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Three Part Question

In [adult patients in status epilepticus] is [IV valproate or IV phenytoin better] at [terminating seizures].

Clinical Scenario

You are called to resus to see an adult with known epilepsy who has been brought in by ambulance in status epilepticus. The seizure is ongoing despite IM and IV midazolam boluses.

A phenytoin infusion is the widely accepted second line treatment for benzodiazepine-resistant seizures, however you are aware of draft guidelines suggesting the use of newer anticonvulsants such as valproate or levetiracetam.

Search Strategy

PubMed
(intravenous OR IV) AND (valproate OR valproic) AND status epilepticus.
Filters used: English language only.

Search Outcome

120 papers were found using the above search strategy. Manual review of search results resulted in relevant two RCTs and two systematic reviews (SRs). One further relevant paper was found on review of the references listed in the SRs.

A PubMed search was performed by the second checker using the search terms \'status phenytoin valproate\' with filters for studies including adults over 19 only and published in the last five years. An additional paper describing a retrospective case series was found using this method.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Misra et al 2006 India	Patients with status epilepticus (operational definition). Patients randomised to IV phenytoin or valprate as first line. 68 patients recruited (target 85).	Prospective RCT (level 2)	Clinical seizure cessation after infusion	65.7% (23/35) for valproate vs 42% (14/33) for phenytoin. p=0.046	Small sample size, therefore study underpowered. Open label study. Study includes 12 children, therefore not wholly applicable to this BET. Study population different to that seen in the typical \'Western\' ED - 55% had CNS infections as the cause of status epilepticus. Also, valproate or phenytoin are not typically used as first line drugs in status epilepticus.
			Seizure freedom at 24 hours	57% (8/14) for valproate vs 43.4% (10/26) for phenytoin. p=0.32
Agarwal et al 2007 India	Patients with benzodiazepine-resistant status epilepticus (operational definition), randomised to IV phenytoin or valproate with age and sex matching. 100 patients recruited - 50 each.	Prospective RCT - level 2.	Cessation of status epilepticus within 20 minutes of starting infusion	88% (44/50) with valproate vs 84% (42/50) with phenytoin. p>0.05	Randomisation method not described in paper. Study includes children, therefore not wholly applicable to this BET. Study population also likely to be different to that seen in the typical \'Western\' ED - 24 patients had infectious granulomas, 22 had CNS infections.
Gilad et al 2008 Israel	Adult patients in status epilepticus (formal definition) or acute repetitive seizures (>2 seizures in 6 hours different to usual pattern). 74 patients recruited - 27 had status epilepticus. Randomised to valproate or phenytoin (2:1 ratio). Both used as first line.	Prospective RCT - level 2.	Clinical seizure cessation without need for rescue medication	87.8% (43/49) with valproate vs 88% (22/25) with phenytoin. p value not listed.	Open label study. Majority of patients recruited had acute repetitive seizures rather than status epilepticus. Subgroup analysis of patients with status epilepticus showed valproate was less effective than phenytoin: clinical seizure cessation in 72.3% (13/18) with valproate vs 77.8% (7/9) with phenytoin. No p values listed.

Comment(s)

The two published systematic reviews found by the search method listed previously (Brigo et al 2011 and Liu et al 2012) both state that there is no significant difference between IV valproate and phenytoin in status epilepticus. While two of the RCTs listed did find there was no significant difference and one showed benefit in using valproate over phenytoin, it is doubtful whether this can be used to guide clinical practice in \'first world\' settings given the differences in aetiology and case mix. Two papers also studied the use of IV valproate or phenytoin as first line treatment for status epilepticus, which is contrary to established practice in \'Western\' medicine, where parenteral benzodiazepines are considered first line therapy. Given that IV phenytoin is widely accepted as second-line therapy for status epilepticus, these studies are not sufficient to recommend the use of IV valproate over phenytoin routinely.

Clinical Bottom Line

There is insufficient evidence that IV valproate is better than IV phenytoin. IV valproate may be considered as second-line therapy for status epilepticus if phenytoin is contra-indicated.

References

1. Misra UK, Kalita J, Patel R Sodium valproate vs phenytoin in status epilepticus: A pilot study Neurology 2006;67:340-342
2. Agarwal P, Kumar N, Chandra R, Gupta G, Antony AR, Garg N Randomized study of intravenous valproate and phenytoin in status epilepticus Seizure 2007;16:527-532
3. Gilad R, Izkovitz N, Dabby R, Rapoport A, Sadeh M, Wellber B, Lampl Y. Treatment of status epilepticus and acute repetitive seizures with i.v. valproic acid vs phenytoin. Acta Neurol Scand 2008;118:296-300