PHENYTOIN PROTEIN-BINDING AND DOSAGE REQUIREMENTS DURING ACUTE AND CONVALESCENT PHASES FOLLOWING BRAIN INJURY

OBJECTIVE: To longitudinally evaluate unbound and total serum phenytoi n concentrations during intravenous phenytoin maintenance dosage and t o determine the relationship among phenytoin protein binding, serum al bumin, and unbound fatty acid concentrations in patients with head inj uries during intensive care unit (ICU) and convalescent care. DESIGN: Serum albumin and phenytoin unbound fraction were determined twice wee kly during ICU and convalescent care in 10 patients receiving phenytoi n following acute brain injury. Phenytoin protein binding was also det ermined in 10 healthy control subjects. MAIN OUTCOME MEASURES: Longitu dinal serum phenytoin concentrations associated with dosage adjustment s targeted to achieve unbound phenytoin serum concentrations between 1 .0 and 2.0 mg/L were documented during ICU and convalescent care. Long itudinal phenytoin protein binding was correlated with serum albumin a nd unbound fatty acid concentrations in neurotrauma patients. RESULTS: ICU patients received intravenous therapy for a mean of 15.0 days. Th e mean +/- SD initial phenytoin intravenous dosage regimen of 6.0 +/- 0.7 mg/kg/d resulted in mean +/- SD total and unbound phenytoin concen trations of 3.2 +/- 2.3 and 0.3 +/- 0.2 mg/L. Two patients had seizure s associated with low phenytoin concentrations. Four patients continue d to receive oral phenytoin therapy during convalescent care; phenytoi n dosage requirements decreased over time in these patients. During ac ute and convalescent care, the phenytoin unbound fraction ranged from 6.0% to 18.3% and correlated with albumin (r(2) = 0.61, p < 0.0001) bu t did not correlate with unbound fatty acid concentrations. The mean p henytoin unbound fraction was 10.1% and 8.9% for the ICU and convalesc ent patients with brain injuries, respectively, and was 7.0% for the h ealthy volunteers. CONCLUSIONS: Phenytoin protein binding was signific antly correlated with albumin and was more variable in ICU and convale scent patients with brain injuries than in healthy volunteers. The hig h dosage requirements and subtherapeutic unbound phenytoin concentrati ons observed during acute care are best explained by increased metabol ism. Phenytoin dosage requirements decreased during convalescence.