IV Valproic Acid vs Phenytoin: Old Standby or the New Challenger?

Abstract & Commentary

By Padmaja Kandula, MD, Assistant Professor of Neurology and Neuroscience, Comprehensive Epilepsy Center, Weill Medical College, Cornell University. Dr. Kandula reports no financial relationships relevant to this field of study. This article originally appeared in the December 2008 issue of Neurology Alert. It was edited by Matthew Fink, MD, and peer reviewed by M. Flint Beal, MD. Dr. Fink is Vice Chairman, Professor of Neurology, Weill Cornell Medical College; Chief of Division of Stroke and Critical Care Neurology, NewYork-Presbyterian Hospital, and Dr. Beal is Professor and Chairman, Department of Neurology, Cornell University Medical College. Drs. Fink and Beal report no financial relationships relevant to this field of study.

Synopsis: Valproic acid and phenytoin were equally effective in the treatment of acute repetitive seizures and status epilepticus.

Source: Gilad R, et al. Treatment of status epilepticus and acute repetitive seizures with i.v. valproic acid vs phenytoin. Acta Neurol Scand. 2008;118:296-300.

Historically, benzodiazepines and phenytoin have been used as first-line therapy in aborting status epilepticus (SE). The rationale for use of these two agents mainly rests on the 1998 results of the Veterans Affairs Cooperative Trial. The greatest response rate was seen in those patients who received benzodiazepines in addition to phenytoin (PHT), rather than PHT alone. Although the intravenous formulation of valproic acid (VPA) was officially approved by the FDA in 1996, the agent was not included in the Veterans Affairs Cooperative Trial and still has not received approval by the FDA for use in SE. Nevertheless, despite the lack of FDA approval, IV VPA continues to be used off-label by clinicians. Therefore, papers such as this one by Gilad et al are critical in defining the exact role of VPA in both acute repetitive seizures (ARS) and SE.

Seventy-four adult patients with either ARS or SE, older than age 18, were included in this open-label study. Patients with baseline abnormal liver function tests or previous toxic serum levels of VPA were excluded from the study. For this study, SE was defined as greater than 30 minutes of continuous seizure activity or two or more sequential seizures without clinical recovery. ARS was defined as two or more repetitive seizures with clinical recovery between seizures during a 5- to 6-hour period. The primary endpoint was cessation of clinical seizure activity within 20 minutes of either VPA or PHT infusion, without rescue medication intervention. The secondary endpoint was assessment of infusion tolerability over the subsequent 24 hours.

The IV VPA patient group received 30 mg/kg given over 20 minutes. The PHT patient group received an infusion of 18 mg/kg, also given over 20 minutes. Patients were treated randomly in the emergency room in a 2:1 ratio of either VPA or PHT infusion. If seizure control was not achieved by infusion of the first study drug, then patients were treated with the other study drug. Patients who failed both study drug infusions were then treated with IV midazolam at a dosage of 0.2 mg/kg and were subsequently transferred to the intensive care unit. Electroencephalography was performed in select cases of clinically suspected non-convulsive status where patients did not regain consciousness.

Forty-nine patients were treated with IV VPA and 25 patients were treated with PHT. Nearly two-thirds of patients in the study experienced breakthrough seizures secondary to subtherapeutic anti-epileptic drug levels or non-compliance. Post-stroke epilepsy made up approximately 25% of patients. Twelve percent of both the IV VPA and IV PHT groups required rescue medication. No significant side effects were found in the VPA group. One patient in the PHT group (no prior cardiac history) experienced ventricular premature beats during the infusion, one experienced vertigo, and one was noted to develop hyponatremia.

Commentary

In this study, IV VPA treatment was as efficacious as IV PHT treatment as first-line treatment for ARS and SE. Other studies also have documented the efficacy of IV VPA; however, lack of uniformity in loading doses of IV VPA and rate of infusion make any definite conclusions about VPA in acute treatment of seizures difficult. Although this particular study was prospective, the open-label nature of the study introduces potential bias. Also, more than two-thirds of the patients were acute repetitive patients, rather than patients in SE, potentially influencing an overall better outcome for either PHT or VPA infusion.

Despite the above design flaws, Gilad et al present some compelling evidence for the use of VPA. This study and others have shown good tolerability of IV VPA. In our center, IV VPA has been used as a second- line (in cases of phenytoin allergy) or third-line agent in the treatment of SE, before the use of phenobarbital, particularly in patients in whom intubation is not being considered. Multiple studies have shown good tolerability of IV VPA at a rate of 6 mg/kg/min.1-6 Theoretically, with an infusion rate of 6 mg/kg/min and dosage of 25-30 mg/kg, in an average 70 kg individual, IV VPA can be administered in approximately 5 minutes. There are also particular instances where VPA would be the agent of choice in aborting status, such as absence of status epilepticus.

As awareness of SE grows, more prompt treatment of this neurologic emergency hopefully will result in less need to proceed to anesthetic agents. Valproic acid, with its relatively rapid onset of action and minimal side effects, may evolve into an attractive choice in the treatment of SE and ARS.

References

1. Ramsay RE, et al. Safety and tolerance of rapidly infused Depacon. A randomized trial in subjects with epilepsy. Epilepsy Res. 2003;52:189-201.

2. Sinha S, Naritoku DK. Intravenous valproate is well tolerated in unstable patients with status epilepticus. Neurology. 2000;55:722-724.

3. Venkataraman V, Wheless JW. Safety of rapid intravenous infusion of valproate loading in epilepsy patients. Epilepsy Res. 1999;35:147-153.

4. Wheless J, Venkataraman V. Safety of high intravenous valproate loading doses in epilepsy patients. J Epilepsy. 1998;11:319-324.

5. Naritoku DK, Mueed S. Intravenous loading of valproate for epilepsy. Clin Neuropharmacol. 1999;22: 102-106.

6. Wheless JW, et al. Rapid infusion with valproate sodium is well tolerated in patients with epilepsy. Neurology. 2004;63:1507-1508.