Unique Pharmacological Characteristics
In contrast to there being only a single depolarizing muscle relaxant, there is a wide selection of nondepolarizing muscle relaxants (Tables 11–5 and 11–6). Based on their chemical structure, they can be classified as benzylisoquinolinium, steroidal, or other compounds. It is often said that choice of a particular drug depends on its unique characteristics, which are often related to its structure; however, for most patients, the differences among the intermediate-acting neuromuscular blockers are inconsequential. Steroidal compounds can be vagolytic, most notably with pancuronium but inconsequentially with vecuronium or rocuronium. Benzylisoquinolines tend to release histamine. Because of structural similarities, an allergic history to one muscle relaxant strongly suggests the possibility of allergic reactions to other muscle relaxants, particularly those in the same chemical class.
TABLE 11–5A summary of the pharmacology of nondepolarizing muscle relaxants. ||Download (.pdf) TABLE 11–5 A summary of the pharmacology of nondepolarizing muscle relaxants.
|Relaxant ||Chemical Structure1 ||Metabolism ||Primary Excretion ||Onset2 ||Duration3 ||Histamine Release4 ||Vagal Blockade5 |
|Atracurium ||B ||+++ ||Insignificant ||++ ||++ ||+ ||0 |
|Cisatracurium ||B ||+++ ||Insignificant ||++ ||++ ||0 ||0 |
|Pancuronium ||S ||+ ||Renal ||++ ||+++ ||0 ||++ |
|Vecuronium ||S ||+ ||Biliary ||++ ||++ ||0 ||0 |
|Rocuronium ||S ||Insignificant ||Biliary ||+++ ||++ ||0 ||+ |
|Gantacurium ||C ||+++ ||Insignificant ||+++ ||+ ||+ ||0 |
TABLE 11–6Clinical characteristics of nondepolarizing muscle relaxants. ||Download (.pdf) TABLE 11–6 Clinical characteristics of nondepolarizing muscle relaxants.
|Drug ||ED95 for Adductor Pollicis During Nitrous Oxide/Oxygen/Intravenous Anesthesia (mg/kg) ||Intubation Dose (mg/kg) ||Onset of Action for Intubating Dose (min) ||Duration of Intubating Dose (min) ||Maintenance Dosing by Boluses (mg/kg) ||Maintenance Dosing by Infusion (mcg/kg/min) |
|Succinylcholine ||0.5 ||1.0 ||0.5 ||5–10 ||0.15 ||2–15 mg/min |
|Gantacurium1 ||0.19 ||0.2 ||1–2 ||4–10 ||N/A ||— |
|Rocuronium ||0.3 ||0.8 ||1.5 ||35–75 ||0.15 ||9–12 |
|Mivacurium ||0.08 ||0.2 ||2.5–3.0 ||15–20 ||0.05 ||4–15 |
|Atracurium ||0.2 ||0.5 ||2.5–3.0 ||30–45 ||0.1 ||5–12 |
|Cisatracurium ||0.05 ||0.2 ||2.0–3.0 ||40–75 ||0.02 ||1–2 |
|Vecuronium ||0.05 ||0.12 ||2.0–3.0 ||45–90 ||0.01 ||1–2 |
|Pancuronium ||0.07 ||0.12 ||2.0–3.0 ||60–120 ||0.01 ||— |
A. Suitability for Intubation
None of the currently available nondepolarizing muscle relaxants equals succinylcholine’s rapid onset of action or short duration. However, the onset of nondepolarizing relaxants can be quickened by using either a larger dose or a priming dose. The ED95 of any drug is the effective dose of a drug in 95% of individuals. For neuromuscular blockers, one often specifies the dose that produces 95% twitch depression in 50% of individuals. One to two times the ED95 or twice the dose that produces 95% twitch depression is usually used for intubation. Although a larger intubating dose speeds onset, it prolongs the duration of blockade. The availability of sugammadex has largely eliminated this concern in regard to the steroidal nondepolarizing muscle relaxant, rocuronium (see Chapter 12).
Muscle groups vary in their sensitivity to muscle relaxants. For example, the laryngeal muscles—whose relaxation is important during intubation—recover from blockade more quickly than the adductor pollicis, which is commonly monitored by the peripheral nerve stimulator.
B. Suitability for Preventing Fasciculations
To prevent fasciculations and myalgias, 10% to 15% of a nondepolarizer intubating dose can be administered 5 min before succinylcholine. Similarly, priming with a small dose of a nondepolarizing relaxant (10% of the total dose) a few minutes before intubation can speed the onset of acceptable intubating conditions when followed by the remaining 90% of the drug to be administered. Dysphagia, diplopia, and patient distress will occasionally develop following administration of a priming or defasciculating dose of nondepolarizing muscle relaxants.
C. Maintenance Relaxation
Following intubation, muscle paralysis may need to be maintained to facilitate surgery, (eg, abdominal operations), to permit a reduced depth of anesthesia, or to control ventilation. There is great variability among patients in response to muscle relaxants. Monitoring neuromuscular function with a nerve stimulator helps to prevent over- and underdosing and to reduce the likelihood of serious residual muscle paralysis in the recovery room. Maintenance doses, whether by intermittent boluses or continuous infusion (Table 11–6), should be guided by the nerve stimulator and clinical signs (eg, spontaneous respiratory efforts or movement). In some instances, clinical signs may precede twitch recovery because of differing sensitivities to muscle relaxants between muscle groups or technical problems with the nerve stimulator. Some return of neuromuscular transmission should be evident prior to administering each maintenance dose, if the patient needs to resume spontaneous ventilation at the end of the anesthetic. When an infusion is used for maintenance, the rate should be adjusted at or just above the rate that allows some return of neuromuscular transmission so that drug effects can be monitored.
D. Potentiation by Inhalational Anesthetics
Volatile agents decrease nondepolarizer dosage requirements by at least 15%. The actual degree of this postsynaptic augmentation depends on the inhalational anesthetic (desflurane > sevoflurane > isoflurane > halothane > N2O/O2/narcotic > total intravenous anesthesia).
E. Potentiation by Other Nondepolarizers
Some combinations of different classes of nondepolarizers (eg, steroidal and benzylisoquinolinium) produce a greater than additive (synergistic) neuromuscular blockade.
F. Autonomic Side Effects
In clinical doses, the nondepolarizers differ in their relative effects on nicotinic and muscarinic cholinergic receptors. Previously used agents (eg, tubocurarine) blocked autonomic ganglia, reducing the ability of the sympathetic nervous system to increase heart contractility and rate in response to hypotension and other intraoperative stresses. In contrast, pancuronium blocks vagal muscarinic receptors in the sinoatrial node, resulting in tachycardia. All newer nondepolarizing relaxants, including atracurium, cisatracurium, mivacurium, vecuronium, and rocuronium, are devoid of significant autonomic effects in their recommended dosage ranges.
Histamine release from mast cells can result in bronchospasm, skin flushing, and hypotension from peripheral vasodilation. Atracurium and mivacurium are capable of triggering histamine release, particularly at higher doses. Slow injection rates and H1 and H2 antihistamine pretreatment ameliorate these side effects.
Only pancuronium, vecuronium, and rocuronium are metabolized to varying degrees by the liver. Active metabolites likely contribute to their clinical effect. Vecuronium and rocuronium depend heavily on biliary excretion. Clinically, liver failure prolongs blockade. Atracurium, cisatracurium, and mivacurium, although extensively metabolized, depend on extrahepatic mechanisms. Severe liver disease does not significantly affect clearance of atracurium or cisatracurium, but the associated decrease in pseudocholinesterase levels may slow the metabolism of mivacurium.
Pancuronium, vecuronium, and rocuronium are partially excreted by the kidneys. The duration of action or pancuronium and vecuronium is prolonged in patients with kidney failure. The elimination of atracurium and cisatracurium is independent of kidney function. The duration of action of rocuronium and mivacurium is not significantly affected by renal dysfunction.
General Pharmacological Characteristics
Some variables affect all nondepolarizing muscle relaxants.
Hypothermia prolongs blockade by decreasing metabolism (eg, mivacurium, atracurium, and cisatracurium) and delaying excretion (eg, pancuronium and vecuronium).
Respiratory acidosis potentiates the blockade of most nondepolarizing relaxants and antagonizes its reversal. This could prevent complete neuromuscular recovery in a hypoventilating postoperative patient. Conflicting findings regarding the neuromuscular effects of other acid–base changes may be due to coexisting alterations in extracellular pH, intracellular pH, electrolyte concentrations, or structural differences between drugs (eg, monoquaternary versus bisquaternary; steroidal versus isoquinolinium).
C. Electrolyte Abnormalities
Hypokalemia and hypocalcemia augment a nondepolarizing block. The responses of patients with hypercalcemia are unpredictable. Hypermagnesemia, as may be seen in preeclamptic patients being managed with magnesium sulfate (or after intravenous magnesium administered in the operating room), potentiates a nondepolarizing blockade by competing with calcium at the motor end-plate.
Neonates have an increased sensitivity to nondepolarizing relaxants because of their immature neuromuscular junctions (Table 11-7). This sensitivity does not necessarily decrease dosage requirements, as the neonate’s greater extracellular space provides a larger volume of distribution.
TABLE 11–7Additional considerations of muscle relaxants in special populations. ||Download (.pdf) TABLE 11–7 Additional considerations of muscle relaxants in special populations.
|Pediatric || |
Succinylcholine: should not be used routinely
Nondepolarizing agents: faster onset
Vecuronium: long-acting in neonates
|Elderly ||Decreased clearance: prolonged duration, except with cisatracurium |
|Obese || |
Dosage 20% more than lean body weight; onset unchanged
Prolonged duration, except with cisatracurium
|Liver disease || |
Increased volume of distribution
Pancuronium and vecuronium: prolonged elimination due to hepatic metabolism and biliary excretion
Pseudocholinesterase decreased; prolonged action may be seen with succinylcholine in severe disease
|Kidney failure || |
Rocuronium: relatively unchanged
Cisatracurium: safest alternative
|Critically ill ||Myopathy, polyneuropathy, nicotinic acetylcholine receptor upregulation |
As noted earlier, many drugs augment nondepolarizing blockade (see Table 11–3). They have multiple sites of interaction: prejunctional structures, postjunctional cholinergic receptors, and muscle membranes.
The presence of neurological or muscular disease can have profound effects on an individual’s response to muscle relaxants (Table 11–8). Cirrhotic liver disease and chronic kidney failure often result in an increased volume of distribution and a lower plasma concentration for a given dose of water-soluble drugs, such as muscle relaxants. On the other hand, drugs dependent on hepatic or renal excretion may demonstrate prolonged clearance (Table 11–7). Thus, depending on the drug chosen, a greater initial (loading) dose—but smaller maintenance doses—might be required in these diseases.
TABLE 11–8Diseases with altered responses to muscle relaxants. ||Download (.pdf) TABLE 11–8 Diseases with altered responses to muscle relaxants.
|Disease ||Response to Depolarizers ||Response to Nondepolarizers |
|Amyotrophic lateral sclerosis ||Contracture/hyperkalemia ||Hypersensitivity |
Systemic lupus erythematosus
|Hypersensitivity ||Hypersensitivity |
|Burn injury ||Hyperkalemia ||Resistance |
|Cerebral palsy ||Slight hypersensitivity ||Resistance |
|Familial periodic paralysis (hyperkalemic) ||Myotonia and hyperkalemia ||Hypersensitivity? |
|Guillain–Barré syndrome ||Hyperkalemia ||Hypersensitivity |
|Hemiplegia ||Hyperkalemia ||Resistance on affected side |
|Muscular denervation (peripheral nerve injury) ||Hyperkalemia and contracture ||Normal response or resistance |
|Muscular dystrophy (Duchenne type) ||Hyperkalemia and malignant hyperthermia ||Hypersensitivity |
|Myasthenia gravis ||Resistance ||Hypersensitivity |
|Myasthenic syndrome ||Hypersensitivity ||Hypersensitivity |
|Myotonia ||Generalized muscular contractions ||Normal or hypersensitivity |
Severe chronic infection
|Hyperkalemia ||Resistance |
The onset and intensity of blockade vary among muscle groups. This may be due to differences in blood flow, distance from the central circulation, or different fiber types. Furthermore, the relative sensitivity of a muscle group may depend on the choice of muscle relaxant. In general, the diaphragm, jaw, larynx, and facial muscles (orbicularis oculi) respond to and recover from muscle relaxation sooner than the thumb. Although they are a fortuitous safety feature, persistent diaphragmatic contractions can be disconcerting in the face of complete adductor pollicis paralysis. Glottic musculature is also quite resistant to blockade, as is often confirmed during laryngoscopy. The dose that produces 95% twitch depression in laryngeal muscles is nearly two times that for the adductor pollicis muscle. Good intubating conditions are usually associated with visual loss of the orbicularis oculi twitch response.
Considering the multitude of factors influencing the duration and magnitude of muscle relaxation, it becomes clear that an individual’s response to neuromuscular blocking agents should be monitored. Dosage recommendations, including those in this chapter, should be considered guidelines that require modification for individual patients. Wide variability in sensitivity to nondepolarizing muscle relaxants is often encountered in clinical practice.
Like all muscle relaxants, atracurium has a quaternary group; however, a benzylisoquinoline structure is responsible for its unique method of degradation. The drug is a mixture of ten stereoisomers.
Atracurium is so extensively metabolized that its pharmacokinetics are independent of renal and hepatic function, and less than 10% is excreted unchanged by renal and biliary routes. Two separate processes are responsible for metabolism.
This action is catalyzed by nonspecific esterases, not by acetylcholinesterase or pseudocholinesterase.
A spontaneous nonenzymatic chemical breakdown occurs at physiological pH and temperature.
A dose of 0.5 mg/kg is administered intravenously for intubation. After succinylcholine, intraoperative relaxation is achieved with 0.25 mg/kg initially, then in incremental doses of 0.1 mg/kg every 10 to 20 min. An infusion of 5 to 10 mcg/kg/min can effectively replace intermittent boluses.
Although dosage requirements do not significantly vary with age, atracurium may be shorter acting in children and infants than in adults.
Atracurium is available as a solution of 10 mg/mL. It must be stored at 2°C to 8°C, as it loses 5% to 10% of its potency for each month it is exposed to room temperature. At room temperature, it should be used within 14 days to preserve potency.
Side Effects & Clinical Considerations
Atracurium triggers dose-dependent histamine release that becomes significant at doses above 0.5 mg/kg.
A. Hypotension and Tachycardia
Cardiovascular side effects are unusual unless doses in excess of 0.5 mg/kg are administered. Atracurium may also cause a transient drop in systemic vascular resistance and an increase in cardiac index independent of any histamine release. A slow rate of injection minimizes these effects.
Atracurium should be avoided in asthmatic patients. Severe bronchospasm is occasionally seen in patients without a history of asthma.
Laudanosine, a tertiary amine, is a breakdown product of atracurium’s Hofmann elimination and has been associated with central nervous system excitation, resulting in elevation of the minimum alveolar concentration and even precipitation of seizures. Concerns about laudanosine are probably irrelevant unless a patient has received an extremely large total dose or has hepatic failure. Laudanosine is metabolized by the liver and excreted in urine and bile.
D. Temperature and pH Sensitivity
Because of its unique metabolism, atracurium’s duration of action can be markedly prolonged by hypothermia and to a lesser extent by acidosis.
E. Chemical Incompatibility
Atracurium will precipitate as a free acid if it is introduced into an intravenous line containing an alkaline solution such as thiopental.
Rare anaphylactoid reactions to atracurium have been described. Proposed mechanisms include direct immunogenicity and acrylate-mediated immune activation. Immunoglobulin E-mediated antibody reactions directed against substituted ammonium compounds, including muscle relaxants, have been described. Reactions to acrylate, a metabolite of atracurium and a structural component of some dialysis membranes, have also been reported in patients undergoing hemodialysis.
Cisatracurium is a stereoisomer of atracurium that is four times more potent. Atracurium contains approximately 15% cisatracurium.
Like atracurium, cisatracurium undergoes degradation in plasma at physiological pH and temperature by organ-independent Hofmann elimination. The resulting metabolites (a monoquaternary acrylate and laudanosine) have no neuromuscular blocking effects. Because of cisatracurium’s greater potency, the amount of laudanosine produced for the same extent and duration of neuromuscular blockade is much less than with atracurium. Metabolism and elimination are independent of kidney or liver failure. Minor variations in pharmacokinetic patterns due to age result in no clinically important changes in duration of action.
Cisatracurium produces good intubating conditions following a dose of 0.1 to 0.15 mg/kg within 2 min and results in muscle blockade of intermediate duration. The typical maintenance infusion rate ranges from 1.0 to 2.0 mcg/kg/min. Thus, it is more potent than atracurium.
Cisatracurium should be stored under refrigeration (2–8°C) and should be used within 21 days after removal from refrigeration and exposure to room temperature.
Side Effects & Clinical Considerations
Unlike atracurium, cisatracurium does not produce a consistent, dose-dependent increase in plasma histamine levels following administration. Cisatracurium does not alter heart rate or blood pressure, nor does it produce autonomic effects, even at doses as high as eight times ED95.
Cisatracurium shares with atracurium the production of laudanosine, pH and temperature sensitivity, and chemical incompatibility.
Mivacurium is a short-acting, benzylisoquinoline, nondepolarizing neuromuscular blocker. It has recently returned to the North American anesthesia market after having been unavailable for a number of years.
Mivacurium, like succinylcholine, is metabolized by pseudocholinesterase. Consequently, patients with low pseudocholinesterase concentration or activity may experience prolonged neuromuscular blockade following mivacurium administration. However, like other nondepolarizing agents, cholinesterase inhibitors will antagonize mivacurium-induced neuromuscular blockade. Edrophonium more effectively reverses mivacurium blockade than neostigmine because neostigmine inhibits plasma cholinesterase activity.
The usual intubating dose of mivacurium is 0.15 to 0.2 mg/kg.
Side Effects & Clinical Considerations
Mivacurium releases histamine to about the same degree as atracurium. The onset time of mivacurium is approximately 2 to 3 min. The main advantage of mivacurium compared with atracurium is its relatively brief duration of action (20–30 min).
Pancuronium consists of a steroid structure on which two modified ACh molecules are positioned (a bisquaternary relaxant). In all of the steroid-based relaxants the steroid “backbone” serves as a “spacer” between the two quaternary amines. Pancuronium resembles ACh enough to bind (but not activate) the nicotinic ACh receptor.
Pancuronium is metabolized (deacetylated) by the liver to a limited degree. Its metabolic products have some neuromuscular blocking activity. Excretion is primarily renal (40%), although some of the drug is cleared by the bile (10%). Not surprisingly, elimination of pancuronium is slowed and neuromuscular blockade is prolonged by kidney failure. Patients with cirrhosis may require a larger initial dose due to an increased volume of distribution but have reduced maintenance requirements because of a decreased rate of plasma clearance.
A dose of 0.08 to 0.12 mg/kg of pancuronium provides adequate relaxation for intubation in 2 to 3 min. Intraoperative relaxation is achieved by administering 0.04 mg/kg initially followed every 20 to 40 min by 0.01 mg/kg.
Children may require moderately larger doses of pancuronium. Pancuronium is available as a solution of 1 or 2 mg/mL and is stored at 2°C to 8°C but may be stable for up to 6 months at normal room temperature.
Side Effects & Clinical Considerations
A. Hypertension and Tachycardia
These cardiovascular effects are caused by the combination of vagal blockade and sympathetic stimulation. The latter is due to a combination of ganglionic stimulation, catecholamine release from adrenergic nerve endings, and decreased catecholamine reuptake. Large bolus doses of pancuronium should be given with caution to patients in whom an increased heart rate would be particularly detrimental (eg, coronary artery disease, hypertrophic cardiomyopathy, aortic stenosis).
Increased atrioventricular conduction and catecholamine release increase the likelihood of ventricular arrhythmias in predisposed individuals. The combination of pancuronium, tricyclic antidepressants, and halothane has been reported to be particularly arrhythmogenic.
Patients who are hypersensitive to bromides may exhibit allergic reactions to pancuronium (pancuronium bromide).
Vecuronium is pancuronium minus a quaternary methyl group (a monoquaternary relaxant). This minor structural change beneficially alters side effects without affecting potency.
Vecuronium is metabolized to a small extent by the liver. It depends primarily on biliary excretion and secondarily (25%) on renal excretion. Although it is a satisfactory drug for patients with kidney failure, its duration of action will be moderately prolonged. Vecuronium’s brief duration of action is explained by its shorter elimination half-life and more rapid clearance compared with pancuronium. After long-term administration of vecuronium to patients in intensive care units prolonged neuromuscular blockade (up to several days) may be present after drug discontinuation, possibly from accumulation of its active 3-hydroxy metabolite, changing drug clearance, and in some patients, leading to the development of a polyneuropathy. Risk factors seem to include female gender, kidney failure, long-term or high-dose corticosteroid therapy, and sepsis. Thus, these patients must be closely monitored, and the dose of vecuronium carefully titrated. Long-term relaxant administration and the subsequent prolonged lack of ACh binding at the postsynaptic nicotinic ACh receptors may mimic a chronic denervation state and cause lasting receptor dysfunction and paralysis. Tolerance to nondepolarizing muscle relaxants can also develop after long-term use. The best approach is to avoid unnecessary paralysis of patients in critical care units.
Vecuronium is equipotent with pancuronium, and the intubating dose is 0.08 to 0.12 mg/kg. A dose of 0.04 mg/kg initially followed by increments of 0.01 mg/kg every 15 to 20 min provides intraoperative relaxation. Alternatively, an infusion of 1 to 2 mcg/kg/min produces good maintenance of relaxation.
Age does not affect initial dose requirements, although subsequent doses are required less frequently in neonates and infants. Women seem to be approximately 30% more sensitive than men to vecuronium, as evidenced by a greater degree of blockade and longer duration of action (this has also been seen with pancuronium and rocuronium). The cause for this sensitivity is likely related to gender-related differences in fat and muscle mass and volume of distribution. The duration of action of vecuronium may be further prolonged in postpartum patients due to alterations in hepatic blood flow or liver uptake.
Side Effects & Clinical Considerations
Even at doses of 0.28 mg/kg, vecuronium is devoid of significant cardiovascular effects. Potentiation of opioid-induced bradycardia may be observed in some patients.
Although it is dependent on biliary excretion, the duration of action of vecuronium is usually not significantly prolonged in patients with cirrhosis unless doses greater than 0.15 mg/kg are given. Vecuronium requirements are reduced during the anhepatic phase of liver transplantation.
This monoquaternary steroid analogue of vecuronium was designed to provide a rapid onset of action.
Rocuronium undergoes no metabolism and is eliminated primarily by the liver and slightly by the kidneys. Its duration of action is not significantly affected by renal disease, but it is modestly prolonged by severe liver failure and pregnancy. Because rocuronium does not have active metabolites, it may be a better choice than vecuronium in the rare patient requiring prolonged infusions in the intensive care unit setting. Elderly patients may experience a prolonged duration of action due to decreased liver mass.
Rocuronium is less potent than most other steroidal muscle relaxants (potency seems to be inversely related to speed of onset). It requires 0.45 to 0.9 mg/kg intravenously for intubation and 0.15 mg/kg boluses for maintenance. Intramuscular rocuronium (1 mg/kg for infants; 2 mg/kg for children) provides adequate vocal cord and diaphragmatic paralysis for intubation, but not until after 3 to 6 min (deltoid injection has a faster onset than quadriceps). The infusion requirements for rocuronium range from 5 to 12 mcg/kg/min. Rocuronium can produce an unexpectedly prolonged duration of action in elderly patients. Initial dosage requirements are modestly increased in patients with advanced liver disease, presumably due to a larger volume of distribution.
Side Effects & Clinical Considerations
Rocuronium (at a dose of 0.9–1.2 mg/kg) has an onset of action that approaches succinylcholine (60–90 s), making it a suitable alternative for rapid-sequence inductions, but at the cost of a much longer duration of action. This intermediate duration of action is comparable to vecuronium or atracurium. Sugammadex permits rapid reversal of dense rocuronium-induced neuromuscular blockade.
Rocuronium (0.1 mg/kg) has been shown to be a rapid (90 s) and effective agent (decreased fasciculations and postoperative myalgias) for precurarization prior to administration of succinylcholine. It has slight vagolytic tendencies.
Gantacurium belongs to a new class of nondepolarizing neuromuscular blockers called chlorofumarates. In preclinical trials, gantacurium demonstrated an ultrashort duration of action, similar to that of succinylcholine. Its pharmacokinetic profile is explained by the fact that it undergoes nonenzymatic degradation by two chemical mechanisms: rapid formation of inactive cysteine adduction product and ester hydrolysis. At a dose of 0.2 mg/kg (ED95), the onset of action has been estimated to be 1 to 2 min, with a duration of blockade similar to that of succinylcholine. Its clinical duration of action ranged from 5 to 10 min. Recovery can be accelerated by edrophonium, as well as by the administration of exogenous cysteine. Cardiovascular effects suggestive of histamine release were observed following the use of three times the ED95 dosage.
CW002 is another investigational nondepolarizing agent. It is a benzylisoquinolinium fumarate ester-based compound with an intermediate duration of action that undergoes metabolism and elimination similar to that of gantacurium.
CASE DISCUSSION Delayed Recovery from General Anesthesia
A 72-year-old man has undergone general anesthesia for robot-assisted laparoscopic prostatectomy. Twenty minutes after conclusion of the procedure, he is still intubated and shows no evidence of spontaneous respiration or consciousness. What is your general approach to this diagnostic dilemma?
Clues to the solution of complex clinical problems are usually found in a pertinent review of the medical and surgical history, the history of drug ingestions, the physical examination, and laboratory results. In this case, the perioperative anesthetic management should also be considered. What medical illnesses predispose a patient to delayed awakening or prolonged paralysis?
Chronic hypertension alters cerebral blood flow autoregulation and decreases the brain’s tolerance to episodes of hypotension. Liver disease reduces hepatic drug metabolism and biliary excretion, resulting in prolonged drug action. Reduced serum albumin concentrations increase free drug (active drug) availability. Hepatic encephalopathy can alter consciousness. Kidney disease decreases the renal excretion of many drugs. Uremia can also affect consciousness. Diabetic patients are prone to hypoglycemia and hyperosmotic, hyperglycemic, and nonketotic coma. A prior stroke or symptomatic carotid bruit increases the risk of intraoperative cerebral vascular accident. Right-to-left heart shunts, particularly in children with congenital heart disease, allow air emboli to pass directly from the venous circulation to the systemic (possibly cerebral) arterial circulation. A paradoxic air embolism can result in permanent brain damage. Severe hypothyroidism is associated with impaired drug metabolism and, rarely, myxedema coma. Does an uneventful history of general anesthesia narrow the differential?
Hereditary atypical pseudocholinesterase is ruled out by uneventful prior general anesthesia, assuming succinylcholine was administered. Decreased levels of normal enzyme would not result in postoperative apnea unless the surgery was of very short duration. Malignant hyperthermia does not typically present as delayed awakening, although prolonged somnolence is not unusual. Uneventful prior anesthetics do not, however, rule out malignant hyperthermia. Persons unusually sensitive to anesthetic agents (eg, geriatric patients) may have a history of delayed emergence. How do drugs that a patient takes at home affect awakening from general anesthesia?
Drugs that decrease minimum alveolar concentration, such as methyldopa, predispose patients to anesthetic overdose. Acute ethanol intoxication decreases barbiturate metabolism and acts independently as a sedative. Drugs that decrease liver blood flow, such as cimetidine, will limit hepatic drug metabolism. Antiparkinsonian drugs and tricyclic antidepressants have anticholinergic side effects that augment the sedation produced by scopolamine. Long-acting sedatives, such as the benzodiazepines, can delay awakening. Does anesthetic technique alter awakening?
Preoperative medications can affect awakening. In particular, opioids and benzodiazepines can interfere with postoperative recovery.
Intraoperative hyperventilation is a common cause of postoperative apnea. Because volatile agents and opioids raise the apneic threshold, the PaCO2 level at which spontaneous ventilation ceases, moderate postoperative hypoventilation may be required to stimulate the respiratory centers. Severe intraoperative hypotension or hypertension may lead to cerebral hypoxia and edema.
Hypothermia decreases minimum alveolar concentration, antagonizes muscle relaxation reversal, and limits drug metabolism. Arterial hypoxia or severe hypercapnia (PaCO2 > 70 mm Hg) can alter consciousness.
Certain surgical procedures, such as carotid endarterectomy, cardiopulmonary bypass, and intracranial procedures, are associated with an increased incidence of postoperative neurological deficits. Subdural hematomas can occur in severely coagulopathic patients. Transurethral resection of the prostate can be associated with hyponatremia from the dilutional effects of absorbed irrigating solution. What clues does a physical examination provide?
Pupil size is not always a reliable indicator of central nervous system integrity. Fixed and dilated pupils in the absence of anticholinergic medication or ganglionic blockade, however, may be an ominous sign. Response to physical stimulation, such as a forceful jaw thrust, may differentiate somnolence from paralysis. Peripheral nerve stimulation also differentiates paralysis from coma. What specific laboratory findings would you order?
Arterial blood gases, plasma glucose, and serum electrolytes may be helpful. Computed tomographic scanning may be necessary if unresponsiveness is prolonged. Increased concentrations of inhalational agent provided by respiratory gas analysis, as well as processed electroencephalogram (EEG) measurements, may assist in determining if the patient is still under the effects of anesthesia. Slow EEG signals can be indicative of both anesthesia and cerebral pathology. Processed EEG awareness monitors can also be employed with the realization that low numbers on the bispectral index can be caused both by anesthetic suppression of the EEG and ischemic brain injury. What therapeutic interventions should be considered?
Supportive mechanical ventilation should be continued in the unresponsive patient. Naloxone, flumazenil, and physostigmine may be indicated, depending on the probable cause of the delayed emergence, if drug effects are suspected and reversal is considered both safe and desirable.