbital is injected into the internal carotid artery (ICA) to determine hemispheric

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dominance and language function. Its primary application is in the setting of brain arteriovenous malformation (BAVM) treatment, but it may also be used for tumor or other vascular malformation procedures. Choice of anesthetic agents should allow for rapid return to a sensorium compatible with neurologic testing.

Deliberate Hypotension The two primary indications for induced hypotension are: 1) testing cerebrovascular reserve in patients undergoing carotid occlusion, and 2) slowing the flow in a feeding artery of BAVMs before glue injection. The most important factor in choosing a hypotensive agent is the ability to safely and expeditiously achieve the desired reduction in blood pressure while maintaining the patient physiologically stable. The choice of agent should be determined by the experience of the practitioner, the patient’s medical condition, and the goals of blood pressure reduction in a particular clinical setting. Intravenous adenosine has been used to induce transient cardiac pause and may be a viable method of partial flow arrest.9

Deliberate Hypertension During acute arterial occlusion or vasospasm, the only practical way to increase collateral blood flow may be an augmentation of the collateral perfusion pressure by raising the systemic blood pressure. The Circle of Willis is a primary collateral pathway in cerebral circulation. However, in as many as 21% of otherwise normal subjects, the circle may not be complete. There are also secondary collateral channels that bridge adjacent major vascular territories, most importantly for the long circumferential arteries that supply the hemispheric convexities. These pathways are known as the pial-to-pial collateral or leptomeningeal pathways. The extent to which the blood pressure has to be raised depends on the condition of the patient and the nature of the disease. Typically, during deliberate hypertension, the systemic blood pressure is raised by 30% to 40% above the baseline or until ischemic symptoms resolve. Phenylephrine is usually the first-line agent for deliberate hypertension and is titrated to achieve the desired level of blood pressure. The risk of causing hemorrhage in the ischemic area must be weighed against the benefits of improving perfusion, but augmentation of blood pressure in the face of acute cerebral ischemia is probably protective in most settings.

Management of Neurologic and Procedural Crises A well thought-out plan, coupled with rapid and effective communication between the anesthesia and radiology teams, is critical for good outcomes. The primary responsibility of the anesthesia team is to preserve gas exchange and, if indicated, secure the airway. Simultaneous with airway management, the first branch in the decision-making algorithm is for the anesthesiologist to communicate with the INR team and determine whether the problem is hemorrhagic or occlusive. In the setting of vascular occlusion, the goal is to increase distal perfusion by blood pressure augmentation with or without direct thrombolysis. If the problem is hemorrhagic, immediate cessation of heparin and reversal with protamine is indicated. As an emergency reversal dose, 1 mg protamine can be given for each 100 units of initial heparin administered that resulted in therapeutic anticoagulation. The ACT can then be used to fine-tune the final protamine dose. Complications of protamine administration include hypotension, true anaphylaxis, and pulmonary hypertension. With the advent of new long-acting direct thrombin inhibitors such as bivalirudin, new strategies for emergent reversal of anticoagulation will need to be developed.

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Bleeding catastrophes are usually heralded by headache, nausea, vomiting, and vascular pain related to the area of perforation. Sudden loss of consciousness is not always the result of intracranial hemorrhage. Seizures, as a result of contrast reaction or transient ischemia, and the resulting postictal state can also result in an obtunded patient. In the anesthetized patient, the sudden onset of bradycardia or the endovascular therapist’s diagnosis of extravasation of contrast may be the only clues of a developing hemorrhage. Most cases of vascular rupture can be managed in the angiography suite; a ventricular catheter is often useful for management. Emergent craniotomy is usually not indicated.

Postoperative Management Patients in the immediate postoperative period after undergoing endovascular surgery are monitored for signs of hemodynamic instability and neurologic deterioration. Blood pressure control, with either induced hypotension or hypertension, may be continued during the postoperative period. After AVM embolization or angioplasty and stenting for atherosclerotic lesion, abrupt restoration of normal systemic pressure to a chronically hypotensive vascular bed may overwhelm autoregulatory capacity and result in hemorrhage or swelling (normal perfusion pressure breakthrough [NPPB]). It is, in part, for this reason that the target range for posttreatment blood pressure should be at or near a patient’s normal pressure in the absence of collateral perfusion pressure inadequacy, with fastidious attention to preventing hypertension. The exact pathophysiology of hemodynamic complications after treatment remains controversial. Complicated cases may go first to computed tomography or some other kind of tomographic imaging; critical care management may need to be extended during transport and imaging.

Specific Procedures The scope of procedures and disease process that are likely to be encountered is presented in Table 1. Intracranial Aneurysm Ablation. The two basic approaches for INR therapy of cerebral aneurysms are occlusion of proximal parent arteries and obliteration of the aneurysmal sac. With the publication of the ISAT trial, coil embolization of intracranial aneurysms has become a routine first-choice therapy for many lesions. The aneurysmal sac may be obliterated by use of coils and balloons. The anesthesiologist should be prepared for aneurysmal rupture and acute subarachnoid hemorrhage (SAH) at all times, either from spontaneous rupture of a leaky sac or direct injury of the aneurysm wall by the vascular manipulation. Angioplasty of Cerebral Vasospasm from Aneurysmal SAH. Angioplasty may be used to treat symptomatic vasospasm with correlating angiographic stenosis refractory to maximal medical therapy.10 Angioplasty is usually reserved for patients who have already had the symptomatic lesion surgically clipped (for fear of rerupture) or for patients in the early course of symptomatic ischemia to prevent transformation of a bland infarct into a hemorrhagic one. A balloon catheter is guided under fluoroscopy into the spastic segment and inflated to mechanically distend the constricted area. It is also possible to perform a “pharmacologic” angioplasty by direct intraarterial infusion. There is the greatest experience with papaverine, but there are potential CNS toxic effects.11 Other agents such as calcium channel blockers (nicardipine and verapamil) are being used. Angioplasty and Stenting for Atherosclerotic Lesion. Angioplasty and stenting to treat atherosclerotic disease involving the cervical and intracranial arteries is an area of intense activity and growing interest.12 Risk of distal thromboembolism is the major

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Interventional Neuroradiologic Procedures and Primary Anesthetic Considerations Procedure

Special diagnostic procedures Superselective angiography and functional testing Carotid test occlusion and therapeutic occlussion Therapeutic procedures Therapeutic embolization of vascular malformation Intracranial arteriovenous malformations (AVM) Dural arteriovenous fistulae (DAVF) Cerebral aneurysms Angioplasty of cerebral vasospasm secondary to SAH* Balloon angioplasty and stent placement for artherosclerotic lesion Thrombolysis of acute thromboembolic stroke Spinal cord lesion Sclerotherapy of venous angiomas

Major Anesthetic Considerations Cerebral ischemia, ICH* Cerebral ischemia, ICH, blood pressure control* Cerebral ischemia, ICH, pulmonary embolism Deliberate hypotension, ICH, pulmonary embolism, postprocedure NPPB* Deliberate hypercapnia Aneurysmal rupture, blood pressure control Cerebral ischemia, ICH, blood pressure control Cerebral ischemia, ICH, bradycardia, concomitant coronary artery disease, postprocedure NPPB ICH, blood pressure control Controlled ventilation Airway swelling, hypoxia, hypoglycemia, intoxication from ethanol

*Blood pressure control refers to deliberate hypo- and/or hypertension. ICH = intracranial hemorrhage; SAH = aneurysmal subarachnoid hemorrhage; NPPB = normal perfusion pressure breakthrough.

issue to be resolved in this procedure. Catheter systems that use some kind of trapping system distal to the angioplasty balloon are being developed. There are multiple ongoing trials to compare the use of stenting with carotid endarterectomy for extracranial carotid disease. It is likely that use of stenting will continue to increase as favorable data supporting its safety and efficacy emerge. Preparation for anesthetic management may include placement of transcutaneous pacing leads in case of severe bradycardia or asystole from carotid body stimulation during angioplasty. Intravenous atropine or glycopyrrolate may be also used in an attempt to mitigate against bradycardia, which almost invariably occurs to some degree with inflation of the balloon. This powerful chronotropic response may be difficult or impossible to prevent or control by conventional means. Adverse effects of increasing myocardial oxygen demand need to be considered in antibradycardia interventions. Potential complications include vessel occlusion, perforation, dissection, spasm, thromboemboli, occlusion of adjacent vessels, transient ischemic episodes, and stroke. Similar to carotid endarterectomy, there is approximately a 5% risk of symptomatic cerebral hemorrhage and/or brain swelling after carotid angioplasty.13 Although the etiology of this syndrome is unknown, it has been associated with cerebral hyperperfusion, and it may be related to poor postoperative blood pressure control. Thrombolysis of Acute Thromboembolic Stroke. In acute occlusive stroke, it is possible to recanalize the occluded vessel by superselective intraarterial thrombolytic therapy. Thrombolytic agents can be delivered in high concentration by a micro-

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catheter navigated close to the clot. Neurologic deficits may be reversed without additional risk of secondary hemorrhage if treatment is completed within 4 to 6 hours of the onset of carotid territory ischemia and 24 hours in the vertebrobasilar territory. One of the impediments in development in this area has been the fear of increasing the risk of hemorrhagic transformation of the patient with acute infarction. Despite an increased frequency of early symptomatic hemorrhagic complications, treatment with intraarterial prourokinase within 6 hours of the onset of acute ischemic stroke with middle cerebral artery occlusion significantly improved clinical outcome at 90 days.14 Details of anesthetic management are reviewed elsewhere.15 Brain Arteriovenous Malformations. Also called cerebral or pial AVMs, brain arteriovenous malformations (BAVMs) are typically large, complex lesions made up of a tangle of abnormal vessels (called the nidus) frequently containing several discrete fistulae served by multiple feeding arteries and draining veins. The goal of the therapeutic embolization is to obliterate as many of the fistulae and their respective feeding arteries as possible. BAVM embolization is usually an adjunct for surgery or radiotherapy, although in rare cases, treatment is aimed at total obliteration. The cyanoacrylate glues offer relatively “permanent” closure of abnormal vessels. Passage of glue into a draining vein can result in acute hemorrhage; in smaller patients, pulmonary embolism of glue can be symptomatic. For these reasons, deliberate hypotension may increase safety of glue delivery. Although less durable, polyvinyl alcohol (PVA) microsphere embolization is also commonly used. If surgery is planned within days after PVA embolization, the rate of recanalization is low and PVA is felt to be easier and safer to work with. Carotid Test Occlusion and Therapeutic Carotid Occlusion. Carotid occlusion, both permanent and temporary, may be used in several circumstances. Skull base tumors frequently involve the intracranial or petrous portion of the carotid artery or its proximal Willisian branches. Large or otherwise unclippable aneurysms may be partly or completely treated by proximal vessel occlusion. To assess the consequences of carotid occlusion in anticipation of surgery, the patient may be scheduled for a test occlusion in which cerebrovascular reserve is evaluated in several ways. A multimodal combination of angiographic, clinical, and physiological tests can be used to arrive at the safest course of action for a given patient’s clinical circumstances. The judicious use of deliberate hypotension can increase the sensitivity of the test.16 Dural Arteriovenous Malformations. Dural AVM is currently considered an acquired lesion resulting from venous dural sinus stenosis or occlusion, opening of potential AV shunts, and subsequent recanalization. Symptoms are varied according to which sinus is involved. Dural AVMs may be fed by multiple meningeal vessels, and therefore, multistaged embolization is often necessary. SAFE may be performed in certain vessels, such as the middle meningeal artery and the ascending pharyngeal artery, to evaluate the blood supply to peripheral cranial nerves and the possible existence of dangerous extra-to-intracranial anastomosis. Dural AV fistulas can induce markedly increased venous pressure and decrease net cerebral perfusion pressure. In addition, the venous hypertension should be factored into estimating safe levels of reductions in systemic arterial pressure, and therefore cerebral perfusion pressure. Venous hypertension of pial veins is a risk factor for intracranial hemorrhage. Vein of Galen Malformations. These are relatively uncommon but complicated lesions that are present in infants and require a multidisciplinary approach, including an anesthesiologist skilled in the care of critically ill neonates. The patients may have intractable congestive heart failure, myocardial lesions, intractable seizures, hydrocephalus, and mental retardation.17

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Spinal Cord Lesions. Embolization may be used for intramedullary spinal AVMs, dural fistulae, or tumors invading the spinal canal. Often, general endotracheal anesthesia with controlled ventilation is used to provide temporary apnea that may increase the ability to see small spinal cord arteries at the limits of angiography imaging resolution and exquisitely sensitive to motion artifact. For selected lesions, intraoperative somatosensory and motor-evoked potentials may be helpful in both anesthetized and sedated patients. Intraoperative wake-up tests may be requested to test neurologic function during embolization. In cases in which wake-up tests might be needed, preoperative discussion of the logistics of the wake-up procedure and the testing process may facilitate the intraoperative management of this part of the procedure. Sclerotherapy of Venous Angiomas. Craniofacial venous malformations are congenital disorders causing significant cosmetic deformities that may impinge on the upper airway and interfere with swallowing. Absolute alcohol (95% ethanol) opacified with contrast is injected percutaneously into the lesion, resulting in a chemical burn to the lesion and eventually shrinking it. The procedures are short (30 to 60 minutes) but painful, and general endotracheal anesthesia is used. Complex airway involvement may require tracheal intubation with fiberoptic techniques.18 Because marked swelling often occurs immediately after alcohol injection, the ability of the patient to maintain a patent airway must be carefully assessed in discussion with the radiologist before extubation. Alcohol has several noteworthy side effects. On injection, it can cause changes in the pulmonary vasculature and create a short-lived shunt or a ventilation– perfusion mismatch. Desaturation on the pulse oximeter is frequently noted after injection. Absolute alcohol may also cause hypoglycemia, especially in younger children. Finally, the predictable intoxication and other side effects of ethanol may be evident after emergence from anesthesia.

References 1. Young WL, Pile-Spellman J: Anesthetic considerations for interventional neuroradiology. Anesthesiology 1994; 80:427–56. 2. Young WL, Pile-Spellman J, Hacein-Bey L, et al.: Invasive neuroradiologic procedures for cerebrovascular abnormalities: Anesthetic considerations. Anesthesiol Clin North America 1997; 15:631–53. 3. Prielipp RC, Wall MH, Tobin JR, et al.: Dexmedetomidine-induced sedation in volunteers decreases regional and global cerebral blood flow. Anesth Analg 2002; 95:1052–9. 4. Arain SR, Ebert TJ: The efficacy, side effects, and recovery characteristics of dexmedetomidine versus propofol when used for intraoperative sedation. Anesth Analg 2002; 95:461–6. 5. Harrigan MR, Levy EI, Bendok BR, et al.: Bivalirudin for endovascular intervention in acute ischemic stroke: Case report. Neurosurgery 2004; 54:218–22; discussion 222–3. 6. Hashimoto T, Gupta DK, Young WL: Interventional neuroradiology–Anesthetic considerations. Anesthesiol Clin North America 2002; 20:347–59, vi. 7. Fiorella D, Albuquerque FC, Han P, et al.: Strategies for the management of intraprocedural thromboembolic complications with abciximab (ReoPro). Neurosurgery 2004; 54:1089–98. 8. Rauch RA, Vinuela F, Dion J, et al.: Preembolization functional evaluation in brain arteriovenous malformations: The ability of superselective Amytal test to predict neurologic dysfunction before embolization. AJNR Am J Neuroradiol 1992;13:309–14. 9. Hashimoto T, Young WL, Aagaard BD, et al.: Adenosine-induced ventricular asystole to induce transient profound systemic hypotension in patients undergoing endovascular therapy. Dose—response characteristics. Anesthesiology 2000; 93:998–1001. 10. Newell DW, Eskridge JM, Mayberg MR, et al.: Angioplasty for the treatment of symptomatic vasospasm following subarachnoid hemorrhage. J Neurosurg 1989; 71:654–60.

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11. Fogarty-Mack P, Pile-Spellman J, Hacein-Bey L, et al.: Superselective intraarterial papaverine administration: Effect on regional cerebral blood flow in patients with arteriovenous malformations. J Neurosurg 1996; 85:395–402. 12. Phatouros CC, Higashida RT, Malek AM, et al.: Carotid artery stent placement for atherosclerotic disease: Rationale, technique, and current status. Radiology 2000; 217:26–41. 13. Meyers PM, Higashida RT, Phatouros CC, et al.: Cerebral hyperperfusion syndrome after percutaneous transluminal stenting of the craniocervical arteries. Neurosurgery 2000; 47:335–43; discussion 343–5. 14. Furlan A, Higashida R, Wechsler L, et al.: Intra-arterial prourokinase for acute ischemic stroke. The PROACT II study: A randomized controlled trial. Prolyse in Acute Cerebral Thromboembolism. JAMA 1999; 282:2003–11. 15. Lee CZ, Litt L, Hashimoto T, et al.: Physiological monitoring and anesthesia considerations of the acute ischemic stroke patient. J Vasc Interv Radiol 2004; 15:S13–9. 16. Marshall RS, Lazar RM, Pile-Spellman J, et al.: Recovery of brain function during induced cerebral hypoperfusion. Brain 2001; 124:1208–17. 17. Setton A, Berenstein A: Interventional neuroradiology. Curr Opin Neurol Neurosurg 1992; 5:870–80. 18. Roberts JT, Pile-Spellman J, Joseph M, et al.: A patient with massive oral—facial venous malformation. J Clin Anesth 1991; 3:76–9.

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CHAPTER 13

V O L U M E

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

ANAPHYLAXIS AND ADVERSE DRUG REACTIONS JERROLD H. LEVY, M.D. PROFESSOR OF ANESTHESIOLOGY DEPUTY CHAIR FOR RESEARCH EMORY UNIVERSITY SCHOOL OF MEDICINE DIRECTOR, CARDIOTHORACIC ANESTHESIOLOGY EMORY HEALTHCARE ATLANTA, GEORGIA

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.

Anaphylaxis and Adverse Drug Reactions Jerrold H. Levy, M.D. Professor of Anesthesiology Deputy Chair for Research Emory University School of Medicine Director, Cardiothoracic Anesthesiology Emory Healthcare Atlanta, Georgia

Any substance that patients are exposed to in the perioperative period, including drugs, blood products, or environmental antigens such as latex, can produce anaphylaxis. All of these agents also have the potential to produce predictable and unpredictable adverse reactions. The most life-threatening form of an adverse reaction is anaphylaxis; however, the clinical presentation of anaphylaxis may in fact represent different immune and nonimmune responses.1 There is confusion in the literature about the term anaphylaxis, and a multitude of descriptive terminologies have been reported to describe the spectrum of reactions. Based on current concepts, anaphylaxis is best defined as a clinical syndrome characterized by acute cardiopulmonary collapse after antigen (foreign substance) exposure. This Refresher Course defines the spectrum of anaphylactic and adverse drug reactions an anesthesiologist may encounter.

Adverse Drug Reactions Adverse drug reactions are common; however, only 6% to 10% are immunologically mediated.2 Although some drug-induced allergic reactions may be classified into one of the four Gell and Coombs hypersensitivity categories, many others cannot be classified because of our lack of mechanistic information. Theoretically, any drug can induce an immune response.1–4 However, some drugs are more likely to elicit clinically relevant immune responses than are others. Most serious predictable adverse drug reactions are toxic and related to either the amount of drug in the body (overdosage), unintended administration route, or known side effects (for example, opioid-related nausea). However, some drugs have direct effects on inflammatory cells (for example, drug-mediated histamine release from mast cells or biologic response modifiers). Unfortunately, patients often refer to any adverse drug effects as being allergic in nature. Anesthetic drugs also have the potential to produce direct effects on the cardiovascular system (for example, propofol-induced vasodilation) complicating the diagnosis of perioperative adverse drug reactions. Unlike most adverse drug reactions, allergic drug reactions are unpredictable and are dose-independent because small amounts of the antigen, including that amount eluted off latex gloves during latex anaphylaxis, can produce life-threatening responses.1

Life-threatening Allergic Reactions (Anaphylaxis) Because any parenterally administered agent can cause death from anaphylaxis, anesthesiologists must diagnose and treat the acute cardiopulmonary changes that can 155

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occur. Recent studies from Europe suggest that perioperative drug-induced anaphylaxis may be increasing. Richet and Portier first used the word anaphylaxis (ana— against, prophylaxis—protection) to describe the profound shock and resulting death that sometimes occurred in dogs immediately after a second challenge with a foreign antigen.5 When life-threatening allergic reactions mediated by antibodies or immune mechanisms occur, they are defined as “anaphylaxis.” Multiple other terms are used in the literature to describe life-threatening reactions that are not immune-mediated. Through the years, these terms have created major confusion because one cannot distinguish the etiology of reactions based on clinical observation. Much of the confusion about anaphylaxis in the literature is because many older anesthetic agents could directly degranulate mast cells.

Pathophysiology of Anaphylaxis Antigen binding to IgE antibodies initiates anaphylaxis. Prior exposure to the antigen or to a substance of similar structure is required to produce sensitization, although an allergic history may be unknown to the patient. On reexposure, antigen binds to bridge two immunospecific IgE antibodies on the surfaces of mast cells and basophils to release a complex series of inflammatory molecules that produce acute cardiopulmonary dysfunction.6–9 The released mediators produce a symptom complex of bronchospasm and upper airway edema in the respiratory system, vasodilation and increased capillary permeability in the cardiovascular system, and urticaria in the cutaneous system.1 Cardiovascular collapse during anaphylaxis results from the effects of multiple mediators on the heart and vasculature.6–9 The vasodilation seen clinically can result from a spectrum of different mediators that interact with vascular endothelium and/or vascular smooth muscle.1,8

Vasodilatory Shock and Anaphylaxis Vasodilatory shock occurs in anaphylaxis resulting from multiple mechanisms, including the excessive activation of vasodilator mechanisms, including unregulated nitric oxide synthesis that activates soluble guanylate cyclase and produces cGMP, and prostacyclin synthesis that activates soluble adenylate cyclase and produces cAMP, both causing dephosphorylation of myosin and hence vasorelaxation.1,8 Nitric oxide synthesis and metabolic acidosis activate the potassium channels in vascular smooth muscle. The resulting vascular hyperpolarization prevents calcium from entering the cell. Hypotension and vasodilatation persist, despite catecholamine therapy.10 Other mediators that are released by non-IgE mechanisms may also produce shock by different mechanisms (for example, protamine induced acute pulmonary vasoconstriction) are discussed in non-IgE-mediated reactions.1

Recognition of Anaphylaxis The onset and severity of the reaction relate to the mediator’s specific end organ effects. Antigenic challenge in a sensitized individual usually produces immediate clinical manifestations of anaphylaxis, but the onset may be delayed 2 to 20 minutes.3,6,9 Individuals vary in the manifestations and course of anaphylaxis because of exposure (oral versus parenteral). A spectrum of reactions exists, ranging from minor clinical

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changes to acute cardiopulmonary collapse, leading to death1 (Table 1). The enigma of anaphylaxis is the unpredictability of occurrence, the severity of the attack, and the lack of an allergic history.1

Non-IgE-mediated Reactions Other immunologic and nonimmunologic mechanisms release inflammatory mediators independent of IgE, creating a clinical syndrome identical to anaphylaxis.11–17 Polymorphonuclear leukocyte (neutrophil) activation can occur after complement activation by immunologic (antibody-mediated: IgM, IgG–antigen activation) or nonimmunologic (heparin–protamine, endotoxin, cardiopulmonary bypass) pathways.11–14 Complement fragments of C3 and C5 (C3a and C5a) are called anaphylatoxins because they release histamine from mast cells and basophils, contract smooth muscle, and increase capillary permeability. In addition, C5a interacts with specific high-affinity receptors on white blood cells and platelets, causing leukocyte chemotaxis, aggregation, and activation.13 Aggregated leukocytes embolize to various organs producing microvascular occlusion and liberation of inflammatory products, including oxygen-free radicals, lysosomal enzymes, and arachidonic acid metabolites (that is, prostaglandins and leukotrienes). Antibodies of the IgG class directed against antigenic determinants or granulocyte surfaces can also produce leukocyte aggregation.15 These antibodies are called leukoagglutinins. Investigators have associated polymorphonuclear leukocyte activation in producing the clinical manifestations of transfusion reactions,15 pulmonary vasoconstriction after protamine reactions,16 and transfusion-related acute lung injury (TRALI).17 Studies currently are examining the potential of C5a inhibition by monoclonal antibodies (Pexelizumab; Alexion Pharmaceuticals Inc., Cheshire, CT) to prevent the adverse effects of complement generation in perioperative settings, and other complement inhibiting strategies are being developed.

Nonimmunologic Release of Histamine Many diverse molecular structures administered during the perioperative period degranulate mast cells to release histamine in a dose-dependent, nonimmunologic

TABLE 1. Systems

Recognition of Anaphylaxis during Anesthesia Symptoms

Respiratory

Dyspnea, chest discomfort

Cardiac

Dizziness, malaise, retrosternal oppression

Cutaneous

Itching, burning

Signs Coughing, wheezing, sneezing, laryngeal edema, decreased pulmonary compliance, fulminant pulmonary edema, acute respiratory distress Disorientation, diaphoresis, loss of consciousness, hypotension, tachycardia, dysrhythmias, decreased systemic vascular resistance, cardiac arrest, pulmonary hypertension Urticaria (hives), flushing, periorbital edema, perioral edema

From Levy JH: Anaphylactic Reactions in Anesthesia and Intensive Care. Stoneham: ButterworthHeinemann, 1992.

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fashion.18–21 Intravenous administration of morphine, atracurium, or vancomycin can release histamine, producing vasodilation and urticaria along the vein of administration.18 Although the cardiovascular effects of histamine release can be treated effectively with intravascular volume administration and/or catecholamines, the responses in different individuals may vary.1 The newer neuromuscular-blocking agents (for example, rocuronium and cisatracurium) are devoid of histamine-releasing effects but can produce direct vasodilation and false-positive cutaneous responses that can confuse allergy testing and interpretation.22,23 The mechanisms involved in nonimmunologic histamine release represent degranulation of mast cells but not basophils through cellular activation and stimulation of phospholipase activity in mast cells.19

Treatment Plan Most anesthetic drugs and agents administered perioperatively have been reported in the literature to produce anaphylaxis.1 Therefore, a plan for the treatment of anaphylactic reactions must be established before the event.1 Airway maintenance, 100% oxygen administration, intravascular volume expansion, and epinephrine are essential to treat the hypotension and hypoxia that results from vasodilation, increased capillary permeability, and bronchospasm6–9,24–26 Table 2 lists a protocol for management of anaphylaxis during general anesthesia, with representative doses for a 70-kg adult. Therapy must be titrated to desired effects with careful monitoring. Severe reactions require aggressive therapy. The route of administration of epinephrine and the dose depends on the patient’s condition.1 Rapid and timely intervention with common sense must be used to treat anaphylaxis effectively.27 Reactions may be protracted with persistent hypotension, pulmonary hypertension and right ventricular dysfunction, lower respiratory obstruction, or laryngeal obstruction that persist 5 to 32 hours despite vigorous therapy.24 Novel therapeutic approaches for anaphylactic shock and/or right ventricular failure are currently under investigation.28–30 During general anesthesia, patients may have altered sympathoadrenergic responses to acute anaphylactic shock. In addition, the patient during spinal or epidural anesthesia may be partially sympaTABLE 2.

Management of Anaphylaxis

Initial therapy 1. Stop administration of antigen 2. Maintain airway with 100% oxygen 3. Discontinue all anesthetic agents 4. Start intravascular volume expansion 5. Give epinephrine (5 to 10 µg intravenous initial bolus with hypotension, titrate as needed; 0.1 to 0.5 mg intravenously with cardiovascular collapse) Secondary treatment 1. Antihistamines (0.5 to 1 mg/kg diphenhydramine) 2. Catecholamine infusions (starting doses: Epinephrine 5 to 10 µg/min or Norepinephrine 5 to 10 µg/min, as infusions titrated to desired effects) 3. Bronchodilators (inhaled albuterol or terbutaline with bronchospasm) 4. Corticosteroids (0.25 to 1 g hydrocortisone; alternately 1 to 2 g methylprednisolone) 5. Airway evaluation (before extubation) 6. Persistant hypotension: consider vasopressin From Levy JH: Anaphylactic Reactions in Anesthesia and Intensive Care. Stoneham, ButterworthHeinemann, 2nd edition, 1992.

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thectomized, needing earlier intervention with even larger doses of epinephrine and other catecholamines.27 Additional hemodynamic monitoring, including radial and pulmonary artery catheterization, may be needed when hypotension persists despite therapeutic interventions as listed. When available, the use of transesophageal echocardiography in an intubated patient can be useful in diagnosing the cause of acute or persistent cardiovascular dysfunction. All patients after anaphylactic reaction should be admitted to an intensive care unit for 24 hours of monitoring because they may develop recurrence of manifestations after successful treatment.1 Based on the efficacy of vasopressin in vasodilatory shock, it should also be considered in the treatment of anaphylactic shock not responding to more traditional therapy.8,29

Pretreatment for Allergic Reactions The anesthesia literature suggests life-threatening hypersensitivity reactions are more likely to occur in patients with a history of allergy, atopy, or asthma. However, this does not make it mandatory to pretreat these patients with antihistamines and/or corticosteroids. There is no data in the literature to suggest that pretreatment is effective for true anaphylactic reactions. Most of the literature on pretreatment is from studies evaluating patients with previous radiocontrast media reactions that are nonimmunologic mechanisms. Although attempts to pretreat patients for anaphylaxis to latex are growing in clinical practice, there is no data to support this as an effective preventative measure. In fact, pretreatment may lull physicians into a false sense of security. Furthermore, even when large doses of corticosteroids have been administered, lifethreatening anaphylactic reactions have occurred.1,25

Management of the Allergic Patient Patients presenting with an allergic history need to be carefully evaluated. Often, patients will complain of allergy when the reaction was a predictable adverse drug reaction. However, for practical and medicolegal purposes, that class of drug should be avoided when the history or records are consistent with an allergic reaction and preservative-free alternatives should be chosen. The problem occurs whenever multiple drugs are simultaneously administered or when patients present with musclerelaxant reactions because of the risk of crossreactivity to the bisquaternary ammonium ions in the molecule. In this situation, skin testing may be required to see what can be administered safely.1

Epidemiology of Anaphylaxis: Agents Implicated Many agents administered in the perioperative period have the potential to produce allergic reactions on reexposure. However, the agents most often reported to cause a perioperative anaphylactic reaction are antibiotics, blood products, latex (rubber), muscle relaxants, and polypeptides (protamine or aprotinin). A recent epidemiologic study reported from 1999 to 2001 from France reported 789 reactions.31 Anaphylaxis, diagnosed on the basis of clinical history, skin tests, and/or specific immunoglobulin E assay, was found in 518 cases (66%) and nonimmune reactions in 271 cases (34%). The most common causes of anaphylaxis were neuromuscular-blocking agents (NMBAs)

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(n = 306, 58.2%), latex (n = 88, 16.7%), and antibiotics (n = 79, 15.1%). Rocuronium (n = 132, 43.1%) and succinylcholine (n = 69, 22.6%) were the most frequently incriminated NMBAs. The positive predictive value of tryptase for the diagnosis of anaphylaxis was 92.6%; the negative predictive value was 54.3%.

Latex Allergy Latex represents an environmental agent often implicated as an important cause of perioperative anaphylaxis. Healthcare workers, children with spina bifida and urogenital abnormalities, and certain food allergies have also been recognized as individuals at increased risk for anaphylaxis to latex.31–36 Brown reported a 24% incidence of irritant or contact dermatitis and a 12.5% incidence of latex-specific IgE positivity in anesthesiologists.34 Of this group, 10% were clinically asymptomatic although IgE-positive. A history of atopy was also a significant risk factor for latex sensitization. Brown suggests these individuals are in their early stages of sensitization and perhaps, by avoiding latex exposure, their progression to symptomatic disease can be prevented.34 Patients allergic to both tropical fruits (for example, bananas, avocados, and kiwis) and stone fruits have also been reported to have antibodies that crossreact with latex.35–37 Multiple attempts are being made to reduce latex exposure to both healthcare workers and patients. If latex allergy occurs, then strict avoidance of latex from gloves and other sources needs to be considered following recommendations as reported by Holzman.33 Because latex is such a widespread environmental antigen, this represents a daunting task. Despite recognizing latex anaphylaxis, multiple other agents, including antibiotics, induction agents, muscle relaxants, nonsteroidal antiinflammatory drugs, protamine, colloid volume expanders, and blood products represent additional etiologic agents often responsible for anaphylaxis in surgical patients.1

Neuromuscular-Blocking Agents NMBAs have several unique molecular features that make them potential allergens. All NMBAs are functionally divalent and are thus capable of crosslinking cell-surface IgE and initiating mediator release from mast cells and basophils without binding or haptenizing to larger carrier molecules.1 NMBAs have also been implicated in epidemiologic studies of anesthetic drug-induced anaphylaxis.38–40 Epidemiologic data from France suggest that NMBAs are responsible for 62% to 81% of reactions, depending on the time period evaluated.31,38 Rocuronium is currently the NMBA most reported from France. We and others have reported previously that aminosteroidal compounds as well as benzylisoquinoline-derived agents produce positive weal and flare responses when injected intradermally.19,22,42 Estimates of anaphylactic reactions in anesthesia vary, but data suggests that false-positive skin tests may overestimate the incidence of rocuronium-induced anaphylactic reactions.19,22,41,42 The differences noted in the incidence of reactions may reflect the potential for false-positive weal and flare responses.41,42 NMBAs can also produce direct vasodilation by multiple mechanisms, which include calcium channel blockade. The false-positive skin tests that were reported to be biopsynegative for mast cell degranulation clearly confound interpreting skin tests in patients who have had life-threatening cardiopulmonary collapse. Dilute solutions of NMBAs need to be used when skin testing for potential allergic reactions to these agents. However, the exact concentration that should be used is unclear. Because skin-testing pro-

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cedures are important in evaluating potential drug allergies, the threshold for direct vasodilating and false-positive effects must be determined whenever subjects are skintested for a particular drug.

Polypeptides and Blood Products Polypeptides are larger molecular-weight molecules that pose greater potential to be antigenic and include aprotinin, latex, and protamine. Diabetic patients receiving protamine containing insulin as neutral protamine Hagedorn (NPH) or protamine insulin have a 10- to 30-fold increased risk for anaphylactic reactions to protamine when used for heparin reversal, with an absolute risk of 0.6% to 2% in this patient population.25,26 Because protamine is often administered concomitantly with blood products, protamine is often implicated as the causative agent in adverse reactions, especially in cardiac surgical patients. Platelet and other allogeneic blood transfusions can produce a series of adverse reactions by multiple mechanisms, and blood products have a greater potential for allergic reactions compared with protamine.1 Although antigen avoidance is one of the most important considerations in preventing anaphylaxis, this is not always possible, especially with certain agents in which alternatives are not available. Protamine is an important example of when alternatives are under investigation, but not currently available. Aprotinin, a bovine derived, ~6,512 dalton molecular weight protein used to reduce bleeding, has had anaphylactic reactions after reexposure for cardiac surgery.43 There were 248 reexposures to aprotinin in 240 patients: 101 adult and 147 pediatric cases. The time between the first and second aprotinin exposures was 344 (interquartile range 1,039) days, and seven reactions to aprotinin were reported (2.8%) that ranged from mild to severe. Patients with an interval less than 6 months since the previous exposure had a statistically higher incidence of adverse reactions than patients with a longer interval (five of 111 or 4.5% versus two of 137 or 1.5%, P < 0.05).43 Suggested web sites: AnaphylaxisWeb.com, Bronchospasm.com.

References 1. Levy JH: Anaphylactic Reactions in Anesthesia and Intensive Care, 2nd ed. Stoneham: Butterworth-Heinemann Publishers; 1992. 2. Gruchalla RS: Drug allergy. J Allergy Clin Immunol 2002; 111(suppl):S548–59. 3. Kemp SF, Lockey RF: Anaphylaxis: A review of causes and mechanisms. J Allergy Clin Immunol 2002; 111(suppl):S548–59. 4. Porter J, Jick H: Drug-induced anaphylaxis, convulsions, deafness, and extrapyramidal symptoms. Lancet 1977; 1:587–8. 5. Portier MM, Richet C: De l’action anaphylactique de certains venins. C R Soc Biol 1902; 54:170–2. 6. Pumphrey RS, Roberts IS: Postmortem findings after fatal anaphylactic reactions. J Clin Pathol 2000; 53:273–6. 7. Prussin C, Metcalfe DD: IgE, mast cells, basophils, and eosinophils. J Allergy Clin Immunol 2002; 111(suppl):S486–94. 8. Landry DW, Oliver JA: The pathogenesis of vasodilatory shock. N Engl J Med 2001; 345:588–95. 9. Delage C, Irey NS: Anaphylactic deaths: A clinicopathologic study of 43 cases. J Forensic Sci 1972; 17:525–40. 10. Levy JH: Cardiovascular changes during anaphylactic reactions in man. J Clin Anesth 1989; 1:426–30.

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11. Levy JH, Tanaka KA: Inflammatory response to cardiopulmonary bypass. Ann Thorac Surg 2003; 75:S715–20. 12. MacGlashan D: Histamine: A mediator of inflammation. J Allergy Clin Immunol 2003; 112 (suppl):S53–9. 13. Walport MJ: Complement. N Engl J Med 2001; 344:1058–66 (part 1); 344:1140–4 (part 2). 14. Jacob HS, Craddock PR, Hammerschmidt DE, Moldow CFR: Complement-induced granulocyte aggregation—An unsuspected mechanism of disease. N Engl J Med 1980; 302:789–94. 15. Kopko PM, Popovsky MA, MacKenzie MR, et al.: HLA class II antibodies in transfusionrelated acute lung injury. Transfusion 2001; 41:1244–8. 16. Morel DR, Zapol WM, Thomas SJ, et al.: C5a and thromboxane generation association with pulmonary vaso- and broncho-constriction during protamine reversal of heparin. Anesthesiology 1987; 66:597–604. 17. Popovsky MA, Abel MD, Moore SB: Transfusion related acute lung injury associated with passive transfer of antileukocyte antibodies. Am Rev Respir Dis 1985; 128:185–9. 18. Levy JH, Brister NW, Shearin WA, et al.: Wheal and flare responses to opioids in humans. Anesthesiology 1989; 70:756–60. 19. Veien M, Szlam F, Holden JT, et al.: Mechanisms of nonimmunological histamine and tryptase release from human cutaneous mast cells. Anesthesiology 2000; 92:1074–81. 20. Levy JH, Adelson D, Walker B: Wheal and flare responses to muscle relaxants in humans. Agents Actions 1991; 34:302–8. 21. Levy JH, Kettlekamp N, Goertz P, Hermens J, Hirshman CA: Histamine release by vancomycin. A mechanism for hypotension in man. Anesthesiology 1987; 67:122–5. 22. Levy JH, Davis GK, Duggan J, Szlam F: Determination of the hemodynamics and histamine release of rocuronium (Org 9426) when administered in increased doses under N20/O2– sufentanil anesthesia. Anesth Analg 1994; 78:318–21. 23. Levy JH, Gottge M, Szlam F, Zaffer R, McCall C: Weal and flare responses to intradermal rocuronium and cisatracurium in humans. Br J Anaesth 2000; 85:844–9. 24. Lee JM, Greenes DS: Biphasic anaphylactic reactions in pediatrics. Pediatrics 2000; 106:762–6. 25. Levy JH, Zaidan JR, Faraj B: Prospective evaluation of risk of protamine reactions in NPH insulin-dependent diabetics. Anesth Analg 1986; 65:739–42. 26. Levy JH, Schwieger IM, Zaidan JR, Faraj BA, Weintraub WS: Evaluation of patients at risk for protamine reactions. J Thorac Cardiovasc Surg 1989; 98:200–4. 27. Caplan RA, Ward RJ, Posner K, Cheney FW: Unexpected cardiac arrest during spinal anesthesia: A closed claims analysis of predisposing factors. Anesthesiology 1988; 68:5–11. 28. Levy JH: New concepts in the treatment of anaphylactoid reactions. Ann Fr Anesth Reanim 1993; 12:223–7. 29. Tsuda A, Tanaka KA, Huraux C, et al.: The in vitro reversal of histamine-induced vasodilation in the human internal mammary artery. Anesth Analg 2001; 93:1453–9. 30. Huraux C, Makita T, Montes F, Szlam F, Levy JH: A comparative evaluation of the effects of multiple vasodilators on human internal mammary artery. Anesthesiology 1998; 88: 1654–9. 31. Mertes PM, Laxenaire MC, Alla F, et al.: Anaphylactic and anaphylactoid reactions occurring during anesthesia in France in 1999–2000. Anesthesiology 2003; 99:536–45. 32. Gold M et al: Intraoperative anaphylaxis: An association with latex sensitivity. J Allergy Clin Immunol 1991; 87:662–6. 33. Holzman RS: Latex allergy: An emerging operating room problem. Anesth Analg 1993; 76:635–41. 34. Brown RH, Schauble JF, Hamilton RG: Prevalence of latex allergy among anesthesiologists: Identification of sensitized but asymptomatic individuals. Anesthesiology 1998; 89:292–9. 35. Lavaud F, Prevost A, Cossart C, et al.: Allergy to latex, avocado, pear, and banana: Evidence for a 30 kd antigen in immunoblotting. J Allergy Clin Immunol 1995; 95:557–64. 36. Blanco C, Carrillo T, Castillo R, et al.: Latex allergy: Clinical features and cross-reactivity with fruits. Ann Allergy 1994; 73:309–14. 37. Lebenbom-Mansour MH, Oesterle JR, Ownsby DR, et al.: The incidence of latex sensitivity in ambulatory surgical patients: A correlation of historical factors with positive serum immunoglobulin E levels. Anesth Analg 1997; 85:44–9. 38. Moneret-Vautrin DA, Mouton C: Anaphylaxie aux myorelaxants: valeur prédictive des intradermoréactions et recherche de l’anaphylaxie croisée. Ann Fr Anesth Réanim 1985; 4:186–91.

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39. Fisher MM, Munro I: Life threatening, anaphylactoid reactions to muscle relaxants. Anesth Analg 1983; 62:559–64. 40. Laxenaire MC: Drugs and other agents involved in anaphylactic shock occurring during anaesthesia. A French multicenter epidemiological inquiry. Ann Fr Anesth Reanim 1993; 12:91–6. 41. Dhonneur G, Combes X, Chassard D, et al.: Skin sensitivity to rocuronium and vecuronium: a randomized controlled prick-testing study in healthy volunteers. Anesth Analg 2004; 98:986–9. 42. Levy JH: Anaphylactic reactions to neuromuscular blocking drugs: Are we making the correct diagnosis? Anesth Analg 2004; 98:881–2. 43. Dietrich W, Spaeth P, Ebell A, Richter JA: Incidence of anaphylactic reactions to aprotinin: Analysis of 248 reexposures to aprotinin. J Thorac Cardiovasc Surg 1997; 113:194–201.

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CHAPTER 14

V O L U M E

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

THE GRAYING OF AMERICA: ANESTHETIC IMPLICATIONS FOR GERIATRIC OUTPATIENTS KATHRYN E. MCGOLDRICK, M.D. PROFESSOR AND CHAIR, DEPARTMENT OF ANESTHESIOLOGY NEW YORK MEDICAL COLLEGE VALHALLA, 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.

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The Graying of America: Anesthetic Implications for Geriatric Outpatients Kathryn E. McGoldrick, M.D. Professor and Chair, Department of Anesthesiology New York Medical College Valhalla, New York

The elderly (≥65 years) population is the fastest growing demographic segment in the United States and many other parts of the developed world. According to the 2000 Census, there are 4.2 million Americans aged 85 years or older, an increase of 30% since 1990. Those 75 to 84 years of age number 12.4 million, an increase of more than 20% since 1990. This reality has profound implications for clinicians, including anesthesiologists and surgeons. Aging, for example, increases the probability that an individual will require a surgical procedure. Whereas approximately 12% of those aged 45 to 60 years undergo surgery annually, this number increases to >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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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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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.

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CHAPTER 15

V O L U M E

T H I R T Y - T H R E 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

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.

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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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

179

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.

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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.

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CHAPTER 16

V O L U M E

T H I R T Y - T H R E 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

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.

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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 <30%) or valvular disease, history of congestive heart failure, significant renal impairment (preoperative creatinine >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.

PERIOPERATIVE MANAGEMENT AND AORTIC VASCULAR SURGERY

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.

References 1. Rutherford RB, Krupski WC: Current status of open versus endovascular stent-graft repair of abdominal aortic aneurysm. J Vasc Surg 2004; 39:1129–39.

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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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CHAPTER 17

V O L U M E

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

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

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.

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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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CHAPTER 18

V O L U M E

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

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

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.

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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References 1. te Velthuis H, Baufreton C, Jansen PG, et al.: Heparin coating of extracorporeal circuits inhibits contact activation during cardiac operations. J Thorac Cardiovasc Surg 1997; 114:117–22. 2. Shore-Lesserson L: Pro: Heparin-bonded circuits represent a desirable option for cardiopulmonary bypass. J Cardiothorac Vasc Anesth 1998; 12:705–9. 3. Aldea GS, O’Gara P, Shapira OM, et al.: Effect of anticoagulation protocol on outcome in patients undergoing CABG with heparin-bonded cardiopulmonary bypass circuits. Ann Thorac Surg 1998; 65:425–33. 4. Aldea GS, Zhang X, Memmolo CA, et al.: Enhanced blood conservation in primary coronary artery bypass surgery using heparin-bonded circuits with lower anticoagulation. J Cardiothorac Surg 1996; 11:85–95. 5. Kipfer B, Englberger L, Gygax E, Nydegger U, Carrel T: Is reduced systemic heparinization justified with heparin-bonded bypass circuits in cardiac surgery?—Experience with and without aprotinin. Transfus Apheresis Sci 2003; 29:17–24. 6. Aldea GS, Soltow LO, Chandler WL, et al.: Limitation of thrombin generation, platelet activation, and inflammation by elimination of cardiotomy suction in patients undergoing coronary artery bypass grafting treated with heparin-bonded circuits. J Thorac Cardiovasc Surg 2002; 123:742–55. 7. Dietrich W: Reducing thrombin formation during cardiopulmonary bypass: Is there a benefit of the additional anticoagulant action of aprotinin? J Cardiovasc Pharmacol 1996; 27:S50–7. 8. Dietrich W, Dilthey G, Spannagl M, Richter JA: Warfarin pretreatment does not lead to increased bleeding tendency during cardiac surgery. J Cardiothorac Vasc Anesth 1995; 9:250–4. 9. Shore-Lesserson L, Manspeizer HE, Bolastig M, et al.: Anticoagulation for cardiac surgery in patients receiving preoperative heparin: Use of the high-dose thrombin time. Anesth Analg 2000; 90:813–8. 10. Montes FR LJ: Can we alter heparin dose-responses with antithrombin III? Anesth Analg 1996; 82:SCA94. 11. Lemmer JH Jr, Despotis GJ: Antithrombin III concentrate to treat heparin resistance in patients undergoing cardiac surgery. J Thorac Cardiovasc Surg 2002; 123:213–7. 12. Nicholson SC, Keeling DM, Sinclair ME, Evans RD: Heparin pretreatment does not alter heparin requirements during cardiopulmonary bypass. Br J Anaesth 2001; 87:844–7. 13. Warkentin TE, Kelton JG: Temporal aspects of heparin-induced thrombocytopenia. N Engl J Med 2001; 344:1286–92. 14. Warkentin TES: Heparin-induced thrombocytopenia and the anesthesiologist. Can J Anaesth 2002; 49:S36–49. 15. Doggrell S: Can bivalirudin and provisional GP IIb/IIIa blockade REPLACE heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention? Exp Opin Pharmacother 2003; 4:1431–3. 16. Merry AF, Raudkivi PJ, Middleton NG, et al.: Bivalirudin versus heparin and protamine in off-pump coronary artery bypass surgery. Ann Thorac Surg 2004; 77:925–31. 17. Vasquez JC, Vichiendilokkul A, Mahmood S, Baciewicz FA Jr: Anticoagulation with bivalirudin during cardiopulmonary bypass in cardiac surgery. Ann Thorac Surg 2002; 74:2177–9. 18. Koster A, Chew D, Grundel M, et al.: Bivalirudin monitored with the ecarin clotting time for anticoagulation during cardiopulmonary bypass. Anesth Analg 2003; 96:383–6. 19. Murkin JM, Shannon NA, Bourne RB, et al.: Aprotinin decreases blood loss in patients undergoing revision or bilateral total hip arthroplasty. Anesth Analg 1995; 80:343–8. 20. Royston D, Bidstrup BP, Taylor KM, Sapsford RM: Reduced blood loss following open heart surgery with aprotinin (Trasylol) is associated with an increase in intraoperative activated clotting time (ACT). J Cardiothorac Anesth 1989; 3(5 Suppl 1):80. 21. Karski JM, Teasdale SJ, Norman PH, et al.: Prevention of postbypass bleeding with tranexamic acid and epsilon–aminocaproic acid. J Cardiothorac Vasc Anesth 1993; 7:431–5. 22. Horrow JC, Van Riper DF, Strong MD, Grunewald KE, Parmet JL: The dose–response relationship of tranexamic acid. Anesthesiology 1995; 82:383–92. 23. Laupacis A, Fergusson D: Drugs to minimize perioperative blood loss in cardiac surgery: meta-analyses using perioperative blood transfusion as the outcome. The International Study of Peri-operative Transfusion (ISPOT) Investigators. Anesth Analg 1997; 85:1258–67.

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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.

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CHAPTER 19

V O L U M E

T H I R T Y - T H R E 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

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.

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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.

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CHAPTER 20

V O L U M E

T H I R T Y - T H R E 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

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

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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),

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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.

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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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