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Background and objectives For neuromuscular blocking agents, an inverse relationship between potency and time to peak effect has been observed. To test the hypothesis that this relationship is due to buffered diffusion, we investigated the influence of dose on time to peak effect. Pharmacokinetic–pharmacodynamic simulations were performed to support the expected relationships between potency, dose, peak effect and time to peak effect. Methods Pigs (20–28 kg body weight) were anaesthetized with ketamine and midazolam, followed by pentobarbital and fentanyl intravenously. Neuromuscular block was measured by stimulating the peroneal nerve supramaximally at 0.1 Hz and measuring the response of the tibialis anterior muscle mechanomyographically. After an initial dose to establish the individual ED 90 of a neuromuscular blocking agent (rocuronium, vecuronium, pipecuronium or d-tubocurarine), five different doses of the same compound were administered to each animal, aiming at 20%, 40%, 60%, 75% or 90% block, in a random order. Doses were given 45 min after complete recovery of the twitch response. Results For rocuronium and pipecuronium, time to peak effect increased with dose, whereas dose did not affect time to peak effect of vecuronium and d-tubocurarine. Simulations predict that time to peak effect decreases with dose if buffered diffusion is taken into account. Conclusions The results suggest that buffered diffusion does not play a dominant role in the time to peak effect of neuromuscular blocking agents. Therefore it is unlikely that the observed inverse relationship between potency and time to peak effect of neuromuscular blocking agents in the clinical range is due to buffered diffusion.

Pipecuronium bromide, a long acting non-depolarizing neuromuscular blocking agent was administered to four groups of 10 patients using the priming technique. The effects of the combination of two different priming doses (0.01 or 0.015 mg kg-1) given at two different time intervals (3 or 4 min) before the 'main' intubating dose (0.07 or 0.065 mg kg-1) were investigated. Onset times were recorded and the intubation conditions were scored and compared with a group of patients receiving the same total amount of pipecuronium (0.08 mg kg-1) in a single bolus injection. Intubating conditions at 90 s after administration of the intubating dose were found to be significantly improved in all primed groups but the onset times, evaluated using the response of the adductor pollicis muscle to a single twitch stimulation, were similar to that observed after the single bolus injection. The optimal priming combination is considered to be 0.01 mg kg-1 of pipecuronium followed 3 to 4 min later by 0.07 mg kg-1.

Background and objective Porcine anaesthesia remains a great problem for cardiac surgery research and especially with cardiopulmonary bypass procedures. This study was designed to develop a suitable anaesthesia model in which miniature pigs could be induced smoothly and be maintained stably during and after a cardiopulmonary bypass procedure. Methods Thirty-one miniature pigs were randomly divided into two groups and induced using ketamine and pentobarbital (K-P group, n = 15) or pentobarbital (P group, n = 16) alone, respectively. Animals in group K-P were induced with intramuscular injections of ketamine 5 mg kg -1 and pentobarbital 20 mg kg -1 body weight, and those in group P were induced with pentobarbital 30 mg kg -1 alone. After intubation and intravenous catheterization, group K-P was maintained by continuous infusion of ketamine and pentobarbital, and pentobarbital was withdrawn after cardiopulmonary bypass started. Group P received a continuous infusion of pentobarbital throughout the operation. In addition, both groups were injected hourly with midazolam and pipecuronium bolus to achieve optimal surgical conditions. Results All of the group K-P animals survived for 24 h postoperatively. Five of the group P animals died from anaesthesia-related respiratory and cardiac arrest: three after induction and two after extubation. The animals in group K-P had more stable haemodynamics and arterial blood gas indices than animals in group P. Furthermore, the percentage of animals achieving satisfactory anaesthetic effects was significantly higher in group K-P than in group P. Conclusion Combination anaesthesia with low-dose ketamine and pentobarbital demonstrated superior haemodynamic and respiratory indices in comparison with pentobarbital. The combination regimen can achieve both hypnosis and analgesia effects with stable circulatory parameters.

The pharmacodynamics and -kinetics of pipecuronium were studied in 12 patients, six of whom received 100-mu-g kg-1 for laryngectomy (Group L), and six who underwent choledochotomy after insertion of the T-drain and were given 50-mu-g kg-1 (Group C). Onset time and clinical duration were 2.3 and 109 min and 2.8 and 39 min in Groups L and C, respectively. All patients could be sufficiently reversed with neostigmine. Terminal half-lives were 101.5 min (Group L) and 179 min (Group C) in a three-exponent decay; the distribution volumes at steady state 0.339 1 kg-1 (Group L) and 0.506 1 kg-1 (Group C); the plasma clearance 3.4 ml kg-1 min-1 (Group L) and 2.5 ml kg-1 min-1 (Group C). Within 24 h, 38.6% and 37% were excreted unchanged in the urine and 4.4% and 1% as 3-desacetyl pipecuronium in Groups L and C, respectively. Within 24 h only 2% was excreted into the bile in Group C. Distribution volume and terminal half-life in Group C were positively correlated with pre-operative serum aminotransferase levels (P

A general relation between the rate of onset and rate of recovery from non-depolarizing blockade has been demonstrated, with recovery consistently about ten times slower than onset. This observation has led to the suggestion that non-depolarizing agents share a common mechanism of action. Rocuronium, a recently introduced steroidal non-depolarizing agent, is claimed to have a very rapid onset but an intermediate duration and appears to test this hypothesis. To investigate this paradox we have calculated the rates of onset and recovery of rocuronium using the isolated human forearm and compared them with those of pipecuronium. The mean ratio of recovery time/onset time for rocuronium was 31.3, which is significantly greater than that for pipecuronium, 11.6 (P < 0.01). Whilst pipecuronium conforms to the same general relation between onset and offset described previously for other non-depolarizing agents, rocuronium appears to have a disproportionately rapid rate of onset for its rate of recovery. This suggests that onset, recovery, or both onset and recovery, from rocuronium blockade occur in a different manner to that of other non-depolarizing agents.

Seventy-five ASA Grades I-III patients (18-85 years, 45-90 kg) were randomized into five groups. All patients received N2O/O2 (2/1) and alfentanil: loading dose (LD) 0.015 mg kg-1 and maintenance dose (MD) 0.045 mg kg-1 h-1 (groups 1-4). Group 1 received propofol (LD 2 mg kg-1 and MD 6 mg kg-1 h-1); Group 2 etomidate (LD 0.3 mg kg-1 and MD 0.6 mg kg-1 h-1); Group 3 midazolam (LD 0.2 mg kg-1 and MD 0.120 mg kg-1 h-1); Group 4 methohexitone (LD 1.5 mg kg-1 and MD 4 mg kg-1 h-1); Group 5 dehydrobenzperidol 0.05-0.23 mg kg-1 and alfentanil (LD 0.100 mg kg-1 and MD 0.060 mg kg-1 h-1). The neuromuscular block induced by pipecuronium (50 micrograms kg-1) was evaluated. No statistically significant differences were found between the five groups as concerned degree of block (expressed as % twitch amplitude in response to the first of the TOF stimuli (Ta1) at intubation, T1 minimum and recovery to Ta1 = 20%, 25% and 75%. Slightly faster intubation was possible when midazolam was used in comparison with propofol, methohexitone or NLA and when etomidate was used in comparison with propofol. A wide range of individual values of maximal neuromuscular blocking activity was found.

The pharmacodynamics and -kinetics of pipecuronium were studied in 12 patients, six of whom received 100 micrograms kg-1 for laryngectomy (Group L), and six who underwent choledochotomy after insertion of the T-drain and were given 50 micrograms kg-1 (Group C). Onset time and clinical duration were 2.3 and 109 min and 2.8 and 39 min in Groups L and C, respectively. All patients could be sufficiently reversed with neostigmine. Terminal half-lives were 101.5 min (Group L) and 179 min (Group C) in a three-exponent decay; the distribution volumes at steady state 0.339 l kg-1 (Group L) and 0.506 l kg-1 (Group C); the plasma clearance 3.4 ml kg-1 min-1 (Group L) and 2.5 ml kg-1 min-1 (Group C). Within 24 h, 38.6% and 37% were excreted unchanged in the urine and 4.4% and 1% as 3-desacetyl pipecuronium in Groups L and C, respectively. Within 24 h only 2% was excreted into the bile in Group C. Distribution volume and terminal half-life in Group C were positively correlated with pre-operative serum aminotransferase levels (P less than 0.005).

The neuromuscular effects of pipecuronium bromide have been evaluated in 90 adult patients anaesthetized with thiopentone, nitrous oxide in oxygen and intravenous fentanyl with or without halothane. Eighty patients received pipecuronium 45 micrograms kg-1 and the remaining ten 70 micrograms kg-1. A separate group of 10 patients received pancuronium in a dose of 60 micrograms kg-1 (equipotent to pipecuronium 45 micrograms kg-1). Neuromuscular block was measured using a single-twitch or train-of-four mode of stimulation. The time to onset of maximum block with pipecuronium 45 micrograms kg-1 varied between 3.5 and 5.7 min depending on the mode of stimulation and the anaesthetic technique used. The time to 25% recovery of this dose varied between 41 and 54 min. The recovery index (time from 25 to 75% recovery) averaged 29 min. These values were generally similar in the group receiving pancuronium 60 micrograms kg-1. The time to onset of complete block with 70 micrograms kg-1 of pipecuronium averaged 2.5 min and the duration to 25% recovery 95 min. There were no significant changes in heart rate and arterial pressure with the use of pipecuronium. The results show pipecuronium to be a drug resembling pancuronium in its neuromuscular effects when used in equipotent doses.

The pharmacokinetics and hepatic disposition of pipecuronium have been investigated in cats with normal and absent renal function. A combined fluorimetric and chromatographic technique was used to determine the concentrations of pipecuronium and its metabolites in the samples. Following intravenous injection of 150 micrograms kg-1, pipecuronium disappeared from the plasma bi-exponentially with half-lives of 9.8 +/- 5.4, 77.7 +/- 9.7 min and 7.2 +/- 5.0, 100, 6 +/- 23.7 min; the Vd was 362.3 +/- 74.9 ml kg-1 and 123.7 +/- 14.6 ml kg-1 and the clearance was 5.0 +/- 0.9 ml min-1 kg-1 and 1.0 +/- 0.1 ml min-1 in the animals with and without renal function, respectively. In the animals with normal kidney function 53%, 12% and 8% of the administered dose of pipecuronium were recovered within 8 h in the urine, bile and liver, respectively. In 'nephrectomized' cats the lack of renal elimination was to a great extent compensated for by increased hepato-biliary elimination. Absence of renal function significantly altered the pharmacokinetic parameters and prolonged the time-course of the neuromuscular blocking effects of pipecuronium. Neither temporary hepatic exclusion nor intraportal administration of pipecuronium indicated any significant role of the liver in handling pipecuronium. Renal excretion seems to be the predominant route of elimination. No metabolites were found in this study.