Intravenous administration of diazepam in patients with chronic liver disease

Abstract

The EEG response and drug kinetics after intravenous infusion of diazepam at 1.0 mg/min until nystagmus, dysarthria, and moderate sedation developed, has been investigated in five normal subjects and 17 patients with chronic liver disease. Diazepam induced adequate premedication with a similar clinical response in all subjects with no adverse reactions. Maximal response was during or within five minutes of infusion. The dose of diazepam required in chronic liver disease was 17.9 ± 1.4 mg (M±SEM) compared with 27±5.4 mg in controls (P<0.01). Dose correlated significantly with serum albumin (P<0.05). Baseline mean dominant frequency (MDF) and slow wave index (SWI) significantly correlated with albumin (P<0.01). After diazepam, the MDF decreased and SWI increased. The change was greatest at the time of maximal clinical response. It was greater in liver disease and was greatest in patients with previous hepatic encephalopathy. In spite of reduced dose requirements in liver disease, there was no significant difference in plasma concentration at the end of drug infusion. This might in part be explained by a significant dose dependent increase in volume of distribution (P<0.01). Differences in EEG response at similar plasma concentrations suggested differences in cerebral sensitivity. The clearance of diazepam decreased in chronic liver disease and correlated with the serum albumin (P<0.01) and also with the clearances of antipyrine (P<0.001), indocyanine green (P<0.001) and d propranolol (P<0.001).