The New England Journal of Medicine

Review Articles

Medical Progress

A NESTHESIOLOGY
First of Two Parts
RICHARD A. WIKLUND, M.D., STANLEY H. ROSENBAUM, M.D.

AND

CENTURY and a half after the first administration of ether, at the Massachusetts General Hospital in Boston, and almost 30 years since the last review of anesthesiology in the Journal, it is fitting to consider recent advances in the field.1 In the late 1960s, the National Institutes of Health decided to support training in clinical anesthesiology.2 Since that time, anesthesia-related deaths have decreased dramatically. In this review, we discuss the preparation of patients for surgery, recent developments in anesthetic agents and techniques, multimodal pain management, and postoperative complications related to anesthesia.
PREOPERATIVE ASSESSMENT AND PREPARATION

termined by an anesthesiologist in a preoperative screening clinic rather than by a surgeon.4 Cancellations of operations due to unresolved medical or laboratory abnormalities are reduced by 88 percent, and the costs of laboratory tests are reduced by 59 percent, or $112 per patient. Unnecessary preoperative laboratory testing results in excessive health care and leads to excess morbidity. A meta-analysis of studies of preoperative chest radiographs (in the absence of specific indications) showed that false positive results leading to invasive procedures and associated morbidity were more frequent than the discovery of new findings leading to a change in management.5 Multiple studies have demonstrated that screening laboratory tests show unexpected abnormal findings infrequently and rarely lead to changes in management that improve the outcome. Narr et al.6 argue that there is little reason to perform screening tests in asymptomatic, low-risk patients; such tests should be performed only if indicated by the history or physical examination.
Cardiac Testing for Noncardiac Surgery

Approximately 28 million patients undergo surgery annually in the United States, and with the increasing age of patients, complex surgical procedures are being performed more frequently in patients with serious coexisting conditions. Mangano has noted that the number of patients over the age of 65 years who undergo noncardiac surgery will increase from 7 million to 14 million over the next three decades, and the number of surgical procedures will increase from 28 million to 40 million per year.3 Increasingly, anesthesiologists direct the preoperative assessment and preparation of patients for surgery with the aim of ensuring safe and efficient care while controlling costs by reducing unnecessary testing and preventable cancellations on the day of surgery. Fischer has shown that requests for preoperative medical consultations are reduced by three quarters when the need for a consultation is de-

From the Department of Anesthesiology, Yale University School of Medicine, 333 Cedar St., New Haven, CT 06520-8051, where reprint requests should be addressed to Dr. Wiklund. 1997, Massachusetts Medical Society.

The diagnosis of coexisting conditions, optimization of medical therapy, assessment of risk, and planning for management are the key elements of preoperative preparation. The rational use of testing is especially important in patients with cardiac disease presenting for noncardiac surgery. A task force of the American College of Cardiology and the American Heart Association has published guidelines for the cardiovascular evaluation of patients undergoing noncardiac surgery.7 The guidelines provide a complex algorithm involving clinical predictors of adverse cardiac events, activities of daily living, and the risk associated with the surgical procedure (Tables 1 and 2). Briefly, for surgery posing a high risk of cardiac events, patients who have either a low capacity for exercise or clinical predictors of a perioperative cardiac event should be referred for noninvasive cardiac testing, and the decision whether to proceed with the surgery should be based on the results. For surgery posing an intermediate risk of cardiac events, noninvasive testing is recommended only in patients with a low capacity for exercise. Noninvasive cardiac testing is not recommended for patients undergoing low-risk surgery, except for those with unstable coronary syndromes. Factors that may modify this approach include the urgency of the surgery, the results of prior cardiac assessments, the presence or absence of a history of cardiac interventions (angioplasty or coronary bypass surgery), and the presence or absence of cardiac

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TABLE 1. CLINICAL PREDICTORS OF PERIOPERATIVE CARDIOVASCULAR EVENTS.*

Minor predictors Advanced age Abnormal electrocardiogram Rhythm other than sinus Low tolerance for exercise History of stroke Uncontrolled systemic hypertension Intermediate predictors Mild angina pectoris Prior myocardial infarction Compensated or prior congestive heart failure Diabetes mellitus Major predictors Unstable coronary syndromes (including acute myocardial infarction) Decompensated congestive heart failure Serious arrhythmias Severe valvular disease *Adapted from the guidelines of the American College of Cardiology and the American Heart Association.7

ridamolethallium or dobutamine testing) is recommended for patients with intermediate clinical predictors of a perioperative cardiac event (Table 1), those with a low tolerance for exercise, or those undergoing surgical procedures associated with a high ( 5 percent) risk of death from cardiac causes or nonfatal myocardial infarction. Studies of the predictive value of pharmacologic stress testing with thallium imaging of myocardial perfusion in patients with known or suspected coronary artery disease have shown that there is little likelihood of a perioperative ischemic event when the test results are normal.8 Abnormal results, however, are not accurate indicators of risk (i.e., they have low specificity). Resting ventricular function provides a more accurate indication of risk in patients with congestive heart failure. An ejection fraction of less than 35 percent in patients undergoing abdominal aortic surgery is known to be associated with the greatest risk of postoperative cardiac decompensation, myocardial infarction, or cardiac death from cardiac causes.9
Perioperative Myocardial Ischemia

TABLE 2. RISK OF CARDIAC EVENTS (DEATH OR NONFATAL MYOCARDIAL INFARCTION) ASSOCIATED WITH NONCARDIAC SURGICAL PROCEDURES.*
RISK OF CARDIAC EVENT NONCARDIAC PROCEDURE

High ( 5%)

Intermediate (15%)

Low ( 1%)

Emergency surgery, especially in an elderly patient Aortic or other major vascular surgery Peripheral vascular surgery Prolonged surgery with major fluid shifts Carotid endarterectomy Head or neck surgery Intraperitoneal or intrathoracic surgery Major orthopedic surgery Prostate surgery Endoscopy Superficial procedure Cataract surgery Breast surgery

*Adapted from the guidelines of the American College of Cardiology and the American Heart Association.7

symptoms. According to the guidelines of the American College of Cardiology and the American Heart Association, preoperative cardiac revascularization is rarely indicated to prepare patients for noncardiac surgery and should be performed only if the criteria for revascularization are met independently of the need for noncardiac surgery. Noninvasive testing should be performed only if the results are likely to change the treatment and improve the outcome. Assessment of myocardial perfusion by means of exercise or pharmacologic stress testing (e.g., dipy-

Perioperative myocardial ischemia is an important clinical marker because of the high incidence of underlying coronary artery disease in patients presenting for elective, noncardiac surgery and because of the role of myocardial ischemia as a cause of postoperative death. Problems include identifying patients at risk for an ischemic event, controlling risk factors, detecting an ischemic event, and selecting the appropriate intervention. Risk factors that can be controlled in the preoperative period include hypertension, angina, arrhythmias, congestive heart failure, and diabetes mellitus. The American College of CardiologyAmerican Heart Association guidelines classify uncontrolled systemic hypertension as a minor clinical predictor of perioperative ischemia, which probably understates the importance of preoperative control of systemic hypertension. It is well known that patients with uncontrolled systemic hypertension have marked changes in blood pressure (high and low) intraoperatively, which are associated with myocardial ischemia.10 Even short-term preoperative antihypertensive therapy with orally administered b-adrenergicblocking agents will reduce these swings in blood pressure and minimize the risk of ischemia.11 Antihypertensive therapy, particularly with b-adrenergicblocking agents or a2-adrenergic agonists (e.g., clonidine), should be continued up to and including the day of surgery. Congestive heart failure and clinically significant arrhythmias require in-depth evaluation and control before elective, noncardiac surgery is performed. Uncontrolled preoperative arrhythmias are aggravated by the stress associated with the induction of anesthesia and intubation of the airway.
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The diagnosis of perioperative myocardial infarction is difficult to establish, since most ischemic episodes in the perioperative period are clinically silent. Charlson et al. found that serial electrocardiography performed on the day of surgery and the first two postoperative days was the most effective strategy for identifying perioperative myocardial infarction.12 Postoperative monitoring of patients with abnormal preoperative electrocardiograms would have identified 88 percent of those with myocardial infarction and 63 percent of those with definite ischemia. Serial electrocardiograms and assays of myocardial creatine kinase may not be sensitive indicators of perioperative ischemia. Ambulatory electrocardiographic (Holter) monitoring may be predictive in some high-risk patients.13 When the test for blood troponin levels becomes generally available, it may prove useful in screening for perioperative ischemia.14 The best timing for elective surgery after myocardial infarction has not been resolved, although the morbidity and mortality associated with reinfarction have probably been reduced. In 1972, Tarhan et al.15 reported perioperative myocardial reinfarction in 28 of 349 patients undergoing noncardiac operations after myocardial infarction. The rate of reinfarction was 37 percent with an interval of less than three months between myocardial infarction and surgery, 16 percent with an interval of three to six months, and 5.6 percent with an interval of more than six months. A decade later, Rao et al.16 reported rates of 5.8, 2.3, and 1.5 percent, respectively. Mortality from reinfarction was high, approximately 50 percent, but these studies were undertaken before the advent of transesophageal echocardiography and thrombolytic therapy or primary angioplasty for acute myocardial infarction. Mortality from perioperative myocardial infarction may have declined because of improved care or increasingly sensitive methods of diagnosing subendocardial infarction.17 In its report, the task force of the American College of Cardiology and American Heart Association implies that these data are outdated and recommends a stratification of the risk during convalescence from an acute myocardial infarction. If exercise stress testing four to six weeks after infarction does not show residual myocardium at risk, the likelihood of reinfarction is thought to be low, and elective, noncardiac surgery can be performed. The report points out that this recommendation is not made on the basis of clinical trials. Diabetes mellitus is an intermediate clinical predictor of perioperative myocardial ischemia not only because of the association between diabetes mellitus and coronary artery disease but also because of the increased incidence of other perioperative complications, including ketoacidosis, stroke, renal failure, and sepsis, in patients with diabetes. Recommendations for the control of blood sugar levels have been
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made on the basis of the extent of surgery and the likelihood of either early or delayed resumption of a normal diet.18 Prevention of hyperglycemia during the perioperative period has been shown to improve wound healing, reduce the risk of infection, and reduce cerebral damage when there is a hypoxic event. However, the risk of severe cerebral injury from inadvertent, unrecognized hypoglycemia outweighs any benefit of strict perioperative control.
Transfusion Practice and Autologous Blood Donation

The risk of viral infection from the transfusion of contaminated blood products needs to be addressed during preoperative preparation. With the use of surrogate markers of non-A, non-B hepatitis and antibodies to hepatitis C virus, the risk of post-transfusion hepatitis C has been reduced to about 3 new cases of hepatitis per 10,000 units transfused.19 Contamination with the human immunodeficiency virus is estimated at about 1 infected unit per 250,000. Rightfully, patients continue to be concerned about the risk of acquiring these diseases. They perceive autologous and directed blood donation as providing protection from transfusion-related complications. Enthusiasm for autologous blood transfusion is waning, however, because of the limited improvement in outcome, markedly increased cost ($4,783 per unit transfused, vs. $68 per unit from an anonymous donor) in some groups of patients, and the possibility that blood from anonymous donors may still be required.20 The cost effectiveness of autologous blood donation is highest for total hip replacement and lowest for hysterectomy and transurethral resection of the prostate. An autologous donation may match the extent of blood loss in patients undergoing total hip replacement; in most patients undergoing hysterectomy or transurethral prostatectomy, however, there is not enough blood loss to warrant transfusion. Over the past two decades, transfusion practice in anesthesiology has been consistent with the recommendations of the American Association of Blood Banks for the use of blood-component therapy21 and the practice guidelines of the American Society of Anesthesiologists Task Force on Blood Component Therapy.22 Although there are no clear target levels for hemoglobin concentrations, transfusion of packed red cells is rarely indicated when the hemoglobin concentration is higher than 10 g per deciliter and is almost always indicated when the hemoglobin concentration is less than 6 g per deciliter. Postoperative anemia and cardiac morbidity are significantly correlated after vascular surgery in high-risk patients with a hematocrit of less than 28 percent.23 Lower hemoglobin concentrations (as low as 7 g per deciliter) are considered acceptable in patients without coexisting disease.24 The need for increased oxygen-carrying capacity in patients with coexisting

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disease is most likely due to their impaired ability to increase cardiac output by any means other than tachycardia. Particularly in patients with diabetes mellitus, a higher hematocrit may be required to prevent ischemic myocardial events triggered by perioperative stress.25 Red-cell salvage procedures (e.g., Cell Saver, Haemonetics) are effective in reducing the use of allogeneic units of packed cells but not other blood components. Excessively high potassium-ion and anticoagulant concentrations can be controlled by cell washing before administration.26 The time required to collect and process blood is the principal disadvantage of red-cell salvage for intraoperative replacement of blood volume. Despite this disadvantage, red-cell salvage is useful in procedures associated with a high volume of blood loss (e.g., orthotopic liver transplantation).27 Blood substitutes offer many advantages over allogeneic blood, including their ease of storage (at room temperature), immediate availability, and absence of a risk of viral infection.28 Products under development and being tested in clinical trials include perfluorocarbon emulsions and polymerized hemoglobin moieties.29 Perfluorocarbon emulsions are solutions with high solubility for nonpolar gases such as oxygen, carbon dioxide, and nitrogen. The surface area of the emulsions is extremely large because of their small size (0.1 mm), which facilitates gas exchange. In addition, these emulsions can flow through vessels with sludged red cells, which may result in greater cerebral protection during cardiopulmonary bypass.30 Perfluorocarbon emulsions have limited oxygen-carrying capacity, since oxygen is carried only in solution. Polymerized hemoglobin moieties have an oxygen-carrying capacity similar to that of corpuscular hemoglobin; thus, the oxygen binding by polymerized hemoglobin moieties follows a sigmoid curve and provides more effective oxygen transport than perfluorocarbon emulsions. Preparations of polymerized hemoglobin moieties can cause renal dysfunction and sensitivity reactions when used in solution. This problem may be resolved to some extent by encapsulating the preparations in membranes that are freely permeable to oxygen. In surgical and obstetrical patients, platelet transfusion is indicated if there is microvascular bleeding and the platelet count is less than 50,000 per cubic millimeter and is rarely required if the platelet count is greater than 100,000 per cubic millimeter. Infusion of fresh-frozen plasma is indicated if coagulopathy has been diagnosed on the basis of the prothrombin and partial-thromboplastin times but is not indicated for the correction of hypovolemia without coagulopathy. Cryoprecipitate is used in patients with hypofibrinogenemia and in some patients with von Willebrands disease.21

NEW ANESTHETIC AGENTS

A large number of new muscle relaxants, potent opioids, agents for the induction of anesthesia, inhalational anesthetics, and local anesthetics have been introduced in the past two decades. We review the controversy over some traditional agents and discuss new or preferred agents and those likely to be introduced in the United States in the future.
Muscle Relaxants

Muscle relaxants were introduced into clinical anesthesiology in the 1940s. Initial skepticism was replaced by enthusiasm because of the ability of these agents to facilitate airway management, control alveolar ventilation, abolish motor reflexes, and provide the skeletal-muscle relaxation required for many surgical procedures. Two general classes of muscle relaxants became available: depolarizing agents (which cause prolonged depolarization of the motor end plate) and nondepolarizing agents (which act through competitive inhibition of acetylcholine at the motor end plate). Succinylcholine has been used as a depolarizing muscle relaxant since Foldes et al. described its pharmacologic characteristics in 1952.31 Because it causes complete muscle relaxation reliably and rapidly, succinylcholine has remained a valued agent for more than four decades. As a result of recent scrutiny, however, the routine use of succinylcholine, in most cases to facilitate endotracheal intubation, has been reduced. Relatively minor but frequent complications of succinylcholine administration include postoperative myalgia, transient elevation of serum potassium levels, and increases in intraocular, intracranial, and intragastric pressure. These are important effects in patients with chronic renal failure, penetrating eye injuries, intracranial disease with elevated intracranial pressure, or gastroesophageal reflux. Succinylcholine is also recognized as a precipitating cause of malignant hyperthermia, a rare but potentially fatal inherited disorder, with an incidence of approximately 1 case in 50,000 adults and 1 in 15,000 children. Persons who are susceptible to malignant hyperthermia are sometimes identified by means of a careful history taking, and the hypermetabolic crisis can usually be controlled with the intravenous administration of dantrolene sodium.32 Although the treatment of malignant hyperthermia with dantrolene sodium has been standardized and mortality has been dramatically reduced, to less than 10 percent, the reliable identification of susceptible persons and an understanding of the genetics of transmission continue to be elusive. A clinical grading score has been developed by the North American Malignant Hyperthermia Registry to help clinicians identify patients susceptible to malignant hyperthermia.33 The gene for the ryanodine receptor responsible
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for the control of calcium flux in skeletal muscle is believed to be closely associated with mutations that are linked to malignant hyperthermia. A single mutation of the gene for the ryanodine receptor in swine (RYR1) has been linked to all cases in all breeds of swine. However, it is likely that a series of mutations cause the disorder in humans, with an absence of linkage in some families, probably indicating a heterogeneous genetic disorder.34 In 1992, Rosenberg and Gronert reported cases of sudden death after the administration of succinylcholine in a small group of young children with previously undiagnosed myopathy.35 As a result, in 1994 the Advisory Committee for Anesthetic and Life Support Drugs of the Food and Drug Administration (FDA) reviewed the use of succinylcholine.36 Although rare, sudden death in children was reported to occur within minutes after the administration of succinylcholine, particularly in association with the inhalational anesthetic halothane. These events were characterized by massive rhabdomyolysis with severe hyperkalemia, and the children did not have a response to dantrolene.37,38 The mechanism of this myopathic crisis is unclear, although children with Duchennes muscular dystrophy appear to be at highest risk.39,40 Succinylcholine continues to be used as an anesthetic agent in children but only for particular indications, such as emergency endotracheal intubation, treatment of laryngospasm, or endotracheal intubation in a child with a full stomach. Nondepolarizing muscle relaxants (Table 3) are often categorized clinically on the basis of the time to the onset of action, the duration of action, and the hemodynamic side effects.41 Anesthesiologists have sought a nondepolarizing muscle relaxant that is free of hemodynamic effects (histamine release or ganglionic blockade), reliably produces a rapid onset of muscle relaxation, and has alternative pathways of elimination. An agent with a short elimination halflife and without a cumulative effect could be administered by continuous infusion, a technique particularly useful for ambulatory surgery.42 One series of nondepolarizing muscle relaxants are metabolized by plasma cholinesterase or nonenzymatic pathways, a clear advantage in patients with multiorgan failure.43,44 However, the release of histamine, causing hypotension and tachycardia, necessitates a slow rate of administration.45 Atracurium, the first drug developed in this series, is metabolized to laudanosine, an epileptogenic compound that freely crosses the bloodbrain barrier and may accumulate in elderly patients and those with renal failure.46 However, its stereoisomer, cisatracurium, causes a minimal release of histamine.47 In critically ill patients undergoing mechanical ventilation, cisatracurium is 2.5 times more potent than atracurium, and plasma levels of laudanosine are 70 percent lower than with atracurium.48 Mivacurium is a short-act1136
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OF

TABLE 3. CLINICAL PROPERTIES NONDEPOLARIZING MUSCLE RELAXANTS.

TIME TO ONSET OF ACTION*

MUSCLE RELAXANT

OF

DURATION ACTION

HEMODYNAMIC EFFECT

minutes

Long-acting Pancuronium Pipecuronium Doxacurium Intermediate-acting Vecuronium Rocuronium Atracurium Cisatracurium Short-acting Mivacurium

45 56 1014 56 23 56 56 23

60 8090 80100 20 20 2025 2025 1520

Tachycardia None None None None Histamine release Minimal histamine release Histamine release

*The onset of action is defined as the achievement of a 90 percent reduction in the control value for the thenar-muscle twitch. The duration of action is defined as the time from the onset of action to a return of the thenar-muscle twitch to 90 percent of the control value.

ing congener of atracurium that is rapidly hydrolyzed by plasma cholinesterase, but histamine release requires a slow rate of administration, and because of the drugs pharmacodynamic characteristics, the optimal relaxation of airway muscles does not occur synchronously with the relaxation of the peripheral (thenar) muscles, which are frequently used to monitor neuromuscular paralysis.49,50 Doxacurium, also derived from atracurium, is useful because of its prolonged duration of action. Vecuronium, derived from pancuronium, has an intermediate duration of action.51 Unlike pancuronium, which produces tachycardia, vecuronium has no hemodynamic effects. Although vecuronium begins to act more rapidly and has a shorter duration of action than pancuronium, the onset of paralysis is slower than with succinylcholine. Rocuronium is also free of hemodynamic effects and begins to act more rapidly than vecuronium, although not as rapidly as succinylcholine.52 The last of the muscle relaxants derived from pancuronium is pipecuronium. Like doxacurium, pipecuronium is suitable for longer surgical procedures or use in the intensive care unit because of its prolonged action.53 The usefulness of nondepolarizing muscle relaxants for the control of respiration in the operating room and the frequent involvement of anesthesiologists in intensive care have led to the use of these agents for airway management and facilitation of long-term respiratory support in intensive care units. For example, in patients with elevated intracranial pressure, the complete paralysis of skeletal muscle induced with these agents prevents rises in intracranial pressure resulting from stimulation of airway reflexes. Reports of prolonged paralysis after the long-

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term administration of vecuronium have led to the conclusion that such muscle relaxants should be used with care, since they may induce myopathy in critically ill patients, especially those with multiorgan failure.54 Myopathy can be minimized by titrating the dose of the muscle relaxant with the use of peripheral-nerve stimulation to prevent excessive paralysis. Prolonged paralysis after long-term therapy with vecuronium may also be due to the slowly excreted active first metabolite, 3-desacetylvecuronium.55 However, prolonged paralysis has also been reported in patients receiving atracurium and cisatracurium, agents whose metabolites do not produce neuromuscular blockade.56,57 These reports suggest that neuromuscular blocking agents may have direct neuromuscular toxicity leading to myopathy and that myopathy is not related to the corticosteroid structure of the pancuronium series of muscle relaxants. What is the preferred nondepolarizing muscle relaxant? Despite the availability of newer derivatives, vecuronium and atracurium continue to be used for many clinical applications. Alternative mechanisms of elimination, the absence of a cumulative effect, and the absence of active metabolites support the choice of atracurium. A minimal cumulative effect and the absence of hemodynamic effects due to histamine release support the choice of vecuronium. Cisatracurium and rocuronium are becoming popular and may replace atracurium and vecuronium, respectively.
Opioids

TABLE 4. POTENCY AND ELIMINATION HALF-LIFE OF OPIOIDS.

RELATIVE POTENCY* ELIMINATION HALF-LIFE
hr

OPIOID

Morphine Alfentanil Fentanyl Remifentanil Sufentanil

1 10 100 250 1000

1.73.3 1.41.5 3.16.6 0.170.33 2.24.6

*The potency of morphine is used as the reference value. Data are from Coda.58

Potent opioids (those that are 10 to 1000 times as potent as morphine) (Table 4) are valuable because of their ability to modulate the sympathetic response (hypertension and tachycardia) to endotracheal intubation and surgical stimulation. Profound respiratory depression and skeletal-muscle rigidity limit the usefulness of these agents in situations in which the direct control of ventilation is not routine. Fentanyl was the first drug developed in a series of potent synthetic, lipid-soluble opioids. Its narcotic effect is rapid in onset. The drug continues to be widely used despite the introduction of sufentanil (which is 10 times more potent) and alfentanil (which is less potent but has one half to one third the duration of action). Sufentanil and fentanyl have replaced morphine as the opioids used in high doses for cardiac anesthesia, because of the marked hemodynamic stability, absence of histamine release, and ablation of adverse reflexive sympathetic activity after their intravenous administration.59 Cardiac output and systemic blood pressure are well maintained, with a relatively slow heart rate, during profound opioidinduced anesthesia. Thus, in patients with ischemic heart disease, the myocardial oxygen demand is decreased and the oxygen supply is maintained within the limits of abnormal coronary anatomy. The duration of action of high-dose opioids, such

as fentanyl and sufentanil, requires prolonged ventilatory support after surgery. Remifentanil is an ester opioid that is rapidly metabolized by plasma esterases and, as a result, has a very short half life in the steady state (three to four minutes) after prolonged administration, even in patients with hepatic or renal failure.60 Because of its rapid clearance, remifentanil is best administered only by continuous intravenous infusion after an initial bolus loading dose. Clinical studies will determine whether the higher cost of remifentanil treatment is offset by a more rapid recovery and a shorter stay in the postanesthesia care unit. Potent opioids may have undesirable central nervous system side effects. Muscle rigidity after the administration of morphine and the fentanyl series of opioids has been well documented.61,62 During surgery, opioid-induced muscle rigidity is easily controlled with muscle relaxants. Postoperative myoclonus and rigidity sufficient to prevent bagmask ventilation have been reported with sufentanil after the antagonism of muscle relaxation with anticholinesterases. Myoclonus and rigidity respond promptly to the intravenous administration of naloxone.63 Central nervous system neurotoxicity has been demonstrated after the administration of high doses of fentanyl, sufentanil, and alfentanil in rats.64 Brain injury occurs in cortical regions and limbic-system structures and is mitigated by blood-pressure control with hexamethonium. It is not known whether highdose narcotics used for opioid-based anesthesia can produce similar neurotoxic effects in humans.
Inhalational Anesthetics

The administration of inhalational drugs for the purpose of inducing a systemic effect has always been the province of anesthesiology. Kinetic models based on solubility variables are well established. Although the hypothesis has not been proved, lipid solubility appears to be basic to the mechanism of
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narcosis produced by inhalational agents.65 Recent evidence suggests the alternative explanation that narcosis may result from conformational changes produced by the binding of inhalational anesthetics at lipophilic sites in functional proteins.66 Studies of polyhalogenated, perhalogenated, or perfluorinated compounds that are soluble in lipids but are nonanesthetics or antagonize typical anesthetics raise questions about the validity of the lipid-solubility explanation of narcosis and suggest ligand-gated ion channels (g-aminobutyric acida) as an alternative site of the production of narcosis.67 The relation between structure and activity has been used to develop inhalational anesthetics that are potent, nonexplosive, and minimally metabolized and that do not have idiosyncratic or dose-related toxic effects on the brain, heart, liver, kidneys, or bone marrow. Nitrous oxide, diethyl ether, and chloroform were the earliest inhalational anesthetics. Unlike ether and chloroform, nitrous oxide is still used widely to supplement the potency of other agents, to serve as a primary anesthetic agent when combined with opioids and muscle relaxants, and to reduce inspired concentrations of oxygen. Enthusiasm for the use of nitrous oxide is waning, however, because of its propensity to cause postoperative nausea and vomiting.68,69 Nitrous oxide has been implicated as a cause of bone marrow depression, fetal abnormalities, and suppression of important enzymatic reactions, such as that catalyzed by methionine synthetase. The inhibition of methionine synthetase is related to the decreased availability of vitamin B12 due to the oxidation of cobalamin by nitrous oxide. Severe neurologic deficits have been reported after prolonged, intraoperative exposure to nitrous oxide in patients with unsuspected vitamin B12 deficiency.70 Halothane is the most commonly used inhalational anesthetic in children in the United States and perhaps in all patients worldwide. Concern about idiosyncratic hepatotoxicity has nearly eliminated the use of the drug in adults in the United States. After years of controversy, it is clear that repeated exposure to halothane has hepatotoxic effects, probably through the interaction of reactive metabolites with hepatocellular proteins, which evoke an autoimmune response with massive hepatic necrosis.71 Hepatotoxicity has not been reported in children, and because of its acceptable odor and high potency, the drug continues to be widely used for inhalational induction of anesthesia in children. Fulminant hepatic failure after exposure to halothane is estimated to occur in 1 of every 30,000 patients exposed to the agent.72 There have been sporadic reports of hepatic necrosis after exposure to the newer inhalational anesthetics, especially enflurane but also isoflurane. The incidence is estimated to be less than 1 in 800,000, with some cases believed to represent cross-reactivity to halothane.73
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The newer inhalational anesthetics are halogenated hydrocarbons that are potent, nonflammable, and minimally metabolized. Their use is not associated with b-adrenergicmediated arrhythmias, such as those associated with the use of halothane. Enhanced muscle relaxation occurs when nondepolarizing muscle relaxants are administered.74 Isoflurane has been the mainstay of inhalational anesthesia in the United States for more than 20 years.75 It is an isomer of its predecessor, enflurane, but is minimally metabolized and is not associated with renal or hepatic toxicity. Blood pressure, heart rate, and cardiac output are better maintained with isoflurane than with halothane. There is some concern, however, that isoflurane may adversely affect myocardial perfusion in patients with coronary artery disease, producing unwanted coronary artery vasodilatation, termed coronary steal, which shunts blood away from already ischemic myocardium.76 Coronary steal requires a specific anatomical relation between occluded coronary vessels and stenotic vessels providing collateral circulation to the ischemic myocardium. This anatomical relation has been reported to be present in 23 percent of patients in the Coronary Artery Surgery Study.77 In patients undergoing coronary artery surgery, however, the incidence of ischemia is the same with a variety of anesthetic agents, whether or not there is a predisposition to coronary steal.78 Newer inhalational agents include desflurane and sevoflurane.79 Desflurane is highly fluorinated, nearly as insoluble as nitrous oxide, and as potent as isoflurane.80 Low solubility leads to the rapid onset of anesthesia and the rapid elimination of the anesthetic agent, and desflurane can be administered as a complete anesthetic in high concentrations of oxygen. Desflurane appears to be completely eliminated by ventilation of the lungs. The drug has not replaced isoflurane, however, because it is expensive and requires special, heated vaporizers for administration. The expense of desflurane limits its use to closed anesthesia circuits with low rates of fresh gas flow, a technique that increases the use of carbon dioxide absorbent and requires monitors for anesthetic-agent analysis. Desflurane produces marked increases in the heart rate after rapid increases in the inspired concentration (neurocirculatory activation), a disturbing hemodynamic event in patients with hypertension and heart disease.81,82 Worsening of increased intracranial pressure due to inhalational anesthetics is a concern in patients undergoing craniotomy. This response is seen with moderate-to-high concentrations of halothane and isoflurane, as well as desflurane,83 but appears to be most pronounced with desflurane. Sevoflurane is a highly fluorinated anesthetic agent that has been used in Japan for general anesthesia in millions of patients without apparent toxic effects.79

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Its only advantage over isoflurane and desflurane is its pleasant odor, which makes it a useful alternative to halothane in children. Unlike the other agents, however, sevoflurane is unstable in the presence of soda lime, used in anesthesia circuits to absorb carbon dioxide. The breakdown of sevoflurane leads to the accumulation of toxic products, including a vinyl ether, termed compound A, which causes renal tubular necrosis and death in animals.84,85 Substantial levels of compound A may accumulate in anesthesia circuits when low rates of fresh gas flowing into the circuit result in substantial rebreathing of exhaled gas.86 The metabolism of sevoflurane results in elevated blood levels of free fluoride, although isosthenuric renal failure has not been reported, as it has with older anesthetic agents that are no longer used (e.g., methoxyflurane).87 Although the blood levels of free fluoride can be relatively high, the duration of high fluoride levels is short.
Nonopioid Intravenous Anesthetics

The second problem concerns the use of this potent intravenous anesthetic by medical personnel not trained to monitor and treat its respiratory and cardiovascular effects. The administration of propofol causes profound respiratory depression, especially if it is combined with intravenous narcotics. In studies with healthy volunteers, the hypoxic ventilatory drive is severely depressed at infusion rates intended to induce conscious sedation.98 For use outside the operating room, careful practice includes following the guidelines of the American Society of Anesthesiologists and making sure that oxygen, artificial respiration, and airway management, including endotracheal intubation, can be provided.99,100 Qualified anesthesia personnel should perform continual monitoring of oxygenation, ventilation, circulation, and temperature.
REFERENCES
1. Ngai SH, Mark LC, Papper EM. Pharmacologic and physiologic aspects of anesthesiology. N Engl J Med 1970;282:479-91, 541-56. 2. Stone FL. The new image. Bull N Y State Acad Anesth 1968;20:427. 3. Mangano DT. Preoperative risk assessment: many studies, few solutions: is a cardiac risk assessment paradigm possible? Anesthesiology 1995;83: 897-901. 4. Fischer SP Development and effectiveness of an anesthesia preoperative . evaluation clinic in a teaching hospital. Anesthesiology 1996;85:196-206. 5. Archer C, Levy AR, McGregor M. Value of routine preoperative chest x-rays: a meta-analysis. Can J Anaesth 1993;40:1022-7. 6. Narr BJ, Hansen TR, Warner MA. Preoperative laboratory screening in healthy Mayo patients: cost-effective elimination of tests and unchanged outcomes. Mayo Clin Proc 1991;66:155-9. 7. ACC/AHA guidelines for perioperative cardiovascular evaluation for noncardiac surgery. Circulation 1996;93:1280-317. 8. Younis L, Stratmann H, Takase B, Byers S, Chaitman BR, Miller DD. Preoperative clinical assessment and dipyridamole thallium-201 scintigraphy for prediction and prevention of cardiac events in patients having major noncardiovascular surgery and known or suspected coronary artery disease. Am J Cardiol 1994;74:311-7. 9. Fiser WP Thompson BW, Thompson AR, Eason C, Read RC. Nuclear , cardiac ejection fraction and cardiac index in abdominal aortic surgery. Surgery 1983;94:736-9. 10. Prys-Roberts C, Meloche R, Foex P Studies of anaesthesia in relation . to hypertension. I. Cardiovascular responses of treated and untreated patients. Br J Anaesth 1971;43:122-37. 11. Stone JG, Foex P, Sear JW, Johnson LL, Khambatta HJ, Triner L. Myocardial ischemia in untreated hypertensive patients: effect of a single small oral dose of a beta-adrenergic blocking agent. Anesthesiology 1988;68: 495-500. 12. Charlson ME, MacKenzie CR, Ales K, Gold JP, Fairclough G Jr, Shires GT. Surveillance for postoperative myocardial infarction after noncardiac operations. Surg Gynecol Obstet 1988;167:407-14. 13. Fleisher LA, Rosenbaum SH, Nelson AH, Jain D, Wackers FJT, Zaret BL. Preoperative dipyridamole thallium imaging and ambulatory electrocardiographic monitoring as a predictor of perioperative cardiac events and long-term outcome. Anesthesiology 1995;83:906-17. 14. Adams JE III, Sicard GA, Allen BT, et al. Diagnosis of perioperative myocardial infarction with measurement of cardiac troponin I. N Engl J Med 1994;330:670-4. 15. Tarhan S, Moffitt EA, Taylor WF, Giuliani ER. Myocardial infarction after general anesthesia. JAMA 1972;220:1451-4. 16. Rao TLK, Jacobs KH, El-Etr AA. Reinfarction following anesthesia in patients with myocardial infarction. Anesthesiology 1983;59:499-505. 17. Landesberg G, Luria MH, Cotev S, et al. Importance of long-duration postoperative ST-segment depression in cardiac morbidity after vascular surgery. Lancet 1993;341:715-9. 18. Hirsch IB, McGill JB, Cryer PE, White PF. Perioperative management of surgical patients with diabetes mellitus. Anesthesiology 1991;74:34659. 19. Donahue JG, Muoz A, Ness PM, et al. The declining risk of posttransfusion hepatitis C virus infection. N Engl J Med 1992;327:369-73.

Propofol was introduced into the practice of anesthesia in the United States in 1989.88 It is widely used, especially in ambulatory-surgery centers, for the induction and maintenance of general anesthesia and for sedation during regional anesthesia.89 Its antiemetic properties and short duration of action make propofol cost effective because of the short recovery time and early discharge after its use in ambulatory surgery. Sedation can be achieved with a low-dose, continuous infusion of propofol to control restlessness and anxiety during noninvasive procedures (e.g., magnetic resonance imaging,90 radiation therapy,91 and endoscopy 92). Propofol has been used in intensive care units to sedate patients requiring controlled ventilation,93 including those recovering from coronary-artery bypass surgery.94 However, hypotension can be substantial, especially after the administration of a bolus dose. Because of its antiemetic properties, propofol has been used to control nausea and vomiting associated with chemotherapy for breast cancer.95 Two important problems are associated with the use of propofol. The first problem is related to its use in the operating room. Because of its solubility characteristics, propofol is prepared in a solution of soybean oil, glycerol, and purified egg phosphatide. Although allergy to the constituents that improve the drugs solubility has not been a major problem, their ability to support bacterial growth has. The administration of bacterially contaminated propofol in the operating room has been reported to cause sepsis and death.96,97 The manufacturer of propofol, the FDA, and medical journals have highlighted the need for anesthesiologists to follow strict guidelines for the labeling and storage of open ampules of the anesthetic.

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20. Etchason J, Petz L, Keeler E, et al. The cost effectiveness of preoperative autologous blood donations. N Engl J Med 1995;332:719-24. 21. Pisciotto PT, Ciavarella D, Kurtz SR, Lane TA, Snyder EL. Blood transfusion therapy: a physicians handbook. 4th ed. Bethesda, Md.: American Association of Blood Banks, 1993. 22. Practice guidelines for blood component therapy: a report by the American Society of Anesthesiologists Task Force on Blood Component Therapy. Anesthesiology 1996;84:732-47. 23. Nelson AH, Fleisher LA, Rosenbaum SH. Relationship between postoperative anemia and cardiac morbidity in high-risk vascular patients in the intensive care unit. Crit Care Med 1993;21:860-6. 24. Perioperative red cell transfusion. National Institutes of Health consensus development conference statement. Vol. 7. No. 4. Bethesda, Md.: NIH Office of Medical Applications of Research, 1988:1-6. 25. Fleisher LA, Rosenbaum SH, Nelson AH, Barash PG. The predictive value of preoperative silent ischemia for postoperative ischemic cardiac events in vascular and nonvascular surgery patients. Am Heart J 1991;122: 980-6. 26. Belani KG, Estrin JA. Biochemical, metabolic and hematologic effects of intraoperative processing of CPDA-1 and AS-1 packed red cells. Anesthesiology 1987;67:Suppl:A156. abstract. 27. Wiklund RA, Fabian JA, Keenan RL. Anaesthesia for major organ transplantation. In: Aitkenhead AR, Jones RM, eds. Clinical anaesthesia. London: Churchill Livingstone, 1996:485-512. 28. Dietz NM, Joyner MJ, Warner MA. Blood substitutes: fluids, drugs, or miracle solutions? Anesth Analg 1996;82:390-405. 29. Hess JR. Blood substitutes. Semin Hematol 1996;33:369-78. 30. Spiess BD, Cochran RP Perfluorocarbon emulsions and cardiopulmo. nary bypass: a technique for the future. J Cardiothorac Vasc Anesth 1996; 10:83-9. 31. Foldes FF, McNall PG, Borrego-Hinojosa JM. Succinylcholine: a new approach to muscular relaxation in anesthesiology. N Engl J Med 1952; 247:596-600. 32. Harrison GG. Control of the malignant hyperpyrexic syndrome in MHS swine by dantrolene sodium. Br J Anaesth 1975;47:62-5. 33. Larach MG, Localio AR, Allen GC, et al. A clinical grading scale to predict malignant hyperthermia susceptibility. Anesthesiology 1994;80: 771-9. 34. MacLennan DH, Phillips MS. Malignant hyperthermia. Science 1992; 256:789-94. 35. Rosenberg H, Gronert GA. Intractable cardiac arrest in children given succinylcholine. Anesthesiology 1992;77:1054. 36. Goudsouzian NG. Recent changes in the package insert for succinylcholine chloride: should this drug be contraindicated for routine use in children and adolescents? (Summary of the discussions of the Anesthetic and Life Support Drug Advisory Meeting of the Food and Drug Administration, FDA building, Rockville, Md., June 9, 1994.) Anesth Analg 1995;80:207-8. 37. Stelzner J, Kretz FJ, Rieger A, Reinhart K. Ansthetikainduzierter Herzstillstand: Kasuistik zweier Suglinge mit zuvor nicht bekannter Muskeldystrophie. Anaesthetist 1993;42:44-6. 38. Delphin E, Jackson D, Rothstein P Use of succinylcholine during elec. tive pediatric anesthesia should be reevaluated. Anesth Analg 1987;66: 1190-2. 39. Jaffe RS, Gronert GA. Neuromuscular disorders and muscle relaxants. In: Cucchiara RF, Michenfelder JD, eds. Clinical neuroanesthesia. New York: Churchill Livingstone, 1991:351-77. 40. Miller ED Jr, Sanders DB, Rowlingson JC, Berry FA Jr, Sussman MD, Epstein RM. Anesthesia-induced rhabdomyolysis in a patient with Duchennes muscular dystrophy. Anesthesiology 1978;48:146-8. 41. Miller RD, Rupp SM, Fisher DM, Cronnelly R, Fahey MR, Sohn YJ. Clinical pharmacology of vecuronium and atracurium. Anesthesiology 1984;61:444-53. 42. Brull SJ, Silverman DG. Intraoperative use of muscle relaxants. Anesth Clin North Am 1993;11:325-44. 43. Hughes R, Chapple DJ. The pharmacology of atracurium: a new competitive neuromuscular blocking agent. Br J Anaesth 1981;53:31-44. 44. Stiller RL, Cook DR, Chakravorti S. In vitro degradation of atracurium in human plasma. Br J Anaesth 1985;57:1085-8. 45. Basta SJ, Savarese JJ, Ali HH, Moss J, Gionfriddo M. Histaminereleasing potencies of atracurium, dimethyl tubocurarine and tubocurarine. Br J Anaesth 1983;55:Suppl 1:105S-106S. 46. Eastwood NB, Boyd AH, Parker CJ, Hunter JM. Pharmacokinetics of 1R-cis 1 R-cis atracurium besylate (51W89) and plasma laudanosine concentrations in health and chronic renal failure. Br J Anaesth 1995;75:4315. 47. Littlejohn IH, Abhay K, el Sayed A, Broomhead CJ, Duvaldestin P, Flynn PJ. Intubating conditions following 1R CIS, 1 R CIS atracurium (51W89): a comparison with atracurium. Anaesthesia 1995;50:499-502.

48. Boyd AH, Eastwood NB, Parker CJ, Hunter JM. Comparison of the pharmacodynamics and pharmacokinetics of an infusion of cis-atracurium (51W89) or atracurium in critically ill patients undergoing mechanical ventilation in an intensive therapy unit. Br J Anaesth 1996;76:382-8. 49. Savarese JJ, Ali HH, Basta SJ, et al. The clinical neuromuscular pharmacology of mivacurium chloride (BW B1090U): a short-acting nondepolarizing ester neuromuscular blocking drug. Anesthesiology 1988;68:72332. 50. Brull SJ, Silverman DG. Pulse width, stimulus intensity, electrode placement, and polarity during assessment of neuromuscular block. Anesthesiology 1995;83:702-9. [Erratum, Anesthesiology 1996;84:1014.] 51. Savage DS, Sleigh T, Carlyle I. The emergence of ORG NC 45, 1- [(2b,3a,5a,16b,17b)-3,17-bis(acetlyoxy)-2-(1-piperidinyl)-androstan16-yl]-1-methylpiperidinium bromide, from the pancuronium series. Br J Anaesth 1980;52:Suppl 1:3S-9S. 52. van den Broek L, Wierda JM, Smeulers NJ, van Santen GJ, Leclercq MG, Hennis PJ. Clinical pharmacology of rocuronium (Org 9426): study of the time course of action, dose requirement, reversibility, and pharmacokinetics. J Clin Anesth 1994;6:288-96. 53. Larijani GE, Bartkowski RR, Azad SS, et al. Clinical pharmacology of pipecuronium bromide. Anesth Analg 1989;68:734-9. 54. Segredo V, Caldwell JE, Matthay MA, Sharma ML, Gruenke LD, Miller RD. Persistent paralysis in critically ill patients after long-term administration of vecuronium. N Engl J Med 1992;327:524-8. 55. Muir AW, Houston J, Green KL, Marshall RJ, Bowman WC, Marshall IG. Effects of a new neuromuscular blocking agent (ORG 9426) in anaesthetized cats and pigs and in isolated nerve-muscle preparations. Br J Anaesth 1989;63:400-10. 56. Meyer KC, Prielipp RC, Grossman JE, Coursin DB. Prolonged weakness after infusion of atracurium in two intensive care unit patients. Anesth Analg 1994;78:772-4. 57. Prielipp RC, Coursin DB, Scuderi PE, et al. Comparison of the infusion requirements and recovery profiles of vecuronium and cisatracurium 51W89 in intensive care unit patients. Anesth Analg 1995;81:3-12. 58. Coda BA. Opioids. In: Barash PG, Cullen BF, Stoelting RK, eds. Clinical anesthesia. 3rd ed. Philadelphia: Raven-Lippincott, 1996:329-58. 59. Lowenstein E, Hallowell P, Levine FH, Daggett WM, Austen WG, Laver MB. Cardiovascular response to large doses of intravenous morphine in man. N Engl J Med 1969;281:1389-93. 60. Brkle H, Dunbar S, Van Aken H. Remifentanil: a novel, short-acting, m-opioid. Anesth Analg 1996;83:646-51. 61. Freund FG, Martin WE, Wong KC, Hornbein TF. Abdominal-muscle rigidity induced by morphine and nitrous oxide. Anesthesiology 1973;38: 358-62. 62. Bowdle TA. Myoclonus following sufentanil without EEG seizure activity. Anesthesiology 1987;67:593-5. 63. Bowdle TA, Rooke GA. Postoperative myoclonus and rigidity after anesthesia with opioids. Anesth Analg 1994;78:783-6. 64. Kofke WA, Garman RH, Janosky J, Rose ME. Opioid neurotoxicity: neuropathologic effects in rats of different fentanyl congeners and the effects of hexamethonium-induced normotension. Anesth Analg 1996;83: 141-6. 65. Eger EI II, Lundgren C, Miller SL, Stevens WC. Anesthetic potencies of sulfur hexafluoride, carbon tetrafluoride, chloroform, and Ethrane in dogs: correlation with the hydrate and lipid theories of anesthetic action. Anesthesiology 1969;30:129-35. 66. Franks NP, Lieb WR. Molecular and cellular mechanisms of general anaesthesia. Nature 1994;367:607-14. 67. Koblin DD, Chortkoff BS, Laster MJ, Eger EI II, Halsey MJ, Ionescu P Polyhalogenated and perfluorinated compounds that disobey the Meyer. Overton hypothesis. Anesth Analg 1994;79:1043-8. 68. Hartung J. Twenty-four of twenty-seven studies show a greater incidence of emesis associated with nitrous oxide than with alternative anesthetics. Anesth Analg 1996;83:114-6. 69. Divatia JV, Vaidya JS, Badwe RA, Hawaldar RW. Omission of nitrous oxide during anesthesia reduces the incidence of postoperative nausea and vomiting: a meta-analysis. Anesthesiology 1996;85:1055-62. 70. Hadzic A, Glab K, Sanborn KV, Thys DM. Severe neurologic deficit after nitrous oxide anesthesia. Anesthesiology 1995;83:863-6. 71. Kenna JG, Jones RM. The organ toxicity of inhaled anesthetics. Anesth Analg 1995;81:Suppl:S51-S66. 72. Summary of the National Halothane Study: possible association between halothane anesthesia and postoperative hepatic necrosis. JAMA 1966;197:775-88. 73. Brown BR Jr, Gandolfi AJ. Adverse effects of volatile anaesthetics. Br J Anaesth 1987;59:14-23. 74. Gencarelli PJ, Miller RD, Eger EI II, Newfield P Decreasing enflurane . concentrations and d-tubocurarine neuromuscular blockade. Anesthesiology 1982;56:192-4.

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75. Stevens WC, Cromwell TH, Halsey MJ, Eger EI II, Shakespeare TF, Bahlman SH. The cardiovascular effects of a new inhalation anesthetic, Forane, in human volunteers at constant arterial carbon dioxide tension. Anesthesiology 1971;35:8-16. 76. Reiz S, Balfors E, Sorensen MB, Ariola S Jr, Friedman A, Truedsson H. Isoflurane a powerful coronary vasodilator in patients with coronary artery disease. Anesthesiology 1983;59:91-7. 77. Buffington CW, Davis KB, Gillispie S, Pettinger M. The prevalence of steal-prone coronary anatomy in patients with coronary artery disease: an analysis of the Coronary Artery Surgery Study Registry. Anesthesiology 1988;69:721-7. 78. Slogoff S, Keats AS, Dear WE, et al. Steal-prone coronary anatomy and myocardial ischemia associated with four primary anesthetic agents in humans. Anesth Analg 1991;72:22-7. 79. Eger EI II. New inhaled anesthetics. Anesthesiology 1994;80:90622. 80. Idem. Desflurane animal and human pharmacology: aspects of kinetics, safety, and MAC. Anesth Analg 1992;75:Suppl:S3-S7. 81. Muzi M, Lopatka CW, Ebert TJ. Desflurane-mediated neurocirculatory activation in humans: effects of concentration and rate of change on responses. Anesthesiology 1996;84:1035-42. 82. Helman JD, Leung JM, Bellows WH, et al. The risk of myocardial ischemia in patients receiving desflurane versus sufentanil anesthesia for coronary artery bypass graft surgery: the S.P Research Group. Anesthesiol.I. ogy 1992;77:47-62. 83. Todd MM, Warner DS, Sokoll MD, et al. A prospective, comparative trial of three anesthetics for elective supratentorial craniotomy: propofol/ fentanyl, isoflurane/nitrous oxide, and fentanyl/nitrous oxide. Anesthesiology 1993;78:1005-20. 84. Gonsowski CT, Laster MJ, Eger EI II, Ferrell LD, Kerschmann RL. Toxicity of compound A in rats: effect of a 3-hour administration. Anesthesiology 1994;80:556-65. 85. Idem. Toxicity of compound A in rats: effect of increasing duration of administration. Anesthesiology 1994;80:566-73. 86. Morio M, Fujii K, Satoh N, et al. Reaction of sevoflurane and its degradation products with soda lime: toxicity of the byproducts. Anesthesiology 1992;77:1155-64. 87. Frink EJ Jr, Ghantous H, Malan TP et al. Plasma inorganic fluoride ,

with sevoflurane anesthesia: correlation with indices of hepatic and renal function. Anesth Analg 1992;74:231-5. 88. Sebel PS, Lowdon JD. Propofol: a new intravenous anesthetic. Anesthesiology 1989;71:260-77. 89. Smith I, White PF, Nathanson M, Gouldson R. Propofol: an update on its clinical use. Anesthesiology 1994;81:1005-43. 90. Bloomfield EL, Masaryk TJ, Caplin A, et al. Intravenous sedation for MR imaging of the brain and spine in children: pentobarbital versus propofol. Radiology 1993;186:93-7. 91. Scheiber G, Ribeiro FC, Karpienski H, Strehl K. Deep sedation with propofol in preschool children undergoing radiation therapy. Paediatr Anaesth 1996;6:209-13. 92. Crawford M, Pollock J, Anderson K, Glavin RJ, MacIntyre D, Vernon D. Comparison of midazolam with propofol for sedation in outpatient bronchoscopy. Br J Anaesth 1993;70:419-22. 93. Chamorro C, de Latorre FJ, Montero A, et al. Comparative study of propofol versus midazolam in the sedation of critically ill patients: results of a prospective, randomized, multicenter trial. Crit Care Med 1996;24: 932-9. 94. Higgins TL, Yared JP, Estafanous FG, Coyle JP, Ko HK, Goodale DB. Propofol versus midazolam for intensive care unit sedation after coronary artery bypass grafting. Crit Care Med 1994;22:1415-23. 95. Borgeat A, Wilder-Smith O, Forni M, Suter PM. Adjuvant propofol enables better control of nausea and emesis secondary to chemotherapy for breast cancer. Can J Anaesth 1994;41:1117-9. 96. Veber B, Gachot B, Bedos JP, Wolff M. Severe sepsis after intravenous injection of contaminated propofol. Anesthesiology 1994;80:712-3. 97. Bennett SN, McNeil MM, Bland LA, et al. Postoperative infections traced to contamination of an intravenous anesthetic, propofol. N Engl J Med 1995;333:147-54. 98. Blouin RT, Seifert HA, Babenco HD, Conard PF, Gross JB. Propofol depresses the hypoxic ventilatory response during conscious sedation and isohypercapnia. Anesthesiology 1993;79:1177-82. 99. Committee on Drugs, Section on Anesthesiology. Guidelines for the elective use of conscious sedation, deep sedation, and general anesthesia in pediatric patients. Pediatrics 1985;76:317-21. 100. Guidelines on sedation and analgesia by nonanesthesiologists. Park Ridge, Ill.: American Society of Anesthesiologists, 1995.

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