British Journal of Anaesthesia (1990); 64: 193-198
NEUROMUSCULAR AND CARDIOVASCULAR EFFECTS OF MIVACURIUM CHLORIDE (BWB1090U) DURING NITROUS OXIDE-FENTANYL-THIOPENTONE AND NITROUS OXIDE-HALOTHANE ANAESTHESIA
SUMMARY Seventy-two adult surgical patients were studied to compare neuromuscular and cardiovascular effects of mivacurium chloride during nitrous oxide-fentanyl-thiopentone (BAL group) or nitrous oxide-halothane (HAL group) anaesthesia. Eighteen patients in the BAL group received an initial bolus of mivacurium, either the ED2S (n = 9) or the ED50 (n = 9) (0.03 and 0.05 mg kg-1). These doses were based on the assumption that the slope of the dose-response curve during nitrous oxide-opioid anaesthesia would be approximately the same as the slope of the neuromuscular response from the first human studies with mivacurium. Twenty-seven additional patients were allocated to subgroups of nine patients to receive mivacurium 0.04. 0.08 or 0.15 mg kg'1. Twenty-seven patients in the HAL group were allocated also to subgroups of nine patients to receive mivacurium 0.03, 0.04 or 0.15 mg kg'1. During stable anaesthesia, mean endtidal halothane concentrations were maintained at 0.49±0.01%. The estimated ED50, ED75 and ED95 for BAL and HAL groups were 0.039, 0.05 and 0.073 mg kg~1 and 0.040, 0.053 and 0.081 mg kg'1, respectively. Halothane did not potentiate maximum block or time to maximum block. Halothane did affect spontaneous recovery. With the 0.15-mg kg-1 dose, time to 95% recovery was prolonged significantly in the HAL group (30.0 fSEM 1.4) min) compared with the BAL group (24.1 (1.5) min). Recovery index from 25% to 75 % recovery was also prolonged significantly in the HAL group (7.0 (0.4) min) compared with the BAL group (5.4 (0.4) min). There were no significant haemodynamic changes in groups
given mivacurium doses up to and including 2 x EDg5 by bolus i. v. administration. KEY WORDS Neuromuscular block: mivacurium.
Mivacurium chloride (BW B1090U) is a new nondepolarizing neuromuscular blocking agent with a shorter duration of action than that of the current clinically available non-depolarizing agents. Previous clinical studies in healthy surgical patients have determined dose—response relationships, neuromuscular block profiles and cardiovascular effects during nitrous oxide-fentanyl-thiopentone [1-4], nitrous oxide—isoflurane [3] and nitrous oxide-enflurane anaesthesia [4]. Controversy exists regarding the neuromuscular potentiating effect of halothane on mivacurium. Sarner and colleagues [5] reported that the ED50 of mivacurium during nitrous oxide-halothane anaesthesia in children was significantly less than that during nitrous oxide-opioid anaesthesia. On the other hand, Goudsouzian and colleagues [6] found no significant difference in the dose-response phase following single bolus administration of mivacurium in children, and Lee and co-workers [7] reported that halothane in adults lacked ROBERT P. FROM*, D.O; KENT S.PEARSON, M.D.; WON W. CHOI, M.D. ; MARTIN D. SOKOLL, M.D., Department of Anes-
thesia, University of Iowa College of Medicine, Iowa City, Iowa, U.S.A. MARTHA ABOU-DONIA, PH.D., Burroughs-
Wellcome Co., Anesthesia/Analgesia Section, Department of Clinical Neurosciences, 3030 Cornwallis Road, Research Triangle Park, North Carolina, U.S.A. Accepted for Publication: July 26, 1989. *Address for correspondence: Department of Anesthesia, University of Iowa Hospitals and Clinics, Iowa City, Iowa 52242, U.S.A.
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R. P. FROM, K. S. PEARSON, W. W. CHOI, M. ABOU-DONIA AND M. D. SOKOLL
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potentiating effects. The purpose of the present study was to determine dose-response relationships, recovery times and haemodynamic side effects during nitrous oxide-halothane anaesthesia and to compare these data with results obtained during nitrous oxide-fentanyl-thiopentone anaesthesia in adult surgical patients.
We studied 72 patients, ASA Physical Status I-II, of both sexes (excluding females of childbearing potential), weighing 40-110 kg, aged 18-70 yr after institutionally approved informed consent was given. Patients were excluded from the study if they had a history of: malignant hyperpyrexia; unusual sensitivity to neuromuscular blocking agents; alcohol or drug abuse; clinically significant psychiatric, neurological, cardiovascular, renal or hepatic disease; asthma; exposure to aminoglycoside antibiotics, trimetaphan, quinidine or lignocaine within 48 h of the study; or exposure to antidepressants or antihistamines within 1 week before the study. In addition, patients were excluded if clinically significant electrocardiographic or laboratory abnormalities were detected by preoperative testing. Patients were premedicated with morphine 0.10-0.15 mg kg"1 and atropine 0.0040.008 mg kg"1 i.m. 45-60 min before induction of anaesthesia with thiopentone 4-8 mg kg"1. Patients in the nitrous oxide—fentanyl-thiopentone anaesthesia group (BAL group, n = 45) received 60-70% nitrous oxide in oxygen with incremental doses of fentanyl 0.05-0.1 mg and thiopentone 25—50 mg to achieve haemodynamic stability and provide adequate anaesthesia. Two subgroups of nine patients received an initial bolus of mivacurium of approximately the ED 25 and ED 50 (0.03 and 0.05 mg kg"1). These doses were based on the assumption that the slope of the dose-response curve during nitrous oxide-opioid anaesthesia would be approximately the same as the slope of the neuromuscular response from the first human studies with mivacurium conducted by J. J. Savarese (personal communication). The combined responses of these 18 patients were used to construct a new dose—response curve with an estimated ED 50 of 0.04 mg kg"1. The remaining groups received the estimated ED95 and 2 x ED 95 doses (0.08 and 0.15 mgkg"1). Anaesthesia in the nitrous oxide-halothane group (HAL group, n = 27) was maintained with
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PATIENTS AND METHODS
60-70% nitrous oxide in oxygen with end-tidal concentrations of 0.4-0.6% halothane. As the interaction between anaesthetics in their effects on minimum alveolar concentration (MAC) appears to be additive, this combination of nitrous oxide and halothane should result in a total MAC of approximately 1.25 [8]. The lower anaesthetic concentrations were used to avoid significant cardiovascular depression. Patients in the HAL group received mivacurium 0.03, 0.05 or 0.15 mg kg"1. Ventilation was controlled with a bag and mask throughout data collection to maintain end-tidal carbon dioxide at 4.7-6 kPa (multiplexed mass spectrometer). Temperature was monitored by an oral or axillary thermistor and maintained at or greater than 35 °C. After attaining a near steady state with each technique (not less than 15 min at 1.25 MAC in the case of halothane) the mechanomyogram of the adductor pollicis muscle was measured by a Grass FT 10 force-displacement transducer. The ulnar nerve was stimulated with two 25-gauge subcutaneous needles using a Grass S48 stimulator delivering square wave pulses at 0.15 Hz, 0.2 ms and supramaximal voltage (at least 20 V above maximum). After stabilization of the twitch response, mivacurium was administered as a rapid bolus (over 2-3 s) into a free flowing peripheral i.v. cannula. The following values were obtained from analysis of twitch recording: maximum block (maximum percent depression of baseline twitch height); onset time (from injection to maximum block); duration of block (from injection to 5%, 25% and 95% recovery); and recovery index (time from 25 % to 75% recovery). The electrocardiogram was monitored continuously. Systolic, diastolic and mean arterial pressures (MAP) were monitored at 1-min intervals. Automated oscillotonometry was used in lower dose groups (0.03, 0.04, 0.05 mg kg"1). In those patients who received drug doses equal to or exceeding the ED95 (0.08 and 0.15 mg kg"1, respectively), an indwelling radial artery cannula was used. Heart rate (HR) and MAP were recorded 1-2 min before drug injection (baseline) and every 1 min up to and including 5 min following the initial bolus dose. Patients were observed for signs of histamine release. All haemodynamic data were collected before laryngoscopy and tracheal intubation and at least 10 min following development of maximum block. The log-probit method of Litchfield and Wil-
EFFECTS OF MIVACURIUM CHLORIDE
RESULTS
The mean (SEM) [range] age, weight and height of patients studied were 30.9 (1.4) [18-61] yr, 77.9 (1.6) [50-110] kg, and 175.1 (1.2) [148-198] cm, respectively. During stable anaesthesia, mean end-tidal halothane concentration was 0.49 + 0.01%. In each group, mivacurium produced a dose-dependent neuromuscular block. When the data were plotted as a log-probit
relationship, slopes and intercepts of the doseresponse curves were not significantly different (fig. 1). The curve for nitrous oxide-fentanylthiopentone anaesthesia (w = 36, r = 0.56, P = 0.001) was slightly above that for nitrous oxidehalothane anaesthesia (w = 18, r = 0.72, P = 0.001) over the doses common to both techniques. Using these curves, estimated ED50, ED75 and ED95 for nitrous oxide-fentanyl-thiopentone and nitrous oxide-halothane anaesthesia were determined as 0.039, 0.050 and 0.073 and 0.040, 0.053 and 0.081, respectively. Dose-response relationships and recovery index for mivacurium are presented in table I. As the mivacurium dose was increased within each group, maximum block increased significantly, while time to maximum block decreased. Time to 95 % recovery and the 25% to 75% recovery index were significantly longer with the 0.15-mg kg"1 dose during nitrous oxide-halothane anaesthesia than during nitrous oxide—fentanyl-thiopentone anaesthesia. During both anaesthetic techniques, neither HR nor MAP changed significantly from baseline at 1, 2 or 5 min after rapid bolus mivacurium doses up to and including 0.15 mg kg"1 (table II). No cardiac arrhythmias were noted following bolus administration of mivacurium in any patient. Cutaneous manifestations of histamine release consisting of flushing over the face and neck were seen occasionally. No allergic phenomena (urticaria or bronchospasm) were noted.
3.0
H99.8
2.5
o
2.0
o o
1.5 1.0
£
0.5
I
0.0
o
-1.5 -2.0
o o o
• o 9
£ -0.5 • " J ^ " -1.0 • 8 O
B
o
B 0 a o
50
1.1
g — a - - BAL group (n=36) — o — HAL group (n=18)
is
-2.5 -3.0 Log dose: 1.45 1.50 1.55 1.60 1.65 1.70 1.75 1.80 1.85 1.90 1.95 Mivacurium (mg kg"1) 0.03 0.04 0.05 0.08
FIG. 1. Log probit dose-response curves for mivacurium during nitrous oxide-fentanyl-thiopentone (BAL group) and nitrous oxide-halothane (HAL group) anaesthesia.
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coxon [9] was used to construct dose-response curves using 0.03-0.08 mg kg"1 doses in each anaesthetic group. A computerized analysis of the dose—response curves was performed by leastsquares linear regression analysis to yield straight line relationships. When computing these lines, the probit of 0 % block was defined to be — 3 and the probit of 100% block was defined to be +3. Slope and intercept of the regression line for mivacurium dose-effect during nitrous oxidefentanyl-thiopentone or nitrous oxide-halothane anaesthesia and dose—response data were compared using unpaired t test [10]. Within-group dose-response data were compared using analysis of variance (ANOVA) and Fisher's Protected Least Square Difference test for multiple comparisons. Two way (time and group) ANOVA with repeated measures on the time factor was used to assess percent haemodynamic change. P < 0.05 was considered significant. Values are expressed as mean (SEM).
195
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TABLE I. Comparison of neuromuscular block and recovery data following administration of mivacurium. Values are mean (SEM). n = Number of patients who achieved block adequate for the study of spontaneous recovery. *P ^ 0.05 vs nitrous oxide—fentanyl-thiopentone anaesthesia
Anaesthesia group
Time to Maximum maximum Group block block size (min) (%)
0.03 0.05 0.15
Nitrous oxidehalothane anaesthesia
0.03 0.05 0.15
9 9 9 9 9 9
37.7 (8.8)
(0.8)
67.8 (6.4)
(0.3)
Time to selected levels of spontaneous recovery (min) 5%
25%
14.3 (2.1)
5.6
10.0 (1.0)
15.3 (1.0)
12.3 (0.7)
15.5 (1.0)
10.3
11.2 (1.2)
24.1 (1.5) 12.6 (1.4) 17.9 (1.7)
18.6 (0.8) (« = 5)
30.0 (1.4)* (n = 5)
5.6
99.7 (0.3) 25.8 (5.7) 70.3 (7.6)
3.3
(0.3)
7.0
6.6
(0.4) 6.6
(0.3)*
100 (0)
2.8
(0.3)
95%
25%-75% recovery index
15.9 (1.2)
5.5
(1.5) 5.4
(0.4) 7.0
(0.9) 7.0
(0.4)* (n = 5)
TABLE II. Cardiovascular changes (mean (SBM)) 1, 2 and 5 min after administration of mivacurium 0.15 mg kg'1 during nitrous oxide fentanyl—thiopentone (BAL group) and nitrous oxide-halothane (HAL group) anaesthesia Percent of baseline value at
Heart rate (beat min BAL group (« = 9) HAL group (n = 9) MAP (mm Hg) BAL group (n = 9) HAL group (n = 9)
DISCUSSION
In this study, a dose-response relationship was established for the neuromuscular actions of mivacurium in adult surgical patients during both nitrous oxide-fentanyl-thiopentone and nitrous oxide-halothane anaesthesia. Within each anaesthetic group, the maximum block developed and time to maximum block were dose-dependent. Increasing the mivacurium dose from 0.03 to 0.15 mg kg"1 significantly increased the maximum block and decreased onset time. Halothane did not appear to augment maximum block and time to maximum block significantly. For mivacurium doses of 0.03 and 0.15 mgkg" 1 , there was no significant increase in maximum
1 min
2 min
5 min
103 (3) 100(1)
99(3) 97(2)
92(2) 93(3)
92(3) 98(1)
96(2) 97(2)
97(2) 96(2)
block or time to maximum block during nitrous oxide-halothane anaesthesia compared with nitrous oxide-fentanyl-thiopentone anaesthesia. These findings agree with those of Lee and colleagues [7] who found lack of potentiation when either enflurane or halothane was added to nitrous oxide—opioid anaesthesia. These findings are also in agreement with the data of Goudsouzian and colleagues [6] who found no significant decrease in the mivacurium dose for children when halothane was added to nitrous oxide-narcotic-thiopentone anaesthesia. Comparing the reported single dose ED95 during different anaesthetic techniques in adults suggests that halothane has less potentiating effects on mivacurium than other agents (table III).
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Nitrous oxidefentanyl-thiopentone anaesthesia
Mivacurium dose (mg kg-1)
EFFECTS OF MIVACURIUM CHLORIDE
197
TABLE III. Reported ££>95 mivacurium doses during various anaesthetic techniques
Weber and colleagues [3] ED95 mg kg"1 dose
Present study ED85 mg kg""1 dose
0.5-0.75% Isoflurane (end-tidal)
0.058 (n = 26)
0.045 (» = 26)
0.067 (« = 33)
Nitrous oxide0.9-1.2% enflurane
0.4-0.6% Halothane
0.052 (n = 32)
0.073 (» = 36)
With respect to spontaneous recovery, nitrous oxide—halothane anaesthesia potentiated the duration of mivacurium neuromuscular block to a greater extent than nitrous oxide-fentanyl-thiopentone anaesthesia. For mivacurium 0.15 mg kg"1, time to 95 % recovery and the 25 % to 75 % recovery index were prolonged significantly—by about 20% in the HAL group. This prolongation in spontaneous recovery time during nitrous oxide-halothane anaesthesia is contrary to the findings of Sarner and colleagues [5] and Goudsouzian and colleagues [6]. Lee and co-workers [7] also found negligible potentiation by halothane with respect to recovery indices in adults. Potent inhalation anaesthetics are known to augment the neuromuscular blocking properties of tubocurarine [11]. Halothane has been shown to enhance the neuromuscular blocking effects of medium or long duration non-depolarizing neuromuscular blockers [12-14]. Desensitization of the postjunctional membrane by anaesthetic agents has been suggested as the mechanism responsible for this effect [15]. Isoflurane has a greater neuromuscular depressant effect alone and in combination with tubocurarine than equivalent doses of halothane [16]. On the other hand, isoflurane and halothane are similar with respect to enhancement of neuromuscular blocking properties of atracurium [17] and vecuronium [18]. Although 1.25 MAC halothane appears to have little potentiating effect on mivacurium during onset, this does not imply that the same relationship holds at greater concentrations. The cardiovascular safety of mivacurium is suggested by absence of clinically significant alterations from baseline HR or MAP during fast bolus administration at doses up to 2 x ED95 with each anaesthetic technique. Arterial pressure changed less than 20% from baseline values. No
0.081 {n = 18)
patient required therapy for hypotension. These observations are similar to those of other reports where cardiovascular and cutaneous side effects were mild and attributed to histamine release [1-3]. Cardiovascular safety is similar to that of atracurium [19]. It is possible that prior use of atropine might have increased baseline HR and influenced vagolytic response or histamine release caused by mivacurium. The doses of atropine were small and given at least 45-60 min before induction of anaesthesia. Relative haemodynamic change from baseline should not be influenced significantly by atropine. Although these data do not suggest any interaction between mivacurium and neuronal uptake of noradrenaline, as has been seen with other neuromuscular blocking drugs [20], a definitive answer to this question requires further study. From this study, it can be concluded that mivacurium is a potent rapid-onset non-depolarizing neuromuscular blocker with a short duration of action. At approximately twice the ED95 dose, mivacurium nearly fulfils criteria suggested by Savarese and Kitz [21] for a short-acting nondepolarizing agent (onset within 1-2 min) and approaches their criteria for a short duration nondepolarizing agent (total duration 10-20 min). Maximum block and time to block produced by mivacurium is not enhanced by 1.25 MAC halothane. Spontaneous recovery is delayed during nitrous oxide-halothane anaesthesia. In clinically useful doses, in healthy adult surgical patients, mivacurium appeared to have no cardiovascular side effects. ACKNOWLEDGEMENT Funded by Burroughs Wellcome Co., Research Triangle Park, North Carolina.
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Caldwell and colleagues [4] ED95 mg kg"1 dose
Nitrous oxide narcotic
198
11. Burn JH, Epstein HG, Feigan GA, Paton WDM. Some pharmacological actions of fluothane. British Medical Journal 1957;2: 479-483. 12. Miller RD, Way WL, Dolan WM, Stevens WC, Eger El II. Comparative neuromuscular effects of pancuronium, gallamine, and succinylcholine during forane and halothane anesthesia in man. Anesthesiology 1971; 35: 509-514. 13. Katz RL, Gissen AJ. Neuromuscular and electromyographic effects of halothane and its interaction with dtubocurarine in man. Anesthesiology 1967; 28: 564-567. 14. Baraka A. Effect of halothane on tubocurarine and suxamethonium block in man. British Journal of Anaesthesia 1968; 40: 602-606. 15. Gissen AJ, Karis JH, Nastuk WL. Effect of halothane on neuromuscular transmission. Journal of the American Medical Association 1966; 197: 770-774. 16. Miller RD, Eger El II, Way WL, Stevens WC, Dolan WM. Comparative neuromuscular effects of forane and halothane alone and in combination with d-tubocurarine in man. Anesthesiology 1971; 35: 38-42. 17. Brandom BW, Cook DR, Woelfel SK, Rudd GD, Fehr B, Lineberry CG. Atracurium infusion requirements in children during halothane, isoflurane, and narcotic anesthesia. Anesthesia and Analgesia 1985; 64: 471^176. 18. Rupp SM, Miller RD, Gencarelli PJ. Vecuroniuminduced neuromuscular blockade during enflurane, isoflurane, and halothane anesthesia in humans. Anesthesiology 1984; 60: 102-105. 19. Sokoll MD, Gergis SD, Mehta M, Ali NM, Lineberry C. Safety and efficacy of atracurium (BW33A) in surgical patients receiving balanced or isoflurane anesthesia. Anesthesiology 1983; 58: 450-455. 20. Salt PJ, Barnes PK, Conway CM. Inhibition of neuronal uptake of noradrenaline in the isolated perfused rat heart by pancuronium and its homologues, Org 6368, Org 7268 and NC 45. British Journal of Anaesthesia 1980; 52: 331-317. 21. Savarese JJ, Kitz RJ. Does clinical anesthesia need new neuromuscular blocking agents? Anesthesiology 1975; 42: 236-239.
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REFERENCES 1. Savarese JJ, Ali HH, Basta SJ, Embree PB, Scott RPF, Sunder N, Weakly JN, Wastila WB, El-Sayad HA. The clinical neuromuscular pharmacology of mivacurium chloride (BW B1090U). Anesthesiology 1988; 68: 723-732. 2. Savarese JJ, Basta SJ, Ali HH, Scott RPF, Sunder N, Gargarian M, Embree PB, Moss J, Gelb C, Weakly JN, Batson AG. Cardiovascular effects of BWB1090U in patients under nitrous oxide-oxygen-thiopental-fentanyl anesthesia. Anesthesiology 1985; 63: A319. 3. Weber S, Brandom BW, Powers DM, Sarner JB, Woelfel SK, Cook DR, Foster VJ, McNulty BF, Weakly JN. Mivacurium chloride (BW B1090U)-induced neuromuscular blockade during nitrous oxide-isoflurane and nitrous oxide-narcotic anesthesia in adult surgical patients. Anesthesia and Analgesia 1988; 67: 495-499. 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 oxide-enflurane anesthesia. Anesthesiology 1989; 70: 31-35. 5. Sarner JB, Brandom BW, Woelfel SK, Dong M, Horn MC, Cook DR, McNulty BF, Foster VJ. Clinical pharmacology of mivacurium chloride (BW B1090U) in children during nitrous oxide-halothane and nitrous oxide-narcotic anesthesia. Anesthesia and Analgesia 1989; 68: 116-121. 6. Goudsouzian NG, Alifimoff JK, Eberly C, Smeets R, Griswold J, Miler V, McNulty BF, Savarese JJ. Neuromuscular and cardiovascular effects of mivacurium in children. Anesthesiology 1989; 70: 237-242. 7. Lee C, Cheng M, Kwan WF, Yang E, Cantley E. Neuromuscular effects of mivacurium chloride in man under enflurane or halothane anesthesia. Anesthesia and Analgesia 1989; 68: S159. 8. Eger El II. Anesthetic Uptake and Action. Baltimore, Maryland: Williams & Wilkins, 1974. 9. Litchfield JT jr, Wilcoxon F. A simplified method of evaluating dose-effect experiments. Journal of Pharmacology and Experimental Therapeutics 1949; 96: 99-113. 10. Zar JH. Biostatistical Analysis, 2nd Edn. Englewood Cliffs, New Jersey: Prentice-Hall Inc., 1974.
BRITISH JOURNAL OF ANAESTHESIA
NEUROMUSCULAR AND CARDIOVASCULAR EFFECTS OF MIVACURIUM CHLORIDE (BWB1090U) DURING NITROUS OXIDE-FENTANYL-THIOPENTONE AND NITROUS OXIDE-HALOTHANE ANAESTHESIA
SUMMARY Seventy-two adult surgical patients were studied to compare neuromuscular and cardiovascular effects of mivacurium chloride during nitrous oxide-fentanyl-thiopentone (BAL group) or nitrous oxide-halothane (HAL group) anaesthesia. Eighteen patients in the BAL group received an initial bolus of mivacurium, either the ED2S (n = 9) or the ED50 (n = 9) (0.03 and 0.05 mg kg-1). These doses were based on the assumption that the slope of the dose-response curve during nitrous oxide-opioid anaesthesia would be approximately the same as the slope of the neuromuscular response from the first human studies with mivacurium. Twenty-seven additional patients were allocated to subgroups of nine patients to receive mivacurium 0.04. 0.08 or 0.15 mg kg'1. Twenty-seven patients in the HAL group were allocated also to subgroups of nine patients to receive mivacurium 0.03, 0.04 or 0.15 mg kg'1. During stable anaesthesia, mean endtidal halothane concentrations were maintained at 0.49±0.01%. The estimated ED50, ED75 and ED95 for BAL and HAL groups were 0.039, 0.05 and 0.073 mg kg~1 and 0.040, 0.053 and 0.081 mg kg'1, respectively. Halothane did not potentiate maximum block or time to maximum block. Halothane did affect spontaneous recovery. With the 0.15-mg kg-1 dose, time to 95% recovery was prolonged significantly in the HAL group (30.0 fSEM 1.4) min) compared with the BAL group (24.1 (1.5) min). Recovery index from 25% to 75 % recovery was also prolonged significantly in the HAL group (7.0 (0.4) min) compared with the BAL group (5.4 (0.4) min). There were no significant haemodynamic changes in groups
given mivacurium doses up to and including 2 x EDg5 by bolus i. v. administration. KEY WORDS Neuromuscular block: mivacurium.
Mivacurium chloride (BW B1090U) is a new nondepolarizing neuromuscular blocking agent with a shorter duration of action than that of the current clinically available non-depolarizing agents. Previous clinical studies in healthy surgical patients have determined dose—response relationships, neuromuscular block profiles and cardiovascular effects during nitrous oxide-fentanyl-thiopentone [1-4], nitrous oxide—isoflurane [3] and nitrous oxide-enflurane anaesthesia [4]. Controversy exists regarding the neuromuscular potentiating effect of halothane on mivacurium. Sarner and colleagues [5] reported that the ED50 of mivacurium during nitrous oxide-halothane anaesthesia in children was significantly less than that during nitrous oxide-opioid anaesthesia. On the other hand, Goudsouzian and colleagues [6] found no significant difference in the dose-response phase following single bolus administration of mivacurium in children, and Lee and co-workers [7] reported that halothane in adults lacked ROBERT P. FROM*, D.O; KENT S.PEARSON, M.D.; WON W. CHOI, M.D. ; MARTIN D. SOKOLL, M.D., Department of Anes-
thesia, University of Iowa College of Medicine, Iowa City, Iowa, U.S.A. MARTHA ABOU-DONIA, PH.D., Burroughs-
Wellcome Co., Anesthesia/Analgesia Section, Department of Clinical Neurosciences, 3030 Cornwallis Road, Research Triangle Park, North Carolina, U.S.A. Accepted for Publication: July 26, 1989. *Address for correspondence: Department of Anesthesia, University of Iowa Hospitals and Clinics, Iowa City, Iowa 52242, U.S.A.
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R. P. FROM, K. S. PEARSON, W. W. CHOI, M. ABOU-DONIA AND M. D. SOKOLL
BRITISH JOURNAL OF ANAESTHESIA
194
potentiating effects. The purpose of the present study was to determine dose-response relationships, recovery times and haemodynamic side effects during nitrous oxide-halothane anaesthesia and to compare these data with results obtained during nitrous oxide-fentanyl-thiopentone anaesthesia in adult surgical patients.
We studied 72 patients, ASA Physical Status I-II, of both sexes (excluding females of childbearing potential), weighing 40-110 kg, aged 18-70 yr after institutionally approved informed consent was given. Patients were excluded from the study if they had a history of: malignant hyperpyrexia; unusual sensitivity to neuromuscular blocking agents; alcohol or drug abuse; clinically significant psychiatric, neurological, cardiovascular, renal or hepatic disease; asthma; exposure to aminoglycoside antibiotics, trimetaphan, quinidine or lignocaine within 48 h of the study; or exposure to antidepressants or antihistamines within 1 week before the study. In addition, patients were excluded if clinically significant electrocardiographic or laboratory abnormalities were detected by preoperative testing. Patients were premedicated with morphine 0.10-0.15 mg kg"1 and atropine 0.0040.008 mg kg"1 i.m. 45-60 min before induction of anaesthesia with thiopentone 4-8 mg kg"1. Patients in the nitrous oxide—fentanyl-thiopentone anaesthesia group (BAL group, n = 45) received 60-70% nitrous oxide in oxygen with incremental doses of fentanyl 0.05-0.1 mg and thiopentone 25—50 mg to achieve haemodynamic stability and provide adequate anaesthesia. Two subgroups of nine patients received an initial bolus of mivacurium of approximately the ED 25 and ED 50 (0.03 and 0.05 mg kg"1). These doses were based on the assumption that the slope of the dose-response curve during nitrous oxide-opioid anaesthesia would be approximately the same as the slope of the neuromuscular response from the first human studies with mivacurium conducted by J. J. Savarese (personal communication). The combined responses of these 18 patients were used to construct a new dose—response curve with an estimated ED 50 of 0.04 mg kg"1. The remaining groups received the estimated ED95 and 2 x ED 95 doses (0.08 and 0.15 mgkg"1). Anaesthesia in the nitrous oxide-halothane group (HAL group, n = 27) was maintained with
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PATIENTS AND METHODS
60-70% nitrous oxide in oxygen with end-tidal concentrations of 0.4-0.6% halothane. As the interaction between anaesthetics in their effects on minimum alveolar concentration (MAC) appears to be additive, this combination of nitrous oxide and halothane should result in a total MAC of approximately 1.25 [8]. The lower anaesthetic concentrations were used to avoid significant cardiovascular depression. Patients in the HAL group received mivacurium 0.03, 0.05 or 0.15 mg kg"1. Ventilation was controlled with a bag and mask throughout data collection to maintain end-tidal carbon dioxide at 4.7-6 kPa (multiplexed mass spectrometer). Temperature was monitored by an oral or axillary thermistor and maintained at or greater than 35 °C. After attaining a near steady state with each technique (not less than 15 min at 1.25 MAC in the case of halothane) the mechanomyogram of the adductor pollicis muscle was measured by a Grass FT 10 force-displacement transducer. The ulnar nerve was stimulated with two 25-gauge subcutaneous needles using a Grass S48 stimulator delivering square wave pulses at 0.15 Hz, 0.2 ms and supramaximal voltage (at least 20 V above maximum). After stabilization of the twitch response, mivacurium was administered as a rapid bolus (over 2-3 s) into a free flowing peripheral i.v. cannula. The following values were obtained from analysis of twitch recording: maximum block (maximum percent depression of baseline twitch height); onset time (from injection to maximum block); duration of block (from injection to 5%, 25% and 95% recovery); and recovery index (time from 25 % to 75% recovery). The electrocardiogram was monitored continuously. Systolic, diastolic and mean arterial pressures (MAP) were monitored at 1-min intervals. Automated oscillotonometry was used in lower dose groups (0.03, 0.04, 0.05 mg kg"1). In those patients who received drug doses equal to or exceeding the ED95 (0.08 and 0.15 mg kg"1, respectively), an indwelling radial artery cannula was used. Heart rate (HR) and MAP were recorded 1-2 min before drug injection (baseline) and every 1 min up to and including 5 min following the initial bolus dose. Patients were observed for signs of histamine release. All haemodynamic data were collected before laryngoscopy and tracheal intubation and at least 10 min following development of maximum block. The log-probit method of Litchfield and Wil-
EFFECTS OF MIVACURIUM CHLORIDE
RESULTS
The mean (SEM) [range] age, weight and height of patients studied were 30.9 (1.4) [18-61] yr, 77.9 (1.6) [50-110] kg, and 175.1 (1.2) [148-198] cm, respectively. During stable anaesthesia, mean end-tidal halothane concentration was 0.49 + 0.01%. In each group, mivacurium produced a dose-dependent neuromuscular block. When the data were plotted as a log-probit
relationship, slopes and intercepts of the doseresponse curves were not significantly different (fig. 1). The curve for nitrous oxide-fentanylthiopentone anaesthesia (w = 36, r = 0.56, P = 0.001) was slightly above that for nitrous oxidehalothane anaesthesia (w = 18, r = 0.72, P = 0.001) over the doses common to both techniques. Using these curves, estimated ED50, ED75 and ED95 for nitrous oxide-fentanyl-thiopentone and nitrous oxide-halothane anaesthesia were determined as 0.039, 0.050 and 0.073 and 0.040, 0.053 and 0.081, respectively. Dose-response relationships and recovery index for mivacurium are presented in table I. As the mivacurium dose was increased within each group, maximum block increased significantly, while time to maximum block decreased. Time to 95 % recovery and the 25% to 75% recovery index were significantly longer with the 0.15-mg kg"1 dose during nitrous oxide-halothane anaesthesia than during nitrous oxide—fentanyl-thiopentone anaesthesia. During both anaesthetic techniques, neither HR nor MAP changed significantly from baseline at 1, 2 or 5 min after rapid bolus mivacurium doses up to and including 0.15 mg kg"1 (table II). No cardiac arrhythmias were noted following bolus administration of mivacurium in any patient. Cutaneous manifestations of histamine release consisting of flushing over the face and neck were seen occasionally. No allergic phenomena (urticaria or bronchospasm) were noted.
3.0
H99.8
2.5
o
2.0
o o
1.5 1.0
£
0.5
I
0.0
o
-1.5 -2.0
o o o
• o 9
£ -0.5 • " J ^ " -1.0 • 8 O
B
o
B 0 a o
50
1.1
g — a - - BAL group (n=36) — o — HAL group (n=18)
is
-2.5 -3.0 Log dose: 1.45 1.50 1.55 1.60 1.65 1.70 1.75 1.80 1.85 1.90 1.95 Mivacurium (mg kg"1) 0.03 0.04 0.05 0.08
FIG. 1. Log probit dose-response curves for mivacurium during nitrous oxide-fentanyl-thiopentone (BAL group) and nitrous oxide-halothane (HAL group) anaesthesia.
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coxon [9] was used to construct dose-response curves using 0.03-0.08 mg kg"1 doses in each anaesthetic group. A computerized analysis of the dose—response curves was performed by leastsquares linear regression analysis to yield straight line relationships. When computing these lines, the probit of 0 % block was defined to be — 3 and the probit of 100% block was defined to be +3. Slope and intercept of the regression line for mivacurium dose-effect during nitrous oxidefentanyl-thiopentone or nitrous oxide-halothane anaesthesia and dose—response data were compared using unpaired t test [10]. Within-group dose-response data were compared using analysis of variance (ANOVA) and Fisher's Protected Least Square Difference test for multiple comparisons. Two way (time and group) ANOVA with repeated measures on the time factor was used to assess percent haemodynamic change. P < 0.05 was considered significant. Values are expressed as mean (SEM).
195
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TABLE I. Comparison of neuromuscular block and recovery data following administration of mivacurium. Values are mean (SEM). n = Number of patients who achieved block adequate for the study of spontaneous recovery. *P ^ 0.05 vs nitrous oxide—fentanyl-thiopentone anaesthesia
Anaesthesia group
Time to Maximum maximum Group block block size (min) (%)
0.03 0.05 0.15
Nitrous oxidehalothane anaesthesia
0.03 0.05 0.15
9 9 9 9 9 9
37.7 (8.8)
(0.8)
67.8 (6.4)
(0.3)
Time to selected levels of spontaneous recovery (min) 5%
25%
14.3 (2.1)
5.6
10.0 (1.0)
15.3 (1.0)
12.3 (0.7)
15.5 (1.0)
10.3
11.2 (1.2)
24.1 (1.5) 12.6 (1.4) 17.9 (1.7)
18.6 (0.8) (« = 5)
30.0 (1.4)* (n = 5)
5.6
99.7 (0.3) 25.8 (5.7) 70.3 (7.6)
3.3
(0.3)
7.0
6.6
(0.4) 6.6
(0.3)*
100 (0)
2.8
(0.3)
95%
25%-75% recovery index
15.9 (1.2)
5.5
(1.5) 5.4
(0.4) 7.0
(0.9) 7.0
(0.4)* (n = 5)
TABLE II. Cardiovascular changes (mean (SBM)) 1, 2 and 5 min after administration of mivacurium 0.15 mg kg'1 during nitrous oxide fentanyl—thiopentone (BAL group) and nitrous oxide-halothane (HAL group) anaesthesia Percent of baseline value at
Heart rate (beat min BAL group (« = 9) HAL group (n = 9) MAP (mm Hg) BAL group (n = 9) HAL group (n = 9)
DISCUSSION
In this study, a dose-response relationship was established for the neuromuscular actions of mivacurium in adult surgical patients during both nitrous oxide-fentanyl-thiopentone and nitrous oxide-halothane anaesthesia. Within each anaesthetic group, the maximum block developed and time to maximum block were dose-dependent. Increasing the mivacurium dose from 0.03 to 0.15 mg kg"1 significantly increased the maximum block and decreased onset time. Halothane did not appear to augment maximum block and time to maximum block significantly. For mivacurium doses of 0.03 and 0.15 mgkg" 1 , there was no significant increase in maximum
1 min
2 min
5 min
103 (3) 100(1)
99(3) 97(2)
92(2) 93(3)
92(3) 98(1)
96(2) 97(2)
97(2) 96(2)
block or time to maximum block during nitrous oxide-halothane anaesthesia compared with nitrous oxide-fentanyl-thiopentone anaesthesia. These findings agree with those of Lee and colleagues [7] who found lack of potentiation when either enflurane or halothane was added to nitrous oxide—opioid anaesthesia. These findings are also in agreement with the data of Goudsouzian and colleagues [6] who found no significant decrease in the mivacurium dose for children when halothane was added to nitrous oxide-narcotic-thiopentone anaesthesia. Comparing the reported single dose ED95 during different anaesthetic techniques in adults suggests that halothane has less potentiating effects on mivacurium than other agents (table III).
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Nitrous oxidefentanyl-thiopentone anaesthesia
Mivacurium dose (mg kg-1)
EFFECTS OF MIVACURIUM CHLORIDE
197
TABLE III. Reported ££>95 mivacurium doses during various anaesthetic techniques
Weber and colleagues [3] ED95 mg kg"1 dose
Present study ED85 mg kg""1 dose
0.5-0.75% Isoflurane (end-tidal)
0.058 (n = 26)
0.045 (» = 26)
0.067 (« = 33)
Nitrous oxide0.9-1.2% enflurane
0.4-0.6% Halothane
0.052 (n = 32)
0.073 (» = 36)
With respect to spontaneous recovery, nitrous oxide—halothane anaesthesia potentiated the duration of mivacurium neuromuscular block to a greater extent than nitrous oxide-fentanyl-thiopentone anaesthesia. For mivacurium 0.15 mg kg"1, time to 95 % recovery and the 25 % to 75 % recovery index were prolonged significantly—by about 20% in the HAL group. This prolongation in spontaneous recovery time during nitrous oxide-halothane anaesthesia is contrary to the findings of Sarner and colleagues [5] and Goudsouzian and colleagues [6]. Lee and co-workers [7] also found negligible potentiation by halothane with respect to recovery indices in adults. Potent inhalation anaesthetics are known to augment the neuromuscular blocking properties of tubocurarine [11]. Halothane has been shown to enhance the neuromuscular blocking effects of medium or long duration non-depolarizing neuromuscular blockers [12-14]. Desensitization of the postjunctional membrane by anaesthetic agents has been suggested as the mechanism responsible for this effect [15]. Isoflurane has a greater neuromuscular depressant effect alone and in combination with tubocurarine than equivalent doses of halothane [16]. On the other hand, isoflurane and halothane are similar with respect to enhancement of neuromuscular blocking properties of atracurium [17] and vecuronium [18]. Although 1.25 MAC halothane appears to have little potentiating effect on mivacurium during onset, this does not imply that the same relationship holds at greater concentrations. The cardiovascular safety of mivacurium is suggested by absence of clinically significant alterations from baseline HR or MAP during fast bolus administration at doses up to 2 x ED95 with each anaesthetic technique. Arterial pressure changed less than 20% from baseline values. No
0.081 {n = 18)
patient required therapy for hypotension. These observations are similar to those of other reports where cardiovascular and cutaneous side effects were mild and attributed to histamine release [1-3]. Cardiovascular safety is similar to that of atracurium [19]. It is possible that prior use of atropine might have increased baseline HR and influenced vagolytic response or histamine release caused by mivacurium. The doses of atropine were small and given at least 45-60 min before induction of anaesthesia. Relative haemodynamic change from baseline should not be influenced significantly by atropine. Although these data do not suggest any interaction between mivacurium and neuronal uptake of noradrenaline, as has been seen with other neuromuscular blocking drugs [20], a definitive answer to this question requires further study. From this study, it can be concluded that mivacurium is a potent rapid-onset non-depolarizing neuromuscular blocker with a short duration of action. At approximately twice the ED95 dose, mivacurium nearly fulfils criteria suggested by Savarese and Kitz [21] for a short-acting nondepolarizing agent (onset within 1-2 min) and approaches their criteria for a short duration nondepolarizing agent (total duration 10-20 min). Maximum block and time to block produced by mivacurium is not enhanced by 1.25 MAC halothane. Spontaneous recovery is delayed during nitrous oxide-halothane anaesthesia. In clinically useful doses, in healthy adult surgical patients, mivacurium appeared to have no cardiovascular side effects. ACKNOWLEDGEMENT Funded by Burroughs Wellcome Co., Research Triangle Park, North Carolina.
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Caldwell and colleagues [4] ED95 mg kg"1 dose
Nitrous oxide narcotic
198
11. Burn JH, Epstein HG, Feigan GA, Paton WDM. Some pharmacological actions of fluothane. British Medical Journal 1957;2: 479-483. 12. Miller RD, Way WL, Dolan WM, Stevens WC, Eger El II. Comparative neuromuscular effects of pancuronium, gallamine, and succinylcholine during forane and halothane anesthesia in man. Anesthesiology 1971; 35: 509-514. 13. Katz RL, Gissen AJ. Neuromuscular and electromyographic effects of halothane and its interaction with dtubocurarine in man. Anesthesiology 1967; 28: 564-567. 14. Baraka A. Effect of halothane on tubocurarine and suxamethonium block in man. British Journal of Anaesthesia 1968; 40: 602-606. 15. Gissen AJ, Karis JH, Nastuk WL. Effect of halothane on neuromuscular transmission. Journal of the American Medical Association 1966; 197: 770-774. 16. Miller RD, Eger El II, Way WL, Stevens WC, Dolan WM. Comparative neuromuscular effects of forane and halothane alone and in combination with d-tubocurarine in man. Anesthesiology 1971; 35: 38-42. 17. Brandom BW, Cook DR, Woelfel SK, Rudd GD, Fehr B, Lineberry CG. Atracurium infusion requirements in children during halothane, isoflurane, and narcotic anesthesia. Anesthesia and Analgesia 1985; 64: 471^176. 18. Rupp SM, Miller RD, Gencarelli PJ. Vecuroniuminduced neuromuscular blockade during enflurane, isoflurane, and halothane anesthesia in humans. Anesthesiology 1984; 60: 102-105. 19. Sokoll MD, Gergis SD, Mehta M, Ali NM, Lineberry C. Safety and efficacy of atracurium (BW33A) in surgical patients receiving balanced or isoflurane anesthesia. Anesthesiology 1983; 58: 450-455. 20. Salt PJ, Barnes PK, Conway CM. Inhibition of neuronal uptake of noradrenaline in the isolated perfused rat heart by pancuronium and its homologues, Org 6368, Org 7268 and NC 45. British Journal of Anaesthesia 1980; 52: 331-317. 21. Savarese JJ, Kitz RJ. Does clinical anesthesia need new neuromuscular blocking agents? Anesthesiology 1975; 42: 236-239.
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REFERENCES 1. Savarese JJ, Ali HH, Basta SJ, Embree PB, Scott RPF, Sunder N, Weakly JN, Wastila WB, El-Sayad HA. The clinical neuromuscular pharmacology of mivacurium chloride (BW B1090U). Anesthesiology 1988; 68: 723-732. 2. Savarese JJ, Basta SJ, Ali HH, Scott RPF, Sunder N, Gargarian M, Embree PB, Moss J, Gelb C, Weakly JN, Batson AG. Cardiovascular effects of BWB1090U in patients under nitrous oxide-oxygen-thiopental-fentanyl anesthesia. Anesthesiology 1985; 63: A319. 3. Weber S, Brandom BW, Powers DM, Sarner JB, Woelfel SK, Cook DR, Foster VJ, McNulty BF, Weakly JN. Mivacurium chloride (BW B1090U)-induced neuromuscular blockade during nitrous oxide-isoflurane and nitrous oxide-narcotic anesthesia in adult surgical patients. Anesthesia and Analgesia 1988; 67: 495-499. 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 oxide-enflurane anesthesia. Anesthesiology 1989; 70: 31-35. 5. Sarner JB, Brandom BW, Woelfel SK, Dong M, Horn MC, Cook DR, McNulty BF, Foster VJ. Clinical pharmacology of mivacurium chloride (BW B1090U) in children during nitrous oxide-halothane and nitrous oxide-narcotic anesthesia. Anesthesia and Analgesia 1989; 68: 116-121. 6. Goudsouzian NG, Alifimoff JK, Eberly C, Smeets R, Griswold J, Miler V, McNulty BF, Savarese JJ. Neuromuscular and cardiovascular effects of mivacurium in children. Anesthesiology 1989; 70: 237-242. 7. Lee C, Cheng M, Kwan WF, Yang E, Cantley E. Neuromuscular effects of mivacurium chloride in man under enflurane or halothane anesthesia. Anesthesia and Analgesia 1989; 68: S159. 8. Eger El II. Anesthetic Uptake and Action. Baltimore, Maryland: Williams & Wilkins, 1974. 9. Litchfield JT jr, Wilcoxon F. A simplified method of evaluating dose-effect experiments. Journal of Pharmacology and Experimental Therapeutics 1949; 96: 99-113. 10. Zar JH. Biostatistical Analysis, 2nd Edn. Englewood Cliffs, New Jersey: Prentice-Hall Inc., 1974.
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