68: Inhalational Anesthetics

The earliest description of the use of an inhalational anesthetic was made by Paracelsus, a Swiss physician and alchemist who prepared a mixture of diethyl ether, alcohol, and water called sweet oil of vitriol. He described the administration of this preparation to hens that fell into what appeared to be a deep sleep from which they recovered unharmed. In 1735, Wilhelm Froben gave this substance its modern name of “ether.” Ether was used topically, particularly via the intranasal route, as a treatment of headache, nervous diseases, and fits.

Modern anesthetic practice often is stated to have begun in 1846 at the Massachusetts General Hospital, when the dentist William Morton gave the first public demonstration of the ability of inhaled ether vapor to alleviate the pain of surgery. Oliver Wendell Holmes chose the Greek-related noun anesthesia (without feeling) to characterize the process.

Observations on circulatory and respiratory physiology eventually led to an understanding of the effects of inhalation gases and vapors. In the last decade of the 18th century, centers for the pneumatic treatment of disease were established in Birmingham and Bristol, England. Experiments with ether that was inhaled via a funnel and with nitrous oxide were conducted at these institutions. After Humphry Davy described his own pleasurable and exhilarating experience when he inhaled the “laughing” gas, many of his colleagues and friends inhaled nitrous oxide to experience its inebriating effects. Davy also described how inhalation of nitrous oxide relieved headache and the pain of an erupting molar tooth. Although Davy recognized the analgesic properties of nitrous oxide and its possible application for surgery, he failed to pursue the idea.

The public soon took up the use of nitrous oxide in the form of nitrous oxide frolics. Audience members at itinerant medicine shows volunteered to experience the exhilarating effects of nitrous oxide inhalation. At one such show in 1844 in Hartford, Connecticut, a man under the influence of nitrous oxide injured his leg but felt no pain. Dr. Horace Wells, a dentist in the audience that day, inhaled nitrous oxide the following day and had his partner painlessly remove a troublesome tooth. A subsequent public demonstration of the use of nitrous oxide for dental extraction was partly unsuccessful, leaving his colleagues doubtful regarding its efficacy and safety and thereby impeding its general acceptance as a surgical anesthetic.

In Great Britain in 1847, James Simpson, an obstetrician, first used ether to relieve the pain of labor. He subsequently adopted chloroform for this purpose because of its more pleasant odor and more rapid induction and emergence. The clergy and other physicians opposed the concept of relieving pain during childbirth, but the method ultimately was accepted after Queen Victoria gave birth to Prince Leopold with chloroform given by John Snow.

Over the next century, several volatile anesthetics were introduced, including ethyl chloride in 1848, divinyl ether in 1933, trichloroethylene in 1934, and ethyl vinyl ether in 1947. All had significant safety problems associated with their use, including combustibility and direct organ toxicity.

Advances in fluorine chemistry led to the cost-effective incorporation of fluorine into molecules used in the development of modern anesthetics. Fluroxene was the first of the new fluorinated anesthetics to be widely used clinically. However, this anesthetic was flammable and hepatotoxic. It was largely replaced by the nonflammable halothane, which was synthesized in 1951 and introduced into clinical practice in 1956. Methoxyflurane was evaluated in humans in 1960 but is no longer used because of nephrotoxicity (Chap. 19) and hepatotoxicity. Other halogenated hydrocarbons with improved clinical properties have been introduced, including enflurane, isoflurane, desflurane, and sevoflurane (Fig. 68–1). The inert gas xenon may be a useful anesthetic and is both cardio- and neuroprotective in experimental studies.⁴³ The clinical use of xenon is limited both by its cost and difficulty to manufacture. Although xenon is environmentally friendly compared with presently used anesthetic gases, its toxicity is relatively unknown but is believed to be minimal.

Inhalational anesthetics remain the most popular anesthetics used for maintenance of anesthesia primarily because they are easily and safely administered by modern anesthesia machines and are rapidly titratable to effect. Inhalational anesthetics used in current clinical practice include nitrous oxide, halothane, isoflurane, sevoflurane, and desflurane.

Because a wide range of chemically distinct xenobiotics can produce anesthesia, a unique receptor for the inhaled anesthetics is improbable. More likely, the volatile anesthetics cause general anesthesia by modulating synaptic function from within cell membranes. Anesthetics interact with many proteins. The most likely, but not yet proven, targets for the inhalational anesthetics are the ion channels that control ion flow across the cytoplasmic membrane.¹¹ An in-depth discussion is beyond the scope of this chapter, but several concepts are important to consider. First, more than 20 different ion channels have been identified, each controlling various anion and cation flows. The results of these ion channel effects include release of inhibitory neurotransmitters and inhibition of excitatory neurotransmitters. In fact, each anesthetic type has variable actions. The receptor for γ-aminobutyric acid type A (GABA_A) is the best studied and plays an important role because GABA_A is an inhibitory neurotransmitter. The interaction of all of these receptor effects produces the condition we refer to as general anesthesia. Many of the adverse effects of the inhalational anesthetics result directly from ion channel effects in nonneural tissue, primarily ­cardiac cell membranes.

Reversible changes in neurologic function cause loss of perception and reaction to pain, unawareness of immediate events, and loss of memory of those events. The common pharmacologic mechanisms for general anesthesia include the physical–chemical behavior of volatile hydrocarbons within the hydrophobic regions of biologic membrane lipids and proteins.

The potency of the various inhaled anesthetics correlates with their physicochemical properties. The dominant theories of the molecular mechanisms by which volatile anesthetics affect membrane function are based on the lipid solubility of the xenobiotics and experimental demonstration of pressure reversal of anesthesia. Anesthetic potency correlates directly with the relative lipid solubility of each xenobiotic, suggesting that the primary molecular actions of anesthetics occur in the lipid portion of cell membranes. This mechanism is known as the Meyer-Overton lipid solubility theory. Potential membrane regions for anesthetic action include the hydrophobic areas of proteins and protein–lipid interface regions, as well as the phospholipid matrix. High pressures (100–200 atm) can reverse the anesthetic effects of several xenobiotics, suggesting that anesthesia results from increasing membrane volume at normal atmospheric pressure, an effect known as the volume expansion theory.

Because the inhaled anesthetics enter the body through the lungs, the factors that influence their absorption by blood and distribution to other tissues, particularly the brain, include the solubility of the xenobiotic in blood, blood flow through the lungs, blood flow distribution to the various organs, solubility of the anesthetic in tissue, and the mass of the tissue. The goal of inhalation anesthesia is to develop and maintain a satisfactory partial pressure of anesthetic in the brain, the primary site of action.

The pharmacokinetics of anesthetics can be linked to their pharmacodynamics by considering anesthetic potency. The linkage exists because anesthesia strives to achieve and maintain a desired alveolar concentration. For the inhaled anesthetics, potency is commonly designated by the minimum alveolar concentration (MAC) of the anesthetic. MAC is the alveolar concentration at 1 atm that prevents movement in 50% of subjects in response to a painful stimulus. MAC is used when comparing the effects of equipotent doses of anesthetics on various organ functions.

Nitrous oxide (N₂O) is the most commonly used inhalational anesthetic in the world, but its safety is debated.²⁷ In 2008, the toxicity of nitrous oxide was exhaustedly reviewed both from its chemical perspective and its clinical activity, and the authors concluded that a ban on its use is not required.⁴⁴ Its advantages include a mild odor, absence of airway irritation, rapid induction and emergence, potent analgesia, and minimal respiratory and circulatory effects. When administered in a modern operating room (OR) using current standards of monitoring to prevent unintentional hypoxia, nitrous oxide is a remarkably safe xenobiotic. Unfortunately, nitrous oxide also has a potential for abuse, particularly among hospital and dental personnel.²⁶ Death and permanent brain injury are reported but do not generally result from direct toxic effects; instead, they are secondary to hypoxia as a result of simple asphyxiation¹⁵ (Chap. 124).

Nitrous oxide is also used as a food additive to generate foam, a property exploited to produce whipped cream. Sold in supermarkets as “bulbs,” death has occurred secondary to asphyxiation, when a homemade mouthpiece “whippets” failed to separate from the user after unconsciousness occurred during use.⁴²

Death also has occurred when patients received commercially prepared nitrous oxide from tanks contaminated with impurities such as nitric oxide or nitrogen dioxide. Pulmonary toxicity resulting from similar contaminants has been reported after illicit preparation of nitrous oxide from the combustion of ammonium nitrate fertilizer.³³

Injury may result from the physical properties of this anesthetic. Nitrous oxide is 35 times more soluble in blood than is nitrogen. When nitrous oxide is inhaled, any compliant air-containing space, such as the bowel, increases in size; noncompliant spaces, such as the eustachian tubes, exhibit an increase in pressure. These effects occur because nitrous oxide diffuses along the concentration gradient from the blood into a closed space much more rapidly than nitrogen can be transferred in the opposite direction. Clinical consequences include rapid progression of a pneumothorax to a tension pneumothorax, tympanic membrane rupture with hearing loss, bowel distension, and tracheal or laryngeal trauma caused by increased endotracheal cuff pressure resulting from replacement of air by a larger volume of nitrous oxide. Nitrous oxide may be particularly dangerous in patients who have suffered air emboli, and its use should be immediately discontinued upon recognition of these events. When intracranial or neuraxial air is injected during placement of an epidural catheter, it also can theoretically expand upon subsequent exposure to nitrous oxide.

Hematologic Effects

Bone marrow supression was first recognized as a complication of long-term nitrous oxide exposure in the 1950s, when the gas was used to sedate intubated patients who had severe tetanus.²⁵ Leukopenia with hypoplastic bone marrow and megaloblastic erythropoiesis typically developed 3 to 5 days after initial exposure and was followed by thrombocytopenia. Recovery usually occurred within 4 days after the anesthetic was discontinued. Healthy patients undergoing routine surgical procedures demonstrate mild megaloblastic bone marrow changes within 12 hours of exposure to 50% nitrous oxide and marked changes within 24 hours.⁴⁰ Critically ill patients may be more sensitive to the effects of nitrous oxide on the bone marrow, with megaloblastic changes described after only one hour of exposure, but changes are unlikely in individuals with less than 6 hours of exposure in the absence of preexistent folate or cobalamin deficiencies.³

The hematologic effects of exposure to nitrous oxide strongly resemble the biochemical characteristics of pernicious anemia.^2,38,39 Vitamin B₁₂, or cyanocobalamin, is a bound coenzyme of cytoplasmic methionine synthase. The cobalt moiety in the enzyme functions as a methyl carrier in its transfer from 5-methyltetrahydrofolate to homocysteine to form methionine (Fig. 68–2). Nitrous oxide oxidizes the cobalt ion, converting vitamin B₁₂ from the active monovalent form (Co⁺) to the inactive divalent form (Co²⁺), which irreversibly inhibits methionine synthase.³⁸ The metabolic consequences of this inhibition are significant because methionine and tetrahydrofolate are required for both DNA synthesis and myelin production. This interference is responsible for the development of bone marrow depression and polyneuropathy resembling the characteristic findings that occur in pernicious anemia.³⁹

Neurologic Effects

Disabling polyneuropathy in health care workers who habitually abused nitrous oxide was first described in 1978.²⁶ This neurologic disorder improved slowly when the patients abstained from further nitrous oxide abuse. This neuropathy is clinically indistinguishable from subacute combined degeneration of the spinal cord associated with pernicious anemia.⁴⁵ The syndrome of nitrous oxide neuropathy is characterized by sensorimotor polyneuropathy, often combined with signs of posterior and lateral spinal cord involvement. Signs and symptoms include numbness and paresthesias in the extremities, weakness, and truncal ataxia. Neurologic changes usually develop only after several months of frequent exposure to nitrous oxide, although neurologic manifestations may develop within days of use in patients with subclinical cyanocobalamin deficiency. Those at risk include individuals who chronically abuse the gas and those who are occupationally exposed for prolonged periods to environments contaminated with high concentrations of nitrous oxide.⁵ Animal studies demonstrate that methionine synthase is inactivated by exposure to greater than 1000 parts per million (ppm) of nitrous oxide. This scenario is highly unlikely in modern ORs, where inhalational anesthetics are scavenged, but it may occur in poorly ventilated dental offices. This problem probably is markedly underdiagnosed because the neurologic changes that occur in mild cases mimic other more common neurologic conditions.⁹

Immunologic Effects

Recently, concern has been raised regarding detrimental effects of nitrous oxide on immune function. Nitrous oxide is associated with varied effects on immune function with evidence of decreased proliferation of human peripheral blood mononuclear cells and decreased neutrophil chemotaxis. A large multicenter controlled trial (ENIGMA) evaluated 2050 patients undergoing major surgery, comparing a group receiving 80% oxygen/20% nitrogen with those receiving 70% nitrous oxide/30% oxygen.³⁵ On subgroup analysis, the group receiving nitrous oxide demonstrated significant increases in the incidence of wound infection, pneumonia, and atelectasis. Because the differences may be related to beneficial effects of high inspired oxygen concentrations rather than detrimental effects of nitrous oxide, follow-up studies (ENIGMA II) are being done to address these methodologic concerns.³⁶

Cardiovascular Effects

The use of nitrous oxide is associated with an increased risk of cardiovascular complications in the perioperative period. Serum homocysteine concentrations increase for days after operative exposure to nitrous oxide.³⁴ This occurs because conversion of homocysteine to methionine is methionine synthase dependent. Increased homocysteine concentrations are an independent risk factor for cardiac morbidity. In the ENIGMA trial, patients anesthetized with nitrous oxide had significantly greater incidence of electrocardiographic abnormalities and cardiac enzyme elevations.³⁶ There was also a trend to a higher incidence of confirmed myocardial infarction in the nitrous oxide group as well as an increased long-term risk of myocardial infarction.²⁷

Treatment

General.

Removal of the acutely affected person from the toxic environment should be the initial intervention. Individuals who have developed toxicity from occupational exposure or abuse of the gas should be educated about the relationship between their activities and their clinical findings.

Specific.

Vitamin B₁₂ may help patients with a vitamin B₁₂ deficiency who develop megaloblastic anemia and neurologic dysfunction after brief exposure to nitrous oxide, but it is not beneficial in patients who have toxicity resulting from more chronic exposure. The reason for the ineffectiveness of vitamin B₁₂ in this situation is uncertain.

The bone marrow abnormalities associated with nitrous oxide toxicity may be reversed by administration of a single 30 mg intravenous (IV) dose of folinic acid (Antidotes in Depth: A10). Methionine has also been successfully used when vitamin B₁₂ treatment alone has failed to improve neurologic symptoms.⁴⁷

The inhaled anesthetics were initially considered biochemically inert. Toxicity after administration was poorly explained, although it is now clear that the metabolites of the inhalational anesthetics are responsible for acute and chronic toxicities, which are predictable and dose related.

Halothane Hepatitis

Two distinct types of hepatotoxicity are associated with halothane use. The first is a mild dysfunction that develops in approximately 20% of exposed patients. Patients often are asymptomatic but exhibit modestly elevated serum aminotransferase concentrations within a few days of anesthetic exposure. Recovery is complete.²² In contrast, a life-threatening hepatitis occurs in approximately 1 in 10,000 exposed patients and produces fatal massive hepatic necrosis in 1 in 35,000 patients.⁴⁸ Because the histologic findings of massive hepatocellular necrosis are indistinguishable from many of the causes of viral hepatitis,⁵² differentiating halothane hepatitis from other causes of hepatitis in the postoperative period is difficult without definitive serologic studies. Jaundice, which is common after anesthesia and surgery, usually results from factors such as preexisting liver disease, blood transfusion, sepsis, or other causes of hepatitis. Thus, halothane hepatitis is a diagnosis of exclusion or inclusion based on the chemical history.

Several studies report an association between multiple exposures to halothane and subsequent development of hepatitis.^37,51,56 In one study, 95% of cases of halothane hepatitis occurred after repeat exposures, 55% of which involved reexposure within 4 weeks.⁵⁶ Under these circumstances, hepatic dysfunction usually is more severe, and the latency before clinical presentation usually is shorter than when the syndrome develops after initial exposure to halothane.⁵¹

Obesity is a risk factor commonly implicated in halothane hepatotoxicity.^1,53 Increased fat stores may act as a “reservoir” for halothane, with slow and prolonged release into the circulation and subsequent increase in production of potentially hepatotoxic metabolites.

Most cases of halothane hepatitis occur in middle-aged patients, with women having twice the risk.²² Genetic factors may play a role in some patients, as indicated by a report of this syndrome in three pairs of related Mexican women.²¹

Mechanism of Toxicity.

Halothane is the most extensively metabolized inhalational anesthetic. Approximately 20% of the absorbed anesthetic undergoes oxidative metabolism, principally by CYP2E1 in the liver, to ­trifluoroacetic acid. Reduction to trifluorochloroethane and difluorochloroethylene is a minor route of halothane metabolism that requires the absence of oxygen and the presence of an electron donor (Fig. 68–3). These volatile metabolites are free radicals, which may directly produce acute hepatic toxicity by irreversibly binding to and destroying hepatocellular structures. Alternatively, by acting as haptens, they may trigger an immune-mediated hypersensitivity response.^41,54 The high percentage of patients with halothane hepatitis who had recent reexposure is most consistent with the latter mechanism in which the first exposure primes the development of antibodies to a haptenized protein.²²

The use of halothane for inhalational anesthesia has markedly decreased in North America with the widespread availability of newer, safer halogenated anesthetics. Halothane is still widely used in some countries because it is inexpensive and provides a smooth induction of anesthesia.

Isoflurane and desflurane are pungent gases that can be airway ­irritants. Isoflurane, desflurane, and sevoflurane all appear to have low hepatotoxic potential. An immune form of hepatitis has been reported with all anesthetics except sevoflurane. Cross-sensitivity may exist, such that prior exposure to one anesthetic triggers hepatotoxicity upon subsequent exposure to a different anesthetic.

Nephrotoxicity

The kidneys are the only other organ at risk for toxicity from modern inhalational anesthetics. Methoxyflurane is an anesthetic that was introduced in 1962. By 1966, it was linked to the development of vasopressin-resistant polyuric renal insufficiency (nephrogenic diabetes insipidus) in 16 of 94 patients receiving prolonged methoxyflurane anesthesia for abdominal surgery¹³ (Chap. 19). Polyuria was associated with a negative fluid balance, elevations of serum sodium and urea nitrogen concentrations, osmolality, and a fixed urinary osmolality approximating that of serum. Kidney abnormalities lasted from 10 to 20 days in most patients but persisted for more than one year in three patients. Subsequent studies demonstrated that kidney toxicity was caused by inorganic fluoride (F^–) released during biotransformation of methoxyflurane.⁵⁰ The risk of toxicity was highly correlated with both the total dose of methoxyflurane (concentration times duration) and the peak serum F^– concentration.¹² The nephrotoxic serum F^– concentration is 50 to 60 μmol/L.¹² The factors that enhance biotransformation such as obesity and enzyme induction also increase the risk of toxicity. Although the precise mechanism by which fluoride produces its toxic effect on the kidneys is not clear, one hypothesis is that fluoride inhibits adenylate cyclase, thereby interfering with the normal action of antidiuretic hormone on the distal convoluted tubules.

Although methoxyflurane is no longer used, lessons learned regarding its toxicity are applied when evaluating the nephrotoxic potential of other fluorinated anesthetics. Of the currently used anesthetics (halothane, isoflurane, desflurane, sevoflurane), only sevoflurane undergoes biotransformation by defluorination.

Approximately 5% of sevoflurane is metabolized. This process occasionally results in sufficient serum F^– concentrations to produce transient decreases in urine-concentrating ability.²⁴ However, clinically evident renal impairment almost never occurs with use of sevoflurane.¹⁸ In volunteer studies, exposure to sevoflurane that resulted in high serum fluoride concentrations did not result in any urine-concentrating defects. In patients with chronic kidney disease (CKD), the risk of postoperative kidney dysfunction is believed to be worse with exposure to inhalational anesthetics. However, studies demonstrate that deterioration of kidney function does not occur after exposure to desflurane and isoflurane,³¹ possibly because intrarenal fluoride concentrations are more important than serum fluoride concentrations in the development of nephrotoxicity.

Sevoflurane reacts with the alkali within carbon dioxide absorbers to produce several degradation products, including a vinyl ether called compound A (CF₂C(CF₃)OCH₂F). Compound A causes renal tubular necrosis in rats, especially at the corticomedullary junction.^23,55 The extent of nephrotoxicity is determined by both the concentration of compound A and the duration of exposure. Compound A is also conjugated, and its breakdown products are nephrotoxic.

Technical Issues.

Extensive clinical experience with several million patients who were exposed to sevoflurane and 4000 closely studied volunteers failed to demonstrate nephrotoxicity.³¹ Higher concentrations of compound A are generated during low-flow anesthesia, use of high concentrations of sevoflurane, and increased temperature conditions. A high fresh-gas flow rate dilutes the concentration of compound A. Concern that higher compound A concentrations are generated when a low fresh-gas flow rate (eg, <2 L/min) is used in a closed circuit led to the current sevoflurane package labeling, which warns against fresh-gas flow rates below 2 L/min in a circle absorber system.³⁰

Some controversy exists regarding the safety of low-flow sevoflurane anesthesia. Although there have been no clinical reports of sevoflurane-induced nephrotoxicity as measured by changes in blood urea nitrogen (BUN), serum creatinine, or creatinine clearance, clinical data demonstrate transient nephrotoxicity when more subtle measurements of glomerular and tubular function are used.^16,18,20 For example, when young, healthy patients without underlying kidney disease were anesthetized with low-flow sevoflurane for a mean of 6.7 hours, transient but statistically significant increases in urinary glucose and protein excretion were documented without any changes in BUN, creatinine, or creatinine clearance.²⁰ The clinical significance of such transient abnormalities in kidney function is uncertain. Regardless, it seems prudent to avoid the practice of low-flow sevoflurane in patients with CKD until clinical data document safety. Newer carbon dioxide absorbents that are free of strong alkali are now available to decrease generation of compound A.

Pharmacology

Desflurane and isoflurane contain a difluoromethoxy moiety that can be degraded to carbon monoxide (CO). This process occasionally results in patient exposure to toxic CO concentrations. CO production resulting from intraoperative desflurane degradation has been reported with carboxyhemoglobin levels as high as 36%.⁷ Although there was no evidence of patient harm in this case, morbidity or mortality could occur at this level in patients with concurrent disease (Chap. 125). The true incidence of CO exposure during clinical anesthesia is unknown. Routine detection of intraoperative CO exposure is now possible using multiwavelength pulse cooximeters, but these more expensive devices are not yet widely used, and conventional pulse oximeters that are routinely used in ORs cannot detect CO.⁸

Carbon monoxide production is inversely proportional to the water content of CO₂ absorbents. Soda lime (a granular mixture of calcium, sodium, and potassium hydroxide) is the most frequently used CO₂ absorbent. It is sold wet (13%–15% water by weight), but may dry with high gas-inflow rates. Higher concentrations of CO are most apt to be present during the first case after a weekend because of drying of CO₂ absorbent from a continuous inflow of dry oxygen over the weekend if the anesthesia machine has not been used.¹⁷

Other factors influence the concentration of CO that may result from anesthetic degradation, including temperature (higher temperature increases CO formation), type of absorbent, choice of anesthetic, and concentration of anesthetic. Strong alkalis, such as potassium and sodium hydroxide, initiate the reaction that forms CO.

Mass spectrometry (available in some ORs) cannot directly detect CO because its molecular weight is equivalent to that of nitrogen, a gas usually present in much greater amounts. In addition, detection of CO by fragmentation products is not possible by mass spectrometry because CO₂ is present in greater amounts and has similar fragmentation products.

Unfortunately, the diagnosis of CO poisoning during anesthesia is dif­ficult because the main clinical features of toxicity are masked by anesthesia,and no routinely available means can identify CO within the breathing ­circuit or detect when the CO₂ absorbent has been desiccated. Delayed neurologic sequelae from intraoperative CO poisoning are likely missed on the anesthesiologist’s postoperative patient evaluation.⁵⁸

The product labels of desflurane and isoflurane have been altered to include a precaution that the CO₂ absorbent should be replaced when a practitioner suspects the absorbent is desiccated. However, the problem associated with this warning is the lack of a reliable method for determining when the absorbent is fully or partially desiccated.

If an anesthetic machine is found with the fresh-gas flow on at the beginning of the day, a reasonable practice is to replace the absorbent. Newer CO₂ absorbents that are less likely to degrade anesthetics are now available. These newer absorbents have decreased amounts of strong bases.

Long-Term Use of Halogenated Anesthetics in Intensive Care Units

Halogenated anesthetics have been used since the 1990s in intensive care units (ICUs) for long-term sedation of patients receiving mechanical ventilation since the 1990s and more recently as part of the treatment for patients with refractory status epilepticus. Use has been limited by concerns regarding atmospheric pollution and high costs (because of a lack of rebreathing systems in the ICU). The development of anesthetic-conserving devices for use with ICU ventilators has addressed these issues. Potential advantages include more rapid wakeup and shorter times to extubation with minimal risk of toxicity.³²

Clinical studies report the use of isoflurane and sevoflurane for ICU sedation. In one study, 19 patients were mechanically ventilated for more than 24 hours in the ICU with sevoflurane used for sedation.³² Toxic effects of sevoflurane were not found even though serum fluoride concentrations often exceeded 50 μmol (the concentration suggested to be the nephrotoxic threshold).¹²

Isoflurane is being used as a first-choice for long-term sedation during mechanical ventilation in some ICUs. Experimental models demonstrate that isoflurane is potentially neurotoxic, primarily through induction of neuronal apoptosis. In rats, isoflurane substantially decreases local glucose utilization in various brain regions, including the thalamus.

Reversible psychomotor dysfunction was reported in 3.6% of 335 patients who received isoflurane for more than 12 hours as a primary sedative during mechanical ventilation in a general ICU.⁴ Psychomotor dysfunction occurred in 42% of patients age 4 years or younger but in only 1.3% of patients older than 4 years. The psychomotor dysfunction only occurred in patients who received the isoflurane for greater than 24 hours.

Isoflurane is an alternate treatment for patients with refractory status epilepticus. Reversible magnetic resonance imaging (MRI) abnormalities developed in two patients who received inhaled isoflurane for a prolonged time (35 and 85 days).¹⁹ Serial MRIs demonstrated the development of hyperintense T2 signals involving the medulla, cerebellar cortex, deep cerebellar nuclei, thalamus, and hypothalamus bilaterally. These abnormalities improved after discontinuation of the isoflurane.

Waste anesthetic gases are defined as inhalation gases and vapors that are released into work areas associated with or adjacent to the administration of a gas or volatile liquid for anesthetic purposes. Because anesthesia machines are not airtight and consist of hundreds of parts, it is inevitable that clinical personnel will be exposed to waste anesthetic gases. Exposure to waste anesthetic gas produces short- and long-term effects. Common short-term effects are lethargy and fatigue in staff members who are exposed to significant quantities of waste anesthetic gas. Chronic long-term effects correlate with the concentration of gas and duration of exposure. Animal studies demonstrate that exposure to high concentrations of nitrous oxide and halogenated xenobiotics can cause cellular, mutagenic, carcinogenic, and teratogenic effects.

The US government has been involved with the regulation and management of waste anesthetic gas since 1970. The OR environment in this country is highly regulated and monitored, but exposure limits vary in other countries and can exceed the concentrations permitted in the United States. Even in a modern working environment with low-leakage anesthesia machines, scavenging systems, and high room ventilation exchange rates, exposure to inhalational anesthetics could not be kept below acceptable threshold concentrations in all cases. However, a cause-and-effect relationship between human exposure to waste anesthetic gases and poor reproductive outcomes could not be identified in an analysis requested by the American Society of Anesthesiologists.¹⁰

Dentists and dental assistants are often exposed to greater concentrations of waste anesthetic gases than are individuals working in well-vented ORs. An epidemiologic survey compared 15,000 dentists who used nitrous oxide in their practices to 15,000 dentists who did not.⁹ A 1.2- to 1.8-fold increase in hepatic, kidney, and neurologic disease was found in the dentists and their chair-side assistants who were chronically exposed to trace concentrations of nitrous oxide. For those with heavy office use of nitrous oxide, a fourfold increase in the incidence of neurologic complaints compared with the nonexposed group was observed. Female dental assistants who were exposed to nitrous oxide had a two- to threefold increase in spontaneous abortion rates, reduced fertility, and a higher rate of congenital abnormalities in their offspring.⁹

Fatal or life-threatening complications occur when halogenated inhalational anesthetics are used for nonanesthetic purposes such as suicide attempts, mood elevation, and topical treatment of herpes simplex labialis. When ingested, halothane usually produces gastroenteritis with vomiting followed by depressed levels of consciousness, hypotension, shallow breathing, bradycardia with extrasystoles, and acute respiratory distress syndrome (ARDS). Coma usually resolves within 72 hours.^14,57 The diagnosis should be suspected when these features occur in a patient with the sweet or fruity odor of halothane on the breath. Supportive care, including endotracheal intubation and nasogastric lavage, should be provided. Full recovery can occur without permanent organ injury.

Intravenous injections of halothane may occur as a suicide attempt or unintentionally during anesthesia induction. A young patient who was found unconscious and hypotensive with ARDS after self-administered IV injection of halothane was not successfully resuscitated.⁶ A 16 year-old girl received an unintentional IV injection of 2.5 mL of halothane during anesthesia induction.⁴⁹ She became unconscious and apneic within 30 seconds but began to awaken within 2 to 3 minutes. Four hours later, she developed ARDS but subsequently made a full recovery.

Transient coma and apnea probably are secondary to a halothane bolus reaching the brain on its first pass through the bloodstream. Redistribution then occurs, explaining the rapid awakening. The ARDS that develops after injection of halothane may result from a direct toxic effect of high concentrations of this hydrocarbon on the pulmonary vascular bed. After injection, the anesthetic likely travels as a bolus during the first passage through the pulmonary circulation because of its poor solubility in blood.

Hospital personnel are involved in most reported cases of halothane abuse by inhalation.⁴⁶ Inhalation of halothane produces a pleasurable sensation similar to that described with glue sniffing (Chap. 84). Death may result from upper airway obstruction after loss of consciousness or from dysrhythmias. Death occurred in a student nurse anesthetist suggested to have applied a full 250 mL bottle of enflurane over 3 hours to “cold sores” on her lower lip.²⁸

• Inhalational anesthetics remain a popular choice for maintenance of anesthesia because of their safety and titratability.

• Toxicity is uncommon and can result from a variety of mechanisms.

• Health care practitioners who use these anesthetics should be knowledgeable about their pharmacology and potential toxicity.

Acknowledgment

Martin Griffel, MD, contributed to this chapter in previous editions.

References