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Clinical pharmacology of mivacurium chloride: A review salvatore
Rational Pharmacology E. Greg Koski, PhD, MD Section Editor
Clinical Pharmacology of Mivacurium Chloride: A Review
Salvatore J. Basta, MD* Department of Anaesthesia, Harvard Medical School, and Department thesia, Massachusetts General Hospital, Boston, MA.
Miuacurium chloride (Mivacron) is a new benzylisoquinolinium choline-like diester neuromuscular blocking drug with an onset of action at equipotent doses that is comparable to atracurium and vecuronium but slower than succinylcholine. Its clinical duration (injection-25% recovery and injection-95% recovq) is twice that of succinylcholine but one-half to one-third that of atracurium and vecuronium. Mivacurium is easy to use as a continuous infusion and when used this way its recovery characteristics are unchanged. It is readily antagonized by anticholinesterase drugs. The EDg, in adults under narcotic-based anesthesia is 0.07-0.08 mglkg. At twice the ED,, (0.15 mglkg) onset time is about 2 to 3 minutes, duration to 25% recovery ti 15 to 20 minutes, and 5-95% recovery time about 14 minutes. The mean infusion rate in adults is 6 pglkglmin (range 2-15) with a 5-95% recovery time of 14 minutes. En.urane and isoflurane require a 20-30% decrease in dosage; halothane, en&rune, and isojlurane prolong the duration of mivacurium 25-30%. The ED,, in children 2 to 12 years of age is slightly higher (0.09-0.11 mglkg) with a faster onset and shorter duration. In these young patients, a dose of 0.2 mglkg has an onset comparable to succinylcholine. Being chemically related to atracurium, mivacurium may cause histamine release. When adminktered rapidly at doses of 0.2 mglkg or greater in adults, histamine release and transient hypotension have been observed. Doses of 0.2 mglkg or higher are not recommended by the manufacturer. Mivacurium is metabolized &y plasma cholinesterase. In vitro, the rate is about 70% that of succinylcholine. In patients with normal or slightly less than normal
*Assistant Professor Address reprint requests to Dr. Basta at the Department of Anesthesia, Massachusetts General Hospital, 32 Fruit Street, Boston, MA 02 114, USA. Received for publication December 24, 1991; revised manuscript accepted for publication December 30, 199 1.
0 1992 Butterworth-Heinemann J. Clin. Anesth. 4~153-163,
1992.
of Anes-
+.sma cholinesterase activity, no prolonged durations of action have been observed. In patients heterozygous for the atypical gene and at a dose of 0.2 mglkg, 50% prolongation has been shown. Those individuals homozygous for the atypical gene are exquisitely sensitive to mivacurium and have a markedly prolonged blockade that is readily reversible. In these patients and those with acquired deficiencies, mivacurium should not be used. The duration of action in elderly patients is comparable to that in the young, while in prerenal transplant patients, its duration is prolonged by about 50%, and in prehepatic trans@ant patients, duration of block is increased threefold. Mivacurium possesses the advantages of short duration, unchanged recovery characteristics following infusions (without phase II block or tachyphylaxis), and precise control. In bolus form, it should be useful for routine, nonemergent intubations, for surgical procedures as short as 30 minutes, and for procedures of 30 to 60 minutes. For prolonged cases or those of unpredictable duration, infmion of mivacurium will be preferable. Keywords: Neuromuscular blockade, nondepolarizing; short-acting; plasma cholinesterase hydrolysis; infusion; pediatrics; cardiovascular effects, histamine.
Introduction Mivacurium chloride (Mivacron) is a new nondepolarizing neuromuscular blocking drug metabolized by plasma cholinesterase that is soon to be released for use in the United States. It is a bis-quaternary diester benzylisoquinolinium compound described chemically as (R-(R*,R* + (E))-2,2’-((1,8-dioxo-4-octene-l&diyl) bis (oxy-3,l_propenediyl)bis( 1,2,3,4-tetrahydro-6,7-dimethoxy-2-methyl-l-(3,4,5-trimethoxyphenyl)methyl)isoquinolinium)chloride and is shown structurally in Figure I. The clinical pharmacology to date indicates that mivacurium may be expected to have an onset of action at equipotent neuromuscular blocking doses comparable to that of atracurium and vecuronium, but with a duration of action that is one-third to one-half as long as that of
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Plasma Cholmesterase
/
\
Figure 1. The chemical structure of mivacurium. The metabolic pathways of hydrolysis of mivacurium by plasma cholinesterase. Pictured here are the monoquaternary ester and the monoquaternary alcohol. Not pictured is the dicarboxylic acid.
those compounds. Compared with succinylcholine, mivacurium has a slower onset and twice the duration of action. As such, the advantage of mivacurium as a neuromuscular blocking drug is greater versatility and greater control of blockade than are available with currently used nondepolarizing relaxants. This review examines dosepotency, dose-onset, and dose-duration relationships for mivacurium, its recovery and reversibility, and its side effects. Mivacurium for intubation, short surgery, maintenance of blockade by infusion, and pediatric procedures is discussed. Metabolism, elimination, and pharmacodynamics also are reviewed.
Dose-Effect Relationships Dose-Potency
Relationship
Savarese et al.’ studied mivacurium in 72 patients who were anesthetized with nitrous oxide (N,O), oxygen (O,), fentanyl, and thiopental sodium at bolus doses ranging from 0.03 mg/kg to 0.3 mg/kg. Using the method of Litchfield and Wilcoxon,* they estimated the dose-response curve by linear regression of probit values corresponding to the depth of neuromuscular blockade. The calculated 95% neuromuscular blocking dose (EDg5) was found to be 0.081 mg/kg with a 95% confidence limit range of 0.063 to 0.103 mg/kg. Nine patients in this study received a bolus dose of 0.1 mglkg and achieved a mean depth of blockade of 95.7% + 2.8% (SEM). All nine patients receiving 0.15 mg/kg achieved complete blockade. during anesthesia From et al3 studied mivacurium 154
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with N,O, fentanyl, and thiopental sodium and during anesthesia with N,O and halothane. The ED,, of 0.073 mg/kg with fentanyl anesthesia agreed with the data in Savarese et al.’ The ED,, with halothane was 0.081 mg/ kg. Thus, these investigator@ found little potentiation of mivacurium-induced blockade by halothane. Caldwell et al.* examined dose-effect relationships for mivacurium in patients anesthetized with N,O and fentanyl and with N,O and enflurane. The EDg5 for the opioid (fentanyl) was 0.067 mg/kg and for enflurane 0.0532 mglkg. This difference was statistically significant and demonstrates that enflurane enhances mivacurium-induced blockade. Weber et al.5 examined the influence of isoflurane and opioid anesthesia on mivacurium blockade in humans. The estimated ED,, value for mivacurium with the opioid was 0.058 mglkg and with isoflurane 0.045 mgfkg. Subsequently, administration of the estimated ED,, under opioid anesthesia (0.06 mg/kg) to nine patients led to a maximum blockade of only 68% 2 37% (SD). Thus, while their ED,, estimate was lower than that of other investigators studying opioid anesthesia, Weber et al. demonstrated approximately 25% enhancement of blockade by isoflurane. Since the ED,, of mivacurium during opioid anesthesia is 0.07 to 0.08 mg/kg, it is about three times as potent as atracurium6 and about 0.7 times as potent as vecuronium.7 While halothane does not enhance the depth of mivacurium-induced blockade, enflurane and isoflurane appear to enhance it by 25% to 30%.
Dose-Onset
Relationship
Savarese et al.’ found that the onset times for mivacurium at doses of 0.1, 0.15, 0.2, 0.25 and 0.3 mglkg during N,O-fentanyl anesthesia in healthy surgical patients were 3.8 + 0.5 minutes, 3.3 + 0.2 minutes, 2.5 t 0.3 minutes, 2.3 * 0.3 minutes, and 1.9 + 0.3 minutes, respectively, clearly a dose-related phenomenon. Several investigators have studied onset times for a dose of mivacurium twice the ED,, (0.15 mg/kg) and found it to be 2.8 f 3.8 minutes.‘,“,j Therefore, mivacurium at doses twice the ED,, appears to have an onset time comparable to that of atracurium (2.3 to 3.2 minutes)6,sand vecuronium (2.7 to 3.8 minutes)g at equipotent doses. Mivacurium certainly has a slower onset time to maximum blockade than succinylcholine.
Dose-Duration
Relationship
It is now fairly standard practice when evaluating new relaxants to document time from injection to various recovery parameters. Time from injection to 25% recovery (clinical duration) and time from injection to 95% recovery are usually examined. It is also desirable to note how these recovery times change after multiples of the ED,,. Savarese et al.’ studied 45 patients during N,Ofentanyl anesthesia at doses of mivacurium ranging from 0.1 mg/kg (ED,,) to 0.3 mg/kg (3.5 to 4 x ED&. For the lowest dose studied, the mean clinical duration was found
Clinical pharmacology of mivacurium:
to be 14.2 k 1.5 minutes (SEM). Increasing the dose threefold extended the mean clinical duration to 25.0 ? 2.8 minutes. Comparable mean values for time to 95% recovery for 0.1 mg/kg and 0.3 mglkg were 24.5 2 1.6 minutes and 36.7 * 4.3 minutes, respectively. At twice the ED,, (0.15 mg/kg), these authors observed recovery times of 16.8 + 1.1 minutes and 26.9 ? 1.6 minutes, respectively. From et ~1.~also evaluated mivacurium in nine patients each at twice the ED,, of mivacurium (0.15 mg/kg) with both N,O-fentanyl and N,O-halothane. They found that mean times for clinical duration and recovery to 95% were 15.5 + 1.0 minutes (SD) and 24.1 + 1.5 minutes with N,O-fentanyl and 18.6 of: 0.8 minutes and 30.0 r?r. 1.4 minutes for N,O-halothane. Weber et d5 examined the recovery characteristics of mivacurium at 0.15 mg/ kg during opioid anesthesia and 0.1 mg/kg during isoflurane anesthesia. The mean clinical durations were 15.9 f 4.2 minutes for the opioid and 15.0 & 4.4 minutes for isoflurane. Time to 95% recovery was 26.0 ? 7.1 minutes for the opioid and 27.3 + 7.2 minutes for isoflurane. Finally, Caldwell et al4 evaluated the time from injection to 90% recovery, comparing mivacurium during opioid-based anesthesia and enflurane anesthesia. At comparable doses of mivacurium (0.04 mg/kg), the respective opioid and halothane recovery times were 15.9 * 6.2 minutes and 22.2 f. 3.1 minutes. At a dose of 0.05 mglkg, which produced 73% 2 26% neuromuscular blockade with opioid anesthesia, and a dose of 0.04 mg/kg, which produced 77% * 24% neuromuscular blockade with enflurane, these authors documented 90% recovery times of 18.6 2 6.8 minutes and 22.2 f 3.1 minutes, respectively. Additional indexes usually examined across dosage groups and with various anesthetic conditions are 25% to 75% recovery time (recovery index) and 5% to 95% recovery time. The largest single study examining these aspects was that of Savarese et al.’ They evaluated doses of mivacurium of 0.1, 0.15 (2 X ED& 0.2 (2.5 x EDg5), 0.25 (3 x ED&, and 0.3 (4 x EDg5) mg/kg, as well as infusions ranging in time from 35 to 324 minutes. No
Table
1.
Dose-Effect
Relationships
for Mivacurium
Basta
differences were found in either recovery index or 5% to 95% recovery time irrespective of the dose given or the duration of the infusion. The recovery index for all bolus dose groups was 6.8 2 0.3 minutes and for the infusion group 6.5 + 0.3 minutes. The time for 5% to 95% recovery for the bolus dose groups was 14.1 ? 0.6 minutes and for the infusion group 14.4 -+ 0.6 minutes. Other investigatorsS-5 have documented similar recovery indexes in opioid anesthesia and have shown a 20% to 30% prolongation during inhalational anesthesia. To summarize the duration data, one can expect a total duration of action of about 25 minutes following mivacurium 0.1 mg/kg during opioid anesthesia. By increasing this dose threefold, one can expect to extend this duration by 50%. If one uses a dose of mivacurium that consistently produces 100% blockade-that is, two times the EDg5, or 0.15 mg/kg-the total duration is about 27 minutes. Doubling this dose to 0.3 mg/kg (3.5 to 4 x ED& extends the duration only about 36%, to 36 minutes. Recovery indexes remain the same across all dosage groups and may be slightly prolonged by inhalational anesthetics. With reference to other neuromuscular blocking drugs, mivacurium induces twice as long a blockade as succinylcholine, but only 30% to 50% as long a blockade as atracurium or vecuronium.g-L3 The pharmacodynamics of mivacurium extracted from these studies are presented in Table 1.
Spontaneous versus Antagonized Recovery Mivacurium is metabolized by plasma cholinesterase.*J4 Although this enzyme is partially and transiently inhibited by anticholinesterase drugs,L5J6 reversal of other nondepolarizing ester neuromuscular blocking drugs metabolized by plasma cholinesterase has not been shown to be a problem. I7 Similarly, Savarese et al. 1administered neostigmine 0.06 mg/kg and atropine 0.03 mg/kg to 8 patients out of 72 receiving mivacurium to test anticholinesterase reversibility. The degree of blockade varied from 67% to 93%. Antagonism occurred to 95% twitch height at 6.3 2 0.5 minutes, compared to 10.3 + 0.5
in Adults under
Nitrous
Oxide-Opioid
Anesthesia* 5% to 95%
Time to
Spontaneous
x ED96
Maximum Blockade (min)
5%’
25%’
1.25 2 2.5 3 -
5 3.5 2.5 2.3 -
11 13 16 19 -
13 16 20 23 -
Recovery Time (min)
25% to 75%
95%’
5% to 95%
Recovery with Reversal (min)
Bolus Dose (mg/ kg) 0.1 0.15 0.2 0.25 Infusion
*Enflurane and isoflurane may decrease dose requirements by 20% to 30%.
7 to 7 to 7 to 7 to 7to9
9 9 9 9
21 26 31 34 -
by 25% to 30%. Halothane,
enflurane,
12 12 13 14 14
to to to to to
15 15 15 15 15
6 6 6 6 6
to to to to to
7 7 7 7 7
and isoflurane may prolong recovery
‘From injection.
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Pharmacology
minutes for spontaneous recovery from 25% to 95% for all other patients in the study. This represented a savings of about 4 minutes when mivacurium was antagonized from a mean blockade of about 76%. Curran et al.I* specifically compared spontaneous and neostigmine-induced recovery from deep mivacurium blockade (95%) in 22 patients. They demonstrated that 5% to 95%, 25% to 75%, and 25% to 95% recovery times were shorter following neostigmine-induced recovery compared with spontaneous recovery. The recovery times were (spontaneous vs. antagonized) 15.1 + 1.4 minutes uersu~ 7.7 + 0.7 minutes, 6.5 + 0.3 minutes uersm 3.0 2 0.2 minutes, and 11.0 ? 0.7 minutes uersuS 5.9 -t 0.4 minutes, respectively. T, ratios were about 80% and did not differ significantly between groups. Thus, mivacurium, when used at a dose of 0.15 mg/kg (2 x ED& and antagonized at 5% recovery, will have a total duration of action of about 20 minutes compared with a spontaneous recovery time of about 25 to 27 minutes. This also raises the issue, yet to be clarified, as to whether mivacurium needs to be antagonized with anticholinesterase drugs in routine practice. Cardiovascular Effects Benzylisoquinolinium neuromuscular blocking drugs (such as mivacurium) have the potential to release histamine.‘” The overall range is exemplified by d-tubocurarine, which releases significant histamine at or below its ED,, for neuromuscular blockade,20 and by doxacurium, which does not release histamine at clinical doses up to and including three times the neuromuscular ED,,.” Savarese et al.** examined mivacurium’s dose-effect relationship for histamine release, decrease in blood pressure (BP), and increase in heart rate in 97 healthy patients under N,O-opioid-barbiturate anesthesia. They examined rapid (10 to 15 seconds) bolus doses of mivacurium ranging from 0.03 mg/kg to 0.3 mg/kg (3.5 to 4 x EDgj). Up to and including 0.15 mg/kg (2 X ED,,), there were no hemodynamic side effects or release of histamine. This has been substantiated by other investigators.:‘.“J” Rapid injections of mivacurium 0.2 (2.5 X ED,,), 0.25 (3 x ED,,), and 0.3 (3.5 to 4 X ED,,) mg/kg were associated with changes in mean arterial pressure (MAP) of 18%, 13%, and 32%, respectively.*’ The authors noted that this depressor response was always transient (1 to 2 minutes) and self-limited, requiring no treatment. Other studies3,j,‘” also have shown this trend for mivacurium to release histamine with rapid bolus doses greater than or equal to 2.5 X ED,,. In an interesting analysis, Savarese et aLX4txamined the frequency of histamine release and the decrease in BP in terms of a percentage occurrence in the different dosage groups for mivacurium given as a rapid bolus. These percentages were plotted on log-probit scales, and a dose-response ratio was calculated. This “ED,,” denoted the dose of mivacurium, administered rapidly, that would result in 50% of patients exhibiting histamine release with a resultant decrease in BP. The derived “ED,,” for histamine release from mivacurium was about 0.24 mgikg with 95%’ 156
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confidence limits of 0.18 to 0.32 mg/kg. This result agrees with the above-cited studies. Savarese et aLZ2 investigated the relationship between the size of the mivacurium dose, the speed of injection, and histamine release. When mivacurium 0.2 mg/kg was given over 30 seconds, no patients released histamine or experienced hemodynamic changes. When mivacurium 0.25 mg/kg (3 x ED,,) was given over 60 seconds, no patients exhibited histamine release or hemodynamic changes. Powers et ~1.‘~evaluated the hemodynamic effects of mivacurium given over 60 seconds to patients undergoing coronary artery bypass grafting (CABG). The doses used were 0.15, 0.2, and 0.25 mg/kg. At the lowest dose, there were no mean changes or individual changes in any hemodynamic variables. In the 0.2 mg/kg group, there were no changes in mean values, but two of nine patients experienced transient hypotension. In the highest dose group, a statistically significant decrease in MAP and systemic vascular resistance (SVR) was found at 2 minutes. This was attributable to a change in MAP and SVR in three of the nine patients, as the other six maintained stable hemodynamics. The authors concluded that doses of mivacurium greater than or equal to 0.2 mg/kg given over 60 seconds with fentanyl and diazepam to patients undergoing CABG were associated with sporadic hypotension. stoops et nl. ?li also evaluated mivacurium in patients undergoing CABS or valve replacement. During O,sufentanil anesthesia, mivacurium 0.15, 0.2, and 0.25 mg/kg was administered over 60 seconds to ASA physical status III and IV patients who were New York Heart Association functional class I-IV. These authors showed no statistically or clinically significant effects in any measured or derived hemodynamic variables at mivacurium 0.15 mgikg. One of 18 patients receiving 0.2 mg/kg and one of nine patients receiving 0.25 mgikg developed transient hypotension. These investigators concluded that mivacurium doses up to and including 0.15 mg/kg given over 60 seconds were safe to use in patients with coronary or valvular heart disease and limited cardiac reserve and would thus be useful during short procedures requiring relaxation. They rejected higher doses secondary to the occasional occurrence of transient hypotension. Thus, mivacurium appears to have a hemodynamic profile and a tendency to release histamine similar to that of atracurium.“,*7 Mivacurium, like atracurium, has not been associated with transient hypotension or histamine release at doses up to and including twice the ED!,, (0.15 mgikg). At doses of 0.2 mg/kg or greatel-, histamine release is seen occasionally but can be prevented by slowing the rate of administration to 30 seconds or more. It is necessary to inject doses of mivacurium 0.25 mg/kg over 60 seconds to prevent histamine release and associated hypotension in healthy patients. Two studie?jJ” have demonstrated the ability to use mivacurium 0.15 mgikg or less safely in patients with coronary artery or valvular heart disease at injection times of 60 seconds. However, higher doses, even if injected slowly, were associated with occasional hypotensive episodes. The
Clinical pharmacology use of H, and H2 histamine antagonists may attenuate hemodynamic effects secondary to histamine release induced by atracurium, 27.28but similar studies with mivacurium have not yet been performed. It is important to understand the hemodynamic effects of mivacurium, as its neuromuscular blocking profile, which allows one to increase the dosage to shorten the onset time without substantially prolonging the neuromuscular effect, will tempt many practitioners to use large doses for intubation. The potential limitations of this technique should be emphasized.
Intubation Because of the well-known undesirable and sometimes serious side effects of succinylcholine, nondepolarizing neuromuscular blocking drugs, usually atracurium or vecuronium, are often used to facilitate routine endotracheal intubation. Although both drugs are useful for intubating within 2.5 to 3 minutes, the duration of action of atracurium and vecuronium is too long for procedures lasting less than 30 minutes.2g,30 Mivacurium at equipotent doses has a duration of action 30% to 50% shorter than that of atracurium and vecuronium and twice as long as that of succinylcholine. Therefore, mivacurium may be a useful alternative to facilitate endotracheal intubation for short surgical procedures. Many studies have examined the utility of mivacurium for routine endotracheal intubation.31-36 In these studies, large doses of mivacurium (at least 0.15 mg/kg; 2 x EDgj) have reliably induced neuromuscular blockade. Since the onset time of mivacurium is comparable to that of other currently used nondepolarizing relaxants, 2 minutes was the earliest attempt at intubation in these studies, which generally used N,O-thiopental sodium-opioid anesthesia. Intubations were graded using similar criteria from “excellent” to “poor” or “impossible.” Excellent was defined as no reaction to intubation and the vocal cords relaxed; good was defined as intubation associated with a slight cough or bucking and the vocal cords relaxed; fair was defined as cord movement, moderate bucking and coughing. [Poor was defined as jaw not relaxed.] Only good to excellent responses were considered acTable 2.
in Adult
Drug Succinylcholine
Infusion Savarese et al.’ studied 44 ASA physical status I and II patients using continuous infusions of mivacurium lastfor
Mivacurium
and
Patients
Pretreatment
Dose (mg/kg)
Time to Intubation (set)
No Yes Yes
1 1 1.5 0.15 (2 x ED,,) 0.2 (2.5 x ED&*+ 0.25 (3 x ED,,)**
<60 >90 60 to 90 180 150 120
Mivacurium
*Not recommended
Basta
ceptable for intubation. At the lowest close of mivacurium used, 0.15 mg/kg, 52 of 63 patients (82%) were graded good to excellent at 2 to 2.5 minutes.3’-34 At 3 minutes, essentially all intubating conditions were excellent.3L At a dose of 0.2 mg/kg (2.5 x EDg5), 43 of 44 intubations (98%) were graded good to excellent.32-35 At a dose of 0.25 mg/kg (3 x ED9J at 2 minutes, 77 of 81 intubations (95%) were graded good to excellent.3*-3j In an interesting study by Shaff et aLs6 intubating conditions were graded from excellent to poor, the percentages of each grade were plotted as frequency versuS both time and dose and converted to log-probit scales. Dose-response relationships for intubation were then constructed. For an intubation time of 2 minutes, the EDjo of mivacurium for good to excellent intubating conditions was 0.13 mg/kg, the ED, was 0.2 mg/kg, and the EDgj was 0.25 mg/kg. These results led to suggested doses and times for routine intubation compared with succinylcholine (Table 2). Several points should be emphasized. Unless succinylcholine is contraindicated and it is necessary to use a relaxant to facilitate endotracheal intubation, current nondepolarizing relaxants, including mivacurium, should not be used for rapid-sequence inductionlintubation. Further, even though doses of mivacurium greater than 0.15 mg/kg decrease the time to achieve good to excellent intubating conditions, only about 1 minute is saved. These doses of mivacurium (0.2 to 0.25 mg/kg) are associated with about a 30% to 50% occurrence of histamine release and decreased BP when given rapidly. Should the clinician feel that it is necessary to use these higher doses, an appropriate increase in injection time (30 seconds for 0.2 mg/kg and 60 seconds for 0.25 mg/kg) is necessary to maintain stable hemodynamics. Thus, based on a small decrease in intubation time and the known hemodynamic profile of mivacurium, I would recommend mivacurium 0.15 mg/kg for routine intubation, anticipating an intubation time of 2.5 to 3 minutes.
Comparative lntubation Doses and Times
Succinylcholine
of mivacurium:
by the manufacturer.
tCan release histamine to attenuate histamine
when given rapidly. release.
Slowing
injection
time to 30 seconds
is necessary
$Can release histamine to attenuate histamine
when given rapidly. release.
Slowing
injection
time to 60 seconds
is necessary
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ing 35 to 324 minutes. They then compared the patients’ 5% to 95% and 25% to 75% recovery times with patients receiving only a single bolus dose of mivacurium under N,O-fentanyl-barbiturate anesthesia. They found a 5% to 95% recovery time of 14.4 -+ 0.6 minutes and a 25% to 75% recovery time (recovery index) of 6.5 + 0.3 minutes. These data were not significantly different from data in patients receiving a single bolus dose. The authors suggested that mivacurium might be particularly useful for maintenance of neuromuscular blockade by continuous infusion. Ali et aL3’ examined the use of mivacurium during continuous infusion in 72 ASA physical status I and II patients during N,O-fentanyl anesthesia. These investigators also studied continuous infusion in patients receiving atracurium (n = 22) or vecuronium (n = 18). The infusion rate required to achieve 90% to 99% twitch suppression was 8.3 kg/kg/min (range 2 to 14 Fg/kg/ min). Recovery times for short infusions (less than 30 minutes) did not differ from those for long infusions (greater than 120 minutes). The 25% to 75% and 5% to 95% recovery times were 6.9 + 0.3 minutes and 14.5 -C 0.4 minutes, respectively. These recovery times were half the recovery times for atracurium infusions (10.9 + 0.3 minutes and 26.6 2 0.4 minutes) and less than half the recovery times for vecuronium (13.8 + 0.9 minutes and 32.0 t 1.2 minutes). Finally, the infusion rate needed in each patient correlated directly with the patient’s plasma cholinesterase activity. Poler et al.31 reported on the utility of mivacurium infusions in 28 ASA physical status I and II women undergoing outpatient laparoscopy under N,O-opioid anesthesia and compared them with a comparable group of women receiving succinylcholine infusions. The required infusion rate for mivacurium to maintain neuromuscular blockade at 15% to 30% of the baseline electromyographic response was about 3 + 0.8 I.i,g/kgl min; the rate for succinylcholine was 37 f 40 Fg/kg/min. The authors observed that mivacurium was as effective as succinylcholine for maintaining blockade by infusion, but spontaneous recovery for mivacurium was slower. When mivacurium was antagonized by anticholinesterases, however, recovery times compared favorably with those for succinylcholine. The authors concluded that mivacurium was an effective alternative to succinylcholine but possessed no real advantages. Caldwell et aLz3 also compared mivacurium and succinylcholine infusions. They reported an infusion rate of mivacurium 6.7 Fg/kg/min (range 4 to 10 n.g/kg/min) to maintain 95% blockade, but they were unable to quote such a rate for succinylcholine, as it was necessary to alter the infusion rate frequently during the study secondary to tachyphylaxis. Additionally, one patient receiving a large cumulative dose of succinylcholine developed Phase II block, was not adequately reversed with edrophonium, and was extubated 1 hour after discontinuing the succinylcholine infusion. The spontaneous recovery index for the other succinylcholine infusions was 4.7 f 3.4 minutes. The mean spontaneous and neostigmine-antagonized recovery indexes for miv158
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acurium were 8.7 +- 3.0 minutes and 4.3 t 2.1 minutes, respectively. et aL3” compared maintenance of neuroGoldberg muscular blockade with both succinylcholine and mivacurium infusions. Their infusion rate of 6.6 -+ 3.1 pg/ kg/min compares favorably with previous studies1.*“,31.37. The time from termination of infusion to 95% recovery was 6.5 minutes for succinylcholine. For spontaneous and anticholinesterase-antagonized recovery with mivacurium, the time to 95% recovery was 16.7 and 7.6 minutes, respectively. Finally, Shanks et al.“” demonstrated a 25% reduction in mivacurium infusion requirements under enflurane anesthesia, from 5.9 t 2.2 l.i.g/kg/min to 4.4 ? 1.5 u,g/ kg/min, and 20% to 30% prolongation of recovery. Thus, mivacurium-induced neuromuscular blockade appears to be easy to produce and maintain, and spontaneous recovery from mivacurium is faster than recovery from atracurium and vecuronium. Spontaneous recovery is generally slower with mivacurium than with succinylcholine, unless the mivacurium blockade is antagonized, in which case the recovery times are equivalent. Mivacurium has advantages over succinylcholine in that it is a nondepolarizing blocker that is not susceptible to tachyphylaxis or Phase II blockade. Its infusion requirements are less with enflurane and probably with isoflurane as well. Its duration of action should be prolonged somewhat by inhalational anesthetics. Suggested infusion guidelines are presented in Table ?. Pediatrics Mivacurium has been studied in children ages 2 to 12.3g-” Goudsouzian et a1.39found an ED,, under N20opioid anesthesia of 0.11 mg/kg and under halothane anesthesia of 0.095 mg/kg, while Sarner et aLdo found an ED,, of 0.103 mg/kg and 0.089 mg/kg under N,O-opioid and halothane anesthesia, respectively. When giving mivacurium 0.2 mg/kg as a rapid bolus dose, Goudsouzian et a1.3Qnoted an onset to complete blockade of 1.6 to 1.9 minutes, with recovery to 5%, 25%, 95% and 25% to 75% of about 8.5, 11, 18, and 4.5 minutes, respectively. No cardiovascular changes were noted. Sarner et a1.j” administered mivacurium 0.25 “g/kg (2.5 x ED,,) in children as a rapid bolus dose. Onset times were 0.8 minutes under halothane and 1.1 minutes under opioid anesthesia. Recovery times to 5%, 25%, and 25% to 75% under opioid and halothane anesthesia were 6.8 ? 1.9 minutes and 11.2 + 3.9 minutes, 9.1 +- 2.6 minutes and 13.6 ? 3.9 minutes, and 4.3 it 2.2 minutes and 4.3 t 1.2 minutes, respectively. In 1 out of 18 children studied, BP decreased by 32%. Alifimoff and Goudsouzian41 studied infusion of mivacurium in children ages 2 to 12 with both opioid and halothane anesthesia. Infusion rates necessary to maintain twitch response at 90% to 99% block were generally higher in the children than those found in adults: 13.0 +- 1.4 pglkglmin and 10.4 ? 0.92 pglkglmin for opioid and halothane anesthesia, respectively, with the infusion rates remaining constant throughout. Spontaneous re-
Clinical pharmaco1og.p of mivacurium: Table 3. Comparative Infusion Rates of Succinylcholine, and Vecuronium in Adults Given Nitrous Oxide-Opioid Infusion Rate
5% to 95% Recovery Time (min)
(wGq+in) Succinylcholine
Mivacurium, Anesthesia*
40 20 to 100)’ 6 (range 2 to 15) 8 (range 2 to 15) 1.5 (range 0.5 to 3.0)
6to
Busta
Atracurium,
25% to 75% Recovery Time (min)
10
3 to 5
(range Mivacurium Atracurium Vecuronium
14 to 15
6.5 to 8.0
25 to 30
10 to 12
30 to 35
13 to 15
*Enflurane and isoflurane may decrease dose requirements and enflurane may prolong recovery by 20% to 30%. tTachyphylaxis
and Phase II block may occur.
covery from termination of infusion at 94% 2 0.2% blockade to 95% recovery under halothane anesthesia was 19.0 ? 5.3 minutes. After edrophonium-induced reversal, recovery time was 6.0 2 2.0 minutes. Similar recovery characteristics for opioid-based anesthesia were found to be 11.8 f 0.78 minutes and 3.3 ? 0.77 minutes, respectively. Comparable responses have been reported by Brandom et a1.42 It is clear from these studies that children require higher bolus doses and infusions of mivacurium than adults on an mg/kg basis. However, Sarner et aL40 demonstrated that when referenced to body surface area (mg/ m*), doses for children did not differ significantly from those for adults, suggesting that the apparent age-related differences may be associated with volume of distribution. Onset times for mivacurium-induced blockade at doses 2 to 2.5 times EDg, (0.2 to 0.25 mg/kg) are shorter in children and may allow intubation within 1 to 2 minutes. Suggested doses and recovery parameters are given in Table 4.
Table 4. Pharmacodynamic Anesthesia*
Bolus Dose (mglkg) x 0.09 to l..l 0.2 0.25 Inficsion (10 ug/kg/min; *Halothane
range
by 25%. Halothane, isoflurane,
Responses
ED,, 1 2 2.5
for Mivacurium
in Children
Metabolism, Elimination, and Pharmacodynamics Mivacurium is a substrate for plasma cholinesterase and is ultimately metabolized to two molecules of a quaternary alcohol and a dicarboxylic acid. A quaternary monoester is also formed as a distinct entity, as is an intermediary metabolite (Figure 1). Both the quaternary monoester and the quaternary alcohol are found in urine and bile (data on file, Burroughs Wellcome Co, Inc., Research Triangle Park, NC). These metabolites produce no neuromuscular, autonomic, or cardiovascular effects. Savarese et al.’ studied the rate of hydrolysis of mivacurium by purified human plasma cholinesterase at 5 mM concentration relative to a matched pair of succinylcholine. The in vitro hydrolysis rate for mivacurium at this substrate concentration was 88% that of succinylcholine. Cook et al. I4 measured the metabolism of mivacurium and succinylcholine in pooled human plasma,
2 to 12 Years of Age during
Nitrous
Time to Maximum Blockade (min)
5%
25%
95%
1 to 5 1 to 3 1 to 2
5 7 7
7 10 9
19 -
Oxide-Opioid
Time to Spontaneous Recovery (min)+ 5% to 95%
-
8 to 24 pglkglmin)
12
will decrease doses and increase recovery times by 20% to 30%.
‘From injection.
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Ratzonal Pharmacology butyrylcholinesterase, acetylcholinesterase, and buffer. There was essentially no metabolism of mivacurium by buffer and minimal metabolism by acetylcholinesterase. The graph of velocity versus substrate concentration for pooled plasma cholinesterase and succinylcholine demonstrated rapid enzyme saturation and a well-demarcated plateau. Mivacurium hydrolysis, however, increased gradually as the substrate concentration increased. For equal multiples of the Km (the Michaelis-Monten constant), mivacurium was hydrolyzed at 70% the rate of succinylcholine. These results help us to understand the short duration of action of mivacurium at normal doses and the 30% to 50% increase in duration of action of mivacurium when increasing the dose threefold (the more substrate to be metabolized, the faster the hydrolysis rate). Ostergaard et al. examined patients with normal plasma cholinesterase genotype and normal to slightly decreased enzyme activity (33 patients),.‘3 heterozygous patients (n = 10) for the usual and atypical gene,*” and homozygous patients (n = 4) for the atypical plasma cholinesterase gene. qj In the first group,4S no correlation was found between recovery and plasma cholinesterase activity with mivacurium 0.1 mg/kg, while recovery was correlated with plasma cholinesterase activity at a dose of 0.2 mg/kg. This tends to support Cook et al.‘“, who found that, since the enzyme differs from person to person, its degree of saturation and velocity of metabolism also differ. It should be noted, however, that Ostergaard et d’s recovery data 43 do not differ from those of other studies. In the group of patients heterozygous for the atypical gene, recovery times were prolonged about 50% following a 0.2 mg/kg dose of mivacurium.‘4 The four patients who were homozygous for the atypical gene received a 0.03 mg/kg dose of mivacurium.4i All developed 100% blockade, and the range of initial recovery was 26 to 128 minutes. Reversal was accomplished with neostigmine at 50% to 70% twitch recovery and occurred in 4 to 12 minutes. Thus, patients homozygous for the usual normal plasma cholinesterase activities at the low end of the normal range or slightly below the normal range recovered from twice the ED,, of mivacurium in the usual fashion, though high doses of mivacurium (greater than or equal to 0.2 mg/kg) showed slight prolongation in patients with plasma cholinesterase activities at or slightly below the lower limit of the normal range. Patients heterozygous for the usual gene and atypical gene will recover 50% more slowly at a dose of 0.2 mg/kg. As expected, patients homozygous for the atypical gene are exquisitely sensitive to mivacurium and should not. receive it. Basta et (11.“”examined the pharmacodynamics of mivacurium in young and elderly patients at a dose of 0.1 mg/kg under N,O-isoflurane anesthesia. Maximum blockade, time to maximum blockade, and time to 5%, 2570, and 95% recovery did not differ between the young and the elderly. Cook et aL4’ found that the duration of mivacurium blockade at a dose of 0.15 mg/kg was prolonged in patients with end-stage renal failure by 50% and in liver transplant patients by a factor of three.
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Finally, mivacurium is a mixture of three isomers: the cis-trans isomer (36%), the trans-trans isomer (58%), and the cis-cis isomer (6%) (data on file, Burroughs Wellcome Co., Inc, Research Triangle Park, NC). The cis-trans and trans-trans isomers are equipotent and rapidly metabolized by plasma cholinesterase. The cis-cis isomer is metabolized in vitro more slowly than the others. Its potency in humans has not been evaluated, but it is less than onetenth the potency of the other isomers in cats (personal communication, Doreen Wray, MD, Department of Anesthesia, The New York Hospital-Cornell Medical Center New York, NY). A stereospecific assay has recently become available and stereospecific pharmacokinetic studies are currently under way (personal communication, John Savarese, MD, and Cynthia Lien, MD, Department of Anesthesia, The New York Hospital-Cornell Medical Center).
Summary In 1975, Savarese and Kitz”” envisioned a need for three classes of nondepolarizing neuromuscular blocking drugs based primarily on duration of action. The first class represented short-acting nondepolarizing drugs capable of producing succinylcholine-like blockade within 1 to 2 minutes, starting recovery within 5 to 10 minutes. Even today, no nondepolarizing relaxants satisfy these criteria, though mivacurium approaches this ideal. A second group of nondepolarizing neuromuscular blocking drugs was termed intermediate-acting, best suited for surgical procedures lasting about 1 hour. Those relaxants would produce complete block within 2 to 3 minutes for a period of 20 to 30 minutes, followed by spontaneous recovery in 40 to 60 minutes. Atracurium and vecuronium currently meet these criteria.6.‘” A third class, the long-acting nondepolarizing relaxants, suitable for long operative procedures, existed in 1975, but all had hemodynamic side effects. The recently introduced relaxants doxacurium4Q,50 and pipecuroniumj’ represent long-acting nondepolarizers devoid of cardiovascular side effects. They produce blockade within 3 to 6 minutes, allow a clinical duration of 45 to 60 minutes, and allow spontaneous recovery in 90 to 180 minutes. In 1988, Savarese et al.’ reported on mivacurium, a nondepolarizing neuromuscular short-acting, new, blocker. This drug does not conveniently fit into any of the above categories. Mivacurium belongs somewhere between the ultra-short-acting depolarizing relaxant succinylcholine and the intermediate-acting relaxants atracurium and vecuronium. Based on a dose of 2 X ED,,, (0.15 mg/kg) under opioid anesthesia, mivacurium has an onset of 2.5 to 3 minutes, a clinical duration of 15 to 20 minutes, an injection-to-95%-recovery time of 25 to 30 minutes, and a recovery index of 6 to 7 minutes. A comparison with succinylcholine, atracurium, and vecuronium is presented in Table5. In many respects, other than onset time, mivacurium compares favorably with succinylcholine. Table 6 lists the advantages, disadvantages, and potential roles for succinylcholine and mivacurium in clinical practice.
Clinical pharmacolo~gy of mivacutium: Table 5. A Pharmacodynamic Comparison AtracuriumlVecuronium (in minutes)*
of Succinylcholine,
Mivacurium,
Ba.sta
and
_
Succinylcholine
Onset to maximal effect Injection to 95% recovery Clinical duration (injection to 25% recovery) Recovery index (25% to 75% recovery) *All doses considered
Table 6.
to be 2
A Comparison
x
Mivacurium
Atracuriuml Vecuronium
Less than 1
2 to 3
3 to 4
Less than 15
25 to 30
40 to 60
5 to 8
15 to 20
25 to 30
3
6 to 7
12 to 15
ED,,.
of Succinylcholine
and Mivacurium
Succinylcholine
Mivacurium
Advantages
Advantages
Rapid onset Ultra-short duration
Short duration Precise control No tachyphylaxis No Phase II block Unchanged recovery following infusions Reversible with anticholinesterases
Disadvantages
Skeletal muscle pain Tachyarrhythmias and bradyarrhythmias Hyperkalemia in susceptible patients Potential for increased intraocular, intragastric, and intracranial pressures Can trigger malignant hyperthermia Confusion concerning masseter spasm (its detection and significance) Sustained contracture in myotonias Phase II block Prolonged action Genetic Atypical plasma cholinesterase Acquired Anticholinesterase medications Severe liver disease Peripartum Others C’.ses Rapid endotracheal Very short surgical
Disadvantages
Potential histamine release at dose ~0.2 mg/kg when given rapidly Slightly prolonged in renal failure Prolonged blockade Genetic See succinylcholine Acquired See succinylcholine Uses Routine nonemergent intubation Procedures lasting less than 30 minutes Procedures lasting 30 to 60 minutes (infusion) Procedures of unpredictable duration (infusion)
intubation procedures
The principal advantages of succinylcholine are its rapid onset and short duration of action. Because of its depolarizing mechanism of action, succinylcholine has side effects and complicaseveral well-known adverse tions. Most of these are uncommon, but some are serious and potentially lethal. The clinical use of succinylcholine is fairly easy to define. Unless contraindicated, succinylcholine is the best neuromuscular blocking drug available for rapid control of the airway in patients with laryngospasm and those needing rapid-sequence intubations for full stomach precautions or symptomatic hiatal hernia. Mivacurium has three main advantages. First, its duration of action is significantly shorter than that of atra-
curium or vecuronium. As such, it can be used at doses up to and including 2 x ED,, (0.15 mg/kg) for routine, nonemergent intubations for short procedures (about 30 minutes). In children 2 to 12 years of age, mivacurium’s onset of action at twice the ED,, (0.2 mg/kg in children) approaches 1 minute and its duration of action is shorter than in adults. It may well replace succinylcholine for short surgical procedures in pediatric anesthesia. Second, because of mivacurium’s lack of cumulative properties, there is no difference in recovery times following repeat doses or continuous infusions. Finally, there is no development of Phase II blockade. These properties should allow mivacurium to be used as a continuous infusion quite readily.
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Rational
Phamucology
Mivacurium has two disadvantages of clinical importance. At doses equal to or greater than 0.2 mg/kg in adults, histamine release with attendant hypotension will become evident in some patients. If doses of this magnitude are used, the injection should be slowed to at least 30 seconds for a dose of 0.2 mglkg and 60 seconds for doses as high as 0.25 mg/kg to attenuate the release of histamine. The minimal acceleration of onset time at these doses does not, in my opinion, warrant their casual or routine use for endotracheal intubation. Mivacurium’s duration of action will be prolonged in patients unable to metabolize it, such as those patients with atypical plasma cholinesterase or acquired defects in plasma cholinesterase activity (due to, for example, anticholinesterase medications, severe liver and renal disease, and the peripartum period). Mivacurium should probably not be used in patients unable to metabolize it. Overall, mivacurium should find an important niche in clinical anesthesia when administered in a fashion consistent with its unique neuromuscular pharmacology. References 1. Savarese JJ, Ali HH, Basta SJ, et al: The clinical neuromuscular pharmacology of mivacurium chloride (BW B1090U). Anesthesiology 1988;68:723-32. 2. Litchfield JT Jr, Wilcoxon F: A simplified method of evaluating dose-effect experimentsj PhamucoZEx~ Ther 1949;95:99113. 3. From RP, Pearson KS, Choi WW, Abou-Donia M, Sokoll MD: Neuromuscular and cardiovascular effects of mivacurium chloride (BW B1090U) during nitrous oxide-fentanyl-thiopentone and nitrous oxide-halothane anaesthesia. Br J Anaesth 1990;64:193-8. 4. Caldwell JE, Kitts JB, Heier T, Fahey MR, Lynam DP, Miller RD: The dose-response relationship of mivacurium chloride in humans during nitrous oxide-fentanyl or nitrous oxideenflurane anesthesia. Anesthesiology 1989;70:31-5. 5. Weber S, Brandom BW, Powers DM, et al: Mivacurium chloride (BW B1090U) induced neuromuscular blockade during nitrous oxide-isoflurane and nitrous oxide-narcotic anesthesia in adult surgical patients. Anesth An&g 1988;67:4959. 6. Basta SJ, Ah HH, Savarese JJ, et al: Clinical pharmacology of atracurium besylate (BW 33A): a new nondepolarizing muscle relaxant. Anesth Analg 1982;61:723-9. 7. Ording H, Skovgaard LT, Engbaek J, Viby-Mogensen J: Doseresponse curves for vecuronium during halothane and neurolept anaesthesia: single bolus versus cumulative method. Actu Anaesthesiol Stand 1985;29: 121-4. 8. Katz RL, Stirt J, Murray AL, Lee CM: Neuromuscular effects of atracurium in man. Anesth An&g 1982;61:730-4. 9. Agoston S, Salt P, Newton D, Bencini A, Boomsma P, Erdmann W: The neuromuscular blocking action of ORG NC45, a new pancuronium derivative, in anaesthetized patients: a pilot study. BrJ Anuesth 1980;52(Suppl):53-9s. 10. Katz RL, Ryan JF: The neuromuscular effects of suxamethonium in man. BrJ Anaesth 1969;41:381-90. 11. Scott RPF, Savarese JJ, Basta SJ, et al: Clinical pharmacol;,gg_“8’. atracurium given in high dose. BrJ Anaesth 1986;58: 12. Gramstad L, Lilleaasen P: Dose-response relation for atracurium, ORG NC45, and pancuronium. BrJ Anuesth 1982;54:64751.
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13. Fahey MR, Morris RB, Miller RD. Sohn YJ, Cronnelly R, Gencarelli P: Clinical pharmacology of ORG NC45 (Norcuron): a new nondepolarizing muscle relaxant. Amdhesiology 198 1;55: 6-11. 14
Cook DR, Stiller RL, Weakly JN, Chakravorti S, Brandom BW, Welch RM: In vitro metabolism of mivacurium chloride (BW B 109OU) and succinylcholine. Anesth An&g 1989;68:452-6.
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Sunew KY, Hicks RG: Effects of neostigmine and pyridostigmine on duration of succinylcholine action and pseudochohnesterase activity. Anesthesiology 1978;49: 188-91.
17. Savarese JJ, Ali HH, Basta S.J, et al: The clinical pharmacology of BW A444U: a nondepolarizing ester relaxant of intermediate duration. Anesthesiology 1983;53:333-41, 18. Curran MJ, Shaff LP, Savarese JJ, Ali HH, Risner M: Comparison of spontaneous recovery and neostigmine-accelerated recovery from mivacurium neuromuscular blockade [Abstract]. Anesthesiology 1988;69:A528. 19. Moss J, Rosow CE: Histamine release by narcotics and muscle relaxants in humans. Anesthesiology 1983;59:330-9. 20. Moss J, Rosow CE, Savarese JJ, Philbin DM, Kniffen FJ: Role of histamine in the hypotensive action of d-tubocurarine in humans. Anesthesiology 1981;55:19-25. 21. Basta SJ, Savarese JJ, Ali HH, et al: Clinical pharmacology of. doxacurium chloride (BW A938U): a new long-acting nondepolarizing muscle relaxant. Anesthesiology 1988;69:472-86. 22. Savarese JJ, Ah HH, Basta SJ, et al: The cardiovascular effects of mivacurium chloride (BW B1090U) in patients receiving nitrous oxide-opiate-barbiturate anesthesia. Anesthesiology 1989;70:386-94. 23. Caldwell JE, Heier T, Kitts JB, Lynam DP, Fahey MR, Miller RD: Comparison of the neuromuscular block induced by mivacurium, suxamethonium or atracurium during nitrous oxidefentanyl anaesthesia. BrJ Anaesth 1989;63:393-9. 24. Savarese JJ, Rosow CE, Embree PB, Schwartz AF, Basta SJ: A quanta1 analysis of the dose-response of mivacurium for plasma histamine increase, facial erythema, and arterial pressure decrease [Abstract]. Anesthesiology 1988;69:A527. 25. Powers D, Simpson K, Morici M, Benckart D, Maher T, ‘Torpey DJ: The hemodynamic effects of mivacurium chloride in patients undergoing coronary artery bypass graft during fentanyVvalium anesthesia [Abstract]. Anesthesiology 1988;69:A530. 26. Stoops CM, Curtis CA, Kovach DA, et al: Hemodynamic effects of mivacurium chloride administered to patients during oxygensufentanil anesthesia for coronary artery bypass grafting or valve replacement. Anesth Analg 1989;68:333-9. 27. Scott RPF, Savarese JJ, Basta SJ. et al: Atrdcurium, clinical strategies for preventing histamine release and attenuating the hemodynamic response. BrJ Anaesth 1985;57:550-5. 28. Hosking MP, Lennon RL, Gronert GA: Combined HI and H? receptor blockade attenuates the cardiovascular effects of highdose atracurium for rapid sequence endotracheal intubation. Anesth Analg 1988;67:1089-92. 29. Gyasi HK, Naguib M, Adu-Gyamfi Y: Atracurium for short surgical procedures: a comparison with succinylcholine. Can Anaesth Socj 1985;32:613-7. 30. Gyasi HK, Williams A, Melloni C, Bevan DR: ORG NC45 for short intraabdominal operations: a comparison with succinylcholine. Can A,mesth SocJ 1983;30:132-5. 31. Poler SM, Luchtefeld G, White PF: Comparison of mivacurium (BW B 109OU) and succinylcholine during outpatient laparoscopy [Abstract]. Anesthesiology 1988;69:A523. 32. Fragen RJ, Shanks CA, Katz JA, et al: Tracheal intubation at
Clinical
33.
34.
35.
36.
37.
38.
39.
40.
41. 42.
two minutes with mivacurium chloride, 0.15 mg/kg and 0.25 mg/kg [Abstract]. Anesthesiology 1988;69:A525. Sears DH, Makela VHM, Katz RL, et al: Efficacy and safety of mivacurium chloride (BW B1090U) for endotracheal intubation in surgical patients during nitrous oxide-narcotic anesthesia [Abstract]. Anesthesiology 1988;69:A876. Ramsey FM, Geffin B, Heslop MJ, Oleksey KM, Risner ME: Safety and efficacy of mivacurium for endotracheal intubation [Abstract]. An&h An&g 1989;68:S232. Goldberg ME, Larijani GE, Azad SS, et al: Comparison of tracheal intubating conditions and neuromuscular blocking profiles after intubating doses of mivacurium chloride or succinylcholine in surgical outpatients. Anesth Analg 1989;69: 93-9. Shaff LP, Curran MJ, Embree PB, Savarese JJ, Ali HH: A quanta1 analysis of the dose-response for trachea1 intubation using mivacurium as the test relaxant [Abstract]. Anesth An&g 1989;68:S253. Ali HH, Savarese JJ, Embree PB, et al: Clinical pharmacology of mivacurium chloride (BW B1090U) infusion: comparison with vecuronium and atracurium. Br J Anaesth 1988;61: 541-6. Shanks CA, Fragen RJ, Pemberton D, et al: The effects of enflurane on mivacurium chloride infusion requirements [Abstract]. Anesthesiology 1988;69:A524. Goudsouzian NG, AlilimoffJK, Eberly C, et al: Neuromuscular and cardiovascular effects of mivacurium in children. Anesthesiology 1989;70:237-42. Sarner JB, Brandom BW, Woelfel SK, et al: Clinical pharmacology of mivacurium chloride (BW B1090U) in children during nitrous oxide-halothane and nitrous oxide-narcotic anesthesia. Anesth Analg 1989;68: 116-21. Alilimoff JK, Goudsouzian NC: Continuous infusion of mivacurium in children. BrJ Anaesth 1989;63:520-4. Brandom BW, Sarner JB, Woelfel SK, et al: Mivacurium in-
43.
44.
45.
46.
47.
48. 49.
50.
5 1.
pharmacology
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Basta
fusion requirements in pediatric surgical patients during nitrous oxide-halothane and during nitrous oxide-narcotic anesthesia. Anesth Analg 1990;71: 16-22. Ostergaard D, Jensen FS, Jensen E, Viby-Mogensen J: Influence of plasma cholinesterase activity on recovery from mivacurium induced neuromuscular blockade [Abstract]. Acta Anuesthesiol Stand 1989;91(Suppl):142. Ostergaard D, Jensen FS, Jensen E, Viby-Mogensen J: Mivacurium-induced neuromuscular blockade in patients heterozygous for the atypical gene for plasma cholinesterase [Abstract]. Anesthesiology 1989;71 :A782. Ostergaard D, Jensen E, Jensen FS, Viby-Mogensen J: The duration of action of mivacurium-induced neuromuscular block in patients homozygous for the atypical plasma cholinesterase gene [Abstract]. Anesthesiology 1991;75:A774. Basta SJ, Dresner DL, Shaff LP, Lai AA, Welch R: Neuromuscular effects and pharmacokinetics of mivacurium in elderly patients under isoflurane anesthesia [Abstract]. Anesth Analg 1989;68:SlS. Cook DR, Freeman JA, Lai AA, et al: Pharmacokinetics of mivacurium in normal patients and in those with hepatic or renal failure. BrJ Anaesth (in press, 1992). Savarese JJ, Kitz RJ: Does clinical anesthesia need new neuromuscular blocking agents? Anesthesiology 1975;42:236-9. Murray DJ, Mehta MP, Choi WW, et al: The neuromuscular and cardiovascular effects of doxacurium chloride in patients receiving nitrous oxide-narcotic anesthesia. Anesthesiology 1988;69:472-7. Basta SJ, Savarese JJ, Ali HH, et al: Clinical pharmacology of doxacurium chloride: a new long-acting nondepolarizing muscle relaxant. Anesthesiology 1988;69:478-86. Tassonyi E, Neidart P, Pittet JF, Morel DR, Gemperle M: Cardiovascular effects of pipecuronium and pancuronium in patients undergoing coronary artery bypass grafting. Anesthesiology 1988;69:793-6.
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Clinical Pharmacology of Mivacurium Chloride: A Review
Salvatore J. Basta, MD* Department of Anaesthesia, Harvard Medical School, and Department thesia, Massachusetts General Hospital, Boston, MA.
Miuacurium chloride (Mivacron) is a new benzylisoquinolinium choline-like diester neuromuscular blocking drug with an onset of action at equipotent doses that is comparable to atracurium and vecuronium but slower than succinylcholine. Its clinical duration (injection-25% recovery and injection-95% recovq) is twice that of succinylcholine but one-half to one-third that of atracurium and vecuronium. Mivacurium is easy to use as a continuous infusion and when used this way its recovery characteristics are unchanged. It is readily antagonized by anticholinesterase drugs. The EDg, in adults under narcotic-based anesthesia is 0.07-0.08 mglkg. At twice the ED,, (0.15 mglkg) onset time is about 2 to 3 minutes, duration to 25% recovery ti 15 to 20 minutes, and 5-95% recovery time about 14 minutes. The mean infusion rate in adults is 6 pglkglmin (range 2-15) with a 5-95% recovery time of 14 minutes. En.urane and isoflurane require a 20-30% decrease in dosage; halothane, en&rune, and isojlurane prolong the duration of mivacurium 25-30%. The ED,, in children 2 to 12 years of age is slightly higher (0.09-0.11 mglkg) with a faster onset and shorter duration. In these young patients, a dose of 0.2 mglkg has an onset comparable to succinylcholine. Being chemically related to atracurium, mivacurium may cause histamine release. When adminktered rapidly at doses of 0.2 mglkg or greater in adults, histamine release and transient hypotension have been observed. Doses of 0.2 mglkg or higher are not recommended by the manufacturer. Mivacurium is metabolized &y plasma cholinesterase. In vitro, the rate is about 70% that of succinylcholine. In patients with normal or slightly less than normal
*Assistant Professor Address reprint requests to Dr. Basta at the Department of Anesthesia, Massachusetts General Hospital, 32 Fruit Street, Boston, MA 02 114, USA. Received for publication December 24, 1991; revised manuscript accepted for publication December 30, 199 1.
0 1992 Butterworth-Heinemann J. Clin. Anesth. 4~153-163,
1992.
of Anes-
+.sma cholinesterase activity, no prolonged durations of action have been observed. In patients heterozygous for the atypical gene and at a dose of 0.2 mglkg, 50% prolongation has been shown. Those individuals homozygous for the atypical gene are exquisitely sensitive to mivacurium and have a markedly prolonged blockade that is readily reversible. In these patients and those with acquired deficiencies, mivacurium should not be used. The duration of action in elderly patients is comparable to that in the young, while in prerenal transplant patients, its duration is prolonged by about 50%, and in prehepatic trans@ant patients, duration of block is increased threefold. Mivacurium possesses the advantages of short duration, unchanged recovery characteristics following infusions (without phase II block or tachyphylaxis), and precise control. In bolus form, it should be useful for routine, nonemergent intubations, for surgical procedures as short as 30 minutes, and for procedures of 30 to 60 minutes. For prolonged cases or those of unpredictable duration, infmion of mivacurium will be preferable. Keywords: Neuromuscular blockade, nondepolarizing; short-acting; plasma cholinesterase hydrolysis; infusion; pediatrics; cardiovascular effects, histamine.
Introduction Mivacurium chloride (Mivacron) is a new nondepolarizing neuromuscular blocking drug metabolized by plasma cholinesterase that is soon to be released for use in the United States. It is a bis-quaternary diester benzylisoquinolinium compound described chemically as (R-(R*,R* + (E))-2,2’-((1,8-dioxo-4-octene-l&diyl) bis (oxy-3,l_propenediyl)bis( 1,2,3,4-tetrahydro-6,7-dimethoxy-2-methyl-l-(3,4,5-trimethoxyphenyl)methyl)isoquinolinium)chloride and is shown structurally in Figure I. The clinical pharmacology to date indicates that mivacurium may be expected to have an onset of action at equipotent neuromuscular blocking doses comparable to that of atracurium and vecuronium, but with a duration of action that is one-third to one-half as long as that of
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Plasma Cholmesterase
/
\
Figure 1. The chemical structure of mivacurium. The metabolic pathways of hydrolysis of mivacurium by plasma cholinesterase. Pictured here are the monoquaternary ester and the monoquaternary alcohol. Not pictured is the dicarboxylic acid.
those compounds. Compared with succinylcholine, mivacurium has a slower onset and twice the duration of action. As such, the advantage of mivacurium as a neuromuscular blocking drug is greater versatility and greater control of blockade than are available with currently used nondepolarizing relaxants. This review examines dosepotency, dose-onset, and dose-duration relationships for mivacurium, its recovery and reversibility, and its side effects. Mivacurium for intubation, short surgery, maintenance of blockade by infusion, and pediatric procedures is discussed. Metabolism, elimination, and pharmacodynamics also are reviewed.
Dose-Effect Relationships Dose-Potency
Relationship
Savarese et al.’ studied mivacurium in 72 patients who were anesthetized with nitrous oxide (N,O), oxygen (O,), fentanyl, and thiopental sodium at bolus doses ranging from 0.03 mg/kg to 0.3 mg/kg. Using the method of Litchfield and Wilcoxon,* they estimated the dose-response curve by linear regression of probit values corresponding to the depth of neuromuscular blockade. The calculated 95% neuromuscular blocking dose (EDg5) was found to be 0.081 mg/kg with a 95% confidence limit range of 0.063 to 0.103 mg/kg. Nine patients in this study received a bolus dose of 0.1 mglkg and achieved a mean depth of blockade of 95.7% + 2.8% (SEM). All nine patients receiving 0.15 mg/kg achieved complete blockade. during anesthesia From et al3 studied mivacurium 154
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with N,O, fentanyl, and thiopental sodium and during anesthesia with N,O and halothane. The ED,, of 0.073 mg/kg with fentanyl anesthesia agreed with the data in Savarese et al.’ The ED,, with halothane was 0.081 mg/ kg. Thus, these investigator@ found little potentiation of mivacurium-induced blockade by halothane. Caldwell et al.* examined dose-effect relationships for mivacurium in patients anesthetized with N,O and fentanyl and with N,O and enflurane. The EDg5 for the opioid (fentanyl) was 0.067 mg/kg and for enflurane 0.0532 mglkg. This difference was statistically significant and demonstrates that enflurane enhances mivacurium-induced blockade. Weber et al.5 examined the influence of isoflurane and opioid anesthesia on mivacurium blockade in humans. The estimated ED,, value for mivacurium with the opioid was 0.058 mglkg and with isoflurane 0.045 mgfkg. Subsequently, administration of the estimated ED,, under opioid anesthesia (0.06 mg/kg) to nine patients led to a maximum blockade of only 68% 2 37% (SD). Thus, while their ED,, estimate was lower than that of other investigators studying opioid anesthesia, Weber et al. demonstrated approximately 25% enhancement of blockade by isoflurane. Since the ED,, of mivacurium during opioid anesthesia is 0.07 to 0.08 mg/kg, it is about three times as potent as atracurium6 and about 0.7 times as potent as vecuronium.7 While halothane does not enhance the depth of mivacurium-induced blockade, enflurane and isoflurane appear to enhance it by 25% to 30%.
Dose-Onset
Relationship
Savarese et al.’ found that the onset times for mivacurium at doses of 0.1, 0.15, 0.2, 0.25 and 0.3 mglkg during N,O-fentanyl anesthesia in healthy surgical patients were 3.8 + 0.5 minutes, 3.3 + 0.2 minutes, 2.5 t 0.3 minutes, 2.3 * 0.3 minutes, and 1.9 + 0.3 minutes, respectively, clearly a dose-related phenomenon. Several investigators have studied onset times for a dose of mivacurium twice the ED,, (0.15 mg/kg) and found it to be 2.8 f 3.8 minutes.‘,“,j Therefore, mivacurium at doses twice the ED,, appears to have an onset time comparable to that of atracurium (2.3 to 3.2 minutes)6,sand vecuronium (2.7 to 3.8 minutes)g at equipotent doses. Mivacurium certainly has a slower onset time to maximum blockade than succinylcholine.
Dose-Duration
Relationship
It is now fairly standard practice when evaluating new relaxants to document time from injection to various recovery parameters. Time from injection to 25% recovery (clinical duration) and time from injection to 95% recovery are usually examined. It is also desirable to note how these recovery times change after multiples of the ED,,. Savarese et al.’ studied 45 patients during N,Ofentanyl anesthesia at doses of mivacurium ranging from 0.1 mg/kg (ED,,) to 0.3 mg/kg (3.5 to 4 x ED&. For the lowest dose studied, the mean clinical duration was found
Clinical pharmacology of mivacurium:
to be 14.2 k 1.5 minutes (SEM). Increasing the dose threefold extended the mean clinical duration to 25.0 ? 2.8 minutes. Comparable mean values for time to 95% recovery for 0.1 mg/kg and 0.3 mglkg were 24.5 2 1.6 minutes and 36.7 * 4.3 minutes, respectively. At twice the ED,, (0.15 mg/kg), these authors observed recovery times of 16.8 + 1.1 minutes and 26.9 ? 1.6 minutes, respectively. From et ~1.~also evaluated mivacurium in nine patients each at twice the ED,, of mivacurium (0.15 mg/kg) with both N,O-fentanyl and N,O-halothane. They found that mean times for clinical duration and recovery to 95% were 15.5 + 1.0 minutes (SD) and 24.1 + 1.5 minutes with N,O-fentanyl and 18.6 of: 0.8 minutes and 30.0 r?r. 1.4 minutes for N,O-halothane. Weber et d5 examined the recovery characteristics of mivacurium at 0.15 mg/ kg during opioid anesthesia and 0.1 mg/kg during isoflurane anesthesia. The mean clinical durations were 15.9 f 4.2 minutes for the opioid and 15.0 & 4.4 minutes for isoflurane. Time to 95% recovery was 26.0 ? 7.1 minutes for the opioid and 27.3 + 7.2 minutes for isoflurane. Finally, Caldwell et al4 evaluated the time from injection to 90% recovery, comparing mivacurium during opioid-based anesthesia and enflurane anesthesia. At comparable doses of mivacurium (0.04 mg/kg), the respective opioid and halothane recovery times were 15.9 * 6.2 minutes and 22.2 f. 3.1 minutes. At a dose of 0.05 mglkg, which produced 73% 2 26% neuromuscular blockade with opioid anesthesia, and a dose of 0.04 mg/kg, which produced 77% * 24% neuromuscular blockade with enflurane, these authors documented 90% recovery times of 18.6 2 6.8 minutes and 22.2 f 3.1 minutes, respectively. Additional indexes usually examined across dosage groups and with various anesthetic conditions are 25% to 75% recovery time (recovery index) and 5% to 95% recovery time. The largest single study examining these aspects was that of Savarese et al.’ They evaluated doses of mivacurium of 0.1, 0.15 (2 X ED& 0.2 (2.5 x EDg5), 0.25 (3 x ED&, and 0.3 (4 x EDg5) mg/kg, as well as infusions ranging in time from 35 to 324 minutes. No
Table
1.
Dose-Effect
Relationships
for Mivacurium
Basta
differences were found in either recovery index or 5% to 95% recovery time irrespective of the dose given or the duration of the infusion. The recovery index for all bolus dose groups was 6.8 2 0.3 minutes and for the infusion group 6.5 + 0.3 minutes. The time for 5% to 95% recovery for the bolus dose groups was 14.1 ? 0.6 minutes and for the infusion group 14.4 -+ 0.6 minutes. Other investigatorsS-5 have documented similar recovery indexes in opioid anesthesia and have shown a 20% to 30% prolongation during inhalational anesthesia. To summarize the duration data, one can expect a total duration of action of about 25 minutes following mivacurium 0.1 mg/kg during opioid anesthesia. By increasing this dose threefold, one can expect to extend this duration by 50%. If one uses a dose of mivacurium that consistently produces 100% blockade-that is, two times the EDg5, or 0.15 mg/kg-the total duration is about 27 minutes. Doubling this dose to 0.3 mg/kg (3.5 to 4 x ED& extends the duration only about 36%, to 36 minutes. Recovery indexes remain the same across all dosage groups and may be slightly prolonged by inhalational anesthetics. With reference to other neuromuscular blocking drugs, mivacurium induces twice as long a blockade as succinylcholine, but only 30% to 50% as long a blockade as atracurium or vecuronium.g-L3 The pharmacodynamics of mivacurium extracted from these studies are presented in Table 1.
Spontaneous versus Antagonized Recovery Mivacurium is metabolized by plasma cholinesterase.*J4 Although this enzyme is partially and transiently inhibited by anticholinesterase drugs,L5J6 reversal of other nondepolarizing ester neuromuscular blocking drugs metabolized by plasma cholinesterase has not been shown to be a problem. I7 Similarly, Savarese et al. 1administered neostigmine 0.06 mg/kg and atropine 0.03 mg/kg to 8 patients out of 72 receiving mivacurium to test anticholinesterase reversibility. The degree of blockade varied from 67% to 93%. Antagonism occurred to 95% twitch height at 6.3 2 0.5 minutes, compared to 10.3 + 0.5
in Adults under
Nitrous
Oxide-Opioid
Anesthesia* 5% to 95%
Time to
Spontaneous
x ED96
Maximum Blockade (min)
5%’
25%’
1.25 2 2.5 3 -
5 3.5 2.5 2.3 -
11 13 16 19 -
13 16 20 23 -
Recovery Time (min)
25% to 75%
95%’
5% to 95%
Recovery with Reversal (min)
Bolus Dose (mg/ kg) 0.1 0.15 0.2 0.25 Infusion
*Enflurane and isoflurane may decrease dose requirements by 20% to 30%.
7 to 7 to 7 to 7 to 7to9
9 9 9 9
21 26 31 34 -
by 25% to 30%. Halothane,
enflurane,
12 12 13 14 14
to to to to to
15 15 15 15 15
6 6 6 6 6
to to to to to
7 7 7 7 7
and isoflurane may prolong recovery
‘From injection.
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minutes for spontaneous recovery from 25% to 95% for all other patients in the study. This represented a savings of about 4 minutes when mivacurium was antagonized from a mean blockade of about 76%. Curran et al.I* specifically compared spontaneous and neostigmine-induced recovery from deep mivacurium blockade (95%) in 22 patients. They demonstrated that 5% to 95%, 25% to 75%, and 25% to 95% recovery times were shorter following neostigmine-induced recovery compared with spontaneous recovery. The recovery times were (spontaneous vs. antagonized) 15.1 + 1.4 minutes uersu~ 7.7 + 0.7 minutes, 6.5 + 0.3 minutes uersm 3.0 2 0.2 minutes, and 11.0 ? 0.7 minutes uersuS 5.9 -t 0.4 minutes, respectively. T, ratios were about 80% and did not differ significantly between groups. Thus, mivacurium, when used at a dose of 0.15 mg/kg (2 x ED& and antagonized at 5% recovery, will have a total duration of action of about 20 minutes compared with a spontaneous recovery time of about 25 to 27 minutes. This also raises the issue, yet to be clarified, as to whether mivacurium needs to be antagonized with anticholinesterase drugs in routine practice. Cardiovascular Effects Benzylisoquinolinium neuromuscular blocking drugs (such as mivacurium) have the potential to release histamine.‘” The overall range is exemplified by d-tubocurarine, which releases significant histamine at or below its ED,, for neuromuscular blockade,20 and by doxacurium, which does not release histamine at clinical doses up to and including three times the neuromuscular ED,,.” Savarese et al.** examined mivacurium’s dose-effect relationship for histamine release, decrease in blood pressure (BP), and increase in heart rate in 97 healthy patients under N,O-opioid-barbiturate anesthesia. They examined rapid (10 to 15 seconds) bolus doses of mivacurium ranging from 0.03 mg/kg to 0.3 mg/kg (3.5 to 4 x EDgj). Up to and including 0.15 mg/kg (2 X ED,,), there were no hemodynamic side effects or release of histamine. This has been substantiated by other investigators.:‘.“J” Rapid injections of mivacurium 0.2 (2.5 X ED,,), 0.25 (3 x ED,,), and 0.3 (3.5 to 4 X ED,,) mg/kg were associated with changes in mean arterial pressure (MAP) of 18%, 13%, and 32%, respectively.*’ The authors noted that this depressor response was always transient (1 to 2 minutes) and self-limited, requiring no treatment. Other studies3,j,‘” also have shown this trend for mivacurium to release histamine with rapid bolus doses greater than or equal to 2.5 X ED,,. In an interesting analysis, Savarese et aLX4txamined the frequency of histamine release and the decrease in BP in terms of a percentage occurrence in the different dosage groups for mivacurium given as a rapid bolus. These percentages were plotted on log-probit scales, and a dose-response ratio was calculated. This “ED,,” denoted the dose of mivacurium, administered rapidly, that would result in 50% of patients exhibiting histamine release with a resultant decrease in BP. The derived “ED,,” for histamine release from mivacurium was about 0.24 mgikg with 95%’ 156
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1992
confidence limits of 0.18 to 0.32 mg/kg. This result agrees with the above-cited studies. Savarese et aLZ2 investigated the relationship between the size of the mivacurium dose, the speed of injection, and histamine release. When mivacurium 0.2 mg/kg was given over 30 seconds, no patients released histamine or experienced hemodynamic changes. When mivacurium 0.25 mg/kg (3 x ED,,) was given over 60 seconds, no patients exhibited histamine release or hemodynamic changes. Powers et ~1.‘~evaluated the hemodynamic effects of mivacurium given over 60 seconds to patients undergoing coronary artery bypass grafting (CABG). The doses used were 0.15, 0.2, and 0.25 mg/kg. At the lowest dose, there were no mean changes or individual changes in any hemodynamic variables. In the 0.2 mg/kg group, there were no changes in mean values, but two of nine patients experienced transient hypotension. In the highest dose group, a statistically significant decrease in MAP and systemic vascular resistance (SVR) was found at 2 minutes. This was attributable to a change in MAP and SVR in three of the nine patients, as the other six maintained stable hemodynamics. The authors concluded that doses of mivacurium greater than or equal to 0.2 mg/kg given over 60 seconds with fentanyl and diazepam to patients undergoing CABG were associated with sporadic hypotension. stoops et nl. ?li also evaluated mivacurium in patients undergoing CABS or valve replacement. During O,sufentanil anesthesia, mivacurium 0.15, 0.2, and 0.25 mg/kg was administered over 60 seconds to ASA physical status III and IV patients who were New York Heart Association functional class I-IV. These authors showed no statistically or clinically significant effects in any measured or derived hemodynamic variables at mivacurium 0.15 mgikg. One of 18 patients receiving 0.2 mg/kg and one of nine patients receiving 0.25 mgikg developed transient hypotension. These investigators concluded that mivacurium doses up to and including 0.15 mg/kg given over 60 seconds were safe to use in patients with coronary or valvular heart disease and limited cardiac reserve and would thus be useful during short procedures requiring relaxation. They rejected higher doses secondary to the occasional occurrence of transient hypotension. Thus, mivacurium appears to have a hemodynamic profile and a tendency to release histamine similar to that of atracurium.“,*7 Mivacurium, like atracurium, has not been associated with transient hypotension or histamine release at doses up to and including twice the ED!,, (0.15 mgikg). At doses of 0.2 mg/kg or greatel-, histamine release is seen occasionally but can be prevented by slowing the rate of administration to 30 seconds or more. It is necessary to inject doses of mivacurium 0.25 mg/kg over 60 seconds to prevent histamine release and associated hypotension in healthy patients. Two studie?jJ” have demonstrated the ability to use mivacurium 0.15 mgikg or less safely in patients with coronary artery or valvular heart disease at injection times of 60 seconds. However, higher doses, even if injected slowly, were associated with occasional hypotensive episodes. The
Clinical pharmacology use of H, and H2 histamine antagonists may attenuate hemodynamic effects secondary to histamine release induced by atracurium, 27.28but similar studies with mivacurium have not yet been performed. It is important to understand the hemodynamic effects of mivacurium, as its neuromuscular blocking profile, which allows one to increase the dosage to shorten the onset time without substantially prolonging the neuromuscular effect, will tempt many practitioners to use large doses for intubation. The potential limitations of this technique should be emphasized.
Intubation Because of the well-known undesirable and sometimes serious side effects of succinylcholine, nondepolarizing neuromuscular blocking drugs, usually atracurium or vecuronium, are often used to facilitate routine endotracheal intubation. Although both drugs are useful for intubating within 2.5 to 3 minutes, the duration of action of atracurium and vecuronium is too long for procedures lasting less than 30 minutes.2g,30 Mivacurium at equipotent doses has a duration of action 30% to 50% shorter than that of atracurium and vecuronium and twice as long as that of succinylcholine. Therefore, mivacurium may be a useful alternative to facilitate endotracheal intubation for short surgical procedures. Many studies have examined the utility of mivacurium for routine endotracheal intubation.31-36 In these studies, large doses of mivacurium (at least 0.15 mg/kg; 2 x EDgj) have reliably induced neuromuscular blockade. Since the onset time of mivacurium is comparable to that of other currently used nondepolarizing relaxants, 2 minutes was the earliest attempt at intubation in these studies, which generally used N,O-thiopental sodium-opioid anesthesia. Intubations were graded using similar criteria from “excellent” to “poor” or “impossible.” Excellent was defined as no reaction to intubation and the vocal cords relaxed; good was defined as intubation associated with a slight cough or bucking and the vocal cords relaxed; fair was defined as cord movement, moderate bucking and coughing. [Poor was defined as jaw not relaxed.] Only good to excellent responses were considered acTable 2.
in Adult
Drug Succinylcholine
Infusion Savarese et al.’ studied 44 ASA physical status I and II patients using continuous infusions of mivacurium lastfor
Mivacurium
and
Patients
Pretreatment
Dose (mg/kg)
Time to Intubation (set)
No Yes Yes
1 1 1.5 0.15 (2 x ED,,) 0.2 (2.5 x ED&*+ 0.25 (3 x ED,,)**
<60 >90 60 to 90 180 150 120
Mivacurium
*Not recommended
Basta
ceptable for intubation. At the lowest close of mivacurium used, 0.15 mg/kg, 52 of 63 patients (82%) were graded good to excellent at 2 to 2.5 minutes.3’-34 At 3 minutes, essentially all intubating conditions were excellent.3L At a dose of 0.2 mg/kg (2.5 x EDg5), 43 of 44 intubations (98%) were graded good to excellent.32-35 At a dose of 0.25 mg/kg (3 x ED9J at 2 minutes, 77 of 81 intubations (95%) were graded good to excellent.3*-3j In an interesting study by Shaff et aLs6 intubating conditions were graded from excellent to poor, the percentages of each grade were plotted as frequency versuS both time and dose and converted to log-probit scales. Dose-response relationships for intubation were then constructed. For an intubation time of 2 minutes, the EDjo of mivacurium for good to excellent intubating conditions was 0.13 mg/kg, the ED, was 0.2 mg/kg, and the EDgj was 0.25 mg/kg. These results led to suggested doses and times for routine intubation compared with succinylcholine (Table 2). Several points should be emphasized. Unless succinylcholine is contraindicated and it is necessary to use a relaxant to facilitate endotracheal intubation, current nondepolarizing relaxants, including mivacurium, should not be used for rapid-sequence inductionlintubation. Further, even though doses of mivacurium greater than 0.15 mg/kg decrease the time to achieve good to excellent intubating conditions, only about 1 minute is saved. These doses of mivacurium (0.2 to 0.25 mg/kg) are associated with about a 30% to 50% occurrence of histamine release and decreased BP when given rapidly. Should the clinician feel that it is necessary to use these higher doses, an appropriate increase in injection time (30 seconds for 0.2 mg/kg and 60 seconds for 0.25 mg/kg) is necessary to maintain stable hemodynamics. Thus, based on a small decrease in intubation time and the known hemodynamic profile of mivacurium, I would recommend mivacurium 0.15 mg/kg for routine intubation, anticipating an intubation time of 2.5 to 3 minutes.
Comparative lntubation Doses and Times
Succinylcholine
of mivacurium:
by the manufacturer.
tCan release histamine to attenuate histamine
when given rapidly. release.
Slowing
injection
time to 30 seconds
is necessary
$Can release histamine to attenuate histamine
when given rapidly. release.
Slowing
injection
time to 60 seconds
is necessary
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ing 35 to 324 minutes. They then compared the patients’ 5% to 95% and 25% to 75% recovery times with patients receiving only a single bolus dose of mivacurium under N,O-fentanyl-barbiturate anesthesia. They found a 5% to 95% recovery time of 14.4 -+ 0.6 minutes and a 25% to 75% recovery time (recovery index) of 6.5 + 0.3 minutes. These data were not significantly different from data in patients receiving a single bolus dose. The authors suggested that mivacurium might be particularly useful for maintenance of neuromuscular blockade by continuous infusion. Ali et aL3’ examined the use of mivacurium during continuous infusion in 72 ASA physical status I and II patients during N,O-fentanyl anesthesia. These investigators also studied continuous infusion in patients receiving atracurium (n = 22) or vecuronium (n = 18). The infusion rate required to achieve 90% to 99% twitch suppression was 8.3 kg/kg/min (range 2 to 14 Fg/kg/ min). Recovery times for short infusions (less than 30 minutes) did not differ from those for long infusions (greater than 120 minutes). The 25% to 75% and 5% to 95% recovery times were 6.9 + 0.3 minutes and 14.5 -C 0.4 minutes, respectively. These recovery times were half the recovery times for atracurium infusions (10.9 + 0.3 minutes and 26.6 2 0.4 minutes) and less than half the recovery times for vecuronium (13.8 + 0.9 minutes and 32.0 t 1.2 minutes). Finally, the infusion rate needed in each patient correlated directly with the patient’s plasma cholinesterase activity. Poler et al.31 reported on the utility of mivacurium infusions in 28 ASA physical status I and II women undergoing outpatient laparoscopy under N,O-opioid anesthesia and compared them with a comparable group of women receiving succinylcholine infusions. The required infusion rate for mivacurium to maintain neuromuscular blockade at 15% to 30% of the baseline electromyographic response was about 3 + 0.8 I.i,g/kgl min; the rate for succinylcholine was 37 f 40 Fg/kg/min. The authors observed that mivacurium was as effective as succinylcholine for maintaining blockade by infusion, but spontaneous recovery for mivacurium was slower. When mivacurium was antagonized by anticholinesterases, however, recovery times compared favorably with those for succinylcholine. The authors concluded that mivacurium was an effective alternative to succinylcholine but possessed no real advantages. Caldwell et aLz3 also compared mivacurium and succinylcholine infusions. They reported an infusion rate of mivacurium 6.7 Fg/kg/min (range 4 to 10 n.g/kg/min) to maintain 95% blockade, but they were unable to quote such a rate for succinylcholine, as it was necessary to alter the infusion rate frequently during the study secondary to tachyphylaxis. Additionally, one patient receiving a large cumulative dose of succinylcholine developed Phase II block, was not adequately reversed with edrophonium, and was extubated 1 hour after discontinuing the succinylcholine infusion. The spontaneous recovery index for the other succinylcholine infusions was 4.7 f 3.4 minutes. The mean spontaneous and neostigmine-antagonized recovery indexes for miv158
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acurium were 8.7 +- 3.0 minutes and 4.3 t 2.1 minutes, respectively. et aL3” compared maintenance of neuroGoldberg muscular blockade with both succinylcholine and mivacurium infusions. Their infusion rate of 6.6 -+ 3.1 pg/ kg/min compares favorably with previous studies1.*“,31.37. The time from termination of infusion to 95% recovery was 6.5 minutes for succinylcholine. For spontaneous and anticholinesterase-antagonized recovery with mivacurium, the time to 95% recovery was 16.7 and 7.6 minutes, respectively. Finally, Shanks et al.“” demonstrated a 25% reduction in mivacurium infusion requirements under enflurane anesthesia, from 5.9 t 2.2 l.i.g/kg/min to 4.4 ? 1.5 u,g/ kg/min, and 20% to 30% prolongation of recovery. Thus, mivacurium-induced neuromuscular blockade appears to be easy to produce and maintain, and spontaneous recovery from mivacurium is faster than recovery from atracurium and vecuronium. Spontaneous recovery is generally slower with mivacurium than with succinylcholine, unless the mivacurium blockade is antagonized, in which case the recovery times are equivalent. Mivacurium has advantages over succinylcholine in that it is a nondepolarizing blocker that is not susceptible to tachyphylaxis or Phase II blockade. Its infusion requirements are less with enflurane and probably with isoflurane as well. Its duration of action should be prolonged somewhat by inhalational anesthetics. Suggested infusion guidelines are presented in Table ?. Pediatrics Mivacurium has been studied in children ages 2 to 12.3g-” Goudsouzian et a1.39found an ED,, under N20opioid anesthesia of 0.11 mg/kg and under halothane anesthesia of 0.095 mg/kg, while Sarner et aLdo found an ED,, of 0.103 mg/kg and 0.089 mg/kg under N,O-opioid and halothane anesthesia, respectively. When giving mivacurium 0.2 mg/kg as a rapid bolus dose, Goudsouzian et a1.3Qnoted an onset to complete blockade of 1.6 to 1.9 minutes, with recovery to 5%, 25%, 95% and 25% to 75% of about 8.5, 11, 18, and 4.5 minutes, respectively. No cardiovascular changes were noted. Sarner et a1.j” administered mivacurium 0.25 “g/kg (2.5 x ED,,) in children as a rapid bolus dose. Onset times were 0.8 minutes under halothane and 1.1 minutes under opioid anesthesia. Recovery times to 5%, 25%, and 25% to 75% under opioid and halothane anesthesia were 6.8 ? 1.9 minutes and 11.2 + 3.9 minutes, 9.1 +- 2.6 minutes and 13.6 ? 3.9 minutes, and 4.3 it 2.2 minutes and 4.3 t 1.2 minutes, respectively. In 1 out of 18 children studied, BP decreased by 32%. Alifimoff and Goudsouzian41 studied infusion of mivacurium in children ages 2 to 12 with both opioid and halothane anesthesia. Infusion rates necessary to maintain twitch response at 90% to 99% block were generally higher in the children than those found in adults: 13.0 +- 1.4 pglkglmin and 10.4 ? 0.92 pglkglmin for opioid and halothane anesthesia, respectively, with the infusion rates remaining constant throughout. Spontaneous re-
Clinical pharmaco1og.p of mivacurium: Table 3. Comparative Infusion Rates of Succinylcholine, and Vecuronium in Adults Given Nitrous Oxide-Opioid Infusion Rate
5% to 95% Recovery Time (min)
(wGq+in) Succinylcholine
Mivacurium, Anesthesia*
40 20 to 100)’ 6 (range 2 to 15) 8 (range 2 to 15) 1.5 (range 0.5 to 3.0)
6to
Busta
Atracurium,
25% to 75% Recovery Time (min)
10
3 to 5
(range Mivacurium Atracurium Vecuronium
14 to 15
6.5 to 8.0
25 to 30
10 to 12
30 to 35
13 to 15
*Enflurane and isoflurane may decrease dose requirements and enflurane may prolong recovery by 20% to 30%. tTachyphylaxis
and Phase II block may occur.
covery from termination of infusion at 94% 2 0.2% blockade to 95% recovery under halothane anesthesia was 19.0 ? 5.3 minutes. After edrophonium-induced reversal, recovery time was 6.0 2 2.0 minutes. Similar recovery characteristics for opioid-based anesthesia were found to be 11.8 f 0.78 minutes and 3.3 ? 0.77 minutes, respectively. Comparable responses have been reported by Brandom et a1.42 It is clear from these studies that children require higher bolus doses and infusions of mivacurium than adults on an mg/kg basis. However, Sarner et aL40 demonstrated that when referenced to body surface area (mg/ m*), doses for children did not differ significantly from those for adults, suggesting that the apparent age-related differences may be associated with volume of distribution. Onset times for mivacurium-induced blockade at doses 2 to 2.5 times EDg, (0.2 to 0.25 mg/kg) are shorter in children and may allow intubation within 1 to 2 minutes. Suggested doses and recovery parameters are given in Table 4.
Table 4. Pharmacodynamic Anesthesia*
Bolus Dose (mglkg) x 0.09 to l..l 0.2 0.25 Inficsion (10 ug/kg/min; *Halothane
range
by 25%. Halothane, isoflurane,
Responses
ED,, 1 2 2.5
for Mivacurium
in Children
Metabolism, Elimination, and Pharmacodynamics Mivacurium is a substrate for plasma cholinesterase and is ultimately metabolized to two molecules of a quaternary alcohol and a dicarboxylic acid. A quaternary monoester is also formed as a distinct entity, as is an intermediary metabolite (Figure 1). Both the quaternary monoester and the quaternary alcohol are found in urine and bile (data on file, Burroughs Wellcome Co, Inc., Research Triangle Park, NC). These metabolites produce no neuromuscular, autonomic, or cardiovascular effects. Savarese et al.’ studied the rate of hydrolysis of mivacurium by purified human plasma cholinesterase at 5 mM concentration relative to a matched pair of succinylcholine. The in vitro hydrolysis rate for mivacurium at this substrate concentration was 88% that of succinylcholine. Cook et al. I4 measured the metabolism of mivacurium and succinylcholine in pooled human plasma,
2 to 12 Years of Age during
Nitrous
Time to Maximum Blockade (min)
5%
25%
95%
1 to 5 1 to 3 1 to 2
5 7 7
7 10 9
19 -
Oxide-Opioid
Time to Spontaneous Recovery (min)+ 5% to 95%
-
8 to 24 pglkglmin)
12
will decrease doses and increase recovery times by 20% to 30%.
‘From injection.
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Ratzonal Pharmacology butyrylcholinesterase, acetylcholinesterase, and buffer. There was essentially no metabolism of mivacurium by buffer and minimal metabolism by acetylcholinesterase. The graph of velocity versus substrate concentration for pooled plasma cholinesterase and succinylcholine demonstrated rapid enzyme saturation and a well-demarcated plateau. Mivacurium hydrolysis, however, increased gradually as the substrate concentration increased. For equal multiples of the Km (the Michaelis-Monten constant), mivacurium was hydrolyzed at 70% the rate of succinylcholine. These results help us to understand the short duration of action of mivacurium at normal doses and the 30% to 50% increase in duration of action of mivacurium when increasing the dose threefold (the more substrate to be metabolized, the faster the hydrolysis rate). Ostergaard et al. examined patients with normal plasma cholinesterase genotype and normal to slightly decreased enzyme activity (33 patients),.‘3 heterozygous patients (n = 10) for the usual and atypical gene,*” and homozygous patients (n = 4) for the atypical plasma cholinesterase gene. qj In the first group,4S no correlation was found between recovery and plasma cholinesterase activity with mivacurium 0.1 mg/kg, while recovery was correlated with plasma cholinesterase activity at a dose of 0.2 mg/kg. This tends to support Cook et al.‘“, who found that, since the enzyme differs from person to person, its degree of saturation and velocity of metabolism also differ. It should be noted, however, that Ostergaard et d’s recovery data 43 do not differ from those of other studies. In the group of patients heterozygous for the atypical gene, recovery times were prolonged about 50% following a 0.2 mg/kg dose of mivacurium.‘4 The four patients who were homozygous for the atypical gene received a 0.03 mg/kg dose of mivacurium.4i All developed 100% blockade, and the range of initial recovery was 26 to 128 minutes. Reversal was accomplished with neostigmine at 50% to 70% twitch recovery and occurred in 4 to 12 minutes. Thus, patients homozygous for the usual normal plasma cholinesterase activities at the low end of the normal range or slightly below the normal range recovered from twice the ED,, of mivacurium in the usual fashion, though high doses of mivacurium (greater than or equal to 0.2 mg/kg) showed slight prolongation in patients with plasma cholinesterase activities at or slightly below the lower limit of the normal range. Patients heterozygous for the usual gene and atypical gene will recover 50% more slowly at a dose of 0.2 mg/kg. As expected, patients homozygous for the atypical gene are exquisitely sensitive to mivacurium and should not. receive it. Basta et (11.“”examined the pharmacodynamics of mivacurium in young and elderly patients at a dose of 0.1 mg/kg under N,O-isoflurane anesthesia. Maximum blockade, time to maximum blockade, and time to 5%, 2570, and 95% recovery did not differ between the young and the elderly. Cook et aL4’ found that the duration of mivacurium blockade at a dose of 0.15 mg/kg was prolonged in patients with end-stage renal failure by 50% and in liver transplant patients by a factor of three.
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Finally, mivacurium is a mixture of three isomers: the cis-trans isomer (36%), the trans-trans isomer (58%), and the cis-cis isomer (6%) (data on file, Burroughs Wellcome Co., Inc, Research Triangle Park, NC). The cis-trans and trans-trans isomers are equipotent and rapidly metabolized by plasma cholinesterase. The cis-cis isomer is metabolized in vitro more slowly than the others. Its potency in humans has not been evaluated, but it is less than onetenth the potency of the other isomers in cats (personal communication, Doreen Wray, MD, Department of Anesthesia, The New York Hospital-Cornell Medical Center New York, NY). A stereospecific assay has recently become available and stereospecific pharmacokinetic studies are currently under way (personal communication, John Savarese, MD, and Cynthia Lien, MD, Department of Anesthesia, The New York Hospital-Cornell Medical Center).
Summary In 1975, Savarese and Kitz”” envisioned a need for three classes of nondepolarizing neuromuscular blocking drugs based primarily on duration of action. The first class represented short-acting nondepolarizing drugs capable of producing succinylcholine-like blockade within 1 to 2 minutes, starting recovery within 5 to 10 minutes. Even today, no nondepolarizing relaxants satisfy these criteria, though mivacurium approaches this ideal. A second group of nondepolarizing neuromuscular blocking drugs was termed intermediate-acting, best suited for surgical procedures lasting about 1 hour. Those relaxants would produce complete block within 2 to 3 minutes for a period of 20 to 30 minutes, followed by spontaneous recovery in 40 to 60 minutes. Atracurium and vecuronium currently meet these criteria.6.‘” A third class, the long-acting nondepolarizing relaxants, suitable for long operative procedures, existed in 1975, but all had hemodynamic side effects. The recently introduced relaxants doxacurium4Q,50 and pipecuroniumj’ represent long-acting nondepolarizers devoid of cardiovascular side effects. They produce blockade within 3 to 6 minutes, allow a clinical duration of 45 to 60 minutes, and allow spontaneous recovery in 90 to 180 minutes. In 1988, Savarese et al.’ reported on mivacurium, a nondepolarizing neuromuscular short-acting, new, blocker. This drug does not conveniently fit into any of the above categories. Mivacurium belongs somewhere between the ultra-short-acting depolarizing relaxant succinylcholine and the intermediate-acting relaxants atracurium and vecuronium. Based on a dose of 2 X ED,,, (0.15 mg/kg) under opioid anesthesia, mivacurium has an onset of 2.5 to 3 minutes, a clinical duration of 15 to 20 minutes, an injection-to-95%-recovery time of 25 to 30 minutes, and a recovery index of 6 to 7 minutes. A comparison with succinylcholine, atracurium, and vecuronium is presented in Table5. In many respects, other than onset time, mivacurium compares favorably with succinylcholine. Table 6 lists the advantages, disadvantages, and potential roles for succinylcholine and mivacurium in clinical practice.
Clinical pharmacolo~gy of mivacutium: Table 5. A Pharmacodynamic Comparison AtracuriumlVecuronium (in minutes)*
of Succinylcholine,
Mivacurium,
Ba.sta
and
_
Succinylcholine
Onset to maximal effect Injection to 95% recovery Clinical duration (injection to 25% recovery) Recovery index (25% to 75% recovery) *All doses considered
Table 6.
to be 2
A Comparison
x
Mivacurium
Atracuriuml Vecuronium
Less than 1
2 to 3
3 to 4
Less than 15
25 to 30
40 to 60
5 to 8
15 to 20
25 to 30
3
6 to 7
12 to 15
ED,,.
of Succinylcholine
and Mivacurium
Succinylcholine
Mivacurium
Advantages
Advantages
Rapid onset Ultra-short duration
Short duration Precise control No tachyphylaxis No Phase II block Unchanged recovery following infusions Reversible with anticholinesterases
Disadvantages
Skeletal muscle pain Tachyarrhythmias and bradyarrhythmias Hyperkalemia in susceptible patients Potential for increased intraocular, intragastric, and intracranial pressures Can trigger malignant hyperthermia Confusion concerning masseter spasm (its detection and significance) Sustained contracture in myotonias Phase II block Prolonged action Genetic Atypical plasma cholinesterase Acquired Anticholinesterase medications Severe liver disease Peripartum Others C’.ses Rapid endotracheal Very short surgical
Disadvantages
Potential histamine release at dose ~0.2 mg/kg when given rapidly Slightly prolonged in renal failure Prolonged blockade Genetic See succinylcholine Acquired See succinylcholine Uses Routine nonemergent intubation Procedures lasting less than 30 minutes Procedures lasting 30 to 60 minutes (infusion) Procedures of unpredictable duration (infusion)
intubation procedures
The principal advantages of succinylcholine are its rapid onset and short duration of action. Because of its depolarizing mechanism of action, succinylcholine has side effects and complicaseveral well-known adverse tions. Most of these are uncommon, but some are serious and potentially lethal. The clinical use of succinylcholine is fairly easy to define. Unless contraindicated, succinylcholine is the best neuromuscular blocking drug available for rapid control of the airway in patients with laryngospasm and those needing rapid-sequence intubations for full stomach precautions or symptomatic hiatal hernia. Mivacurium has three main advantages. First, its duration of action is significantly shorter than that of atra-
curium or vecuronium. As such, it can be used at doses up to and including 2 x ED,, (0.15 mg/kg) for routine, nonemergent intubations for short procedures (about 30 minutes). In children 2 to 12 years of age, mivacurium’s onset of action at twice the ED,, (0.2 mg/kg in children) approaches 1 minute and its duration of action is shorter than in adults. It may well replace succinylcholine for short surgical procedures in pediatric anesthesia. Second, because of mivacurium’s lack of cumulative properties, there is no difference in recovery times following repeat doses or continuous infusions. Finally, there is no development of Phase II blockade. These properties should allow mivacurium to be used as a continuous infusion quite readily.
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Rational
Phamucology
Mivacurium has two disadvantages of clinical importance. At doses equal to or greater than 0.2 mg/kg in adults, histamine release with attendant hypotension will become evident in some patients. If doses of this magnitude are used, the injection should be slowed to at least 30 seconds for a dose of 0.2 mglkg and 60 seconds for doses as high as 0.25 mg/kg to attenuate the release of histamine. The minimal acceleration of onset time at these doses does not, in my opinion, warrant their casual or routine use for endotracheal intubation. Mivacurium’s duration of action will be prolonged in patients unable to metabolize it, such as those patients with atypical plasma cholinesterase or acquired defects in plasma cholinesterase activity (due to, for example, anticholinesterase medications, severe liver and renal disease, and the peripartum period). Mivacurium should probably not be used in patients unable to metabolize it. Overall, mivacurium should find an important niche in clinical anesthesia when administered in a fashion consistent with its unique neuromuscular pharmacology. References 1. Savarese JJ, Ali HH, Basta SJ, et al: The clinical neuromuscular pharmacology of mivacurium chloride (BW B1090U). Anesthesiology 1988;68:723-32. 2. Litchfield JT Jr, Wilcoxon F: A simplified method of evaluating dose-effect experimentsj PhamucoZEx~ Ther 1949;95:99113. 3. From RP, Pearson KS, Choi WW, Abou-Donia M, Sokoll MD: Neuromuscular and cardiovascular effects of mivacurium chloride (BW B1090U) during nitrous oxide-fentanyl-thiopentone and nitrous oxide-halothane anaesthesia. Br J Anaesth 1990;64:193-8. 4. Caldwell JE, Kitts JB, Heier T, Fahey MR, Lynam DP, Miller RD: The dose-response relationship of mivacurium chloride in humans during nitrous oxide-fentanyl or nitrous oxideenflurane anesthesia. Anesthesiology 1989;70:31-5. 5. Weber S, Brandom BW, Powers DM, et al: Mivacurium chloride (BW B1090U) induced neuromuscular blockade during nitrous oxide-isoflurane and nitrous oxide-narcotic anesthesia in adult surgical patients. Anesth An&g 1988;67:4959. 6. Basta SJ, Ah HH, Savarese JJ, et al: Clinical pharmacology of atracurium besylate (BW 33A): a new nondepolarizing muscle relaxant. Anesth Analg 1982;61:723-9. 7. Ording H, Skovgaard LT, Engbaek J, Viby-Mogensen J: Doseresponse curves for vecuronium during halothane and neurolept anaesthesia: single bolus versus cumulative method. Actu Anaesthesiol Stand 1985;29: 121-4. 8. Katz RL, Stirt J, Murray AL, Lee CM: Neuromuscular effects of atracurium in man. Anesth An&g 1982;61:730-4. 9. Agoston S, Salt P, Newton D, Bencini A, Boomsma P, Erdmann W: The neuromuscular blocking action of ORG NC45, a new pancuronium derivative, in anaesthetized patients: a pilot study. BrJ Anuesth 1980;52(Suppl):53-9s. 10. Katz RL, Ryan JF: The neuromuscular effects of suxamethonium in man. BrJ Anaesth 1969;41:381-90. 11. Scott RPF, Savarese JJ, Basta SJ, et al: Clinical pharmacol;,gg_“8’. atracurium given in high dose. BrJ Anaesth 1986;58: 12. Gramstad L, Lilleaasen P: Dose-response relation for atracurium, ORG NC45, and pancuronium. BrJ Anuesth 1982;54:64751.
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34.
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39.
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41. 42.
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44.
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