Neurocritical Care

, Volume 12, Issue 2, pp 165–172 | Cite as

Prospective, Randomized, Single-Blinded Comparative Trial of Intravenous Levetiracetam Versus Phenytoin for Seizure Prophylaxis

  • Jerzy P. Szaflarski
  • Kiranpal S. Sangha
  • Christopher J. Lindsell
  • Lori A. Shutter
Original Article

Abstract

Background

Anti-epileptic drugs are commonly used for seizure prophylaxis after neurological injury. We performed a study comparing intravenous (IV) levetiracetam (LEV) to IV phenytoin (PHT) for seizure prophylaxis after neurological injury.

Methods

In this prospective, single-center, randomized, single-blinded comparative trial of LEV versus PHT (2:1 ratio) in patients with severe traumatic brain injury (sTBI) or subarachnoid hemorrhage (NCT00618436) patients received IV load with either LEV or fosphenytoin followed by standard IV doses of LEV or PHT. Doses were adjusted to maintain therapeutic serum PHT concentrations or if patients had seizures. Continuous EEG (cEEG) monitoring was performed for the initial 72 h; outcome data were collected.

Results

A total of 52 patients were randomized (LEV = 34; PHT = 18); 89% with sTBI. When controlling for baseline severity, LEV patients experienced better long-term outcomes than those on PHT; the Disability Rating Scale score was lower at 3 months (P = 0.042) and the Glasgow Outcomes Scale score was higher at 6 months (P = 0.039). There were no differences between groups in seizure occurrence during cEEG (LEV 5/34 vs. PHT 3/18; P = 1.0) or at 6 months (LEV 1/20 vs. PHT 0/14; P = 1.0), mortality (LEV 14/34 vs. PHT 4/18; P = 0.227). There were no differences in side effects between groups (all P > 0.15) except for a lower frequency of worsened neurological status (P = 0.024), and gastrointestinal problems (P = 0.043) in LEV-treated patients.

Conclusions

This study of LEV versus PHT for seizure prevention in the NSICU showed improved long-term outcomes of LEV-treated patients vis-à-vis PHT-treated patients. LEV appears to be an alternative to PHT for seizure prophylaxis in this setting.

Keywords

Levetiracetam Phenytoin Fosphenytoin Seizure prevention ICU SAH TBI Long-term outcomes GCS GOS DRS 

Notes

Acknowledgments

This study was supported by a grant from UCB Inc., Principal Investigator: Lori A. Shutter, MD. This study was presented in part at the Neurocritical Care Society Meetings in 2008 and 2009. Data Safety Monitoring Board included Drs. Andrew Ringer, MD (Department of Neurosurgery) and Michael D. Privitera, MD (Department of Neurology).

Disclosure of Conflicts of Interest

Jerzy P. Szaflarski, MD, PhD has received grant support from the American Academy of Neurology, Davis Phinney Foundation/Sunflower Revolution, National Institutes of Health, UCB Pharma Inc., and The University Research Council at the University of Cincinnati. He has served as a paid consultant and/or speaker for Abbott Laboratories, American Academy of Neurology, Pfizer and UCB, Inc. Kiranpal S. Sangha, Pharm.D—has nothing to disclose. Christopher J. Lindsell, PhD—has received grant support from Abbott POC. Lori A. Shutter, MD has received grant support for the Department of Defense, National Institute of Health, and UCB Pharma, Inc. She has served as a paid consultant and/or speaker for Integra Lifesciences and the Brain Trauma Foundation.

References

  1. 1.
    Hesdorffer D. Risk factors. In: Engel J, Pedley T, editors. Epilepsy: a comprehensive textbook. Philadelphia: Wolters Kluwer, Lippincott–Raven Publishers; 2007. p. 57–63.Google Scholar
  2. 2.
    Claassen J, Hirsch LJ, Frontera JA, et al. Prognostic significance of continuous EEG monitoring in patients with poor-grade subarachnoid hemorrhage. Neurocrit Care. 2006;4:103–12.CrossRefPubMedGoogle Scholar
  3. 3.
    Claassen J, Jette N, Chum F, et al. Electrographic seizures and periodic discharges after intracerebral hemorrhage. Neurology. 2007;69:1356–65.CrossRefPubMedGoogle Scholar
  4. 4.
    Lowenstein DH. Epilepsy after head injury: an overview. Epilepsia. 2009;50(Suppl 2):4–9.CrossRefPubMedGoogle Scholar
  5. 5.
    Szaflarski JP, Rackley AY, Kleindorfer DO, et al. Incidence of seizures in the acute phase of stroke: A population-based study. Epilepsia. 2008;49(6):974–81.CrossRefPubMedGoogle Scholar
  6. 6.
    Vespa PM, Nuwer MR, Nenov V, et al. Increased incidence and impact of nonconvulsive and convulsive seizures after traumatic brain injury as detected by continuous electroencephalographic monitoring. J Neurosurg. 1999;91:750–60.CrossRefPubMedGoogle Scholar
  7. 7.
    Kilpatrick CJ, Davis SM, Hopper JL, Rossiter SC. Early seizures after acute stroke. Risk of late seizures. Arch Neurol. 1992;49:509–11.PubMedGoogle Scholar
  8. 8.
    So EL, Annegers JF, Hauser WA, O’Brien PC, Whisnant JP. Population-based study of seizure disorders after cerebral infarction. Neurology. 1996;46:350–5.PubMedGoogle Scholar
  9. 9.
    Temkin NR. Preventing and treating posttraumatic seizures: the human experience. Epilepsia. 2009;50(Suppl 2):10–3.CrossRefPubMedGoogle Scholar
  10. 10.
    Chang BS, Lowenstein DH. Practice parameter: antiepileptic drug prophylaxis in severe traumatic brain injury: report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2003;60:10–6.PubMedGoogle Scholar
  11. 11.
    Jones KE, Puccio AM, Harshman KJ, et al. Levetiracetam versus phenytoin for seizure prophylaxis in severe traumatic brain injury. Neurosurg Focus. 2008;25:E3.CrossRefPubMedGoogle Scholar
  12. 12.
    Michaelides C, Thibert R, Shapiro M, Kinirons P, John T, Manchharam D, et al. Tolerability and dosing experience of intravenous levetiracetam in children and infants. Epilepsy Res. 2008;81:143–7.CrossRefPubMedGoogle Scholar
  13. 13.
    Milligan T, Hurwitz S, Bromfield E. Efficacy and tolerability of levetiracetam versus phenytoin after supratentorial neurosurgery. Neurology. 2008;71:665–9.CrossRefPubMedGoogle Scholar
  14. 14.
    Patel NC, Landan IR, Levin J, Szaflarski J, Wilner AN. The use of levetiracetam in refractory status epilepticus. Seizure. 2006;15:137–41.CrossRefPubMedGoogle Scholar
  15. 15.
    Ruegg S, Naegelin Y, Hardmeier M, Winkler DT, Marsch S, Fuhr P. Intravenous levetiracetam: treatment experience with the first 50 critically ill patients. Epilepsy Behav. 2008;12:477–80.CrossRefPubMedGoogle Scholar
  16. 16.
    Szaflarski JP, Meckler JM, Szaflarski M, Shutter LA, Privitera MD, Yates SL. Levetiracetam use in critically ill patients. Neurocrit Care. 2007;7:140–7.CrossRefPubMedGoogle Scholar
  17. 17.
    Bratton SL, Chestnut RM, Ghajar J, et al. Guidelines for the management of severe traumatic brain injury. J Neurotrauma. 2007;24(Suppl 1):S7–95.PubMedGoogle Scholar
  18. 18.
    Claassen J, Mayer SA, Kowalski RG, Emerson RG, Hirsch LJ. Detection of electrographic seizures with continuous EEG monitoring in critically ill patients. Neurology. 2004;62:1743–8.PubMedGoogle Scholar
  19. 19.
    Rhoney DH, Tipps LB, Murry KR, Basham MC, Michael DB, Coplin WM. Anticonvulsant prophylaxis and timing of seizures after aneurysmal subarachnoid hemorrhage. Neurology. 2000;55:258–65.PubMedGoogle Scholar
  20. 20.
    Fountain N. Should levetiracetam replace phenytoin for seizure prophylaxis after neurosurgery? Epilepsy Curr. 2009;9:71–2.CrossRefPubMedGoogle Scholar
  21. 21.
    Klitgaard H, Matagne A, Gobert J, Wulfert E. Evidence for a unique profile of levetiracetam in rodent models of seizures and epilepsy. Eur J Pharmacol. 1998;353:191–206.CrossRefPubMedGoogle Scholar
  22. 22.
    Loscher W, Honack D, Rundfeldt C. Antiepileptogenic effects of the novel anticonvulsant levetiracetam (ucb L059) in the kindling model of temporal lobe epilepsy. J Pharmacol Exp Ther. 1998;284:474–9.PubMedGoogle Scholar
  23. 23.
    Loscher W, Reissmuller E, Ebert U. Anticonvulsant efficacy of gabapentin and levetiracetam in phenytoin-resistant kindled rats. Epilepsy Res. 2000;40:63–77.CrossRefPubMedGoogle Scholar
  24. 24.
    Stratton SC, Large CH, Cox B, Davies G, Hagan RM. Effects of lamotrigine and levetiracetam on seizure development in a rat amygdala kindling model. Epilepsy Res. 2003;53:95–106.CrossRefPubMedGoogle Scholar
  25. 25.
    Hanon E, Klitgaard H. Neuroprotective properties of the novel antiepileptic drug levetiracetam in the rat middle cerebral artery occlusion model of focal cerebral ischemia. Seizure. 2001;10:287–93.CrossRefPubMedGoogle Scholar
  26. 26.
    Marini H, Costa C, Passaniti M, et al. Levetiracetam protects against kainic acid-induced toxicity. Life Sci. 2004;74:1253–64.CrossRefPubMedGoogle Scholar
  27. 27.
    Vespa P. Continuous electroencephalography for subarachnoid hemorrhage has come of age. Neurocrit Care. 2006;4:99–100.CrossRefPubMedGoogle Scholar
  28. 28.
    Kilbride RD, Costello DJ, Chiappa KH. How seizure detection by continuous electroencephalographic monitoring affects the prescribing of antiepileptic medications. Arch Neurol. 2009;66:723–8.CrossRefPubMedGoogle Scholar
  29. 29.
    Orta DS, Chiappa KH, Quiroz AZ, Costello DJ, Cole AJ. Prognostic implications of periodic epileptiform discharges. Arch Neurol. 2009;66:985–91.CrossRefPubMedGoogle Scholar
  30. 30.
    Privitera M, Hoffman M, Moore JL, Jester D. EEG detection of nontonic–clonic status epilepticus in patients with altered consciousness. Epilepsy Res. 1994;18:155–66.CrossRefPubMedGoogle Scholar

Copyright information

© Humana Press Inc. 2009

Authors and Affiliations

  • Jerzy P. Szaflarski
    • 1
    • 2
    • 3
  • Kiranpal S. Sangha
    • 4
    • 5
  • Christopher J. Lindsell
    • 6
  • Lori A. Shutter
    • 1
    • 3
    • 7
  1. 1.Department of NeurologyUniversity of Cincinnati Academic Health CenterCincinnatiUSA
  2. 2.Cincinnati Epilepsy Center at the University HospitalCincinnatiUSA
  3. 3.The University of Cincinnati Neuroscience InstituteCincinnatiUSA
  4. 4.Department of Pharmacy ServicesThe University HospitalCincinnatiUSA
  5. 5.James L. Winkle College of Pharmacy, University of CincinnatiCincinnatiUSA
  6. 6.Department of Emergency MedicineUniversity of Cincinnati Academic Health CenterCincinnatiUSA
  7. 7.Department of NeurosurgeryUniversity of Cincinnati Academic Health CenterCincinnatiUSA

Personalised recommendations