OPINIONS IN SMALL ANIMAL ANESTHESIA
0195-5616/92 $0.00
+ .20
NEUROMUSCULAR BLOCKING AGENTS Susan V. Hildebrand, DVM
MECHANISM OF ACTION
Normally a stimulus carried by the motor nerve causes release of acetylcholine from the nerve terminal. Acetylcholine crosses the synaptic junction toward the motor end plate on the muscle and attaches to receptors there. Receptor attachment leads to depolarization of the muscle cell and subsequent muscle contraction. Muscle contraction ends when acetylcholine is broken down by acetylcholinesterase that is closely associated with the motor end plate. Acetylcholine breakdown products are taken up by the nerve ending for recycling to· produce more acetylcholine within the nerve ending. Neuromuscular blocking agents affect both prejunctional and postjunctional receptors. Relaxant occupation of the postjunctional receptors prevents acetylcholine from interacting with them. This results in diminished strength of muscle contraction or reduced evoked tension. Cholinergic receptors on the motor nerve terminal (prejunctional receptors) differ from those on the motor end plate and seem to influence the release of transmitter from the motor nerve terminal. 21 Relaxant interference with prejunctional receptors probably causes fade. 1 Fade refers to a weakening of neuromuscular transmission and is seen as failure to sustain muscle contraction in response to train-of-four or tetanic stimuli. Degree of fade varies with different muscle relaxants, but in all cases, fade is slower to develop than is depressed strength of contraction. From the Department of Surgery, University of California, Davis, School of Veterinary Medicine, Davis, California VETERINARY CLINICS OF NORTH AMERICA: SMALL ANIMAL PRACTICE VOLUME 22 • NUMBER 2 • MARCH 1992
341
342
NEUROMUSCULAR BLOCKING AGENTS
UNDESIRABLE EFFECTS AND AUTONOMIC SAFETY MARGIN
The ideal muscle relaxant would affect only the neuromuscular junction. Although recently developed relaxants have relatively minor side effects, the neuromuscular blocking agents first used in anesthesia had a number of undesirable side effects related both to neuromuscular blockade and to effects on other systems, especially cardiovascular function. 19 Cardiovascular function is affected by muscle relaxants because of interaction with nonneuromuscular cholinergic receptors, both nicotinic and muscarinic. Cardiovascular changes may be due to effects on sympathetic ganglia, vagus nerve, and histamine-releasing cells. In addition! depolarizing relaxants can cause release of potassium from muscles and painful muscle contraction. Neuromuscular blocking agents are generally classified as either depolarizing or nondepolarizing. The depolarizing relaxants such as succinylcholine mimic the effects of acetylcholine, and side effects such as bradycardia or tachycardia, hypertension, and cardiac dysrhythmias may result from their administration. The nondepolarizing relaxants block cholinergic receptors. Autonomic side effects of the nondepolarizers can include tachycardia and hypotension, as a result of vagal and ganglionic blockade, as well as histamine release. Curare causes considerable ganglionic blockade and histamine release. Gallamine, and to a lesser extent, pancuronium, cause tachycardia as a result of vagal blockade. The newer relaxants are unlikely to cause cardiovascular dysfunction. NONDEPOLARIZING RELAXANTS
Nondepolarizing muscle relaxants are bulky, inflexible molecules. They are quaternary ammonium compounds that do not cross lipid barriers. Gallamine is an exception, as it can cross the placenta. 5 CURARIFORM RELAXANTS
The first neuromuscular blocking agent used in humans was dtubocurarine, or curare. 5 Because curare had the undesirable side effects of histamine release and hypotension as a result of ganglionic blockade, other curare derivative molecules were synthesized. Dimethyltubocurarine (Metocurine) and gallamine (Flaxedil) were improvements over curare, but still had undesirable cardiovascular effects. Their elimination was dependent on hepatic and renal function; thus cumulative administration or organ insufficiency meant prolonged activity. Recently developed curariform relaxants, atracurium (Tracrium), mivacurium (BW 10900), and doxacurium (BW938U), are considered to cause mild histamine release and have negligible cardiovascular effects.
NEUROMUSCULAR BLOCKING AGENTS
343
Atracurium Besylate
Atracurium's degree of neuromuscular blockade, duration of action, and duration of recovery have been shown to be reproducible and reliable in several species. 8·14 The atracurium molecule is unstable and undergoes spontaneous breakdown by means of the temperaturedependent and pH-dependent process called Hofmann elimination. 14 Atracurium can be stored for prolonged periods at 4°C, but at 37°C and pH 7.4, degradation is rapid by this mechanism. Atracurium also undergoes ester hydrolysis. The contribution of ester hydrolysis to atracurium's degradation has not been well defined. Reduction of plasma cholinesterase does not seem to influence atracurium's breakdown rates. 14 Atracurium's breakdown products do not have neuromuscular blocking activity; however, one, laudanosine, causes central nervous system arousal. Laudanosine might increase anesthetic minimal alveolar concentration (MAC) requirements or cause convulsions, but neither of these potential problems have become clinically relevant. Onset of action of atracurium is in part dose dependent but generally occurs in 2 to 5 minutes. Atracurium is also suitable for administration as an infusion. Atracurium should be prepared for infusion in normal saline, to minimize degradation by Hofmann elimination.6 Because atracurium does not depend on hepatic, renal, or cholinesterase function to terminate its activity, once the muscle begins to recover its strength, it does so at a predictable and rapid rate. Cardiovascular effects of atracurium are minimal. Atracurium is considered to cause mild histamine release. Large bolus doses may cause clinical signs of histamine release; however, these do not occur if the dose is given slowly over 1 minute. 20 Atracurium is provided as a 10 mg/mL concentration in 10-mL multiple-dose vials and must be stored at 4°C.
Mivacurium and Doxacurium
Until recently, the only bis cholinium ester in clinical use was succinylcholine. 18 Two nondepolarizing relaxants with comparable onset and duration of action to succinylcholine have been developedmivacurium and doxacurium. These compounds are hydrolyzed by plasma cholinesterase. Mivacurium chloride (BW 1090U) is a nondepolarizing relaxant with a rapid onset and a short duration of action. 2•15·16·23 Mivacurium is hydrolyzed at approximately 88% the rate of succinylcholine. Mivacurium apparently can be antagonized successfully by anticholinesterase drugs, although reversal may not be necessary. Mivacurium is slightly more potent than atracurium. In humans given mivacurium, intubation of the trachea is possible in 60 seconds. Duration of ED95 is approxi-
344
NEUROMUSCULAR BLOCKING AGENTS
mately 25 minutes. There is little cumulative activity or increase in duration with doses 2 and 3 times ED95. Like atracurium, mivacurium causes mild histamine release. Doxacurium (BW A938U) has a potency approximately twice that of pancuronium and mivacurium and a duration approximately 3 times mivacurium. 3 •7 •9 •13 Doxacurium has minimal cardiovascular side effects9 •10 and has no cumulative effect. PANCURONIUM BROMIDE AND VECURONIUM BROMIDE
Pancuronium and vecuronium are steroid-based nondepolarizing muscle relaxants without corticosteroid activity. Pancuronium (Pavulon) is a rapidly acting relaxant that does not release histamine or cause ganglionic blockade. 5 It does, however, have some vagolytic action, although hypertension and tachycardia are not as pronounced as for gallamine. Pancuronium does have cumulative effects. Between 10% and 30% of pancuronium undergoes hepatic metabolism. Three metabolites are produced, one of which has slightly less than half the neuromuscular blocking capability of pancuronium. Reversal of pancuronium may be difficult if total dose was excessive, if the last dose was administered shortly before the end of anesthesia, or if the patient has hepatic or renal disease. Vecuronium (ORG NC45, Norcuron) is a relatively new relaxant closely related to pancuronium. 12 Vecuronium is slightly more potent than pancuronium. Duration of action is approximately one half that of pancuronium. Vecuronium is excreted largely unchanged in the bile and to a lesser extent in the urine. Cumulative effects are minimal. Vecuronium is the best relaxant developed to date with regard to cardiovascular stability. ANTAGONISM OF MUSCLE RELAXATION
In most cases, a relaxant antagonist or reversal agent is given to ensure adequate muscle strength in recovery. 11 Nondepolarizing relaxants are antagonized by anticholinesterases that prevent acetylcholine from breaking down. This increases the acetylcholine in the neuromuscular junction, which competes with the relaxant for receptor sites. There are three drugs that can be used for reversal of relaxants: edrophonium, neostigmine, and pyridostigmine. Because of a relatively slow onset time and prolonged duration, pyridostigmine is not commonly used. Edrophonium provides a slightly more rapid reversal than neostigmine, and their duration of action is comparable with equipotent reversal doses. Atropine should probably be used with both agents to prevent bradycardia, hypotension, and salivation. Reversal of relaxants should not be attempted until the twitch response shows some spontaneous recovery.
NEUROMUSCULAR BLOCKING AGENTS
345
A number of situations contribute to difficult reversal of neuromuscular blocking agents. 11 ' 22 Attempts to reverse a profound block may be ineffective. The more time between the last dose of relaxant and reversal, the better the response. With the old relaxants, impaired hepatic, renal, or cholinesterase function contributed considerably to prolonged relaxant activity. For the new relaxants, especially atracurium, severe impairment of those functions should not prolong duration of action. For the old relaxants, alteration in acid-base status could make reversal impossible. 11 For atracurium, duration of action could be increased by acidemia and low body temperature, although studies indicate that altered duration as a result of pH is minimal. 8 Altered intracellular and extracellular potassium may alter transmembrane potential and augment neuromuscular blockade. Other medications can prolong neuromuscular blockade. 22 Aminoglycosides can produce neuromuscular blockade by themselves and have been shown to influence the activity of muscle relaxants. The block produced by aminoglycoside antibiotics can be unusual and difficult to reverse. EQUIPMENT
Ventilation must be provided either manually or mechanically. Means of monitoring the degree of neuromuscular blockade is essential. Such monitoring is easily accomplished using a hand-held peripheral nerve stimulator, preferably one that delivers both train-of-four and 50Hz tetanic stimulus. Neuromuscular blockade is evaluated by placing contact or needle electrodes on either side of a peripheral nerve, such as the facial, ulnar, or superficial peroneal, whichever is most accessible. Muscle response, or twitch response, to the stimulus is observed. The nerve is stimulated before administration of relaxant to determine prerelaxant muscle strength. First, train-of-four (TOF) stimulation is used. This mode refers to 4 single stimuli given in succession, one every half second, over 2 seconds. In the unparalyzed animal, four separate twitch responses are seen with each of the four stimuli in the train. TOF should not be repeated more frequently than every 12 seconds. TOF is not painful but could lead to arousal in the very lightly anesthetized animal. Second, tetanic stimulation is applied. This is a rapid stimulus mode (50 Hz). The nerve and muscle cannot function quickly enough to give 50 separate, distinct twitches in a second. What is observed is a constant contraction of the muscle until the tetanic stimulus ceases. A tetanic stimulus is generally given for 5 seconds duration and not more frequently than every 20 seconds. Tetanic stimulus is painful and elicits a response in an animal that is not adequately anesthetized. Both TOF and tetanic stimulus response give information regarding two aspects of neuromuscular blockade. First, evoked strength is evaluated. The strength of the muscle response to nerve stimulus is
346
NEUROMUSCULAR BLOCKING AGENTS
related to occupation of postjunctional receptors by muscle relaxant. The unparalyzed twitch is crisp, and the difference in the twitch strength is easily observed when relaxants are given. Second, fade is evaluated. Fade refers to the inability of the muscles to sustain the strength generated by a TOF or tetanic stimulus. Fade is the result of prejunctional (nerve ending) receptor occupation by relaxant. Depolarizing relaxants such as succinylcholine do not act at prejunctional receptors unless the second phase block occurs. Fade is easily detected by observing the change in character of the 4 twitches of the TOF or of the tetanic response over 5 seconds. The first twitch in the train is the strongest, with the remaining 3 each diminishing in strength. As the block becomes more profound, the 4th, 3rd, and 2nd twitches in the train disappear in that order. Eventually, depending on the dose of relaxant given, the 1st twitch in the train disappears. Twitch responses of the facial muscles and the extremities are not identical, with facial muscles more resistant to the effect of relaxants. The twitch responses must therefore be interpreted accordingly.
References 1. Bowman WC, Marshall IG, Gibb AJ: Is there feedback control of transmitter release at the neuromuscular junction? In Katz RL, ed: Muscle Relaxants: Basic and Clinical Aspects. New York, Grune & Stratton, 1985, pp 39-52 2. Caldwell JE, Kitts JB, Heier T, et a): The dose-response relationship of mivacurium chloride in humans during nitrous oxide-fentanyl or nitrous oxide-enflurane anesthesia. Anesthesiology 70:31-35, 1989 3. Deriaz H, Coutade A, Lienhart A: Dose-response relationship of BW A938U under balanced anesthesia: A comparative study with pancuronium. Anesthesiology 67:A369, 1987 4. Durant NN: The physiology of neuromuscular transmission. In Katz RL, ed: Muscle Relaxants: Basic and Clinical Aspects. New York, Grune & Stratton, 1985, pp 19-38 5. Feldm
0195-5616/92 $0.00
+ .20
NEUROMUSCULAR BLOCKING AGENTS Susan V. Hildebrand, DVM
MECHANISM OF ACTION
Normally a stimulus carried by the motor nerve causes release of acetylcholine from the nerve terminal. Acetylcholine crosses the synaptic junction toward the motor end plate on the muscle and attaches to receptors there. Receptor attachment leads to depolarization of the muscle cell and subsequent muscle contraction. Muscle contraction ends when acetylcholine is broken down by acetylcholinesterase that is closely associated with the motor end plate. Acetylcholine breakdown products are taken up by the nerve ending for recycling to· produce more acetylcholine within the nerve ending. Neuromuscular blocking agents affect both prejunctional and postjunctional receptors. Relaxant occupation of the postjunctional receptors prevents acetylcholine from interacting with them. This results in diminished strength of muscle contraction or reduced evoked tension. Cholinergic receptors on the motor nerve terminal (prejunctional receptors) differ from those on the motor end plate and seem to influence the release of transmitter from the motor nerve terminal. 21 Relaxant interference with prejunctional receptors probably causes fade. 1 Fade refers to a weakening of neuromuscular transmission and is seen as failure to sustain muscle contraction in response to train-of-four or tetanic stimuli. Degree of fade varies with different muscle relaxants, but in all cases, fade is slower to develop than is depressed strength of contraction. From the Department of Surgery, University of California, Davis, School of Veterinary Medicine, Davis, California VETERINARY CLINICS OF NORTH AMERICA: SMALL ANIMAL PRACTICE VOLUME 22 • NUMBER 2 • MARCH 1992
341
342
NEUROMUSCULAR BLOCKING AGENTS
UNDESIRABLE EFFECTS AND AUTONOMIC SAFETY MARGIN
The ideal muscle relaxant would affect only the neuromuscular junction. Although recently developed relaxants have relatively minor side effects, the neuromuscular blocking agents first used in anesthesia had a number of undesirable side effects related both to neuromuscular blockade and to effects on other systems, especially cardiovascular function. 19 Cardiovascular function is affected by muscle relaxants because of interaction with nonneuromuscular cholinergic receptors, both nicotinic and muscarinic. Cardiovascular changes may be due to effects on sympathetic ganglia, vagus nerve, and histamine-releasing cells. In addition! depolarizing relaxants can cause release of potassium from muscles and painful muscle contraction. Neuromuscular blocking agents are generally classified as either depolarizing or nondepolarizing. The depolarizing relaxants such as succinylcholine mimic the effects of acetylcholine, and side effects such as bradycardia or tachycardia, hypertension, and cardiac dysrhythmias may result from their administration. The nondepolarizing relaxants block cholinergic receptors. Autonomic side effects of the nondepolarizers can include tachycardia and hypotension, as a result of vagal and ganglionic blockade, as well as histamine release. Curare causes considerable ganglionic blockade and histamine release. Gallamine, and to a lesser extent, pancuronium, cause tachycardia as a result of vagal blockade. The newer relaxants are unlikely to cause cardiovascular dysfunction. NONDEPOLARIZING RELAXANTS
Nondepolarizing muscle relaxants are bulky, inflexible molecules. They are quaternary ammonium compounds that do not cross lipid barriers. Gallamine is an exception, as it can cross the placenta. 5 CURARIFORM RELAXANTS
The first neuromuscular blocking agent used in humans was dtubocurarine, or curare. 5 Because curare had the undesirable side effects of histamine release and hypotension as a result of ganglionic blockade, other curare derivative molecules were synthesized. Dimethyltubocurarine (Metocurine) and gallamine (Flaxedil) were improvements over curare, but still had undesirable cardiovascular effects. Their elimination was dependent on hepatic and renal function; thus cumulative administration or organ insufficiency meant prolonged activity. Recently developed curariform relaxants, atracurium (Tracrium), mivacurium (BW 10900), and doxacurium (BW938U), are considered to cause mild histamine release and have negligible cardiovascular effects.
NEUROMUSCULAR BLOCKING AGENTS
343
Atracurium Besylate
Atracurium's degree of neuromuscular blockade, duration of action, and duration of recovery have been shown to be reproducible and reliable in several species. 8·14 The atracurium molecule is unstable and undergoes spontaneous breakdown by means of the temperaturedependent and pH-dependent process called Hofmann elimination. 14 Atracurium can be stored for prolonged periods at 4°C, but at 37°C and pH 7.4, degradation is rapid by this mechanism. Atracurium also undergoes ester hydrolysis. The contribution of ester hydrolysis to atracurium's degradation has not been well defined. Reduction of plasma cholinesterase does not seem to influence atracurium's breakdown rates. 14 Atracurium's breakdown products do not have neuromuscular blocking activity; however, one, laudanosine, causes central nervous system arousal. Laudanosine might increase anesthetic minimal alveolar concentration (MAC) requirements or cause convulsions, but neither of these potential problems have become clinically relevant. Onset of action of atracurium is in part dose dependent but generally occurs in 2 to 5 minutes. Atracurium is also suitable for administration as an infusion. Atracurium should be prepared for infusion in normal saline, to minimize degradation by Hofmann elimination.6 Because atracurium does not depend on hepatic, renal, or cholinesterase function to terminate its activity, once the muscle begins to recover its strength, it does so at a predictable and rapid rate. Cardiovascular effects of atracurium are minimal. Atracurium is considered to cause mild histamine release. Large bolus doses may cause clinical signs of histamine release; however, these do not occur if the dose is given slowly over 1 minute. 20 Atracurium is provided as a 10 mg/mL concentration in 10-mL multiple-dose vials and must be stored at 4°C.
Mivacurium and Doxacurium
Until recently, the only bis cholinium ester in clinical use was succinylcholine. 18 Two nondepolarizing relaxants with comparable onset and duration of action to succinylcholine have been developedmivacurium and doxacurium. These compounds are hydrolyzed by plasma cholinesterase. Mivacurium chloride (BW 1090U) is a nondepolarizing relaxant with a rapid onset and a short duration of action. 2•15·16·23 Mivacurium is hydrolyzed at approximately 88% the rate of succinylcholine. Mivacurium apparently can be antagonized successfully by anticholinesterase drugs, although reversal may not be necessary. Mivacurium is slightly more potent than atracurium. In humans given mivacurium, intubation of the trachea is possible in 60 seconds. Duration of ED95 is approxi-
344
NEUROMUSCULAR BLOCKING AGENTS
mately 25 minutes. There is little cumulative activity or increase in duration with doses 2 and 3 times ED95. Like atracurium, mivacurium causes mild histamine release. Doxacurium (BW A938U) has a potency approximately twice that of pancuronium and mivacurium and a duration approximately 3 times mivacurium. 3 •7 •9 •13 Doxacurium has minimal cardiovascular side effects9 •10 and has no cumulative effect. PANCURONIUM BROMIDE AND VECURONIUM BROMIDE
Pancuronium and vecuronium are steroid-based nondepolarizing muscle relaxants without corticosteroid activity. Pancuronium (Pavulon) is a rapidly acting relaxant that does not release histamine or cause ganglionic blockade. 5 It does, however, have some vagolytic action, although hypertension and tachycardia are not as pronounced as for gallamine. Pancuronium does have cumulative effects. Between 10% and 30% of pancuronium undergoes hepatic metabolism. Three metabolites are produced, one of which has slightly less than half the neuromuscular blocking capability of pancuronium. Reversal of pancuronium may be difficult if total dose was excessive, if the last dose was administered shortly before the end of anesthesia, or if the patient has hepatic or renal disease. Vecuronium (ORG NC45, Norcuron) is a relatively new relaxant closely related to pancuronium. 12 Vecuronium is slightly more potent than pancuronium. Duration of action is approximately one half that of pancuronium. Vecuronium is excreted largely unchanged in the bile and to a lesser extent in the urine. Cumulative effects are minimal. Vecuronium is the best relaxant developed to date with regard to cardiovascular stability. ANTAGONISM OF MUSCLE RELAXATION
In most cases, a relaxant antagonist or reversal agent is given to ensure adequate muscle strength in recovery. 11 Nondepolarizing relaxants are antagonized by anticholinesterases that prevent acetylcholine from breaking down. This increases the acetylcholine in the neuromuscular junction, which competes with the relaxant for receptor sites. There are three drugs that can be used for reversal of relaxants: edrophonium, neostigmine, and pyridostigmine. Because of a relatively slow onset time and prolonged duration, pyridostigmine is not commonly used. Edrophonium provides a slightly more rapid reversal than neostigmine, and their duration of action is comparable with equipotent reversal doses. Atropine should probably be used with both agents to prevent bradycardia, hypotension, and salivation. Reversal of relaxants should not be attempted until the twitch response shows some spontaneous recovery.
NEUROMUSCULAR BLOCKING AGENTS
345
A number of situations contribute to difficult reversal of neuromuscular blocking agents. 11 ' 22 Attempts to reverse a profound block may be ineffective. The more time between the last dose of relaxant and reversal, the better the response. With the old relaxants, impaired hepatic, renal, or cholinesterase function contributed considerably to prolonged relaxant activity. For the new relaxants, especially atracurium, severe impairment of those functions should not prolong duration of action. For the old relaxants, alteration in acid-base status could make reversal impossible. 11 For atracurium, duration of action could be increased by acidemia and low body temperature, although studies indicate that altered duration as a result of pH is minimal. 8 Altered intracellular and extracellular potassium may alter transmembrane potential and augment neuromuscular blockade. Other medications can prolong neuromuscular blockade. 22 Aminoglycosides can produce neuromuscular blockade by themselves and have been shown to influence the activity of muscle relaxants. The block produced by aminoglycoside antibiotics can be unusual and difficult to reverse. EQUIPMENT
Ventilation must be provided either manually or mechanically. Means of monitoring the degree of neuromuscular blockade is essential. Such monitoring is easily accomplished using a hand-held peripheral nerve stimulator, preferably one that delivers both train-of-four and 50Hz tetanic stimulus. Neuromuscular blockade is evaluated by placing contact or needle electrodes on either side of a peripheral nerve, such as the facial, ulnar, or superficial peroneal, whichever is most accessible. Muscle response, or twitch response, to the stimulus is observed. The nerve is stimulated before administration of relaxant to determine prerelaxant muscle strength. First, train-of-four (TOF) stimulation is used. This mode refers to 4 single stimuli given in succession, one every half second, over 2 seconds. In the unparalyzed animal, four separate twitch responses are seen with each of the four stimuli in the train. TOF should not be repeated more frequently than every 12 seconds. TOF is not painful but could lead to arousal in the very lightly anesthetized animal. Second, tetanic stimulation is applied. This is a rapid stimulus mode (50 Hz). The nerve and muscle cannot function quickly enough to give 50 separate, distinct twitches in a second. What is observed is a constant contraction of the muscle until the tetanic stimulus ceases. A tetanic stimulus is generally given for 5 seconds duration and not more frequently than every 20 seconds. Tetanic stimulus is painful and elicits a response in an animal that is not adequately anesthetized. Both TOF and tetanic stimulus response give information regarding two aspects of neuromuscular blockade. First, evoked strength is evaluated. The strength of the muscle response to nerve stimulus is
346
NEUROMUSCULAR BLOCKING AGENTS
related to occupation of postjunctional receptors by muscle relaxant. The unparalyzed twitch is crisp, and the difference in the twitch strength is easily observed when relaxants are given. Second, fade is evaluated. Fade refers to the inability of the muscles to sustain the strength generated by a TOF or tetanic stimulus. Fade is the result of prejunctional (nerve ending) receptor occupation by relaxant. Depolarizing relaxants such as succinylcholine do not act at prejunctional receptors unless the second phase block occurs. Fade is easily detected by observing the change in character of the 4 twitches of the TOF or of the tetanic response over 5 seconds. The first twitch in the train is the strongest, with the remaining 3 each diminishing in strength. As the block becomes more profound, the 4th, 3rd, and 2nd twitches in the train disappear in that order. Eventually, depending on the dose of relaxant given, the 1st twitch in the train disappears. Twitch responses of the facial muscles and the extremities are not identical, with facial muscles more resistant to the effect of relaxants. The twitch responses must therefore be interpreted accordingly.
References 1. Bowman WC, Marshall IG, Gibb AJ: Is there feedback control of transmitter release at the neuromuscular junction? In Katz RL, ed: Muscle Relaxants: Basic and Clinical Aspects. New York, Grune & Stratton, 1985, pp 39-52 2. Caldwell JE, Kitts JB, Heier T, et a): The dose-response relationship of mivacurium chloride in humans during nitrous oxide-fentanyl or nitrous oxide-enflurane anesthesia. Anesthesiology 70:31-35, 1989 3. Deriaz H, Coutade A, Lienhart A: Dose-response relationship of BW A938U under balanced anesthesia: A comparative study with pancuronium. Anesthesiology 67:A369, 1987 4. Durant NN: The physiology of neuromuscular transmission. In Katz RL, ed: Muscle Relaxants: Basic and Clinical Aspects. New York, Grune & Stratton, 1985, pp 19-38 5. Feldm
