F: ANESTHETICS AND RELATED MEDICATIONS

HISTORY AND EPIDEMIOLOGY

Local anesthetics block excitation of and transmission along a nerve axon in a predictable and reversible manner. In contrast to the nonselective effects of a general anesthetic, the anesthesia produced is selective to the chosen body part. Because local anesthetics do not require the circulation as an intermediate carrier and usually are not transported to distant organs, their actions are largely confined to the structures with which they come into direct contact. Local anesthetics are used to provide analgesia in various parts of the body by topical application, injection in the vicinity of peripheral nerve endings and major nerve trunks, or via instillation within the ophthalmic, epidural or subarachnoid spaces. The various local anesthetics differ with regard to their potency, duration of action, and degree of effects on sensory and motor nerve fibers. Toxicity is either local or systemic. With systemic toxicity, central nervous system (CNS) and cardiovascular effects are of greatest concern.

Until the 1880s, the only available analgesics were centrally acting depressants such as alcohol and opioids, which blunted the perception of pain rather than addressing the underlying cause. In 1860, the chemist Albert Niemann extracted the active alkaloid cocaine (Chap. 75) from the leaves of the coca shrub (Erythroxylon coca). Over the next 2 decades, the local anesthetic properties of the drug were identified. In 1884, Koller performed glaucoma surgery with only topical cocaine anesthesia.⁵⁴

Although the clinical benefits of cocaine anesthesia were significant, so were its toxic and addictive potential. At least 13 deaths were reported in the first 7 years after the introduction of cocaine in Europe, and within 10 years after the introduction of cocaine as a regional anesthetic, reviews of “cocaine poisoning” appeared in the literature.^89,111 The toxicity of cocaine, coupled with the tremendous advantages it provided for surgery, led to a search for less toxic substitutes.

After the elucidation of the chemical structure of cocaine (the benzoic acid methyl ester of the alkaloid ecgonine) in 1895, other amino esters were examined. Synthetic compounds with local anesthetic activity were introduced but were highly toxic or irritating or had an impractically brief clinical effect. In 1904, Einhorn synthesized procaine, but its short duration of action limited its clinical utility. Research turned to focus on synthesis of local anesthetics with more prolonged durations of action.

The potent, long-acting local anesthetics dibucaine and tetracaine were synthesized in 1925 and 1928, respectively, and were introduced into clinical practice shortly thereafter. These anesthetics were not safe for regional anesthetic techniques because of potential systemic toxicity secondary to the combination of high potency, delayed metabolism, and the larger volumes of drug required for regional anesthesia compared with local anesthesia. On the other hand, these anesthetics were very useful for spinal anesthesia, which required much smaller volumes.

Lofgren synthesized lidocaine in 1943 from a series of aniline derivatives. This amino amide combined high tissue penetrance and a moderate duration of action with acceptably low systemic toxicity. Additionally, unlike amino ester anesthetics, the metabolites of lidocaine did not include para-aminobenzoic acid (PABA), responsible for allergic reactions. Subsequent to the release of lidocaine in 1944, several other amino amide compounds were introduced into clinical practice including mepivacaine (1956), prilocaine (1959), bupivacaine (1963), etidocaine (1971), and ropivacaine (1996).

Considering the frequency of local anesthetic use, both within and outside health care facilities, clinically significant toxic reactions are relatively uncommon. In reports of fatalities resulting from toxic exposures reported to US poison control centers, local anesthetics are rarely implicated, representing fewer than 0.5% of cases (Chap. 130). Iatrogenic poisonings result from inadvertent injection of a therapeutic dose into a blood vessel, repeated use of a therapeutic dose, or unintentional administration of a toxic dose. The amide local anesthetics have largely replaced the esters in clinical use because of their increased stability and relative absence of hypersensitivity reactions (see Pharmacology later). Poisoning from topical benzocaine is relatively common because of the large number of nonprescription products available for treatment of teething and hemorrhoids. With nonprescription use, toxic effects after exposure are typically mild, and death rarely occurs. Toxicity usually occurs as a therapeutic misadventure, the potential for child abuse or neglect should be evaluated if the patient is younger than 2 years, and potential suicide should be evaluated in older children and adults.

Benzocaine spray is the most important cause of severe acquired methemoglobinemia in the hospital setting (Chap. 124).³³ Between November 1997 and March 2002, the US Food and Drug Administration (FDA) received 198 reported adverse events secondary to benzocaine products. A total of 132 cases (66.7%) involved definite or probable methemoglobinemia; most were serious adverse events, and 2 deaths occurred.⁹⁸ In these cases, a single spray of unspecified duration of 20% benzocaine was the dose most commonly reported. In 2003 and again in 2006, the FDA issued advisories regarding the use of benzocaine spray for topical mucosal anesthesia before intubation, upper endoscopy, and transesophageal echocardiography. In 2006, the US Veterans Health Administration halted the use of benzocaine spray for topical anesthesia. At this point in time, any continued use of topical benzocaine spray should be undertaken with extreme caution after careful assessment of risks, benefits, and alternatives, with antidotal therapy readily available.

PHARMACOLOGY

Local anesthetics fall into one of two chemically distinct groups: amino esters and amino amides (Fig. 64–1). The basic structure of all local anesthetics consists of three major components: a lipophilic, aromatic ring connected by an ester or amide linkage to a short alkyl intermediate chain that in turn is bound to a hydrophilic tertiary (or less commonly, secondary) amine. The amine group acts as a base, accepting protons and becoming charged at a higher pH.

The proportion of charged molecules is dependent upon the pKa of the specific local anesthetic.

All local anesthetics function primarily by reversibly binding to specific receptor proteins within the membrane-bound sodium channels of conducting tissues. These receptors are reached only via the cytoplasmic (intracellular) side of the cell membrane. Blockade of ion conductance through the sodium channel eventually leads to failure to initiate and propagate action potentials (Fig. 64–2). The analgesic effect results from inhibiting axonal transmission of the nerve impulse in small-diameter myelinated Aδ (“fast pain”) and unmyelinated C (“slow pain”) nerve fibers carrying pain and temperature sensation. Conduction block of these fibers occurs at lower local anesthetic concentrations than required for the larger fibers responsible for touch, motor function, and proprioception.³⁰ This likely occurs in myelinated nerves because smaller fibers have closer spacing of the nodes of Ranvier. Given that a fixed number of nodes must be blocked for conduction failure to occur, the shorter critical length of nerve is reached sooner by the locally placed anesthetic in small fibers.⁴⁶ For unmyelinated fibers, the smaller diameter limits the distance that such fibers can passively propagate the electrical impulse. Differential nerve blockade is also related to voltage- and time-dependent affinity of local anesthetics to the sodium channels.

The sodium channel exists in three classes (Chap. 15 and Fig. 15–2). At resting membrane potential or in the hyperpolarized membrane, the channel is closed to sodium conductance. With an appropriate activating stimulus, the channel opens, allowing rapid sodium influx and membrane depolarization. Milliseconds later, the channel is inactivated, terminating the fast sodium current. Local anesthetic blockade is much stronger for channels that are activated (open) or inactivated than for channels that are resting. Analogous to the use-dependent kinetics of class I antidysrhythmics, pain fibers have a higher firing rate and longer action potential (ie, more time with the sodium channel open or inactivated) than other fiber types and therefore are more susceptible to local anesthetic action.⁶²

These effects also occur in conductive tissues in the heart and brain that rely on sodium current. Although sodium channel blockade initially was believed to be the sole cause of systemic toxicity, mechanisms are more complex, especially in the heart, and occur at systemic concentrations lower than previously thought.⁹¹ Recent proteomics analyses suggest that phosphatidyl-3-kinase (PI3K) plays a central role in pathways associated with bupivacaine-associated neurotoxicity.¹⁴⁵

Growing evidence indicates that local anesthetics directly affect many other organ systems and functions such as the coagulation, immune, and respiratory systems, all at concentrations much lower than those required to achieve sodium channel blockade.^20,61,62 For example, lidocaine inhibited muscarinic signaling in Xenopus oocytes at less than 50% of the concentration required for sodium channel blockade.⁶² Study of these less well-described effects may help elucidate both therapeutic and toxic phenomena that are incompletely explained.

The primary determinant of the onset of action of a local anesthetic is its pK_a, which affects its lipophilicity (Table 64–1). All local anesthetics are weak bases, with a pK_a between 7.8 and 9.3. At physiologic pH (7.4), xenobiotics with a lower pK_a have more uncharged molecules capable of crossing nerve cell membranes, producing a faster onset of action than xenobiotics with a higher pK_a. The onset of action also is influenced by the total dose of local anesthetic administered, which effects the concentration responsible for diffusion.

Local anesthetic potency is highly correlated with the lipid solubility of the xenobiotic. Therefore, the aromatic side of the anesthetic is the primary determinant of potency. The hydrophilic amine is important in occupying the sodium channel, which involves an ionic interaction with the charged form of the tertiary amine. The length of the intermediate chain is another determinant of local anesthetic activity, with three to seven carbon equivalents providing maximal activity.³⁰ Shorter or longer intermediate chain lengths are associated with rapid loss of local anesthetic action, suggesting that a critical length of physical separation between the aromatic group and the tertiary amine is required for sodium channel blockade to occur.

The degree of protein binding influences the duration of action of a local anesthetic. Anesthetics with greater protein binding remain associated with the neural membrane for a longer time interval and therefore have longer durations of action.³⁰ When high serum concentrations are achieved, a higher degree of protein binding increases the risk for cardiac toxicity.

PHARMACOKINETICS

A distinction must be made between local disposition (distribution and elimination) and systemic disposition of the anesthetic. Local distribution is influenced by several factors, including spread of local anesthetic by bulk flow, diffusion, transport via adjacent blood vessels, and binding to proximate tissues. Local elimination occurs through systemic absorption, transfer into the general circulation, and local hydrolysis of amino ester anesthetics. Systemic absorption decreases the amount of local anesthetic that is available for anesthetic effect, thereby limiting the duration of the block. Systemic absorption depends on the avidity of binding of local anesthetics to tissues near the site of injection and on local perfusion. Both these factors vary with the site of injection. In general, areas with greater blood flow will have more rapid and complete systemic uptake of local anesthetic; for example, intravenous (IV) > tracheal > intercostal > paracervical > epidural > brachial plexus > sciatic > subcutaneous.

Because of their lipophilicity, local anesthetics readily cross cell membranes, the blood–brain barrier, and the placenta. After being absorbed, systemic tissue distribution is highly dependent on tissue perfusion. After local anesthetics enter the venous circulation, they pass through the lungs, where significant uptake occurs, thereby lowering peak arterial concentrations. Thus, the lungs serve as a buffer against systemic toxicity, but the capacity of the lungs to accumulate drug is saturable.⁸⁰ Part of the reason why most local anesthetic–induced seizures result from unintentional intravascular bolus injection rather than absorptive uptake is that lung uptake of these drugs exceeds 90%. The very high peak venous concentrations produced by rapid injection usually are necessary to produce toxic arterial concentrations.

All local anesthetics, except cocaine, cause peripheral vasodilation by direct relaxation of vascular smooth muscle. Vasodilation enhances vascular absorption of the local anesthetic. Addition of epinephrine (5 mcg/mL or 1:200,000) to the local anesthetic solution decreases the rate of vascular absorption, thereby improving the depth and prolonging the duration of local action, and mitigating risk of systemic toxicity. Local anesthetic mixed with epinephrine also decreases bleeding into the surgical field and serves as a marker for inadvertent intravascular injection (by producing tachycardia) when a test dose of the mixture is injected through a needle or catheter.⁹⁵ Significant drawbacks to epinephrine use include uncomfortable side effects such as palpitations and tremors, local tissue ischemia, and life-threatening systemic adverse reactions in susceptible patients (eg, myocardial ischemia and hypertensive crises). Inadvertent intravascular injection of local anesthetics mixed with epinephrine can be fatal, although generally the epinephrine in these mixtures is very dilute.⁸⁶

The two classes of local anesthetics undergo metabolism by different routes (Chap. 75). The amino esters are rapidly metabolized by plasma cholinesterase to the major metabolite, PABA. The amino amides are metabolized more slowly in the liver to a variety of metabolites that do not include PABA.²⁹ Patients with enzymatic mutations or low or absent concentrations of plasma cholinesterase (pseudocholinesterase) are at increased risk for systemic toxicity from amino ester local anesthetics. Factors that decrease hepatic blood flow or impair hepatic function increase the risk for toxic reactions to the amino amides and make management of serious reactions more difficult. Patient age, as it relates to liver enzyme activity and plasma protein binding, influences the rate of metabolism of local anesthetics. Whereas lidocaine’s terminal half-life after IV administration averaged 80 minutes in volunteers aged 22 to 26 years, the half-life was 138 minutes in those aged 61 to 71 years (Chap. 32).¹⁰³ Newborns with immature hepatic enzyme systems have prolonged elimination of amino amides, which is associated with seizures when high continuous infusion rates are used.^1,92 Lidocaine elimination is reduced by congestive heart failure or coadministration of xenobiotics that reduce hepatic blood flow, thus explaining the increased risk of toxicity with cimetidine and propranolol.¹¹⁷ Propranolol and cimetidine also potentially decrease lidocaine clearance by inhibiting hepatic CYP450 enzymes, including CYP1A2 and CYP3A4 involved in lidocaine N-deethylation and 3-hydroxylation in humans.¹³⁷

Local anesthetics are often mixed to take advantage of desirable pharmacokinetics. In theory, rapid-acting, relatively short-duration local anesthetics such as chloroprocaine and lidocaine can be combined with the longer latency, long-acting tetracaine or bupivacaine to enable an immediate and prolonged anesthetic response. In practice, the advantages of the mixtures are small, and toxicities are additive.⁶ Administration of one local anesthetic increases the free plasma fraction of another by displacement from protein-binding sites.⁶⁷

Local anesthetics usually cannot penetrate intact skin in sufficient quantities to produce reliable anesthesia.¹⁴ Efficient skin penetration requires the combination of a high water content and a high concentration of the water-insoluble base form of the local anesthetic. This combination of properties is achieved by mixing lidocaine and prilocaine in their base forms in a 1:1 ratio (eutectic mixture of local anesthetics {EMLA}).¹⁸ Application for at least 45 minutes is required to achieve adequate dermal analgesia. Local anesthetic uptake continues for several hours during application. A liposomal formulation of 4% lidocaine (ELA-Max) facilitates skin absorption.⁴⁹ It is as effective as lidocaine–prilocaine base for topical anesthesia.^40,71 In addition, a 4% tetracaine gel preparation is used in children for topical skin anesthesia with an onset of action and efficacy at least as good as lidocaine–prilocaine base without any systemic side effects

The low molecular weight of local anesthetics is associated with rapid absorption and subsequent elimination and therefore relatively short duration of action. Recently, a liposomal bupivacaine formulation was introduced as a long acting postsurgical anesthetic.^22,85 After local infiltration, the product has a terminal half-life 9.8-fold greater than that of plain bupivacaine. Significantly elevated plasma bupivacaine concentrations were observed for 96 hours after local infiltration of the liposomal formulation but do not correlate with local efficacy.^3,64 Current manufacturer recommendations warn against use of all local anesthetics within 96 hours of liposomal bupivacaine administration because local infiltration has the potential to precipitate an immediate release of local anesthetic from the liposomal formulation, with subsequent systemic toxicity.

CLINICAL MANIFESTATIONS OF TOXICITY

Although the most common adverse reactions to local anesthetics are vasopressor syncopal events associated with injection, the following sections focus on their local and systemic toxicity.¹³⁴

Toxic Reactions

Regional Side Effects and Tissue Toxicity

At a sufficient concentration, all local anesthetics are directly cytotoxic to nerve cells. However, in clinically relevant doses, they rarely produce localized nerve damage.^73,102 Significant direct neurotoxicity results from intrathecal injection or infusion of local anesthetics for spinal anesthesia. In this setting, lidocaine has an increased risk for both persistent lumbosacral neuropathy and a syndrome of painful but self-limited postanesthesia buttock and leg pain or dysesthesia referred to as transient neurologic symptoms.⁶⁶ Nerve damage often is attributed to the use of excessively concentrated solutions or inappropriate formulations. Several reports of cauda equina syndrome are associated with use of hyperbaric 5% lidocaine solutions for spinal anesthesia. Hyperbaric solutions are denser than cerebrospinal fluid. This neurotoxicity appears to be a phenomenon that occurs when the anesthetic is injected through narrow-bore needles or through continuous spinal catheters. This process results in very high local concentrations of the anesthetic that might pool around the sacral roots because of inadequate mixing.¹¹⁸ The mechanism of this neurotoxicity is unknown but is believed to be independent of sodium channel blockade.⁶⁶ Because an equally effective block can be achieved with injection of larger volumes of lower concentration, 5% lidocaine is generally avoided and bupivacaine used instead. There is a significant (up to 10-fold) increase in the development of new neurologic dysfunction after receiving a neuraxial block in patients with preexisting peripheral neuropathy, a fact emphasizing the importance of informed consent and risk communication.⁵⁷

Similar severe neurotoxic reactions occur after massive subarachnoid injection of chloroprocaine during attempted epidural anesthesia.¹¹⁵ The neurotoxicity initially was attributed to use of the antioxidant sodium bisulfite and the low pH of the commercial solution rather than use of the anesthetic itself.¹³⁶ Despite reformulation without bisulfite, subsequent animal data suggest that chloroprocaine itself is responsible for the neurotoxicity.¹³¹ Skeletal muscle changes are observed after intramuscular injection of local anesthetics, especially the more potent, longer acting local anesthetics. The effect is reversible, and muscle regeneration is complete within 2 weeks after injection of local anesthetics.¹⁰

Although rare, after peripheral nerve or plexus block, transient or prolonged postoperative neuropathy is well recognized. Likely mechanisms include direct injury of the nerve related to intraneuronal injection and local anesthetic neurotoxicity. The frequency of peripheral neuropathies reported after peripheral nerve blockade varies from 0% to more than 5%.¹⁵ Direct visualization of peripheral nerves via ultrasonography reduces this complication, avoiding traumatic injury and allowing for injection of less local anesthetic to produce adequate nerve block.^80,126 In one study, intraneural injection occurred in 17% of supraclavicular or interscalene blocks, but ultrasonographic identification prevented further injection.⁸ Analysis of 12,668 ultrasound-guided nerve blocks for peripheral regional anesthesia found that the incidences of postoperative neurologic symptoms lasting longer than 5 days and 6 months were 0.18% and 0.008%, respectively.¹²⁶ Visualization of the target site via ultrasound guidance also decreases local anesthetic systemic toxicity, likely because of reduced incidence of inadvertent vascular puncture.⁸

Systemic Side Effects and Toxicity

Allergic Reactions

Allergic reactions to local anesthetics are extremely rare. Fewer than 1% of all adverse drug reactions caused by local anesthetics are immunoglobulin (Ig) E mediated.⁴⁹ In one study designed to determine the prevalence of true local anesthetic allergy in patients referred to an allergy clinic for suspected hypersensitivity, skin prick and intradermal testing results were negative for all 236 participants tested.¹¹ As noted, the amino esters are responsible for the majority of true allergic reactions. When hydrolyzed, the amino ester local anesthetics produce PABA, a known allergen (Chap. 46). Cross-sensitivity to other amino ester anesthetics is common. Some multidose commercial preparations of amino amides contain the preservative methylparabens (Chap. 46), chemically related to PABA, and most likely the cause of the much rarer allergic reactions attributed to amino amides. Preservative-free amino amides, including lidocaine, are appropriate for use in patients who have reactions to drug preparations containing methylparabens unless the patient is specifically sensitive to lidocaine. If the patient with a history of allergic reaction to a particular anesthetic requires a local anesthetic, a paraben preservative-free drug from the opposite class can be chosen because there is no cross-reactivity between the amides and esters.

Methemoglobinemia

Methemoglobinemia is a frequent adverse effect of topical and oropharyngeal benzocaine and is occasionally reported with lidocaine, tetracaine, or prilocaine use. Most reports of methemoglobinemia associated with local anesthetics are the result of an excessive dose or a break in the normal mucosal barrier for topical anesthetics (Chap. 124).

Benzocaine is initially metabolized to aniline and then further metabolized to phenylhydroxylamine and nitrobenzene, which are both potent oxidizing agents (Chap. 124). Although reports describe methemoglobinemia resulting from standard doses of benzocaine topical oropharyngeal spray given for laryngoscopy or gastrointestinal upper endoscopy, affected patients commonly have abnormal mucosal integrity as occurs with thrush or mucositis.^38,98 Prilocaine is an amino ester local anesthetic primarily used in obstetric anesthesia because of its rapid onset of action and low systemic toxicity in both the mother and fetus. Use of large doses of prilocaine lead to the development of methemoglobinemia.^59,82 An aniline derivative, prilocaine undergoes hepatic metabolism to produce ortho-toluidine, another oxidizing agent.⁵⁹ A direct relationship exists between the amount of epidural prilocaine administered and the incidence of methemoglobinemia. A dose greater than approximately 8 mg/kg is generally necessary to produce effects and symptoms, which are often not apparent until several hours after epidural administration of the drug. Lidocaine–prilocaine cream, often used in the outpatient setting for minor dermal procedures, is associated with significant methemoglobinemia, more commonly in children than in adults.⁵³ Standard doses of lidocaine–prilocaine cream used for circumcision in term neonates are associated with minimal production of methemoglobin, but risks may be increased in neonates with metabolic disorders.¹²⁹ The diagnosis of methemoglobinemia is suggested by cyanosis unresponsive to oxygen in individuals with normal cardiopulmonary examinations and known oxidant exposure and presence of chocolate brown blood. It is confirmed by direct measurement of methemoglobin with a cooximeter. When clinically indicated, we recommend treating affected patients with symptomatic methemoglobinemia with IV methylene blue (Chap. 124 and Antidotes in Depth: A43).

Local Anesthetic Systemic Toxicity

Systemic toxicity for all local anesthetics correlates with serum concentrations. Factors that determine the concentration include dose; rate of administration; site of injection (absorption occurs more rapidly and completely from vascular areas, such as with neck and intercostal blocks); the presence or absence of a vasoconstrictor; and the degree of tissue–protein binding, fat solubility, and pK_a of the local anesthetic.⁹⁷ The brain and heart are the primary target organs for systemic toxicity because of their rich perfusion, moderate tissue–blood partition coefficients, lack of diffusion limitations, and presence of cells that rely on voltage-gated sodium channels to produce an action potential.

Recommendations for maximal local anesthetic doses designed to minimize the risk for systemic toxic reactions were developed but remain controversial.¹²⁷ These maximal recommended doses aim to prevent infiltration of excessive drug. However, because most episodes of systemic toxicity from local anesthetics, with the exception of methemoglobinemia from topical drug, occur secondary to unintentional intravascular injection rather than from overdosage, limiting the maximal dose will not prevent most toxic systemic reactions.¹²³

Toxicity is also related to the metabolism of a given local anesthetic. The rapidity of elimination from the plasma influences the total dose delivered to the CNS or heart. The amino esters are rapidly hydrolyzed in the plasma and eliminated, explaining their relatively low potential for systemic toxicity. The amino amides have a much greater potential for producing systemic toxicity because termination of the therapeutic effect of these drugs is achieved through redistribution and slower metabolic inactivation.⁴⁵ Another factor that creates difficulty in specifying the minimal toxic plasma concentration of lidocaine results from the fact that its N-dealkylated metabolites are pharmacologically active and monoethylglycylxylide has a prolonged half life (Chap. 57 and Fig. 57-3). Although these factors make it difficult to establish safe doses of local anesthetics, Table 64–2 summarizes the estimates of minimal toxic IV doses of various local anesthetics.

Central Nervous System Toxicity

Systemic toxicity in humans usually presents initially with CNS abnormalities. Intravenous infusion studies in volunteers demonstrate an inverse relationship between anesthetic potency and dose required to induce signs of CNS toxicity.¹²⁵ A similar relationship exists between the convulsive concentration and the relative anesthetic potency. In humans, seizures are reported at serum concentrations of approximately 2 to 4 mcg/mL for bupivacaine and etidocaine. Concentrations in excess of 10 mcg/mL are usually required for production of seizures when less potent drugs such as lidocaine are administered. Despite the strong relationship between local anesthetic potency and CNS toxicity, several other factors influence the CNS effects, including the rate of injection, drug interactions, and acid–base status.³²

The rapidity with which a particular serum concentration is achieved influences anesthetic toxicity. Volunteers tolerated an average dose of 236 mg of etidocaine and a serum concentration of 3 mcg/mL before onset of CNS effects and symptoms when the anesthetic was infused at a rate of 10 mg/min. However, when the infusion rate was increased to 20 mg/min, the same individuals only tolerated an average of 161 mg which produced a serum concentration of approximately 2 mcg/mL.¹²⁴

Both metabolic and respiratory acidoses increase local anesthetic induced CNS toxicity. Acidemia decreases plasma protein binding, increasing the amount of free drug available for CNS diffusion despite promoting the charged form of the amine group. The convulsive threshold of various local anesthetics is inversely related to arterial PCO₂.^34,41,42 Hypercarbia lowers the seizure threshold by several mechanisms: (1) increased cerebral blood flow, which increases drug delivery to the CNS; (2) increased conversion of the drug base to the active cation in the presence of decreased intracellular pH; and (3) decreased plasma protein binding, which increases the amount of free drug available for diffusion into the brain.^19,34,41,42 In general, CNS depressants minimize the signs and symptoms of CNS excitation and increase the threshold for local anesthetic–induced seizures. Flumazenil increases the sensitivity of the CNS to the amino amide anesthetics.¹⁷

A gradually increasing serum lidocaine concentration usually produces a stereotypical pattern of signs and symptoms (Fig. 64–3). In an awake patient, the initial effects include tinnitus, lightheadedness, circumoral numbness, disorientation, confusion, auditory and visual disturbances, and lethargy. Subjective side effects occur at serum concentrations between 3 and 6 mcg/mL. Significant psychological effects of local anesthetics are also reported. Near-death experiences and delusions of actual death are described as specific symptoms of local anesthetic toxicity.⁸⁷ Thus, the appearance of psychological symptoms during administration of local anesthetics should not be disregarded as unrelated nervous reactions or effects of sedatives given as premedication but rather as a possible early sign of CNS toxicity.

Clinical signs, usually excitatory, then develop, and include shivering, tremors, and ultimately generalized tonic–clonic seizures.¹⁰⁶ Objective CNS toxicity usually is evident at lidocaine concentrations between 5 and 9 mcg/mL. Seizures typically occur at concentrations above 10 mcg/mL, with higher concentrations producing coma, apnea, and cardiovascular collapse. The excitatory phase has a wide range of intensity and duration, depending on the chemical properties of the local anesthetic. With the highly lipophilic, highly protein-bound local anesthetics, the excitement phase is brief and mild. Toxicity from large IV boluses of bupivacaine often present without CNS excitement, with bradycardia, cyanosis, and coma as the first signs.¹²⁰ Rapid intravascular injection of lidocaine produces a brief excitatory phase followed by generalized CNS depression with respiratory arrest. Seizures are reported after even small doses injected into the vertebral or carotid artery (as rarely occurs during stellate ganglion block).⁷² A relative overdose produces a slower onset of effects (usually within 5–15 minutes of drug injection), with irritability progressing to seizures.

The mechanism of the initial CNS excitation involves selective sodium channel blockade of cerebral cortical inhibitory pathways in the amygdala.^130,135 The resulting increase in unopposed excitatory activity leads to seizures. As the concentration increases further, both inhibitory and excitatory neurons are blocked, and generalized CNS depression ensues. Levobupivacaine causes increased neuronal excitation and neurotoxicity by inhibition of KCNQ2/3 channels, an effect reversed by the channel activator retigabine.²⁵

Cardiovascular Toxicity

Cardiovascular side effects are the most feared manifestations of local anesthetic toxicity. Shock and cardiovascular collapse are related to effects on vascular tone, inotropy, and dysrhythmias related to indirect CNS and direct cardiac and vascular effects of the local anesthetic. Animal studies and clinical observations clearly demonstrate that for most local anesthetics, CNS toxicity develops at significantly lower serum concentrations than those needed to produce cardiac toxicity. With the exception of bupivacaine, local anesthetics have a high cardiovascular: CNS toxicity ratio.^{72,100,101,120}

Some of the discrepancy between the incidence of CNS and cardiac toxicity result from a detection bias. Not only can the treating physicians fail to recognize cardiac effects because of preoccupation with CNS manifestations of toxicity, but early cardiac toxicity is often quite subtle. An experimental study attempting to identify early warning signs of bupivacaine-induced cardiac toxicity in pigs evaluated bupivacaine induced changes in cardiac output, heart rate, blood pressure, and electrocardiogram (ECG).¹⁰⁸ A 40% reduction in cardiac output was not associated with significant change in heart rate or blood pressure, the latter secondary to a direct vasoconstrictive effect of bupivacaine at the concentrations produced.²³ If cardiac toxicity develops, management is exceedingly difficult.

Changes in systemic vascular tone induced by local anesthetics are mediated by direct effect on vascular smooth muscle or indirectly via effects on spinal cord sympathetic outflow. Predictably, sympathetic blockade after spinal anesthesia or epidural anesthesia above the T5 dermatome results in peripheral venodilation and arterial dilation. Shock results when high doses of anesthetic are used in hypovolemic patients. Local anesthetics have a biphasic effect on peripheral vascular smooth muscle. Whereas lower doses produce direct vasoconstriction, higher doses are associated with severe cardiovascular toxicity and cause vasodilation, contributing to cardiovascular collapse.

All local anesthetics directly produce a dose dependent decrease in cardiac contractility, with the effects roughly proportional to their peripheral anesthetic effect. Although the classic anesthetic action of sodium channel blockade in heart muscle accounts in large part for the negative inotropy by affecting excitation–contraction coupling, it does not explain the entire difference in myocardial depression produced by different anesthetics.³⁶ Poorly understood effects on calcium handling or effects of the intracellular drug directly on contractile proteins or mitochondrial function underlie these effects.^36,43 Bupivacaine impairs regulation of glucose homeostasis through inhibition of protein kinase B (Akt) and activation of 5′-adenosine monophosphate activated protein kinase (AMPK) activities: interacts with peripheral δ- and κ-opioid receptors; and inhibits myosin phosphatase target subunit I (MYPTI), protein kinase C (PKC), and phosphorylation-dependent inhibitory protein of myosin phosphatase (CPI-17).^27,109

Blockade of the fast sodium channels of cardiac myocytes decreases maximum upstroke velocity (V_max) of the action potential (Chaps. 15 and 16 and Fig. 15–2). This effect slows impulse conduction in the sinoatrial and atrioventricular (AV) nodes, the His-Purkinje system, and atrial and ventricular muscle.²⁸ These changes are reflected on ECG by increases in PR interval and QRS complex duration. At progressively higher anesthetic concentrations, hypotension, sinus arrest with junctional rhythm, and eventually cardiac arrest occur.⁵ Asystole is described in patients who received unintentional IV bolus injections of 800 to 1,000 mg of lidocaine.^5,44 Cardiovascular toxicity of local anesthetics usually occurs after a sudden increase in serum concentration, as in unintentional intravascular injection. Cardiovascular toxicity is rare in other circumstances because high serum concentrations are necessary to produce this effect and because CNS toxicity precedes cardiovascular events, providing a warning. Cardiac toxicity usually is not observed with lidocaine use in humans until the serum lidocaine concentration greatly exceeds 10 mcg/mL unless the patient is also receiving xenobiotics that depress sinus and AV nodal conduction such as calcium channel blockers, β-adrenergic antagonists, or cardioactive steroids. Intravascular lidocaine injection used to diminish pain associated with IV propofol injection was associated with episodes of bradycardia (heart rate <30 beats/min) and sinus arrest in a 69-year-old man later diagnosed with sick sinus syndrome.⁶⁹

Animal studies compared the dose or serum concentrations of local anesthetics required to produce irreversible circulatory collapse with those necessary to produce seizures.^33,100,101 The cardiovascular collapse:CNS toxicity (CC:CNS) ratio for lidocaine is approximately 7; therefore, CNS toxicity should become evident well before potentially cardiotoxic concentrations are reached. In contrast, bupivacaine is significantly more cardiotoxic than most other local anesthetics commonly used, with a CC:CNS ratio of 3:7. Inadvertent intravascular injection produces near simultaneous signs of CNS and cardiovascular toxicity. Bupivacaine produces myocardial depression out of proportion to its anesthetic potency and, more importantly, causes refractory ventricular dysrhythmias.¹²² The enhanced cardiovascular toxicity of bupivacaine relates to enhanced CNS effects at cardiovascular centers, direct effects on myocyte metabolism, and important differences related to sodium channel blockade.¹³² Although lidocaine and bupivacaine both block sodium channels in the open or inactivated states, lidocaine quickly dissociates from the channel at diastolic potentials, allowing rapid recovery from block during diastole (known as fast on–fast off kinetics). Therefore, sodium channel blockade with lidocaine is much more pronounced at rapid heart rates (accounting for the antidysrhythmic effects for ventricular tachycardia).⁸⁶ In contrast, at high concentrations, bupivacaine rapidly binds to and slowly dissociates from sodium channels (fast on–slow off kinetics), with significant block accumulating at all physiologic heart rates.²⁸ Accordingly, at heart rates of 60 to 150 beats/min, approximately 70 times more lidocaine is needed than bupivacaine to produce an equal effect on V_max of the action potential. Enhanced conduction block in Purkinje fibers and ventricular muscle cells sets up a reentrant circuit responsible for the ventricular tachydysrhythmias induced by bupivacaine.⁹³

Bupivacaine is problematic both in terms of having the highest potential for cardiovascular toxicity and for the refractoriness of its toxicity to conventional therapy. Bupivacaine has an asymmetrically substituted carbon, and the kinetics of sodium channel binding are stereospecific.⁷⁵ The S (levo)-enantiomer levobupivacaine is significantly less cardiotoxic than the R (dextro)-enantiomer despite having similar anesthetic properties.^7,91 Consequently, bupivacaine, the racemic mixture of both enantiomers, is more cardiotoxic than levobupivacaine, which contains only the levo-enantiomer.⁵² The stereospecific effect on sodium channels seems to differ between the heart and the peripheral nerves because the local anesthetic potency of levobupivacaine is the same as, or perhaps even greater than, that of bupivacaine.^39,104 Ropivacaine is a pure enantiomer and is less cardiotoxic than bupivacaine, but it is also slightly less potent as an anesthetic.^112,113

Effects other than sodium channel blockade contribute to cardiotoxicity. Lipophilic local anesthetics such as bupivacaine directly impair mitochondrial energy transduction via two mechanisms: (1) uncoupling of oxygen consumption and adenosine triphosphate (ATP) synthesis and (2) inhibition of complex I in the respiratory chain.¹²² These effects are related to the lipophilic properties of the drug rather than to stereospecific effects on ion channels. Lidocaine has no effect on mitochondrial respiration, and ropivacaine has less effect than bupivacaine.¹⁴² There is no difference between the two bupivacaine enantiomers. These effects occur with higher concentrations of the local anesthetic, as occur after unintentional intravascular injection.

Low-dose bupivacaine-induced cardiotoxic effects are described in humans under certain circumstances and at concentrations that are not associated with seizures in pigs.^68,140 Severe cardiac toxicity is described after injection of a small subcutaneous dose of bupivacaine in a patient with secondary carnitine deficiency.¹⁴⁰ Myocytes are highly dependent on oxidation of free fatty acids for energy. Interference with this mechanism via bupivacaine-induced inhibition of carnitine–acylcarnitine translocase contributes to the cardiotoxicity of lipophilic local anesthetics (Chap. 48, Fig. 48–3, and Antidotes in Depth: A10).¹⁴¹ Bupivacaine produce dysrhythmias by blocking GABAergic neurons that tonically inhibit the autonomic nervous system.⁵⁹ In addition to its other effects on the heart, bupivacaine induces a marked decrease in cardiac contractility by altering Ca²⁺ release from sarcoplasmic reticulum.⁸⁴

In a large series of patients receiving bupivacaine, systemic toxicity occurred in only 15 of 11,080 nerve blocks.⁹⁶ Of these patients, 80% manifested seizures; the other 20% had milder symptoms. Bupivacaine use, particularly at 0.75% concentration, is associated with severe cardiovascular depression, ventricular dysrhythmias, and even death.¹¹⁶ Pregnant women were disproportionately affected. Some of these patients required prolonged resuscitation, and restoration of adequate spontaneous circulation proved exceedingly difficult.¹¹⁶ In 1983, 49 incidents of cardiac arrest or ventricular tachycardia occurring over a 10-year period were presented to the FDA Anesthetic and Life Support Advisory Committee. Among these cases, 0.75% bupivacaine was used in 27 obstetric patients with 10 deaths, and 0.5% bupivacaine was used in 8 obstetric patients with 6 deaths. Among the 14 nonobstetric patients, 5 died. The overall mortality rate was 43% (21 of 49). Partly as a result of these reports, in 1984, the FDA withdrew approval of bupivacaine 0.75% for use as obstetric anesthesia.¹¹⁶

Acid–base and electrolyte status influence the cardiac toxicity of a given drug because all depressant properties are potentiated by acidosis, hypoxia, or hypercarbia.¹⁶ Table 64–3 outlines the spectrum of acute local anesthetic reactions.

DIAGNOSTIC TESTING

In cases of possible local anesthetic toxicity, the patient should be attached to continuous cardiac monitoring, and an ECG should be obtained to detect dysrhythmias and conduction disturbances. Serum electrolytes, blood urea nitrogen, creatinine, and blood gas analysis should be obtained to help assess the cause of cardiac dysrhythmias. Cooximetry should be obtained in patients in whom methemoglobinemia is suspected clinically. Rapid, sensitive assays are available for measuring concentrations of lidocaine and its monoethylglycinexylidide (MEGX) metabolite. When properly interpreted, the results of these assays are used to prevent lidocaine toxicity and to identify lidocaine toxicity in the nontherapeutic setting (Chap. 57, Fig. 57-3). Assays for determining serum concentrations of other local anesthetics are not routinely available. Treatment should never be delayed while waiting for results of xenobiotic concentration determinations.

TREATMENT

If toxicity results from ingestion of liquid medications, it is reasonable to give oral activated charcoal within 1 to 2 hours of ingestion, provided airway protective reflexes are intact. Contaminated mucous membranes should be washed off. Neither hemodialysis nor hemoperfusion has proven utility.

Treatment of Local Anesthetic Central Nervous System Toxicity

At the first sign of possible CNS toxicity, administration of the drug must be discontinued. One hundred percent oxygen should be supplied immediately, and ventilation should be supported if necessary. Patients with minor symptoms usually do not require treatment, provided adequate respiratory and cardiovascular functions are maintained. The patient must be followed closely so that progression to more severe effects can be detected.

Although most seizures caused by local anesthetics are self-limited, they should be treated quickly because the hypoxia and acidemia produced by prolonged seizures increase both CNS and cardiovascular toxicity.^99,101 Intubation is not mandatory, and the decision to intubate must be individualized. Maintaining adequate ventilation is of proven value. Modest hyperventilation extracorporeal life support (ECLS) is reasonable to produce respiratory alkalemia. By decreasing CNS extraction of drug, lowering extracellular potassium, and hyperpolarizing the neuronal cell membrane, normalizing (lowering) PCO₂ decreases the affinity for, or accelerates separation of, the local anesthetic from the sodium channel. Ultra-short-acting barbiturates and benzodiazepines are recommended for treatment of local anesthetic–induced seizures, but either of these medication groups can also exacerbate circulatory and respiratory depression.^32,94 Propofol 1 mg/kg IV was as effective as thiopental 2 mg/kg IV in stopping bupivacaine induced seizures in rats and was used successfully in a patient with uncontrolled muscle twitching secondary to local anesthetic toxicity.^13,55 However, propofol causes significant bradydysrhythmias and even asystole, especially when used with other xenobiotics that cause bradycardia. Based on currently available data, benzodiazepines are recommended as the first-line treatment for local anesthetic CNS toxicity. Neuromuscular blockers are proposed as adjunctive treatment for local anesthetic–induced seizures. They block muscular activity, decreasing oxygen demand and lactic acid production. However, neuromuscular blockers should never be used to treat seizures per se because they have no anticonvulsant effect and can make clinical diagnosis of ongoing seizures problematic by abolishing muscle contractions. To avoid this potentially lethal complication, chemical paralysis should be used only to facilitate endotracheal intubation if needed, unless continuous electroencephalography is also used. If used, short-acting neuromuscular blockers are desirable, facilitating subsequent repeated neurologic assessments. Succinylcholine is not routinely recommended because of significant side effects, including hyperkalemia and dysrhythmias. Given less potential for adverse cardiac effects, nondepolarizing neuromuscular blockers such as rocuronium are preferentially recommended (Chap. 66).

When severe systemic toxicity occurs, the cardiovascular system must be monitored closely because cardiovascular depression often goes unnoticed while seizures are being treated. Because local anesthetic–induced myocardial depression occurs even with preserved blood pressure, it is important to be aware of early signs of cardiac toxicity, including ECG changes.

Treatment of Local Anesthetic Cardiovascular Toxicity

Treatment of cardiovascular toxicity is complicated by the complex effects of local anesthetics on the heart. Initial therapy should focus on correcting the physiologic derangements that potentiate the cardiac toxicity of local anesthetics, including hypoxemia, acidemia, and hyperkalemia.^16,119 Prompt support of ventilation and circulation limits hypoxia and acidemia. Early recognition of potential cardiac toxicity is critical to achieving a good outcome because patients with cardiac toxicity that goes unrecognized for any interval are more difficult to resuscitate.⁹ If a potentially massive intravascular local anesthetic injection is suspected, maximizing oxygenation of the patient before cardiovascular collapse occurs is critical.

Standard Advanced Cardiac Life Support (ACLS) protocols should be followed when dealing with most local anesthetic cardiac toxicity. Bupivacaine-induced dysrhythmias often are refractory to cardioversion, defibrillation, and pharmacologic treatment. Lidocaine, phenytoin, magnesium, bretylium, amiodarone, calcium channel blockers, and combined therapy with clonidine and dobutamine were all used in animal models with variable results.^37,88,90 Lidocaine competes with bupivacaine for cardiac sodium channels and at high doses may displace it. Anecdotal reports suggest that lidocaine has occasionally helped in this application.³¹ However, concern exists about additive CNS effects when lidocaine is used to treat bupivacaine cardiac toxicity, and its use in this manner cannot be routinely recommended.

With toxicity from the longer acting, highly lipid-soluble, protein-bound amide local anesthetics (bupivacaine and etidocaine), if the patient does not respond promptly to therapy, cardiopulmonary resuscitation is expected to be difficult and prolonged (1–2 hours) before depression of the cardiac conduction system spontaneously reverses as a result of redistribution and metabolism of the drugs.^2,114 Vital organ perfusion is seriously compromised during CPR despite optimal chest compression. The significance of this problem increases with the duration of resuscitation; therefore, rapid initiation of is recommended when practical. Cardiopulmonary bypass resulted in successful outcomes in some cases of lidocaine and bupivacaine overdose.^47,81 Cardiopulmonary bypass provides circulatory support that is far superior to that provided by closed-chest cardiac massage. The improved perfusion prevents tissue hypoxia and the development of metabolic acidosis, which in turn decreases the binding of local anesthetics to myocardial sodium channel receptors. Hepatic blood flow is better maintained, enhancing local anesthetic metabolism, and increased myocardial blood flow helps redistribute local anesthetics out of the myocardium.⁸¹ Increasingly, ECLS using venoarterial extracorporeal membrane oxygenation (VA-ECMO) is being used in the management of critically ill overdose patients in both the emergency department and intensive care unit environments.³⁵

Atropine supplemented with electrical pacing is reasonable to treat bradycardia. Cardiac pacing was used successfully for treatment of cardiac arrest after unintentional administration of a 2-g bolus of lidocaine into a cardiopulmonary bypass circuit as the patient was being removed from bypass.¹⁰⁷ Pharmacologic therapy was unsuccessful, and resumption of bypass was necessary. Forty-five minutes after the injection, AV pacing restored perfusion and permitted discontinuation of bypass.

Use of sodium bicarbonate early in resuscitation to prevent acidemia-mediated potentiation of cardiac toxicity is reasonable.³¹ Although a canine model of bupivacaine-induced cardiotoxicity demonstrated utility of high dose insulin compared with saline or dextrose, its use cannot be routinely recommended at this time (Antidotes in Depth: A21).²⁶

Intravenous Lipid Emulsion

While investigating the relationship between lipid metabolism and bupivacaine toxicity, a rat study of bupivacaine induced asystolic arrest showed that pretreatment with IV lipid emulsion (ILE) increased the toxic dose of bupivacaine by 50%.¹⁴³ In addition, a dose of bupivacaine that was uniformly fatal in control rats resulted in universal survival in animals that also received fat emulsion.¹⁴³ Subsequent studies of local anesthetic toxicity demonstrated accelerated return of cardiac function and systemic vascular resistance after ILE both in isolated hearts and in intact animals.^{21,58,139,140}

Numerous case reports describe successful use of ILE (in various formulations) to treat patients (including pregnant and pediatric patients) in cardiac arrest after regional anesthesia with various local anesthetics, including bupivacaine, ropivacaine, and levobupivacaine (Antidotes in Depth: A23).^12,60

The most recent guidelines by the American Society of Regional Anesthesia and Pain Medicine (ASRA) suggest dosing for a patient in cardiac arrest is a 1.5-mL/kg bolus of 20% ILE over 1 minute while continuing chest compressions followed by continuous infusion of 0.25 mL/kg/min.¹⁰⁵ For persistent cardiovascular collapse, it is reasonable to repeat the bolus once or twice and double the infusion rate. If there is evidence of recovery, it is reasonable to continue the infusion for at least 10 minutes after stability. After initiating standard ACLS protocols, including ensuring adequate oxygenation and ventilation, we recommend that ILE be given as soon as possible after signs of significant local anesthetic toxicity become manifest (Antidotes in Depth: A23).¹⁴³ Initiation of VA-ECMO in association with ILE use is associated with fat deposition in the VA-ECMO circuit and increased blood clot formation within the circuit.⁷⁴ However, given that ILE administration can be accomplished more readily than initiation of VA-ECMO, it is reasonable to administer ILE to the severely intoxicated patient even if the patient eventually is transitioned to VA-ECMO.

Prevention of Systemic Toxicity of Local Anesthetics

Despite the development of new, relatively less toxic amino amide local anesthetics such as levobupivacaine and ropivacaine, severe CNS and cardiovascular effects remain a risk. Several cases of ropivacaine-induced cardiac arrest are reported.^24,70 In these cases, patients with both asystolic arrest and ventricular fibrillation–associated arrest were successfully resuscitated. Nonetheless, it is clear that prevention is more prudent and effective than treatment of toxicity. The keys to prevention are to use the lowest possible anesthetic concentration and volume consistent with effective anesthesia and to avoid a significant intravascular injection. The latter is accomplished by ensuring extravascular placement demonstrated repetitively by ultrasonographic guidance and by careful, slow aspiration of a needle or catheter before injection; injection of a small test dose of anesthetic mixed with epinephrine to assess a cardiovascular response if injection is intravascular; and use of slow, fractional dosing of large-volume injections with vigilance for early signs of CNS and cardiac toxicity.

SUMMARY

• Local anesthetics are frequently used xenobiotics that provide surgical analgesia and acute and chronic pain relief.

• The analgesic effect of local anesthetics is primarily caused by inhibition of neural conductance secondary to sodium channel blockade.

• Systemic toxicity, which primarily affects the heart and brain, is also largely related to sodium channel blockade.

• Severe systemic toxicity usually occurs secondary to inadvertent intravascular injection.

• If cardiovascular collapse and cardiac arrest occur, especially in the setting of bupivacaine toxicity, resuscitation is difficult and prolonged. In addition to standard ACLS protocols emphasizing maintenance of oxygenation and ventilation, ILE is recommended.

• Cardiopulmonary bypass is useful because it provides cardiovascular support, limits exacerbating factors such as tissue hypoxia and acidemia, and improves hepatic blood flow, thereby increasing local anesthetic metabolism, but it is difficult to initiate in a timely manner. Although increasingly available, extracorporeal life support will be limited by the use of ILE, which has been noted to clog the VA-ECMO circuit.

Acknowledgment

Brian Kaufman, MD; Staffan Wahlander, MD; and David R. Schwartz, MD, contributed to this chapter in previous editions.

REFERENCES

INTRODUCTION

The use of intravenous lipid emulsion (ILE) as an antidote is best studied for the treatment of local anesthetic systemic toxicity. However, it is also used for the treatment of overdose from other lipophilic xenobiotics such as calcium channel blockers, cyclic antidepressants, insecticides, and β-adrenergic antagonists, among many others.

HISTORY

Lipid emulsion was used as one component of parenteral nutrition for more than 40 years and is also used as a diluent for intravenous (IV) drug delivery of highly lipophilic xenobiotics such as amphotericin and propofol. More recently, liposomal suspensions containing local anesthetics such as bupivacaine were formulated that slowly release xenobiotics to increase their duration of anesthetic effect.

Bupivacaine toxicity is uncommon and sometimes refractory to Advanced Cardiac Life Support measures (Chap. 64). In the setting of local anesthetic–induced cardiovascular collapse, fatalities occur. Previously, cardiopulmonary bypass was essentially the only effective treatment for these patients.⁴ Intravenous lipid emulsion (ILE) was initially evaluated in animal models of bupivacaine toxicity with some reported efficacy. Because of the success in animal models and the limitations of other therapies, ILE was attempted in humans with local anaesthetic toxicity. Multiple reports are published that suggest benefit.^34,41 Intravenous lipid emulsion was subsequently recommended by several anesthesia and medical toxicology specialty societies for the treatment of local anesthetic toxicity, especially bupivacaine.⁵⁶ The most commonly proposed mechanism of action is the entrapment of local anesthetic in the serum lipid phase thus, likely decreasing the amount of xenobiotic at the site of toxicity.

In 2008, the first case of nonlocal anaesthetic toxicity treated with ILE was published. After this report, ILE was evaluated in animal models of toxicity from a multitude of lipid-soluble xenobiotics. Based on these studies, ILE was used in many cases of human and animal clinical poisoning.⁴¹

PHARMACOLOGY

Chemistry and Preparation

Lipid emulsion is composed of two types of lipids, triglycerides and phospholipids. Triglycerides are hydrophobic molecules that are formed when three fatty acids are linked to one glycerol. The fatty acid chain lengths vary, producing different triglycerides. The primary triglycerides in lipid emulsions are linoleic, linolenic, oleic, palmitic, and stearic acids; their concentrations vary slightly in the different commercially available formulations. These long-chain triglycerides (12 or more carbons) are extracted from safflower oil or soybean oil (or both), depending on the brand.²⁵ Newer lipid emulsions containing long-chain triglycerides in addition to medium-chain triglycerides (6–12 carbons) are derived from coconut, olive, and fish oils, and their availability and cost vary.⁵¹

Phospholipids contain two fatty acids bound to glycerol and a phosphoric acid moiety that is located at the third hydroxyl group. Phospholipids are amphipathic; the nonpolar fatty acids are hydrophobic, and the polar phosphate head is hydrophilic. This imparts important pharmacologic properties to this carrier molecule, allowing it to solubilize nonpolar xenobiotics in aqueous serum.

The lipids are dispersed in the serum by forming an emulsion of small lipid droplets, in which the phospholipids form a layer around a triglyceride core. The hydrophobic fatty acid component of the phospholipid molecule is directed toward the triglycerides while the hydrophilic glycerol component is directed outward away from the triglyceride core. The presence of small amounts of glycerol, which is hydrophilic, allows the lipid droplets to be suspended as an emulsion in water and serum.

The lipid emulsion per se is a white, milky liquid. It is sterile and nonpyrogenic with an average pH of 8 (range, 6–9). Lipid emulsions are isoosmotic solutions (260–310 mOsm/L) made for parenteral use and thus are easily delivered through a peripheral or central vein⁴⁹ and intraosseously.¹⁶

Lipid emulsions have different globule sizes depending on their uses.¹³ Microemulsions containing droplet sizes less than 0.1 µm are used for drug delivery. Miniemulsions containing droplet sizes greater than 0.1 µm but less than 1.0 µm are used for parenteral nutrition and are the ones used off label in clinical toxicology. Droplet sizes in commercially available nutritional lipid emulsions range from 0.4 to 0.5 µm. Phospholipid emulsifiers such as egg phosphatide are added and prevent droplet coalescence. After IV administration, lipid emulsions are found in the serum as lipid droplets that resemble chylomicrons and turn the serum turbid or milky.¹⁰ Macroemulsions containing droplet sizes greater than 1.0 µm are used for chemoembolization. These macroemulsions contain chemotherapeutics that are delivered intraarterially directly into the tumor blood supply. The lipid droplets occlude the artery and slowly release the chemotherapeutic.

Related Lipid Formulations

Most case reports that support the treatment of local anesthetic toxicity with ILE use branded Intralipid or standard long-chain triglyceride mixtures. Other lipid emulsions, that contain mixtures of long-chain and medium-chain triglycerides, are also reportedly successful in clinical cases of poisoning.^29,81 However, formulations containing oleic acid are theoretically problematic at high doses because IV sodium oleate is used in animal models to induce acute respiratory distress syndrome (ARDS) and ingestion of sodium oleate was reported to produce severe respiratory distress.^58,68

Controversy exists as to whether or not lipid emulsions containing both long- and medium-chain triglyceride mixtures are more effective at partitioning xenobiotics than are long-chain trigycerides.⁴³ In one rodent model of bupivacaine toxicity, although the rate of return to spontaneous circulation was identical in both groups, asystole recurred 15 to 45 minutes after ILE administration, and serum and cardiac bupivacaine concentrations were lower in the group treated with the long-chain mixtures.⁴³ In human serum, a mixture of long- and medium-chain triglycerides increased the extraction of bupivacaine, ropivacaine, and mepivacaine compared with long-chain triglyceride mixtures alone.⁶⁶ However, in a rodent model of bupivacaine toxicity, long- and medium-chain mixtures were equally effective in reversing bupivacaine toxicity, but the long-chain mixture resulted in fewer recurrences of asystole and lower myocardial bupivacaine concentrations.⁴⁴

Mechanism of Action

The mechanisms of action of parenteral lipid emulsion in toxicology are not clearly understood. The three proposed mechanisms of action of ILE are modulation of intracellular metabolism; a lipid sink, sponge, or conduit mechanism; and activation of ion channels.

Modulation of Intracellular Metabolism

In experimental models of poisoning from xenobiotics that alter intracellular energy metabolism, toxicity was successfully treated with ILE, suggesting that repairing or circumventing this dysfunction is involved. Bupivacaine blocks carnitine-dependent mitochondrial lipid transport and inhibits adenosine triphosphatase (ATPase) synthetase in the electron transport chain.^9,85 Verapamil inhibits intracellular processing of fatty acids,^38,39 but it also inhibits insulin release and produces insulin resistance.³⁹ This reduces the consumption of free fatty acid during shock, perhaps caused by the high oxygen demand required of fatty acid oxidation.²⁶ The cyclic antidepressant amitriptyline depresses human myocardial contraction independent of an effect on conduction²⁹ and inhibits medium- and short-chain fatty acid metabolism.⁸¹ Propranolol changes intracellular energy from primarily fatty acid to carbohydrate-dependent metabolism.⁴⁶

Theoretically, the addition of excess fatty acids overcomes blocked or inhibited enzymes by mass action, providing energy to an energy “starved” heart, reversing toxicity. Some support for this mechanism comes from the ability of ILE to reverse myocardial depression resulting from myocardial ischemia.⁷⁶ In a canine model using 10 minutes of regional myocardial ischemia, treatment with ILE after ischemia resulted in improved systolic wall contraction. In the same canine model, pretreatment with oxfenicine, which blocks carnitine palmitoyltransferase-1, blocked the beneficial effect of lipid emulsion.³⁹ This finding suggests that the effects of ILE on myocardial contraction after ischemia are mediated by mitochondrial metabolism. However, other authors reported increased myocardial free fatty acid (FFA) uptake and increased oxygen consumption in dogs given an infusion of ILE without any change in left ventricular pressure, heart rate, or cardiac output.⁵³ Moreover, in a human septic shock model studying the various substrates used by the myocardium, the contribution of FFAs as a myocardial energy source was markedly diminished (12% versus 54% in the control group), but that of lactate was increased (36% versus 12%). The observed shift in myocardial substrate extraction was associated with a discrepancy between measured myocardial oxygen consumption: 41% of myocardial oxygen consumption was not explained by the utilization of commonly available substrates extracted from coronary circulation.¹² This raises the question as to whether or not an exogenous source of FFAs such as provided by lipid emulsion, is actually useful in a xenobiotic induced shock state.

Unfortunately, there is limited experimental evidence to support a modulation of intracellular energy metabolism as the mechanism of action of the ILE. Some evidence comes from experimental studies in bupivacaine toxicity. In an isolated rat heart model of bupivacaine-induced cardiotoxicity, doses of lipid emulsion in the perfusate that were thought to be too low to significantly decrease bupivacaine concentrations reversed bupivacaine-induced cardiac dysfunction.⁷³ Similarly, in an in vivo model of bupivacaine-induced toxicity rodents pretreated with a single dose of a fatty acid oxidation inhibitor (CVT-4325) were unable to be rescued by ILE, suggesting that lipid emulsion works by providing energy in the form of FFAs.⁶⁰ Although these results suggest that lipid emulsion works by a mechanism other than binding bupivacaine and suggest a metabolic effect, other studies support the theory that lipid emulsion works by a nonmetabolic mechanism. In one study, verapamil toxicity was induced in rodents that were pretreated with the fatty acid oxidation inhibitor oxfenicine or control solution. Both groups were then resuscitated with ILE.² There were no significant differences in survival time and mean arterial pressure between the oxfenicine-treated and control groups. Analogous to some models of bupivacaine toxicity, this study suggests that in verapamil toxicity, ILE works by a mechanism other than mitochondrial energy supply.

Lipid Sink, Sponge, or Conduit Mechanism

This mechanism theorizes that lipid emulsion “soaks up” lipid-soluble xenobiotic, removing it from the site of toxicity. In a variation of this proposed mechanism, ILE sequesters the xenobiotic out of the aqueous plasma, which bathes the tissue, and within a nonaqueous part of the plasma that is not in contact with the site of toxicity. Intravenous lipid emulsion is also thought to alter the distribution of lipid-soluble xenobiotics and redistribute them away from the site of toxicity into an area with high lipid content (ie, create a “lipid conduit”). Some experimental support comes from studies of bupivacaine toxicity.

Stronger evidence for the lipid sink or sponge mechanism is seen in the effect of lipid emulsion on the pharmacokinetics and tissue distribution of bupivacaine in rats. Lipid emulsion decreased the distribution of bupivacaine into tissue, resulting in decreased concentrations in the brain and myocardium.⁶⁹ Similarly, in a pharmacokinetic study of clomipramine toxicity, after infusion of lipid emulsion into the peritoneal cavity, concentrations of clomipramine increased and volume of distribution decreased in addition to an increase in blood pressure.²⁷ In a pharmacokinetic study of amiodarone toxicity, ILE pretreatment resulted in higher concentrations of amiodarone and higher blood pressures compared with pretreatment with saline.⁵⁷ In a well-perfused swine model, ILE decreased amitriptyline concentrations in the brain by 25% and decreased the heart-to-plasma amitriptyline ratio.²⁹ In a successful resuscitation from bupropion overdose, bupropion concentrations increased dramatically after ILE administration.⁷⁷ Concentrations also increased after successful treatment of verapamil.¹⁸ These findings in experimental models and case reports are used to support the lipid sink or sponge model, in which ILE removes a xenobiotic away from the compartment of toxicity, although the increased concentrations is also explained by an increased perfusion of tissues and release of the drug.

Additional indirect evidence supports the lipid sink or sponge and a nonmetabolic mechanism. Although the myocardium can utilize fatty acids for metabolism, the central nervous system (CNS) does not use fatty acids to a substantial degree, implying that the reversal of sedation results from xenobiotic removal from the CNS as opposed to an altered metabolism. This reversal of CNS effects was demonstrated in two animal models of thiopental sedation,^8,67 but in another animal model of thiopental anesthesia, ILE increased the CNS effects. These findings are also used to support the lipid sink or sponge mechanism because in this model, it was proposed that the lipid emulsion maintained a high serum thiopental concentration, permitting subsequent thiopental diffusion into the CNS.³⁷

The degree of lipid solubility of a xenobiotic is measured using the partition coefficients log P or log D. Both measure the xenobiotic distribution between a lipophilic organic phase (usually octanol) and a polar aqueous phase (usually water) and report the logarithm of the ratio of concentration of the xenobiotic between the two phases. Whereas log P measures the partition of the nonionized form of the xenobiotic between the two phases, log D measures the partition of both the nonionized and the ionized form of the xenobiotic and varies based on pH. Whereas log P is reported across a range of often unspecified pH values, the log D at pH of 7 is considered by the editors of this text as an acceptable evaluation of lipid solubility in normal plasma. Conditions that vary the lipid solubility are likely clinically important because they will alter the amount of xenobiotic partitioning into the serum lipid. In an in vitro model, the distribution of bupivacaine and ropivacaine in lipid emulsion decreased at lower pH.⁴⁸

Activation of Ion Channels

Lipid emulsion was also hypothesized to activate either or both Ca²⁺ and Na⁺ channels. Linolenic and stearic acids decreased bupivacaine-induced Na⁺ channel blockade in an experimental model of human embryonic kidney cell expression of human cardiac Na⁺ channels bathed in lipid emulsion.⁵⁴ Fatty acids directly activated myocardial Ca²⁺ channels and induced a dose-dependent increase in the Ca²⁺ current, promoting dysrhythmias. Oleic, linoleic, and linolenic acids act directly on the Ca²⁺ channel to increase Ca²⁺ current.³¹ None of these studies are representative of the administration of ILE in humans or animals, and the amount of ILE used in this setting cannot be converted to a meaningful dosing regimen.

Mechanism of Action: Conclusion

Despite the lack of definitive studies on mechanisms of action, the lipid sink, conduit, and sponge model is the most compelling because beneficial effects from ILE are most frequently noted for lipid-soluble xenobiotics independent of their mechanisms of toxicity.¹⁹ Multiple consequential mechanisms of action may exist, and depending on the xenobiotic, the mechanisms of action likely vary and are multifactorial.

Pharmacokinetics

Lipid droplets that are smaller than 1 µm are primarily removed from circulation as they move through the capillaries of adipose and hepatic tissue. The capillary endothelium in these tissues contains lipoprotein lipase, which hydrolyzes triglycerides, releasing fatty acids and glycerol that then diffuses into the cells. Fatty acids enter the cardiac myocyte either by passive diffusion or protein-mediated transport.⁷²

The half-life of intravenously administered lipid emulsion is 30 to 60 minutes and can vary substantially depending on the patient’s clinical status, lipid emulsion dose, and droplet size.¹⁷ More than 2.5 g of lipid/kg/d (12.5 mL/kg of 20% ILE or 875 mL in a 70-kg person) overwhelms lipoprotein lipase activity, resulting in decreased clearance.⁵⁹ Mean droplet sizes vary across lipid emulsion formulations and the number of fat globules per milliliter of lipid emulsion solution are affected by the time to expiration date, storage temperature, and possibly plastic bag versus glass containers.¹³ Larger droplet sizes have slower clearances and are removed by reticuloendothelial phagocytosis. Solutions containing larger than recommended droplets are considered unstable and increase the risk of triglyceride accumulation in various target organs. These larger droplets are more likely to induce an inflammatory response, obstruct the microvasculature, and produce capillary fat emboli. The liver is the organ most commonly involved in accumulation of larger lipid emulsion droplets.¹³

Pharmacodynamics

When inside the cells, fatty acids are used as energy or resynthesized into triglycerides and stored. For use as energy, triglycerides are transported into the mitochondria by carnitine palmitoyltransferase, where they undergo β oxidation sequentially releasing acetylcoenzyme A (acetyl-CoA) as the fatty acid chain is reduced in length. These acetyl-CoA molecules enter the citric acid cycle, where they ultimately generate adenosine triphosphate (ATP) (Figs. 11–3 and 11–9). Although glucose, lactate, and fatty acid metabolism all are used in the production of acetyl-CoA, fatty acid metabolism produces the largest amount of energy. For example, whereas 1 mole of glucose produces 36 moles of ATP, 1 mole of stearic acid produces 146 moles of ATPs;⁸⁶ the metabolism of longer fatty acid chains may produce even more ATP.

ROLE IN LOCAL ANESTHETIC TOXICITY

The swine model appropriateness to evaluate lipid resuscitation therapy was questioned. Certain species of swine develop complement activation-related pseudoallergy (CARPA), an acute hypersensitivity reaction to liposomes. Complement activation-related pseudoallergy is characterized by mottling, hypoxia, and cardiovascular instability, which might compromise ILE resuscitation. This was thought to explain the incongruous effect of ILE in these swine models and hypotension when ILE is administered in some swine models.^29,83 However, subsequent adequately powered studies reported no difference in the hemodynamic parameters of swine treated with ILE and a veterinary literature review on the use of ILE in pets does not mention this rare pseudoallergy as a contraindication.^11,24

Based on the experimental evidence in bupivacaine toxicity, ILE was reportedly successfully used in several reported human cases of cardiovascular collapse from local anesthetic overdose. The first human case occurred after the inadvertent IV administration of bupivacaine and mepivacaine during an interscalene block.⁶⁴ The patient developed cardiac arrest and was treated with cardiopulmonary resuscitation (CPR) and Advanced Cardiac Life Support (ACLS) for 20 minutes but only had return of spontaneous circulation after administration of the first dose of ILE (100 mL of 20% ILE followed by 0.5 mL/kg/min for 2 hours). Of note, cardiac catheterization revealed total occlusion of the right coronary artery, and the patient was discharged with an implantable cardiac defibrillator.

In addition to its use during resuscitation, ILE was used to treat milder clinical scenarios of local anesthetic toxicity such as altered consciousness and cardiac dysrhythmias without loss of pulse. A recent review of 76 human case reports documented using ILE for resuscitation for local anesthetic toxicity, and the majority report some improvement, especially with bupivacaine toxicity.³⁴ The nature of the clinical findings as well as the dose and the duration of ILE administration reported were heterogenous. The absence of a control group and publication bias inherent to case reporting remains significant confounders in interpretation.³⁴ A randomized trial with healthy volunteers and subtoxic doses of local anesthetics given to reach the threshold of early neurotoxicity gave 120 mL of ILE 20% and could not find a difference between its groups.¹⁵ Another study used 1.5 mL/kg of 20% ILE in pretreatment for a dose of 1 mL/kg of lidocaine and found no difference in the lipid phase entrapment of lidocaine or in patient electroencephalographic patterns.³⁰

For local anesthetic poisoning, earlier recommendations limited use of ILE to situations after the failure of standard resuscitative measures. As a result of the experimental evidence and many successful case reports, some authors recommend adding ILE at the first signs of local anesthetic toxicity, but others suggest using it only in the setting of cardiovascular collapse. In the latter setting, ILE should be used concomitantly with CPR and ACLS, and high doses of epinephrine should be avoided.⁸⁴

We recommend administering ILE when there is rapid progression of bupivacaine toxicity affecting the CNS (agitation, confusion, seizures) or cardiovascular system (hypertension, tachycardia, ventricular dysrhythmias, hypotension, conduction blocks). In the setting of cardiovascular collapse, ILE is recommended with CPR and standard ACLS. Lipid emulsion should be stored for easy and rapid access in operating rooms or in areas where local anesthetics are frequently used.

ROLE IN NON–LOCAL ANESTHETIC TOXICITY

After the experience with bupivacaine toxicity, ILE was evaluated for toxicity of calcium channel blockers, cyclic antidepressant, β-adrenergic antagonists, organic phosphorus compounds, amiodarone, cocaine, and many other xenobiotics, with conflicting results.⁴¹

Based on some positive experimental evidence, ILE use was expanded to non–local anesthetic toxicity. Intravenous lipid emulsion was successfully used to resuscitate a 17-year-old patient with prolonged cardiovascular collapse after bupropion and lamotrigine overdose. In this case, the patient experienced seizures and received ACLS and CPR for 70 minutes, with return of spontaneous circulation after ILE administration (a bolus of 100 mL of 20%). Asystole recurred 90 minutes after ILE administration and resolved with epinephrine.⁷⁰

To date, the latest and most exhaustive systematic review⁴¹ found more than 159 case reports, 137 of which are in humans, three low-quality randomized control trials.^20,36,42,74 and one observational study of ILE for resuscitation in non–local anesthetic toxicity.²⁰

The first randomized trial explored the efficacy of 10 mL/kg of 10% ILE on 30 patients with various sedative-hypnotic poisonings. The trial unfortunately suffers from serious methodological flaws in the authors’ selection bias, lack of blinding, and outcome measurement in which the statistically significant outcome represents a change of 1 point on the pre- and postintubation Glasgow Coma Scale.⁷⁴ The other two studies on tricyclic antidepressant overdoses did not show a difference in mortality rate.³⁶ An isoflurane study gave 2 mL/kg of 30% ILE to patients receiving anesthesia for various procedures. It reported a benefit of 4 and 5 minutes in time to eye opening and time to exit of the operating room, respectively, between the groups but no difference on time to extubation.⁴² Other case studies report improvement with varied amounts of ILE for poisonings with diverse amounts of amlodipine, diltiazem, verapamil, atenolol, nebivolol, propranolol, carvedilol, flecainide, haloperidol, amitriptyline, dosulepin, doxepin, imipramine, quetiapine, venlafaxine, carbamazepine, lamotrigine, phenobarbital, diphenhydramine, bupropion, hydroxychloroquine, cocaine, and bromadiolone.

Subsequently, the largest case series of ILE was published reporting an overall survival rate of 69% in 25 of 36 patients poisoned with various non–local anesthetics such as calcium channel blockers and β-adrenergic antagonists (10 of 36), cyclic antidepressant (5 of 36), or bupropion (3 of 36).⁵² This study failed to demonstrate a meaningful increase in mean arterial pressure (MAP) a priori defined as a sustained increase of 10 mm Hg for 1 hour even in the survivor-only group. Wide variability in the dosing regimen, total lipid emulsion amount, and additional treatment received was noted. Despite successful reports, data on the efficacy of ILE are severely limited by reporting biases, therapeutic effects resulting from additional coadministered therapies, and coingestant xenobiotic toxicity. A study on fatality cases of the US National Poison Database system from 2006 to 2016 reported more than 450 cases of unsuccessful use of ILE for various overdoses, attesting to the fact that this therapy requires controlled studies to determine its effectiveness and adverse effect profile when used for poisonings.^71a

The Lipid Emulsion Workgroup, composed of representative of all major toxicology associations, published evidence-based recommendations in which ILE was recommended for cardiac arrest from bupivacaine toxicity and after failure of other modalities in amitriptyline, bupropion, and toxicity from other local anesthetics. The workgroup could not find evidence to recommend ILE in other situations because of a lack of data or balance between risks and possible benefits.²¹ Based on the current data available from animal models and clinical case reports, the Lipid Emulsion Workgroup published recommendations that ILE is a reasonable consideration in cardiac arrest from bupivacaine toxicity and serious hemodynamic instability from a bupropion, amitriptyline, and other local anaesthetics after conventional treatments failed.²¹ However, given the lack of data, which yield overall neutral opinions from the Lipid Emulsion workgroup, the authors of this textbook provide the following recommendation pending new available evidence. Lipid emulsion can be administered for patients with hemodynamic instability refractory to standard resuscitation measures when the risk-to-benefit ratio of interaction with other pharmacological or specific antidotal therapies or extracorporeal life support (ECLS) measures such as extracorporeal membrane oxygenation (ECMO) is carefully evaluated. Thus it is reasonable that lipid emulsion be used in the setting of severe toxicity (prolonged cardiovascular instability with nonperfusion or poor perfusion caused by hypotension, or dysrhythmias or seizures) resulting from a lipid soluble xenobiotic(s) despite maximal treatment with standard resuscitation measures even if the current available evidence for the efficacy of this therapy is of very low grade. Standard antidotal therapy and resuscitative measures are shown to be superior or equivalent to lipid emulsion and should not be abandoned in a rush to administer ILE.

ADVERSE EFFECTS AND SAFETY ISSUES

The adverse effects attributed to ILE administration are infrequently reported in the poisoning literature.⁷ A systematic review evaluated all possible adverse effects with ILE given for parenteral nutrition or poisoning up to 14 days. Potential complications of ILE include acute kidney injury, cardiac arrest, ventilation perfusion mismatch, ARDS, venous thromboembolism, hypersensitivity, fat embolism, fat overload syndrome, pancreatitis, extracorporeal circulation machine circuit obstruction, allergic reaction, and increased susceptibility to infection.²⁸

Because of the limited number of case reports, complications or toxicity from ILE at dosages exceeding the daily recommended amount for parenteral nutrition remains a concern. Pulmonary toxicity is reported when ILE is used as a source of parenteral nutrition. In patients with ARDS, 500 mL of 20% ILE administered over 8 hours resulted in increased pulmonary artery pressures, pulmonary shunting, increased pulmonary vascular resistance, and decreased partial pressures of oxygen in the alveoli/fraction of inspired oxygen ratio (PAO₂/FIO₂).⁷⁹ Similar results were found in patients with ARDS administered 500 mL of 10% ILE over 4 hours, resulting in an increase in pulmonary shunting and a decrease in the fraction of PAO₂/FIO₂.³⁵ The pulmonary effect of ILE in ARDS may be related to infusion rate. In patients with ARDS, 500 mL of 20% ILE infused over 5 hours resulted in an increase in pulmonary pressures, but a slower infusion over 10 hours left pulmonary pressures unchanged.⁴⁷

In these studies, when pulmonary effects occurred, they were mild and resolved after the ILE infusion was stopped or within 3 to 4 hours. Larger doses may result in clinically significant toxicity and more prolonged effects. However, studies using lipid emulsions with medium-chain triglycerides have shown less pulmonary toxicity.^17,71

Intravenous lipid emulsion causes pulmonary toxicity by at least two mechanisms. Intravenous lipid emulsion may occlude the pulmonary vasculature with microfat emboli. Macrophages containing lipid droplets are demonstrated in the bronchioalveolar lavage fluid of ARDS patients treated with ILE.⁴⁰ Experimental evidence also suggests that a substantial amount of the high concentrations of linoleic acid in ILE is converted to arachidonic acid and then into vasoactive prostaglandins. Indomethacin, an inhibitor of prostaglandin synthesis, prevented any pulmonary vascular effect caused by ILE in one sheep model.⁵⁰

Elevated triglycerides and pancreatitis are reported when ILE is used for parenteral nutrition. The precise mechanism of ILE-induced pancreatitis is unknown but may be the result from the large concentration of triglycerides forming large lipid droplets that obstruct the small vessels of the pancreas, leading to ischemia. Lipase then degrades the triglycerides, releasing cytotoxic FFAs. Laboratory assays differ in how they measure triglycerides.

Hyperamylasemia and pancreatitis were reported in two cases of ILE use in treatment of xenobiotic toxicity. After successful resuscitation with ILE from bupivacaine-induced cardiac arrest, an elevated amylase concentration without associated elevated lipase or associated symptoms was reported.⁷⁷ Elevated lipase concentrations were reported after administering ILE to a 13-year-old girl who developed delayed seizures and cardiac arrest after amitriptyline ingestion. Lipase concentrations peaked at 1,849 IU/L 5 days after ILE and were associated with elevated triglycerides and abdominal pain.⁴⁰

Large doses or rapid infusions of ILE have the potential to induce a fat overload syndrome. Fat overload syndrome is characterized by hyperlipemia, fever, fat infiltration, hepatomegaly, jaundice, splenomegaly, anemia, leukopenia, thrombocytopenia, coagulation disturbances, seizures, and coma. Multiple end-organ dysfunction is attributed to inadequate clearance of lipids and sludging in the lungs, brain, kidney, retina, and liver. Because of the rapid redistribution of most local anesthetics, prolonged ILE infusion should not be required (Chap. 64). However, many other lipid-soluble xenobiotics have a long duration of toxicity, and prolonged and repeated ILE infusions, if given, increase the risk of fat overload syndrome.

Particularly when administered early in the clinical course of an oral overdose, ILE has the potential to increase gastrointestinal absorption or facilitate distribution of lipid-soluble xenobiotics, resulting in increased toxicity. In an orogastric model of amitriptyline and verapamil overdose, ILE increased amitriptyline concentrations and resultant toxicity.^62,63 Gastric decontamination should be performed under these circumstances.

Intravenous lipid emulsions also have the potential to interact with other essential antidotes and especially epinephrine and vasopressin.^5,31,33 If an antidote is lipid soluble, it may be incorporated by the ILE and result in decreased effectiveness. Intravenous lipid emulsion was also used with several other medications during resuscitation for toxicity, including atropine, amiodarone, sodium bicarbonate, magnesium sulfate, calcium chloride, naloxone, and metaraminol.^6,37,65,80

The addition of ILE to high dose insulin (HDI) therapy was evaluated in a model of severe verapamil toxicity, and there were no improvements in hemodynamics, metabolic parameters, or survival.³ Also, ILE did not improve hypotension in a swine model of amitriptyline-induced toxicity⁷⁸ Therefore, although other resuscitative xenobiotics should be used as indicated, there is no evidence yet to support or refute the simultaneous use of ILE and bicarbonate or HDI therapy.

Hyperlipidemia after using ILE interferes with many laboratory studies, making them uninterpretable.²³ This interference lasts for several hours and is dependent in part on the type of laboratory system used. Intravenous lipid emulsion variably alters analytical test results and results in erroneous measurement, no significant effect, or the inability to perform a laboratory test. In vitro testing of ILE demonstrated that colorimetric methods were more prone to the effects of ILE than potentiometric methods. In the setting of ILE, glucose measurement by colorimetric method did not accurately report hypoglycemia. For example, a glucose concentration of 48.6 mg/dL (2.7 mmol/L) may be falsely reported as 223.2 mg/dL (12.4 mmol/L). Centrifugation at 140,000 g for 10 minutes minimized most interference. Troponin-I, sodium, potassium, chloride, calcium, bicarbonate, or urea assays had the least interference. Albumin and magnesium assays demonstrated significant interference. Amylase, lipase, phosphate, creatinine, total protein, alanine aminotransferase, creatine kinase, and bilirubin became unmeasurable.²² The effect of ILE on toxic drug concentrations assays is largely unknown. Ideally, analytic testing should be performed before ILE administration.²³

DOSING AND ADMINISTRATION

Although the optimal dosing regimen for human poisonings remains undefined, several animal models evaluate the effects of high-dose ILE. In both rodent and canine models of verapamil toxicity, 12.4- and 7-mL/kg boluses of 20% ILE were given,^3,75 and in a rabbit model of clomipramine, 12 mL/kg of 20% ILE was used.⁴⁹ In a small rodent model, the median lethal dose of ILE 20% was reported at 67 mL/kg,³² which is much higher than the current recommended clinical doses, but an LD₅₀ cannot be use to guide safety. In a model of IV verapamil toxicity in which ILE was administrated 5 minutes after the start of the verapamil infusion, higher doses up to a maximum of 18.6 mL/kg of 20% ILE were more effective in improving blood pressure, acidemia, and mean time survival than lower doses. Higher doses than 18.6 mL/kg improved hemodynamic parameters transiently but resulted in overall decreased survival times than the 18.6-mL/kg dose but twice the time than the 12.4-mL/kg dose.⁶¹ These animal models used large doses of xenobiotic and were designed to produce a rapid onset of toxicity; it is difficult to extrapolate their findings to typical human overdose cases. One controlled human study used as much as 10 mL/kg of 10% ILE with questionable clinical results and did not report on adverse effects.⁷⁴

Dosing was initially arbitrarily defined for local anesthetic toxicity, specifically bupivacaine, with generalization of this dosing regimen to poisoning by other local anesthetics and other xenobiotics. The American Society of Regional Anesthesia and Pain Management, the Association of Anesthetists of Great Britain and Ireland, and the American Heart Association⁵⁵ accepted similar guidelines and recommendations on the use of ILE in local anesthetic toxicity.

These societies recommend a dose of 1.5 mL/kg bolus of 20% ILE followed by 0.25 mL/kg/min or 15 mL/kg/h to run for 30 to 60 minutes.⁵⁵ They suggest repeating this bolus several times for persistent dysrhythmias and that the infusion rate can be increased if blood pressure decreases.

The precise dose of ILE for non–local anesthetics has not been studied, and it is not known if boluses or infusion are more effective. The reasonable safe total dose is also unknown but would depend on the degree of toxicity and response to previous doses of ILE.

The most common route of administration is IV either peripherally or via central catheters. The intraosseous route was also, albeit seldom, reported as successful.¹⁶

The American College of Medical Toxicology published interim guidance on the use of ILE in lipophilic xenobiotic toxicity.¹ When ILE is used, they recommend a bolus dose of 1.5 mL/kg of 20% ILE. They also recommend that repeat boluses of ILE can be administered for persistent severe symptoms and that that the bolus “may” be followed by an infusion for 30 to 60 minutes of 0.25 mL/kg/min or to a maximum total dose of 10 mL/kg. To date, no experimental, animal, or human clinical studies exist to inform on what benefit, if any, could be expected from any infusion of ILE. We agree on a maximum total dose of 10 mL/kg.

Propofol is formulated as a 10% lipid emulsion, but it is not recommended for use in ILE therapy because of the adverse effect of the propofol from the dose needed to achieve the doses of lipid typically used in ILE therapy.⁸² A 1.5-mL/kg bolus of 20% ILE equates to 3 mL/kg of the 10% lipid emulsion in the propofol solution. A normal dose of propofol (1%) for general anesthesia is 2.5 mg/kg or 0.25 mL/kg.⁶⁸ If propofol is used as a ILE therapy, it would deliver a bolus of 12 times the recommended dose of propofol. This would exacerbate any drug-induced hypotension and bradycardia and therefore is not recommended.

Pregnancy and Lactation

Intravenous lipid emulsion is a Pregnancy Category C pharmaceutical. It is not known whether ILE can cause fetal harm when administered to gravid patients. Few cases of ILE resuscitation have been published in pregnant patients.^14,45 Potentially, large doses can result in elevated triglyceride concentrations, and lipid globules may occlude placental vasculature. The risk of potential toxicity should be weighed against potential benefit to the pregnant woman and fetus. There is no reported risk of ILE on breastfeeding infants.

FORMULATION AND ACQUISITION

Lipid emulsion is available in parenteral formulation of 5%, 10%, 20%, and 30% solutions. The 20% solution is the formulation we recommend and the one used most often. The 30% solution is a pharmacy bulk admixture and is used to prepare dilute concentrations. The 30% solution should be diluted before administration and has not been used clinically for xenobiotic toxicity.

SUMMARY

• Lipid emulsion is recommended for the treatment of local anesthetic systemic toxicity, particularly bupivacaine, in the case of rapidly progressive toxicity or cardiac arrest.

• In local anesthetic systemic toxicity, a bolus of ILE is recommended if still needed after standard resuscitation medications and should be stored where local anesthetics are administered.

• Lipid emulsion use for other xenobiotics is only reasonable when severe toxicity resulting from a lipid-soluble xenobiotic persists despite maximal treatment with standard resuscitation measures.

• When used for either local anesthetic or non–local anesthetic toxicity, we recommend a bolus dose of 1.5 mL/kg of 20% ILE. Repeat boluses of ILE are reasonable for persistent severe signs and symptoms to a maximum total dose of 10 mL/kg.

• The IV route is preferred although in absence of IV access, the intraosseous route can be used.

REFERENCES

HISTORY AND EPIDEMIOLOGY

Paracelsus, a Swiss physician and alchemist, is credited with the earliest use of an inhalational anesthetic when he 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 began 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 had limited success, 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 while receiving chloroform administered 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 of these inhalational anesthetics 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. 27) and hepatotoxicity. Other halogenated hydrocarbons with improved clinical properties were introduced, including enflurane, isoflurane, desflurane, and sevoflurane (Fig. 65–1). The inert gas xenon holds promise as a useful anesthetic and is both cardio- and neuroprotective in experimental studies.⁴⁷ 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.

PHARMACOLOGY

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 are available as either volatile liquids (halothane, isoflurane, sevoflurane, and desflurane) or as compressed gases (nitrous oxide).

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. The most likely, but not yet proven, targets for the inhalational anesthetics are the ion channels that control ion flow across the cytoplasmic membrane.¹³ 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 are 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 is important 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 non-neural 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 with lipids and proteins within the hydrophobic regions of biologic membrane.

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 anesthetic and experimental demonstration of pressure reversal of anesthesia. Anesthetic potency correlates directly with the relative lipid solubility of each gaseous anesthetic, suggesting that the primary molecular actions occur in the lipid portion of cell membranes. This mechanism described by the Meyer-Overton lipid solubility theory.³⁷ Potential membrane regions for anesthetic action include the hydrophobic areas of proteins and protein–lipid interface regions, as well as the phospholipid matrix. High atmospheric pressures can reverse the effects of several anesthetics, suggesting that anesthesia results from increasing membrane volume at normal atmospheric pressure, an effect described by the volume expansion theory.³³

PHARMACOKINETICS

The route of exposure of inhaled anesthetics are the lungs. Factors that influence their absorption by blood and distribution to other tissues, particularly the brain, include anesthetic solubility, pulmonary pathology, lung and tissue blood flow, and tissue solubility. The goal of inhalational anesthesia is to develop and maintain a satisfactory partial pressure of anesthetic in the brain, the primary site of action.

The pharmacokinetics of anesthetics are linked to their pharmacodynamic effects through the concept of 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. The MAC is the alveolar concentration at 1 atm that prevents movement in 50% of participants in response to a painful stimulus (ie, it is the analgesic median effective concentration {EC₅₀}). Minimum alveolar concentration is used when comparing the effects of equipotent doses of anesthetics on various organ functions.

NITROUS OXIDE

Nitrous oxide (N₂O), a compresses gas, is the most commonly used inhalational anesthetic in the world, but its safety is debated.³⁰ 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 remarkably safe. Unfortunately, nitrous oxide also has a potential for abuse because of its euphoric effects, particularly among hospital and dental personnel.²⁹ 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 asphyxiation (Chap. 121).¹⁷

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 homemade mouthpieces failed to separate from the user after unconsciousness occurred during use.⁴⁶ Recreational abuse of nitrous oxide among teenagers and adults of all ages is on the rise. In 2015, the National Institute on Drug Abuse reported that 527,000 people aged 12 years or older reported using inhalants, and many of them used whippets. This is most assuredly an underestimate of true usage.

Death also 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 was reported after illicit preparation of nitrous oxide from the combustion of ammonium nitrate fertilizer.³⁶

Injury results 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 is 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 suppression 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.²⁸ 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 discontinuation of the anesthetic. 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 of exposure.⁴⁴ Critically ill patients appear to 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 vitamin B₁₂ deficiencies.³

The hematologic effects of exposure to nitrous oxide strongly resemble the biochemical characteristics of pernicious anemia.^2,42,43 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. 65–2). 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.⁴² 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.⁴³

Neurologic Effects

Disabling polyneuropathy in health care workers who habitually abused nitrous oxide was first described in 1978.²⁹ 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.⁴⁸ 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. Magnetic resonance imaging (MRI) findings typically show abnormal signal involving in the posterior and anterior spinal cord columns (Fig. 65–3).²⁴

Neurologic changes usually develop after several months of frequent exposure to nitrous oxide, although neurologic manifestations may develop within days of use in patients with subclinical vitamin B₁₂ 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.⁶ Animal studies demonstrate that methionine synthase is inactivated by exposure to greater than 1,000 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 underdiagnosed because the neurologic changes that occur in mild cases mimic other more common neurologic conditions.¹¹

Immunologic Effects

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. The ENIGMA trial evaluated patients undergoing major surgery comparing nitrous oxide–based and nitrous oxide–free anesthesia, and showed an increase in secondary outcomes including wound infection, pneumonia, and atelectasis.³⁸ However, ENIGMA-II, the follow-up trial with a much larger sample size of 7,112 patients, did not demonstrate any differences in any of the previous reported results.⁴⁰

Cardiovascular Effects

Concern over nitrous oxide and increased risk of cardiovascular complications is mostly theoretical. Nitrous oxide increases postoperative homocysteine concentrations and impairs endothelial function by inhibiting an enzyme that converts homocysteine to methionine.³⁹ Chronic homocysteinemia is associated with cardiovascular disease. Although the initial ENIGMA trial³⁸ showed an increase of long-term myocardial infarctions, the most recent ENIGMA-II, with a much larger sample size and a study design that specifically evaluated cardiovascular complications, did not demonstrate any difference (8% versus 8%; P = 0.64).⁴⁰

Treatment

General

Removal of the acutely affected person from the toxic environment should be the initial intervention in addition to ensuring adequate oxygenation and ventilation. 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

Acute overdose of nitrous oxide can lead to life-threatening hypoxia. Patients admitted with respiratory compromise should be administered supplemental oxygen and monitored for 24 hours. Supportive treatment such as intensive care unit (ICU) care and mechanical ventilation is warranted in the presence of severe respiratory failure.

The treatment regimen for the neurologic sequelae of vitamin B₁₂ deficiency from nitrous oxide toxicity includes parenteral vitamin B₁₂ and oral methionine. Vitamin B₁₂ is recommended in a manner similar to that used in the treatment of pernicious anemia by either (1) intramuscular injection of 1,000 mcg vitamin B₁₂ daily for 1 week followed by weekly injection of 1,000 mcg for 4 to 9 weeks and then monthly injection of 1,000 mcg until clinical resolution or (2) daily oral administration of 1,000 to 2,000 mcg of vitamin B₁₂ until clinical resolution.⁵⁰

Up to 20% of the population may have unrecognized vitamin B₁₂ deficiency from dietary restriction, malabsorption, or autoimmune gastritis, which is exacerbated when exposed to nitrous oxide.⁵⁰ It is worth noting that in some of the early case reports, before recognition of vitamin B₁₂ deficiency in nitrous oxide toxicity, many had improvement of symptoms simply after cessation. Methionine was also successfully used when vitamin B₁₂ treatment alone failed to improve neurologic effects. There is no guideline for dosing vitamin B₁₂ for patients with nitrous oxide toxicity, although case reports have used a 3-g daily oral regimen.⁵¹

The bone marrow abnormalities associated with nitrous oxide toxicity should be treated with a single 30-mg intravenous (IV) dose of folinic acid (Antidotes in Depth: A12).

HALOGENATED HYDROCARBONS

The volatile anesthetics which are liquids under standard conditions with a very high vapor pressure, were initially considered biochemically inert. Toxicity after administration was poorly explained. 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 mild elevated serum aminotransferase concentrations within a few days after anesthetic exposure. Recovery is usually complete.²⁵ In contrast, appearance of serum aminotransferase concentrations above 10 times the upper normal limits indicates a life-threatening hepatitis that occurs in approximately 1 in 10,000 exposed patients and produces fatal massive hepatic necrosis in 1 in 35,000 patients.⁴ Because the histologic findings of massive hepatocellular necrosis are indistinguishable from many of the causes of viral hepatitis,⁵⁵ differentiating halothane hepatitis from other causes of hepatitis in the postoperative period is difficult. Jaundice, which is common after anesthesia and surgery, can result from many factors such as preexisting liver disease, perioperative hypotension, blood transfusion, sepsis, or other causes of hepatitis. Thus, halothane hepatitis is a diagnosis of exclusion or inclusion based on the clinical history and time course.

Several studies report an association between multiple exposures to halothane and subsequent development of hepatitis.^48,54,59 In one study, 95% of cases of halothane hepatitis occurred after repeated exposures, 55% of which involve reexposure within 4 weeks.⁵⁹ Under these circumstances, hepatic dysfunction usually is more severe, and the latency before clinical presentation usually is shorter compared with the initial exposure.⁵⁴

Obesity is a risk factor commonly implicated in halothane ­hepatotoxicity.^1,56 Increased fat stores 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.²⁵ Genetic factors likely play an important role in some patients, as indicated by a case report of this syndrome in three pairs of related Mexican women.²³

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. 65–4). These volatile metabolites are free radicals, which directly produce acute hepatic toxicity by irreversibly binding to and destroying hepatocellular structures. Alternatively, by acting as haptens, they trigger an immune-mediated hypersensitivity response.^45,57 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.²⁵

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. Rare case reports of hepatitis are still reported with all anesthetics but at a much lower incidence compared to halothane. Cross-sensitivity may exist, such that prior exposure to one anesthetic triggers hepatotoxicity upon subsequent exposure to a different anesthetic.

Nephrotoxicity

The kidneys are at risk for toxicity from modern inhalational anesthetics. Methoxyflurane is an anesthetic that was introduced in 1962. By 1966, this anesthetic 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 surgery (Chap. 27).¹⁵ 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 3 of the 17 patients.¹⁵ Subsequent studies demonstrated that ­kidney toxicity was caused by inorganic fluoride released during biotransformation of methoxyflurane.⁵³ The risk of toxicity was highly correlated with both the total dose of methoxyflurane (concentration times duration) and the peak serum fluoride concentration.¹⁴ The nephrotoxic serum fluoride concentration is 50 to 60 µmol/L.¹⁴ 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 in 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 applicable 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 by defluorination, occasionally resulting in sufficient serum fluoride concentrations to produce transient decreases in urine-concentrating ability.²⁷ However, clinically ­evident renal impairment almost never occurs with use of sevoflurane.²⁰ 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,³² 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.^26,58 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 4,000 closely studied volunteers failed to demonstrate nephrotoxicity.³⁴ 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.¹⁸

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.^18,20,22 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.²² 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 compound A generation.

INHALATION ANESTHETIC–RELATED CARBON MONOXIDE POISONING

Pharmacology

Desflurane and isoflurane contain a difluoromethoxy moiety that can be degraded to carbon monoxide (CO). This process occasionally results in toxic exposure to patients. Carboxyhemoglobin levels as high as 36% were reported from intraoperative desflurane degradation.⁸ Although there was no evidence of patient harm in this case, morbidity or mortality could occur at this level in patients (Chap. 122). The true incidence of carbon monoxide exposure during clinical anesthesia is unknown. Routine detection of intraoperative carbon monoxide exposure is now possible using multiwavelength pulse cooximeters, but these devices are not widely adopted, and conventional pulse oximeters used in ORs cannot detect carbon monoxide (Chaps. 28 and 122).⁹

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, reducing its effectiveness at removing CO. Higher concentrations of carbon monoxide 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 if the anesthesia machine was not in use.¹⁹

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

Mass spectrometry (available in some ORs) cannot directly detect carbon monoxide because its molecular weight is equivalent to that of nitrogen, a gas usually present in much greater amounts. In addition, detection of carbon monoxide 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 carbon monoxide poisoning during anesthesia is difficult because the main clinical features of toxicity are masked by anesthesia, and no routinely available means can identify carbon monoxide within the breathing circuit or detect when the CO₂ absorbent is desiccated. Delayed neurologic sequelae from intraoperative carbon monoxide poisoning are typically missed on the anesthesiologist’s postoperative patient evaluation because the delayed manifestations may develop days following the procedure.⁶¹

The product label of desflurane and isoflurane advises that the CO₂ absorbent should be replaced when a practitioner suspects the absorbent is desiccated. However, this warning fails to account for the lack of a reliable method of actionable data to determine 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 ICUs for long-term sedation of patients receiving mechanical ventilation and more recently as part of the treatment for patients with refractory status epilepticus. Use is limited by concerns regarding atmospheric pollution, but also ambient ICU air, 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.³⁵

Clinical studies report the use of isoflurane and sevoflurane for ICU sedation. In one study, 19 patients were mechanically for more than 24 hours in the ICU with sevoflurane used for sedation.³⁵ Toxic effects of sevoflurane were not found even though serum fluoride concentrations often exceeded 50 µmol/L (the concentration suggested to be the nephrotoxic threshold).¹⁴

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.⁵ Psychomotor dysfunction occurred in 42% of patients aged 4 years or younger but in only 1.3% of patients older than 4 years.

Isoflurane is an alternate treatment for patients with refractory status epilepticus. Reversible MRI abnormalities developed in two patients who received inhaled isoflurane for a prolonged time (35 and 85 days).²¹ 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.

CHRONIC EXPOSURE TO WASTE ANESTHETIC GASES

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 the United States 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.¹²

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 with 15,000 dentists who did not.¹¹ 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.¹¹

ABUSE OF HALOGENATED VOLATILE ANESTHETICS

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, a volatile liquid, usually produces gastroenteritis with vomiting followed by depressed levels of consciousness, hypotension, hypothermia, shallow breathing, respiratory failure, and bradycardia with varying degrees of heart block and extrasystoles. A depressed level of consciousness is attributed to large amount halothane that is absorbed from gastric mucosa, which also causes systemic vasodilation resulting in hypotension and ­hypothermia.^16,60 The diagnosis should be suspected when these features occur in a patient with the sweet or fruity odor of halothane on the breath. If suspected, nasogastric lavage is recommended to remove the reminder of halothane that is still in the stomach. Case reports have used ice-cold saline for hourly gastric lavage with success. The gastric aspirate also smelled of halothane.⁶⁰ Supportive care, including mechanical ventilation, fluid and electrolyte resuscitation, inotropic support, electrolytes correction, antidysrhythmics, normothermia, and antibiotics, 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 unable to be resuscitated.⁷ A 16-year-old girl received an unintentional IV injection of 2.5 mL of halothane during anesthesia ­induction.⁵² 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 most likely results from a direct toxic effect of high concentrations of the hydrocarbon on the pulmonary vasculature. 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.⁴⁹ Inhalation of halothane produces a pleasurable sensation similar to that described with other inhaled hydrocarbons, such as the solvents in glue and paint (Chap. 81). 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.³¹

SUMMARY

• Inhalational anesthetics remain a popular choice for maintenance of anesthesia due to their safety profile and titratability. Toxicity is uncommon when properly administered and monitored.

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

• Nitrous oxide abuse, typically in the form of “whippets,” is common and can lead acutely to life-threatening hypoxia. It causes bone marrow suppression and disabling polyneuropathy with chronic abuse. Treatment is supportive in acute setting, and patients with long-term hematologic and neurologic sequelae are treated with vitamin B₁₂, methionine, and folinic acid.

• Halothane, an older halogenated hydrocarbon, is no longer used in North America but is still in widespread use around the world and is associated with fulminant hepatitis.

• Sevoflurane is associated with production of compound A, which can cause renal tubular necrosis; however, it is not shown to cause acute kidney injury in vivo.

• Abuse of halogenated volatile anesthetics is rare; treatment is supportive.

Acknowledgment

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

REFERENCES

HISTORY AND EPIDEMIOLOGY

Curare is the generic term for the resinous arrowhead poisons used to paralyze hunted animals.¹¹⁶ The curare alkaloids are derived from the bark of the Strychnos vine, and the most potent alkaloids, the toxiferines, are derived from Strychnos toxifera. Fortunately for the hunters who used curare, ingestion of their prey did not cause paralysis. Sir Walter Raleigh discovered the use of curare in Guyana in 1595, and he was the first person to bring curare to Europe. Curare played a pivotal role in the discovery of the mechanism of neuromuscular transmission. In 1844, Claude Bernard placed a small piece of dry curare under the skin of a live frog and observed that the frog became limp and died.⁸ He performed an immediate autopsy and discovered that the heart was beating. Because direct muscle stimulation produced contraction but nerve stimulation did not, Bernard concluded that curare paralyzed the motor nerves. He later observed, however, that bathing the isolated nerve did not affect neuromuscular transmission, leading him to conclude: “Curare must act on the terminal plates of motor nerves.”¹⁸ Curare was used by Nobel Laureate physiologists Charles Sherrington, John Eccles, and ­Bernard Katz to further elucidate neuromuscular physiology. Its first clinical use was described in 1878 when Hunter used curare to treat patients with tetanus and seizures.¹¹⁶ In 1932, Raynard West used curare to reduce the muscular rigidity of hemiplegia.¹¹⁶

Curare (d-tubocurarine) was introduced into clinical anesthesia in 1943 by Harold Griffith and Enid Johnson.⁴³ Endotracheal intubation during general anesthesia was not common those days, so d-tubocurarine was administered in a dose that spared the diaphragm and maintained spontaneous ventilation. It was not until 1954 when Henry Beecher found that patients receiving d-tubocurarine had a sixfold increase in respiratory-related anesthesia mortality that artificial ventilation and reversal of residual d-­tubocurarine became a routine practice.⁹ Use of d-tubocurarine spanned almost 40 years until it was replaced by superior nondepolarizing neuromuscular blockers that caused less histamine release and hypotension.

Around the same time in the 1950s that curare gained popularity in the operating room, succinylcholine also came to clinical use to facilitate orotracheal intubation.⁹ In the nonmedical world, succinylcholine carried a reputation of being the “person poison.”³ This came to media attention when a high-profile killing case involving an anesthesiologist Dr. Carl Coppolino and his mistress were accused of murdering his wife and the mistress’s husband in 1966 and 1967, respectively, by injecting succinylcholine.⁷⁷ In 1983, shortly after Dr. Michael Swango began his internship at Ohio State University ­Hospital, patients began dying inexplicably, and he was relieved of his duties.¹⁰⁹ Following switching residencies and jobs for 14 years, prosecutors secured Swango’s guilty plea for the murder of three victims. The toxicological analysis of the 7-year-old remains of Thomas Sammarco revealed succinylcholine in the liver and gallbladder and its metabolite succinylmonocholine in multiple organs, which assisted in the conviction.

With the advent of new modalities of drug delivery, toxicologists must be attuned to possible malicious intent. Emergency personnel responding to a 911 call observed the widow removing an insulin pump reservoir from her dead husband’s body with the stated intent to donate the costly equipment.⁵ A natural cause of death was presumed, yet surprisingly, forensic analysis revealed etomidate and laudanosine (a metabolite of atracurium) in the ­victim’s liver.

Understanding the pharmacokinetics and pharmacodynamics of the depolarizing and nondepolarizing neuromuscular blockers (NDNMBs) is critical to maximizing benefit while minimizing toxicity.

MECHANISM OF NEUROMUSCULAR TRANSMISSION AND BLOCK

The purpose of a NMB is to selectively and reversibly inhibit signal transmission at the skeletal neuromuscular junction (NMJ). All NMBs possess at least one positively charged quaternary ammonium moiety that binds to the postsynaptic nicotinic acetylcholine (nACh) receptor at the NMJ, inhibiting its normal activation by acetylcholine (ACh). The nACh receptor is a ligand-gated ion channel that consists of 4 different protein subunits in a pentameric structure surrounding a central channel. The nACh receptor found in human skeletal muscle is present in 2 primary forms: a mature type found at the NMJ (α1₂βεδ) or as a fetal (immature) type found on muscle at extrajunctional regions of the muscle fiber (α1₂βγδ). Figure 66–1 provides an overview normal neuromuscular transmission and excitation–­contraction coupling.

Skeletal muscle paralysis can occur by several mechanisms. For example, tetrodotoxin blocks voltage-sensitive sodium channels, preventing action potential conduction in the motor neuron (Chap. 39). On the other hand, botulinum toxin blocks ACh release from the presynaptic neuron by inhibiting the binding of ACh-containing vesicles to the neuronal membrane in the region of the synaptic cleft (Chap. 38). Modulation of postsynaptic ACh receptor activity at the NMJ may produce paralysis by one of two mechanisms: depolarizing (phase I block) and nondepolarizing (phase II block). Succinylcholine is the only depolarizing neuromuscular blocker (DNMB) in current clinical use. High doses of nicotine also cause a depolarizing block. All other drugs discussed are NDNMBs.

The process of DNMB requires several steps. First, two molecules of succinylcholine must bind to each α site of the nACh receptor. This action causes a prolonged open state of the nACh receptor ion channel. The initial depolarization generates a muscle action potential and usually causes brief contractions (fasciculations). In contrast to ACh, succinylcholine is not hydrolyzed efficiently by acetylcholinesterase (AChE) located in the synaptic cleft. Thus, the effect of succinylcholine lasts much longer than ACh. Succinylcholine persistence at the ACh receptor causes a sustained local muscle endplate depolarization that, in turn, causes the voltage-gated sodium channel in the perijunctional region to remain in a prolonged inactive state, inducing a desensitization block. The muscle is temporarily refractory to presynaptic release of further ACh (phase I block).

The NDNMBs cause skeletal muscle paralysis by competitively inhibiting the effects of ACh and thus preventing muscle depolarization. One molecule of an NDNMB bound to a single nACh receptor (also on the α site) is sufficient to competitively inhibit normal channel activation. Because the NDNMBs do not block voltage-gated sodium channels on the skeletal muscle membrane, direct electrical stimulation with a current sufficient to cause membrane depolarization will still elicit a muscular contraction. The NDNMBs are classified by duration of action as ultra-short, short, intermediate, and long. They are also classified by chemical structure as either a synthetic benzylisoquinolinium or an aminosteroid (Table 66–1).

The NDNMBs also block nACh receptors on the prejunctional nerve terminal and inhibit ACh-stimulated ACh production and release by blocking local autoregulation of available ACh.⁹⁸ This effect reduces the available pool of ACh and augments the extent of neuromuscular block.¹¹

PHARMACOKINETICS

The NMBs are highly water soluble and relatively insoluble in lipids. Thus, they are rapidly distributed in the extracellular space and very slowly permeate lipid membranes such as the gut, placenta, and the normal blood–brain barrier. For this reason, they are devoid of central nervous system (CNS) effects. Because these drugs distribute in the extracellular space, their dose is based on ideal body mass. Thus, in obese patients, estimation of drug requirement based on total body mass results in the administration of an excessive dose.

The speed of onset of an NMB is inversely related to its molar potency (ie, ED₉₅ expressed as moles NMB drug per kilogram body weight).^59,60 Stated differently, the greater the affinity of the NDNMB for the ACh receptor, the fewer molecules per kilogram of tissue are required to produce a given degree of ACh receptor occupancy. Atracurium is the only NDNMB that does not follow this generalization because it is a mixture of 10 isomers, each having a unique receptor affinity (cisatracurium consists of only one isomer).

In general, small, fast-contracting muscles such as the extraocular muscles are more susceptible to neuromuscular block than are larger, slower muscles such as the diaphragm. This is the so-called respiratory-sparing effect. After an intravenous (IV) bolus of NDNMB, paralysis of the diaphragm is coincident with paralysis of laryngeal muscles because high tissue perfusion results in rapid drug distribution and diffusion into the NMJ of all tissues.²⁵ However, recovery from NMB is fastest for the diaphragm and intercostal muscles; intermediate for the large muscles of the trunk and extremities; and slowest for the adductor pollicis, larynx, pharynx, and extraocular muscles.²⁵

COMPLICATIONS OF NEUROMUSCULAR BLOCKERS

Complications associated with the use of NMBs include (1) problems associated with the care of a paralyzed patient (eg, inability to secure a definitive airway, undetected hypoventilation resulting from ventilator or airway problems, impaired ability to monitor neurologic function, unintentional patient awareness, peripheral nerve injury, deep vein thrombosis, and skin breakdown); (2) immediate side effects; and (3) delayed effects occurring after prolonged drug exposure.^85,86

Consciousness

Even though NMBs do not affect consciousness, misconceptions about these drugs persist.⁷³ The pupillary light reflex, an important indicator of midbrain function, is preserved in healthy subjects who receive NDNMBs because pupillary function is mediated by muscarinic cholinergic receptors, for which the NMBs have no affinity.⁴²

Histamine Release

Neuromuscular blockers may elicit dose- and injection rate–related nonimmunologic (non–IgE-mediated) histamine release from tissue mast cells by an uncertain mechanism (Table 66–1). The NMBs most commonly associated with histamine release are atracurium and succinylcholine.⁸¹

Anaphylaxis

Anaphylactic reactions are rare, with an incidence of 1 in 3,500 to 1 in 20,000 and up to 60% are related to NMBs.⁸¹ Part of this variability is due to difficulty in determining the exact exposures in the operative setting when numerous xenobiotics and, blood products NMBs are administered simultaneously. Rocuronium and succinylcholine are the two most cited offenders among all NMB-associated anaphylaxis.^66,115

Control of Respiration

At subparalyzing doses, NDNMBs blunt the peripheral hypoxic ventilatory response (HVR) but not the ventilatory response to hypercapnia.^30,31 Hypoxic ventilatory response returns to normal when chemical paralysis is completely reversed. Hypoventilation resulting from blunting of the HVR, especially when combined with the residual effects of other xenobiotics used during anesthesia such as opioids or inhalational anesthetics, causes delayed respiratory failure after general anesthesia.

Autonomic Side Effects

Nicotinic ACh receptors found in autonomic ganglia, similar to those at the NMJ, are pentamers composed of α and β subunits. In general, they are less susceptible to block by NMBs.⁷⁴ There is one notable exception. At the same dose that produces neuromuscular block, tubocurarine also blocks nACh receptors at the parasympathetic ganglia, causing tachycardia, and at the sympathetic ganglia, blunting the sympathetic response.¹⁰² In combination with tubocurarine-related histamine release, the sympathetic block causes significant hypotension, particularly in patients with heart failure or hypovolemia.¹¹ This is an important reason why tubocurarine is no longer available in the United States.

The muscarinic receptors (M₁−M₅) are members of the seven-­transmembrane G-protein–coupled receptor family. As such, they are structurally unique and mostly unaffected by NMBs. At clinical doses, pancuronium elicits dose- and injection rate–related increases in heart rate, blood pressure, cardiac output, and sympathetic tone.^26,103,110 This is attributed to a selective block of parasympathetic transmission at the cardiac muscarinic receptors, an atropine-like effect,¹⁰³ block of presynaptic (feedback) muscarinic ­receptors at sympathetic nerve terminals, and perhaps an indirect norepinephrine-releasing effect at postganglionic fibers.²⁶

Dysrhythmias such as bradycardia, junctional rhythms, ventricular ­dysrhythmias, and asystole occur rarely after use of succinylcholine. ­Dysrhythmias most likely result from stimulation of the cardiac muscarinic receptors and can be prevented by pretreatment with 15 to 20 mcg/kg of IV atropine. Bradycardia is uncommon, but it may be especially severe in ­children during anesthetic induction when large or repeated doses of ­succinylcholine are given.

INTERACTIONS OF NEUROMUSCULAR BLOCKERS WITH OTHER XENOBIOTICS AND PATHOLOGIC CONDITIONS

The NMBs have significant interactions with many xenobiotics and coexisting medical conditions. These interactions affect the neuromuscular system at any level from the CNS to the muscle itself (Table 66–2).^94,114

In most neuromuscular diseases, such as muscular dystrophy, ­Guillain-Barré syndrome, myasthenia gravis, and postpolio syndrome, the sensitivity to NDNMB is increased, so a small dose of NMB produces a profound degree of block.^2,13,45 However, persons with myasthenia gravis typically demonstrate resistance to the effects of succinylcholine.^2,13 In individuals with myopathy in whom the specific cause is not yet known, succinylcholine should be avoided because of the possible sensitivity to malignant hyperthermia (MH), hyperkalemia, or rhabdomyolysis. In place of succinylcholine, a short-acting NDNMB can be used to lessen the chance of prolonged weakness.

Many pathologic conditions potentiate the duration or intensity of NDNMB, such as respiratory acidosis, hypokalemia, hypocalcemia, hypermagnesemia, hypophosphatemia, hypothermia, shock, and liver or kidney failure.⁹⁷ Alternatively, acute sepsis and inflammatory conditions are associated with mild resistance to the effect of NDNMB.⁸⁸

PHARMACOLOGY OF SUCCINYLCHOLINE

Succinylcholine is a bis-quaternary ammonium ion composed of two molecules of ACh joined end to end at the acetate groups.²⁸ After a conventional IV induction dose of 1 mg/kg, typical plasma concentrations are approximately 62 mcg/mL.⁹⁰

Succinylcholine is hydrolyzed primarily by plasma cholinesterase (PChE, also known as pseudocholinesterase or butyrylcholinesterase; BChE, EC 3.1.1.8) and to a slight extent by alkaline hydrolysis. Hydrolysis is a two-step reaction; first succinylmonocholine and choline are formed, and then succinic acid and choline are formed. The latter two are normal products of intermediary metabolism. The first reaction is approximately six times faster than the second reaction. Less than 3% of the administered dose is excreted unchanged in the urine.⁴⁰ After an IV bolus, the plasma succinylcholine concentration increases abruptly, and there is a rapid onset of NMJ block. Later, the plasma succinylcholine concentration undergoes a rapid decline as a result of drug redistribution to extravascular tissues and hydrolysis in plasma. Finally, succinylcholine leaves the NMJ to reenter the plasma as a result of reversal of the concentration gradient.^39,55

At an induction dose of 1 mg/kg IV, succinylcholine theoretically increases cerebral blood flow, cortical electrical activity, intracranial pressure (ICP),⁶¹ and intraocular pressure, but the clinical implication is unclear. Most data come from small nonrandomized studies involving ICP, and results are mixed. In addition, there has not been sufficient evidence that supports routine use of NDMBs as a pretreatment for succinylcholine.

TOXICITY OF SUCCINYLCHOLINE

The important adverse drug reactions associated with succinylcholine include anaphylaxis, prolonged drug effect, hyperkalemia, acute rhabdomyolysis in patients with muscular dystrophy, MH in susceptible patients, masseter spasms or trismus in patients with congenital myopathies, and cardiac dysrhythmias. This is especially relevant for children who present with undiagnosed or a cyclically subtle myopathy.

PROLONGED EFFECT

The effects of succinylcholine last for several hours if metabolism is significantly slowed because of decreased PChE concentration, abnormal PChE activity (genetic variant or drug inhibition), or a phase II block.²⁰ Acquired PChE deficiency is caused by hepatic disease, malnutrition, plasmapheresis, or pregnancy.²⁰ Inactivation of PChE results from fluoride poisoning, organic phosphorus compounds, or carbamates. However, even with only 20% to 30% of normal PChE activity, the clinical duration of succinylcholine is less than doubled.³⁵

Many genetic variants of PChE are known. The most common atypical PChE (atypical type, homozygous; incidence 1:3,000) can be assayed by its resistance to inhibition by the local anesthetic dibucaine.⁹⁵ A history of uneventful exposure to succinylcholine excludes the possibility of atypical PChE except in the case of hepatic transplantation. Dibucaine inhibits the ability of normal PChE to hydrolyze benzoylcholine by more than 70% (ie, dibucaine number >70), heterozygous atypical PChE by 40% to 60%, and homozygous atypical PChE by 30% or less. Dibucaine number is an effective method of identifying patients at increased risk for prolonged neuromuscular blockade from succinylcholine. The lower the number, the greater likelihood there will be prolonged neuromuscular blockade from atypical reasonable PChE activity. Fresh-frozen plasma or PChE concentrates are infused to hasten recovery in the case of a genetic enzyme defect or an acquired PChE deficiency. However, to avoid the risks of transfusion, it is best to provide supportive care, simply keep the patient sedated, intubated, and ventilated until the drug is metabolized. In this setting, spontaneous reversal usually occurs within 3 to 4 hours, although in rare cases, full recovery requires up to 12 hours.²⁰ When the duration of succinylcholine is very prolonged, blood samples should be drawn for measurement of PChE concentration and activity.

Prolonged nondepolarizing block also occurs when unusually large IV doses of succinylcholine (3–5 mg/kg) are given over minutes.⁶⁸ This is called phase II block, and it can be partially reversed by neostigmine.

Interestingly, pseudocholinesterase is also involved in metabolism of cocaine. Plasma cholinesterase catalyzes the hydrolysis of cocaine, and low PChE concentrations are associated with increased risk of cocaine toxicity.^24,51,92 There have been few small studies demonstrating that exogenously administered PChE degrades cocaine more quickly and is theoretically able to treat cocaine-induced toxicity.^16,75,78,105

HYPERKALEMIA

Succinylcholine 1 mg/kg IV typically causes a transient serum K⁺ concentration increase of approximately 0.5 mEq/L within minutes of administration both in normal individuals and in persons with kidney failure. The acute hyperkalemic response to succinylcholine is greatly exaggerated with coexisting myopathy or proliferation of extrajunctional muscle ACh receptors. However, the mortality rate is highest (approaching 30%) when rhabdomyolysis is present.⁴⁴ Severe, precipitous, potentially life-threatening hyperkalemia also occurs after succinylcholine administration in several conditions associated with proliferation of ACh receptors. These conditions include denervation caused by head or spinal cord injury, stroke, neuropathy, prolonged use of NDNMBs because of muscle pathology direct trauma, crush or compartment syndrome, or muscular dystrophy; critical illness due to hemorrhagic shock, neuropathy, myopathy, or prolonged immobility; thermal burn or cold injury; and sepsis lasting several days. After a neurologic injury, susceptibility to hyperkalemia begins within 4 to 7 days and persist for an extended period of time. In patients who have been in the intensive care unit (ICU) for more than 1 week, succinylcholine should be avoided altogether because of the risk of hyperkalemic cardiac arrest, which is associated with a mortality rate of at least 19%.^7,10,44 Severe hyperkalemia can be mitigated, but not prevented, by a small dose of an NDNMB (10%–30% ED₉₅ of the NDNMB or 5%–15% of the intubation dose). This dose should be sufficient to prevent succinylcholine-­induced muscle fasciculations.¹⁰⁶

Severe or even fatal hyperkalemia is reported in a few patients who received succinylcholine immediately after exsanguinating hemorrhage or massive trauma. The mechanism for this condition differs from that after neurologic injury because of inadequate time for proliferation of extrajunctional ACh receptors. Succinic acid, a tricarboxylic acid cycle intermediate that is also a metabolite of succinylcholine, facilitates activation of voltage-gated sodium channels in a dose-dependent fashion, increasing skeletal muscle excitability.⁴⁶ In hemorrhagic shock, accumulation of succinic acid as a result of cell breakdown and anaerobic metabolism possibly augments the potassium-releasing effect of succinylcholine.

RHABDOMYOLYSIS

Severe hyperkalemia rarely occurs in the absence of a clinical history that readily discloses an obvious risk factor, with one important exception. Acute or delayed onset of rhabdomyolysis, hyperkalemia, ventricular dysrhythmias, cardiac arrest, and death are reported in apparently healthy children who were subsequently found to have an undiagnosed myopathy.⁶⁴ Since March 1995, a black box warning on the package insert has stated that succinylcholine should be avoided in elective surgery in children, particularly in children younger than 8 years of age, because of the risk of a previously undiagnosed skeletal myopathy, especially Duchenne muscular dystrophy. Sudden cardiac arrest occurring immediately after succinylcholine administration should always be assumed to be caused by hyperkalemia. If fever, muscle rigidity, and elevated lactate concentration or metabolic and respiratory acidosis are also present, the presumptive diagnosis of MH should prompt immediate therapy with dantrolene.

MALIGNANT HYPERTHERMIA

Malignant hyperthermia is a syndrome characterized by extreme skeletal muscle hypermetabolism. It is most often initiated after exposure to an anesthetic that triggers a cycle of abnormal calcium release from the skeletal muscle sarcoplasmic reticulum and can have a variable presentation.¹⁰⁰ Malignant hyperthermia is observed in patients with underlying muscle diseases, such as muscular dystrophy and myotonia. It is also strongly linked to three rare genetic myopathies, central core disease, King Denborough syndrome, and multiminicore disease.

Although MH is linked with rare congenital myopathies, it typically affects individuals who are otherwise healthy.⁶³ It is inherited as an autosomal dominant trait with variable penetrance.⁷⁶ Triggering xenobiotics that can precipitate an attack of MH include succinylcholine and volatile inhalational anesthetics (the prototypical xenobiotic is halothane). In individuals considered MH susceptible, xenobiotics that can be administered safely include NDNMBs, nitrous oxide, propofol, ketamine, etomidate, benzodiazepines, barbiturates, opioids, and local anesthetics.

In human MH, there is a causal association with several unique defects involving a skeletal muscle receptor or regulatory protein, especially defects involving the voltage sensitive calcium release channel found in skeletal muscle; the type 1 ryanodine receptor (or RYR1, chromosome 19q13.1). Mutations of the RYR1 receptor are detected in 50% to 70% of patients with MH, and more than 200 different mutations are described^12,50 (Fig. 66–1). The structurally distinct type 2 ryanodine receptor (RYR2) is the primary type expressed in cardiac muscle, and this could explain why the myocardium is relatively spared in the early phase of MH (with the exception of an acute hyperdynamic response).⁹⁹ The existence of multiple mutations across multiple alleles means that genetic testing is not likely to prove useful in detecting all individuals who are MH susceptible or to exclude the risk of MH.

Although the prevalence of a genetic disorder associated with MH is between 1 in 3,000 and 1 in 8,500, the observed incidence of fulminant MH in patients exposed to general anesthesia when triggering anesthetic agents are used is 1 in 62,000 and 1 in 84,000.^93,100 Each year in the United States, there are an estimated 700 cases of MH.⁶² Even in those who are MH susceptible after exposure to anesthesia with known triggers, clinical manifestations develop less than half the time. For this reason, a previous uneventful anesthetic exposure does not preclude development of MH on a subsequent exposure.⁴ In the operating room, MH most often presents abruptly soon after initial exposure to a triggering anesthetic, although the onset of MH may be delayed several hours during the anesthesia⁸⁴ or occur as long as 12 hours after surgery. In addition, recrudescence of MH occurs within 24 to 36 hours after an initial episode in up to 25% of patients.

The immediate systemic manifestations of MH result from extreme skeletal muscle hypermetabolism. The uncontrolled release of calcium from the terminal cisternae of the sarcoplasmic reticulum causes skeletal muscle contraction. Although generalized muscular rigidity is a specific sign of MH, it is only observed in 40%; masseter spasm is a finding observed in 27% of MH patients.⁶³ Futile calcium cycling by sarcoplasmic Ca²⁺-ATPase rapidly depletes intracellular adenosine triphosphate and leads to anaerobic metabolism. Clinically, MH presents as skeletal muscle hypermetabolism with an increase in cardiac output and sinus tachycardia; increased CO₂ production causes hypercapnia; increased O₂ consumption can cause: mixed venous O₂ desaturation (below the normal value of 75%), arterial hypoxemia, anaerobic metabolism, metabolic acidosis, elevated lactate concentration, cyanosis, and skin mottling; and excess heat production that leads to a rapid increase in core temperature with hyperthermia.⁴⁷ Other clinical findings include tachycardia, cardiac dysrhythmias, hyperkalemia, rhabdomyolysis, and disseminated intravascular coagulopathy.

The earliest signs of MH include an early and rapid increase in CO₂ production, causing an increase in arterial, venous, and end-tidal CO₂, followed by or associated with tachycardia; tachypnea; hypertension or labile blood pressure; and skeletal and jaw muscle rigidity. Despite the name of the syndrome, hyperthermia is not a universal finding in MH, and moreover, it may be a late sign.¹¹³ Acute potassium release from skeletal muscle cells produce life-threatening hyperkalemia. Subsequent rhabdomyolysis exacerbates the elevation of potassium by causing acute kidney injury. In late-stage MH, cardiac decompensation results from hyperkalemia, heart failure, vascular collapse, or myocardial ischemia (especially with coexisting coronary artery disease).

The differential diagnosis of MH includes antipsychotic malignant syndrome, propofol infusion syndrome, serotonin toxicity, thyroid storm, pheochromocytoma, baclofen withdrawal, tetanus, meningitis, poisoning by salicylates, amphetamines, cocaine, or antimuscarinics, unintentional intraoperative hyperthermia, environmental heat stroke, and transfusion reactions (Chap. 29). Of note, early septic shock is also associated with hypermetabolism, increased cardiac output, and fever; however, in contrast to MH, early septic shock is associated with an elevated mixed venous O₂ saturation (typically >75%).

Rarely, MH is triggered by severe exercise in a hot climate, IV potassium (which depolarizes the muscle membrane), antipsychotics, or infection.^23,54 There is of a possible link between MH and exertional heat illness (EHI) or exertional rhabdomyolysis (eg, a patient with exertional rhabdomyolysis who at a later time develops MH).^14,15 There is no evidence that patients with heat-related illness have MH, even if, on occasion, some patients appear to improve following many interventions including dantrolene. Furthermore, a presumptive diagnosis of heat-related illness does not necessarily exclude the diagnosis of MH, and one must maintain clinical suspicion for possible MH, especially because environmental factors can be a sole precipitating factor in the absence of anesthetics.⁵⁰

One theory of the pathogenesis of MH suggests that MH-triggering xenobiotics interact with an abnormal RYR1 channel, causing it to stay in a prolonged open state and leading to rapid efflux of calcium from the skeletal muscle sarcoplasmic reticulum into the myoplasm. Succinylcholine prolongs muscle depolarization, leading to an elevated myoplasmic calcium concentration. This action initiates the voltage sensitive calcium release channel of the sarcoplasmic reticulum.⁴⁴ However, not all cases of MH can be explained by an RYR1 mutation.³⁶ For example, MH is also associated with defects in the CACNA1S protein that encodes a subunit of the skeletal muscle L-type calcium channel (known as the dihydropyridine receptor) and possibly with certain disorders of sodium channels (observed in the myotonic disorders).^36,83

The antidote for MH is dantrolene, and the key aspects of MH therapy are rapid initial diagnosis, discontinuation of triggering anesthetics, active cooling, and immediate therapy with dantrolene (within minutes). By partially blocking calcium release from skeletal muscle sarcoplasmic reticulum, ­dantrolene rapidly reverses the signs and symptoms of hypermetabolism (Antidotes in Depth: A24). The precise mechanism of dantrolene activity is not known, but it modulates several calcium pathways.⁵⁰ Before the introduction of dantrolene, the mortality rate of MH was 64%.⁶² When patients with acute MH are treated immediately with dantrolene, removal of triggering agents, and supportive measures (volume resuscitation, active cooling, control of hyperkalemia), the mortality rate is less than 5%.⁶² Factors associated with an increase in mortality rate are a muscular body habitus, development of disseminated intravascular coagulation, and a longer duration of anesthesia before the peak in end-tidal carbon dioxide.⁶² Even if administration is delayed for hours or days, dantrolene still improves survival after an acute episode of MH. Patients with significant dysrhythmias can be treated with standard antidysrhythmics; however, calcium channel blockers must not be given with dantrolene because they precipitate ­hyperkalemia and severe hypotension¹⁰¹ (Table 66–3).