Summary of evidence and Expert Committee recommendations
An application was submitted by Drs Satinder Aneja and Suvasini Sharma, Department of Pediatrics, Lady Hardinge Medical College and Kalawati Saran Children’s Hospital, New Delhi, for the addition of an intravenous formulation of valproic acid (sodium valproate) to the complementary list of the EML and EMLc for the treatment of established status epilepticus in adults and children.
Status epilepticus (SE) is considered as a medical emergency. Based on recent understanding of the pathophysiology, it is now considered that any seizure that lasts more than 5 minutes needs to be treated as SE (1). First-line treatment for SE is a benzodiazepine (lorazepam, diazepam, midazolam or clonazepam) given rectally, orally, IM or IV depending on the situation and the drug type (2). However, approximately one third of SE patients fail to respond to initial treatment with benzodiazepines and are considered to have established SE (ESE) (3).
Some 12–30% of adults with a new diagnosis of epilepsy present in SE (2). The annual incidence of SE in Europe is estimated at between 9.9 and 17.1 per 100 000 people, and in the United States at between 18.1 and 41 per 100 000 people (4-7). The incidence of SE varies with age, showing a bimodal distribution with peaks in early childhood and in elderly individuals (6-8). The condition is associated with an overall mortality of 8% in children and 30% in adults. An additional 5–10% of people suffering from SE have permanent sequelae, such as permanent vegetative state or cognitive difficulties (2). The standardized mortality ratio (SMR), the relative risk of mortality compared with the general population, for patients with long-term mortality associated with SE is 2.8 (95% CI: 2.1–3.5). In those aged more than 65 years SMR is 2.2 (95% CI: 1.6–2.9) and in those aged less than 65 years it is 5.1 (95% CI: 2.8–8.0) (9).
While benzodiazepines mainly potentiate GABA-induced chloride influx, sodium valproate is associated with multiple mechanisms of action: frequency-dependent prolongation of sodium channel inactivation, attenuation of calcium-mediated transient currents and augmentation of GABA (10). In addition, benzodiazepines have a relatively short duration of action. It is therefore proposed that for the maintenance of action, and thus the treatment
of established SE, IV sodium valproate might be added to benzodiazepines.
Limited evidence is available to guide the treatment of benzodiazepine-refractory status epilepticus. Currently, the first phase III clinical trial of ESE, the Established Status Epilepticus Treatment Trial (ESETT) is being carried out in children and adults to determine which of fosphenytoin, levetiracetam and sodium valproate is the most effective in terminating ESE (3).
The following studies presented effectiveness and safety results of use of IV sodium valproate in the treatment of established SE:
■ Yasiry & Shorvon, 2014 (11). Meta-analysis yielded a mean effect size for the efficacy of sodium valproate in benzodiazepine-resistant convulsive status epilepticus of 75.7% (95% CI: 63.7–84.8%). Efficacy of phenytoin was 50.2% (95% CI: 34.2–66.1%) and that of phenobarbital 73.6% (95% CI: 58.3–84.8%).
■ Malamiri, Ghaempanah, Khosroshahi, Nikkhah, Bavarian & Ashrafi, 2012 (12). This randomized, double-blind study compared the efficacy and safety of IV sodium valproate with IV phenobarbital in children with status epilepticus not responding to IV diazepam. No difference in efficacy in terms of seizure cessation was found (27/30 in the sodium valproate group versus 23/30 in the phenobarbital group). Seizure recurrence rates within 24 hours were higher in the phenobarbital (12/23) group compared with the sodium valproate group (4/27) (Fisher exact test, P = 0.004). The overall occurrence of clinical adverse effects was higher in the phenobarbital group (22/30) than in the valproate group (7/30) (Fisher exact test, P < 0.001).
■ Agarwal, Kumar, Chandra, Gupta, Antony & Garg, 2007 (13). In a randomized, open-label trial of sodium valproate versus phenytoin in patients (adults and children) with status epilepticus who did not respond to first-line IV diazepam, there was a statistically nonsignificant difference for reducing risk of non-cessation of seizures between IV valproate and IV phenytoin (6/50 versus 8/50; RR 0.75; 95% CI: 0.28–2.00). The overall occurrence of clinical adverse effects was higher in the phenytoin (8/50) group than in the valproate (5/50) group.
The incidence of adverse events for IV sodium valproate in SE overall is limited (10–20%) and includes dizziness, thrombocytopenia, and mild hypotension, which was independent of infusion rates. Cardiovascular and respiratory tolerability is good even for high doses and fast infusion rates (up to 30 mg/kg at 10 mg/kg per minute) (14). Mild hyperammonaemia and mild thrombocytopenia have been reported in a few patients. Overall, the efficacy–
safety profile could be considered favourable.
In January 2015, the Medicines and Healthcare Products Regulatory Agency (MHRA) strengthened its warnings on the use of valproate in women of childbearing potential, based on the information that children exposed to valproate in the womb are at an approximately 11% risk of malformations at birth compared with a 2–3% risk for children in the general population (15-17).
Hepatic failure resulting in fatalities has occurred in patients receiving sodium valproate (18). Patients with a hepatic disease or hepatic dysfunction should not be given IV sodium valproate.
There are no data on cost–effectiveness, and no systematic cost comparison data available. The cost of IV sodium valproate differs from country to country. In Australia sodium valproate IV is around 60 Australian dollars per 400 mg vial, phenobarbital $A4 per vial and phenytoin $A3 per vial. In India, by contrast, sodium valproate for injection is around Rs6 per 100 mg (Rs24 or US$ 0.4 for 400 mg), IV phenytoin Rs5 per 100 mg, and IV phenobarbital Rs12 per 100 mg (US$ 1 is about Rs60). For a 10-kg child, at the standard 20 mg/kg dose, the cost would be Rs12 for IV sodium valproate, Rs10 for IV phenytoin and Rs24 for IV phenobarbital.
Patients with status epilepticus who receive IV sodium valproate will need monitoring of vital signs, oxygenation and respiratory efforts. Liver function tests and complete blood counts are also needed.
The Expert Committee acknowledged that there is limited evidence available in favour of IV sodium valproate for the treatment of benzodiazepine-refractory status epilepticus. While recognizing the importance of effective management strategies for benzodiazepine-refractory status epilepticus and emphasizing the need for high-quality head-to-head randomized controlled trials to compare the effectiveness and safety of antiepileptic medicines in SE, the Expert Committee recognizes the difficulty of ascertaining whether some antiepileptic medicines are more effective than others.
Randomized controlled trials comparing antiepileptic medicines (phenytoin, carbamazepine, valproic acid) in children and adults with convulsive epilepsy provide indirect evidence of the role of valproic acid in the treatment of SE (48, 49). It is unlikely that there is a clinically relevant difference between valproic acid and the other antiepileptic medicines. All antiepileptic medicines are associated with important adverse effects. Sodium valproate is associated with a higher risk of fetal malformations if taken in pregnancy. Rarely, sodium valproate has been associated with fulminant hepatic failure and hyperammonemia, particularly in young children (14).
The Committee noted advice from the WHO Mental Health and Substance Abuse Department which stated that the Guideline Development Group, on review of synthesized evidence following GRADE methodology, has suggested a conditional recommendation for IV sodium valproate to be preferred to IV phenobarbital or IV phenytoin, despite similar efficacy, because of its superior risk–benefit profile. The Expert Committee therefore considered it was reasonable to recommend addition of IV valproic acid (sodium valproate) to the complementary list of the EML and EMLc for the treatment of benzodiazepine-refractory status epilepticus.
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