A randomized, double-blind study of phenytoin for the prevention of post-traumatic seizures

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Clinical Question

In patients with traumatic brain injury, does phenytoin prevent early and/or late post-traumatic seizures?

https://www.ncbi.nlm.nih.gov/pubmed/2115976

Bottom Line

Phenytoin prevents post-traumatic seizures for the first week after severe TBI.

Major Points

Post-traumatic seizures (PTS) are a common complication of traumatic brain injury. Antiepileptic drugs (AEDs) have been used for PTS prophylaxis for decades, but prior to the Temkin trial, there was not conclusive literature to guide their use in this setting. Much of the existing literature focused on phenytoin, a commonly used AED for PTS prophylaxis. Some retrospective studies supported its use, while several prospective, double-blind trials failed to show benefit over placebo. However, these studies were criticized because they lacked statistical power and often phenytoin levels were either not measured or subtherapeutic. The Temkins study aimed to evaluate the effectiveness of high therapeutic levels of phenytoin in preventing early (24-hours to 7-days after injury) and late (after day 7) PTS.

In this study, patients were randomized to receive either phenytoin or placebo for a year post-injury. Of 586 recruited patients, 404 met eligibility requirements with 208 assigned to the phenytoin group and 196 to the placebo group. The groups had similar baseline characteristics with regard to demographics, cause of injury, and severity of injury. Drug levels were measured throughout the study with dosage adjustments made as needed to keep levels in the high therapeutic range. During the first week of the study, the phenytoin group had a significantly lower rate of seizures (3.6% vs. 14.2%, P<0.001). However, there was no between-group significant difference in the rate of seizures between day 8 and year 1 (21.5% vs. 15.7%, P>0.2) or by the end of year 2 (27.5% vs. 21.1%, P>0.2). The authors conclude that phenytoin reduces the incidence of seizures in the first week after injury, but not after.

The results of the trial led to level II recommendation to medicate TBI patients with phenytoin for 7 days for seizure prophylaxis [1]. Despite recommendation for phenytoin as the first-line AED, levatiracetam has become a popular alternative. Levatiracetam has a superior side effect profile compared to phenytoin and does not require drug level monitoring. One retrospective analysis of 90 patients evaluated effectiveness of levatiracetam (18 patients) compared to phenytoin (72 patients) for seizure prophylaxis and found similar incidence of EEG-proven PTS[2]. A prospective trial comparing efficacy of phenytoin with levatiracetam for preventing early PTS found no difference in seizure rate, adverse drug reactions, or mortality between the two[3]. Both phenytoin and levatiracetam continue to be frequently used AEDs for PTS prophylaxis in the first week after traumatic brain injury.

Guidelines

  • Phenytoin is recommended to decrease the incidence of early post-traumatic seizures (Level IIA, class 2)
  • Prophylactic use of phenytoin is not recommended for preventing late post-traumatic seizures (Level IIA, class 2) [4]

Design

  • Single center, randomized, double-blind trial
  • N=404
    • Phenytoin (n=208)
    • Placebo (n=196)
  • Setting: Single Level I trauma center in the United States
  • Enrollment: November 1983 – December 1987
  • Mean follow-up: 24 months
  • Analysis: intention to treat
  • Primary outcome: incidence of seizure during early (drug-loading to day 7) and late (after day 7) post-traumatic periods
  • Secondary outcome: mortality; adverse events of phenytoin

Population

Inclusion Criteria

At least one of the following:

  • Cortical concussion visible on CT scanning
  • A subdural, epidural, or intracerebral hematoma
  • A depressed skull fracture
  • A penetrating head wound
  • A seizure within 24 hours of injury
  • A score of 10 or less on the Glasgow Coma Scale on admission

Exclusion Criteria

  • Age less than 16 years
  • Interval of more than 24 hours between injury and loading of the study drug
  • Pregnancy or lactation
  • Inability to speak English
  • History of severe alcoholism
  • Previous head injury
  • Premorbid history of seizures or administration of anti-seizure medication before study-drug loading
  • Previous neurosurgery involving penetration of the dura
  • Previous neurologic condition that could predispose patient to seizures

Baseline Characteristics

Characteristics are phenytoin vs. placebo group

  • Mean age (years): 34 vs. 34
  • Sex (% male): 78 vs. 75
  • Marital status (% single): 74 vs. 75
  • Race (% white): 86 vs. 87
  • External cause of injury (% of group)
    • Automobile: 34 vs. 31
    • Motorcycle: 18 vs. 19
    • Pedestrian: 13 vs. 12
    • Fall: 15 vs. 15
    • Assault, fight, suicide attempt: 14 vs. 11
    • Other: 6 vs. 11
  • Severity of injury (% of group)
    • GCS less than or equal to 10: 60 vs. 67
    • Cortical contusion: 49 vs. 49
    • Depressed skull fracture: 17 vs. 16
    • Subdural hematoma: 35 vs. 42
    • Epidural hematoma: 18 vs. 16
    • Intracerebral hematoma: 20 vs. 18
    • Penetrating head wound: 8 vs. 7
    • Seizure within 24 hours: 6 vs. 8

Interventions

  • Patients randomized to receive phenytoin or placebo for one year
  • Initial dose of 20mg/kg was given within 24 hours of injury
  • Serum phenytoin levels were measured three times weekly in intensive care, at least weekly in acute care, and during clinic follow-up visits 1, 3, 6, 9, and 12 months after injury
  • Dosages were adjusted in phenytoin group to keep levels in high therapeutic range; similar adjustments were made in placebo group to ensure blinding
  • At the end of 12 months, patients were tapered off phenytoin or placebo
  • Patients were followed for 24 months

Outcomes

Comparisons are phenytoin vs placebo

Primary Outcomes

Early seizures (drug loading to day 7)
3.6% vs. 14.2% (P<0.001)
Late seizures (day 8 to year 2)
By year 1: 21.5% vs. 15.7% (P>0.2)
By year 2: 27.5% vs. 21.1% (P>0.2)

Adverse Events

  • Rash (25 vs. 17 patients)
  • Other reactions, including leukopenia and elevated liver function tests (12 vs. 8 patients)

Funding

The study was supported by a grant from the National Institutes of Health and a grand from Waner-Lambert/Parke-Davis.

Further Reading