Can intravenous sodium valproate be the first-line treatment in status epilepticus? A comparison study with intravenous phenytoin

Background: Status epilepticus (SE) is a serious neurological condition and requires prompt treatment. Sodium valproate has been used to treat SE successfully but its role as the first-line antiepileptic drug (AED) is still controversial. We aimed to compare the efficacy of intravenous sodium valproate and phenytoin head-to-head as the firstline AED treatment in SE. Methods: We enrolled patients diagnosed as SE during 2003-2010 who aged more than 15 years, received either intravenous sodium valproate or intravenous phenytoin as the first line treatment. Clinical characters and outcomes of SE were recorded and studied. The differences of outcomes between sodium valproate and phenytoin group were executed by descriptive statistics. Results: During the study period, there were 37 and 17 SE patients who received intravenous phenytoin and intravenous sodium valproate as the first-line treatment, respectively. There was no significant difference between phenytoin and sodium valproate group in all outcome variables including numbers of patients with clinically seizure controlled, non-dependent patients, and death, time to seizure control, and duration of hospitalization. No serious cardiovascular event such as hypotension occurred in both groups. Conclusion: Intravenous sodium valproate is as effective as intravenous phenytoin as the first-line treatment in SE with no significant cardiovascular compromise. Background Status epilepticus (SE) is an emergency condition that required proper and prompt treatment to prevent morbidity and mortality. Intravenous phenytoin is a main medication to treat SE. Recent and new antiepileptic drugs (AED) such as sodium valproate, lacosamide, levetiracetam or topiramate has potential benefit in treatment of SE [1-4]. Previous studies showed that intravenous sodium valproate may be a potential AED to be a effective in SE [1, 5]. It may be used as the first-line AED in SE with a good seizure control [5]. There is limited head to head clinical trial to compare the efficacy of intravenous phenytoin and sodium valproate in SE. This study aims to investigate the efficacy of both medications in the treatment of SE as the first-line AED. Methods We enrolled SE patients treated at Srinagarind hospital, Khon Kaen University, Thailand between 2003 and 2010. The inclusion criteria were patients with age more than 15 years, received either intravenous phenytoin or intravenous sodium valproate as the first line treatment. Data was retrieved from medical record including baseline characteristics, previous medical illnesses, causes of SE, laboratory findings, and outcomes of treatment. The outcomes of treatment were number of patients with clinically controlled, time to seizure control, admission duration, patient status after treatment, and death. Time to seizure control identified by the total minutes spent from the start of SE treatment to the time until no clinical evidence of seizure. Patient status after treatment was defined by patient functional capacity after discharge from the hospital and categorized as dependent or non-dependent status. The dependent status was a condition that the patients need someone to assist them to do activity daily of life. Baseline characteristics between phenytoin and sodium valproate group were compared by descriptive statistics. All outcome variables were also tested for the differences between those treated with phenytoin and sodium valproate. Potential clinical factors were included in the multiple logistic regression analysis to predict the significant or the most different outcome. The study protocol was approved by the ethical committee on human research of Khon Kaen University (HE541319). Results During the study period, there were 37 and 17 SE patients who received intravenous phenytoin and intravenous sodium valproate as the first-line treatment, respectively. There was no statistical significant difference in baseline clinical variables between both groups (Table 1). The median age was higher and the median time to start SE treatment was longer in sodium valproate group. The percentages of patients with male gender, epilepsy, and antiepileptic drug withdrawal were also higher in sodium valproate group. However, there was no statistical significant in terms of causes and pre-existing conditions of SE in both groups (Table 2 and 3). Regarding the treatment outcomes (Table 4), there was no significant difference between phenytoin and sodium valproate group in all outcome variables. The differences of numbers of clinically seizure controlled and death however were almost reached statistical significant level (p value = 0.057, and 0.052, respectively). The time to seizure control, duration of hospitalization, and the number of nondependent patients were better in sodium valproate group. No serious cardiovascular event such as hypotension occurred in both groups. Even though the percentage of non-dependent patients was not statistical significant between both groups, the difference of percentage between both groups was highest among five outcome variables (76.47% vs 54.05% or 22.42%). Potential clinical factors were analyzed by multiple logistic regression to find the predictors for this outcome. Serum albumin level was the only significant factor for non-dependent status of SE patients. The adjusted odds ratio was 3.000 (95% confidence interval 1.047, 8.601, p value 0.041). Discussion This study showed that intravenous sodium valproate is equally effective as intravenous phenytoin as the first-line treatment of SE. The intravenous sodium valproate had better all outcome variables (Table 4). Two outcome variables (numbers of seizure controlled and numbers of death) were almost reached the statistical significant level (p value 0.057 and 0.052, respectively). Our previous study [5] showed that intravenous sodium valproate can control SE better if used as the first-line compared to the second-line treatment (75% vs 35%). A meta-analysis of 5 randomized controlled trial also showed that intravenous sodium valproate had similar seizure control outcome in SE to intravenous phenytoin. Even though some causes or pre-existing conditions such as AED withdrawal induced SE may be easier to control [6], there was no statistical significance between both groups regarding these two factors (Table 2 and 3). The reason that intravenous sodium valproate was used commonly in our hospital during the study period is due to lack of intravenous phenobarbital. There was no serious cardiovascular compromise in patients received intravenous sodium valproate. It indicated that intravenous sodium valproate is safe and effective to use as the first-line treatment in SE. Previous studies also showed comparable efficacy of intravenous sodium valproate in SE compare to intravenous phenytoin. The most different outcome between intravenous sodium valproate and phenytoin is the number of non-dependent status patients (22.42%). Serum albumin was the only significant predictor for being non-dependent in SE patients (adjusted odds ratio 3.000). Increasing serum albumin level by 1 gm/dL increases the likelihood to be non-dependent by 3 times regardless of other characters. The explanation of this finding is that serum albumin is a marker for nutritional status. In other words, if SE patient is quite healthy prior to SE occurrence, the patient will have better functional status [6]. There are some limitations in the present study. The retrospective study design had incomplete data collection. However, the outcomes were recorded and the data provided almost significant outcomes. The other limitation is small number of patients in each group. Prospective study comparing intravenous phenytoin and intravenous sodium valproate as the first-line treatment in SE patients is needed to confirm that intravenous sodium valproate can be used as the first-line AED in SE