NMB and reversal.pdf

22 Neuromuscular Blockers and Reversal Drugs CYNTHIA A. LIEN AND MATTHIAS EIKERMANN CHAPTER OUTLINE Historical Perspective Neuromuscular Blocking Agents Clinical Utility Effects in Different Muscle Groups Monitoring Neuromuscular Function Modes of Stimulation Train-of-Four Double-Burst Stimulation S...

22 Neuromuscular Blockers and Reversal Drugs CYNTHIA A. LIEN AND MATTHIAS EIKERMANN CHAPTER OUTLINE Historical Perspective Neuromuscular Blocking Agents Clinical Utility Effects in Different Muscle Groups Monitoring Neuromuscular Function Modes of Stimulation Train-of-Four Double-Burst Stimulation Structure–Activity Relationships Neuromuscular Blocking Activity Onset of Block Recovery From Neuromuscular Block Neuromuscular Blocking Agents Depolarizing Neuromuscular Blocking Agents: Succinylcholine Structure and Metabolism Pharmacodynamics Adverse Effects Nondepolarizing Neuromuscular Blocking Agents Benzylisoquinolinium Compounds Steroidal Compounds Postoperative Residual Neuromuscular Block Respiratory Effects Risk of Airway Collapse Sensitivity of the Musculature of the Airway to Residual Block Use in Critical Care Antagonism of Residual Neuromuscular Block Anticholinesterases Determinants of Speed and Adequacy of Recovery Adverse Effects Dosing Pharmacokinetics and Pharmacodynamics Sugammadex Emerging Developments Fumarates Calabadion Historical Perspective The nondepolarizing neuromuscular blocking agent (NMBA) d-tubocurarine has been used for 500 years as a paralyzing poison. In the 16th century, Sir Walter Raleigh reported that hunters in South America were using darts and arrows dipped in curare to paralyze their living targets. Curare, the poison of the plant Strychnos toxifera, and its active component, d-tubocurarine, were isolated in the 1930s.1,2 d-Tubocurarine was introduced into clinical practice in 1942 to induce neuromuscular block.3 It was not widely used until the second half of the 20th century, when maintenance of neuromuscular blockade during surgery became widely accepted.4 Clinical use of these agents facilitates endotracheal intubation and mechanical ventilation, improving surgical conditions,4 and recent data suggest that neuromuscular blocking agents have the potential to improve the outcome in patients with respiratory distress syndrome.5 Since the introduction of d-tubocurarine into clinical practice, the use of NMBAs has become common. In 2010, more than 100 million patients received NMBAs throughout the world, 80% of them nondepolarizing NMBAs. While the use of NMBAs has allowed the development of modern anesthesia and surgery,6 their use is not without risk. Shortly after the introduction of NMBAs into clinical practice, Beecher and Todd reported an increased mortality in patients who had received NMBAs as part of their anesthetic.7 While their conclusions on cause and effect have been criticized,8 it has now become clear that residual effects of NMBAs can adversely impact patient outcome.9,10 As reported by Beecher, unrecognized residual paralysis negatively affects ability to breathe and protect the airway. While the introduction of the intermediate-acting NMBAs rocuronium, vecuronium, and cisatracurium into clinical practice in the early 1990s initially decreased the incidence of residual neuromuscular blockade,11 more recent data indicate that as surgical and anesthetic practices and the definition of inadequate recovery of neuromuscular function have evolved, the incidence of residual neuromuscular block, even with these shorter-acting compounds, remains high.12,13 Neuromuscular Blocking Agents Clinical Utility Administration of NMBAs for tracheal intubation decreases the incidence of postoperative upper airway trauma-related symptoms14–16 428 Downloaded for Vicente Gonzalez ([email protected]) at Florida International University from ClinicalKey.com by Elsevier on April 29, 2024. For personal use only. No other uses without permission. Copyright ©2024. Elsevier Inc. All rights reserved. CHAPTER 22 Neuromuscular Blockers and Reversal Drugs 428.e1 Abstract Keywords Nondepolarizing neuromuscular blocking agents were introduced into clinical practice more than 60 years ago. Throughout the world, millions of patients receive neuromuscular blocking agents as part of their general anesthetic each year. With use, increased recognition of complications, pharmacologic advances, the ability to monitor depth of neuromuscular blockade, and changes in surgical practice, a better understanding of neuromuscular blockade and its reversal is developing. Because of this, long-acting neuromuscular blocking agents are rarely, if ever, used in the clinical setting; new neuromuscular blocking agents that can be easily reversed and new reversal agents that can reverse even profound neuromuscular blockade are being developed. The goal of this work is to ensure that neuromuscular blockade can be easily, quickly, and reliably reversed and that the safety of providing neuromuscular blockade intraoperatively will increase. neuromuscular blockade residual neuromuscular blockade nondepolarizing neuromuscular blocking agents reversal agents sugammadex neostigmine Downloaded for Vicente Gonzalez ([email protected]) at Florida International University from ClinicalKey.com by Elsevier on April 29, 2024. For personal use only. No other uses without permission. Copyright ©2024. Elsevier Inc. All rights reserved. CHAPTER 22 Neuromuscular Blockers and Reversal Drugs 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.23 In clinical practice, the response of the adductor pollicis muscle to stimulation of the ulnar nerve is recommended for monitoring, 100 80 T1 (%) by decreasing the likelihood of tissue trauma, including vocal cord injury and resulting postoperative hoarseness.15 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.17 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.18 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.19 Whether profound paralysis (post-tetanic count of 1–3) always improves surgical conditions is currently a matter of debate19–21; 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.22 429 Laryngeal adductors 60 40 Adductor pollicis 20 0 0 5 10 15 20 25 30 35 40 Time (min) Fig. 22.1 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.) 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 block24,25 (Fig. 22.1). This has been attributed to different blood flow to these different muscles.26 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. Monitoring Neuromuscular Function The degree of interpatient variability regarding the effects of NMBAs and the potential adverse consequences of their residual effects at the conclusion of an anesthetic are the reasons for the importance of adequately monitoring their effects in clinical practice. Unfortunately, it is not possible to detect reliably residual neuromuscular block with either clinical tests of muscle strength27 or with commonly used qualitative monitors of neuromuscular function.28,29 Reduced strength of contraction during repetitive stimulation of a peripheral nerve is observed with neuromuscular transmission failure, as in myasthenia gravis,30 and during recovery from NMBAs. Proper muscle function requires different degrees of reserve in terms of neuromuscular transmission depending on the test chosen to assess strength. The ability of a test to measure the effects of an NMBA increases with the force of output required to pass the Downloaded for Vicente Gonzalez ([email protected]) at Florida International University from ClinicalKey.com by Elsevier on April 29, 2024. For personal use only. No other uses without permission. Copyright ©2024. Elsevier Inc. All rights reserved. 430 SE C T I O N II Nervous System test. Assessment of fade during a supramaximal 100 Hz tetanic stimulation can detect subtle effects of NMBAs, whereas twitch height after low-frequency stimulation (e.g., 0.1–1 Hz) decreases only after blockade of 90% of acetylcholine receptors.31 This is clinically important, as clinicians typically assess neuromuscular function using nontetanic stimulation of peripheral skeletal muscles, usually TOF or double-burst stimulation (DBS). While tetanus will detect more subtle degrees of neuromuscular block, it is not a commonly used monitor of residual neuromuscular block. Tetanic stimulation is exceptionally uncomfortable for the patient who is not deeply anesthetized. In addition, interpretation of the significance of fade in the response to tetanic stimulation is difficult and the degree of fade has not been correlated with the TOF response. Therefore, its utility is of relatively limited clinical value. Modes of Stimulation Train-of-Four The technique of train-of-four monitoring was introduced into clinical practice in 1970.32 For measurement of the TOF response, muscle contraction is induced by stimulation of the corresponding motor nerve 4 times with a frequency of 2 Hz. Any superficial neuromuscular unit can be monitored in this fashion. In response to TOF stimulation, the TOF ratio (TOFR) is the ratio of the amplitude of the fourth response to the first response.33 If neuromuscular transmission is intact, TOF stimulation causes 4 twitches with essentially identical amplitudes and a resulting TOFR of 0.9 to 1.0. In contrast, after complete relaxation, TOF stimulation does not result in any muscle contraction and the TOF count (number of responses to TOF stimulation) is zero. Return of the first twitch is described as a TOF count of 1. This is followed by consecutive recovery of the second, third, and fourth twitches (TOF counts of 2, 3, and 4, respectively). Once the fourth response to stimulation has returned, the fade between the first and the fourth twitch responses can be measured as the TOFR. For example, if the amplitude of the fourth twitch is 50% of the amplitude of the first twitch, the TOFR is 0.5. The TOF count can also be used to estimate the recovery of the first twitch in the TOF to baseline values. When the first response in the TOF returns, strength of the first response is approximately 10% of baseline values. Similarly, return of the second, third, and fourth responses corresponds to recovery of the first twitch in the TOF to approximately 20, 35, and 45% of baseline values. While the TOF will measure residual paralysis, ability to accurately detect degree of fade in the TOF response is not reliable once the TOFR has recovered to 40% or more.34 In other words, it is impossible to reliably detect fade in the TOFR if there is anything less than 60% fade, and a TOFR of 92% looks and feels the same as a TOFR of 52%. Double-Burst Stimulation DBS was developed to improve detection of residual neuromuscular block.29 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 ED95 (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.14 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.35 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.14 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.36,37 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.38 As shown in Fig. 22.2,14 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 doses39–41 (see Fig. 22.2). This emphasizes the importance of monitoring depth of neuromuscular block throughout surgery to avoid overdosing. While the most commonly used monitors of depth of neuromuscular block are qualitative monitors,42 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),43 as twitch height at a TOFR between 0.4 and 1.0 is likely to be perceived as 4 responses that are similar.30,44 Optimally, quantitative methods for measurement of the evoked muscular response should be used. Commercially available techniques include mechanomyography, electromyography, kinemyography, and acceleromyography.45,46 Structure–Activity Relationships Neuromuscular Blocking Activity Structure–activity relationships of NMBAs can affect neuromuscular blocking activity, pharmacokinetic properties, and side effect profiles.47,48 Since the early classification of NMBAs as rigid bulky molecules with amine functions incorporated into ring structures,49 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).144 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 Downloaded for Vicente Gonzalez ([email protected]) at Florida International University from ClinicalKey.com by Elsevier on April 29, 2024. For personal use only. No other uses without permission. Copyright ©2024. Elsevier Inc. All rights reserved. CHAPTER 22 Neuromuscular Blockers and Reversal Drugs Rocuronium 0.1 mg/kg Rocuronium 1 mg/kg 80 Recovery time (min) Twitch (ACM) 100 80 60 40 20 0 Baseline 60 40 20 0 Peak effect A: Low dose NMBA: variability of peak effect A 431 B Peak effect TOF-ratio 0.8 B: High dose NMBA: variability of recovery time Fig. 22.2 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.) Helical domains within each subunit (M1, M2, M3, and M4) N terminus from the 4 subunits ACh α M1 M4 M2 β M3 ACh δ Na = K > Ca Lipid bilayer ε α 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.) four transmembrane domains (M1, M2, M3, and M4). The M2 domain of each subunit creates the central ion pore (see Fig. 22.3). 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 Ca2+ 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 agonists50,51 and competitive antagonists.52 The fetal α-γ binding site is generally more sensitive than the mature α-ε one.52 The α-γ binding site has up to a 500-fold greater affinity for d-tubocurarine than does the α-δ Fig. 22.4 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.) binding site.53 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.54 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.55,56 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-tubocurarine57 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.57 Different Downloaded for Vicente Gonzalez ([email protected]) at Florida International University from ClinicalKey.com by Elsevier on April 29, 2024. For personal use only. No other uses without permission. Copyright ©2024. Elsevier Inc. All rights reserved. 432 SE C T I O N II Nervous System affinities at each of these sites might account for some of the synergism observed when different NMBAs are administered to the same patient.58 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 acetylcholinecontaining 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.59 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.60,61 concentration gradient to the acetylcholine receptors of the neuromuscular junction. This has been found for the aminosteroid compounds,65 a series of tetrahydroisoquinolinium chlorofumarates,66 3 structurally unrelated compounds with long durations of action67 and for compounds of different durations of action and structure.68 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 ED95 greater than 0.1 mg/kg is necessary for a rapid onset of effect.69 In order to exert its effect, an NMBA must be able to enter the neuromuscular junction, which is facilitated by its lipophilicity.70 The speed of onset of neuromuscular block after administration of an NMBA is also related to the speed of recovery of neuromuscular function.71 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).70,72–74 Because of this, equipotent doses of mivacurium75 or succinylcholine76 have a slower onset of effect in patients who are homozygous for atypical butyrylcholinesterase. 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.61,77,78 300 Onset of neuromuscular block is proportional to the dose of NMBA administered and is typically described in terms of multiples of the ED95 (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),35 more frequent and severe side effects,62,63 and the limited benefit of increasing the dose beyond a certain point.64 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 TABLE Intubating Doses of Neuromuscular 22.1 Blocking Agents Neuromuscular Blocking Agent Approximate ED95 (mg/kg) Intubating dose (× ED95) Pancuronium 0.07 1–1.5 Rocuronium 0.30 2–4 Vecuronium 0.05 2–4 Atracurium 0.25 2 Cisatracurium 0.05 3–5 Concentration (µg/L) Onset of Block 200 A B B 100 A 0 0 5 10 15 20 Time (min) Fig. 22.5 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.) Downloaded for Vicente Gonzalez ([email protected]) at Florida International University from ClinicalKey.com by Elsevier on April 29, 2024. For personal use only. No other uses without permission. Copyright ©2024. Elsevier Inc. All rights reserved. CHAPTER 22 Neuromuscular Blockers and Reversal Drugs O 2 3 O A 17 16 H Vecuronium O O O N+ H N H H HO H H Depolarizing Neuromuscular Blocking Agents: Succinylcholine O N H N+ O Neuromuscular Blocking Agents Rocuronium O C N+ H H O B short durations of action and are metabolized by butyrylcholinesterase. Two more recently studied compounds, gantacurium79–81 and CW002,81–83 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.84,85 O H N + H H Pancuronium O Fig. 22.6 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.68,69 Replacement of the methyl group at the quaternary nitrogen with a larger allyl group contributes to a decrease in potency.68,70,71. CH3 O + CH3 N CH2 CH2 O C CH3 CH3 Acetylcholine CH3 + O O CH3 + CH3 N CH2 CH2 O C CH2 CH2 C O CH2 CH2 N CH3 CH3 433 CH3 Succinylcholine Fig. 22.7 The chemical structure of succinylcholine. It is comprised of 2 molecules of acetylcholine groups bound together at their acetate methyl groups. 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 Structure and Metabolism Succinylcholine is comprised of 2 molecules of acetylcholine bound at their acetate methyl groups (see Fig. 22.7). This structural similarity to acetylcholine allows it to stimulate acetylcholine receptors as an agonist, causing muscle depolarization. Unlike acetylcholine, it is not a substrate for the acetylcholinesterase found at the neuromuscular junction that terminates normal neuromuscular transmission. Rather, its neuromuscular blocking activity is terminated by diffusion out of the neuromuscular junction into plasma, where it is hydrolyzed by butyrylcholinesterase (also known as plasma cholinesterase) to succinylmonocholine and choline. While succinylmonocholine is also a depolarizing agent, it is less potent than its parent compound succinylcholine. The hydrolysis of succinylcholine by butyrylcholinesterase accounts for its short elimination half-life, which is estimated to be less than 1 minute.86 Pharmacodynamics The ED95 of succinylcholine is 0.3 to 0.6 mg/kg.87,88 Because of its mechanism of action, rapid clearance and relative lack of potency (ED95 > 0.1 mg/kg), its onset of effect is faster than that of any other available neuromuscular blocking drug. A dose of 1 mg/kg results in complete block in 1 minute,89,90 and recovery to a twitch height of 90% in 13 minutes or less.91 Slightly larger doses may be required to achieve complete neuromuscular block of all muscles during tetanic stimulation.92 Recovery of neuromuscular function after administration of succinylcholine is prolonged by reduced concentration or activity of butyrylcholinesterase. Reduced butyrylcholinesterase—whether because of malnutrition, chronic disease, pregnancy, or medications—prolongs the duration of action of succinylcholine.93–101 Since spontaneous recovery occurs faster than with any available nondepolarizing NMBA, the increased duration of action is not usually appreciated in the clinical setting. Significant decreases in butyrylcholinesterase activity can double the time required for full recovery of 100% twitch response from 10 to 22 minutes.91 In contrast, patients who are homozygous for atypical butyrylcholinesterase metabolize succinylcholine much more slowly such that the depolarizing NMBA becomes a long-acting neuromuscular blocking agent. The dibucaine number is used to identify individuals who have an atypical genotype for butyrylcholinesterase. Dibucaine inhibits normal butyrylcholinesterase more than it does the abnormal Downloaded for Vicente Gonzalez ([email protected]) at Florida International University from ClinicalKey.com by Elsevier on April 29, 2024. For personal use only. No other uses without permission. Copyright ©2024. Elsevier Inc. All rights reserved. 434 SE C T I O N II Nervous System enzyme. It will inhibit normal butyrylcholinesterase activity by about 80%; in individuals who are homozygous for the atypical variant, dibucaine inhibits the activity by only 20%. The enzyme activity of individuals who are heterozygous for atypical butyrylcholinesterase is inhibited by approximately 50%. Clinical management of patients homozygous for atypical butyrylcholinesterase who have received succinylcholine involves conservative management with ventilator support and continued sedation until spontaneous recovery. Prolonged block with succinylcholine, based on monitoring of neuromuscular function, appears similar to that of a nondepolarizing agent with fade in the TOF response. Administration of an anticholinesterase to facilitate recovery of neuromuscular function is unlikely to be effective since it will also inhibit butyrylcholinesterase,102–104 further slowing hydrolysis of the compound. Adverse Effects Adverse effects associated with administration of succinylcholine are numerous (Table 22.2), most of which are due to its depolarizing action. Since it stimulates autonomic nervous system cholinergic receptors, all types of arrhythmias–including tachycardia, bradycardia, junctional rhythms, and ventricular dysrhythmias—may occur (see Chapter 13). To some extent, cardiac dysrhythmias following succinylcholine administration are dose related. Large doses can cause tachycardia105 and, in adults, administration of a second dose within a few minutes of the first can cause bradycardia or a nodal rhythm.106 Succinylcholine also lowers the threshold for arrhythmias induced by circulating catecholamines and increases circulating catecholamine levels.107 Succinylcholine activates acetylcholine receptors, causing depolarization and activation of perijunctional voltage-gated Na+ channels, which allows generation of muscle contraction to neural stimulation (see Chapter 21). Opening of muscle acetylcholine receptors and voltage-gated Na+ channels allows Na+ influx and K+ efflux. In healthy patients, this typically results in an increase in plasma K+ of 0.5 mEq/L. In patients with significant burns,108 hemiparesis, or any other pathologic process that causes proliferation of extrajunctional nicotinic receptors,109–114 the response to succinylcholine can be exaggerated due to activation of α-7 receptors, which have a prolonged response to agonists, as well as extrajunctional nicotinic receptors.115 The resulting hyperkalemia can be great enough to result in dysrhythmias and cardiac arrest. Critically ill patients could be at high risk of hyperkalemia after succinylcholine because one or more factors producing nicotinic receptor upregulation can be present. The risk of hyperkalemia after succinylcholine injection is strongly associated with the length of ICU stay; TABLE Adverse Effects of Succinylcholine 22.2 Cardiac dysrhythmias Hyperkalemia Myalgias Masseter spasm Increased intracranial pressure Increased intragastric pressure Increased intraocular pressure succinylcholine should not be administered for that reason in patients who stayed in an ICU for longer than 1 to 2 weeks.116,117 The mechanisms of increases in intragastric, intracranial, and intraocular pressure are probably less clinically relevant and have not been fully elucidated but include muscular contraction due to activation of acetylcholine receptors and cortical neuronal activation by stretch receptors. The observed increases can be attenuated by prior administration of small doses of nondepolarizing NMBAs, such as 3 mg d-tubocurarine, 1 mg pancuronium, or 1 mg vecuronium, 2 to 3 minutes prior to administration of succinylcholine.118-120 When administered with volatile anesthetics to susceptible patients, succinylcholine can trigger malignant hyperthermia, although by itself it is a weak trigger.121 A recent review article122 describes the pharmacology of triggering agents in malignant hyperthermia (see Chapter 21). 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 ED95 of 0.2 to 0.25 mg/kg123 and an intermediate duration of action. Following administration of two times the ED95, maximal block occurs in 2.5 minutes, recovery to 10% of baseline twitch amplitude (approximately 1 twitch in the TOF) occurs in 40 minutes,124 and complete spontaneous recovery of neuromuscular function in about 60 minutes.123 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.125,126 While some studies have found that ester hydrolysis can be responsible for metabolism of as much as 66% of an atracurium dose,127 and that renal elimination can have a larger role in the pharmacokinetics of atracurium than initially appreciated,128 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.125,129 Alkalosis increases resistance to atracuriuminduced neuromuscular block,130 while hypothermia slows the temperature-dependent breakdown so that less atracurium is required to maintain a given depth of neuromuscular block.131,132 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.123,133,134 Thus, sequential doses administered at the same point in spontaneous recovery have the same recovery characteristics as the preceding dose. With continuous Downloaded for Vicente Gonzalez ([email protected]) at Florida International University from ClinicalKey.com by Elsevier on April 29, 2024. For personal use only. No other uses without permission. Copyright ©2024. Elsevier Inc. All rights reserved. CHAPTER 22 Neuromuscular Blockers and Reversal Drugs CH3O O N CH3 CH3O + 435 O CH2 CH C O (CH2)5 O C CH CH2 Pentamethylenediacrylate Laudanosine OCH3 OCH3 Hofmann elimination CH3O + CH3O X N CH3 O O CH2 CH2 C O (CH2)5 OCH3 CH3 O C CH CH2 N OCH3 – + OCH3 Monoacrylate CH3O OCH3 Laudanosine OCH3 Hofmann elimination CH3O + CH3O X N CH3 O O CH2 CH2 C O (CH2)5 CH3 O C CH2 CH2 – N OCH3 X OCH3 OCH3 Atracurium OCH3 + CH3O – OCH3 Ester hydrolysis CH3O + CH3O X Quaternary acid N CH3 O CH2 CH2 C OH O + HO (CH2)5 CH3 O C CH2 CH2 OCH3 + N – OCH3 X OCH3 CH3O OCH3 – OCH3 Ester hydrolysis O HO (CH2)5 OH + CH3 HO C CH2 CH2 Pentamethylene-1,5-diol OCH3 + N OCH3 X CH3O Quaternary alcohol – OCH3 Quaternary acid Fig. 22.8 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.) infusion, no dosing revisions are required to maintain a stable depth of neuromuscular block, even with prolonged infusions.135,136 With prolonged infusions of atracurium, the elimination halflife is about 20 minutes137–140 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.139,141,142 Similarly, elimination half-life is not prolonged in patients with cirrhosis.143 Normal aging is accompanied by a number of physiologic changes, including decreases in hepatic and renal blood flow and Downloaded for Vicente Gonzalez ([email protected]) at Florida International University from ClinicalKey.com by Elsevier on April 29, 2024. For personal use only. No other uses without permission. Copyright ©2024. Elsevier Inc. All rights reserved. 436 SE C T I O N II Nervous System function along with changes in the anatomy and function of the neuromuscular junction.144 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.145 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.146 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.147,148 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. 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× ED95) is 45 minutes. Doubling the dose to 4× ED95 increases it to 68 minutes and doubling it again to 8× ED95 increase it by another 23 minutes, equivalent to the elimination half-life of the compound.149 Hofmann elimination accounts for 77% of total clearance of cisatracurium and renal elimination 16%.152 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.153 In spite of these pharmacokinetic changes in patients with renal dysfunction, no prolongation of the duration of action is found following a bolus dose.154 As with atracurium, both volume of distribution and clearance of cisatracurium are increased in patients with hepatic failure.155 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.155 Recovery from cisatracurium-induced neuromuscular block occurs over the same time course in elderly surgical patients as it does in young adults.156,157 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%.156,157 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. 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 (ED95 of 0.05 mg/kg)147 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.147 For this reason, doses of 3 to 5 times the ED95 are recommended for endotracheal intubation.148 In contrast to atracurium, administration of these large doses is not associated with histamine release and the resultant hypotension or tachycardia.149,150 Like atracurium, cisatracurium undergoes Hofmann elimination. Clearance, elimination half-life, and volume of distribution are the same when doses of the ED95 or twice the ED95 are administered.151 The clinical duration of action (the time required from CH3O CH3 + CH3O N CH2 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. H O C C O H 3C O (CH2)5 O C CH2 CH2 OCH3 + N OCH3 H OCH3 OCH3 CH3O CH3O Fig. 22.9 Chemical structure of cisatracurium. Cisatracurium is the 1 R-cis 1′ R-cis stereoisomer that is one of 10 stereoisomers comprising atracurium. CH3O OCH3 +N CH3O CH3 O H O (CH2)3OCCH2CH2C CCH2CH2CO(CH2)3 H CH2 OCH3 OCH3 N+ H H CH3O CH3 OCH3 CH2 2CI− OCH3 CH3O OCH3 Fig. 22.10 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. Downloaded for Vicente Gonzalez ([email protected]) at Florida International University from ClinicalKey.com by Elsevier on April 29, 2024. For personal use only. No other uses without permission. Copyright ©2024. Elsevier Inc. All rights reserved. CHAPTER 22 Neuromuscular Blockers and Reversal Drugs The ED95 of mivacurium is 0.08 mg/kg and its in vitro elimination half-life is 3.1 minutes. 158 Its short duration is due to metabolism by butyrylcholinesterase158,159 to quaternary amino alcohols and quaternary monoesters.97 These metabolites are excreted in the urine with half-lives of 90 minutes.160 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. 161 Following administration of 0.2 mg/kg mivacurium (2.5× ED95 dose) to facilitate intubation, recovery to a TOFR of 0.7 occurred in less than 30 minutes,162 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.163 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.164,165 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.159,166,167 The short duration of action of mivacurium can lead to inadequate intubating conditions following administration of a 2× ED95 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.168 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.159 Hemodynamic side effects of large doses of mivacurium can be mitigated by use of divided doses to administer a large dose without histamine release.169 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.156,157 Its long duration of action is due to its primary elimination through the kidney.156 While it undergoes some deacetylation in the liver,156 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,170–172 which contributes to the relative resistance of these patients to pancuronium-induced block.173 However, clearance of pancuronium in these patients is decreased, and elimination half-life and duration of action are prolonged.170–172 437 As would be predicted, clearance of pancuronium is decreased and elimination half-life is prolonged in patients with renal failure.174,175 Similarly, clearance is decreased and duration of action of pancuronium is prolonged in patients of advanced age.176 With an increase in duration of action of about 30 minutes from 44 minutes to 73 minutes,176 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 (ED95 is 0.05 mg/kg) with a duration of action of 40 minutes.35,177,178 Typically, twice the ED95 is administered to facilitate tracheal intubation. Doses of 5 to 6 times the ED95 can be administered for more rapid onset of effect 179 without significant hemodynamic side effects.180 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 bile181,182 and 20% to 30% is eliminated in the urine.183,184 The remainder of the compound is metabolized by the liver to 3-desacetylvecuronium, 17-desacetylvecuronium and 3,17-desacetylvecuronium182,185 (Fig. 22.11). The 3-desacetyl metabolite has neuromuscular blocking activity.185,186 While only 5% is excreted in the urine as the 3-desacetyl metabolite,187 the prolonged duration of action of vecuronium in critically ill patients with renal failure has been attributed to accumulation of this metabolite.188 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.184,189–191 Decreased vecuronium infusion rates are required to maintain a stable depth of block191 and maintenance doses have an increased duration of action192 in patients with renal failure. Although vecuronium can be used safely in these patients, dose requirements can be unpredictable.193 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 prolonged194,195 in patients with either cholestasis or cirrhosis. Accordingly, the duration of action of vecuronium is increased in this patient population.183,194,196 In elderly patients, the clearance of vecuronium is decreased by 30% to 55%197,198 and elimination half-life is increased by 60%.197 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 vecuronium197,199 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 study198 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 study198 is difficult to explain but might be due to administration Downloaded for Vicente Gonzalez ([email protected]) at Florida International University from ClinicalKey.com by Elsevier on April 29, 2024. For personal use only. No other uses without permission. Copyright ©2024. Elsevier Inc. All rights reserved. 438 Nervous System SE C T I O N II OH N+ 17 CH3 N O CH3 C O H 17-Desacetyl vecuronium 17 Deacetylation O O O C CH3 O C CH3 17 N O N+ CH3 N+ Deacetylation CH3 N 3 3 H3C C O HO H H 3-Desacetyl vecuronium 2 Vecuronium 1 Deacetylation OH 17 N+ N CH3 3 HO Relative potency H 3,17-Desacetyl vecuronium 35 Fig. 22.11 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.) of vecuronium just sufficient to establish neuromuscular block before being allowed to recover. Rocuronium Rocuronium (see Fig. 22.6) has an intermediate duration of action35 and an onset that is more rapid than either vecuronium or atracurium.200 With an ED95 of 0.3 mg/kg,201–204 it is about six times less potent than vecuronium.201 A dose of 2 times the ED95, rocuronium has an onset of less than 2 minutes and a clinical duration of less than 40 minutes.35 Increasing the dose of rocuronium to shorten its onset of effect increases its duration of action.35 Rocuronium, like vecuronium, is eliminated primarily through hepatobiliary excretion with < 1% metabolism.205 Since only 10% is eliminated through the kidneys,206 it is even less dependent on renal elimination than vecuronium. In patients with renal failure, the clearance of rocuronium is either marginally decreased207 or unchanged,208 the volume of distribution is increased, and the elimination half-life is prolonged.208 The duration of action of single and repeat doses of rocuronium can be prolonged in patients with hepatic failure.209–211 This is due to a decrease in its clearance and an increase in its volume of distribution.209,210,212 Advanced age impacts the pharmacokinetics and duration of action of rocuronium. The duration of effect of repeat doses is prolonged213 and the clinical duration of 0.6 mg/kg is almost doubled.214 Clearance of the compound is significantly decreased in this patient population.214 Postoperative Residual Neuromuscular Block Postoperative residual neuromuscular block is not uncommon after an anesthetic during which NMBAs have been administered.11,40,41 More than 30 years ago, an evaluation of neuromuscular transmission following surgery found residual paralysis (TOFR < 0.7) in 42% of patients who had received gallamine, pancuronium, or d-tubocurarine.44 Intermediate-acting NMBAs were not yet available when that study was done. More recent studies report that residual block from intermediate-acting NMBAs can be present in one-third to two-thirds of patients following anesthesia.11,26,215 The frequency of residual neuromuscular blockade depends on the manner in which depth of block is monitored and the approaches used to reverse neuromuscular block at the conclusion of procedures.33,216–219 Pulmonary function—as defined by respiratory rate, tidal volume, forced expiratory volume, and forced vital capacity—is usually recovered once the TOFR is greater than or equal to 0.6 at the adductor pollicis muscle. Based on this information, a TOFR of 0.6 was historically felt to be adequate recovery from the effects of NMBAs. Recent data, though, suggest that even lesser degrees of neuromuscular blockade can adversely affect respiratory function, airway patency, and airway protective reflexes (i.e., coughing and swallowing). Downloaded for Vicente Gonzalez ([email protected]) at Florida International University from ClinicalKey.com by Elsevier on April 29, 2024. For personal use only. No other uses without permission. Copyright ©2024. Elsevier Inc. All rights reserved. CHAPTER 22 Neuromuscular Blockers and Reversal Drugs 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 TABLE Effects of Partial Neuromuscular Block on 22.3 Respiration MONITORING OF ADDUCTOR POLLICIS MUSCLE Ventilatory Function TOFR = 0.5 TOFR = 0.8 TOFR = 1.0 Tidal volume Normal Normal Normal Forced vital capacity ↓↓ Normal Normal Pharyngeal function (swallowing) ↓↓↓ ↓↓ ↓ Upper airway patency (closing pressure) ↓↓↓ ↓↓ ↓ Hypoxic respiratory response ↓↓ ↓↓ Normal TOFR, Train-of-four ratio. ↓↓↓: Consistently impaired ↓↓: Frequently impaired ↓: Usually normal risk of upper airway collapse.42,45,215,220–224 A TOFR of 0.8, and possibly even 0.9, is associated with alterations in upper airway closing pressure (Pcrit), upper airway dilatory muscle function, and airway volume during inspiration.219 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.222,225 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.225,226 Partial paralysis markedly increases Pcrit to less negative values219 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 Pcrit and airflow are shown in Fig. 22.12. As a result of the susceptibility of the upper airway to collapse during inspiration with minimal 0.12 –20 * * –30 * –40 Pcrit Onset of flow limitation –50 –60 A * Phasic genioglossus activity (MTA, AU) Mask pressure (cm H2O) 0 –10 * Baseline TOF 0.5 TOF 0.8 TOF 1.0 439 0.10 0.08 Baseline TOF 0.5 # 0.06 0.04 0.02 #* * * 0.00 –35 –30 –25 –20 –15 –10 B –5 Mask pressure (cm H2O) Fig. 22.12 Effects of neuromuscular blockade on upper airway patency. Panel A displays the upper airway critical closing pressure (Pcrit) 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 H2O. 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 H2O (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). Downloaded for Vicente Gonzalez ([email protected]) at Florida International University from ClinicalKey.com by Elsevier on April 29, 2024. For personal use only. No other uses without permission. Copyright ©2024. Elsevier Inc. All rights reserved. 0 +5 SE C T I O N II Nervous System degrees of neuromuscular block, forced inspiratory volume in 1 second (FIV1) is markedly impaired, while forced expiratory volume is maintained during partial paralysis. 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 block219,226 (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.225,227,228 Difficulty swallowing can lead to aspiration.227,228 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,229 differences in fiber size, or differences in fiber-type composition.230 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.231 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).232 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 risk226,227,233–235 and health care–related costs.236 While the symptoms of residual neuromuscular block are difficult to recognize,31,215,237,238 the subtle effects of NMBAs can result in clinically significant consequences.239,240 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.241 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.233,242,243 In addition to the effects of propofol and other anesthetics on airway tone,244 even very low levels of residual block can impair skeletal muscle strength237 and increase patient discomfort after an anesthetic,245–247 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.236 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.236 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.22 Use in Critical Care The most common indications for NMBAs in the intensive care unit (ICU) are to facilitate emergent intubation and mechanical ventilation in patients with acute respiratory failure, to reduce oxygen consumption, to prevent shivering, and to control intracranial hypertension.248 However, the use of NMBAs in critically ill patients is associated with side effects that are summarized in Table 22.4. The use of NMBAs can be associated with a decrease in procedure-related complications.249 However, severe complications can occur when insufficiently experienced individuals use NMBAs to facilitate emergent airway management.250 In order to control excessive ventilatory drive in patients with severe ARDS, short-term use of NMBAs in the ICU for treatment can be of some benefit5 (Fig. 22.13). As stated in the Clinical Practice Guidelines for Sustained Neuromuscular Blockade in the Adult Critically Ill Patient, NMBAs can be administered by continuous intravenous infusion early in the course of ARDS for patients with a PaO2/FIO2 less than 150.251 The mechanisms underlying this beneficial effect are unknown, but it is possible that lower TABLE Undesirable Effects of Neuromuscular Blocking 22.4 Agents in Critically Ill Patients Effect Mechanism Muscle weakness Persistent failure of neuromuscular transmission Critical illness polyneuropathy Immobilization-induced atrophy of diaphragm Impairment of ventilation– perfusion distribution Decreased right ventricular end-diastolic volume Spontaneous breathing abolished Posttraumatic stress syndrome Awareness during paralysis 1.0 0.9 0.8 Probability of survival 440 Cisatracurium 0.7 0.6 Placebo 0.5 0.4 0.3 0.2 0.1 0.0 0 10 20 30 40 50 60 70 80 90 Days after enrollment Fig. 22.13 Probability of survival through day 90 in patients with acute respiratory distress syndrome receiving cisatracurium to facilitate mechanical ventilation compared to those not receiving a neuromuscular blocking agent. (Adapted from Papazian L, Forel J-M, Gacouin A, et al. Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med. 2010;363:1107–1116.) Downloaded for Vicente Gonzalez ([email protected]) at Florida International University from ClinicalKey.com by Elsevier on April 29, 2024. For personal use only. No other uses without permission. Copyright ©2024. Elsevier Inc. All rights reserved. CHAPTER 22 Neuromuscular Blockers and Reversal Drugs transpulmonary pressures are associated with reduced barotrauma. However, reduction in transpulmonary pressure can also be achieved using sedative agents that lack the adverse effects of NMBAs.252 Both the benefits and risks of the use of NMBAs in critically ill patients must be considered when deciding on their use. For example, lack of spontaneous ventilation might decrease the incidence of barotrauma but, in patients with ARDS, breathing spontaneously with ventilator support improves matching of ventilation and perfusion. Additional data suggest that NMBAs exacerbate mechanical ventilation-induced diaphragmatic dysfunction253 and ICU-acquired muscle weakness.254 Data suggest that partial neuromuscular blockade facilitates lung-protective ventilation during partial ventilatory support while maintaining diaphragm activity in sedated patients with lung injury.255 Peripheral nerve stimulation with train-of-four assessment in conjunction with clinical assessment should be used for monitoring the depth of neuromuscular blockade.254 Antagonism of Residual Neuromuscular Block There are several means of enhancing recovery of neuromuscular function. These include increasing acetylcholine concentration at the neuromuscular junction or decreasing plasma concentrations of the NMBA through encapsulation and increased metabolism or increased elimination through the kidneys or liver (Fig. 22.14).256 Anticholinesterases Anticholinesterases used for reversal of neuromuscular blockade inhibit acetylcholinesterases at the neuromuscular junction,257 which ACh increases the concentration of acetylcholine at the motor endplate to overcome competitive block of nicotinic receptors by NMBAs.258 Cholinesterase inhibitors are the principal drugs used for reversal of NMBAs and, in some countries, remain the only option. There is significant variation in antagonism of residual neuromuscular blockade. In contrast to most European countries, where routine antagonism is not the typical practice,259 the majority of anesthesiologists in the United States antagonize the residual effects of nondepolarizing NMBAs at the end of surgery. This is accomplished through the combined administration of a cholinesterase inhibitor (e.g., neostigmine) and an antimuscarinic agent, such as glycopyrrolate.27,42 Routine antagonism of neuromuscular block is recommended by some anesthesiologists to ensure complete recovery in all patients regardless of whether depth of block was monitored objectively.28,260,261 This practice is not without risk, however, as cholinesterase inhibitors can themselves induce muscle weakness when given in the absence of residual of neuromuscular blockade. Additionally, administering an anticholinesterase does not facilitate elimination of the NMBA from the body. Neostigmine blocks acetylcholine receptors, increasing the availability of acetylcholine at the neuromuscular junction. Excessive acetylcholine can cause both a depolarizing and open-channel block.262 Determinants of Speed and Adequacy of Recovery Antagonism of nondepolarizing neuromuscular block with anticholinesterases requires a variable amount of time that depends on several factors. Time from administration to peak effect varies with presynaptic acetylcholine reserve and spontaneous rate of recovery from neuromuscular blockade. The rate of spontaneous recovery depends on the NMBA used, the dose administered, patient temperature, the presence of metabolic abnormalities such as hypokalemia, and concomitant medications. Anticholinesterases Elimination Inactive metabolite Degradation ACh release NMBA AChE Choline and acetate Binding inactivation ACh Host molecule AChE inhibitors Cell membrane 441 nAChR Fig. 22.14 Pathways to increase available acetylcholine at the nicotinic acetylcholine receptor and decrease neuromuscular blocking agent (NMBA). Acetylcholine and NMBA compete for the same binding sites in the receptor at the neuromuscular junction. Possible means to increase acetylcholine concentration include inhibiting acetylcholinesterase (AChE) to decrease its metabolism to choline and acetate. To decrease the NMBA at the neuromuscular junction, its plasma concentration has to decrease. This happens through its elimination in the urine or bile, its metabolism to inactive compounds—as occurs with atracurium, cisatracurium, mivacurium, and gantacurium—and its encapsulation by a host molecule such as sugammadex (a selective relaxant binding agent). Downloaded for Vicente Gonzalez ([email protected]) at Florida International University from ClinicalKey.com by Elsevier on April 29, 2024. For personal use only. No other uses without permission. Copyright ©2024. Elsevier Inc. All rights reserved. 442 SE C T I O N II Nervous System should be administered only once spontaneous recovery of neuromuscular function has begun. During anticholinesterase-facilitated antagonism, recovery of neuromuscular transmission is the function of primarily two processes: ongoing spontaneous recovery of neuromuscular function as the NMBA is eliminated from the neuromuscular junction and the increase in acetylcholine at the neuromuscular junction due to the effect of the anticholinesterase. It takes longer to antagonize profound neuromuscular block than it does moderate or shallow neuromuscular block.263 Additionally, recovery of muscle strength after administration of anticholinesterase depends on the rate of spontaneous recovery from the NMBA. 264 Anticholinesterase-facilitated recovery from an intermediate-acting NMBA occurs more quickly than that induced with a long-acting compound. Speed of recovery also depends on the anticholinesterase used for reversal. Recovery from a moderate depth of block occurs more quickly following the administration of edrophonium than neostigmine.265 If the NMBA is not metabolized more quickly than the anticholinesterase, neuromuscular block can recur (recurarization). Both neostigmine and edrophonium antagonize 90% of d-tubocurarine-induced neuromuscular block for a period of 1 to 2 hours,266 after which neuromuscular block will recur if the NMBA has not been completely eliminated from the plasma. There is a limit to what an anticholinesterase can effectively antagonize; profound neuromuscular blockade cannot be reversed. Once the maximum dose of neostigmine (0.07 mg/kg) has been administered, acetylcholinesterase has been maximally inhibited and administration of additional anticholinesterase will not produce greater recovery from residual neuromuscular blockade.264 Adverse Effects The effects of anticholinesterases are not limited to the motor endplate, and administration of these compounds increases acetylcholine concentration at nerve terminals in areas other than the neuromuscular junction.267 The muscarinic and nicotinic acetylcholine receptors in the parasympathetic system can also be activated,268,269 Dosing The optimal dose of anticholinesterase depends on the depth of block, duration of action of the NMBA used, timing of the last dose of NMBA relative to administration of the anticholinesterase, and the monitoring technique used. Fig. 22.15 summarizes current recommendations for dosing of anticholinesterases.27 Ideally, anticholinesterases should be administered only when necessary (i.e., in the presence of residual paralysis). Without objective monitoring of neuromuscular function, it is not possible to discriminate between TOFR values of 0.4 or 0.9. Thus, patients who have completely recovered from NMBAs occasionally receive unwarranted anticholinesterase, putting them at risk of anticholinesterase-induced muscle With quantitative neuromuscular transmission monitoring With peripheral nerve stimulator TOF ratio TOF ratio 0.9 Reversal not required causing pronounced vagal effects, such as bradycardia, prolonged QT interval and asystole.270 Other muscarinic parasympathetic side effects include bronchospasm, increased bronchial and pharyngeal secretions, miosis, and increased intestinal tone. Therefore, anticholinesterases are typically administered in combination with antimuscarinic drugs, such as glycopyrrolate or atropine. These compounds block muscarinic, but not nicotinic, receptors27 so that neuromuscular block can be antagonized while muscarinic effects are minimized. Antimuscarinic compounds increase the risk of tachyarrhythmias and other effects of antagonism of muscarinic receptor, such as urinary retention, blurred vision, photophobia, mydriasis, xerostomia, dry skin, constipation, nausea, urinary retention, insomnia, and dizziness. Unnecessary administration of anticholinesterases can itself cause muscle weakness.39,231 Weakness of the airway dilator muscle genioglossus can lead to upper airway collapse during inspiration. In rats, unnecessary administration of neostigmine (> 0.6 mg/ kg) causes diaphragmatic dysfunction. 271 Anticholinesterase administration to healthy volunteers after complete spontaneous recovery from neuromuscular block increased airway collapsibility to the same degree as occurs with a TOFR of 0.5 and reduced compensatory genioglossus activity in response to negative airway pressure.272 Neostigmine 0.0150.025 mg/kg Neostigmine 0.020.05 mg/kg No TOF response Delay reversal until TOF count =2 No fade Neostigmine 0.0150.025 mg/kg Fade Neostigmine 0.05 mg/kg Delay reversal until TOF count =2 Neostigmine 0.04 mg/kg Fig. 22.15 Neostigmine dosing. The dose of neostigmine depends on both how depth of neuromuscular block is monitored and the degree of recovery. As little as 0.015 to 0.025 mg kg−1 of neostigmine is required at a train-of-four (TOF) count of 4 with no fade, whereas 0.04 to 0.05 mg kg−1 is needed at a TOF count of 2 or 3. If only a single twitch or none at all can be evoked, neostigmine will not reverse neuromuscular block and antagonism is best delayed until a TOF count of 2 is achieved. (From Kopman AF, Eikermann M. Antagonism of non-depolarising neuromuscular block: current practice. Anaesthesia. 2009;64(Suppl 1):22–30). Downloaded for Vicente Gonzalez ([email protected]) at Florida International University from ClinicalKey.com by Elsevier on April 29, 2024. For personal use only. No other uses without permission. Copyright ©2024. Elsevier Inc. All rights reserved. CHAPTER 22 Neuromuscular Blockers and Reversal Drugs 443 weakness. The administration of anticholinesterases should optimally be guided by quantitative evaluation of the TOFR. The typical dose of neostigmine for antagonism of profound neuromuscular block (a TOF count of 2) is 0.05 mg/kg and 0.015 to 0.025 mg/ kg for antagonism of lesser degrees of neuromuscular block (a TOF count of 4 with no fade).27,273 Profound block with a TOF count below 2 should not be antagonized with neostigmine because of the risk of inadequate recovery of neuromuscular function.267,274 No anticholinesterase is required if the TOFR is greater than 0.9 as determined by monitoring with a quantitative monitor of neuromuscular function. Pharmacokinetics and Pharmacodynamics Bolus doses of either neostigmine or edrophonium result in peak plasma concentrations within 5 to 10 minutes that decrease rapidly, followed by a slower decline that corresponds to the elimination phase.266,275 A 2-compartment analysis finds results that are similar for both drugs. The volume of distribution of these anticholinesterases is 0.7 to 1.4 L/kg and their elimination half-lives are 60 to 120 minutes. Clearance is 8 to 16 mL/kg/min, which is greater than the glomerular filtration rate since anticholinesterases are actively secreted. Therefore, in patients with renal failure, in whom the duration of action of NMBAs is likely to be increased, clearance of anticholinesterases is also reduced and elimination half-life increased. This makes dose adjustment of anticholinesterases in patients with renal dysfunction unnecessary. The anticholinesterases have markedly different onset characteristics, possibly due to the different potency of each agent. Neostigmine is more potent than edrophonium and smaller doses are required to antagonize residual neuromuscular block. During a steady-state infusion of NMBA, the onset of action of edrophonium is 1 to 2 minutes and that of neostigmine is 7 to 11 minutes.266,275 Similar results have been obtained with neostigmine as an antagonist of either pancuronium or vecuronium or edrophonium as an antagonist of metocurine. Edrophonium has approximately one-twelfth the potency of neostigmine, and its potency increases as spontaneous recovery from neuromuscular block occurs.252 Sugammadex The use of encapsulating agents to reverse neuromuscular blockade is relatively new and offers a unique recovery profile following reversal of rocuronium-induced neuromuscular blockade. Following intravenous administration, molecular containers, such as sugammadex, bind free intravascular guest molecules, resulting in a concentration gradient between the intravascular compartment and the neuromuscular junction. Sugammadex, a selective relaxant binding agent, was specifically designed to bind the steroidal NMBAs rocuronium and vecuronium (Fig. 22.16). As a result of its administration, free NMBA concentration in the plasma decreases, NMBA moves along its diffusion gradient away from the neuromuscular junction, and block of neuromuscular transmission disappears (Fig. 22.17).276–279 During sugammadexfacilitated recovery, the total concentration of NMBA in the plasma (free and sugammadex bound) increases.280 Sugammadex significantly reduces time to recovery from rocuronium-induced neuromuscular blockade compared to neostigmine reversal (TOF ≥ 0.9, 107 ± 61 sec vs. 1044 ± 590 sec, respectively).281 It more rapidly reverses rocuronium-induced neuromuscular blockade than neostigmine antagonizes cisatracurium-induced neuromuscular blockade.282,283 As a consequence of its rapid reversal of steroidal NMBAs, sugammadex may be an option to reverse neuromuscular Fig. 22.16 Interaction of the cyclodextrin, sugammadex, with the steroidal neuromuscular blocking agent (NMBA) rocuronium. Hydrophobic portions of the NMBA are located within the cyclodextrin ring. Hydrophilic portions remain exposed to plasma. blockade in the cannot intubate–cannot ventilate scenario following administration of a large dose of rocuronium.284,285 Its effective use in this manner, though, requires that it be available in the anesthesiologist’s workstation.286 While sugammadex reversal of neuromuscular blockade can help to eliminate postoperative residual paralysis,287 its use does not guarantee complete recovery of neuromuscular function.288,289 Correct dosing of sugammadex requires that depth of the blockade is monitored and that enough sugammadex is administered to reverse the existing blockade. Residual neuromuscular blockade occurs in approximately 5% of patients who receive sugammadex if neuromuscular monitoring is not used.290 Recurarization, or incomplete reversal after sugammadex, occurs when the number of circulating sugammadex molecules is insufficient to bind a critical number of the rocuronium molecules that are present. One molecule of sugammadex encapsulates one molecule of rocuronium and when a large dose of rocuronium is reversed with an inadequate dose of sugammadex, previously redistributed rocuronium may be mobilized and cause neuromuscular blockade.291 Reintroducing neuromuscular blockade after reversal with sugammadex, as may be warranted in laryngospasm or the need to reintubate a patient, presents challenges since any free sugammadex will bind with rocuronium that is administered. In a case series,292 0.6 mg/kg rocuronium reestablished neuromuscular blockade in patients who had received sugammadex 3 hours earlier. If, however, that interval was 2 hours or less, more than 0.6 mg/ kg (or 2× the ED95) was required. When a small dose (2 mg/kg) of sugammadex has been administered, 0.6 mg/kg rocuronium may be sufficient to reintroduce neuromuscular blockade even shortly after sugammadex administration.293 Succinylcholine (1 mg/ kg) has also been used successfully to reintroduce neuromuscular blockade 3 hours after the administration of sugammadex.294 Sugammadex has been used to treat rocuronium-induced anaphylaxis.295,296 The efficacy, though, of sugammadex is not Downloaded for Vicente Gonzalez ([email protected]) at Florida International University from ClinicalKey.com by Elsevier on April 29, 2024. For personal use only. No other uses without permission. Copyright ©2024. Elsevier Inc. All rights reserved. 444 SE C T I O N II Rocuronium Nervous System Placebo [%] 100 50 A Rocuronium 12:44:39 PM 12:54:39 PM 1:04:39 PM 1:13:54 PM 1:23:09 PM 1:32:24 PM 1:41:39 PM 1:50:54 PM 2:00:09 PM 2:09:24 PM Sugammadex [%] 100 50 B 8:55:44 AM 9:05:44 AM 9:15:59 AM 9:25:59 AM 9:36:14 AM 9:46:14 AM 9:56:29 AM 10:06:29 AM 10:17:44 AM Fig. 22.17 The speed of antagonism of rocuronium-induced block with sugammadex. In the top panel, a placebo was administered 3 minutes after rocuronium, 0.6 mg/kg. Recovery of twitch height is indicated by the blue lines and the TOFR by the red dots. In the lower panel, sugammadex 8 mg/kg was administered 3 minutes following the same dose of rocuronium. One minute after administration of sugammadex, the TOFR was 0.9. (Adapted from Gijsenbergh F, Ramael S, Houwing N, et al. First human exposure of Org 25969, a novel agent to reverse the action of rocuronium bromide. Anesthesiology. 2005;103:695–703.) consistent.297–299 Additionally, sugammadex or the sugammadex– rocuronium complex may cause an anaphylactic reaction.297,300–303 Administration of sugammadex has been associated with severe bradycardia.304,305 The risk of this, though, is lower than the risk associated with the use of neostigmine.306,307 Other adverse effects of sugammadex are likely related to either displacement of endogenous molecules or to nonspecific binding as occurs in the case of coagulation factor Xa and oral contraceptives.308,309 Following administration of sugammadex, women of child-bearing potential should use nonhormonal birth control to protect against unwanted pregnancy.310 This requirement has led to a revision of anesthesia informed consent or additional information being distributed postoperatively to patients who have received sugammadex.311 Sugammadex administration has also been reported to have an effect on blood hemostasis. In healthy volunteers, sugammadex induced a dose-dependent, transient prolongation of activated partial thromboplastin time (APTT) and prothrombin time (PT)/ international normalized ratio (INR).312 However, although sugammadex increased the partial thromboplastin time in a randomized, control trial of almost 1200 patients, it did not increase the risk of bleeding when compared to patients who did not receive the selective relaxant binding agent.313 In extensive studies of displacement conducted with sugammadex and 300 drugs, only 3 (flucloxacillin, fusidic acid, and toremifene) had the potential for a displacement interaction with sugammadex.314,315 Therefore, the effects of administration of sugammadex should be carefully considered when either toremifene or fusidic acid have been administered.316 Emerging Developments Fumarates The fumarates share structural elements with mivacurium. Like mivacurium, they have 3 methyl groups between the quaternary nitrogen and the most proximal oxygen at each end of the carbon chain. This structural feature is different from either atracurium or cisatracurium, each of which has 2 methyl groups in this position, suggesting that Hofmann degradation does not contribute significantly to elimination of mixed-onium chlorofumarates.317 In contrast to benzylisoquinoliniums, the chlorofumarates have 4 chiral centers, 2 of which are quaternary ammoniums. Additionally, the head groups of these compounds are distinct.79 Primate studies have shown that onset of these compounds is inversely related to potency. While the chlorofumarates are potent (ED95 < 0.2 mg/kg), they Downloaded for Vicente Gonzalez ([email protected]) at Florida International University from ClinicalKey.com by Elsevier on April 29, 2024. For personal use only. No other uses without permission. Copyright ©2024. Elsevier Inc. All rights reserved. CHAPTER 22 Neuromuscular Blockers and Reversal Drugs have rapid onsets and very short durations of action.79 One of the chlorofumarates, gantacurium, has been administered to human volunteers.63,64 Maximal onset of block at the adductor pollicis and laryngeal adductors following doses approximating 2 and 3 times the ED95 were comparable to onset of block following administration of succinylcholine63 (Table 22.5). As with atracurium and cisatracurium, the fumarates were chosen for development because of, in addition to their pharmacodynamic profile, their unique means of elimination from plasma.79–81 Gantacurium is broken down by 2 different pathways; one is a slow, pH-sensitive hydrolysis and the other is adduction of the naturally occurring amino acid cysteine (addition of a cysteine molecule to the NMBA, rendering a new compound; Fig. 22.18). This adduction reaction replaces the chlorine and saturates the fumarate double bond. The resultant product is structurally different than gantacurium and can no longer interact with the acetylcholine receptor. This unique means of inactivation likely accounts for its ultrashort duration of effect.64 It also provides a novel means of shortening recovery from chlorofumarate-induced neuromuscular block.82 L-cysteine has an elimination half-life of 1 to 2 hours. 445 Exogenous cysteine administered to dogs during the early phases of spontaneous recovery of neuromuscular function or 1 minute after administration of gantacurium significantly shortens the time required to complete recovery compared to either spontaneous recovery or edrophonium-facilitated recovery. In rhesus monkeys, TABLE Comparison of Onset of Block by Gantacurium 22.5 and Succinylcholine Minutes to Maximal Block* Neuromuscular Blocking Agent Dose (mg/kg) Laryngeal Adductors Adductor Pollicis 0.36 1.1 ± 0.3 1.7 ± 0.2 0.54 0.9 ± 0.2 1.5 ± 0.3 1.0 0.8 ± 0.3 1.5 ± 0.2 Gantacurium Succinylcholine *Note that the laryngeal muscles are blocked faster than the thumb. OMe MeO MeO HO2C OMe S O Cl Me N+ O Cysteine adduct (inactive) + OMe Me MeO OMe OMe O OMe + OMe N 2 Cl– (II) N OMe O Cysteine (rapid) OMe Me O N OH MeO MeO O OMe OMe O N + (I) Me 2 Cl– OH OMe MeO OMe OMe GW 280430A pH sensitive hydrolysis (slow) Cl O OMe O MeO OMe O N + + OMe Me Cl– MeO HO MeO OMe Me N+ Cl– OMe Ester hydrolysis products (inactive) Fig. 22.18 Degradation and inactivation of gantacurium (GW 280430A), an asymmetric chlorofumarate. Gantacurium is inactivated by 2 pathways: rapid adduction of cysteine to yield an inactive cysteine adduct and a slower pH-sensitive hydrolysis to yield ester hydrolysis products. (From Savarese JJ, Belmont MR, Hashim MA, et al. Preclinical pharmacology of GW280430A (AV430A) in the rhesus monkey and in the cat: a comparison with mivacurium. Anesthesiology. 2004 Apr;100(4):835–845.) Downloaded for Vicente Gonzalez ([email protected]) at Florida International University from ClinicalKey.com by Elsevier on April 29, 2024. For personal use only. No other uses without permission. Copyright ©2024. Elsevier Inc. All rights reserved. OMe OMe 446 SE C T I O N II Nervous System doses of 8 times the ED95 of gantacurium have a duration of action of approximately 14 minutes. Administration of L-cysteine (10 mg/ kg) 1 minute after administration of gantacurium results in return of complete neuromuscular function within 1 to 2 minutes. The rapid reversal of fumarate-induced neuromuscular block by administration of L-cysteine has the potential to decrease the frequency of residual neuromuscular block.318 Two analogs of the asymmetric fumarate gantacurium, CW002 and CW011, have been synthesized to undergo slower L-cysteine adduction, yielding compounds with intermediate durations of action.81,82,319 A trial in anesthetized volunteers demonstrated that CW002 was a potent nondepolarizing NMBA with an intermediate duration of action.320 Its ED95 was 0.077 mg/kg, onset of maximal effect occurred in 3.3 minutes, clinical duration of action was 34 minutes, and complete spontaneous recovery occurred in 59 to 86 minutes after a dose of 1.8× ED95. This dose had no cardiopulmonary side effects and did not release histamine. Additional volunteer trials are required to determine whether its recovery and ease of antagonism are improved over that provided by compounds that are currently available. Calabadion A new class of reversal agent, the calabadions, provides an expanded (including reversal of benzylisoquinolines) spectrum of possible indications in that they reverse the effects of steroidal and benzylisoquinolinium NMBAs.84,85 Clinical trials are planned; this reversal agent may provide yet another way to influence our expectations for recovery of neuromuscular function at the conclusion of an anesthetic. Key Points Quantitative monitoring is required to ensure the adequacy of neuromuscular function prior to tracheal extubation at the conclusion of an anesthetic. It should be used to guide dosing of both neuromuscular blocking drugs and their reversal agents. A TOFR of less than 0.9 constitutes inadequate recovery of neuromuscular function. Inadequate recovery of neuromuscular function results in postoperative respiratory complications, delayed discharge from the postanesthesia care unit, and decreased patient satisfaction with recovery following an anesthetic. In spite of the use of NMBAs with an intermediate duration of action, postoperative residual neuromuscular block is not an infrequent occurrence. Upper airway collapse occurs in the presence of subtle degrees of neuromuscular block. Anticholinesterases do not guarantee adequate recovery of neuromuscular function and large doses can cause muscle weakness via depolarizing block. Availability of newer drugs, such as the selective relaxant binding agent sugammadex, to facilitate recovery of neuromuscular function should decrease the incidence of postoperative residual neuromuscular block. The effects of neuromuscular blocking agents that are extensively metabolized can be rapidly antagonized by increasing their metabolism. Key References Kopman AF, Klewicka MM, Kopman DJ, et al. Molar potency is predictive of the speed of onset of neuromuscular block for agents of intermediate, short, and ultrashort duration. Anesthesiology. 1999;90:425–431. Times to peak effect of equipotent doses of five different neuromuscular blocking agents—succinylcholine, mivacurium, cisatracurium, vecuronium, and rocuronium—with different durations of action, structures, and mechanisms of action were studied. The relationship between onset and potency, that less potent compounds have a more rapid onset of effect, that had been demonstrated for long-acting NMBAs was found to also apply to compounds with different durations of action. (Ref. 68). Koscielniak-Nielsen ZJ, Bevan JC, et al. Onset of maximum neuromuscular block following succinylcholine or vecuronium in 4 age groups. Anesthesiology. 1993;79:229–234. Subparalyzing doses of NMBAs were used to determine maximal onset of effect on patients of 4 different age groups: 1 to 3 years, 3 to 10 years, 20 to 40 years, and 60 to 80 years. Older subjects had slower onsets of maximal effect of NMBA. When large doses of NMBAs are administered to facilitate endotracheal intubation, time to onset of maximal effect cannot be distinguished. (Ref. 38). Martyn JA, Richtsfeld M. Succinylcholine-induced hyperkalemia in acquired pathologic states: Etiologic factors and molecular mechanisms. Anesthesiology. 2006;104:158–169. This is a review article describing the molecular mechanisms for hyperkalemia following administration of succinylcholine. The nicotinic α-7 acetylcholine receptor, which is