Valproic acid and status epilepticus

You are working in trauma when a patient arrives with altered mental status requiring intubation, and a negative work-up who seemingly wakes up after a trial of ativan, trying to grab his endotracheal tube. You consult Neurology with concern for status epilepticus, who suggest a fosphenytoin load. As the patient has systolic blood pressure in the 80s, you consider valproic acid as the next intervention for presumed status epilepticus.

Clincal Question: 

Is VPA an effective next-line therapy for status epilepticus after benzodiazepines?

Literature:

One of the first articles found with a quick pubmed search is from 2006 in Neurology, a small unblinded RCT of 68 patients in status epilepticus as defined as 2 or more convulsive seizures w/o full recovery of consciousness between the seizures or continuous convulsive seizures lasting for more than 10 minutes. Patients were consecutively enrolled then randomized to a VPA group (n=35) which received sodium valproate 30 mg/kg in 100 mL saline infused over 15 minutes, or the PHT group (n=33) which received phenytoin sodium 18 mg/kg in 100 mL saline infused immediately at a rate of 50 mg/minute. They found that SE was aborted by VPA in 23 (66%) and by PHT in 14 (42%) (p = 0.046), and in refractory patients, as a second choice, VPA was effective in 15 of 19 patients (79%), whereas PHT was effective in 3 of 12 patients (25%) (p value = 0.004). As for side effects and relating to my case, 2 patients who received PHT had CV effects (not elaborated) while 0 of the VPA group though this was not significant.

Another article from 2008 by Gilad et al., similarly prospectively enrolled 74 patients in SE (2 or more consecutive clinical seizures, or continued seizure activity >30min) or acute repetitive seizure/acute refractory seizure (ARS) (2 or more w/in 5-6hrs) and gave either VPA as 30mg/kg over 20min in 50mL saline or PHT as 18mg/kg over 20min in 100mL saline. They found seizure discontinued in 43/49 (87.8%) of the VPA patients, with similar results in the PHT group in which seizures of 22/25 (88%) patients were well controlled. They noted that 3 pts had side fx of cardiac arrhythmia, hypoNa, or vertigo in the PHT group, and none in the VPA (p 0.035). This study was certainly small, but I think it should be noted that of the PHT group 12/25 had exposure to PHT in the past while only 11/49 of the VPA group (p = .03).

Furthermore, in April 2014 ACEP released its policy on the valuation and management of adult patients with seizures in the emergency department. Item #4 “In ED patients with generalized convulsive status epilepticus who continue to have seizures despite receiving optimal dosing of a benzo, which agent or agents should be administered next to terminate seizures?” directly applies to my question. As a Level B recommendation, they state “Valproate appears to be safe and effective in refractory status epilepticus and was not associated with hypotension. In conclusion, it appears that IV valproate is an acceptable treatment option for refractory status epilepticus and may work as well as phenytoin.” My last comment is that I was unable to find any studies w/ direct comparison of fosphenytoin vs VPA, and the ACEP literature review did not find any as well. The policy and lit review does cite a number of articles detailing CV effects of both PHT and fosphenytoin.

Take Home: 

In the setting of hypotension, valproic acid may be considered instead of fosphenytoin for the treatment of status epilepticus.

References: 

1) Misra UK1, Kalita J, Patel R. Sodium valproate vs phenytoin in status epilepticus: a pilot study.Neurology. 2006 Jul 25;67(2):340-2.
2) Gilad R, Izkovitz N, Dabby R, Rapoport A, Sadeh M, Weller B, Lampl Y. Treatment of status epilepticus and acute repetitive seizures with i.v. valproic acid vs phenytoin.Acta Neurol Scand. 2008 Nov;118(5):296-300
3) American College of Emergency Physicians Clinical Policies Subcommittee (Writing Committee) on Seizures:, Huff JS, Melnick ER, Tomaszewski CA, Thiessen ME, Jagoda AS, Fesmire FM. Clinical Policy: Critical Issues in the Evaluation and Management of Adult Patients Presenting to the Emergency Department With Seizures. Ann Emerg Med. 2014 Apr;63(4):437-447.