Management of generalised convulsive status epilepticus (SE): A prospective randomised controlled study of combined treatment with intravenous lorazepam with either phenytoin, sodium valproate or levetiracetam – Pilot study

Highlights

• 150 patients: randomised to phenytoin (50), valproate (50) and levetiracetam (50).

• Phenytoin group: seizures were controlled in 68% with lorazepam + phenytoin.

• Valproate group: seizures were controlled in 68% with lorazepam + valproate.

• Levetiracetam group: seizures were controlled in 78% with lorazepam + levetiracetam.

• Phenytoin, valproate, and levetiracetam are safe and equally efficacious.

Summary

Objective

This study was conducted to compare the efficacy of phenytoin, valproate and levetiracetam in patients with GCSE.

Methods

This randomised controlled prospective study was conducted on 150 patients to compare the efficacy of phenytoin (n = 50), valproate (n = 50) and levetiracetam (n = 50) along with lorazepam in patients with GCSE. All recruited patients received i.v. lorazepam (0.1 mg/kg) followed by one of the 3 AEDs viz. phenytoin (20 mg/kg), valproate (30 mg/kg), and levetiracetam (25 mg/kg). Those who remained uncontrolled with 1st AED, received the other two AEDs sequentially. Clinical, imaging, EEG, etiological factors were analysed. Predictors of poor seizure control and outcome at discharge and at one month follow-up were assessed.

Results

In the phenytoin subgroup, the seizures could be controlled in 34 (68%) with lorazepam + phenytoin infusion. In the valproate subgroup (n = 50), seizures could be controlled in 34 (68%) with lorazepam + valproate infusion. In the levetiracetam subgroup (n = 50), seizures could be controlled in 39 (78%) with lorazepam + levetiracetam infusion. There was no statistically significant difference between the subgroups (p = 0.44). Overall, following lorazepam and 1st AED, 107/150 (71.3%) were controlled; with addition of 2nd AED, 130/150 (86.7%) and by adding 3rd AED, 138/150 (92%) were controlled. Fifteen out of 110 (13.6%) expired within 1 month of SE: phenytoin-6; valproate-4; and levetiracetam-5. Interestingly, 3 patients in the levetiracetam had post-ictal psychosis.

Significance

Phenytoin, valproate, and levetiracetam are safe and equally efficacious following lorazepam in GCSE. The choice of AEDs could be individualised based on co-morbidities. SE could be controlled in 92% of patients with AEDs only and anaesthetics were not required in them.

Introduction

Status epilepticus (SE) is a common neurological emergency with significant mortality and morbidity (Logroscino et al., 2005, Rossetti et al., 2008). Benzodiazepines are drugs of choice in patients with convulsive status epilepticus (Treiman et al., 1998). The approved standard parenteral anti-epileptic drugs (AEDs) for the management of SE require have relative contraindications in those with systemic illnesses and hence require caution or require dose adjustment viz. phenytoin in patients with cardiac failure, and sodium valproate in patients with hepatic failure. Besides, they have several drug interactions with other medications. Intravenous levetiracetam has shown promising results in case reports and retrospective studies (Alvarez et al., 2011, Berning et al., 2009, Knake et al., 2008, Eue et al., 2009, Misra et al., 2012).

There are no systematic randomised controlled trials comparing phenytoin, valproate and levetiracetam in generalised convulsive SE (GCSE). The need for the same has been emphasised in many reviews (Yasiry and Shorvon, 2014, Prasad et al., 2007). As per the current guidelines, SE uncontrolled with benzodiazepines and another AED i.e. phenytoin or valproate, should be managed with anaesthetic agents like midazolam, thiopentone or propofol (Meierkord et al., 2010). Difficulties arise due to non-availability of ICU care in resource poor settings where there is a huge demand-supply gap.

This study was conducted to ascertain and compare the efficacy of phenytoin, sodium valproate and levetiracetam along with lorazepam in the management of GCSE, and to determine the possible causes of uncontrolled seizures.