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  • 2. The ASA Refresher Courses in Anesthesiology CME Program Subscribers to ASA Refresher Courses in Anesthesiology are eligible to earn AMA PRA Category 1 Credit(s)t. Please visit or see page iv at the beginning of this volume for complete details. Accreditation and Designation Statement The American Society of Anesthesiologists is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The American Society of Anesthesiologists designates this educational activity for a maximum of 1 AMA PRA Category 1 Credit(s)t. Physicians should only claim credit commensurate with the extent of their participation in the activity. Author Disclosure Information Drs. Kopmen and Lien have disclosed that they have no financial interests in or significant relationship with any commercial companies pertaining to this educa- tional activity.  2009 c The American Society of Anesthesiologists, Inc. ISSN 0363-471X ISBN 978-1-6054-7424-3 An educational service to the profession under the auspices of The American Society of Anesthesiologists, Inc. Published for The Society by Lippincott Williams & Wilkins 530 Walnut Street Philadelphia, Pennsylvania 19106-3621 Library of Congress Catalog Number 74-18961. PERMISSION TO PHOTOCOPY ARTICLES: This publication is protected by copyright. Permis- sion to reproduce copies of articles for noncommercial use must be obtained from the Copyright Clearance Center, 222 Rosewood Dr., Danvers, MA 01923; (978) 750-8400, FAX: (978) 750-4470,
  • 3. Physiology and Pharmacology of Neuromuscular Transmission: New Developments That May Change Your Practice David Kopman, M.D. Assistant Professor of Anesthesiology Weill Cornell Medical Center New York, New York Cynthia A. Lien, M.D. Professor of Anesthesiology Weill Cornell Medical Center New York, New York In the more than 60 years since d-tubocurarine was introduced into the clinical practice of anesthesia, great strides have been made in our understanding of the pharmacology of neuromuscular blocking agents (NMBAs). The neuromuscular junction and neuromuscular transmission allow translation of a neuronal electrical impulse into a motor action potential and subsequent muscular contraction. An appreciation for the complexity of the system is essential because it helps one both understand the mechanism by which neuromuscular blocking drugs exert their pharmacologic effect and rationally deliver, monitor, and reverse these agents. The Neuromuscular Junction: Prejunctional Components Motor neurons travel from the ventral horn of the spinal cord to the neuromuscular junction. The axon is responsible for transmitting the action potential to the muscle from the spinal cord. The necessary enzymes and other proteins needed by the nerve ending to synthesize, store, and release acetylcholine are synthesized in the cell body and transported through the axon to the nerve ending. As each nerve approaches a muscle, it branches many times to allow for the formation of junctions with multiple muscle fibers. Immediately before the terminal axon approaches the muscle to become the prejunctional component of the motor nerve terminal, it loses its myelin sheath. The nerve terminal contains the synaptic vesicles in which acetylcholine is stored. When an action potential reaches the nerve terminal, vesicles fuse with the terminal membrane, releasing acetylcholine into the synaptic cleft. Both nicotinic and muscarinic receptors are found presynaptically on the motor nerve terminal. These prejunctional receptors seem to modulate the release of acetylcholine into the neuromuscular junction and have been variously assigned both excitatory and inhibitory roles.1,2 Prejunctional nicotinic receptors are activated by acetylcholine and function in a positive feedback control system that maintains availability of acetylcholine when demand for it is high. They are involved Copyright Ó2009 American Society of Anesthesiologists, Inc. 107
  • 4. 108 KOPMAN AND LIEN in the mobilization of acetylcholine, but not in the process of acetylcholine release. Blockade of these receptors by nondepolarizing neuromuscular blockers may underlie the fade phenomenon seen with tetanic and train-of-four stimulation. The presynaptic nicotinic receptor is structurally distinct from the postsynaptic acetylcholine receptor (AchR). Although it, like the postsynaptic receptor, is composed of five subunits, it contains only a and b subunits (a3, b2). Synergism between nondepolarizing NMBAs of different structures has been attributed, in part, to their different effects on the presynaptic nicotinic receptors. The Neuromuscular Junction: Postjunctional Components At the motor end plate, the myocyte forms a recess into which the motor nerve terminal fits. This recess is characterized by multiple secondary junctional clefts. The distance between the motor nerve unit and the shoulder of the junctional cleft is 60 nm and it is across this distance that acetylcholine must travel to reach the receptors of the motor end plate. Most of the released acetylcholine (approximately 80%) never reaches the AchR because it is hydrolyzed by acetylcholinesterase at the neuromuscular junction. Nicotinic AchRs are found throughout the muscle membrane but are concentrated at the tops of the secondary junctional clefts. Mature AchRs are composed of five subunits: two a, one b, one d, and one e.3 The a subunits contain the major portion of the AchR binding site. There are two binding sites on each AchR, one at the a--d and one at the a--e subunit interface.4 Recent evidence indicates that each of these binding sites has different affinities for the NMBAs and that the a-d binding site is the more dominant one in determining receptor affinity for pancuronium, vecuronium, and cisatracurium.5 The five subunits that comprise the AchR are arranged in a cylinder that spans the membrane of the motor end plate. The receptors have a central pore for ion movement into and out of the muscle fiber. Neuromuscular Transmission: Prejunctional Events Synchronized release of acetylcholine from presynaptic vesicles in an amount sufficient to generate a muscle action potential occurs when a neural action potential reaches the nerve terminal. The rapid release of acetylcholine when an impulse arrives at the motor nerve terminal necessitates that only those vesicles close to the membrane of the nerve terminal can participate in the process of exocytosis. Repetitive nerve stimulation results in trains of electrical impulses. These cause vesicles to move toward the motor nerve terminal for subsequent release allowing for the posttetanic potentiation observed during neuromuscular block. The increased release of acetylcholine allows for a transient increase in apparent muscle strength as the concentration of available acetylcholine increases relative to the concentration of NMBA. Botulinum toxin interferes with the fusion of the vesicle to the cell membrane and prevents release of acetylcholine. When injected into the muscle groups, it causes weakness and, ultimately, increased expression of AchRs.6
  • 5. PHARMACOLOGY OF NEUROMUSCULAR BLOCKING AGENTS 109 Neuromuscular Transmission: Postjunctional Events When released, acetylcholine diffuses across the junctional cleft to the motor end plate where it binds to the a subunits of the AchR. When both a subunits are occupied simultaneously by agonists, the channel of the receptor opens allowing the influx of calcium and sodium and subsequently the efflux of potassium as the ions move down their concentration gradients. After a nerve impulse, thousands of AchRs are activated and an end plate potential is generated. With the influx of sodium that accompanies the activation of the AchRs, the membrane potential of the muscle cell, which is approximately À80 mV in the rested state, increases to þ 40 mV. When an adequate number of end plate potentials accumulate, adjacent voltage-gated sodium channels in the muscle membrane are opened and a muscle action potential, which activates muscle contraction, is started. Neuromuscular Transmission and Neuromuscular Blocking Drugs The depolarizing NMBA succinylcholine binds to the AchR and mimics the effects of acetylcholine. Therefore, whether one succinylcholine molecule and one acetylcholine molecule or either two acetylcholine or two succinylcholine molecules are bound to a single AchR, the channel will open, allowing for the influx of sodium. In contrast to acetylcholine, however, succinylcholine is not a substrate for acetylcholinesterase; therefore, it is not rapidly metabolized in the junctional cleft. To be broken down, it must move into the plasma where it is metabolized by butyrylcholinesterase. As long as it remains in the junctional cleft, it remains available to repeatedly bind to and activate the AchR. Nondepolarizing NMBAs exert their effect by occupying one or both of the binding sites on AchRs. With acetylcholine effectively excluded from receptor binding sites by a NMBA, receptors cannot be activated and their ion channels remain closed. By preventing ion flux through the AchR, no end plate potentials are generated on the muscle fiber and, consequently, muscle action potentials and subsequent muscle contraction are prevented. Recovery from Nondepolarizing Neuromuscular Blocking Drugs The competitive block generated by nondepolarizing NMBAs is terminated by an increase in acetylcholine concentration relative to NMBA concentration in the neuromuscular junction. This can occur by either or both of two mechanisms. As the plasma concentrations of the agents decrease, the agents migrate from the neuromuscular junction back into the plasma, where they are either metabolized such as cisatracurium and mivacurium or from which they are eliminated such as vecuronium, rocuronium, and the long-acting agents. Alternatively, the inhibition of acetylcholinesterase by the administration of an anticholinesterase agent such as neostigmine allows acetylcholine released into the neuromuscular junction to remain available to bind to the AchR and thus initiate muscle contraction.
  • 6. 110 KOPMAN AND LIEN What Constitutes Adequate Clinical Recovery from Nondepolarizing Neuromuscular Block? In the early 1970s, Ali et al.7--9 first described what has subsequently become the standard technique for evaluating recovery after the administration of nondepolariz- ing neuromuscular blocking drugs, the train-of-four ratio. This technique uses four supramaximal stimuli delivered in quick succession (2 Hz) to the ulnar nerve to induce four responses in the adductor pollicis brevis muscle. The ratio of the amplitude of the fourth evoked response as compared with the first is defined as the train-of-four fade ratio (TOFR) (Fig. 1). Ali et al.10 published a follow-up study correlating TOFR with impairment in the mechanical ventilatory function in eight healthy conscious volunteers who were given small incremental doses of tubocurarine. They found that when the TOFR had returned to a value of 0.70, the vital capacity and peak expiratory flow rate had returned to 90% of control, and negative inspiratory force was back to 80% of control. They concluded that recovery to this degree represented adequate return of mechanical respiratory reserve. It should be noted, however, that it was not until the TOFR was 0.90 that negative inspiratory force recovered to 90% of control. The authors also reported that all eight volunteers reported experiencing lightheadedness, diplopia, masseter muscle weakness, and facial tingling, and one reported difficulty in swallowing, after recovery to a TOFR of greater than 0.7. In a third study from the same group, the effects of nondepolarizing NMBAs were allowed to spontaneously resolve, whereas neuromuscular and respiratory functions were evaluated using both clinical criteria (hand grasp, head lift, tongue protrusion, sustained eye-opening) and evoked responses (TOFR).11 The investigators observed that clinical criteria for extubation, including vital capacity of at least 10 to 15 ml/kg, inspiratory force of at least À25 cm H2O, PaCO2 between 35 and 45 mmHg, and a respiratory rate of less than 25 per minute, correlated well with TOFR of greater than FIG. 1. The degree of twitch response at the adductor pollicis after train-of-four (TOF) stimulation of the ulnar nerve. The depicted TOF fade ratio is 0.64.
  • 7. PHARMACOLOGY OF NEUROMUSCULAR BLOCKING AGENTS 111 0.70. These three studies essentially established a TOFR of greater than or equal to 0.70 as the threshold for adequate recovery from nondepolarizing neuromuscular blocking drugs for the next two decades. Eriksson et al.12 demonstrated that partial vecuronium-induced neuromuscular blockade (a TOFR of 0.70) reduces the respiratory response to hypoxia, an effect likely mediated by the blockade of nicotinic receptors located on the carotid body. In 1997, Kopman et al.13 correlated clinical signs and symptoms of motor weakness with TOFR in 10 healthy awake subjects administered mivacurium by intravenous infusion. Subjects were asked to carry out a series of tasks, including 5-second head and leg lifts, biting a wooden tongue depressor between their upper and lower incisors such that the investigator could not pull it out of their mouths, and having their grip strength measured. At a TOFR of 0.70, 8 of 10 subjects could perform a 5-second head lift. However, at this level of block, several subjects could not sip water from a straw, because they could not make a tight seal with their lips. In addition, more than half of the subjects were unable to retain a wooden tongue depressor between their incisor teeth. Grip strength was decreased on average by more than 40% at a TOFR of 0.70, and even at a TOFR of 0.90, measurable effects were noted in most individuals. All subjects reported visual disturbances, including diplopia, at TOFR of 0.9. Seven subjects reported feeling that their vision was still abnormal a full 45 to 90 minutes after the TOFR returned to 1.0. None of the subjects felt ‘‘street-ready’’ at a TOFR of 0.7, which corroborated the author’s conclusion that they all had significant clinical signs of residual neuromuscular blocking at that time. Eriksson et al.14 used simultaneous videomanometry and mechanomyography to assess the functional status of the pharynx in partially paralyzed awake human subjects. Under fluoroscopic guidance, a catheter with four pressure transducers was inserted into 14 subjects such that the most distal transducer was located in the cervical esophagus, whereas the most proximal one was at the base of the tongue. Subjects were then asked to swallow small boluses of iodine contrast while manometric and radiographic data were recorded. All subjects were then administered vecuronium by intravenous infusion and swallow studies were repeated when the TOFRs recorded at the adductor pollicis muscle were 0.60, 0.70, 0.80, and 0.90. All volunteers had episodes of misdirected swallowing and aspiration of contrast material into the larynx, although not into the trachea, at TOFR values of 0.60 to 0.80. Significantly, none of the episodes of aspiration were accompanied by coughing or a subjective sense of discomfort. No episodes of aspiration were noted when the TOFR recovered to a value greater than or equal to 0.9. Although Ali et al.10 showed that a TOFR of 0.70 correlates with adequate recovery of mechanical ventilatory parameters in most patients, the more recent data discussed previously indicate that this is not the whole story. At TOFR of 0.70, signs and symptoms of significant residual paralysis are common. On the basis of available evidence, a return to a TOFR of 0.7 can no longer be considered optimal or even adequate neuromuscular recovery. The modern standard of recovery is now considered to be at TOFR of greater than or equal to 0.90. Residual Curarization in the Recovery Room Viby-Mogensen et al.15 published a report documenting an alarming incidence of residual neuromuscular blockade after the administration of NMBAs (tubocurarine,
  • 8. 112 KOPMAN AND LIEN pancuronium, and gallamine) in patients arriving in the recovery rooms of three Danish hospitals. Of the 72 patients in the study, 12% had TOFRs of less than 0.40, 20% had TOFRs of less than 0.60, and 40% had TOFRs of less than 0.70 on arrival in the postanesthesia care unit. Although this study is nearly 30 years old and the long- acting NMBAs given to patients in this study have been largely replaced with drugs with considerably shorter durations of action, the incidence of postoperative residual curarization remains unacceptably high today.16--19 Multiple factors are responsible for the continued incidence of postoperative residual curarization. First, the ability of clinicians to detect fade during train-of-four stimulation is notoriously poor. Most trained observers lose the ability to detect fade during train-of-four stimulation when the postoperative residual curarization exceeds 0.40.20 Thus, most clinicians cannot detect clinically inadequate recovery from neuromuscular blockade with a conventional peripheral nerve stimulator. Anesthesiologists today also routinely use much greater multiples of the ED95 of intermediate-duration drugs such as rocuronium and cisatracurium than were ever used with traditional long- acting drugs such as tubocurarine and pancuronium. Clinicians may also have unrealistic expectations regarding both the rate of spontaneous recovery from nondepolarizing neuromuscular blocking as well as the ability of neostigmine to reverse profound residual paralysis. Postoperative Residual Curarization: Does It Really Matter? Does postoperative residual curarization increase postoperative morbidity? Outcome data addressing the issue are scant. Berg et al.21 randomized 691 patients scheduled for abdominal, orthopedic, or gynecologic surgery to receive one of three NMBAs (pancuronium, vecuronium, or atracurium). All patients had TOFR measured mechano- myographically on arrival in the postanesthesia care unit and were then followed for signs of pulmonary complications for 6 days postoperatively. They found that patients in the pancuronium group, unlike those in either of the other groups, who arrived in the postanesthesia care unit with a TOFR of less than 0.70 had a significantly greater incidence of radiographically demonstrable postoperative pulmonary complications than those whose TOFR exceeded 0.70. In 2008, Murphy et al.22 published similar findings. They collected data on 7,459 patients admitted to their postanesthesia care unit after having received a general anesthetic and identified the occurrence of 61 critical respiratory events in those patients. Forty-two of the 61 patients noted to have experienced a critical respiratory event were then compared with matched control subjects. Of the 61 identified patients, only one did not receive a neuromuscular blocking drug. Acceptable neuromuscular recovery, defined as a TOFR of greater than 0.90, was present in just 9.5% of patients with a critical respiratory event as compared with 90.5% of control subjects. Severe residual paralysis (TOFR of less than 0.70) was present in 73.8% of the cases but in none of the matched control subjects. The authors concluded that ‘‘unrecognized residual paresis is an important contributing factor to postoperative critical respiratory events.’’ New Approaches to Manipulation of Neuromuscular Transmission: Sugammadex and Gantacurium Neostigmine-induced antagonism of nondepolarizing neuromuscular blockade has its limitations. When maximal inhibition of acetylcholinesterase activity has been
  • 9. PHARMACOLOGY OF NEUROMUSCULAR BLOCKING AGENTS 113 achieved, additional administration of neostigmine will not further antagonize any remaining residual block. As long as the concentration of the NMBA at the neuromuscular junction remains high, adequate recovery of skeletal muscle function will remain unattainable no matter how much neostigmine is administered. Two new drugs, currently under development, offer a possible way out of this quandary. Sugammadex Sugammadex is a new reversal agent with a novel chemical structure. It is a cyclodextrin, a member of a family of water-soluble crystalline oligosaccharides that have long been used in the industry to solubilize lipophilic compounds. Sugammadex (sometimes referred to in research publications as ORG 25969) is a highly soluble g-cyclodextrin with a hydrophobic cavity that can encapsulate steroidal neuromuscular blocking drugs.23 By encapsulating susceptible NMBAs, the muscle relaxant is rendered unavailable to interact with the postsynaptic nicotinic receptors of the neuromuscular junction. Sugammadex has a very high affinity for rocuronium and vecuronium (less so for pancuronium). When given in an adequate dosage, the plasma concentration of unbound or free relaxant decreases rapidly to very low levels. As a consequence, the NMBA more rapidly diffuses from the myoneural junction based on the newly established concentration gradient. Thus, we now have, for the first time, a mechanism by which a profound nondepolarizing block can be promptly and satisfactorily antagonized. When 12 mg/kg sugammadex is given just 3 minutes after a 1.2-mg/kg bolus of rocuronium, a return to a TOFR of 0.90 can be expected in less than 3 minutes.24 The advantages of the drug vis-a-vis edrophonium or neostigmine ` were clearly shown in a recent study by Sacan et al.25 (Table 1). Unfortunately, sugammadex is not yet (December 2008) available in North America. In Europe, where it was recently introduced, a very high acquisition cost may further limit its widespread acceptance. Gantacurium Gantacurium is one of several enantiomeric bisquarternary compounds identified as an asymmetric chlorofumarate.26--28 This class of compounds incorporates 1-benzyl and 1-phenyltetrahydroisoquinolinium groups in the same molecule. Gantacurium was first identified from this series of neuromuscular blockers as TABLE 1. Reversal of Rocuronium With Sugammadex and Anticholinesterases25 Edrophonium Neostigmine Sugammadex (N ¼ 20, All Groups) (1.9 mg/kg) (0.07 mg/kg) (4 mg/kg) Total dose rocuronium (mg) 73730 79726 73722 Interval post last dose (minutes) 40716 35718 41719 T1 at reversal (%) 1278 12714 677 N with TOF Z0.90 within 5 minutes 0 1 30 N with TOF Z0.70 within 30 minutes 7 9 20 Reversal of rocuronium sugammadex versus neostigmine versus edrophomium. TOF ¼ train of four.
  • 10. 114 KOPMAN AND LIEN having an ultrashort duration of action and a safety margin for cardiovascular effects similar to that of mivacurium. As opposed to mivacurium and atracurium, which are composed of a mixture of isomers, this synthetic compound is characterized as a single isomer. The stereochemistry of the compound is derived from its orientation about each of its six asymmetric centers. In rhesus monkeys, the potency of gantacurium is identical to that of mivacurium (0.06 mg/kg).29 Its onset, however, is significantly faster and its recovery is shorter than that of mivacurium. Hemodynamic changes indicative of histamine release, transient decreases in blood pressure, and increases in heart rate are observed at doses of 3.2 mg/kg. Smaller doses caused less than a 10% change in mean arterial pressure and heart rate. On the basis of these data, the margin of safety for histamine release was determined to be 53 (ED for histamine release/ED95 neuromuscular blocking). In this same study, the margin of safety for histamine release associated with the administration of mivacurium was 13. In humans, gantacurium has pharmacodynamic properties that mimic those of succinylcholine. A study in anesthetized human volunteers evaluated the onset and recovery profiles of 430A in the thumb and larynx.30 The pattern of blockade resembled that of succinylcholine, with fully paralyzing doses (2--3 Â ED95 or 0.38 to 0.54 mg/kg) producing a 100% block of train-of-four within 60 to 70 seconds in the larynx (Table 2). To date, there has been one published trial of gantacurium in human volunteers receiving a nitrous oxide--opioid anesthetic.31 In this study of 11 individuals, the ED95 of the compound was 0.19 mg/kg. Administration of two times the ED95 caused 100% neuromuscular blocking at the adductor pollicis within 1.7 minutes and administration of three times the ED95 caused 100% block within 1.5 minutes. Complete recovery to a train-of-four ratio of 90% after the administration of an ED95 dose occurs within 10 minutes and within 12 to 15 minutes after the administration of doses as large as 0.72 mg/kg (4 Â ED95). Recovery intervals are not lengthened by increasing the dose of gantacurium (Table 3). Recovery was accelerated by administration of edrophonium (0.5 mg/kg). Gantacurium seems to be degraded by two chemical mechanisms, neither of which is enzymatic.32 The chlorine in the molecule allows for a unique form of inactivation. Preliminary studies with gantacurium in human blood indicate that the major metabolite of the compound is mixed onium thiazolidine. This compound is formed through the adduction of cysteine, a nonessential amino acid, to the TABLE 2. Onset of Maximal Block and Spontaneous Recovery to 25% or 95% Twitch Height After the Administration of Gantacurium or Succinylcholine (Mean7SD) Minutes to Maximum Block T1 ¼ 25% T1 ¼ 95% Gantacurium 0.36 mg/kg LA 1.170.3 7.271.1 12.972.1 AP 1.770.2 7.070.5 12.271.3 Gantacurium 0.54 mg/kg LA 0.970.2 9.372.9 16.174.1 AP 1.570.3 9.371.5 15.273.0 Succinylcholine 1 mg/kg LA 0.870.3 6.171.7 11.371.9 AP 1.570.2 8.571.5 12.172.0 AP ¼ adductor pollicis; LA ¼ laryngeal adductors.
  • 11. PHARMACOLOGY OF NEUROMUSCULAR BLOCKING AGENTS 115 TABLE 3. Recovery Intervals After the Administration of Gantacurium (Mean7SD) Dose (mg/kg) Recovery Interval (minutes) 0.18 0.30 0.36 0.40 0.45 0.54 0.72 T1 5--95% 6.570.8 7.871.9 6.470.9 7.672.3 7.272.8 6.971.7 7.171.2 T1 25--75% 2.770.5 3.370.9 2.570.3 3.471.2 3.171.2 3.071.1 3.271.1 T1 25% to 5.171.1 5.471.5 4.971.1 5.472.1 5.671.8 5.071.6 5.270.8 TOFR Z0.9 TOFR ¼ train-of-four fade ratio. compound at the site of the chlorine molecule. The adduction process occurs rapidly. The second process of inactivation occurs more slowly and involves hydrolysis of the ester bond adjacent to the chlorine substitution. This process yields inactive hydrolysis products. Intravenous administration of exogenous cysteine to monkeys rapidly reverses the gantacurium-induced block.33 Administration of cysteine (10 mg/kg) 2 minutes after the administration of 8 Â ED95 gantacurium shortened the 5% to 95% recovery interval by 2 1 minutes and the total duration of block (the time from administration 2 of gantacurium to a train-of-four ratio Z0.9) by 6 1 minutes. Cysteine (10 mg/kg) will 2 facilitate complete recovery of the neuromuscular function even when administered within 1 minute of gantacurium. Summary Both the neuromuscular junction and neuromuscular transmission have been studied extensively. They remain incompletely understood by most clinical anesthes- iologists. Ongoing research continues to elucidate details regarding the specifics of neuromuscular transmission. Studies with blocking agents and compounds that reverse their effects capitalize on these details. Inadequate recovery from NMBAs continues to be an all-too-common occurrence after the administration of these drugs. There is growing evidence that postoperative residual curarization places patients at increased risk of developing postoperative pulmonary complications. We hope that faster- and shorter-acting NMBAs and faster-acting and more effective reversal agents will lead to improvements in safety for patients undergoing paralysis during general anesthesia. References 1. Bowman WC, Prior C, Marshall IG: Presynaptic receptors in the neuromuscular junction. Ann NY Acad Sci 1990; 604:69--81. 2. Bowman WC: Pharmacology of Neuromuscular Function. London, Butterworth and Co Ltd, 1990. 3. Naguib M, Flood P, McArdle JJ, Brenner HR: Advances in neurobiology of the neuromuscular junction: Implications for the anesthesiologist. Anesthesiology 2002; 96:202. 4. Pedersen SE, Cohen JB: D-tubocurarine binding sites are located at alpha-gamma and alpha-delta subunit interfaces of the nicotinic acetylcholine receptor. Proc Natl Acad Sci 1990; 87:2785. 5. Dilger JP, Vidal AM, Liu M, et al.: Roles of amino acids and subunits in determining the inhibition of nicotinic acetylcholine receptors by competitive antagonists. Anesthesio- logy 2007; 106:1186--95.
  • 12. 116 KOPMAN AND LIEN 6. Frick CG, Richtsfeld M, Sahani ND, et al.: Long-term effects of botulinum toxin on neuromuscular function. Anesthesiology 2007; 106:1139--46. 7. Ali HH, Utting JE, Gray TC: Stimulus frequency in the detection of neuromuscular block in man. Br J Anaesth 1970; 42:967--78. 8. Ali HH, Utting JE, Gray TC: Quantitative assessment of residual antidepolarizing block (Part 1). Br J Anaesth 1971; 43:473--7. 9. Ali HH, Utting JE, Gray TC: Quantitative assessment of residual antidepolarizing block (Part 2). Br J Aneesth 1971; 43:478--85. 10. Ali HH, Wilson RS, Savarese JJ, Kitz RJ: The effect of d-tubocurarine on indirectly elicited train-of-four muscle response and respiratory measurements in humans. Br J Anaesth 1975; 47:570--4. 11. Brand JB, Cullen DJ, Wilson NE, Ali HH: Spontaneous recovery from nondepolarizing neuromuscular block: Correlation between clinical and evoked responses. Anesth Analg 1977; 56:55--8. 12. Eriksson LI, Sato M, Severinghaus JW: Effect of a vecuronium-induced partial neuromuscular block on hypoxic ventilatory response. Anesthesiology 1993; 78:693--9. 13. Kopman AF, Yee PS, Neuman GG: Correlation of the train-of-four fade ratio with clinical signs and symptoms of residual curarization in awake volunteers. Anesthesiology 1997; 86:765--71. 14. Eriksson LI, Sundman E, Olsson R, et al.: Functional assessment of the pharynx at rest and during swallowing in partially paralyzed humans: Simultaneous videomanometry and mechanomyography of awake human volunteers. Anesthesiology 1997; 87:1035--43. 15. Viby-Mogensen J, Jorgensen BC, Ørding H: Residual curarization in the recovery room. Anesthesiology 1979; 50:539--41. 16. Debaene B, Plaud B, Dilly MP, Donati F: Residual paralysis in the postanesthesia care unit after a single intubating dose of nondepolarizing muscle relaxant with an intermediate duration of action. Anesthesiology 2003; 98:1042--8. 17. Baillard C, Gehan G, Reboul-Marty J, et al.: Residual curarization in the recovery room after vecuronium. Br J Anaesth 2000; 84:394--5. 18. Hayes AH, Mirakhur RK, Breslin DS, Reid JE, McCourt KC: Postoperative residual block after intermediate-acting neuromuscular blocking drugs. Anaesthesia 2001; 56:312--8. 19. Gatke MR, Viby-Mogensen J, Rosenstock C, Jensen FS, Skovgaard LT: Postoperative muscle paralysis after rocuronium: Less residual block when accelomyography is used. Acta Anaesthesiol Scand 2002; 46:207--13. 20. Viby-Mogensen J, Jensen NH, Engbaek J, et al.: Tactile and visual evaluation of the response to train-of-four nerve stimulation. Anesthesiology 1985; 63:440--3. 21. Berg H, Viby-Mogensen J, Roed J, et al.: Residual neuromuscular block is a risk factor for postoperative pulmonary complications: A prospective, randomized and blinded study of postoperative pulmonary complications after atracurium, vecuronium and pancuro- nium. Acta Anaesthesiol Scand 1997; 41:1095--1103. 22. Murphy GS, Szokol JW, Marymont JH, et al.: Residual neuromuscular blockade and critical respiratory events in the postanesthesia care unit. Anesth Analg 2008; 107:130--7. 23. Bom A, Bradley M, Cameron K, et al.: A novel concept of reversing neuromuscular block: Chemical encapsulation of rocuronium bromide by a cyclodextrin-based synthetic host. Agnew Chem Int Ed 2002; 41:265--70. 24. Puhringer FK, Rex C, Sielenkamper AW, et al.: Reversal of profound, high-dose rocuronium-induced neuromuscular blockade by sugammadex at two different time points: An international, multicenter, randomized, dose-finding, safety assessor-blinded, phase II trial. Anesthesiology 2008; 109:188--97. 25. Sacan O, White PF, Tufanogullari B, Klein K: Sugammadex reversal of rocuronium- induced neuromuscular blockade: A comparison with neostigmine--glycopyrrolate and edrophonium--atropine. Anesth Analg 2007; 104:569--74. 26. Boros EE, Bigham EC, Mook RA, et al.: Bis- and mixed-tetrahydroisoquinolinium chlorofumarates: New ultra-short-acting nondepolarizing neuromuscular blockers. J Med Chem 1999; 42:206--9. 27. Samano V, Ray JA, Thompson JB, et al.: Synthesis of ultra-short-acting neuromuscular blocker GW 0430: A remarkably stereo- and regioselective synthesis of mixed tetrahydroisoquinolinium chlorofumarates. Org Lett 1999; 1:1993--6.
  • 13. PHARMACOLOGY OF NEUROMUSCULAR BLOCKING AGENTS 117 28. Boros EE, Samano V, Ray JA, et al.: Neuromuscular blocking activity and therapeutic potential effect of mixed-tetrahydroisoquinolinium halofumarates and halosuccinates in rhesus monkeys. J Med Chem 2003; 46:2502--15. 29. Savarese JJ, Belmont MR, Hashim MA, et al.: Preclinical pharmacology og GW280430A (AV430A) in the rhesus monkey and in the cat. Anesthesiology 2004; 100:835--45. 30. Belmont MR, Lien CA, Savarese JJ, et al.: Neuromuscular blocking effects of GW280430A at the adductor pollicis and larynx in human volunteers. Br J Anaesth 1999; 82:A41. 31. Belmont MR, Lien CA, Tjan J, et al.: Clinical pharmacology of GW280430A in humans. Anesthesiology 2004; 100:768--73. 32. Boros EE, Samano V, Ray JA, et al.: Neuromuscular blocking activity and therapeutic potential of mixed-tetrahydroisoquinolinium halofumarates and halosuccinates in rhesus monkeys. J Med Chem 2003; 46:2502--15. 33. Belmont MR, Horochiwsky Z, Eliazo RF, Savarese JJ: Reversal of AV430A with cysteine in rhesus monkeys (abstract). Anesthesiology 2004; 101:A1180.