Three Part Question
In [a child with a traumatic brain injury] does [phenytoin prophylaxis] prevent [subsequent seizures and/or improve neurological outcome]?
A 12 year old boy is admitted to the paediatric intensive care unit after a motor vehicle collision, where he sustained a severe closed head injury. He lost consciousness at the scene and was intubated in the Emergency Department for a Glasgow Coma Score of 8 and no gag reflex. The boy has no history of seizure activity in the past or at the scene. Your local "Traumatic Brain Injury Protocol" recommends that he receive phenytoin for seizure prophylaxis. You have recently cared for a child who nearly died from phenytoin hypersensitivity syndrome and would like to know if there is a good indication for the drug.
Medline using the Pubmed interface
(Craniocerebral Trauma/ AND Epilepsy, Post-Traumatic/ AND phenytoin/) AND Therapy filter
52 articles; after "therapy" filter - 4 relevant,
|Author, date and country
||Study type (level of evidence)
|McQueen JK et al,|
|164 patients ages 5 to 65 with serious head injuries (pts with seizures 1st week post injury excluded)||Double blind RCT (1b)||Late seizures ||No significant differences;Late sz ARR = -0.77% (CI = -9.59 to +8.04)||Loss to follow up at 2 years 1.2% (5% if include deaths)
Authors note based on low incidence of events, future trials will have to be ~6x larger than theirs to detect an effect.|
|Overall mortality||Mortality ARR = -3.45% (CI = -9.56 to +2.66)|
|Skin rashes||Rash ARR = -4.7% (CI = -10.32 to +0.91)|
|Young B et al,|
|41 head injured children; (total study 244 pts, adult data published separately with similar results)||Double blind RCT (2b)||(Early Seizures – data not published in this study, was collected for total study), Late Seizures, Overall Mortality||No significant differences, Late sz ARR = -5.75% (CI = -23.16 to +11.66); Mortality = 4.55% (CI = -14.88 to +23.88)||Loss to follow up at 2 years 26% for overall study for children (1 withdrawn, 4 deaths in first wk not included in analysis of final 41 pts), otherwise no loss to follow up.|
|Temkin NR et al,|
|404 patients with serious head trauma,16 years of age and older||Double blind RCT (1b) for early seizure outcome, but for late seizure outcome large loss to follow up in both groups at 2 years, thus (2b)||Early Seizures - Seizures in 1st week post injury||3.6% in treatment arm, 14.2% placebo, RR=0.27 (CI= 0.12-0.62)||24% loss to follow up at 24 months (22.5% in treatment group, 25% in placebo group).|
|Late Seizures - Seizures from Day 8 to the end of the year||No significant difference; 21.5% treatment 15.7% placebo RR=1.2 (CI = 0.71-2.02)|
|Overall mortality, skin rashes||No significant difference; Mortality ARR = - 2.64% (CI = -10.74 to +5.27); Rash ARR = - 3.35% (CI = -9.27% to +2.58)|
|Schierhout G et al,|
|6 controlled trials, 1218 randomized patients – includes studies with both adults and children, some studies used other anti-epileptics than phenytoin||Systematic review (1a)||Early seizures (seizures in 1st 7 days post-injury) Late seizures (sz after 1st 7 days post-injury)||RR for early sz prevention 0.34 (CI=0.21-0.54); NNT = 10; No ? mortality, RR=1.15 (CI = 0.89-1.51)||The early seizure prevention values represent 4 studies with phenytoin & 2 with other agents. Studies very heterogeneous in relation to late seizure outcome.|
|Mortality Neurologic disability, (Glasgow Outcome Score)||No ? in death & neurologic disability RR= 0.96 (CI=0.72-1.26);No ? in late seizures; Pooled RR =1.28 (CI=0.90-1.81)|
In addition to determining the potential efficacy of phenytoin as prevention for post-traumatic epilepsy, there are other important outcomes to bear in mind. Although anti-epileptics appear to decrease the rate of early seizures, this has not been demonstrated to result in a lower rate of post traumatic epilepsy, mortality or improved cognitive outcome. [1,3] In addition, multiple studies have shown that continued use of phenytoin in this population is associated with "negative effects on cognitive performance". 
One must also consider that phenytoin is not a benign drug. Although studies have not revealed a high rate of side effects in patients treated with phenytoin for one week post-injury, physicians must still be aware of the potential for not only serious but potentially fatal reactions to the drug. A search of the literature for adverse reactions to prophylactic phenytoin in head injured patients yielded case reports of intravenous site reactions , exfoliative dermatitis , granulocytopenia  and transient hemiparesis . In other patient populations, phenytoin has been associated with permanent B cell immunodeficiency  and fatal phenytoin hypersensitivity syndrome. There have also been multiple publications that demonstrate that total phenytoin levels can be normal in a trauma patient, yet be associated with high free, unbound levels due to low albumin levels. This may be associated with a higher rate of side effects at normal "therapeutic" levels. 
Recently, a Consensus guideline was published stating "the routine use of seizure prophylaxis later than 1 week following head injury is not recommended".  They recommend using a risk benefit analysis to decide whether phenytoin or carbamazepine should be considered for high-risk patients in the first week post- injury.
Clinical Bottom Line
1. In the first 7 days after serious head injury, phenytoin does prevent seizures in some patients, (NNT=10) but has not been shown to decrease mortality or post-traumatic epilepsy. For high risk patients, a physician must weigh the potential risks and benefits before making a decision. 2. If phenytoin is used in trauma patients, measure free, "unbound" phenytoin levels to avoid toxicity. 3. There is currently no indication for prophylactic phenytoin beyond the first week post head injury.
- McQueen JK, Blackwood DH, Harris P et al. Low risk of late post-traumatic seizures following severe head injury: implications for clinical trials of prophylaxis. J Neurol Neurosurg Psychiatry 1983;46(10):899-904.
- Young B, Rapp RP, Norton JA et al. Failure of prophylactically administered phenytoin to prevent post-traumatic seizures in children. Childs Brain 1983;10(3):185-92.
- Temkin NR, Dikmen SS, Wilensky AJ et al. A randomized, double-blind study of phenytoin for the prevention of post-traumatic seizures. N Engl J Med 1990;323(8):497-502.
- Schierhout G and Roberts I. Anti-epileptic drugs for preventing seizures following acute traumatic brain injury (Cochrane Review). In:The Cochrane Library 2001;Issue 3:Oxford:update software.
- Smith KR jr, Goulding PM, Wilderman D, et al. Neurobehavioral effects of phenytoin and carbamazepine in patients recovering from brain trauma: a comparative study. Arch Neurol 1994;51(7):653-60.
- Anderson GD, Lin Y, Temkin NR, et al. Incidence of intravenous site reactions in neurotrauma patients receiving valproate or phenytoin. Ann Pharmacother 2000;34(6):697-702.
- Rapp RP, Norton JA, Young B, et al. Cutaneous reactions in head-injured patients receiving phenytoin for seizure prophylaxis Neurosurgery 1983;13(3):272-5.
- Gabl M, Kostron H. Diphenylhydantoin induced granulocytopenia following seizure prophylaxis after a depressed skull fracture. Zentralbl Neurochir 1986;47(4):339-41.
- Sandyk R. Transient hemiparesis caused by phenytoin toxicity. A case report. S Afr Med J 1983;64(13):493.
- Guerra IC, Fawcett WA, Redmon AH, et al. Permanent intrinsic B cell immunodeficiency caused by phenytoin hypersensitivity. J Allergy Clin Immunol 1986;77(4):603-7.
- Mahadeva U, Al-Mrayat M, Steer K, et al. Fatal phenytoin hypersensitivity syndrome. Postgrad Med J 1999;75(890):734-6.
- Bauer LA, Edwards WA, Dellinger EP, et al. Importance of unbound phenytoin serum levels in head trauma patients. J Trauma 1983;23(12):1058-60.
- The Brain Trauma Foundation. The American Association of Neurological Surgeons. The Joint Section on Neurotrauma and Critical Care. Role of antiseizure prophylaxis following head injury. J Neurotrauma 2000;17(6-7):549-53.