Chapter 34. Monitoring and Managing Neuromuscular Blockade

1. Muscle response to stimulation can be measured by mechanomyography, electromyography, acceleromyography, and direct palpation.

2. Commonly used patterns of stimulation are a single twitch, train of four, double burst, tetanic, and posttetanic count.

3. Succinylcholine, a depolarizing neuromuscular blocking drug (NMBD), is metabolized by plasma cholinesterase. Atypical pseudocholinesterases cannot metabolize pseudocholinesterase at a normal rate, and prolonged neuromuscular blockade may result.

4. Immobility, prolonged use of NMBDs, and upper and lower motor neuron disease may cause a proliferation of extrajunctional receptors. These receptors affect severe hyperkalemia when stimulated with succinylcholine.

5. Nondepolarizing NMBDs are benzylisoquinoline (mivacurium, atracurium, cisatracurium) and steroidal molecules (vecuronium, rocuronium, pancuronium).

6. The degradation of atracurium, cisatracurium, and mivacurium is independent of organ-specific elimination.

7. Pancuronium and vecuronium are metabolized in the liver to derivatives that are cleared by the kidney and that exhibit neuromuscular blocking activities. These derivatives accumulate with prolonged administration and renal insufficiency.

8. Reversal agents increase the concentration of acetylcholine in the junctional clefts to compete with the NMBDs to restore muscle activity.

9. Clinical criteria, in addition to evoked responses, should be used to assess the recovery of neuromuscular blockade.

10. Residual neuromuscular blockade is a persistent and common clinical problem.

Muscle relaxation can be achieved by direct central nervous system depression with volatile inhalation anesthetics or by neural blockade either at the peripheral nerve or with drugs that act at the neuromuscular junction. Neuromuscular blocking drugs (NMBD) are essential in anesthetic practice to facilitate tracheal intubation and provide optimum surgical conditions for a variety of procedures. The use of NMBDs is to significantly reduce the concentration of volatile anesthetics required to provide adequate analgesia. NMBDs have no inherent analgesic or amnestic properties, and their use is contraindicated if artificial ventilation is not possible.

In 1850, Pelouze and Bernard demonstrated that curare, the arrow poison used by certain South American Indian tribes, abolished the effect of nerve stimulation on muscle but did not affect the excitability of either nerve or muscle. Curare and nicotine were thought to act directly on muscle through "receptive substances" rather than by action on axonal endings until stimulation of the vagus nerve was demonstrated to produce a substance, later identified as acetylcholine (ACh), as transmitter at the myoneural junction of voluntary muscle.

Basic Myoneural Structure

A motor unit is a series of muscle fibers that is innervated by the same motor nerve.1 This nerve enters skeletal muscle and ramifies to an extent that depends on the function of the specific muscle. For example, each muscle fiber of an extraocular eye muscle is innervated by a single neuron. In contrast, muscles that contract for more coarse activities (eg, maintenance of posture) have multiple fascicles that are innervated by a single nerve fiber.

Stimulation of a single motor nerve leads to contraction of all the muscle fibers contained within the particular motor unit. As the axons terminate in troughs on the surface of the muscle fibers, their myelin sheaths are lost. The neuromuscular junction is the synapse that is formed at the endplate region of the muscle membrane and bare terminal of the motor nerve (Figs. 34-1 and 34-2). The synaptic cleft is a 50-nm-wide extracellular space that spans the short distance between the neuronal and muscle cell membranes.

Synthesis of Acetylcholine

Neuromuscular transmission begins with synthesis of the enzyme choline acetyltransferase in the organelle-rich cell body of the axon followed by distal intracellular transport to the nerve terminal where it is concentrated (Fig. 34-1). The choline acetyltransferase catalyzes the synthesis of ACh from acetyl-coenzyme A (acetyl-CoA) and choline. Hydrolysis of ACh in the junctional cleft is the primary source of choline. Most of the ACh (∼60%) is stored in thousands of synaptic vesicles of the nerve terminal. These are arranged in a triangular pattern with the apex of each triangle close to a thickened area of the prejunctional membrane (Figs. 34-1 and 34-2). This so-called active zone may be part of a system that orients and controls the site of release of ACh from the synaptic vesicles. The remainder of neural ACh is free in the cytoplasm. In the absence of nerve impulses, spontaneous release of small amounts of ACh depolarizes the postjunctional membrane to a small extent. These 0.5- to 1.5-mV depolarizations, called miniature endplate potentials, are approximately 0.01 the magnitude of a standard endplate potential and are not significant enough to trigger muscle contraction. According to the quantum theory,2 calcium-mediated fusion of synaptic vesicles with the presynaptic membrane simultaneously releases approximately 200 to 400 quanta of ACh into the synaptic cleft. Each quantum contains 500 to 25000 molecules of ACh. Motor neuron action potentials propagate via voltage-responsive ion channels that, in turn, open channels in the nerve terminal that serve as pathways for the influx of ionized calcium at the active zone.

Acetylcholine Receptors

The postsynaptic membrane is highly folded, increasing its surface area to allow a high concentration of nicotinic postjunctional receptors (Figs. 34-1 and 34-2). Each receptor is composed of 5 integral linear protein subunits arranged as a rosette in the membrane: 2 α and 1 each of β, δ, and ε. Each subunit contains 4 helical domains. The sites of binding for ACh and NMBD are on the extracellular α-subunits, although the receptors span the entire muscle cell membrane contacting both extracellular and intracellular spaces. The binding sites for ACh on the 2 α-subunits are not identical and can be characterized into high- and low-affinity sites based on their binding of competitive antagonists. Both sites must be occupied by ACh to propagate a muscle cell depolarization (Fig. 34-2). After ACh binds to the active site of both α-subunits, the receptor undergoes a conformational change, opening a central channel within the 5 subunits. The structure of this channel permits the transit of sodium, potassium, and calcium ions while blocking anions and larger cations. When nondepolarizing NMBDs bind to either α-subunit, the channels cannot open and a neuromuscular blockade occurs (Fig. 34-3A).

Depolarization and Muscle Contraction

Most of the released ACh molecules cross the synaptic clefts, bind to postjunctional receptors, and induce depolarization of the muscle cell. Depolarizations are created by the influx of sodium through specific channels, decreasing the membrane potential from –90 to +50 mV. During depolarization, as the membrane potential approximates 0 mV, potassium channels open, and sodium channels close to limit the voltage flux to +10 mV. The action potential is self-propagating after a threshold has been reached through a decrease in the adjacent membrane potential of approximately 15 mV, which opens sodium channels and depolarizes the membrane.

Depolarization is an all-or-none process. After it has begun, it continues until the entire membrane has depolarized. The strengths of individual contractions are independent of the individual action potential amplitudes. They depend on the sum of repetitive, additive, and fused contractions of different motor units. Calcium is released from the sarcoplasmic reticulum of the muscle upon depolarization to activate actin–myosin coupling within myofibrils resulting in contraction. Upon completion of depolarization, the ionic gradient is restored via an Na+/K+-dependent adenosine triphosphate (ATPase) to repolarize the membrane, and a refractory period follows during which time depolarization is not possible. After depolarization is completed, the concentration of ACh markedly decreases in the synaptic cleft by diffusion through the postjunctional receptor. ACh is further reduced by degradation into acetate and choline by acetylcholinesterase, a key enzyme that is concentrated in the basal lamina of the muscle cell.

Prejunctional Receptors

The response of muscle contraction is also modulated by prejunctional receptors of the motor neuron. It is theorized that released ACh interacts with prejunctional nicotinic, and possibly muscarinic, receptors to further augment transmitter release. These receptors are believed to control a sodium-specific ion channel in contrast to the nonspecific cation channels of the postjunctional receptors. Sodium is essential for the synthesis and mobilization of ACh, but it is not directly involved in the release process. Therefore, nondepolarizing NMBD can bind to these ion channels, decrease the mobilization of ACh, and reduce its release from nerves that are stimulated with high-frequency stimuli. The clinical equivalent is seen in the fade to tetanic and train-of-four (TOF) stimulation.

Extrajunctional Receptors

Muscle cells can also exhibit a variable number of extrajunctional receptors that are embryologic remnants of the muscle cell membrane. In fetuses, these receptors are found throughout the muscle cell membrane. With maturation, extrajunctional receptors become markedly reduced while junctional receptors predominate. In addition to differences in their location, extrajunctional receptors have γ-subunits substituted for the ε-subunit of the junctional receptor. Extrajunctional receptors also have short half-lives of less than 1 day compared with the longer than 1-week half-lives of junctional receptors. Compared with junctional receptors, they are less sensitive to stimulation by ACh but have channels that remain open approximately 4 times longer than the postjunctional receptors. The clinical significance of extrajunctional receptors becomes evident when they proliferate in response to upper and lower neuron damage, muscular injury and disease (some muscular dystrophies, disuse atrophy, and even cast immobilization), and trauma associated with major burns.3

We have described the basic mechanisms controlling the contraction of a single muscle fiber. This knowledge must be extrapolated to the bedside analysis of the contraction of anatomically distinct muscles to assess the patient's degree of neuromuscular blockade.

Objectives of clinical monitoring are as follows:

• Titration of NMBD doses to the desired level of paralysis
• Detection of unusual sensitivity, resistance, or altered clearance of a relaxant in the course of the anesthetic
• Evaluation of whether neuromuscular blockade can be pharmacologically reversed
• Assessment of the adequacy of reversal to ensure that residual neuromuscular blockade is not present

The depth of neuromuscular blockade often is assessed by a measurement of the contraction of the adductor pollicis muscle as elicited by stimulation of the ulnar nerve at the wrist with surface electrodes.4 When the ulnar nerve is not accessible, stimulation of several other peripheral nerves is useful (Fig. 34-4). The stimulus used to evoke muscle contraction usually is a rectangular waveform of 0.2-millisecond duration.4,5 It is important to adequately clean and lightly abrade the skin for optimum adherence of surface electrodes and to minimize the impedance of the skin to prevent reduction in the applied current intensity.

Patterns of Stimulation

There are 5 patterns of stimulation.

1. Single-twitch stimulus (Fig. 34-5) usually is given at a frequency of 0.1 Hz, that is, 1 stimulus every 10 seconds.4,6 The current is incrementally increased until a maximum twitch height is obtained. A current that is slightly greater than that used to achieve maximum twitch height is called the supramaximal stimulus. After an NMBD is administered, the decrements in twitch height are compared as percentages of the control twitch. This stimulus pattern is most often used to establish the basic pharmacodynamic properties of an NMBD. For example, the ED95 is the dose at which the twitch height is depressed by 95% of maximal height. The primary shortcoming of a single-twitch stimulus is the requirement for a control response before the administration of the NMBD.

2. TOF stimulation (TOF; Fig. 34-6) is the most commonly used stimulus.4,7,8 Each train consists of 4 stimuli at 2 Hz (4 stimuli in 2 seconds) that are again repeated every 10 to 12 seconds. In the absence of neuromuscular blockade, the TOF evokes 4 twitches of equal strength when the abducted thumb is palpated after stimulation of the ulnar nerve. Because the strength of the first twitch (T1) is compared with the second, third, and fourth twitches, control twitches are not required. With the onset of neuromuscular blockade, release of ACh by the first stimulus often evokes an adequate contraction. However, the ability of neurons to replenish and release ACh progressively diminishes with each stimulus of the TOF in the successive train. This can be manifested in 2 ways. First, with the onset of neuromuscular blockade, the amplitude of the fourth twitch (T4) decreases with successive stimuli. Second, within each TOF, there is a clear decrement between T4 and T1. The ratio of T4 to T1 can be easily compared if it is objectively measured. In clinical practice, when the strength of the first twitch is reduced to 75% of the maximal height, only 3 twitches will be demonstrable. With increased neuromuscular blockade to a T1 of 20%, 2 twitches will be observed. At 90% suppression of T1, only 1 twitch will be perceptible. These patterns are reversed as muscle activity returns and can be used with other clinical criteria to help determine the patient's suitability for extubation. Initial studies demonstrated that at T4/T1 = 0.75, awake patients can sustain a 5-second head lift, generate a vital capacity of 15 to 20 mL/kg with an inspiratory force of –25 cm H2O, and cough effectively.9

3. Tetanic stimulation is used in conjunction with the TOF. When a profound depth of neuromuscular blockade has been established, the twitch response to TOF stimulation is abolished.4,6 With stimulation at a tetanic frequency of 50 Hz for 5 seconds, increased quanta of ACh are released into the synaptic cleft. The increased ACh causes a sustained muscle contraction during the stimulus and also augments its own subsequent release if a single TOF stimulus follows. This enhanced response after tetanic stimulation is called posttetanic potentiation (Fig. 34-5). A posttetanic count can be obtained when a stimulation of 1 Hz is can be applied 3 seconds after tetanus. A posttetanic count of 10 has been found to coincide with the appearance of the first twitch of the TOF. A posttetanic count of 1 indicates that the first twitch of the TOF should appear in approximately 30 minutes when pancuronium is used or 8 minutes with vecuronium and atracurium.10 In the absence of a posttetanic twitch, the blockade is sufficiently profound to suggest that immediate administration of reversal agents will not be effective.

4. Double-burst stimulation (DBS) was devised to increase the manual perception of fade.4,11,12 DBS consists of 2 short bursts of 3 stimuli at 50 Hz separated by 750 milliseconds. The responses to each burst are close enough to be palpated as a strong single muscle contraction. Any fade that is manifested with a partial blockade may be easier to detect between the sets of stimuli with DBS than with TOF. In the absence of fade to DBS, there is a 90% chance that TOF is 0.6 or greater, and a 75% chance that TOF is less than 0.6 when fade is present.

Methods Used to Quantify Muscle Responses4,13 (Fig. 34-7)

Mechanomyography is an extremely accurate method that has been used for research on the basic pharmacodynamics properties of NMBDs. An isometric tension of a known preload is placed on the thumb. The thumb is attached to a transducer that measures the force of contraction of the adductor pollicis brevis muscle.

Electromyography (EMG) monitors compound motor unit action potentials that are generated a few milliseconds after the stimulus is delivered to a nerve. Two sensing electrodes are placed over a specific muscle and a ground electrode applied between the stimulating and sensing electrodes. The thenar, hypothenar, and first dorsal interosseous muscles of the hand are usually studied. Although each muscle cell responds in an all-or-none fashion, the amplitude of the EMG signal is proportional to the number of individual action potentials. In principle, the advantage of EMG is that it is closest to direct assessment of function of the neuromuscular junction.

Acceleromyography measures the isotonic acceleration across a joint with a small piezoelectric transducer.14 This technique considers that the acceleration of a muscle is directly proportional to the force of contraction (assuming the muscle mass is constant). Acceleromyography is simple to perform and is clinically useful. One disadvantage is the inconsistency of the response.

Direct palpation of an abducted thumb during contractions evoked by ulnar nerve stimulation is the most common method used to assess neuromuscular blockade. With palpation, the clinician measures both the force of isometric contraction and the force of acceleration. Although it is a subjective assessment of neuromuscular blockade and has a considerable margin of error even in the hands of experienced clinicians,15 direct palpation with TOF remains the standard in routine clinical practice.

Pharmacokinetics and pharmacodynamics are 2 important concepts pertinent to understanding the pharmacology of NMBD.

Pharmacokinetics

Pharmacokinetics is the mathematical description of the plasma concentration of the drug over time. The plasma concentration of a drug is initially high after an intravenous (IV) bolus and is followed by a rapid decline toward equilibrium during the distribution phase as a result of transfer between blood and tissue compartments. The initial volume of distribution (VI) is the distribution space of the vessel-rich organs in contrast to the volume of distribution at steady state (Vdss), which is the apparent volume needed to explain the drug concentration after equilibrium between blood and the various tissues. The distribution half-life (t1/2α) defines the time needed for the blood concentration to decline by 50% and occurs before the elimination phase begins. This is quantified from the slope of the natural log of the blood concentration–time curve in the distribution phase. The t1/2α is 2 to 10 minutes for the nondepolarizing NMBD. During the elimination phase, plasma levels of a relaxant decline at a slower rate than during the distribution phase because of excretion of the drug or its metabolite via the kidneys or the liver, spontaneous degradation, or a combination of both. The elimination half-life (t1/2β) is computed from the slope of the natural log of the blood concentration–time curve for the elimination phase and is the time required for the plasma drug concentration to decrease by 50%. The t1/2β is sensitive to changes in either the volume of distribution at steady state or the clearance (CL). The latter is defined as the volume of blood that is completely cleared of the drug per unit time. Whereas the t1/2β can range from 2.5 minutes (mivacurium) to approximately 2 hours (pancuronium), CL can vary from 2 to 100 mL/kg/min. Figures 34-11, 34-12, and 34-13 and Table 34-6 compare the Vdss, CL,and t1/2β of the currently used neuromuscular blockers in adults and children.

Pharmacodynamics

Pharmacodynamics is the principle of pharmacology that is most applicable to the clinical use of NMBDs. Pharmacodynamics includes the characterization of the therapeutic, pharmacologic, and toxic effects of the drug as well as the mechanism of drug action at the receptor. Dose–response studies of NMBD have established the relationship between increasing doses of a drug and the extent of neuromuscular blockade. When a dose is simply plotted against response, comparisons of 1 NMBD with another become difficult. The ED95 of an NMBD is the dose that blocks neuromuscular transmission to the point of reducing the height of single controlled twitches by 95%. To estimate the ED95 of a relaxant and determine appropriate doses for intubation, a straight-line dose–response curve is needed. A log-dose probit analysis assigns an arbitrary number (probit) to each level of blockade (including 0% response and 100% response) to generate a straight line and facilitate the determination of the extent of block versus dose (Fig. 34-8). The potency of different NMBD then can be compared by examining the slope and parallelism of these straight lines. Different slopes and the absence of parallelism may indicate different mechanisms of blockade.

Although it is desirable to know the concentration–response relationships at the site of drug action, it usually is not possible to do so. An assumption is that a close relationship exists between the concentration of the drug in the plasma and the concentration at postjunctional receptors. This type of relationship for NMBDs is determined during continuous infusions at steady-state conditions, and comparisons between relaxants are noted by concentration in plasma at steady state and 50% paralysis (Cpss50). Dose–response relationships (ED50) and concentration–response relationships (Cpss50) are altered by disease states, normal differences in physiology, and drug interactions and are reflected in differing dose requirements or plasma levels required to achieve the desired degree of blockade.

Onset and Recovery of Neuromuscular Blockade

The onset time of an NMBD is the time to the maximum neuromuscular blockade. It is inversely related to potency.16,17 Rapid plasma clearance contributes to a fast onset because the maximum drug effect occurs when the concentrations in the plasma and at the neuromuscular junction are equal. As the plasma concentration is decreasing, the effective concentration at the neuromuscular junction is increasing. Recovery from neuromuscular blockade begins immediately after both the plasma and junctional concentrations of the NMBD decrease. Therefore, when NMBDs have both equal potencies and equilibration rates, the drug with the faster clearance will cause a neuromuscular blockade more rapidly and of lesser magnitude than the NMBD with the slower clearance. A rapid onset and greater peak effect can be obtained by increasing the dose of the more rapidly cleared NMBD as long as there are no side effects with the increased dose. Thus, whereas high-potency, low-clearance drugs have slow onsets, low-potency, rapid-clearance drugs have fast onsets. Succinylcholine (SCh) has the fastest onset time to maximum effect (Table 34-1; Fig. 34-9). Recovery of NMBD is the spontaneous return to a percentage of activity, for example, the time to 25% of the original twitch height (also called the recovery index). The onset and recovery times for NMBDs are compared in Figs. 34-9 and 34-10.

The nondepolarizing NMBDs have faster onset times, less intense effects, and more rapid recoveries at the diaphragm and intrinsic muscles of the larynx than at the adductor pollicis.18,19 This characteristic allows tracheal intubation at lesser degrees of neuromuscular blockade than evidenced at the adductor pollicis under adequate anesthesia. This is especially important for mivacurium because it is possible to have sufficient relaxation of laryngeal muscles while the adductor pollicis and other muscles still have activity. Furthermore, when the adductor pollicis twitch is abolished using small doses of mivacurium (≤0.15 mg/kg), the laryngeal muscles may already be recovering and intubation may be difficult.

The most common use for NMDBs is to facilitate endotracheal intubation during general anesthesia. This is especially important during a rapid sequence induction to swiftly intubate the trachea to protect the lungs from gastric contents. The standard drug for such rapid intubation remains SCh (Table 34-1). When SCh is contraindicated, either an awake intubation can be performed or nondepolarizing relaxants can be administered. Conditions appropriate for intubation can be achieved within 2 minutes after administration of large doses of rocuronium, pancuronium, and cisatracurium, although the duration of neuromuscular blockade will be prolonged. To minimize unwanted cardiovascular side effects that may be produced with high doses of pancuronium, atracurium, or mivacurium, a divided dose technique may be used. The rationale for the divided dose technique is the initial binding of a large number of postjunctional receptors by a subparalytic dose of a nondepolarizing relaxant, called the "priming dose," which is insufficient to produce cardiovascular side effects. The balance of receptors subsequently is blocked to facilitate intubation within a short time after administration of the second dose of the NMBD.20 For example, using the divided dose technique for mivacurium,21 excellent intubation conditions were achieved by 90 seconds and were identical to those obtained after rocuronium was administered at 3 (0.9 mg/kg) and 4 (1.2 mg/kg) times the ED95.22

There are several caveats for the priming principle.23 In some studies, the priming and intubating doses were determined after induction of anesthesia24-26 and may not be appropriate for an urgent anesthetic when the patient has a full stomach. Individual patients differ in their sensitivity and response to relaxants. Some patients are not adequately relaxed after 90 seconds, and during light anesthesia, they may cough, jerk, vomit, or have laryngospasm. Many patients have diplopia from the priming dose, and in some patients, more troublesome effects of neuromuscular blockade develop, such as difficulty swallowing, airway obstruction, or inadequate ventilation. Without exception, after a priming dose is given, constant monitoring for these adverse effects is mandatory. Any comorbidity that impairs muscle blood flow (eg, decreased blood volume or decreased cardiac output) will delay delivery of the NMBD to the neuromuscular junction and slow the onset of neuromuscular blockade.27

SCh is the only depolarizing NMBD in current use (Table 34-1 and Fig. 34-3B).3 Because it is structurally 2 molecules of Ach linked together via the acetyl moieties (Fig. 34-14), SCh reacts with nicotinic receptors at the neuromuscular junction and in autonomic ganglia. Additional SCh binding to muscarinic postganglionic receptors in the heart, secretory glands, and smooth muscle is responsible for many of this drug's side effects. The customary dose for intubation is 1.0 mg/kg (Table 34-1). It has been suggested that a dose of 0.6 mg/kg is efficacious while the time to a return to spontaneous ventilation is decreased.28

The rapid onset and brief duration of action of SCh are this drug's major advantages. They result from rapid metabolism of SCh in plasma to succinylmonocholine (a metabolite of minimal potency). The enzyme responsible for this activity is butyrylcholinesterase, usually referred to as plasma cholinesterase. The rapid metabolism of SCh by plasma cholinesterase is responsible for its brief duration of action because relatively few of the injected molecules survive intact to reach the motor endplate (Fig. 34-3B). However, SCh molecules that reach the endplate are very resistant to metabolism by acetylcholinesterase, and neuromuscular blockade ends as SCh diffuses away from the neuromuscular junction.

Two alleles control the quantity and quality of plasma cholinesterase (Table 34-2). The normal gene is homozygous in 96% of patients. The activity of SCh is moderately prolonged in the 4% of patients who are heterozygous with normal and 1 atypical gene. It is greatly prolonged in the remainder of patients who are homozygous for the atypical gene. A clinical test for assessing these genetic differences uses the local anesthetic dibucaine, which inhibits the activity of normal, but not the atypical, plasma cholinesterase. A dibucaine number above 80 (showing marked inhibition of the enzyme) indicates normal pseudocholinesterase, a dibucaine number below 30 indicates a homozygote for the atypical enzyme, and dibucaine numbers between these values indicate heterozygotes. A more recent approach has been genotyping plasma cholinesterase variants and correlating the results with enzyme activity.29

Rare genes code for 2 additional atypical plasma cholinesterases.30 The fluoride-resistant gene produces an atypical plasma cholinesterase that is not inhibited in vitro by the addition of a fluoride ion. The extremely poor degradation of SCh by this enzyme results in a greatly prolonged neuromuscular blockade. Another atypical enzyme produced by the "silent gene" is incapable of metabolizing SCh.

Decreased amounts of plasma cholinesterase that cause prolonged responses to SCh occasionally are problematic in patients with severe liver disease and in peripartum patients. Inhibition of plasma cholinesterase by echothiophate eyedrops, anticholinesterases, organophosphate insecticides, hexafluorenium, phenelzine, and some cytotoxic tumor agents also prolong the duration of SCh's neuromuscular blockade. In the absence or inhibition of SCh metabolism, the drug is eliminated from plasma by redistribution and slow renal elimination.

Phase I and Phase II Blockade (Table 34-3)

Because of its structural similarity to ACh, SCh's interaction with the postjunctional receptors (Fig. 34-3B) creates an initial depolarization that spreads to adjacent membranes, causing disorganized contractions of motor units called fasciculations. Because SCh is not metabolized in the junctional cleft, the receptors and membranes remain depolarized and unresponsive to further stimuli, and paralysis ensues. After SCh diffuses away from the receptors, the membranes repolarize and again become responsive to normal neuromuscular transmission. This sequence of events is known as depolarization blockade or phase I blockade. It is characterized by (1) fasciculations, (2) decreased response to single nerve stimuli, (3) absence of fade to tetanus, (4) minimal fade to TOF, (5) no posttetanic facilitations, (6) enhancement of block by anticholinesterase agents, and (7) rapid recovery. However, given prolonged exposure of the neuromuscular junction to SCh, there is a conformational change at the receptors. The block that results, termed phase II block, resembles that obtained with nondepolarizing NMBD. This level of paralysis is characterized by (1) marked fade of tetanus and TOF (>50% fade), (2) posttetanic potentiation, (3) a tendency toward prolonged recovery in at least 50% of patients, and (4) the ability to reverse with anticholinesterases after plasma levels of SCh have been allowed to decrease (after waiting at least 10 minutes).

The establishment of a phase II blockade depends on the dose of SCh and the duration of SCh exposure. When inhalation agents are used to maintain anesthesia, a phase II block usually is heralded by a tachyphylaxis to SCh over a cumulative dose range between 10 and 12 mg/kg. The identification of greater than 50% fade on the TOF alerts the practitioner to the presence of phase II block, allows recovery to be followed over time, and permits the assessment of reversal after a plateau in recovery has been reached in patients in whom phase II blockade is prolonged.

Side Effects

Hyperkalemia

In normal patients, the depolarization induced by SCh administration causes an increase in serum potassium level of 0.5 to 1.0 mEq/L. In some patients with elevated baseline serum potassium levels, this modest increase in potassium level after SCh administration will not cause a cardiac dysrhythmia.31 However, the rapid increase in potassium from normal levels after SCh administration can be life threatening in patients with burns, massive tissue trauma, disuse atrophy, hemiparesis, spinal cord trauma, and neuromuscular disorders (eg, Guillain-Barré disease, amyotrophic lateral sclerosis, Friedreich ataxia).3 Possible mechanisms for SCh-induced hyperkalemia are (1) loss of motor nerve control over motor endplates that results in a proliferation of extrajunctional receptors, (2) damaged muscle membranes, and (3) defective muscle membranes in certain muscle diseases. In the acutely injured state, the critically dangerous period begins after a grace period of 48 to 72 hours. With burns and trauma, this period of SCh susceptibility can persist until recovery is well under way, even for months. Patients with neuronal injuries, such as spinal cord trauma, can have exaggerated responses for more than 6 months. The use of SCh in children is justified only for rapid sequence inductions. It is not warranted for routine pediatric use based on the increased risk of hyperkalemia in children with as yet undiagnosed congenital myopathies.

Increased Intraocular Pressure

SCh can increase the intraocular pressure (IOP). Increased IOP reaches a maximum approximately 2 minutes after SCh is administered and disappears in approximately 6 minutes. This increased IOP traditionally has been considered important for the patient with an open-eye injury wherein an increased IOP may cause irreversible loss of vitreous or global contents. However, studies from institutions with great experience with acute eye injuries have not shown adverse effects from use of SCh.32-34 Pretreatment with a nondepolarizing relaxant, followed by deep anesthetic induction and SCh for intubation, may prevent an increase in IOP. Alternatively, conditions for rapid endotracheal intubation can be obtained using large doses of nondepolarizing NMBD (2 or 3 times ED95), with the understanding that neuromuscular blockade will be greatly prolonged.

Increased Intragastric Pressure

Increased intragastric pressure of approximately 40 cm H2O occurs after SCh administration. This is blunted by pretreatment using a nondepolarizing drug followed by a larger dose of SCh (1.5 mg/kg) to achieve good intubating conditions. However, this increased gastric pressure is not believed to be clinically relevant because it is counterbalanced by an even greater increase in lower esophageal sphincter tone. Therefore, SCh is the most widely used drug for rapid sequence induction of patients with a suspected full stomach.

Increased Intracranial Pressure

Increased intracranial pressure can occur via muscle fasciculations, creating a venous pressure elevation in epidural and jugular veins, and through increased cerebral blood flow. Pretreatment with a nondepolarizing relaxant prevents this increase. However, an insufficient depth of anesthesia and hypercapnia are even more significant factors increasing intracranial pressure than the minor effects of SCh.

SCh produces muscle contraction rather than relaxation in patients with myotonia congenita or myotonia dystrophica that can be severe enough to prevent intubation and ventilation. These contractures usually are self-limited and are not inhibited by nondepolarizing agents. Rhabdomyolysis and myoglobinuria can occur with SCh administration in some susceptible patients (eg, those with myopathies or glycogen storage diseases). Finally, SCh is a triggering agent to be avoided in patients susceptible to malignant hyperthermia.

Classification

Nondepolarizing NMBDs are classified by their duration of action and their chemical composition. The approximate duration of neuromuscular blockade provided by a single dose of these drugs may be short (<20 minutes), intermediate (45-60 minutes), or long (>1 hour). The currently available NMBDs are either benzylisoquinolines (Fig. 34-15) or steroidal molecules (Fig. 34-17). The benzylisoquinolines are based on the structure of D-tubocurarine (curare [dTC]), a naturally occurring substance obtained from the vine Chondodendron tomentosum found in the Amazon jungle. Curare is no longer commercially available. Pancuronium, the parent chemical of the steroidal NMBD, was formulated from the compound malouetine used by African tribesmen as arrowhead poison. Pancuronium is still used in clinical practice.

A brief discussion of the clinical pharmacology of commonly used nondepolarizing NMBDs is provided, beginning with the benzylisoquinolines in order of the duration of their neuromuscular blockade. Factors associated with either increased resistance and increased sensitivity to nondepolarizing relaxants are summarized in Tables 34-4 and 34-5, respectively. Table 34-6 lists the characteristics of non-depolarizing NMBDs in normal adults.

Benzylisoquinolines (Fig. 34-15)

Mivacurium (Short Acting)

Mivacurium is a bisquaternary benzylisoquinoline diester with ED95 = 0.08 mg/kg, onset of 3.5 minutes (Fig. 34-9), recovery time to 25% of baseline twitch of 15 minutes, and total duration of approximately 25 minutes (Fig. 34-10).35,36 It is no longer marketed in the United States but is still widely used in other countries. It is a relaxant with both a high potency and a high clearance rate. Although mivacurium is assumed to have an intermediate potency, its high potency is demonstrable in patients with atypical plasma cholinesterase, and its rapid clearance is partly based on destruction of the compound as well as its distribution. Because these characteristics are antagonistic, mivacurium has a slower onset than expected.

At comparable doses, mivacurium has twice the duration of SCh and half the duration of intermediate drugs such as atracurium and vecuronium (Fig. 34-10). The onset time can be shortened to 2 minutes by increasing the dose threefold. This increases the duration of the block by 20%.35 Mivacurium can cause histamine release when large doses are given by IV bolus.37 In approximately 50% of patients, histamine is released when 3 times the ED95 of mivacurium (0.25 mg/kg) is given within less than 30 seconds. However, when mivacurium was administered in a divided dose regimen of 0.15 mg/kg followed by 0.1 mg/kg 30 seconds later, histamine release did not occur, and good-to-excellent intubation conditions were achieved 90 seconds after the initial dose.21,22 Mivacurium-induced blockade can be maintained by continuous infusion without alteration in its recovery characteristics.

The short duration of block produced by mivacurium (Fig. 34-10) is the result of rapid metabolism by plasma cholinesterase35,38 at approximately 70% to 80% the rate of SCh hydrolysis.38 Biochemical genetic analysis has shown that the K variant of the plasma cholinesterase gene prolongs recovery from mivacurium.39 As a nondepolarizing agent, it is competitively reversed by anticholinesterases by augmenting the concentration of ACh at the neuromuscular junction.35 However, recovery may be slowed after reversal with neostigmine in the presence of a dense block (the absence of a twitch or 1 twitch on TOF stimulation). This delayed recovery is the result of a concomitant inhibition of plasma cholinesterase slowing the hydrolysis of mivacurium by 20 to 60 minutes and markedly prolonging neuromuscular block in patients with low baseline levels of plasma cholinesterase. Therefore, before attempting reversal of mivacurium with anticholinesterases, there should be evidence of recovery manifested by the appearance of at least 2 twitches in response to TOF stimulation. Edrophonium may be a better choice of anticholinesterase to reverse the action of mivacurium because it inhibits plasma cholinesterase to a lesser degree than does neostigmine. The recovery after a mivacurium infusion has been compared to recovery after infusions of atracurium, vecuronium, and SCh. Mivacurium blockade recovers from 5% to 95% approximately 15 minutes after stopping an infusion regardless of the duration of infusion.35 It has half the duration of recovery of atracurium and vecuronium40 and equals the best of phase II–type recoveries of SCh41 given by infusion. Because mivacurium does not depend on organ metabolism for elimination, there is no tendency toward accumulation. It behaves consistently across age groups and in patients with comorbid disease states with normal plasma cholinesterase activity and hepatic synthetic function (Figs. 34-11, 34-12, and 34-13).

Atracurium and Cisatracurium

Atracurium and cisatracurium (Fig. 34-15) are bisquaternary benzylisoquinoline diesters with similar intermediate durations of action (Figs. 34-9 and 34-10) that produce 95% blockade.42,43 They are unique nondepolarizing blocking drugs that were specifically synthesized to degrade spontaneously and are independent of organ elimination. At physiologic temperature and pH, the Hofmann elimination reaction breaks down both drugs to produce a tertiary amine, laudanosine, and a monoacrylate compound.43,44 Laudanosine at high plasma levels can cause cerebral excitation and seizure activity in animals, but this has not been a clinical problem in humans. Atracurium is additionally metabolized by nonspecific plasma esterases to a quaternary alcohol and acid.45

Atracurium has an elimination half-life of approximately 20 minutes, and its plasma clearance rate is 5 to 6 mL/kg/min46 (Figs. 34-11, 34-12, and 34-13) This elimination half-life is approximately 7 times shorter than that of long-acting relaxants, with a clearance rate approximately 4 times faster. The pharmacodynamics and pharmacokinetics of atracurium are relatively unaltered in patients with renal failure47 or hepatic failure,46 in infants and children,45,48 in elderly adults,49 and when given by continuous infusion50 (Figs. 34-10, 34-11, 34-12, and 34-13). Repeated administration or infusion shows no tendency for accumulation as evidenced by increased recovery times42 (Fig. 34-16). Atracurium causes release of histamine and hypotension when administered at doses greater than 2.5 times its ED95, especially when given as a rapid bolus (<15 seconds). When doses below 0.5 mg/kg are given or when a large dose of atracurium (>0.6 mg/kg) is given slowly over 15 to 75 seconds, few patients elicit histamine release and hypotension (Fig. 34-9).51

Cisatracurium is one of the 1R-cis,1'R-cis configurations of one of the 10 isomers of atracurium and is approximately 4 times as potent as atracurium. The ED95 is 0.05 mg/kg, with an onset time of 7.5 minutes to complete blockade (2 minutes longer than atracurium), a clinical duration of 45 minutes, and a time to greater than 70% TOF ratio of 67 minutes (Figs. 34-9, 34-10, 34-11, 34-12, and 34-13).44 Cisatracurium recovery indices are unaffected by the total dose of relaxant or method of administration. In contrast to atracurium, doses of cisatracurium as great as 8 times the ED95 have been administered rapidly without any evidence of histamine release.

Steroidal Muscle Relaxants (Fig. 34-17)

Vecuronium is the monoquaternary analog of the steroidal relaxant pancuronium.52 Vecuronium is a more potent NMBD than pancuronium,53 with half to one-third of its duration of action (Fig. 34-10) by demethylation at the 2 position of the D ring, the position of the steroid nucleus that is responsible for its potency. It is a lipophilic compound that is easily absorbed by the liver and excreted into the bile mostly as the unchanged drug, the predominant method of elimination.53 The action of this drug can be prolonged in patients with liver disease.54 Vecuronium is metabolized in the liver to 3-desacetylvecuronium, 17-desacetylvecuronium, and 3,17-desacetylvecuronium.55 The 3-desacetylvecuronium has neuromuscular blocking properties at approximately half the potency of vecuronium. This metabolite is eliminated by the kidneys (Fig. 34-12), which may account for the prolonged block when vecuronium is given as a continuous infusion to facilitate mechanical ventilation of patients in the intensive care unit (ICU) who have compromised renal function.56,57 Recovery times are increased in infants younger than 1 year of age based on their increased sensitivity to vecuronium and larger volume of distribution and decreased clearance rate.58

Vecuronium does not have effects on heart rate and blood pressure through modification of the A ring of the steroidal nucleus.59 At doses above 0.1 mg/kg, it may inhibit the enzyme histamine-N-methyltransferase,60 which may contribute to occasional reports of histamine-like reactions to vecuronium.61,62 This may be a concern, especially when other drugs that release histamine (eg, the antibiotic vancomycin) are administered or when histamine-rich organs are manipulated during a surgical procedure.60

Rocuronium is the 2-morpholino, 3-desacetyl 16-N-allylpyrrolidino derivative of vecuronium.63 It was developed specifically to have a rapid onset of action (Fig. 34-9). It achieves this effect partly by being approximately 6 times less potent than vecuronium and by having a similar molecular weight.16 This results in a larger number of molecules reaching the neuromuscular junction per circulation time and may contribute to the more rapid development of its neuromuscular blockade. Rocuronium undergoes rapid uptake by the liver because of its relative lipophilicity. Unchanged rocuronium has been found in the urine (8.7%) and in the bile (>50%), indicating dual pathways for its elimination.64 The rapid redistribution of rocuronium from the neuromuscular junction contributes to its intermediate duration of action at lower doses (Fig. 34-10). The pharmacokinetics of this drug have been reported to be altered in patients with major renal65 and hepatic66 disease (Figs. 34-11, 34-12, and 34-13). In both infants and elderly patients, the changes in the pharmacokinetics of rocuronium increases the duration of action.67 Rocuronium does not produce alterations in heart rate and blood pressure.68

The ED95 of rocuronium is 0.3 mg/kg, with a recovery index of 8 minutes and a clinical duration of less than 20 minutes. Mean onset times at 2× ED95 (0.6 mg/kg), 3× ED95 (0.9 mg/kg), and 4× ED95 (1.2 mg/kg) are approximately 90, 75, and 55 seconds, respectively, with ranges of 48 to 156, 48 to 144, and 36 to 84 seconds, respectively.69 These are the most rapid onset times at equipotent doses of any nondepolarizing relaxant currently available. It has been suggested that appropriate doses, this drug in may be useful as an alternative to SCh for rapid intubation of the trachea.69 Because rocuronium depends on organs of elimination for its termination of action,70 it has a dose-related escalation of clinical duration. At 2, 3, and 4 times the ED95 dose, expected durations to 25% recovery are 37 (range, 23-75), 53 (range, 25-88), and 73 (range, 38-150) minutes, respectively (Fig. 34-10).69 In addition, recovery from lengthy rocuronium infusions is markedly slower than from single doses of moderate quantity (eg, 0.6 mg/kg).

Pancuronium (Figs. 34-9 and 34-10) is predominantly eliminated by the kidneys and has a prolonged duration of neuromuscular blockade in patients with renal insufficiency (Fig. 34-12). Whereas clearance of pancuronium is minimally altered in patients with obstructive hepatic disease, the volume of distribution at steady state is increased (Figs. 34-11 and 34-12).71 This implies that in patients with hepatic disease, greater doses may be needed to establish neuromuscular blockade that might be prolonged. In elderly patients, the duration of action is prolonged secondary to compromised clearance of the drug. Approximately 10% to 20% of the injected dose of pancuronium is metabolized in the liver to 3 metabolites: 3-hydroxypancuronium, 17-hydroxypancuronium, and 3,17-dihydroxypancuronium. The 3-hydroxy metabolite is about half as potent as the parent compound and is cleared by the kidneys.

Pancuronium has a tendency to increase heart rate, blood pressure, and cardiac output through a vagolytic action at muscarinic receptors in the autonomic nervous system and via inhibition of catecholamine reuptake at sympathetic nerve terminals.

Intermittent IV bolus doses of nondepolarizing NMBDs to maintain adequate levels of surgical paralysis are readily accomplished by giving one-fifth to one-third the original dose titrated against some objective criteria (eg, number of twitches in the TOF, clinical evaluation of abdominal relaxation). This process usually is necessary every 40 to 60 minutes, although more frequent supplemental doses are needed with the short-and intermediate-acting agents. An appropriate option for maintaining more constant and prolonged neuromuscular blockade is a continuous infusion to achieve steady-state plasma levels of drug within a therapeutic window. The infusion of NMBD can be titrated to achieve a stable depth of neuromuscular blockade (usually 1 or 2 responses to TOF) permitting a rapid reversal when needed, for example, for daily assessment of a patient's neurologic status.

SCh has been given in the past by IV infusion for maintenance of neuromuscular blockade but is no longer routinely used for this purpose. During infusion of SCh, neuromuscular blockade can change from phase I to phase II block in approximately two-thirds of patients receiving a nitrous–narcotic anesthetic, with an extremely variable time of onset. Approximately half of these patients recover rapidly (5%-95% recovery in 15 minutes). The remaining half recover to approximately 75% in roughly 30 minutes and require reversal with an anticholinesterase drug.72 Inhalational anesthetics hasten the onset of phase II block, which usually is heralded by tachyphylaxis. The key to successful use of SCh as a continuous infusion is to recognize the presence of phase II block (TOF fade >50%) and to not attempt to reverse until a plateau of recovery has been reached.

Vecuronium and rocuronium by infusion have been used with considerable success. After maintaining steady-state paralysis of approximately 95% and then discontinuing the infusion, mean recovery time to 25% is approximately 13 minutes, and mean 5% to 95% recovery times are approximately 32 minutes.73 However, there is an age-dependent decrease in the steady-state drug infusion requirement and an increased recovery time required for patients older than 60 years of age.58 These and other findings suggest that disease states or age that alters organ elimination generally decrease maintenance drug infusion requirements and slow the speed of recovery to some extent with vecuronium. This is especially true for long-term infusions in patients with renal failure because the 3-desacetyl metabolite of vecuronium, which is a potent neuromuscular blocking compound, is eliminated by the kidney.59,74

Atracurium and cisatracurium have similar recovery characteristics after infusions in healthy patients. The 25% recovery time after infusion is approximately 12.5 minutes, and the 5% to 95% mean recovery time is 26.6 minutes during oxygen, nitrous oxide, and narcotic anesthesia. Unlike vecuronium, atracurium and cisatracurium show no tendency toward prolonged recovery in disease states, such as renal failure, cirrhosis, and hepatic failure, or at the extremes of age because of its spontaneous degradation by the Hofmann elimination reaction and metabolism by nonspecific plasma cholinesterases.

Mivacurium, because of its metabolism by human plasma cholinesterase at 70% the rate of SCh, has significant clinical potential for maintenance of blockade by continuous infusion. During balanced anesthesia, the time from discontinuing the infusion of mivacurium to 25% recovery was 5.7 minutes, with a 5% to 95% recovery time of 13.6 minutes.40 Its recovery characteristics are much shorter than those of atracurium, cisatracurium, vecuronium, and rocuronium and compare favorably with the short recovery times achieved with SCh.

NMBDs in the ICU can be valuable adjuncts for managing intubated and mechanically ventilated patients.75-77 Neuromuscular blockade may be helpful for diminishing the risk of barotrauma by reducing peak airway pressures, minimizing oxygen consumption in hypothermic patients by preventing shivering, decreasing intraabdominal pressure, and stopping respiratory activity that is asynchronous with the ventilatory cycle when all other treatments have failed. NMBD also can be given to help mechanically ventilated patients with unusual problems (status epilepticus, tetanus, botulism) who are resistant to conventional methods of treatment. The administration of cisatracurium for 48 hours during the early stages of severe acute respiratory distress syndrome improved the 90-day survival76 from potentially several mechanisms, including allowing for better lung-protective ventilation, improvement in oxygenation through a reduction in oxygen consumption of muscle, and improving ventilation/perfusion matching.77 The use of NMBD in critically ill patients must be balanced with the most serious side effect of severe myopathy.59,75-82 This critical illness myopathy is characterized by marked atrophy of type I and type II muscle fibers, little evidence of inflammation, and sparing of the motor and sensory nerves.81 Although the steroidal muscle relaxants have been implicated because the myopathy associated with their use is similar to the myopathy caused by exogenous corticosteroid administration,59,82 all classes of NMBD may contribute to myopathy. In the ICU, the underlying complex systemic disease processes (including sepsis and burns), prolonged immobility, ventilator dependence, use of various drugs that may affect the neuromuscular system,75 and the initial more frequent use of the steroidal muscle relaxants compared with the benzylisoquinolines in ICU patients have confounded studies of myopathy caused by prolonged neuromuscular blockade.77

Atracurium and cisatracurium can be given to critically ill patients with renal failure.81 The epileptogenic effects of laudanosine, a metabolite of the Hofmann degradation, have not been reported in patients receiving atracurium infusions. The highest plasma concentrations of laudanosine measured in human plasma during continuous infusions in the ICU are below 6 mcg/mL, far lower than the 17 mcg/mL needed to produce seizures in animals.84

Pancuronium, because it is the NMBD in longest use, frequently was given to ICU patients before the availability of the benzylisoquinoline NMBD and sedatives, such as propofol, to facilitate mechanical ventilation. Because of its cardiovascular effects, pancuronium may be a poor choice for patients in whom dysrhythmias and tachycardia would be detrimental. Furthermore, because pancuronium is primarily excreted by the kidneys, patients with compromised renal function may experience a prolonged duration of effect, causing confusion over the patient's neurologic status.83

Vecuronium is eliminated primarily by biliary clearance and only minimally by renal clearance. When vecuronium was administered as an infusion to maintain approximately 80% blockade in patients with renal and respiratory failure, recovery to control twitch height after stopping the infusion took from 6 to 37 hours compared with an approximately 1-hour recovery for cisatracurium.59 A prolonged recovery may occur secondary to accumulation of the 3-desacetyl metabolite of vecuronium that has approximately 50% of the parent compound's neuromuscular blocking activity and is cleared by the kidney.57

Residual neuromuscular blockade (RNMB) in patients admitted to the postanesthesia care unit (PACU) is a persistent problem.85-89 RNMB is associated with impaired pharyngeal function, weakness of upper airway muscles, some attenuation of the hypoxic ventilator response, and the unpleasantness of feeling muscle weakness.90 Recurarization is the term that initially was coined for patients who were re-paralyzed after seemingly adequate reversal of neuromuscular blockade in the operating room. This term is a misnomer because it is realistically a failure to adequately reverse neuromuscular blockade.

One long-standing guide for clinicians has been a return to TOF ratio = 0.7 as an indicator for the return of sufficient muscular function to permit endotracheal extubation6,91 in concert with the sum total of multiple clinical observations such as respiratory function and the ability to follow commands (Table 34-7). If adequate recovery is based on the level of pharyngeal function, recovery to TOF ratios above 0.9 has been advocated.92 Even with a recovery of the TOF to 0.9, upper airway integrity in some patient may continue to be compromised.93 However, this ratio is based on quantitative evaluation (eg, with acceleromyography) instead of qualitative observations.90 The use of intermediate-acting NMBDs can reduce the risk of RNMB but does not completely eliminate this possibility. Interestingly, although patients treated with rocuronium had longer returns to TOF 0.9 compared with those treated with cisatracurium, the number of patients with RNMB was higher with cisatracurium.94 It is believed that clinicians have compensated for the longer action of rocuronium by stopping its administration sooner.94

Reversal of neuromuscular blockade by the administration of an anticholinesterase (eg, neostigmine or edrophonium) (Fig. 34-18) is routinely needed in the operating room or PACU. Through inhibition of acetylcholinesterase activity, the concentration of ACh will increase and be available to compete with the nondepolarizing NMBD. A muscarinic antagonist is simultaneously administered to limit any untoward effects of ACh (bradycardia, bronchospasm, or gastrointestinal hyperactivity). Because the anticholinesterase and muscarinic antagonist should have similar durations, the usual drug pairs that are commonly given are neostigmine and glycopyrrolate or edrophonium and atropine. The timing of the administration of anticholinesterases is important. Profound neuromuscular blockade with NMBD that is dependent on organ elimination may require up to 80 minutes for full recovery.95-97 In routine clinical practice, upon return of the TOF to a single twitch, adequate recovery from neuromuscular blockade to allow successful extubation usually requires at least 15 to 20 minutes.89

In lieu of acetylcholinesterase inhibitors,98 drug-specific reversal agents may provide rapid reversal of neuromuscular blockade. A γ-cyclodextrin, sugammadex, has been synthesized to reverse a profound neuromuscular blockade after rocuronium99 or vecuronium100 administration. Sugammadex encapsulates the steroidal NMBD, decreases its free concentration in the plasma, and thereby removes the NMBD from the neuromuscular junction. The sugammadex–NMBD complex is cleared by the kidneys. Although available in Europe, sugammadex has not been approved for use in the United States because of the risks of hypersensitivity and allergic reactions.

Gantacurium is an ultra–short-acting nondepolarizing NMBD.101 It is an asymmetrical isoquiolinium diester of chlorofumaric acid. Its brief duration of action is attributable to a rapid combination with L-cysteine, forming an inactive compound. The duration of action for a dose 5 times the ED95 is 7 to 13 minutes. Analogs of gantacurium that have intermediate durations of action have been synthesized. Gantacurium and its analogs can be reversed rapidly by IV administration of L-cysteine.

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• Segredo V, Caldwell JE, Matthay MA, et al. Persistent paralysis in critically ill patients after long-term administration of vecuronium. N Engl J Med. 1992;327:524.