TEMKIN 1990: Prophylactic Phenytoin after Head Injury (1990)

“Prophylactic phenytoin is effective in preventing post-traumatic seizures during the first week after severe head injury, but not thereafter.”

— The Temkin et al. Study Group

1. Publication Details

  • Trial Title: A randomized, double-blind study of phenytoin for the prevention of post-traumatic seizures.
  • Citation: Temkin NR, Dikmen SS, Wilensky AJ, Keihm J, Chabal S, Winn HR. A randomized, double-blind study of phenytoin for the prevention of post-traumatic seizures. N Engl J Med. 1990;323(8):497-502. doi:10.1056/NEJM199008233230801.
  • Published: August 23, 1990, in The New England Journal of Medicine.
  • Author: Nancy R. Temkin, Ph.D.
  • Funding: National Institute of Neurological Disorders and Stroke.

2. Keywords

Traumatic Brain Injury (TBI), Head Injury, Post-Traumatic Seizures, Seizure Prophylaxis, Phenytoin, Anticonvulsants.

3. The Clinical Question

In adult patients with serious head injury (Population), does prophylactic treatment with phenytoin (Intervention) compared to placebo (Comparison) reduce the incidence of post-traumatic seizures (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Post-traumatic seizures are a common and serious complication of traumatic brain injury (TBI), divided into early (within 7 days) and late (>7 days) seizures. Prophylactic anticonvulsants, particularly phenytoin, were widely used to prevent them.
  • Knowledge Gap: The efficacy of prophylactic phenytoin was based on smaller, often inconclusive studies. It was unclear if phenytoin prevented both early and late seizures and whether any benefit outweighed its potential side effects. A large, definitive, placebo-controlled trial was needed.
  • Proposed Hypothesis: The authors hypothesized that prophylactic phenytoin would be effective in preventing both early and late post-traumatic seizures.

5. Study Design and Methods

  • Design: A prospective, multicenter, randomized, double-blind, placebo-controlled trial.
  • Setting: Four medical centers in Seattle, Washington.
  • Trial Period: Enrollment from 1984 to 1988.
  • Population:
    • Inclusion Criteria: Patients of any age with a serious head injury, defined by the presence of an intracranial hematoma, depressed skull fracture, penetrating brain injury, or early seizures within the first 24 hours.
    • Exclusion Criteria: Allergy to phenytoin, pregnancy, or severe systemic illness likely to be fatal.
  • Intervention: Phenytoin, administered as an intravenous loading dose followed by oral or intravenous maintenance doses to achieve therapeutic serum levels (10-20 µg/mL).
  • Control: Matching placebo, administered in the same manner.
  • Management Common to Both Groups: All patients received standard neurocritical care for their head injury. Serum drug levels were monitored in both groups, with clinicians blinded to the results.
  • Power and Sample Size: The trial was powered to detect a 50% reduction in the seizure rate, requiring approximately 400 patients.
  • Outcomes:
    • Primary Outcome: The occurrence of one or more post-traumatic seizures. The timing of seizures (early vs. late) was a key pre-specified analysis.
    • Secondary Outcomes: Included mortality, neurological outcome, and adverse effects of the study drug.

6. Key Results

  • Enrollment and Baseline: 404 patients were randomized (208 to phenytoin, 196 to placebo). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome:
    • Overall Seizures: There was a trend toward fewer seizures in the phenytoin group, but this did not reach statistical significance (14.9% vs 21.4%; P=0.08).
    • Early Seizures (Day 1-7): Phenytoin significantly reduced the incidence of early seizures compared to placebo (3.6% vs 14.2%; P<0.001).
    • Late Seizures (Day 8 onward): Phenytoin had no effect on the incidence of late seizures (12.5% vs 9.2%; P=0.32).
  • Secondary Outcomes: There were no significant differences in mortality or long-term neurological outcomes between the two groups.
  • Adverse Events: Adverse effects, primarily rash, were more common in the phenytoin group.

7. Medical Statistics

  • Analysis Principle: An intention-to-treat analysis was performed.
  • Statistical Tests Used: The primary outcome was analyzed using the log-rank test.
  • Primary Outcome Analysis: Time to first seizure was compared between the two groups.
  • Key Statistic(s) Reported:
    • Early Seizures (Day 1-7): 3.6% (phenytoin) vs 14.2% (placebo); P<0.001.
  • Interpretation of Key Statistic(s):
    • P-value:
      • Calculation: The reported p-value was <0.001.
      • Clinical Meaning: The p-value of <0.001 is far below the 0.05 threshold, indicating a highly statistically significant difference in the rate of early seizures. This result is very unlikely to be due to chance. A result is conventionally considered statistically significant if the p-value is less than 0.05.
  • Clinical Impact Measures (for Early Seizures):
    • Absolute Risk Reduction (ARR):
      • Formula: ARR = (Risk in Control Group) – (Risk in Intervention Group).
      • Calculation: ARR = 14.2% – 3.6% = 10.6%.
      • Clinical Meaning: For every 100 high-risk TBI patients treated with phenytoin, about 11 will be prevented from having an early seizure.
    • Number Needed to Treat (NNT):
      • Formula: NNT = 1 / ARR.
      • Calculation: NNT = 1 / 0.106 = 9.4, rounded to 10.
      • Clinical Meaning: Approximately 10 patients with severe head injury need to be treated with phenytoin to prevent one patient from having a seizure in the first week.
  • Subgroup Analyses: The benefit was consistent across different types of head injury.

8. Strengths of the Study

  • Study Design and Conduct: This was a methodologically rigorous, multicenter, randomized, double-blind, placebo-controlled trial.
  • Blinding and Monitoring: The meticulous blinding, including monitoring of serum levels in both groups, is a major strength.
  • Clear, Time-Defined Outcomes: The pre-specified analysis of early versus late seizures was crucial and provided a clear, nuanced answer.

9. Limitations and Weaknesses

  • Internal Validity (Bias): No major limitations to internal validity.
  • External Validity (Generalizability): The trial was conducted before the widespread use of levetiracetam, which is now a common alternative to phenytoin and has a more favorable side-effect profile.
  • Other: The study included patients of all ages, though the vast majority were adults.

10. Conclusion of the Authors

“Phenytoin is effective in preventing post-traumatic seizures in the first seven days after severe head injury. However, the prophylactic use of phenytoin does not prevent the development of late seizures (epilepsy).”

11. To Summarize

  • Impact on Current Practice: This was a landmark, practice-changing trial. It definitively established the role of prophylactic phenytoin in the management of severe TBI. It created the standard of care that is still reflected in guidelines today: a 7-day course of an anticonvulsant is recommended to prevent early seizures, but treatment beyond this period is not indicated for prophylaxis against late seizures (epilepsy).
  • Specific Recommendations:
    • Patient Selection: For adult patients with severe traumatic brain injury at high risk for seizures.
    • Actionable Intervention: Administer a 7-day course of an anticonvulsant (phenytoin or, by modern extension, levetiracetam).
    • Expected Benefit: A significant reduction in the incidence of early post-traumatic seizures, with an NNT of approximately 10.
  • What This Trial Does NOT Mean: This trial does not mean that anticonvulsants prevent the development of post-traumatic epilepsy. It clearly showed no benefit for preventing late seizures.
  • Implementation Caveats: The decision to use prophylaxis must balance the benefit of preventing early seizures against the side-effect profile of the chosen drug.

12. Context and Related Studies

  • Building on Previous Evidence: This trial was designed to provide a definitive answer to a question that had been addressed by many smaller, inconclusive studies.
  • Influence on Subsequent Research: The findings of this trial have been remarkably durable and have been consistently incorporated into TBI guidelines for over 30 years. Subsequent research has focused on comparing phenytoin to newer anticonvulsants with better safety profiles, such as the 2010 trial by Jones et al., which showed levetiracetam to be a safe and effective alternative.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: What is the optimal anticonvulsant agent for prophylaxis (phenytoin vs. levetiracetam)?
  • Future Directions: The focus of research has shifted to comparing the efficacy and safety of different anticonvulsant agents and developing strategies to prevent the development of late post-traumatic epilepsy, a goal which has so far remained elusive.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The question was of fundamental importance to neurocritical care and neurotrauma, addressing a common and morbid complication.
  • Methods: The study’s design (multicenter, randomized, double-blind, placebo-controlled) was of the highest quality and is a model for a well-conducted trial.
  • Results: The trial had a clear, nuanced result. It was “negative” for the overall prevention of seizures but strongly “positive” for the prevention of early seizures, while also being clearly “negative” for the prevention of late seizures. This level of detail was crucial.
  • Conclusions and Applicability: The authors’ conclusion is a direct and precise interpretation of the data. The results are highly applicable and have formed the unshakable foundation of clinical practice guidelines for post-traumatic seizure prophylaxis for decades.

16. Disclaimer and Contact

This summary is provided by the Academic Committee of ESBICM (ACE) to facilitate the understanding of this study; readers are advised to refer to the original trial document for a deeper understanding. If you find any information incorrect, or missing, or it needs an update or have a request for a specific critical care trial summary, kindly write to us at academics[at]esbicm.org.

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