Abstracts

Rationale: Status epilepticus is a medical emergency with a mortality of up to 30% in adults. There remains limited evidence to guide second line management for benzodiazepine refractory status epilepticus. Literature supporting the use of levetiracetam as a second line agent is growing and has been reflected in the American Epilepsy Society guidelines for the management of convulsive status epilepticus, recommending doses up to 4500 mg, higher than what is recommended by the manufacturer’s label. Levetiracetam has been preferred in a variety of patient populations due to its favorable side effect profile and limited drug interactions, including liver transplant. There have been sparse reports of levetiracetam hepatotoxicity, with most sources citing a <1% incidence. We sought to evaluate the levetiracetam as an under-recognized cause of hepatotoxicity in patients treated for status epilepticus in a single center cohort of neurointensive care patients. Methods: We retrospectively identified consecutive cases of status epilepticus where levetiracetam was used as part of the treatment in a single center neurointensive care unit. Liver injury was defined as alanine aminotransferase (ALT) greater than 5 times upper limit of normal or alkaline phosphatase (ALP) 2 times upper limit of normal. Cases of cardiac arrest were excluded unless liver injury occurred greater than 5 days post arrest. Each chart was individually reviewed for data abstraction. Roussel Uclaf Causality Assessment Method (RUCAM), a well-established tool used to assess causality in cases of suspected drug induced liver injury, was applied to each case to objectively determine if levetiracetam could be attributed to liver injury. RUCAM consists of 7 items including (1) type of liver injury (hepatocellular or cholestatic/mixed), (2) timing of liver injury in relation to drug exposure, (3) risk factors, (4) timing and exposure to concomitant drugs with known hepatotoxicity, (5) exclusion of other etiologies of liver injury, (6) previous reports of hepatotoxicity with drug, and (7) response to drug re-challenge. Item 4 was scored conservatively if patient was exposed to any other antiepileptic drugs or antibiotics. Item 5 was scored conservatively as most patients were treated with pressors for shock. Results: Fifty-two consecutive cases of status epilepticus were identified between 1/1/2016 and 7/7/2016. Twelve cases had evidence of hepatocellular or cholestatic liver injury. Four cases of cardiac arrest were excluded and 2 were included due to liver injury occurring greater than 5 days post arrest. Of 8 cases analyzed, 3 had hepatocellular injury and 5 had cholestatic/mixed injury. There was 1 case of probable and 3 cases of possible levetiracetam hepatotoxicity. The case of probable levetiracetam hepatotoxicity had evidence of liver injury within 6 days of starting levetiracetam, ALT peaked at 2241 U/mL, and improved by more than 50% within 2 days of stopping levetiracetam. Viral and obstructive etiologies of liver injury were ruled out. One case of possible levetiracetam hepatotoxicity had evidence of liver injury within 12 days of starting levetiracetam, peak ALP of 323 and improved by more than 50% within 7 days of stopping levetiracetam. Other etiologies were not specifically ruled out. Of 3 cases of possible levetiracetam cholestatic hepatotoxicity, 2 cases improved without cessation of levetiracetam and scored 3 on RUCAM, borderline between possible and unlikely. Conclusions: Levetiracetam is used frequently to treat critically ill patients with status epilepticus. We report several cases of possible levetiracetam hepatotoxicity within a short time span in a single center neurointensive care population being treated for status epilepticus, suggesting that the incidence of levetiracetam hepatotoxicity may be higher than previously reported. However, RUCAM is less reliable when applied retrospectively and has poor inter-rater reliability. The findings of this study are subject to bias due to the retrospective nature and the population of critically ill where many confounders exist that may contribute to liver injury. More rigorous and prospective research is needed to clarify levetiracetam’s potential for hepatotoxicity in the critically ill. Funding: No funding