Veterans Affairs Status Epilepticus Cooperative Study Group

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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.
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Clinical Question

What is the best initial agent for seizure termination in patients presenting in overt and subtle generalized convulsive status epilepticus when choosing between four options: diazepam (0.15 mg/kg of body weight) followed by phenytoin (18 mg/kg), lorazepam (0.1 mg per kilogram), phenobarbital (15 mg/kg), or phenytoin (18 mg/kg).

Bottom Line

Intention to treat analysis did not detect any differences between the four treatment groups in either patients having overt or subtle generalized status epilepticus. In a paired analysis for overt generalized convulsive status epilepticus, lorazepam is more effective than phenytoin as an initial agent.

Major Points

Generalized status epilepticus (GSE) is a neurological emergency with a high associate rate of mortality and morbidity. Historically, this has been defined as more than 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 was done because it was recognized that seizures extending past 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. [1] [2] [3]

The optimal initial treatment of GSE depends on setting and available expertise. Prior to the Veterans Affairs Status Epilepticus Cooperative Study, a small head to head trial had shown a higher rate of seizure control with IV lorazepam compared to diazepam.[4] There was a dearth of RCT evidence comparing other commonly used initial agents such as phenytoin or phenobarital. This trial showed better seizure control with lorazepam compared to phenytoin as an initial agent in the context of overt generalized convulsive status epilepticus. The subsequent RAMPART study showed that IM Midazolam is non-inferior to IV lorazepam in prehospitalized patients with GSE.

Guidelines

Emergent treatment for status epilepticus (Adapted from 2014 Neurocritical Care Society's Guidelines for the Evaluation and Management of Status Epilepticus):

  • Lorazepam (Class I, level A) Recommended dose: 0.1 mg/kg IV up to 4 mg per dose, may repeat in 5–10 min
  • Midazolam (Class I, level A) Recommended dose: 0.2 mg/kg IM up to maximum of 10 mg
  • Diazepam (Class IIa, level A) Recommended dose: 0.15 mg/kg IV up to 10 mg per dose, may repeat in 5 min
  • Phenytoin/fosphenytoin (Class IIb, level A) Recommended dose: 20 mg phenytoin equivalence/kg IV, may give additional 5 mg/kg
  • Phenobarbital (Class IIb, level A) Recommended dose: 20 mg/kg IV, may give an additional 5–10 mg/kg
  • Valproate Sodium (Class IIb, level A) Recommended dose: 20–40 mg/kg IV, may give an additional 20 mg/kg
  • Levetiracetam (Class IIb, level C) Recommended dose: 1,000–3,000 mg IV, 20–60 mg/kg IV in pediatrics

Design

  • Multicenter, double-blind, randomized controlled trial
  • N=570
    • Overt GSE: 395
      • Lorazepam: 100
      • Phenobarbital:92
      • Diazepam + phenytoin: 99
      • Phenytoin: 104
    • Subtle GSE: 175
      • Lorazepam: 46
      • Phenobarbital:41
      • Diazepam + Phenytoin: 47
      • Phenytoin: 41
  • Setting: 16 Veterans Affairs medical centers and 6 affiliated university hospitals in the US
  • Enrollment: July 1, 1990-June 30, 1995
  • Analysis: Intention-to-treat
  • Primary outcome: Clinical and electrical evidence of termination of seizure within 20 minutes of start of treatment without recurrence in the 20-60 minute period after treatment initiation

Population

Inclusion Criteria

  • Evidence of overt or subtle generalized convulsive status epilepticus at the time of evaluation (defined as seizure activity for more than 10 minutes or two or more seizures within 10 minutes without return to baseline).
  • Age over 18

Exclusion Criteria

  • Termination of seizure at time of assessment
  • Pregnancy
  • A neurological emergency requiring immediate surgical 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

For Overt GSE
  • Age (yr±SD): 58.6±15.6
  • Veteran (%): 70.1
  • Male sex (%): 82.3
  • Not previously treated for current episode (%): 51.3
  • History of acute seizures (%): 54.2
  • History of epilepsy (%): 42.4
  • History of status epilepticus (%): 12.8
  • Median duration of status epilepticus at enrollment (hr) 2.8
  • Causal factors (%):
    • Remote neurological cause:69.5
    • Acute neurological cause:27.3
    • Life-threatening medical condition:32.0
    • Cardiopulmonary arrest:6.3
    • Toxic effects of therapeutic or recreational drug:6.3
    • Alcohol withdrawal:6.5

For Subtle GSE

  • Age (yr±SD): 62.0±15.1
  • Veteran (%): 80.6
  • Male sex (%): 85.1
  • Not previously treated for current episode (%): 51.5
  • History of acute seizures (%): 25.4
  • History of epilepsy (%): 12.7
  • History of status epilepticus (%): 4.5
  • Median duration of status epilepticus at enrollment (hr) 5.8
  • Causal factors (%):
    • Remote neurological cause:34.3
    • Acute neurological cause:37.3
    • Life-threatening medical condition:56.7
    • Cardiopulmonary arrest:38.1
    • Toxic effects of therapeutic or recreational drug:5.2
    • Alcohol withdrawal:0.7

Interventions

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

    • Lorazepam 0.1 mg/kg, at 2 mg/min, drug solution concentrations of 4 mg/ml
    • Phenobarbital 15 mg/kg, at 100 mg/min, drug solution concentrations of 100 mg/ml
    • Diazepam + Phenytoin 0.15 and 18 mg/kg, at 5 and 50 mg/min, drug solution concentrations of 5 and 50 mg/ml
    • Phenytoin 18 mg/kg, at 50 mg/min, drug solution concentrations of 50 mg/ml
  • 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

Primary Outcomes

Results given in format: lorazepam vs. phenobarbital vs. diazepam and phenytoin vs. phenytoin (no significant difference between groups)

Rate of seizure termination within 20 minutes of treatment initiation without recurrence in first hour post treatment (among all enrolled)
Overt GSE (%):67.0 vs. 63.0 vs. 59.6 vs. 51.0
Subtle GSE (%):26.1 vs. 24.4 vs. 23.4 vs. 19.5
Rate of seizure termination within 20 minutes of treatment initiation without recurrence in first hour post treatment (among those with verified GSE)
Overt GSE (%): 64.9 vs. 58.2 vs. 55.8 vs. 43.6
Subtle GSE (%): 17.9 vs. 24.2 vs. 8.3 vs. 7.7

Adverse Events

Results given in format: lorazepam vs. phenobarbital vs. diazepam and phenytoin vs. phenytoin

  • In Overt GSE group, number of patients: 97 vs. 91 vs. 95 vs. 101
    • Hypoventilation(%): 10.3 vs. 13.2 vs. 16.8 vs. 9.9
    • Hypotension (%): 25.8 vs. 34.1 vs. 31.6 vs. 27.0
    • Cardiac-rhythm disturbance (%): 7.2 vs. 3.3 vs. 2.1 vs. 6.9
  • In Subtle GSE group, number of patients: 39 vs. 33 vs. 36 vs. 26
    • Hypoventilation(%): 12.8 vs. 15.2 vs. 2.9 vs. 7.7
    • Hypotension (%): 59.0 vs. 48.5 vs. 58.3 vs. 57.7
    • Cardiac-rhythm disturbance (%): 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

Further Reading

  1. Lowenstein DH. Current concepts: status epilepticus. N Engl J Med. 1998;338(14):970
  2. Meldrum BS, Horton RW. Physiology of status epilepticus in primates. Arch Neurol. 1973;28(1):1–9.
  3. Mazarati AM. Time-dependent decrease in the effectiveness of antiepileptic drugs during the course of self-sustaining status epilepticus. Brain Res. 1998;814(1–2):179
  4. Leppik IE, Derivan AT, Homan RW, Walker J, Ramsay RE, Patrick B. Double-blind study of lorazepam and diazepam in status epilepticus. JAMA. 1983;249(11):1452–4