Veterans Affairs Status Epilepticus Cooperative Study Group

Published

Veterans Affairs Status Epilepticus Cooperative Study Group. "A Comparison of Four Treatments for Generalized Convulsive Status Epilepticus". New England Journal of Medicine. 1998. 339(12):792-798.
PubMed • Full text • PDF

Clinical Question

Among patients with status epilepticus, which antiepileptic (lorazepam, phenobarbital, diazepam+phenytoin, or phenytoin alone) results in the largest proportion of 20 minute seizure termination without recurrence at 1 hour?

Bottom Line

Among patients with status epilepticus, lorazepam, phenobarbital, diazepam+phenytoin, and phenytoin alone were similarly effective, and lorazepam was more effective than phenytoin, as assessed by 20 minute seizure termination without recurrence at 1 hour.

Major Points

Generalized status epilepticus (GSE) is a neurological emergency with a high associated rate of mortality and morbidity. Historically, this has been defined as >30 minutes of continuous seizure activity or recurrent seizure activity without return to baseline. In more recent years, the definition was revised to more than 5 minutes of continuous seizure activity or recurrent seizure activity. This updated definition recognizes that seizures >5 minutes are much less likely to spontaneously terminate and animal studies suggested that permanent neuronal injury and resistance to treatment may set in between 5-30 minutes. Optimal management of GSE was unclear, and a prior small head-to-head trial had shown a higher rate of seizure control with IV lorazepam compared to diazepam. But there was a dearth of RCT evidence comparing other commonly used initial agents such as phenytoin or phenobarbital.

Published in 1998, the VA Status Epilepticus Cooperative Study randomized 570 patients with GSE to lorazepam, phenobarbital, phenytoin, or diazepam followed by phenytoin. Successful treatment was defined as resolution of clinical and EEG evidence of seizure activity within 20 minutes of treatment initiation, without recurrence by 60 minutes after therapy was initiated. The study demonstrated better seizure control with lorazepam compared to phenytoin as an initial agent in the context of overt convulsive GSE. The subsequent RAMPART trial (2012) found IM midazolam to be non-inferior to IV lorazepam in prehospitalized patients with GSE.

Guidelines

NCS Guidelines for the Evaluation and Management of Status Epilepticus (2012, adapted)

• Lorazepam (Class I, level A)
• Midazolam (Class I, level A)
• Diazepam (Class IIa, level A)
• Phenytoin/fosphenytoin (Class IIb, level A)
• Phenobarbital (Class IIb, level A
• Valproate Sodium (Class IIb, level A)
• Levetiracetam (Class IIb, level C)

Design

• Multicenter, double-blind, randomized controlled trial
• N=570
  • Overt GSE, N=395
    • Lorazepam (n=100)
    • Phenobarbital (n=92)
    • Diazepam + phenytoin (n=99)
    • Phenytoin alone (n=104)
  • Subtle GSE, N=175
    • Lorazepam (n=46)
    • Phenobarbital (n=41)
    • Diazepam + Phenytoin (n=47)
    • Phenytoin alone (n=41)
• Setting: 16 Veterans Affairs medical centers and 6 affiliated university hospitals in the US
• Enrollment: 1990-1995
• Analysis: Intention-to-treat (the "all" analysis), though the authors also performed an analysis among the subset with "verified" status
• Primary outcome: Proportion with successful treatment

Population

Inclusion Criteria

• Overt or subtle generalized convulsive status epilepticus, defined as seizure activity for >10 minutes or ≥2 seizures within 10 minutes without return to baseline
• Aged &ge'18

Exclusion Criteria

• Termination of seizure at time of assessment
• Pregnancy
• Requiring immediate neurosurgical intervention
• Contraindication to therapy with hydantoin, benzodiazepine, or barbiturate drugs
• If patients with repeated episodes of generalized convulsive status epilepticus were inadvertently enrolled more than once, only the first episode was included

Baseline Characteristics

From the overt GSE group

• Demographics: Age 59 years, male sex 82%, Veteran 71%
• Medical history: Acute seizures 54%, epilepsy 42%, status epilepticus 13%
• No prior treatment for current episode: 51%
• Duration of status at enrollment: 3h
• Causal factors: Remote neurological cause 70%, acute neurological cause 27%, life threatening medical condition 32%, cardiopulmonary arrest 6%, medication or recreational drugs 6%, EtOH withdrawal 6%

Interventions

• Randomized to one of four following interventions as initial treatment: 

  • Lorazepam 0.1 mg/kg, at 2 mg/min
  • Phenobarbital 15 mg/kg, at 100 mg/min
  • Diazepam+Phenytoin 0.15 mg/kg+18 mg/kg, at 5mg/min+50 mg/min
  • Phenytoin alone 18 mg/kg, at 50 mg/min
• Secondary treatments were provided to aid in concealment of drug identity of initial treatment if it failed:
  • Phenytoin was provided to those randomized to lorazepam or phenobarbital
  • Lorazepam was provided to those randomized to diazepam + phenytoin or phenytoin alone
• Tertiary treatments were provided to aid in concealment of drug identity of initial treatment if secondary treatment failed:
  • Phenobarbital was provided to those randomized to lorazepam, diazepam + phenytoin, or phenytoin alone.
  • Lorazepam was provided to those randomized to phenobarbital

Outcomes

Presented as lorazepam vs. phenobarbital vs. diazepam+phenytoin vs. phenytoin alone.

Primary Outcomes

Proportion with successful treatment

Defined as seizure termination within 20 minutes of treatment initiation without recurrence in first hour post treatment.

Verified generalized convulsive status epilepticus:

Overt GSE: 64.9% vs. 58.2% vs. 55.8% vs. 43.6% (χ² P=0.02)

Lorazepam vs. phenytoin: P=0.002

There were no differences between other arms in pairwise comparisons.

Subtle GSE: 17.9% vs. 24.2% vs. 8.3% vs. 7.7% (χ² P=0.18)

All enrolled (intention-to-treat):

Overt GSE: 67.0% vs. 63.0% vs. 59.6% vs. 51.0% (χ² P=0.12)

Subtle GSE: 26.1% vs. 24.4% vs. 23.4% vs. 19.5% (χ² P=0.91)

Adverse Events

Hypoventilation

Overt GSE: 10.3% vs. 13.2% vs. 16.8% vs. 9.9%

Subtle GSE: 12.8% vs. 15.2% vs. 2.9% vs. 7.7%

Hypotension

Overt GSE: 25.8% vs. 34.1% vs. 31.6% vs. 27.0%

Subtle GSE: 59.0% vs. 48.5% vs. 58.3% vs. 57.7%

Arrhythmia

Overt GSE: 7.2% vs. 3.3% vs. 2.1% vs. 6.9%

Subtle GSE: 7.7% vs. 9.1% vs. 5.6% vs. 0.0%

Criticisms

• Definition of status epilepticus use in the study was 10 minutes compared to the more commonly used 5 minutes definition used in recent years
• The definition of subtle convulsive status epilepticus likely included a population of what is now called non-convulsive status epilepticus as the criteria in the study was "with or without subtle convulsive movements".
• The population was predominantly male limiting the study's applicability

Funding

• Department of Veterans Affairs Medical Research Service Cooperative Studies Program
• Lorazepam and dummy lorazepam Tubexes donated by Wyeth-Ayerst Laboratories