More harm than good: Antiseizure prophylaxis after traumatic brain injury does not decrease seizure rates but may inhibit functional recovery. (Petrillo)

Bhullar IS, Johnson D, Paul JP, Kerwin AJ, Tepas JJ 3rd, Frykberg ER. More harm than good: Antiseizure prophylaxis after traumatic brain injury does not decrease seizure rates but may inhibit functional recovery. J Trauma Acute Care Surg. 2014 Jan;76(1):54-61.

BACKGROUND: The purposes of this study were to examine the current Brain Trauma Foundation recommendation for antiseizure prophylaxis with phenytoin during the first 7 days after traumatic brain injury (TBI) in preventing seizures and to determine if this medication affects functional recovery at discharge.

METHODS: The records of adult (age ≥ 18 years) patients with blunt severe TBI who remained in the hospital at least 7 days after injury were retrospectively reviewed from January 2008 to January 2010. Clinical seizure rates during the first 7 days after injury and functional outcome at discharge were compared for the two groups based on antiseizure prophylaxis, no prophylaxis (NP) versus phenytoin prophylaxis (PP). Statistical analysis was performed using χ.

RESULTS: A total of 93 adult patients who met the previously mentioned criteria were identified (43 [46%] NP group vs. 50 [54%] PP group). The two groups were well matched. Contrary to expectation, more seizures occurred in the PP group as compared with the NP group; however, this did not reach significance (PP vs. NP, 2 [4%] vs. 1 [2.3%], p = 1). There was no significant difference in the two groups (PP vs. NP) as far as disposition are concerned, mortality caused by head injury (4 [8%] vs. 3 [7%], p = 1), discharge home (16 [32%] vs. 17 [40%], p = 0.7), and discharge to rehabilitation (30 [60%] vs. 23 [53%], p = 0.9). However, with PP, there was a significantly longer hospital stay (PP vs. NP, 36 vs. 25 days, p = 0.04) and significantly worse functional outcome at discharge based on Glasgow Outcome Scale (GOS) score (PP vs. NP, 2.9 vs. 3.4, p < 0.01) and modified Rankin Scale score (2.3 ± 1.7 vs. 3.1 ± 1.5, p = 0.02).

CONCLUSION: PP may not decrease early posttraumatic seizure and may suppress functional outcome after blunt TBI. These results need to be verified with randomized studies before recommending changes in clinical practice and do not apply to penetrating trauma.

LEVEL OF EVIDENCE: Therapeutic study, level IV; epidemiologic study, level III.

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Therapeutic hypothermia decreases phenytoin elimination in children with traumatic brain injury. (Carmean)

Empey PE, de Mendizabal NV, Bell MJ, Bies RR, Anderson KB, Kochanek PM, Adelson PD, Poloyac SM; for the Pediatric TBI Consortium: Hypothermia Investigators. Therapeutic hypothermia decreases phenytoin elimination in children with traumatic brain injury. Crit Care Med. 2013 Oct;41(10):2379-2387.

OBJECTIVE: Preclinical and clinical studies have suggested that therapeutic hypothermia, while decreasing neurologic injury, may also lead to drug toxicity that may limit its benefit. Cooling decreases cytochrome P450 (CYP)-mediated drug metabolism, and limited clinical data suggest that drug levels are elevated. Fosphenytoin is metabolized by cytochrome P450 2C, has a narrow therapeutic range, and is a commonly used antiepileptic medication. The objective of this study was to evaluate the impact of therapeutic hypothermia on phenytoin levels and pharmacokinetics in children with severe traumatic brain injury.

DESIGN: Pharmacokinetic analysis of subjects participating in a multicenter randomized phase III study of therapeutic hypothermia for severe traumatic brain injury.

SETTING: ICU at the Children’s Hospital of Pittsburgh.

PATIENTS: Nineteen children with severe traumatic brain injury.


MEASUREMENTS AND MAIN RESULTS: A sum of 121 total and 114 free phenytoin levels were evaluated retrospectively in 10 hypothermia-treated and nine normothermia-treated children who were randomized to 48 hours of cooling to 32-33°C followed by slow rewarming or controlled normothermia. Drug dosing, body temperatures, and demographics were collected during cooling, rewarming, and posttreatment periods (8 d). A trend toward elevated free phenytoin levels in the hypothermia group (p = 0.051) to a median of 2.2 mg/L during rewarming was observed and was not explained by dosing differences. Nonlinear mixed-effects modeling incorporating both free and total levels demonstrated that therapeutic hypothermia specifically decreased the time-variant component of the maximum velocity of phenytoin metabolism (Vmax) 4.6-fold (11.6-2.53 mg/hr) and reduced the overall Vmax by ~ 50%. Simulations showed that the increased risk for drug toxicity extends many days beyond the end of the cooling period.

CONCLUSIONS: Therapeutic hypothermia significantly reduces phenytoin elimination in children with severe traumatic brain injury leading to increased drug levels for an extended period of time after cooling. Pharmacokinetic interactions between hypothermia and medications should be considered when caring for children receiving this therapy.

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A prospective multicenter comparison of levetiracetam versus phenytoin for early posttraumatic seizure prophylaxis. (from Journal of Acute Care & Surgery, March 2013 – Petrillo)

J Trauma Acute Care Surg. 2013 Mar;74(3):766-73. PMID: 23425733

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BACKGROUND: Brain Trauma Foundation guidelines recommend seizure prophylaxis for preventing early posttraumatic seizure (PTS). Phenytoin (PHE) is commonly used. Despite a paucity of data in traumatic brain injury, levetiracetam (LEV) has been introduced as a potential replacement, which is more costly but does not require serum monitoring. The purpose of this study was to compare the efficacy of PHE with that of LEV for preventing early PTS.

METHODS: Consecutive blunt traumatic brain injury patients undergoing seizure prophylaxis were prospectively enrolled at two Level 1 trauma centers during a 33-month period. Seizure prophylaxis was administered according to local protocol. Patients were monitored prospectively throughout their hospital stay for clinical evidence of seizure activity. PHE was compared with LEV with clinical early PTS as the primary outcome measure, defined as a seizure diagnosed clinically, occurring within 7 days of admission.

RESULTS: A total of 1,191 patients were screened for enrollment, after excluding 378 (31.7%) who did not meet inclusion criteria; 813 (68.3%) were analyzed (406 LEV and 407 PHE). There were no significant differences between LEV and PHE in age (51.7 [21.3] vs. 53.6 [22.5], p = 0.205), male (73.9% vs. 68.8%, p = 0.108), Injury Severity Score (ISS) (20.0 [10.0] vs. 21.0 [10.6], p = 0.175), Marshall score of 3 or greater (18.5% vs. 14.7%, p = 0.153), or craniectomy (8.4% vs. 11.8%, p = 0.106). There was no difference in seizure rate (1.5% vs.1.5%, p = 0.997), adverse drug reactions (7.9% vs. 10.3%, p = 0.227), or mortality (5.4% vs. 3.7%, p = 0.236).

CONCLUSION: In this prospective evaluation of early PTS prophylaxis, LEV did not outperform PHE. Cost and need for serum monitoring should be considered in guiding the choice of prophylactic agent.

LEVEL OF EVIDENCE: Therapeutic study, level III.