Diazepam Kinetics in Patients with Severe Burns

Because of the increased tolerance of burn patients to sedatives and anesthetic drugs, the effects of severe thermal injury on the pharmacokinetics of diazepam following a single 5− to 10-mg intravenous dose were evaluated in eight patients with burns covering an average of 65% of body surface at a mean of 17 days after injury. Pharmacokinetic parameters were determined from multiple plasma diazepam concentrations measured for 7 days after administration of the diazepam. Eight healthy control subjects, matched with patients for age and sex, were studied identically. The elimination half-life of diazepam was greater, although not significantly so, in burn patients than in control patients (72 and 36 h, respectively). Volume of distribution was also increased in burn patients (2.88 v 1.53 L/kg, P < 0.1), but clearance was comparable in the two groups (0.64 v 0.53 ml/min/kg). However, these results were confounded by a significantly greater free fraction of diazepam in the plasma of burn patients than in control patients (3.43% v 1.24%, P < 0.01). After correction for differences in binding, the volume of distribution of unbound diazepam was comparable between groups (94 v 131 L/kg; not significant), but clearance of free diazepam was significantly reduced in burn patients (24 v 46 ml/min/kg, P < 0.05). If the present data can also be applied to other drugs, then the increased tolerance of patients with burns to sedative and anesthetic drugs cannot be explained on a pharmacokinetic basis but may instead be related to qualitative changes in receptors or in responses of target organs in the central nervous system of burn patients. The reduced clearance of diazepam may be attributable to burn injury and/or concomitant administration of other drugs. Repeated administration of diazepam following burns may result in extraordinary accumulation of drug in the body.