C. Schopfer

Plasma Concentrations of Laudanosine, but Not of Atracurium, Are Increased during the Anhepatic Phase of Orthotopic Liver Transplantation in Pigs

To quantify the changes in plasma concentrations of atracurium and laudanosine induced by the lack of hepatic function and circulation, the authors studied nine domestic pigs (22-25 kg) undergoing an orthotopic liver transplantation, and three control animals without surgery, using atracurium as the muscle relaxant. After intubation facilitated by isoflurane 2-3%, anesthesia was maintained with isoflurane (0.5% in oxygen) and fentanyl (4 micrograms.kg-1.hr-1). Ventilation was controlled to keep end-tidal CO2 at 35-40 mmHg, body temperature maintained at 35.5-37.5 degrees C, and arterial pH at 7.35-7.50. The right sciatic nerve was stimulated with a nerve stimulator delivering a single twitch at 0.1 Hz with 0.2-ms duration, at supramaximal stimulation. The force of the corresponding evoked isometric muscle contraction was continuously measured by a force-displacement transducer. A single iv bolus of atracurium (2 mg/kg) was given to obtain a 90-95% twitch depression, followed 5 min later by a constant-rate iv infusion of atracurium at 120 micrograms.kg-1.min-1 maintained during the entire investigation. Blood samples for plasma atracurium and laudanosine concentrations were drawn every 15 min. In the control group, plasma concentrations of atracurium remained stable between 6.5-8.0 micrograms/ml following initial bolus injection; plasma concentrations of laudanosine increased during the first 60 min, then remained stable between 0.69-0.74 micrograms/ml up to the end of the study. In animals undergoing transplantation, plasma concentrations of atracurium remained stable between 10-12 micrograms/ml, despite a 90-min duration of liver exclusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Vecuronium neuromuscular blockade reflects liver function during hepatic autotransplantation in pigs

BackgroundRapid assessment of hepatic function early after reperfusion of the liver graft is of great importance, because it may allow for prompt detection of incipient hepatic graft failure. The current study was undertaken to determine whether the continuous recording of neuromuscular transmission could be used as an on-line assessment of hepatic function during liver transplantation when a muscle relaxant with high hepatic uptake is used. MethodsWe quantified and compared the effect of liver exclusion and graft reperfusion on the level of vecuronium-induced neuromuscular blockade in nine pigs studied twice within 3 days. During the 1st day (control session), an intravenous infusion of vecuronium was administered to maintain a constant 90–95% twitch depression during 180 min. The twitch response was then allowed to recover spontaneously to 75% of its prerelaxant value. Neuromuscular transmission was continuously measured on the right anterior leg using an acceleration transducer. During the same time period, the metabolic rate of 14C-labeled aminopyrine (a well-established quantitative test of the liver microsomal function) was determined by measuring the excretion of 14CO2 in expired air after administration of an intravenous bolus of 14C-labeled aminopyrine. Two days later, the pigs underwent a hepatic autotransplantation, during which vecuronium was administered to maintain a constant 90–95% twitch depression. After reperfusion of the liver graft, the vecuronium Infusion rate was maintained at its anhepatic level, and the recovery index of the neuromuscular blockade (the time from 25% to 75% recovery of twitch height) was calculated. The aminopyrine breath test was performed during the last 30 min of the anhepatic phase, and during 3 h after reperfusion of the liver graft. ResultsDuring control studies, the mean infusion rate of vecuronium was 1.30 ± 0.33 mg · kg-1 · h-1 and the recovery index was 3.4 ± 0.5 min. During liver dissection, the infusion rate of vecuronium was similar to the control value (1.18 ± 0.16 mg · kg-1 · h-1), then considerably decreased to 0.05 ± 0.03 mg · kg-1 · h-1 during the anhepatic phase. After reperfusion of the liver graft, the recovery index was markedly prolonged to 35.5 ± 15.8 min, indicating a prolongation of the recovery of neuromuscular blockade by a factor of 10.4. Excretion of 14CO2 was equal to zero during the anhepatic phase and then increased to 0.19 ± 0.11% during the 1st h after reperfusion of the liver graft, an excretion rate corresponding to 11.2% of control conditions. The relationship between individual changes in the recovery index of the neuromuscular blockade and 14CO2 excretion in expired air after reperfusion of the liver graft showed a strong significant correlation (r = 0.71). ConclusionsThese results indicate that, compared with the control studies, there is a similar decrease in the recovery rate of vecuronium-induced neuromuscular blockade and in the metabolic rate of 14C-labeled aminopyrine during the progressive recovery of hepatic function Immediately after un-clamping of the liver vessels. Metabolism of 14C-labeled aminopyrine increased progressively during the reperfusion phase. Therefore, recording of neuromuscular transmission during liver transplantation could serve as a continuous and easy to perform assessment of liver graft function provided that a muscle relaxant with a high hepatic uptake is used for neuromuscular blockade.

Pharmacokinetics of arteether in dog

SummaryA pharmacokinetic study has been conducted in six beagle dogs after i.m. administration of 25 mg/kg of arteether, a qinghaosu (artemisinin) derivative of high anti-malarial activity.Arteether plasma concentrations were measured during a 24 h period using HPLC with an electrochemical detector in the reductive mode. The pharmacokinetic parameters were established using an open two-compartment model.Results showed a relatively rapid absorption phase: T1/2ka was 0.300 ± 0.096 h and a mean elimination half-life of 27.95 ±11.93 h. Cmax was 110 ± 16 ng/ml, Cltot/F was 1.69 ± 0.34 ml/min and AUC was 2797 ± 476 ng/ml/h.

Pharmacokinetics of pipecuronium in infants, children and adults

SummaryIn order to explain the reported shorter clinical duration of action of cumulative ED95 of pipecuronium in infants as compared to children or adults, the pharmacokinetic profiles of pipecuronium were compared in infants (n=6; mean age 6.8 months; mean weight 7.3 kg) in children (n=6; mean age 4.6 years; mean weight 19.2 kg) and in adults (n=7; mean age 42 years; mean weight 58.2 kg).Equipotent doses (2 × ED95) of pipecuronium were injected i.v. as single bolus and arterial blood was sampled for 4–5 h. Pipecuronium was quantified by complex formation with [125I]-labelled rose bengal. Pharmacokinetic parameters were calculated using a two-compartment open model. The median for the distribution half-life of pipecuronium was 2.54 min (interquartile range: 1.0–2.5 min) in infants and 2.04 min (0.26–2.04 min) in children; both were significantly shorter than in adults (5.75 [3.7–9.7] min). The plasma clearance of pipecuronium was significantly decreased in infants (1.50 [0.6–1.5] ml.min−1.kg−1;P<0.05) as compared to children and adults (2.27 [0.88–2.27] and 2.45 [1.7–3.2] ml.min−1. kg−1, respectively). The total volume of distribution was similar in all three groups.We conclude that the pharmacokinetic features of pipecuronium are age-dependent: differences as compared to adults consisted of a faster distribution in both infants and children and a slower elimination in infants. The pharmacokinetic profile of pipecuronium does not explain the faster recovery from neuromuscular blockade in infants as compared to children. Because of the low total plasma clearance in infants, pipecuronium dosage should be carefully monitored to avoid accumulation and prolonged paralysis.

Pharmacokinetics of atracurium besylate in the pig after a single i.v. injection.

SummaryA pharmacokinetic study of atracurium besylate was performed in the pig after a single i.V. bolus injection of 2 mg/kg, the dose needed to produce surgical neuromuscular blockade. The plasma concentration values were obtained by high performance liquid chromatography. Using a two-compartment pharmacokinetic model, the elimination half life was found to be 28.6±6.3 min (mean ± SEM), the total volume of distribution 341+56 ml/kg and the plasma clearance 8.7+1.1 ml/min/kg. Although the doses required to obtain a satisfactory neuromuscular blockade as well as the plasma level, volume of distribution and plasma clearance values were higher in the pig than in man, the distribution and elimination half-lives were similar to those recently reported.