Seizure Prophylaxis in Traumatic Brain Injury: A Comparative Study of Levetiracetam and Phenytoin Cerebrospinal Fluid Levels in Trauma Patients with Signs of Increased Intracranial Pressure Requiring Ventriculostomy

Background One of the most common life-threatening injuries to trauma patients arriving in the emergency department (ED) is traumatic brain injury (TBI). Traditionally, intravenous medications have been given as seizure prophylaxis in patients demonstrating signs of increased intracranial pressure (ICP), as post-traumatic seizures in trauma patients are associated with higher morbidity and mortality. Medications traditionally given for this indication such as phenytoin have been established to reach therapeutic levels in the cerebrospinal fluid (CSF) quickly and are effective in preventing post-traumatic seizures but often have a large side-effect profile. A newer medication that is being used for seizure prophylaxis in patients with epilepsy is levetiracetam. Levetiracetam typically has a better side effect profile, but it has not been demonstrated that the drug reaches therapeutic levels in the CSF as quickly as phenytoin. Studies have shown levetiracetam and phenytoin to be equivocal in the prevention of post-TBI seizure prophylaxis. Methods This was a prospective, randomized, case-control study at a Level II trauma center of adult patients (age >1= 18 years) who suffered severe TBI (sTBI) requiring the placement of an external ventricular drain (EVD) from May 2017 to June 2018. Twelve patients were randomly placed into one of two groups for the administration of antiepileptic medication (either levetiracetam or phenytoin), allowing for the subsequent serial collection of CSF for the analysis of therapeutic levels of antiepileptic medications. Levetiracetam or phenytoin was administered at standardized fixed doses per our neurosurgical center standard protocol. CSF was collected before either drug was administered, 60 minutes after completion of administration and 360 minutes after completion of drug administration. Data analysis was performed to compare the time frame for which therapeutic levels of the medications were achieved in the CSF. The published steady-state and therapeutic CSF level of levetiracetam is 32 mcg/ml and phenytoin is 2 mcg/ml. Results A trend was observed in which the closer the fixed dosage approximated the weight-based dosing of phenytoin, the more their CSF phenytoin level increased (and approximated the therapeutic range) with an associated R-squared value of 0.6274. This trend was not found in patients receiving levetiracetam. Conclusions Levetiracetam does not reach levels needed for seizure prophylaxis in human CSF when loaded at standard dosing regimens in the acute setting. Phenytoin does reach levels needed for seizure prophylaxis in human CSF with standardized regimen dosing when dosages approximate weight-based dosing. If needed, in the acute setting phenytoin should have additional doses given prior to six hours after the loading dose to achieve therapeutic CSF levels.