Mivacurium When Precedent by Pancuronium Becomes a Long-acting Muscle Relaxant

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.

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.

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.

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.

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.