Abstract
The two main antiseizure medications (ASMs) used in a prophylactic use are phenytoin (Dilantin) and levetriacetam (Keppra), so the pharmacokinetics of these medications in the setting of hypothermia will be reviewed. Given that phenytoin is cleared primarily by the liver, the effects of hypothermia on liver metabolism is affected by blood flow to the liver, intrinsic clearance by the cytochrome P450 system, and the fraction of drug bound to protein (Zhou and Poloyac, 2011). The last two factors are the most important for phenytoin as it is heavily protein bound and metabolized by the CYP2C9 system. In a study of 14 patients with traumatic brain injury who were cooled to 34°C for 72 hours, the clearance of phenytoin was decreased 67% but protein binding did not change, thus showing that therapeutic hypothermia exerted its effects by inhibiting the cytochrome system in the liver (Iida et al., 2001). It should be noted that for other drugs metabolized through the CYP450 system, similar decreased drug clearance should be expected. These drugs include midazolam (CYP3A), diazepam (CYP2C9), phenobarbital (CYP2C9), pentobarbital (CYP2D6), and carbamazepine (CYP2C9). For levetriacetam, which is primarily excreted in the urine by renal elimination, the main factors at play are filtration, active secretion, and reabsorption. For levetiracetam, 66% of the dose is actively secreted unchanged in the urine, which is based primarily on the glomerular and tubular function. Given this, ASMs should be dose adjusted during hypothermia to account for changes in liver and kidney function. Consultation with an ICU pharmacist should be pursued.