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Clinical Science  |   March 1996
Mivacurium When Precedent by Pancuronium Becomes a Long-acting Muscle Relaxant
Author Notes
  • (Erkola) Staff Anesthesiologist, Department of Anaesthesia, Maria Hospital of Helsinki City Hospital, Helsinki, Finland.
  • (Rautoma) Resident in Anesthesiology, Department of Anaesthesia, Maria Hospital of Helsinki City Hospital, Helsinki, Finland.
  • (Meretoja) Chief of Anaesthesia, Children's Hospital University of Helsinki, Helsinki, Finland.
  • Received from Maria Hospital of Helsinki City Hospital, Helsinki, Finland. Submitted for publication March 7, 1995. Accepted for publication November 21, 1995. Support and mivacurium supplied by the Wellcome Foundation Ltd. Presented in part at the annual meeting of the American Society of Anesthesiologists, San Francisco, California, October 15–19, 1994.
  • Address reprint requests to Dr. Erkola: Department of Anaesthesia, Maria Hospital, Lapinlahdenkatu 16, FIN-00180 Helsinki, Finland.
Article Information
Clinical Science
Clinical Science   |   March 1996
Mivacurium When Precedent by Pancuronium Becomes a Long-acting Muscle Relaxant
Anesthesiology 3 1996, Vol.84, 562-565. doi:
Anesthesiology 3 1996, Vol.84, 562-565. doi:
IN clinical practice, there may be a need for a deep neuromuscular block, e.g., for the fascial closure of an abdominal wall near the end of a surgical procedure. If a long-acting muscle relaxant has been used, it may be clinically appropriate to administer a short-acting muscle relaxant during this phase to facilitate recovery from neuromuscular block. Our objective was to study characteristics of nondepolarizing block when mivacurium is administered during the recovery from pancuronium-induced neuromuscular block.
Methods and Materials
The study protocol was approved by the local ethics committee for human investigations. After written informed consent, 41 ASA physical status 1–2 patients, aged 20–65 yr, received 10 or 70 micro gram/kg of mivacurium at 25% neuromuscular recovery after pancuronium or mivacurium.
Fifteen milligrams midazolam was given orally to all patients 30–45 min before induction of anesthesia. Anesthesia was induced with 20 micro gram/kg alfentanil, followed by 2.5 mg/kg intravenous propofol. Nitrous oxide in oxygen (2:1) was used as a fresh gas from the time of mask application to the end of the study. Anesthesia was maintained by continuous infusion of 6–10 mg *symbol* kg sup -1 *symbol* h sup -1 propofol. Incremental doses of alfentanil up to 50 micro gram *symbol* kg sup -1 *symbol* h sup -1 were given according to clinical needs.
During anesthesia, electrocardiogram and hemoglobin oxygen saturation were monitored continuously, and noninvasive blood pressure was recorded every 3 to 5 min. Ventilation was controlled to maintain end-tidal carbon dioxide at 5.0–5.5%. Palmar skin temperature of the hand, where neuromuscular function was monitored, was maintained at > 33 degrees Celsius.
Neuromuscular function was monitored by electromyographic (EMG) response of the adductor pollicis muscle to evoked supramaximal ulnar nerve stimulation (Relaxograph, Datex, Helsinki, Finland). The ulnar nerve was stimulated and the EMG response recorded using surface electrodes attached on the wrist and on adductor pollicis muscle in the hand and on the volar surface of the base of the forefinger. A train-of-four nerve stimulation was delivered at 20-s intervals. The forearm and the thumb were attached to a dorsal splint without pretension to maintain immobility. The neuromuscular function monitor was calibrated after the induction of anesthesia and before the administration of any muscle relaxant.
After a stable EMG signal, which took 5–15 min, a cumulative three-dose log-probit dose-response curve for pancuronium was established. The first and second doses of pancuronium were 25 and 15 micro gram/kg, respectively. The final individual dose was estimated to produce a 95% neuromuscular block. [1] In the control group, an ED95dose 100 micro gram/kg of mivacurium, was administered. [2] If a 90% neuromuscular block was not achieved, an additional 50 micro gram/kg mivacurium dose was given. Tracheal intubation was performed when the neuromuscular block was > 90%. When the first EMG response (T1) in the train-of-four series of responses recovered to 25% after pancuronium or mivacurium, each patient received a dose of 10 or 70 micro gram/kg mivacurium. Thereafter, a full spontaneous recovery of the neuromuscular function was recorded in every patient. Criteria for full recovery were a steady-state recovery of T1response and a TOF ratio greater or equal to 0.70. Thereafter, anesthesia was continued as indicated by individual patient care.
After the three doses of pancuronium and after 100 micro gram/kg mivacurium, the maximal neuromuscular block was determined, and the time from the administration of pancuronium to 25% neuromuscular recovery was recorded. After 10 or 70 micro gram/kg mivacurium, the time from administration to maximal block was measured, and time to 10%, 25%, 50%, 75%, 90%, and 95% recovery of T1response and the recovery index, i.e., T1recovery from 25% to 75%, were recorded. TOF ratios were calculated when T1had recovered to 25%, 50%, 75%, 90%, and 95%. Finally, the time from the administration of 10 or 70 micro gram/kg mivacurium to recovery of a TOF ratio to 0.70 was analyzed.
For statistical analysis, analysis of variance (ANOVA) was used. A P value less than 0.05 was considered statistically significant. If ANOVA gave a significant P value, further group comparisons were made using Scheffe's F test. Data are presented as mean+/-SD.
Results
Patient characteristics are shown in Table 1. They did not differ between the groups. The mean (+/-SD) palmar skin temperature was 34.0+/-0.5 degrees C and did not differ between the groups. The mean end-tidal carbon dioxide varied from 4.9 to 5.2% in different groups.
Table 1. Demographic Data
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Table 1. Demographic Data
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Mivacurium (100 micro gram/kg) produced an average of 87 +/-18% neuromuscular block. Mivacurium (10 micro gram/kg) given at 25% T1recovery after mivacurium did not produce an increase in twitch depression in seven of ten patients (Figure 1). After 70 micro gram/kg mivacurium, T1recovered to 25% in 10+/-4 min (Figure 1and Table 2). Recovery index following 70 micro gram/kg mivacurium averaged 5+/-2 min. Maximum neuromuscular blocks and onset times to maximum block are presented in Table 3.
Figure 1. Spontaneous electromyography recovery of neuromuscular block after 10 (triangles) or 70 (circles) micro gram/kg mivacurium given at T sub 1 25% during recovery from pancuronium (closed symbols) or mivacurium (open symbols) block. Groups differed (P < 0.05) from each others at every EMG recovery level besides mivacurium groups at 90% and 95% T1recovery levels.
Figure 1. Spontaneous electromyography recovery of neuromuscular block after 10 (triangles) or 70 (circles) micro gram/kg mivacurium given at T sub 1 25% during recovery from pancuronium (closed symbols) or mivacurium (open symbols) block. Groups differed (P < 0.05) from each others at every EMG recovery level besides mivacurium groups at 90% and 95% T1recovery levels.
Figure 1. Spontaneous electromyography recovery of neuromuscular block after 10 (triangles) or 70 (circles) micro gram/kg mivacurium given at T sub 1 25% during recovery from pancuronium (closed symbols) or mivacurium (open symbols) block. Groups differed (P < 0.05) from each others at every EMG recovery level besides mivacurium groups at 90% and 95% T1recovery levels.
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Table 2. Spontaneous Recovery Times after 10 or 70 micro gram/kg Mivacurium Given at T125% during Recovery from Pancuronium or Mivacurium Block
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Table 2. Spontaneous Recovery Times after 10 or 70 micro gram/kg Mivacurium Given at T125% during Recovery from Pancuronium or Mivacurium Block
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Table 3. Maximum Neuromuscular Block and Onset Time to Maximum Block after Mivacurium 10 or 70 micro gram/kg Given at T125% during Recovery from Pancuronium or Mivacurium Block
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Table 3. Maximum Neuromuscular Block and Onset Time to Maximum Block after Mivacurium 10 or 70 micro gram/kg Given at T125% during Recovery from Pancuronium or Mivacurium Block
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On average, 69+/-15 micro gram/kg pancuronium produced a 96+/-2% neuromuscular block. The time from administration of pancuronium until T125% recovery was 38+/-12 min. In the pancuronium group, after 70 micro gram/kg mivacurium, a 100% neuromuscular block lasted for 35+/-7 min. The times from the administration of 10 or 70 micro gram/kg mivacurium until T125% recovery were 28 +/-8 min and 54+/-7 min, respectively (P < 0.001), and the recovery indexes following 10 or 70 micro gram/kg mivacurium were 26 +/-4 and 22+/-6 min, respectively.
In the pancuronium group, times from the administration of 10 or 70 micro gram/kg mivacurium until TOF ratio 0.7 were 94+/-16 min and 111+/-14 min, respectively, and in the mivacurium group these times were 12+/-4 min and 22+/-8 min, respectively (P < 0.0001). Other recovery times and TOF ratios at different levels of T1recovery are presented in Table 2and Table 4. The time-courses of mivacurium-induced neuromuscular block in different groups are presented in Figure 1.
Table 4. Train-of-four Ratio (T4/T1) Percentages at Different Levels of T1Recovery
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Table 4. Train-of-four Ratio (T4/T1) Percentages at Different Levels of T1Recovery
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Discussion
The main finding of this study was that even a very small dose of 10 micro gram/kg mivacurium, given at T125% during neuromuscular recovery from a pancuronium block caused a prolonged neuromuscular block. This dose of mivacurium, which is 1/10–1/7 of ED95dose and less than ED10dose [2] caused a clinical duration (time from the administration to T125% recovery) of 28 min when given during pancuronium block. In contrast, during mivacurium block, the effect of the additional 10 micro gram/kg mivacurium dose was transient: in only three of ten patients, a small increase in twitch depression was observed. The clinical duration of 70 micro gram/kg mivacurium given after mivacurium lasted about 10 min while after pancuronium this mivacurium dose increased the clinical duration twofold from 28 to 54 min (Figure 1and Table 2).
Only a few studies have examined the interaction between mivacurium and long-acting nondepolarizing muscle relaxants. In a study in which 40 micro gram/kg of mivacurium was given at T125% during recovery from doxacurium block, the clinical duration was prolonged by 2.5-fold, to 27 min when compared with that following a pure mivacurium block. [3] In the current study, 10 micro gram/kg mivacurium during pancuronium block caused the same clinical duration. Thus, pancuronium seems to potentiate the mivacurium block more than does doxacurium.
It has been suggested that the first relaxant administered (usually longer acting) dominates the neuromuscular block so that the duration of relaxants given subsequently changes to resemble that of the first. [4] The long elimination half-life (T1/2 beta) of the underlying relaxant prolongs the effects of the subsequent shorter-acting drug. In addition, structural similarity or dissimilarity between the interacting relaxants may have effects. [5] The structurally different relaxants may potentiate each other more than structurally similar relaxants. [4] A theory presumes that structurally similar relaxants may bind at the same time to both alpha-subunits of a postsynaptic acetylcholine receptor and structurally different relaxants do so less intensely. [6] Thus, more receptors are occupied when structurally different relaxants are given simultaneously. This could explain, e.g., different effects of pancuronium and doxacurium on mivacurium block.
Pancuronium inhibits plasma pseudocholinesterase activity more than other nondepolarizing relaxants. [7–9] This is clinically evident when a subparalyzing dose of pancuronium, usually 0.01 mg/kg, is used to prevent succinylcholine-induced side effects. Other nondepolarizing relaxants antagonize the following succinylcholine block, but pancuronium pretreatment prolongs the duration of succinylcholine block. [10] In the current study, the concentration of pancuronium during mivacurium block could decrease the rate of mivacurium metabolism and hence prolong the clinical duration of mivacurium. However, the current study did not investigate the underlying mechanism. Whether the mechanism of action for the prolongation of mivacurium block after pancuronium is pharmacodynamic or pharmacokinetic requires additional studies.
In conclusion, after pancuronium induced neuromuscular block, mivacurium is not a short-acting drug.
The authors thank the nurse anesthetists of Maria Hospital of Helsinki City Hospital, for caring for the patients and for technical assistance.
REFERENCES
Meretoja OA, Wirtavuori K: Two-dose technique to create an individual dose-response curve for atracurium. ANESTHESIOLOGY 1989; 70:732-6.
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Patel R, Katz R, Chung A, Foster S, Calmes S: The effect of mivacurium on a preestablished doxacurium or mivacurium block (abstract). ANESTHESIOLOGY 1994; 81:A1068.
Rashkovsky OM, Agoston S, Ket JM: Interaction between pancuronium bromide and vecuronium bromide. Br J Anaesth 1985; 57:1063-6.
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Foldes FF: Enzymes of acetylcholine metabolism, Enzymes in Anesthesiology. Edited by Foldes FF. New York, Springer, 1978, pp 91-168.
Bowman WC: Non-relaxant properties of neuromuscular blocking drugs. Br J Anaesth 1982; 54:147-60.
Erkola O. Salmenpera A, Kuoppamaki R: Five non-depolarizing muscle relaxants in precurarization. Acta Anaesthesiol Scand 1983; 27:427-32.
Figure 1. Spontaneous electromyography recovery of neuromuscular block after 10 (triangles) or 70 (circles) micro gram/kg mivacurium given at T sub 1 25% during recovery from pancuronium (closed symbols) or mivacurium (open symbols) block. Groups differed (P < 0.05) from each others at every EMG recovery level besides mivacurium groups at 90% and 95% T1recovery levels.
Figure 1. Spontaneous electromyography recovery of neuromuscular block after 10 (triangles) or 70 (circles) micro gram/kg mivacurium given at T sub 1 25% during recovery from pancuronium (closed symbols) or mivacurium (open symbols) block. Groups differed (P < 0.05) from each others at every EMG recovery level besides mivacurium groups at 90% and 95% T1recovery levels.
Figure 1. Spontaneous electromyography recovery of neuromuscular block after 10 (triangles) or 70 (circles) micro gram/kg mivacurium given at T sub 1 25% during recovery from pancuronium (closed symbols) or mivacurium (open symbols) block. Groups differed (P < 0.05) from each others at every EMG recovery level besides mivacurium groups at 90% and 95% T1recovery levels.
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Table 1. Demographic Data
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Table 1. Demographic Data
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Table 2. Spontaneous Recovery Times after 10 or 70 micro gram/kg Mivacurium Given at T125% during Recovery from Pancuronium or Mivacurium Block
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Table 2. Spontaneous Recovery Times after 10 or 70 micro gram/kg Mivacurium Given at T125% during Recovery from Pancuronium or Mivacurium Block
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Table 3. Maximum Neuromuscular Block and Onset Time to Maximum Block after Mivacurium 10 or 70 micro gram/kg Given at T125% during Recovery from Pancuronium or Mivacurium Block
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Table 3. Maximum Neuromuscular Block and Onset Time to Maximum Block after Mivacurium 10 or 70 micro gram/kg Given at T125% during Recovery from Pancuronium or Mivacurium Block
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Table 4. Train-of-four Ratio (T4/T1) Percentages at Different Levels of T1Recovery
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Table 4. Train-of-four Ratio (T4/T1) Percentages at Different Levels of T1Recovery
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