British Journal of Anaesthesia 1991; 67: 289-295
NEUROMUSCULAR AND CLINICAL EFFECTS OF MIVACURIUM CHLORIDE IN HEALTHY ADULT PATIENTS DURING NITROUS OXIDE-ENFLURANE ANAESTHESIAf D. R. GOLDHILL, J. P. WHITEHEAD, R. S. EMMOTT, A. P. GRIFFITH, B. J. BRACEY AND P. J. FLYNN
further 30-s delay or by use of a 0.2-mg kg~1 dose. Recovery to 11/7c of 5% occurred on average in 12-13 min irrespective of dose. Thereafter, mivacurium infusions commenced at 8-10 fig kg-1 min'1 were adjusted at intervals of at least 3 min to achieve 11 lie in the range 1-10%. Mean duration of infusion was 58 (3.4) min and mean infusion rate after a 15-min stabilization period was 6.6 (range 2.3-12.9) fig kg-'min'1. On cessation of infusions, spontaneous recovery from 11 fie 8% (1.0%) to 14:11 = 0.7 took 17 (1.2) min. Neostigmine 0.04 mg kg-1 or edrophonium 0.75mg kg'1 evoked recovery from 11lie 9% (SEM 1.2% and 1.0%, respectively) to 14:11 = 0.7 in 11 (0.6) and 8 (0.9) min (both P < 0.001 vs spontaneous recovery). KEY WORDS Neuromuscular relaxants: mivacurium.
PATIENTS AND METHODS
The study was approved by the Committee on Safety of Medicines and the local Ethics Committee. Forty five patients requiring nasotracheal intubation for elective oral surgical procedures gave written informed consent. They were of physical status ASA I or II, and not taking antihistamines or medications known to affect neuromuscular function. Premedication 60D . R. GOLDHIIX, M.B., B.S., F.CANAES.J J. P. WHITBHEAD, M.B., CH.B., F.C.ANAES.; R. S. E M M O T T , M.B., CH.B., F.C.ANAES. J A. P. GRIFFITH, M.B., B.A.O., B.CH., F.F.A.R.C.S.I. ; B. J. BRACEY, M.B., B.S., M.R.C.P., F.C.ANAES.; P. J. FLYNN, M.B., D.CH.,
D.OBST., F.F.A.R.C.S.I.; Anaesthetics Unit, The Royal London Hospital, Whitechapel, London El IBB. Accepted for Publication: February 22, 1991. t Presented in part at the Anaesthetic Research Society, London Meeting, November 1989.
Downloaded from http://bja.oxfordjournals.org/ at Cornell University Library on April 26, 2015
Mivacurium chloride (BW B1090U) is a new nondepolarizing neuromuscular blocking agent. PreWe have studied the effects of mivacurium after vious clinical trials in the United States [1-9] have induction of anaesthesia with alfentanH-propofol shown that it has a shorter duration of action than in healthy adult oral surgical patients. Anaes- currently approved non-depolarizing agents and thesia was maintained with nitrous oxide and may be suitable for providing neuromuscular 0.75% (end-tidal) enflurane in oxygen after block for procedures of brief duration when nasotracheal intubation. Recordings were made suxamethonium is not desired, and for mainof the rectified compound adductor pollicis tenance of neuromuscular block by infusion. We have assessed onset times and conditions at electromyogram in response to train-of-four (TOF) ulnar nerve stimulation. First and fourth tracheal intubation after fast bolus administration TOF responses were defined as 11 and 14. with of mivacurium. A slow bolus injection group was 71 suppression referenced to pre-mivacurium 11 included also, as mivacurium may be associated height (1c). Onset times (mean (SEM)) to 90% with cutaneous flushing and arterial hypotension 11 suppression were 2.5 (0.2), 2.1 (0.3) and 1.6 caused by systemic release of histamine [8]. (0.1) min, respectively, after mivacurium 0.15 mg Infusion requirements were ascertained under kg-1 (n=18) and 0.2mgkg-' (n=18) as anaesthesia with nitrous oxide and enflurane, and 5-s boluses and 0.2mgkg~1 over 30 s (n = 9). the time for spontaneous recovery of neuroIntubating conditions 2 min after 0.15 mg kg-1 muscular function was compared with that were good to excellent and not improved by a achieved after neostigmine or edrophonium. SUMMARY
290
end-tidal concentration of 0.75% (Datex Normac) and ventilation was controlled to maintain an end-tidal partial pressure of carbon dioxide 4.45.4 kPa (Datex Normocap). Nasopharyngeal and palmar temperatures were maintained greater than 35 °C and 33 °C, respectively. All patients received an infusion of mivacurium 0.5 mg ml"1 in 5 % glucose to extend neuromuscular block for the duration of surgery. Infusions were commenced after EMG recovery from the initial bolus of mivacurium was evident (Tl/Tc > 5%). An initial infusion rate of 10 ug kg"1 min"1 was used in the first nine patients studied, but in subsequent patients this was modified to 8 ug kg"1 min"1. The rate was then adjusted by increments of 1 ug kg"1 min"1 at intervals of at least 3 min to achieve and maintain T l / T c in the range 1-10% (90-99% Tl suppression). Infusions were administered using a Ohmeda 9000 syringe pump and a dedicated i.v. cannula. Towards the end of surgery the infusion was discontinued and group B patients allowed to recover spontaneously from the effects of mivacurium. Residual neuromuscular block was antagonized with neostigmine 40 ug kg"1 and atropine 20 ug kg"1 in group A patients, and with edrophonium 750 jig kg"1 preceded by atropine 10 ug kg"1 in group C patients. EMG monitoring was continued until the T4:T1 ratio (the ratio of the height of the 4th response (T4) of the TOF to Tl) reached at least 0.7. Anaesthesia was discontinued and, after spontaneous ventilation was established, the trachea was extubated. ' For each patient, the times from bolus injection to 90% and to maximal Tl suppression, Tl suppression at intubation, intubation scores and times for initial recovery of T l / T c to 5% and 10 % were noted. (All times were from completion of injection of mivacurium.) Changes in infusion rate, mean infusion rate and infusion duration were recorded. After infusions, T l / T c at antagonism (groups A and C) or at cessation of infusion (group B) was noted, and the time for recovery to T4:T1 ratios of 0.5 and 0.7 recorded. Patient data were analysed with one-way analysis of variance (ANOVA). Neuromuscular data were analysed using one-way ANOVA, Student-NewmanKeuls test, and Bonferroni t tests as appropriate. Chi square was used to analyse intubation scores. P < 0.05 was considered statistically significant. Non-invasive cardiovascular monitoring was performed according to normal anaesthetic prac-
Downloaded from http://bja.oxfordjournals.org/ at Cornell University Library on April 26, 2015
90 min before induction of anaesthesia consisted of oral atropine 1 mg and temazepam 20-30 mg. Electrocardiographic and non-invasive arterial pressure monitoring (Datascope Accutorr) commenced in the anaesthetic room. Adhesive, prejelled silver-silver chloride surface electrodes were positioned on the wrist and hand, and connected to a Datex Relaxograph in order to detect the evoked gated integrated rectified compound electromyographic (EMG) response of the adductor pollicis muscle to supramaximal trainof-four (TOF) ulnar nerve stimulation (0.1-ms square-wave stimuli at 2 Hz for 2 s; train frequency 0.05 Hz). The hand from which EMG recordings were obtained was immobilized with the thumb abducted, and the arm was wrapped in cotton wool to minimize heat loss. Palmar and core temperatures were monitored with skin and nasopharyngeal probes. After i.v. induction of anaesthesia with alfentanil 0.5-1.0mg and propofol 2.0-2.5mg kg"1, a stable baseline EMG recording was obtained. Rectified EMG output from the Relaxograph was recorded continuously on a Gould 220 chart recorder for later analysis. The height of the first response (Tl) of the TOF at baseline was defined as the control response (Tc). Before tracheal intubation, anaesthesia was maintained with 66 % nitrous oxide in oxygen, and increments of alfentanil and propofol as clinically indicated. Mivacurium 2 mg ml"1 was administered at least 2 min after the last increment of alfentanil or propofol. Patients were studied in three groups. The first 18 patients (group A) were allocated randomly to receive an initial dose of mivacurium 0.15 mg kg"1 (subgroup Al) or O^mgkg" 1 (subgroup A2) as a rapid, 5-s bolus via a peripheral vein, and trachea! intubation was attempted 2.5 min later. The next 18 patients (group B) were similarly allocated randomly to receive mivacurium 0.15 mg kg"1 (subgroup Bl) or O^mgkg" 1 (subgroup B2) by rapid, 5-s bolus, but with tracheal intubation 2 min after the injection of mivacurium. The final nine patients (group C) received mivacurium 0.2 mg kg"1 over 30 s, with tracheal intubation attempted 2 min later. Intubating conditions were graded on an interval scale from 1 = excellent to 4 = not possible, according to the observed state of relaxation of the vocal cords and the severity of coughing or passing the tracheal tube. After successful tracheal intubation, enflurane was added to the inspired gases to achieve an
BRITISH JOURNAL OF ANAESTHESIA
CLINICAL EFFECTS OF MIVACURIUM
291
TABLE I. Details of patients and total doses of propofol and alfentantil given before the initial attempt at trachea! intubation (mean (SD)) Group or subgroup Al A2 Bl B2
Age (yr)
Height (cm)
Sex (M:F)
Propofol (mg kg"1)
66.3 (14.2) 68.7 (14.3) 71.8 (9.4) 73.6 (11.1) 64.0 (7.3)
28.3 (9.3) 26.7 (6.6) 27.8 (6.0) 26.2 (4.0) 28.2 (10.0)
165.8 (9.2) 167.7 (9.7) 174.2 (8.4) 171.7 (9.2) 168.4 (5.8)
3:6
2.91 (0.52) 3.90 (1.49) 2.72 (0.67) 3.20 (0.27) 3.61 (1.11)
3:6 6:3 5:4 3:6
Alfentanil ("g kg"1) 14.8 (3.3) 15.7 (4.8) 17.1 (3.3) 13.9 (1.9) 15.3 (1.8)
TABLE II. Onset of block (mean (SEM) [range]). Times are taken from the end of mivacurium injection. t n = 17; X n = 15. Rapid bolus dose = 5 J; slow bolus dose = 30 s. *P < 0.05 Time to % T l suppression (min) Dose (mg kg"1) 0.15 Rapid (n = 18) 0.20 Rapid
(„ = 18) 0.20 Slow (" = 9)
Time to % T l recovery (min)
90%
Maximal
5%
10%
2.5 (0.2) [1.6-3.7] 2.1 (0.3) [0.8-4.4] 1.6(0.1)* [1.2-2.7]
3.7 (0.3)* [1.7-6.0] 2.6 (0.3) [1.1-5.1] 2.4 (0.2) [1.8-3.1]
11.5(0.9) [5.9-18.7] |12.7 (0.9) [8.5-19.9] 13.3 (0.8) [8.5-16.9]
+ 12.8 (0.8) [7.9-20.4] $ 14.2 (0.9) [9.5-22.1] 15.0(0.9) [10.5-19.6]
received initial 5-s boluses of mivacurium 0.15 mg kg"1 (subgroups Al and Bl) or O^mgkg" 1 (subgroups A2 and B2). There were no significant differences in onset and early recovery data between subgroups that received identical initial mivacurium doses over 5 s; such data were analysed in combination and are summarized in table II. Mean onset times (from end of injection) to 90 % and to maximal T l suppression after mivacurium 0.15 mg kg"1 were slower than those after 0.2 mg kg"1, although the difference in times to 90% suppression between the two doses when administered over 5 s was not statistically significant. Tl suppression of 100% was produced in all but two patients; one reached 97 % suppression after a dose of 0.15 mg kg"1, and another achieved maximal Tl suppression of only RESULTS 90 % after mivacurium 0.2 mg kg"1 administered Patient groups were comparable with respect to over 5 s. weight, age, height and total doses of propofol and Data from three patients in whom oral tracheal alfentanil received before the initial attempt at intubation was performed (n = 1) or unexpectedly tracheal intubation (table I). There were no difficult insertion of the tracheal tube through the significant differences between patients who nasal passage was encountered (n = 2) were extice. Clinical signs of histamine release, such as cutaneous flushing were documented. In addition, arterial pressure (AP) and heart rate (HR) were recorded immediately before and every 1 min for 10 min after the initial dose of mivacurium. Baseline AP and HR were denned as values immediately preceding administration of mivacurium. In order to avoid the compounding haemodynamic effects of tracheal intubation, analyses were made only of the maximum change in HR and mean arterial pressure (MAP) from baseline observed in the period after mivacurium but before tracheal intubation. Paired t tests and Fisher's Exact tests were used to analyse these changes and significance taken at P < 0.05.
Downloaded from http://bja.oxfordjournals.org/ at Cornell University Library on April 26, 2015
C
Weight (kg)
BRITISH JOURNAL OF ANAESTHESIA
292
TABLE I I I . Trachtal intubation data (mean (SEM) [range]). Intubation scores: 1 = excellent (easy passage of tube, no cough, cords relaxed); 2 = good (slight cough /buck, cords relaxed); 3 = poor (moderate cough/buck, cords moderately adducted); 4 = not possible (cords tightly adducted). Times are from completion of mivacurium injection. Rapid bolus dose = 5 s; slow bolus dose = 30 s
Mivacurium dose (mg kg'1)
Time of attempt (min)
Tl suppression at attempt (%)
1
2
3
4
Al
0.15 Rapid
2.5
4
3
0
2
Bl
0.15 Rapid
2.0
2
5
0
0
A2
0.20 Rapid
2.5
6
2
1
0
B2
0.20 Rapid
2.0
3
4
0
1
C
0.20 Slow
2.0
87.8 (3.7) [72-100] 72.4 (8.2) [36-100] 88.1 (7.3) [42-100] 91.9(2.8) [75-100] 94.3(1.4) [87-100]
5
4
0
0
Group or subgroup
TABLE IV. Infusion data (mean (SEM) [range]) combined for all patients except: *excludes data from two patients in whom duration of infusion was < IS min
Tl suppression at start of infusion (%) (n = 45) Mean duration of infusion (min) (n = 45) Mean infusion rate first 15 min (ug kg"1 min"1) (n = 43) Mean infusion rate after 15 min (ug kg"1 min-1) (n = 43)
81.8 (1.7) [45-92] 57.8 (3.4) [10-121] 8.4 (0.2)* [6.2-11.3] 6.6 (0.4)* [2.3-12.9]
the first 15 min, regular changes in infusion rates were generally necessary. After this time, infusion rates usually remained stable (fig. 1), although 1-ug kg"1 min"1 changes in infusion rate to correct drift outside the target T l / T c range occasionally resulted in temporary overcorrection. Mean infusion rate for all patients in the period after the 15-min stabilization was 6.6 ug kg"1 min"1 (range 2.3-12.9 ug kg"1 min"1). There was a negative trend between individual times from initial bolus administration of mivacurium to 5% T l / T c recovery and post-15 min infusion rates (fig. 2); whilst tests for equality of slopes of regression lines failed to demonstrate significant differences related to size of initial dose, pooled regression analyses were felt to be inappropriate. On termination of infusions, mean T l / T c , and T l / T c ranges at the time of administration of anticholinesterase were similar in group A and group C patients, and comparable to those at termination of infusion in group B patients in whom spontaneous recovery was allowed (table V). Occasional patients in all three groups were
Downloaded from http://bja.oxfordjournals.org/ at Cornell University Library on April 26, 2015
eluded from analyses of intubation scores. Data from the remaining patients are summarized in table III. Intubating conditions were generally good to excellent 2 or 2.5 min after mivacurium 0.15 mg kg"1; whilst in two patients the trachea could not be intubated at 2.5 min, all patients given this dose in whom tracheal intubation was attempted at 2 min displayed at least good conditions. The two patients presented early in the study, and inexperience may have been partly responsible for the failures. Mean T l suppression at 2 min after mivacurium 0.15 mg kg"1 was 72 %—less than that at 2.5 min in comparable patients given the same dose (88 %). Mean Tl suppression was greater in patients given mivacurium 0.2 mg kg"1 compared with those who received the lesser dose, but no significant benefit in terms of superior intubating scores was demonstrated. Slowing the rate of injection of a 0.2-mg kg"1 dose did not influence conditions at 2 min, although it should be stressed that timings were taken from completion of injection. Mean times from administration of the mivacurium bolus to 5% and 10% Tl recovery were 11—13 min and 13—15 min, respectively, with no significant relation to dose or to initial speed of administration (table II). One patient did not achieve sufficient T l suppression to be included in these recovery times, and in another three patients the mivacurium infusion was started after recovery to Tl of 5%, but before recovery to 10%. There was no discernible bolus dose or group related differences in infusion data, which were pooled, therefore, for all patients (table IV). Over
Intubation score
CLINICAL EFFECTS OF MIVACURIUM 43 ^
12 -
!?
32
20
1 *• -
• c
-I-
F
E
40
293
E
10 ^
2
8
CO
} 20% of baseline were observed in one of 18 patients (6%) who received a rapid 0.15-mg kg"1 bolus, compared with five of 18 (28%) and three of nine (33%) patients after a rapid or slow 0.2-mg kg"1 dose, respectively (P > 0.05). There was no difference relating to dose or to speed of administration in the incidence of flushing (five of 18 patients after mivacurium 0.15 mg kg"1; six of 18 after rapid O^mgkg" 1 ; three of nine after 0.2 mg kg"1 over 30 s). No other untoward perioperative events attributable to mivacurium were observed.
TABLE V. Recovery data (mean (SEM) [range]). Group A patients received neostigmine 40 fig kg 1; group B patients allowed to recover spontaneously; group C patients received edrophomum 750 fig kg'1. -\T1 at cessation of infusion. Significant differences: * P < 0 . 0 5 compared with neostigmine; ***P < 0.001 compared with spontaneous recovery
Tl recovery
Time to T4 :T1 ratio (min)
Group
n
type
(%)
0.5
0.7
A
18
Neostigmine
9.1 (1.2) [3-22]
B
18
Spontaneous
7.8 (1.0>t
C
9
Edrophonium
[1-16] 9.0(1.0) [5-14]
7.6 (0.5)*** [4.9-12.4] 13.8(1.0) [7.2-24.2] 5.8 (0.8)*** [2.1-9.1]
11.2(0.6)*** [7.2-17.8] 17.1 (1.2) [10.2-29.8] 8.2 (0.9)* [4.1-12.1]
Downloaded from http://bja.oxfordjournals.org/ at Cornell University Library on April 26, 2015
"i
8 -
o (0
o
•
10 -
CO
2
CD
12 •
BRITISH JOURNAL OF ANAESTHESIA
294
and colleagues [3]. However, as with atracurium and vecuronium [1, 3, 11], we observed a marked The doses of mivacurium used (0.15 and 0.2 mg (more than five-fold) variation in individual kg"1) were selected as appropriate to facilitate infusion rates. As recovery from mivacurium is tracheal intubation at 2-2.5 min, and on the basis largely a result of breakdown by plasma pseudoof published work approximate to 2.0 and cholinesterase [5], part of this variation may be a 2.5 x EDB6 estimates during opioid anaesthesia result of interpatient differences in activity of this [7]. Larger doses may (with priming) produce enzyme [1,7]. Our results may also show that favourable intubating conditions at 90 or even 60 s individual sensitivity to mivacurium in terms of [6], but may not be clinically useful because of longer recovery time after bolus doses may be untoward cardiovascular effects which are dose- expressed also as lower infusion requirements, as dependent at doses in excess of 0.15 mg kg"1 [3, shown previously [9], but we would hesitate to 8]. Enflurane is reported to potentiate the neuro- suggest that recovery time may broadly predict muscular effects of mivacurium [4] and its stable infusion rate outside our prevailing study administration was delayed until after tracheal conditions. intubation and the development of 90% Tl When competitive neuromuscular blocking suppression. drugs are used, attainment of a T4: Tl ratio of 0.7 Thiopentone was the induction agent used in is widely believed to equate with clinically previous studies, whereas our patients received adequate recovery [12, 13], although some propofol. Our results on onset of block are similar workers argue that even further recovery is to those reported previously during opioid an- necessary to ensure airway protection [14], esaesthesia, with no evidence to suggest that a single pecially when using EMG monitoring [15]. We do bolus dose of propofol alters the action of not yet know if these data are applicable to mivacurium. Whilst it is recognized that ease of mivacurium, and elected to use an EMG T4:T1 tracheal intubation depends on other factors in of 0.7 as the end-point of our neuromuscular addition to the degree of neuromuscular block, monitoring. Spontaneous recovery to a T4:T1 of intubating conditions at 2 min were adequate in 0.7 took 17 min, approximately 50% as long as most patients after mivacurium 0.15 mg kg"1, with that shown earlier for atracurium under comno significant benefit in waiting a further 30 s or in parable conditions [11]. Whilst edrophonium was increasing the dose to 0.2 mg kg"1. It may be shown to be superior to neostigmine in inappropriate to compare these findings with accelerating recovery, no work has yet been those of other workers, as tracheal intubation was performed on the relative potencies of these agents performed via the nasal route. Tl recovery to when antagonizing mivacurium-induced block, 10% of Tc was more than twice as rapid as that and the doses used may not have been strictly reported after vecuronium during enflurane an- comparable. No patient demonstrated evidence of aesthesia [10], and about twice that after an inadequate muscle power in the period after intubating dose of suxamethonium [2,3]. It attainment of an EMG T4:T1 of 0.7, but subtle should be stressed, however, that mivacurium was alterations in ventilatory mechanics were not not administered initially during stable enflurane evaluated. anaesthesia in this study. We were unable to In contrast with previous findings after thiodemonstrate any differences in early recovery pentone-opioid induction [8], we failed to demtimes between the two doses, which is not very onstrate any significant differences in AP and HR surprising in view of their similarity and the changes in the period immediately after rapid relatively small number of patients studied. injection between the two doses used. This may After an initial period of stabilization, infusions possibly have been the result of our use of propofol of mivacurium provided controllable neuro- at induction, or the use of atropine in premuscular block for up to 2 h. An initial rate of medication. We suggest, however, that a 30% 10 ug kg"1 min"1, advocated previously during incidence of decreases1 in MAP ^ 20 % after opioid anaesthesia [1], proved too great for our mivacurium 0.2 mg kg" , even with slow injection, patients during enflurane anaesthesia and a lesser may be clinically unacceptable. Cutaneous initial rate was thus adopted. Our mean infusion flushing was noted in approximately 30% of rate of 6.6 ug kg"1 min"1 is almost identical to that patients, and there was no relationship with dose during enflurane anaesthesia reported by Caldwell or speed of injection. In view of the similarity in DISCUSSION
Downloaded from http://bja.oxfordjournals.org/ at Cornell University Library on April 26, 2015
CLINICAL EFFECTS OF MIVACURIUM
295
1
efficacy between 0.15- and 0.2-mg kg" doses and the reported haemodynamic effects of greater doses, we conclude that there seems little clinical justification in the use of a dose of mivacurium exceeding 0.15 mg kg"1.
6.
7.
ACKNOWLEDGEMENT Mivacurium chloride was supplied by The Wellcome Research Laboratories, Beckenham, Kent.
8.
1. Ali HH, Savarese JJ, Embree PB, Basta SJ, Stout RG, Bottros LH, Weakly JN. CUnical pharmacology of mivacurium chloride (BW B1090U) infusion: comparison with vecuronium and atracurium. British Journal of Anaesthesia 1988; 61: 541-546. 2. Brandom BW, Woelfel SK, Cook DR, Weber S, Power DM, Weakly JN. Comparison of mivacurium and suxamcthonium administered by bolus and infusion. British Journal of Anaesthesia 1989; 62: 488-493. 3. 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 oxide-fentanyl anaesthesia. British Journal of Anaesthesia 1989; 63: 393-399. 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-cnflurane anesthesia. Anesthesiology 1989; 70: 31-35. 5. Cook DR, Stiller RL, Weakly JN, Chakravorn S,
10. 11. 12.
13. 14. 15.
Downloaded from http://bja.oxfordjournals.org/ at Cornell University Library on April 26, 2015
9. REFERENCES
Brandom BW, Welch RM. In vitro metabolism of mivacurium chloride (BW B1090U) and succinylcholine. Anesthesia and Analgesia 1989; 68: 452-456. Savarese JJ, Ali HH, Basta SJ, Embree PB, Risner MF. Sixty-second tracheal intubation with BW B1090U after fentanyl-thiopental induction. Anesthesiology 1987; 67: A351. Savarese JJ, Ali HH, Basta SJ, Embree PB, Scon RPS, Sunder N, Weakly JN, Wastila WB, El-Sayad HA. The clinical neuromuscular pharmacology of mivacurium chloride (BW B1090U). Anesthesiology 1988; 68: 723-732. Savarese JJ, Ali HH, Basta SJ, Scott RPF, Embree PB, Wastila WB, Abou-Donia MM, Gelb C. The cardiovascular effects of mivacurium chloride (BW B1090U) in patients receiving nitrous oxide-opiate-barbiturate anesthesia. Anesthesiology 1989; 70: 386-394. Shanks CA, Fragen RJ, Pemberton RN, Katz JA, Risner ME. Mivacurium-induced neuromuscular blockade following single bolus doses and with continuous infusion during either balanced or enflurane anesthesia. Anesthesiology 1989; 71: 362-366. Feldman SA, Liban JB. Vecuronium—A variable dose technique. Anaesthesia 1987; 42: 199-201. Eagar BM, Flynn PJ, Hughes R. Infusion of atracurium for long surgical procedures. British Journal of Anaesthesia 1984; 56: 447-152. Ali HH, Kitz RJ. Evaluation of recovery from nondepolarising neuromuscular block, using a digital neuromuscular transmission analyser: preliminary report. Anesthesia and Analgesia 1973; 52: 740-744. Viby-Mogensen J. Clinical assessment of neuromuscular transmission. British Journal of Anaesthesia 1982; 54: 209-223. Pavlin EG, Holle RH, Schoene RB. Recovery of airway protection compared with ventilation in humans after paralysis with curare. Anesthesiology 1989; 70: 381-385. Kopman AF. The relationship of evoked electromyographic and mechanical responses following atracurium in humans. Anesthesiology 1985; 63: 208-211.
NEUROMUSCULAR AND CLINICAL EFFECTS OF MIVACURIUM CHLORIDE IN HEALTHY ADULT PATIENTS DURING NITROUS OXIDE-ENFLURANE ANAESTHESIAf D. R. GOLDHILL, J. P. WHITEHEAD, R. S. EMMOTT, A. P. GRIFFITH, B. J. BRACEY AND P. J. FLYNN
further 30-s delay or by use of a 0.2-mg kg~1 dose. Recovery to 11/7c of 5% occurred on average in 12-13 min irrespective of dose. Thereafter, mivacurium infusions commenced at 8-10 fig kg-1 min'1 were adjusted at intervals of at least 3 min to achieve 11 lie in the range 1-10%. Mean duration of infusion was 58 (3.4) min and mean infusion rate after a 15-min stabilization period was 6.6 (range 2.3-12.9) fig kg-'min'1. On cessation of infusions, spontaneous recovery from 11 fie 8% (1.0%) to 14:11 = 0.7 took 17 (1.2) min. Neostigmine 0.04 mg kg-1 or edrophonium 0.75mg kg'1 evoked recovery from 11lie 9% (SEM 1.2% and 1.0%, respectively) to 14:11 = 0.7 in 11 (0.6) and 8 (0.9) min (both P < 0.001 vs spontaneous recovery). KEY WORDS Neuromuscular relaxants: mivacurium.
PATIENTS AND METHODS
The study was approved by the Committee on Safety of Medicines and the local Ethics Committee. Forty five patients requiring nasotracheal intubation for elective oral surgical procedures gave written informed consent. They were of physical status ASA I or II, and not taking antihistamines or medications known to affect neuromuscular function. Premedication 60D . R. GOLDHIIX, M.B., B.S., F.CANAES.J J. P. WHITBHEAD, M.B., CH.B., F.C.ANAES.; R. S. E M M O T T , M.B., CH.B., F.C.ANAES. J A. P. GRIFFITH, M.B., B.A.O., B.CH., F.F.A.R.C.S.I. ; B. J. BRACEY, M.B., B.S., M.R.C.P., F.C.ANAES.; P. J. FLYNN, M.B., D.CH.,
D.OBST., F.F.A.R.C.S.I.; Anaesthetics Unit, The Royal London Hospital, Whitechapel, London El IBB. Accepted for Publication: February 22, 1991. t Presented in part at the Anaesthetic Research Society, London Meeting, November 1989.
Downloaded from http://bja.oxfordjournals.org/ at Cornell University Library on April 26, 2015
Mivacurium chloride (BW B1090U) is a new nondepolarizing neuromuscular blocking agent. PreWe have studied the effects of mivacurium after vious clinical trials in the United States [1-9] have induction of anaesthesia with alfentanH-propofol shown that it has a shorter duration of action than in healthy adult oral surgical patients. Anaes- currently approved non-depolarizing agents and thesia was maintained with nitrous oxide and may be suitable for providing neuromuscular 0.75% (end-tidal) enflurane in oxygen after block for procedures of brief duration when nasotracheal intubation. Recordings were made suxamethonium is not desired, and for mainof the rectified compound adductor pollicis tenance of neuromuscular block by infusion. We have assessed onset times and conditions at electromyogram in response to train-of-four (TOF) ulnar nerve stimulation. First and fourth tracheal intubation after fast bolus administration TOF responses were defined as 11 and 14. with of mivacurium. A slow bolus injection group was 71 suppression referenced to pre-mivacurium 11 included also, as mivacurium may be associated height (1c). Onset times (mean (SEM)) to 90% with cutaneous flushing and arterial hypotension 11 suppression were 2.5 (0.2), 2.1 (0.3) and 1.6 caused by systemic release of histamine [8]. (0.1) min, respectively, after mivacurium 0.15 mg Infusion requirements were ascertained under kg-1 (n=18) and 0.2mgkg-' (n=18) as anaesthesia with nitrous oxide and enflurane, and 5-s boluses and 0.2mgkg~1 over 30 s (n = 9). the time for spontaneous recovery of neuroIntubating conditions 2 min after 0.15 mg kg-1 muscular function was compared with that were good to excellent and not improved by a achieved after neostigmine or edrophonium. SUMMARY
290
end-tidal concentration of 0.75% (Datex Normac) and ventilation was controlled to maintain an end-tidal partial pressure of carbon dioxide 4.45.4 kPa (Datex Normocap). Nasopharyngeal and palmar temperatures were maintained greater than 35 °C and 33 °C, respectively. All patients received an infusion of mivacurium 0.5 mg ml"1 in 5 % glucose to extend neuromuscular block for the duration of surgery. Infusions were commenced after EMG recovery from the initial bolus of mivacurium was evident (Tl/Tc > 5%). An initial infusion rate of 10 ug kg"1 min"1 was used in the first nine patients studied, but in subsequent patients this was modified to 8 ug kg"1 min"1. The rate was then adjusted by increments of 1 ug kg"1 min"1 at intervals of at least 3 min to achieve and maintain T l / T c in the range 1-10% (90-99% Tl suppression). Infusions were administered using a Ohmeda 9000 syringe pump and a dedicated i.v. cannula. Towards the end of surgery the infusion was discontinued and group B patients allowed to recover spontaneously from the effects of mivacurium. Residual neuromuscular block was antagonized with neostigmine 40 ug kg"1 and atropine 20 ug kg"1 in group A patients, and with edrophonium 750 jig kg"1 preceded by atropine 10 ug kg"1 in group C patients. EMG monitoring was continued until the T4:T1 ratio (the ratio of the height of the 4th response (T4) of the TOF to Tl) reached at least 0.7. Anaesthesia was discontinued and, after spontaneous ventilation was established, the trachea was extubated. ' For each patient, the times from bolus injection to 90% and to maximal Tl suppression, Tl suppression at intubation, intubation scores and times for initial recovery of T l / T c to 5% and 10 % were noted. (All times were from completion of injection of mivacurium.) Changes in infusion rate, mean infusion rate and infusion duration were recorded. After infusions, T l / T c at antagonism (groups A and C) or at cessation of infusion (group B) was noted, and the time for recovery to T4:T1 ratios of 0.5 and 0.7 recorded. Patient data were analysed with one-way analysis of variance (ANOVA). Neuromuscular data were analysed using one-way ANOVA, Student-NewmanKeuls test, and Bonferroni t tests as appropriate. Chi square was used to analyse intubation scores. P < 0.05 was considered statistically significant. Non-invasive cardiovascular monitoring was performed according to normal anaesthetic prac-
Downloaded from http://bja.oxfordjournals.org/ at Cornell University Library on April 26, 2015
90 min before induction of anaesthesia consisted of oral atropine 1 mg and temazepam 20-30 mg. Electrocardiographic and non-invasive arterial pressure monitoring (Datascope Accutorr) commenced in the anaesthetic room. Adhesive, prejelled silver-silver chloride surface electrodes were positioned on the wrist and hand, and connected to a Datex Relaxograph in order to detect the evoked gated integrated rectified compound electromyographic (EMG) response of the adductor pollicis muscle to supramaximal trainof-four (TOF) ulnar nerve stimulation (0.1-ms square-wave stimuli at 2 Hz for 2 s; train frequency 0.05 Hz). The hand from which EMG recordings were obtained was immobilized with the thumb abducted, and the arm was wrapped in cotton wool to minimize heat loss. Palmar and core temperatures were monitored with skin and nasopharyngeal probes. After i.v. induction of anaesthesia with alfentanil 0.5-1.0mg and propofol 2.0-2.5mg kg"1, a stable baseline EMG recording was obtained. Rectified EMG output from the Relaxograph was recorded continuously on a Gould 220 chart recorder for later analysis. The height of the first response (Tl) of the TOF at baseline was defined as the control response (Tc). Before tracheal intubation, anaesthesia was maintained with 66 % nitrous oxide in oxygen, and increments of alfentanil and propofol as clinically indicated. Mivacurium 2 mg ml"1 was administered at least 2 min after the last increment of alfentanil or propofol. Patients were studied in three groups. The first 18 patients (group A) were allocated randomly to receive an initial dose of mivacurium 0.15 mg kg"1 (subgroup Al) or O^mgkg" 1 (subgroup A2) as a rapid, 5-s bolus via a peripheral vein, and trachea! intubation was attempted 2.5 min later. The next 18 patients (group B) were similarly allocated randomly to receive mivacurium 0.15 mg kg"1 (subgroup Bl) or O^mgkg" 1 (subgroup B2) by rapid, 5-s bolus, but with tracheal intubation 2 min after the injection of mivacurium. The final nine patients (group C) received mivacurium 0.2 mg kg"1 over 30 s, with tracheal intubation attempted 2 min later. Intubating conditions were graded on an interval scale from 1 = excellent to 4 = not possible, according to the observed state of relaxation of the vocal cords and the severity of coughing or passing the tracheal tube. After successful tracheal intubation, enflurane was added to the inspired gases to achieve an
BRITISH JOURNAL OF ANAESTHESIA
CLINICAL EFFECTS OF MIVACURIUM
291
TABLE I. Details of patients and total doses of propofol and alfentantil given before the initial attempt at trachea! intubation (mean (SD)) Group or subgroup Al A2 Bl B2
Age (yr)
Height (cm)
Sex (M:F)
Propofol (mg kg"1)
66.3 (14.2) 68.7 (14.3) 71.8 (9.4) 73.6 (11.1) 64.0 (7.3)
28.3 (9.3) 26.7 (6.6) 27.8 (6.0) 26.2 (4.0) 28.2 (10.0)
165.8 (9.2) 167.7 (9.7) 174.2 (8.4) 171.7 (9.2) 168.4 (5.8)
3:6
2.91 (0.52) 3.90 (1.49) 2.72 (0.67) 3.20 (0.27) 3.61 (1.11)
3:6 6:3 5:4 3:6
Alfentanil ("g kg"1) 14.8 (3.3) 15.7 (4.8) 17.1 (3.3) 13.9 (1.9) 15.3 (1.8)
TABLE II. Onset of block (mean (SEM) [range]). Times are taken from the end of mivacurium injection. t n = 17; X n = 15. Rapid bolus dose = 5 J; slow bolus dose = 30 s. *P < 0.05 Time to % T l suppression (min) Dose (mg kg"1) 0.15 Rapid (n = 18) 0.20 Rapid
(„ = 18) 0.20 Slow (" = 9)
Time to % T l recovery (min)
90%
Maximal
5%
10%
2.5 (0.2) [1.6-3.7] 2.1 (0.3) [0.8-4.4] 1.6(0.1)* [1.2-2.7]
3.7 (0.3)* [1.7-6.0] 2.6 (0.3) [1.1-5.1] 2.4 (0.2) [1.8-3.1]
11.5(0.9) [5.9-18.7] |12.7 (0.9) [8.5-19.9] 13.3 (0.8) [8.5-16.9]
+ 12.8 (0.8) [7.9-20.4] $ 14.2 (0.9) [9.5-22.1] 15.0(0.9) [10.5-19.6]
received initial 5-s boluses of mivacurium 0.15 mg kg"1 (subgroups Al and Bl) or O^mgkg" 1 (subgroups A2 and B2). There were no significant differences in onset and early recovery data between subgroups that received identical initial mivacurium doses over 5 s; such data were analysed in combination and are summarized in table II. Mean onset times (from end of injection) to 90 % and to maximal T l suppression after mivacurium 0.15 mg kg"1 were slower than those after 0.2 mg kg"1, although the difference in times to 90% suppression between the two doses when administered over 5 s was not statistically significant. Tl suppression of 100% was produced in all but two patients; one reached 97 % suppression after a dose of 0.15 mg kg"1, and another achieved maximal Tl suppression of only RESULTS 90 % after mivacurium 0.2 mg kg"1 administered Patient groups were comparable with respect to over 5 s. weight, age, height and total doses of propofol and Data from three patients in whom oral tracheal alfentanil received before the initial attempt at intubation was performed (n = 1) or unexpectedly tracheal intubation (table I). There were no difficult insertion of the tracheal tube through the significant differences between patients who nasal passage was encountered (n = 2) were extice. Clinical signs of histamine release, such as cutaneous flushing were documented. In addition, arterial pressure (AP) and heart rate (HR) were recorded immediately before and every 1 min for 10 min after the initial dose of mivacurium. Baseline AP and HR were denned as values immediately preceding administration of mivacurium. In order to avoid the compounding haemodynamic effects of tracheal intubation, analyses were made only of the maximum change in HR and mean arterial pressure (MAP) from baseline observed in the period after mivacurium but before tracheal intubation. Paired t tests and Fisher's Exact tests were used to analyse these changes and significance taken at P < 0.05.
Downloaded from http://bja.oxfordjournals.org/ at Cornell University Library on April 26, 2015
C
Weight (kg)
BRITISH JOURNAL OF ANAESTHESIA
292
TABLE I I I . Trachtal intubation data (mean (SEM) [range]). Intubation scores: 1 = excellent (easy passage of tube, no cough, cords relaxed); 2 = good (slight cough /buck, cords relaxed); 3 = poor (moderate cough/buck, cords moderately adducted); 4 = not possible (cords tightly adducted). Times are from completion of mivacurium injection. Rapid bolus dose = 5 s; slow bolus dose = 30 s
Mivacurium dose (mg kg'1)
Time of attempt (min)
Tl suppression at attempt (%)
1
2
3
4
Al
0.15 Rapid
2.5
4
3
0
2
Bl
0.15 Rapid
2.0
2
5
0
0
A2
0.20 Rapid
2.5
6
2
1
0
B2
0.20 Rapid
2.0
3
4
0
1
C
0.20 Slow
2.0
87.8 (3.7) [72-100] 72.4 (8.2) [36-100] 88.1 (7.3) [42-100] 91.9(2.8) [75-100] 94.3(1.4) [87-100]
5
4
0
0
Group or subgroup
TABLE IV. Infusion data (mean (SEM) [range]) combined for all patients except: *excludes data from two patients in whom duration of infusion was < IS min
Tl suppression at start of infusion (%) (n = 45) Mean duration of infusion (min) (n = 45) Mean infusion rate first 15 min (ug kg"1 min"1) (n = 43) Mean infusion rate after 15 min (ug kg"1 min-1) (n = 43)
81.8 (1.7) [45-92] 57.8 (3.4) [10-121] 8.4 (0.2)* [6.2-11.3] 6.6 (0.4)* [2.3-12.9]
the first 15 min, regular changes in infusion rates were generally necessary. After this time, infusion rates usually remained stable (fig. 1), although 1-ug kg"1 min"1 changes in infusion rate to correct drift outside the target T l / T c range occasionally resulted in temporary overcorrection. Mean infusion rate for all patients in the period after the 15-min stabilization was 6.6 ug kg"1 min"1 (range 2.3-12.9 ug kg"1 min"1). There was a negative trend between individual times from initial bolus administration of mivacurium to 5% T l / T c recovery and post-15 min infusion rates (fig. 2); whilst tests for equality of slopes of regression lines failed to demonstrate significant differences related to size of initial dose, pooled regression analyses were felt to be inappropriate. On termination of infusions, mean T l / T c , and T l / T c ranges at the time of administration of anticholinesterase were similar in group A and group C patients, and comparable to those at termination of infusion in group B patients in whom spontaneous recovery was allowed (table V). Occasional patients in all three groups were
Downloaded from http://bja.oxfordjournals.org/ at Cornell University Library on April 26, 2015
eluded from analyses of intubation scores. Data from the remaining patients are summarized in table III. Intubating conditions were generally good to excellent 2 or 2.5 min after mivacurium 0.15 mg kg"1; whilst in two patients the trachea could not be intubated at 2.5 min, all patients given this dose in whom tracheal intubation was attempted at 2 min displayed at least good conditions. The two patients presented early in the study, and inexperience may have been partly responsible for the failures. Mean T l suppression at 2 min after mivacurium 0.15 mg kg"1 was 72 %—less than that at 2.5 min in comparable patients given the same dose (88 %). Mean Tl suppression was greater in patients given mivacurium 0.2 mg kg"1 compared with those who received the lesser dose, but no significant benefit in terms of superior intubating scores was demonstrated. Slowing the rate of injection of a 0.2-mg kg"1 dose did not influence conditions at 2 min, although it should be stressed that timings were taken from completion of injection. Mean times from administration of the mivacurium bolus to 5% and 10% Tl recovery were 11—13 min and 13—15 min, respectively, with no significant relation to dose or to initial speed of administration (table II). One patient did not achieve sufficient T l suppression to be included in these recovery times, and in another three patients the mivacurium infusion was started after recovery to Tl of 5%, but before recovery to 10%. There was no discernible bolus dose or group related differences in infusion data, which were pooled, therefore, for all patients (table IV). Over
Intubation score
CLINICAL EFFECTS OF MIVACURIUM 43 ^
12 -
!?
32
20
1 *• -
• c
-I-
F
E
40
293
E
10 ^
2
8
CO
} 20% of baseline were observed in one of 18 patients (6%) who received a rapid 0.15-mg kg"1 bolus, compared with five of 18 (28%) and three of nine (33%) patients after a rapid or slow 0.2-mg kg"1 dose, respectively (P > 0.05). There was no difference relating to dose or to speed of administration in the incidence of flushing (five of 18 patients after mivacurium 0.15 mg kg"1; six of 18 after rapid O^mgkg" 1 ; three of nine after 0.2 mg kg"1 over 30 s). No other untoward perioperative events attributable to mivacurium were observed.
TABLE V. Recovery data (mean (SEM) [range]). Group A patients received neostigmine 40 fig kg 1; group B patients allowed to recover spontaneously; group C patients received edrophomum 750 fig kg'1. -\T1 at cessation of infusion. Significant differences: * P < 0 . 0 5 compared with neostigmine; ***P < 0.001 compared with spontaneous recovery
Tl recovery
Time to T4 :T1 ratio (min)
Group
n
type
(%)
0.5
0.7
A
18
Neostigmine
9.1 (1.2) [3-22]
B
18
Spontaneous
7.8 (1.0>t
C
9
Edrophonium
[1-16] 9.0(1.0) [5-14]
7.6 (0.5)*** [4.9-12.4] 13.8(1.0) [7.2-24.2] 5.8 (0.8)*** [2.1-9.1]
11.2(0.6)*** [7.2-17.8] 17.1 (1.2) [10.2-29.8] 8.2 (0.9)* [4.1-12.1]
Downloaded from http://bja.oxfordjournals.org/ at Cornell University Library on April 26, 2015
"i
8 -
o (0
o
•
10 -
CO
2
CD
12 •
BRITISH JOURNAL OF ANAESTHESIA
294
and colleagues [3]. However, as with atracurium and vecuronium [1, 3, 11], we observed a marked The doses of mivacurium used (0.15 and 0.2 mg (more than five-fold) variation in individual kg"1) were selected as appropriate to facilitate infusion rates. As recovery from mivacurium is tracheal intubation at 2-2.5 min, and on the basis largely a result of breakdown by plasma pseudoof published work approximate to 2.0 and cholinesterase [5], part of this variation may be a 2.5 x EDB6 estimates during opioid anaesthesia result of interpatient differences in activity of this [7]. Larger doses may (with priming) produce enzyme [1,7]. Our results may also show that favourable intubating conditions at 90 or even 60 s individual sensitivity to mivacurium in terms of [6], but may not be clinically useful because of longer recovery time after bolus doses may be untoward cardiovascular effects which are dose- expressed also as lower infusion requirements, as dependent at doses in excess of 0.15 mg kg"1 [3, shown previously [9], but we would hesitate to 8]. Enflurane is reported to potentiate the neuro- suggest that recovery time may broadly predict muscular effects of mivacurium [4] and its stable infusion rate outside our prevailing study administration was delayed until after tracheal conditions. intubation and the development of 90% Tl When competitive neuromuscular blocking suppression. drugs are used, attainment of a T4: Tl ratio of 0.7 Thiopentone was the induction agent used in is widely believed to equate with clinically previous studies, whereas our patients received adequate recovery [12, 13], although some propofol. Our results on onset of block are similar workers argue that even further recovery is to those reported previously during opioid an- necessary to ensure airway protection [14], esaesthesia, with no evidence to suggest that a single pecially when using EMG monitoring [15]. We do bolus dose of propofol alters the action of not yet know if these data are applicable to mivacurium. Whilst it is recognized that ease of mivacurium, and elected to use an EMG T4:T1 tracheal intubation depends on other factors in of 0.7 as the end-point of our neuromuscular addition to the degree of neuromuscular block, monitoring. Spontaneous recovery to a T4:T1 of intubating conditions at 2 min were adequate in 0.7 took 17 min, approximately 50% as long as most patients after mivacurium 0.15 mg kg"1, with that shown earlier for atracurium under comno significant benefit in waiting a further 30 s or in parable conditions [11]. Whilst edrophonium was increasing the dose to 0.2 mg kg"1. It may be shown to be superior to neostigmine in inappropriate to compare these findings with accelerating recovery, no work has yet been those of other workers, as tracheal intubation was performed on the relative potencies of these agents performed via the nasal route. Tl recovery to when antagonizing mivacurium-induced block, 10% of Tc was more than twice as rapid as that and the doses used may not have been strictly reported after vecuronium during enflurane an- comparable. No patient demonstrated evidence of aesthesia [10], and about twice that after an inadequate muscle power in the period after intubating dose of suxamethonium [2,3]. It attainment of an EMG T4:T1 of 0.7, but subtle should be stressed, however, that mivacurium was alterations in ventilatory mechanics were not not administered initially during stable enflurane evaluated. anaesthesia in this study. We were unable to In contrast with previous findings after thiodemonstrate any differences in early recovery pentone-opioid induction [8], we failed to demtimes between the two doses, which is not very onstrate any significant differences in AP and HR surprising in view of their similarity and the changes in the period immediately after rapid relatively small number of patients studied. injection between the two doses used. This may After an initial period of stabilization, infusions possibly have been the result of our use of propofol of mivacurium provided controllable neuro- at induction, or the use of atropine in premuscular block for up to 2 h. An initial rate of medication. We suggest, however, that a 30% 10 ug kg"1 min"1, advocated previously during incidence of decreases1 in MAP ^ 20 % after opioid anaesthesia [1], proved too great for our mivacurium 0.2 mg kg" , even with slow injection, patients during enflurane anaesthesia and a lesser may be clinically unacceptable. Cutaneous initial rate was thus adopted. Our mean infusion flushing was noted in approximately 30% of rate of 6.6 ug kg"1 min"1 is almost identical to that patients, and there was no relationship with dose during enflurane anaesthesia reported by Caldwell or speed of injection. In view of the similarity in DISCUSSION
Downloaded from http://bja.oxfordjournals.org/ at Cornell University Library on April 26, 2015
CLINICAL EFFECTS OF MIVACURIUM
295
1
efficacy between 0.15- and 0.2-mg kg" doses and the reported haemodynamic effects of greater doses, we conclude that there seems little clinical justification in the use of a dose of mivacurium exceeding 0.15 mg kg"1.
6.
7.
ACKNOWLEDGEMENT Mivacurium chloride was supplied by The Wellcome Research Laboratories, Beckenham, Kent.
8.
1. Ali HH, Savarese JJ, Embree PB, Basta SJ, Stout RG, Bottros LH, Weakly JN. CUnical pharmacology of mivacurium chloride (BW B1090U) infusion: comparison with vecuronium and atracurium. British Journal of Anaesthesia 1988; 61: 541-546. 2. Brandom BW, Woelfel SK, Cook DR, Weber S, Power DM, Weakly JN. Comparison of mivacurium and suxamcthonium administered by bolus and infusion. British Journal of Anaesthesia 1989; 62: 488-493. 3. 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 oxide-fentanyl anaesthesia. British Journal of Anaesthesia 1989; 63: 393-399. 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-cnflurane anesthesia. Anesthesiology 1989; 70: 31-35. 5. Cook DR, Stiller RL, Weakly JN, Chakravorn S,
10. 11. 12.
13. 14. 15.
Downloaded from http://bja.oxfordjournals.org/ at Cornell University Library on April 26, 2015
9. REFERENCES
Brandom BW, Welch RM. In vitro metabolism of mivacurium chloride (BW B1090U) and succinylcholine. Anesthesia and Analgesia 1989; 68: 452-456. Savarese JJ, Ali HH, Basta SJ, Embree PB, Risner MF. Sixty-second tracheal intubation with BW B1090U after fentanyl-thiopental induction. Anesthesiology 1987; 67: A351. Savarese JJ, Ali HH, Basta SJ, Embree PB, Scon RPS, Sunder N, Weakly JN, Wastila WB, El-Sayad HA. The clinical neuromuscular pharmacology of mivacurium chloride (BW B1090U). Anesthesiology 1988; 68: 723-732. Savarese JJ, Ali HH, Basta SJ, Scott RPF, Embree PB, Wastila WB, Abou-Donia MM, Gelb C. The cardiovascular effects of mivacurium chloride (BW B1090U) in patients receiving nitrous oxide-opiate-barbiturate anesthesia. Anesthesiology 1989; 70: 386-394. Shanks CA, Fragen RJ, Pemberton RN, Katz JA, Risner ME. Mivacurium-induced neuromuscular blockade following single bolus doses and with continuous infusion during either balanced or enflurane anesthesia. Anesthesiology 1989; 71: 362-366. Feldman SA, Liban JB. Vecuronium—A variable dose technique. Anaesthesia 1987; 42: 199-201. Eagar BM, Flynn PJ, Hughes R. Infusion of atracurium for long surgical procedures. British Journal of Anaesthesia 1984; 56: 447-152. Ali HH, Kitz RJ. Evaluation of recovery from nondepolarising neuromuscular block, using a digital neuromuscular transmission analyser: preliminary report. Anesthesia and Analgesia 1973; 52: 740-744. Viby-Mogensen J. Clinical assessment of neuromuscular transmission. British Journal of Anaesthesia 1982; 54: 209-223. Pavlin EG, Holle RH, Schoene RB. Recovery of airway protection compared with ventilation in humans after paralysis with curare. Anesthesiology 1989; 70: 381-385. Kopman AF. The relationship of evoked electromyographic and mechanical responses following atracurium in humans. Anesthesiology 1985; 63: 208-211.
