Disposition of Infusions of Atracurium and Its Metabolite, Laudanosine, in Patients in Renal and Respiratory Failure in an Itu

Abstract

A study of plasma atracurium and laudanosine concentrations was undertaken in 14 critically ill patients who received a bolus dose of atracurium 0.6 mg kg-1 followed by an infusion of 0.6 mg kg-1 h-1 for a period of 11-47 h. Seven of the patients had normal renal function and seven were in acute renal failure. In both groups plasma concentrations of atracurium reached a plateau of approximately 1300 ng ml-1 within 30 min of the bolus dose. The drug disappeared from the plasma within 120 min after discontinuation of the infusion. There was no difference between the two groups with respect to the pharmacokinetic parameters derived for atracurium. In the patients with normal renal function, plasma laudanosine concentration reached a plateau of approximately 1200 ng ml-1 within 10 h. In patients with renal failure there was a greater variation in the plasma laudanosine concentration: the highest value recorded was 4300 ng ml-1. Patients with renal failure had a significantly longer mean elimination half-life for laudanosine (1418 min v. 375 min; P less than 0.05) and Vd (4.52 litre kg-1 v. 2.40 litre kg-1; P less than 0.01) than the patients with normal renal function.

Clinical Pharmacokinetics of Neuromuscular Blocking Drugs

“…In normal patients, plasma laudanosine concentrations reached a plateau of 1200 ,ug/L, but in renal failure the highest value was 4300 Ilg/L. Peak laudanosine concentrations after single bolus doses (table Y) were well below those observed during infusion (Parker et al 1988) or those causing convulsions in dogs (17 OOO,ug/L) [Chapple et al 1985]. Since 'safe' concentrations of laudanosine in humans are not known, atracurium infusions should be used with extreme caution in patients with hepatic or renal disease.…”

“…Consequently, plasma laudanosine concentrations will accumulate after multiple doses or during continuous atracurium infusion. The importance of renal function in laudanosine elimination is emphasised by Parker et al (1988). After a bolus dose of atracurium 0.6 mg/ kg, followed by continuous infusion at 0.6 mg/kg/ h for 10 to 47h, the t'llll of laudanosine was prolonged to 1418 min in critically ill patients from 375 min in patients with normal renal function.…”

Chirality and anaesthetic drugs: A review and an update

“…Moreover, its use by continuous infusion in critically ill patients can lead to the accumulation of laudanosine, a product of Hofmann degradation, which is epileptogenic in animals. [4041] Atracurium has four chiral centres in its bis-benzylisoquinolinium structure and the marketed product is a mixture of 10 optical and geometric isomers: three cis–cis, four cis–trans and three trans–trans isomers. [42] Cisatracurium is R-R’ optical isomer of the cis–cis configuration, which represents about 15% of atracurium mixture.…”

New Neuromuscular Blocking Drugs

“…54 After a bolus dose of 0.5 mg of atracurium per kilogram in patients with renal failure, the peak plasma laudanosine concentration is 0.3 mg per milliliter 55 ; after continuous infusions of atracurium (at least 0.6 mg per kilogram per hour) for 30 hours in patients with multiple organ failure who are undergoing intensive therapy, the plasma laudanosine concentration may reach 4.3 mg per milliliter. 56 In no instance, however, has any adverse effect been attributed to the accumulation of laudanosine.…”