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We examined the pharmacokinetics and pharmacodynamics of atracurium besylate and its metabolites in children after orthotopic liver transplantation (OLT), as a suitable model for critically ill children. Ten children were studied after OLT on return to the intensive care unit (ICU). The mean (range) age was 36 (7-78) months, and weight 6-24.2 kg. Atracurium was started at induction of anaesthesia and adjusted in the ICU according to clinical need. Neuromuscular block was measured using accelerometry (TOFguard) and the train-of-four (TOF) ratio or count. Arterial plasma samples for atracurium and metabolites taken before, 12-hourly during, and at frequent intervals after the infusion were analysed by HPLC. The mean (range) maximum infusion rate during steady-state conditions was 1.44 (0.48-3.13) mg kg(-1) h(-1) and the duration of infusion 36.9 (22.5-98.4) h. Tachyphylaxis was not observed. The mean terminal half-life (t1/2) for atracurium was 18.8 (12-32.3) min. The steady-state plasma clearance (CLss) was 13.9 (7.9-20.3) ml min(-1) kg(-1) and the terminal volume of distribution (Vz) 390 (124-551) ml kg(-1); both were higher than in adults after successful OLT. The maximum concentration (Cmax) of laudanosine was 1190 (400-1890) ng ml(-1) and t1/2 was 3.9 (1.1-6.7) h. The renal clearance of laudanosine was 0.9 (0.1-2.5) ml min(-1) kg(-1) and increased with urine flow, but there was no significant relationship with serum creatinine. EEG spikes were confirmed in one child only; the corresponding laudanosine Cmax was 720 ng ml(-1). Monoquaternary alcohol Cmax was 986 (330-1770) ng ml(-1) and t1/2 42.9 (30-57.7) min. Mean recovery time on stopping the atracurium infusion to a TOF ratio >0.75 was 23.6 (12-27) min. Atracurium is an effective and safe neuromuscular blocking agent in this population. Laudanosine concentrations are not excessive if graft function is satisfactory.

Objective: To evaluate and compare the safety and efficacy of cisatracurium (51W89) and atracurium administered by continuous infusion to critically ill patients requiring neuromuscular blocking agents to facilitate mechanical ventilation., Design: Open, randomized, multicenter study of patients receiving cisatracurium or atracurium infusion to facilitate mechanical ventilation., Setting: Five university teaching hospital intensive care units in the United Kingdom., Patients: Sixty-one adult patients requiring neuromuscular blocking agents to facilitate mechanical ventilation., Interventions: Bolus doses followed by continuous infusions of cisatracurium or atracurium were administered. Onset, maintenance, and recovery of neuromuscular blockade were measured, using transcutaneous ulnar nerve stimulation and an accelerometer., Measurements and Main Results: Forty patients received cisatracurium (mean duration 48.1 +/- 4.2 [SEM] hrs), and 21 patients received atracurium (mean duration 46.1 +/- 5.8 hrs). The infusion rate for patients receiving cisatracurium was 3.1 +/- 0.2 microg/kg/min, and for patients receiving atracurium 10.4 +/- 0.9 microg/kg/min. There were no significant differences in mean times to 70% recovery of Train-of-Four ratio (cisatracurium 60 mins, atracurium 57 mins), although there was considerable interpatient variation (20 to 175 mins with cisatracurium vs. 35 to 85 mins with atracurium). One patient who received cisatracurium exhibited intermittent bronchospasm during and after the study period., Conclusions: Cisatracurium, an isomer of atracurium, appears to be a suitable agent for providing muscle relaxation in critically ill patients.

Objective: To determine the pharmacokinetics and pharmacodynamics of the neuromuscular blocking agent atracurium besylate in patients with fulminant hepatic failure (FHF)., Design: Open study of patients receiving atracurium infusions to facilitate mechanical ventilation., Setting: Intensive care unit in a tertiary referral university teaching hospital., Patients: Ten encephalopathic patients with FHF requiring mechanical ventilation while awaiting orthotopic liver transplantation. Three patients died before transplantation could be performed, three died after transplantation, and four survived following successful transplantation., Methods: Plasma, urine and dialysate fluid were analysed for atracurium and its metabolites using HPLC. Neuromuscular blockade was measured using transcutaneous ulnar nerve stimulation and an accelerometer. Electroencephalography and liver function tests were performed daily., Results: Patients received atracurium infusions for a period ranging from 38 to 217 h. Six patients required continuous arteriovenous haemodiafiltration (CAVHD) to replace renal function. Atracurium mean steady state clearance was 8.6 ml/min/kg, and train-of-four recovery ratio to 75% took 63 min (range 32-108). Laudanosine clearance was markedly reduced in the non-survivors; the half-life was 38.5 hrs compared with 5.3 h in the 4 patients who underwent successful transplantation. Laudanosine accumulation could be observed in all patients before transplantation, but kinetics returned to normal after successful transplantation. The highest laudanosine level recorded was 6,860 ng/ml. There was no evidence of adverse central neurological effects attributable to laudanosine. CAVHD did not contribute significantly to clearance of atracurium or its metabolites., Conclusions: Atracurium kinetics and dynamics are near-normal even in patients with fulminant hepatic failure and renal failure; laudanosine accumulation will occur, but this is not associated with measurable central neurological effects. Implantation of a functioning liver graft results in clearance of laudanosine, which seems to be independent of renal function. Atracurium is an appropriate choice for producing neuromuscular blockade for periods of several days in patients with fulminant hepatic failure and renal impairment.