Clinical Utility

Administration of NMBAs for tracheal intubation decreases the incidence of postoperative upper airway trauma-related symptoms by decreasing the likelihood of tissue trauma, including vocal cord injury and resulting postoperative hoarseness. Administering NMBAs to mechanically ventilated patients with acute respiratory distress syndrome (ARDS) in the intensive care unit for a short period may improve their outcome. Neuromuscular blockade decreases the need to overdose anesthetics in order to decrease reflex movement. It also facilitates surgical exposure and minimizes potentially deleterious complications of intraoperative patient movement. It is not, however, a substitute for an adequate depth of anesthesia. While neuromuscular blockade decreases the likelihood of patient movement, it does not guarantee the absence of pain, recall, and patient movement throughout a surgical procedure; patients can move even when their response to neuromuscular stimulation is significantly reduced (1 or 2 responses to train-of-four [TOF] stimulation).

Since spontaneous recovery of neuromuscular function after administration of a neuromuscular blocking agent does not happen quickly and is not instantaneous even with the administration of an appropriate dose of an anticholinesterase, maintaining a deep level of relaxation throughout a surgical procedure, especially ocular or laparoscopic surgery, might not allow enough time during closure for complete recovery of neuromuscular function. There are a number of possible solutions to ensure adequate recovery of muscle strength at the end of a surgical procedure. First, NMBAs are not always required to optimize surgical conditions. Alternatively, depth of block can be allowed to decrease as the surgical procedure nears completion, allowing for a greater degree of spontaneous recovery before administration of the anticholinesterase. Most recently, it has been possible to use a selective relaxant binding agent rather than an anticholinesterase to facilitate recovery from either rocuronium- or vecuronium-induced neuromuscular block. The “optimal” depth of neuromuscular block to provide the best surgical conditions depends on both the surgical procedure and the anesthetics that are being administered. Administration of volatile anesthetics potentiates NMBAs. Whether profound paralysis (post-tetanic count of 1–3) always improves surgical conditions is currently a matter of debate ; additional work is necessary to determine whether increased use of deep levels of neuromuscular blockade improves or worsens patient outcomes, such as an increase in the odds of hospital readmission within 30 days after surgery. An association between the intraoperative dose of NMBA and 30-day readmission after abdominal surgery has been demonstrated.

Effects in Different Muscle Groups

The effects of NMBAs are different in different muscles owing to their physiologic differences ( Chapter 21 ). The diaphragm is less susceptible to the effects of NMBAs than either peripheral muscles or pharyngeal upper airway dilator muscles. Additionally, recovery of diaphragmatic function occurs more rapidly than in muscles of the extremity, such as the adductor pollicis, which is the muscle commonly used in clinical practice for monitoring depth of neuromuscular block following administration of an intubating dose of a nondepolarizing NMBA. The resistance of the diaphragm to neuromuscular blockade can be explained by the release of a greater number of acetylcholine-containing vesicles from presynaptic terminals following neural stimulation and the presence of a greater number of postjunctional nicotinic acetylcholine receptor binding sites than exist in peripheral muscles.

In clinical practice, the response of the adductor pollicis muscle to stimulation of the ulnar nerve is recommended for monitoring, as recommendations for dosing of NMBAs are based on the response of this neuromuscular unit to stimulation. When used, its response is assessed by either visual or tactile evaluation. While other superficially located neuromuscular units can be monitored, their response to neuromuscular stimulation will be different than that of the adductor pollicis in the same patient. This occurs because different neuromuscular units have different sensitivities to NMBAs and different time courses for onset of and recovery from neuromuscular block ( Fig. 22.1 ). This has been attributed to different blood flow to these different muscles. Typically, when a patient’s arms are tucked and not available for monitoring, the posterior tibial nerve that innervates the plantar muscles of the foot, the common peroneal nerve that through the deep peroneal nerve innervates the muscles of the anterior compartment of the leg, or the facial nerve that innervates the muscles used for expression, may be used for monitoring depth of neuromuscular blockade. When dosing of NMBAs based on the results of monitoring at these different sites, the differences in their response to neural stimulation must be considered. The mimetic muscles recover more quickly than those of the periphery and the depth of block in response to a dose of an NMBA is less profound than that in the arm or the leg. While different sites can be monitored, dosing recommendations for NMBAs are based on the response of the adductor pollicis to stimulation of the ulnar nerve.

Onset of and recovery from vecuronium-induced neuromuscular block (0.07 mg/kg) at the larynx and the adductor pollicis. The larynx is relatively resistant to neuromuscular blockade.

(Adapted from Donati F, Meistelman C, Plaud B. Vecuronium neuromuscular blockade at the adductor muscles of the larynx and adductor pollicis. Anesthesiology . 1991;74:833–837.)

Modes of Stimulation

Double-Burst Stimulation

DBS was developed to improve detection of residual neuromuscular block. Fade in the strength of the second response relative to the first response is used to determine whether residual neuromuscular block is present. Fade in the response to stimulation is equivalent to the fade detected with TOF stimulation; however, the reliability of qualitative monitoring with DBS is improved over that of TOF monitoring. DBS allows detection of fade when the second response is 60% of the first response. This occurs because the presence of the second and third responses to TOF stimulation makes the comparison of the strength of the fourth response to that of the first response more difficult. With DBS, either 2 or 3 short bursts of high-frequency tetanic stimuli are administered, followed by a second series of 2 or 3 short bursts of tetanic stimuli, each resulting in a single muscular contraction. With full recovery from neuromuscular block, 2 equal responses occur with DBS.

Typically, NMBA doses of two times the ED ₉₅ (the dose required to cause, on average, 95% suppression of muscle response to stimulation) or greater are administered to facilitate tracheal administration in a reasonable time after induction of anesthesia. However, smaller doses of NMBA might be adequate to optimize intubating conditions during deep anesthesia. While recovery is monitored with either TOF or DBS, onset of block is typically determined with the response to single-twitch stimuli. For this pattern of stimulation, supramaximal stimuli are applied at a frequency of 0.1 Hz, or once every 10 seconds. Onset of neuromuscular blockade is defined as the fade in twitch response with each subsequent stimulus. When larger doses of NMBA are administered, onset of 100% neuromuscular block occurs more quickly and is more likely to develop in all patients. Doubling the dose of rocuronium from 0.6 to 1.2 mg/kg shortens the average onset time from 1.5 minutes to just under 1 minute, and decreasing the dose slows onset time.

When monitoring the effect of NMBAs administered to facilitate tracheal intubation, monitoring at the muscles of the face more accurately indicates adequacy of neuromuscular block in the upper airway. When lower doses of NMBAs are administered, depth of block at a particular time (60 or 90 seconds after administration) cannot be guaranteed since onset of NMBAs is quite variable. As shown in Fig. 22.2 , patients developed 0% to 80% neuromuscular block following administration of 0.1 mg/kg rocuronium. Just as onset of block is variable with small doses of NMBAs, recovery is quite variable following administration of larger doses (see Fig. 22.2 ). This emphasizes the importance of monitoring depth of neuromuscular block throughout surgery to avoid overdosing.

Variability of peak effect and recovery times determined with mechanomyography in response to low-dose (A) or high-dose (B) rocuronium in 20 children aged 2 to 8 years. In one child, rocuronium 0.1 mg/kg did not decrease muscle strength whereas muscle strength was almost completely abolished in another. After rocuronium 1 mg/kg, recovery of a train-of-four ratio to 0.9 varied from 30 to 85 minutes.

(Adapted from Eikermann M, Hunkemoller I, Peine L, et al. Optimal rocuronium dose for intubation during inhalation induction with sevoflurane in children. Br J Anaesth . 2002;89:277–281.)

While the most commonly used monitors of depth of neuromuscular block are qualitative monitors, quantitative monitors of depth of block are also available. Without using these quantitative devices, clinicians can reliably detect only severe residual neuromuscular block (TOFR < 0.4), as twitch height at a TOFR between 0.4 and 1.0 is likely to be perceived as 4 responses that are similar. Optimally, quantitative methods for measurement of the evoked muscular response should be used. Commercially available techniques include mechanomyography, electromyography, kinemyography, and acceleromyography.

Neuromuscular Blocking Activity

Structure–activity relationships of NMBAs can affect neuromuscular blocking activity, pharmacokinetic properties, and side effect profiles. Since the early classification of NMBAs as rigid bulky molecules with amine functions incorporated into ring structures, much has changed in our understanding of the relationships between their structures and function as neuromuscular blockers.

Postjunctional nicotinic acetylcholine receptors are pentameric members of the superfamily of ligand-gated ion channels. The mature form consists of 5 subunits: 2-alpha (α), 1-delta (δ), 1-beta (β) and 1-epsilon (ε); ( Fig. 22.3 ). In the immature (fetal) form of the receptor, the ε subunit is replaced by a gamma (γ) subunit. The N- and C-terminal ends of each subunit are extracellular, with the protein traversing the lipid bilayer membrane 4 times—creating four transmembrane domains (M1, M2, M3, and M4). The M2 domain of each subunit creates the central ion pore (see Fig. 22.3 ).

Schematic representation of the pentameric nicotinic acetylcoline receptor spanning the lipid bilayer. The acetylcholine binding sites are located at the interface of the α-ε and α-δ subunits. Each subunit contains 4 domains (M1–4) that span the lipid bilayer. Influx of Na+ is the same as efflux of K+, which is greater than the influx of Ca+. Ach, Acetylcholine; Ca, Ca+; K, K+; Na, Na+.

(Adapted from Naguib M, Flood P, McArdle JJ, et al. Advances in neurobiology of the neuromuscular junction: Implications for the anesthesiologist. Anesthesiology. 2002;96:202–231.)

The agonist binding sites of the acetylcholine receptor are located at the interface of the α-δ and α-ε subunits, where the N-terminus of each subunit works with that of the other to form the acetylcholine binding site. In order for the central pore of the receptor to open, allowing for influx of Na ⁺ and Ca ²⁺ and efflux of K ⁺ , two agonist molecules must be bound to the receptor. The two binding sites are not identical (the δ-subunit contributes to one receptor and the ε-subunit contributes to the other). These differences lead to varying affinity at each of the sites for agonists and competitive antagonists. The fetal α-γ binding site is generally more sensitive than the mature α-ε one. The α-γ binding site has up to a 500-fold greater affinity for d-tubocurarine than does the α-δ binding site. In mature receptors, the α-δ binding site appears to be more important than the α-ε site in determining receptor affinity for pancuronium, vecuronium, and cisatracurium.

The complexity of fitting large molecules, such as NMBAs, into acetylcholine receptor agonist binding sites ( Fig. 22.4 ) implies that conformational changes in the NMBA are required. While these compounds are large, they can bend and fold and will seek a conformation requiring minimal energy. Interaction of the γTyr117 with the 2-N and 13′ positions of d-tubocurarine suggests that allosteric changes in either the antagonist or receptor occur with binding. Several different sites of interaction in the binding site are involved in binding the agonist or antagonist. Different affinities at each of these sites might account for some of the synergism observed when different NMBAs are administered to the same patient.

A structural model of the interface of the acetylcholine binding site in human muscle nicotinic acetylcholine receptor. Each binding site in the acetylcholine receptor has different affinities for neuromuscular blocking agents.

(From Dilger PD, James P, Vidal BA, et al. Roles of amino acids and subunits in determining the inhibition of nicotinic acetylcholine receptors by competitive antagonists. Anesthesiology 2007;106:1186–1195.)

In addition to opening the ion channel of postjunctional acetylcholine receptors, neuromuscular transmission is modulated by a population of prejunctional cholinergic receptors. These prejunctional nicotinic and muscarinic receptors on the motor nerve endings are involved in modulating the release of acetylcholine into the neuromuscular junction. Prejunctional nicotinic receptors are activated by acetylcholine and function in a positive feedback control system that serves to maintain the availability of acetylcholine when demand is high. Their activation mobilizes acetylcholine-containing synaptic vesicles toward the release sites in the presynaptic membrane of the motor nerve terminal but not the actual process of acetylcholine release. These presynaptic receptors are morphologically different than those at the postjunctional membrane and consist of 3 α subunits and 2 β subunits. All NMBAs tested—including mivacurium, atracurium, cisatracurium, d-tubocurarine, pancuronium, rocuronium, and vecuronium—inhibit presynaptic nicotinic acetylcholine receptors in a concentration-dependent fashion, with concentrations causing 50% inhibition of response in the micromolar range. Vecuronium and d-tubocurarine are the most potent inhibitors of this receptor subtype; mivacurium is the least potent. Inhibition of this presynaptic receptor by NMBAs is primarily competitive, but d-tubocurarine and vecuronium also produce noncompetitive inhibition. The effect of blockade of these presynaptic receptors during periods of stress, such as TOF or tetanic stimulation, likely accounts for the fade observed in the TOF response with small doses of NMBA, such as those administered prior to succinylcholine to decrease the incidence and severity of fasciculations of NMBAs.

Onset of Block

Onset of neuromuscular block is proportional to the dose of NMBA administered and is typically described in terms of multiples of the ED ₉₅ (the dose causing 95% suppression of twitch response; Table 22.1 ). The use of larger doses of NMBAs is limited for a number of reasons, including an increase in the duration of action (the time required from administration to recovery of twitch height to 25% of baseline, which increases with increasing dose), more frequent and severe side effects, and the limited benefit of increasing the dose beyond a certain point.

Potency is inversely related to onset of neuromuscular block; the more potent a compound, the slower its onset of effect. Larger doses of NMBAs with a lower potency are administered, increasing the driving force for diffusion of these agents down their concentration gradient to the acetylcholine receptors of the neuromuscular junction. This has been found for the aminosteroid compounds, a series of tetrahydroisoquinolinium chlorofumarates, 3 structurally unrelated compounds with long durations of action and for compounds of different durations of action and structure. Pharmacokinetic modeling with a fixed number of acetylcholine receptors shows that there is a set requirement for the number of antagonist molecules needed to establish block; an ED ₉₅ greater than 0.1 mg/kg is necessary for a rapid onset of effect.

In order to exert its effect, an NMBA must be able to enter the neuromuscular junction, which is facilitated by its lipophilicity. The speed of onset of neuromuscular block after administration of an NMBA is also related to the speed of recovery of neuromuscular function. This appears to be due to the more rapid equilibration between the plasma and effect compartment with drugs that are metabolized or redistributed more quickly ( Fig. 22.5 ). Because of this, equipotent doses of mivacurium or succinylcholine have a slower onset of effect in patients who are homozygous for atypical butyrylcholinesterase.

Theoretical changes following a bolus dose of neuromuscular blocking agent (NMBA), in its concentration in plasma (blue and purple lines) and in the biophase (orange and pink lines) over time. The concentration of the NMBA in plasma decreases as a result of its clearance from plasma (curve A) . The concentration in the biophase increases because of transfer of NMBA from plasma to the biophase. When the concentrations in plasma and biophase are similar (arrow A) , the maximum concentration in the biophase is reached and the peak effect is obtained. The time required for equilibration between plasma and the biophase determines the onset time. If the NMBA is administered in the same dose but has a reduced clearance (curve B) , equilibration occurs later (arrow B) and at a higher maximum concentration in the biophase. Onset time is prolonged and the peak effect is greater.

(Adapted from Beaufort TM, Nigrovic V, Proost JH, et al. Inhibition of the enzymic degradation of suxamethonium and mivacurium increases the onset time of submaximal neuromuscular block. Anesthesiology . 1998;89:707–714.)

Understanding some of the factors impacting onset of neuromuscular block has led to the development of NMBAs with a faster onset of effect. Structural changes in the steroidal NMBAs have yielded compounds with a rapid onset of effect ( Fig. 22.6 ). In clinical practice, these structural changes provide a real alternative to succinylcholine when intubation within 60 seconds is required. Rocuronium, 1 to 1.2 mg/kg, provides rapid onset of neuromuscular block and can be used effectively in the setting of a rapid sequence induction and intubation.

The chemical structures of vecuronium, rocuronium, and pancuronium. The acetyl ester in the steroid nucleus of vecuronium is absent in rocuronium. Changing the substitution at positions 2 and 16 likely contributes to the more rapid onset of block of rocuronium. Replacement of the methyl group at the quaternary nitrogen with a larger allyl group contributes to a decrease in potency. .

Recovery From Neuromuscular Block

As the understanding of the adverse effects of residual neuromuscular blockade is increasingly appreciated, development of NMBAs with a shorter duration of action has become a priority. The two ways to shorten recovery from neuromuscular block involve decreasing the concentration of NMBA at the acetylcholine receptor relative to acetylcholine ( Fig. 22.7 ). This can be done through increasing the metabolism of the NMBA to rapidly remove it from the neuromuscular junction or inhibiting the activity of acetylcholinesterase so that the availability of acetylcholine at the neuromuscular junction is increased. Both mivacurium and succinylcholine have short durations of action and are metabolized by butyrylcholinesterase. Two more recently studied compounds, gantacurium and CW002, are inactivated through adduction of the amino acid cysteine at the fumarate double bond. Administration of exogenous cysteine shortens the duration of action of CW002 through its rapid inactivation so that acetylcholine available at the neuromuscular junction is more effective. Sugammadex, a selective relaxant binding agent, is a cyclodextrin that encapsulates steroidal NMBAs so that they can no longer bind to the acetylcholine receptor (see the section Antagonism of Residual Neuromuscular Block , to follow). Calabadions provide a broader (increased binding selectivity) and expanded (reversal of benzylisoquinolines) spectrum of indications.

The chemical structure of succinylcholine. It is comprised of 2 molecules of acetylcholine groups bound together at their acetate methyl groups.

Depolarizing Neuromuscular Blocking Agents: Succinylcholine

Nondepolarizing Neuromuscular Blocking Agents

Benzylisoquinolinium Compounds

There are currently two NMBAs of this class available in the United States: atracurium and cisatracurium. Both are intermediate-acting compounds, with a clinical duration of action of 20 to 50 minutes.

Atracurium

Atracurium ( Fig. 22.8 ), a bisquaternary ammonium benzylisoquinoline compound, is relatively potent with an ED ₉₅ of 0.2 to 0.25 mg/kg and an intermediate duration of action. Following administration of two times the ED ₉₅ , maximal block occurs in 2.5 minutes, recovery to 10% of baseline twitch amplitude (approximately 1 twitch in the TOF) occurs in 40 minutes, and complete spontaneous recovery of neuromuscular function in about 60 minutes.

Degradation and inactivation of atracurium. Atracurium undergoes either Hofmann elimination to yield a monoacrylate and laudanosine or ester hydrolysis to yield a quaternary alcohol and a quaternary acid. Laudanosine, the major product, is excreted in urine and bile.

(Adapted from Basta SJ, Ali HH, Savarese JJ, et al. Clinical pharmacology of atracurium besylate [BW 33A]: A new non-depolarizing muscle relaxant. Anesth Analg. 1982:61;723–729.)

Atracurium was the first NMBA introduced into clinical practice that does not undergo elimination by enzyme-catalyzed hydrolysis or excretion by the kidneys or liver. Chemical degradation to inactive products by Hofmann elimination (see Fig. 22.8 ) is primarily responsible for its inactivation; enzymatic ester hydrolysis and renal elimination have lesser roles. While some studies have found that ester hydrolysis can be responsible for metabolism of as much as 66% of an atracurium dose, and that renal elimination can have a larger role in the pharmacokinetics of atracurium than initially appreciated, its spontaneous degradation is unique and allows for relatively consistent pharmacokinetics and pharmacodynamics even in patients with advanced hepatic and renal disease.

Hofmann elimination is a spontaneous, base-catalyzed, nonenzymatic chemical reaction by which atracurium is cleaved into two molecules. Alkalosis increases resistance to atracurium-induced neuromuscular block, while hypothermia slows the temperature-dependent breakdown so that less atracurium is required to maintain a given depth of neuromuscular block. The ester hydrolysis involved in atracurium metabolism is catalyzed by a nonspecific esterase distinct from the butyrylcholinesterase hydrolysis for hydrolysis of succinylcholine and mivacurium.

Since recovery from atracurium-induced neuromuscular block occurs by nonsaturable chemical degradation rather than metabolism or redistribution, there is little to no cumulative effect with repeat doses or continuous infusion. Thus, sequential doses administered at the same point in spontaneous recovery have the same recovery characteristics as the preceding dose. With continuous infusion, no dosing revisions are required to maintain a stable depth of neuromuscular block, even with prolonged infusions.

With prolonged infusions of atracurium, the elimination half-life is about 20 minutes with a clearance of 4.5 to 10 mL/kg/min, greater than that of long-acting NMBAs. Because of the relative lack of renal or hepatic elimination of atracurium compared to steroidal NMBAs, the pharmacokinetics and duration of action of atracurium are not affected by renal disease. Similarly, elimination half-life is not prolonged in patients with cirrhosis.

Normal aging is accompanied by a number of physiologic changes, including decreases in hepatic and renal blood flow and function along with changes in the anatomy and function of the neuromuscular junction. In spite of the changes at the neuromuscular junction, the depth of block at a given plasma concentration of NMBA is the same in young and elderly individuals. It appears that observed differences in the effects of NMBAs associated with aging are due to altered pharmacokinetics. As expected, prolongation of the effect of NMBAs in the elderly is less pronounced or not apparent for compounds that rely less on the kidney and liver for their elimination. For example, the duration of block with atracurium is not increased with advanced age. Subsequent studies have shown that while the clearance of atracurium is similar in elderly and young patients, elimination half-life is prolonged in the elderly. Clearance remains constant because, while elimination through the renal pathway is decreased in the elderly, clearance through pathways that are not end organ dependent is increased.

Cisatracurium

Cisatracurium ( Fig. 22.9 ) is the 1 R-cis 1′R-cis stereoisomer of the 10 stereoisomers that comprise atracurium and has been available since 1995. Its development involved isolation and testing of individual stereoisomers from the mixture that are found in atracurium, with selection and further development of the one with fewer side effects. It is approximately 3-fold more potent than atracurium (ED ₉₅ of 0.05 mg/kg) and, like atracurium, has an intermediate duration of action. Because of its greater potency, however, its onset of effect is considerably slower than that of atracurium. For this reason, doses of 3 to 5 times the ED ₉₅ are recommended for endotracheal intubation. In contrast to atracurium, administration of these large doses is not associated with histamine release and the resultant hypotension or tachycardia.

Chemical structure of cisatracurium. Cisatracurium is the 1 R-cis 1′ R-cis stereoisomer that is one of 10 stereoisomers comprising atracurium.

Like atracurium, cisatracurium undergoes Hofmann elimination. Clearance, elimination half-life, and volume of distribution are the same when doses of the ED ₉₅ or twice the ED ₉₅ are administered. The clinical duration of action (the time required from administration of a dose to recovery of 25% T1 height) defines the earliest time that reversal of residual neuromuscular block is recommended. The duration of action of 0.1 mg/kg cisatracurium (2× ED ₉₅ ) is 45 minutes. Doubling the dose to 4× ED ₉₅ increases it to 68 minutes and doubling it again to 8× ED ₉₅ increase it by another 23 minutes, equivalent to the elimination half-life of the compound.

Hofmann elimination accounts for 77% of total clearance of cisatracurium and renal elimination 16%. The slight dependence on renal elimination likely contributes to the increase in elimination half-life of 14% and decrease in clearance of 13% observed in patients with renal failure. In spite of these pharmacokinetic changes in patients with renal dysfunction, no prolongation of the duration of action is found following a bolus dose. As with atracurium, both volume of distribution and clearance of cisatracurium are increased in patients with hepatic failure. Elimination half-life is unchanged; thus, the clinical duration of action and 25% to 75% recovery interval (the time required to recover from 25% to 75% of baseline muscle strength) is unchanged in patients with liver failure.

Recovery from cisatracurium-induced neuromuscular block occurs over the same time course in elderly surgical patients as it does in young adults. An increase in the volume of distribution and no change in the clearance in the elderly likely account for the prolongation of elimination half-life by up to 28%. The decrease in renal function that occurs with normal aging could account for these pharmacokinetic differences. The prolonged elimination half-life of cisatracurium in the geriatric patient does not affect recovery from neuromuscular block induced with a bolus dose of the NMBA.

Mivacurium

Mivacurium ( Fig. 22.10 ) is the only short-acting nondepolarizing neuromuscular blocking agent available. While its availability in the United States has decreased since 2006, it is available throughout Europe.

Chemical structure of mivacurium. Mivacurium is a bis-benzylisoquinolinium diester compound. Like atracurium, it consists of a series of stereoisomers. The 3 stereoisomers that comprise mivacurium are a cis-trans , a trans-trans , and a cis-cis isomer based on the orientation of the methylated phenolic groups.

The ED ₉₅ of mivacurium is 0.08 mg/kg and its in vitro elimination half-life is 3.1 minutes. Its short duration is due to metabolism by butyrylcholinesterase to quaternary amino alcohols and quaternary monoesters. These metabolites are excreted in the urine with half-lives of 90 minutes. Since they are less than 1/100th as potent as mivacurium, they are unlikely to contribute to neuromuscular block. In a study of the impact of mivacurium in unsedated volunteers, subtle symptoms of weakness persisted after full recovery of muscle strength. Following administration of 0.2 mg/kg mivacurium (2.5× ED ₉₅ dose) to facilitate intubation, recovery to a TOFR of 0.7 occurred in less than 30 minutes, which is shorter than recovery following administration of comparable doses of any other NMBA.

Mivacurium is comprised of a mixture of 3 stereoisomers, one of which—the cis-cis isomer—is less than one-tenth as potent as the trans-trans and cis-trans isomers. The pharmacodynamics and pharmacokinetics of mivacurium are due largely to the more potent trans-trans and cis-trans isomers. The half-lives of these isomers are 2 to 3 minutes and their clearances are more than 50 mL/kg/min, with the cis-trans isomer having a clearance of 100 mL/kg/min. These rapid clearances are due to extensive metabolism by butyrylcholinesterase. In patients who are homozygous for atypical butyrylcholinesterase, mivacurium behaves as a long-acting neuromuscular blocking agent.

Doses of 0.15 to 0.25 mg/kg mivacurium have been used to facilitate endotracheal intubation. Onset of maximal effect of these doses ranges from 2 to 3.3 minutes. The short duration of action of mivacurium can lead to inadequate intubating conditions following administration of a 2× ED ₉₅ dose as it is being metabolized while a block is developing. Recommendations have been made to monitor onset of NMBAs at the orbicularis oculi rather than the adductor pollicus since the more centrally located neuromuscular unit of the orbicularis oculi more accurately represents onset of block in the muscles of the airway than response of the adductor pollicis to stimulation. Use of the larger doses of mivacurium, 0.3 mg/kg, administered as a rapid intravenous bolus, can cause hypotension and tachycardia—especially in hemodynamically compromised patients. These hemodynamic changes are due to histamine release that occurs with administration of mivacurium at 0.2 mg/kg or greater. Hemodynamic side effects of large doses of mivacurium can be mitigated by use of divided doses to administer a large dose without histamine release.

Steroidal Compounds

Pancuronium

Pancuronium (see Fig. 22.6 ) is the only available NMBA with a long duration of action. It was the first of the steroidal agents introduced into clinical practice (1968). While once widely used, its use has become increasingly infrequent since the introduction of shorter-acting compounds. Doses of 0.08 and 0.1 mg/kg used for tracheal intubation have durations of action (the time from administration to 25% recovery of muscle function) of 86 and 100 minutes, respectively. Its long duration of action is due to its primary elimination through the kidney. While it undergoes some deacetylation in the liver, it is primarily eliminated through the kidney—resulting in its long duration of action.

Patients with liver disease due to either cholestasis or cirrhosis have an increase in the volume of distribution of pancuronium, which contributes to the relative resistance of these patients to pancuronium-induced block. However, clearance of pancuronium in these patients is decreased, and elimination half-life and duration of action are prolonged.

As would be predicted, clearance of pancuronium is decreased and elimination half-life is prolonged in patients with renal failure. Similarly, clearance is decreased and duration of action of pancuronium is prolonged in patients of advanced age. With an increase in duration of action of about 30 minutes from 44 minutes to 73 minutes, there is an appreciable increase in the interval at which repeat doses are to be administered to maintain a stable depth of block in elderly individuals.

Vecuronium

Vecuronium (see Fig. 22.6 ) was the first nondepolarizing NMBA with an intermediate duration of action to be introduced into clinical practice. With both a shorter duration of action and a lack of hemodynamic side effects, it set a standard against which all subsequent NMBAs were compared. Vecuronium is a potent NMBA (ED ₉₅ is 0.05 mg/kg) with a duration of action of 40 minutes. Typically, twice the ED ₉₅ is administered to facilitate tracheal intubation. Doses of 5 to 6 times the ED ₉₅ can be administered for more rapid onset of effect without significant hemodynamic side effects.

Vecuronium is the 2-desmethyl derivative of pancuronium. The lack of one methyl group at the quaternary ammonium of the 2 position increases its lipid solubility and significantly alters its degree of metabolism. While it undergoes more hepatic metabolism than pancuronium, it is primarily eliminated unchanged in the urine and bile: up to 40% is cleared through the bile and 20% to 30% is eliminated in the urine. The remainder of the compound is metabolized by the liver to 3-desacetylvecuronium, 17-desacetylvecuronium and 3,17-desacetylvecuronium ( Fig. 22.11 ). The 3-desacetyl metabolite has neuromuscular blocking activity. While only 5% is excreted in the urine as the 3-desacetyl metabolite, the prolonged duration of action of vecuronium in critically ill patients with renal failure has been attributed to accumulation of this metabolite.

Metabolism of vecuronium. Metabolism in the liver leads to the primary metabolite, 3-desacetyl vecuronium, which is almost as potent as vecuronium and is cleared more slowly from the plasma.

(From Agoston S, Seyr M, Khuenl-Brady KS, et al. Use of neuromuscular blocking agents in the intensive care unit. Anesthesiol Clin North Am . 1993;11:345–359.)

The elimination half-life of vecuronium is not as reliably prolonged and the clearance not consistently decreased in patients with renal failure as they are with pancuronium. This is likely because the liver is the primary route of clearance of vecuronium. There is a tendency for elimination half-life and duration of action to be increased with renal failure. Decreased vecuronium infusion rates are required to maintain a stable depth of block and maintenance doses have an increased duration of action in patients with renal failure. Although vecuronium can be used safely in these patients, dose requirements can be unpredictable.

The impact of hepatic failure on the pharmacodynamics of vecuronium is more predictable owing to its dependence on the liver for its elimination. Volume of distribution is increased, clearance is decreased, and elimination half-life prolonged in patients with either cholestasis or cirrhosis. Accordingly, the duration of action of vecuronium is increased in this patient population.

In elderly patients, the clearance of vecuronium is decreased by 30% to 55% and elimination half-life is increased by 60%. This results in a 3-fold prolongation of the 25% to 75% recovery interval (the time from recovery from 25% of baseline muscle strength to 75% of muscle strength) of vecuronium following either a bolus dose of 0.1 mg/kg or an infusion to maintain 90% suppression of twitch height for 90 minutes. In one study of the dynamics and kinetics of vecuronium in the elderly, after discontinuation of a steady-state infusion of vecuronium to 70% to 80% depression of twitch response, there was no difference in recovery interval between groups. The difference in the results of this study is difficult to explain but might be due to administration of vecuronium just sufficient to establish neuromuscular block before being allowed to recover.

Rocuronium

Rocuronium (see Fig. 22.6 ) has an intermediate duration of action and an onset that is more rapid than either vecuronium or atracurium. With an ED ₉₅ of 0.3 mg/kg, it is about six times less potent than vecuronium. A dose of 2 times the ED ₉₅ , rocuronium has an onset of less than 2 minutes and a clinical duration of less than 40 minutes. Increasing the dose of rocuronium to shorten its onset of effect increases its duration of action.

Rocuronium, like vecuronium, is eliminated primarily through hepatobiliary excretion with < 1% metabolism. Since only 10% is eliminated through the kidneys, it is even less dependent on renal elimination than vecuronium. In patients with renal failure, the clearance of rocuronium is either marginally decreased or unchanged, the volume of distribution is increased, and the elimination half-life is prolonged. The duration of action of single and repeat doses of rocuronium can be prolonged in patients with hepatic failure. This is due to a decrease in its clearance and an increase in its volume of distribution.

Advanced age impacts the pharmacokinetics and duration of action of rocuronium. The duration of effect of repeat doses is prolonged and the clinical duration of 0.6 mg/kg is almost doubled. Clearance of the compound is significantly decreased in this patient population.

Respiratory Effects

A summary of the effects of subtle degrees of residual neuromuscular block on respiratory function and pharyngeal patency is presented in Table 22.3 . In volunteers, even slight neuromuscular block, as reflected by a TOFR at the adductor pollicis muscle of 0.8 to 0.9, impairs the hypoxic ventilatory response and increases the risk of upper airway collapse. A TOFR of 0.8, and possibly even 0.9, is associated with alterations in upper airway closing pressure (P _crit ), upper airway dilatory muscle function, and airway volume during inspiration. Of note, tidal volume, vital capacity, and lung volume are typically normal at this low level of residual neuromuscular block. Thus, residual neuromuscular block can be present in the muscles of the upper airway at levels of block at which the respiratory muscles are unaffected. These effects are difficult to measure and can go undetected by the clinician.

Risk of Airway Collapse

To maintain upper airway patency during inspiration, the forces generated by the respiratory “pump” muscles, which decrease intraluminal upper airway pressure and therefore tend to collapse the airway, have to be balanced by reflex dilating forces of the pharyngeal musculature. In the absence of neuromuscular block, this stability is maintained in part by the genioglossus muscle, the activity of which almost quadruples at negative pharyngeal pressures. This compensatory increase in the activity of the genioglossus muscle with inspiration is markedly impaired during even minimal neuromuscular block (TOFR = 0.8; see Fig. 22.12 ). This leads to an increase in airway collapsibility and a decrease in airflow with inspiration. Partial paralysis markedly increases P _crit to less negative values so that the airway collapses more easily during inspiration. The relationship between the decrease in genioglossus activity caused by neuromuscular block and its effects on P _crit and airflow are shown in Fig. 22.12 . As a result of the susceptibility of the upper airway to collapse during inspiration with minimal degrees of neuromuscular block, forced inspiratory volume in 1 second (FIV ₁ ) is markedly impaired, while forced expiratory volume is maintained during partial paralysis.

Effects of neuromuscular blockade on upper airway patency. Panel A displays the upper airway critical closing pressure (P _crit ) and the airway pressure associated with the beginning of flow limitation during inspiration in awake healthy volunteers at baseline before neuromuscular blockade, with impaired neuromuscular transmission at train-of-four (TOF) ratios of 0.5 and 0.8 and after recovery of the TOF ratio to unity. Upper airway closing pressure (blue bars) significantly increased during partial neuromuscular blockade and was still abnormal once the TOF ratio recovered to unity. Evidence of flow limitation (purple bars) was first observed at an average pressure of −12 cm H ₂ O. With a TOF ratio of 0.5 or 0.8, flow limitation occurred at significantly less negative values of mask pressure, indicating impairment of airway integrity. P < 0.05 versus baseline. Panel B shows genioglossus muscle activity as a function of negative mask pressure without (circles) and with (triangles) partial neuromuscular blockade at a TOF ratio of 0.5. Genioglossus activity increases markedly as negative pressure is applied, but this effect is attenuated with partial neuromuscular block. P < 0.05 versus baseline (same mask pressure); P < 0.05 versus mask pressure +5 cm H ₂ O (same level of neuromuscular function). AU, Arbitrary units; MTA, moving time average.

(Adapted from Eikermann M, Vogt FM, Herbstreit F, et al. The predisposition to inspiratory upper airway collapse during partial neuromuscular blockade. Am J Respir Crit Care Med . 2007;175:9–15).

In addition to maintenance of airway patency, the genioglossus muscle has an integral role in swallowing. Genioglossus activity during swallowing and maximum voluntary tongue contraction are impaired during residual neuromuscular block (see Table 22.3 ). An increased incidence of misdirected swallowing and a decreased upper esophageal sphincter resting tone occur with minimal neuromuscular blockade (TOFR = 0.5–1) and persists even with recovery of the TOFR to unity.

Difficulty swallowing can lead to aspiration. Although the pharyngeal constrictor muscle is minimally affected, there is reduced upper esophageal sphincter tone with partial neuromuscular blockade. The greater vulnerability of the upper airway muscles to NMBAs cannot be explained by a higher density of nicotinic acetylcholine receptors, differences in fiber size, or differences in fiber-type composition. Some evidence suggests that the sensitivity of the airway dilator muscles to the effects of NMBAs may be explained at least in part by the rapid firing rate of the motor neurons innervating the muscle. Neuromuscular blocking drugs produce a progressive failure of neuromuscular transmission with increasing rates of stimulation. The TOF stimulation that is typically used to test the strength of the adductor pollicis uses a stimulation rate of 2 Hz. In contrast, the firing frequency of the genioglossus muscle during quiet breathing is significantly greater. It is also greater than that of the diaphragm (8–13 Hz as compared to 15–25 Hz at the genioglossus). This may explain the greater sensitivity of the genioglossus muscle to NMBAs and why the genioglossus muscle is more susceptible to NMBAs than the adductor pollicis, as assessed by stimulation at 2 Hz.

Sensitivity of the Musculature of the Airway to Residual Block

There is a growing body of evidence that postoperative residual block results not only in physiologic impairment but also in increased perioperative risk and health care–related costs. While the symptoms of residual neuromuscular block are difficult to recognize, the subtle effects of NMBAs can result in clinically significant consequences. The incidence of critical respiratory events—including hypoxemia, hypoventilation, and upper airway obstruction following anesthesia—increases with both the dose and duration of action of an NMBA. Minimal neuromuscular block, defined by a TOFR of 0.7 or 0.8, is associated with an increased incidence of adverse respiratory events, including airway obstruction, moderate to severe hypoxemia, and the development of atelectasis and pneumonia. In addition to the effects of propofol and other anesthetics on airway tone, even very low levels of residual block can impair skeletal muscle strength and increase patient discomfort after an anesthetic, which can delay readiness for discharge after an ambulatory surgical procedure.

Residual neuromuscular block can also have economic consequences. Length of stay in the postanesthesia care unit is significantly longer in patients with a TOFR less than 0.9 compared to patients with a greater degree of recovery of neuromuscular transmission. This results in delayed discharge and substantially increases the chance that other patients will have to wait to enter the recovery area because of lack of available of space. In addition, large doses of NMBAs have been associated with increased costs of care and an increased risk of readmission to the hospital within 30 days.