Duration of the pharmacodynamic interaction between pancuronium and mivacurium

The aim of this study was to determine for how long the duration of action of increments of mivacurium can be influenced by previous pancuronium administration. Fifteen patients, ASA I or II, undergoing general anaesthesia for major abdominal surgery were investigated. The post-tetanic count (PTC) was measured at the adductor pollicis muscle. Pancuronium 0.1 mg kg-1 was injected first. At recovery of the 10th response of the PTC (PTC10), a second dose of pancuronium was injected (0.02 mg kg-1). On recovery to PTC10, a bolus of mivacurium (0.04 mg kg- 1) was given and regularly repeated at recovery of PTC10 until the end of surgery. The mean duration of the second dose of pancuronium was 53 min (SD 13 min) and of the first dose of mivacurium, 66 min (SD 14 min) (P < 0.01). The duration of action of further mivacurium boluses decreased significantly until the fifth dose. It took 222 minutes (95% confidence interval 190, 253 min) after the second pancuronium dose before the duration of action of mivacurium returned to normal values and became constant and predictable.      

Potentiation of mivacurium blockade by low dose of pancuronium: a pharmacokinetic study

BACKGROUND: Mivacurium is potentiated by pancuronium to a much greater extent than other relaxants. In a previous investigation we suggested that this potentiation could be due to the ability of pancuronium to inhibit plasma cholinesterase activity, but we did not measure plasma concentrations of mivacurium. In the current study we performed a pharmacokinetic analysis by measuring the plasma concentration of mivacurium when preceded by administration of a low dose of pancuronium. METHODS: After induction of general anesthesia with propofol and fentanyl and orotracheal intubation, 10 patients (pancuronium-mivacurium group) received 15 microg/kg pancuronium followed 3 min later by 0.1 mg/kg mivacurium, whereas 10 other patients (mivacurium group) received saline followed by 0.13 mg/kg mivacurium 3 min later. Plasma cholinesterase activity was measured before and 3 and 30 min after pancuronium dosing in the pancuronium-mivacurium group and was measured before and after administration of saline in the mivacurium group. Arterial plasma concentrations of mivacurium and its metabolites were measured at 0.5, 1, 1.5, 2, 4, 10, 20, and 30 min after injection. Neuromuscular blockade was assessed by mechanomyography. RESULTS: Plasma cholinesterase activity decreased by 26% in the pancuronium-mivacurium group 3 min after injection of pancuronium (P < 0.01) and returned to baseline values 30 min later; however, no significant variation was observed in the mivacurium group. The clearances of the two most active isomers (Cis-Trans and Trans-Trans) were lower in the pancuronium-mivacurium group (17.6 +/- 5.1, 14.7 +/- 5.3 ml. min-1. kg-1, respectively) than in the mivacurium group (32.4 +/- 20.2, 24.8 +/- 13.5 ml. min-1. kg-1; P < 0.05). CONCLUSIONS: A subparalyzing dose of pancuronium decreased plasma cholinesterase activity and the clearance of the two most active isomers of mivacurium. Pancuronium potentiates mivacurium more than other neuromuscular blocking agents because, in addition to its occupancy of postsynaptic acetylcholine receptors, it slows down the hydrolysis of mivacurium.     

Recovery of neuromuscular function after atracurium and pancuronium maintenance of pancuronium block

The study was undertaken to determine whether a neuromuscular blockade induced with pancuronium but maintained with atracurium was associated with a shorter time to complete recovery after administration of neostigmine than if the blockade was maintained with pancuronium alone. Anaesthesia consisted of thiopentone, N₂O/O₂/enflurane and fentanyl, and the neuromuscular blockade, induced by pancuronium 0.1 mg · kg^?1 was monitored by the force of contraction of adductor pollicis during major abdominal surgery lasting 2–5 hr. In 24 patients — Group 1 — atracurium 0.07 mg · kg^?1 was repeated when the first twitch of the train-of-four (TOF) returned to 25% of control (T₁/ TC 25). In 28 patients — Group 2 — pancuronium 0.015 mg · kg^?1 was given at similar recovery of T₁/ TC. At the end of surgery, neostigmine 0.07 mg · kg^?1 and glycopyrrolate 0.015 mg · kg^?1 were given to reverse the residual neuromuscular blockade which was indicated by a T₁/TC of less than 25% in all patients. The time from injection of the reversal drugs to a TOF ratio of 70% was similar in both groups (Group 1, 11.6 ± 7.6 min; Group 2, 10.1 ± 6 min; P = NS), but the recovery index was smaller in Group 2 (Group 1, 4 ± 2.6 min; Group 2, 2.61 ± 1.2 min; P < 0.05). Furthermore, there was no difference between groups in the duration of action of each redose. The study showed that when compared with pancuronium, equipotent doses of atracurium were not associated with (a) a shorter time to complete recovery from a neuromuscular blockade induced with pancuronium or (b) a shorter duration of action.     

Potency and hourly maintenance requirement of combinations of mivacurium and pancuronium in adults

Purpose

To evaluate the dose-response and maintenance requirements of a combination of mivacurium and pancuronium (cMP) in clinical practice.

Methods

In a randomised, open clinical study, 70 patients, 17–50 yr of age, were anaesthetised with propofol, alfentanil and nitrous oxide in oxygen. Thirty patients received mivacurium and 20 patients received pancuronium to establish dose-response curves for these agents. Hourly maintenance requirements of mivacurium and pancuronium to maintain 90–95% neuromuscular blockade (NMB) were determined. Thereafter, 20 additional patients received cMP in incremental doses to establish a cumulative dose-response curve for cMP followed by maintenance doses of cMP NMB was recorded by adductor pollicis electromyography.

Results

The ED₉₅ values for mivacurium and pancuronium were 100 and 66μg·kg^?1, respectively; and for the cMP 2:1 (in mg:mg basis), 32 μg·kg^?1 mivacurium together with 16 μg·kg^?1 pancuronium. This cMP was 1.8 times more potent than one parent agent (P < 0.0001 ). When cMP 2:1 was used, 60% of normal maintenance requirement of pancuronium reduced the requirement of mivacurium by > 90%. If cMP 20:1 was used, then 20% of normal maintenance requirement of pancuronium reduced the requirement of mivacurium by > 70%. Neostigmine 35 μg·kKg^?1 given at T₁ 10% recovery following cMP reversed the NMB to a TOF ratio of 0.70 in 9.5 ±3.9 min.

Conclusion

These results reflect considerable synergism between mivacurium and pancuronium. The cMP is near intermediate-acting and the NMB is easily reversed with neostigmine. By using cMR it may be possible to save some pharmacological costs during maintenance of anaesthesia.     

Model-based control of neuromuscular block using mivacurium: design and clinical verification

BACKGROUND: Short-acting agents for neuromuscular block (NMB) require frequent dosing adjustments for individual patient's needs. In this study, we verified a new closed-loop controller for mivacurium dosing in clinical trials. METHODS: Fifteen patients were studied. T1% measured with electromyography was used as input signal for the model-based controller. After induction of propofol/opiate anaesthesia, stabilization of baseline electromyography signal was awaited and a bolus of 0.3 mg kg-1 mivacurium was then administered to facilitate endotracheal intubation. Closed-loop infusion was started thereafter, targeting a neuromuscular block of 90%. Setpoint deviation, the number of manual interventions and surgeon's complaints were recorded. Drug use and its variability between and within patients were evaluated. RESULTS: Median time of closed-loop control for the 11 patients included in the data processing was 135 [89-336] min (median [range]). Four patients had to be excluded because of sensor problems. Mean absolute deviation from setpoint was 1.8 +/- 0.9 T1%. Neither manual interventions nor complaints from the surgeons were recorded. Mean necessary mivacurium infusion rate was 7.0 +/- 2.2 microg kg-1 min-1. Intrapatient variability of mean infusion rates over 30-min interval showed high differences up to a factor of 1.8 between highest and lowest requirement in the same patient. CONCLUSIONS: Neuromuscular block can precisely be controlled with mivacurium using our model-based controller. The amount of mivacurium needed to maintain T1% at defined constant levels differed largely between and within patients. Closed-loop control seems therefore advantageous to automatically maintain neuromuscular block at constant levels.     

Time course of potentiation of mivacurium by halothane and isoflurane in children

We studied 40 children, aged 1-15 yr, to analyse the time course of potentiation of mivacurium produced by halothane and isoflurane. A steady infusion requirement of mivacurium to maintain 90% neuromuscular block was established during thiopentone-alfentanil-nitrous oxide- oxygen anaesthesia. Patients were then allocated randomly to receive 1 MAC end-tidal concentration of either halothane (group Hal) or isoflurane (group Iso) while neuromuscular block was maintained at 90%. Both volatile agents decreased the infusion requirements of mivacurium in an exponential manner in that maximal potentiation occurred only after 30-80 min. Maximal reduction in infusion rate (32% in group Hal and 70% in group Iso; P < 0.0001) did not depend on the age of the child but became established sooner the younger the child in the case of isoflurane (P = 0.002).      

The use of low-dose mivacurium to facilitate insertion of the laryngeal mask airway

Ninety patients were assigned randomly in a double-blind manner to receive 0.9% sodium chloride, mivacurium 0.04 mg.kg⁻¹ or mivacurium 0.08 mg.kg⁻¹ intravenously, followed by propofol 2.5 mg.kg⁻¹. A laryngeal mask airway (LMA) was inserted 90 s later. The LMA was positioned correctly during the first attempt in 87% of patients and this was not significantly altered by the use of mivacurium. However, mivacurium decreased the incidence of swallowing, coughing, movement and laryngospasm (p < 0.05). LMA insertion was graded as easy in 88% of patients who had mivacurium, compared with 50% in patients who had propofol alone (p < 0.05). The conditions during LMA insertion were similar after 0.04 or 0.08 mg.kg⁻¹ of mivacurium. Patients were apnoeic for a mean (SD) time of 0.67 (0.72) min after propofol alone, compared with 1.72 (1.06) min and 3.05 (1.36) min in patients who also received mivacurium 0.04 and 0.08 mg.kg⁻¹, respectively (p < 0.01). Patients who received mivacurium had a lower incidence of postoperative sore throat (24–30% vs. 53%) (p < 0.05). In conclusion, low-dose mivacurium facilitates LMA insertion and decreases the incidence of postoperative sore throat.     

Neostigmine antagonism of succinyl-choline phase II block: A comparison with pancuronium

To assess the efficacy of neostigmine antagonism of succinylcholine phase II block, succinylcholine infusions were given to 17 patients for durations varyingfrom 44 to 192 minutes. A control group (17 patients) received a pancuronium infusion for similar times. Ninety per cent neuromuscular block was maintained in these two groups by adjustment of the infusion rates and, in a third group, with intermittent doses of pancuronium. Neuromuscular transmission was monitored with train-of-four stimulation every 12 seconds and anaesthesia was maintained with N₂O-0₂-enfiurane. Ten minutes after the infusion was stopped, atropine and neostigmine were given to all patients who received pancuronium and to 11 patients in the succinylcholine group whose train-of-four ratio (T4IT1) was less than 0.7, During the subsequent 15 minutes, recovery was more rapid in the succinylcholine group than in either the pancuronium-infusion or pan-curonium-bolus groups. It is concluded that succinyl-choline-induced phase II block can be safely and rapidly antagonized with neostigmine.     

Neostigmine antagonism of succinylcholine phase II block: a comparison with pancuronium

To assess the efficacy of neostigmine antagonism of succinylcholine phase II block, succinylcholine infusions were given to 17 patients for durations varying from 44 to 192 minutes. A control group (17 patients) received a pancuronium infusion for similar times. Ninety per cent neuromuscular block was maintained in these two groups by adjustment of the infusion rates and, in a third group, with intermittent doses of pancuronium. Neuromuscular transmission was monitored with train-of-four stimulation every 12 seconds and anaesthesia was maintained with N2O-O2-enflurane. Ten minutes after the infusion was stopped, atropine and neostigmine were given to all patients who received pancuronium and to 11 patients in the succinylcholine group whose train-of-four ratio (T4/T1) was less than 0.7. During the subsequent 15 minutes, recovery was more rapid in the succinylcholine group than in either the pancuronium-infusion or pancuronium-bolus groups. It is concluded that succinylcholine-induced phase II block can be safely and rapidly antagonized with neostigmine.     

Conditions of intubation and neuromuscular block induced by mivacurium: comparison with succinylcholine]

OBJECTIVE: To compare the clinical conditions for intubation and neuromuscular parameters after a high dose of mivacurium (0.25 mg/kg; 3 x SD95) administered in 30 s to those obtained after use of the usual dose of succinylcholine (1 mg/kg). PATIENTS AND METHODS: Eighty-two patients, 37 in the succinylcholine group and 45 in the mivacurium group, were studied. Intubating conditions were assessed on a scale of 3 to 12 points analyzing ease of laryngoscopy, relaxation of vocal cords and presence of cough 60 seconds after administration of the drug. Neuromuscular parameters were acceleration of the thumb induced by supramaximal train-of-four stimulation of the cubital nerve. Heart rate and non-invasive mean blood pressure were recorded throughout surgery. Cutaneous flush was looked for after administration of the relaxant. RESULTS: Time to onset of effect (159 s versus 82 s) and times to recovery after mivacurium were significantly longer than with succinylcholine. Mivacurium afforded excellent/good conditions for intubation in 95.6% of cases, with a neuromuscular blockade at intubation of 52.68%. No significant hemodynamic changes or side effects were observed. CONCLUSIONS: Given the moderate conditions of intubation achieved at 60 s, mivacurium can not be recommended as a relaxant in situations that require a rapid induction sequence. In elective surgery, 0.25 mg/kg of mivacurium can, however, be considered an alternative to succinylcholine.     

Antagonism of mivacurium block with edrophonium from various degrees of spontaneous recovery

Seventy adult patients received mivacurium 0.15 mg kg^–1during anaesthesia with thiopentone, nitrous oxide and 0.5%halothane. Neuromuscular block was monitored using mechanomyographyand train-of-four stimulation. Edrophonium 0.75 mg kg^–1was administered 5 or 10 min after mivacurium, or when the firstresponse in the TOF (T1) had recovered to 5, 10, 25 or 50% ofcontrol in groups of 10 patients each. A control group was allowedto recover spontaneously. The mean time taken from administrationof mivacurium to attaining a TOF ratio of 0.7 was between 19.3and 24.9 min in the groups given edrophonium, regardless ofthe time of administration, compared with 26.7 min in the spontaneousrecovery group. The differences, however, were not significantamong the groups showing little advantage in antagonizing mivacuriumblock.