Journal of Neurology

, Volume 263, Issue 5, pp 861–870 | Cite as

Cardiovascular adverse effects of phenytoin

  • B. Guldiken
  • J. Rémi
  • Soheyl NoachtarEmail author


Phenytoin is an established drug in the treatment of acute repetitive seizures and status epilepticus. One of its main advantages over benzodiazepines is the less sedative effect. However, the possibility of cardiovascular adverse effects with the intravenous use of phenytoin cause a reluctance to its usage, and this has lead to a search for safer anticonvulsant drugs. In this study, we aimed to review the studies which evaluated the safety of phenytoin with respect to cardiovascular adverse effects. The original clinical trials and case reports listed in PUBMED in English language between the years of 1946–2014 were evaluated. As the key words, “phenytoin, diphenylhydantoin, epilepsy, seizure, cardiac toxicity, asystole, arrhythmia, respiratory arrest, hypotension, death” were used. Thirty-two clinical trials and ten case reports were identified. In the case reports, a rapid infusion rate (>50 mg/min) of phenytoin appeared as the major cause of increased mortality. In contrast, no serious cardiovascular adverse effects leading to death were met in the clinical trials which applied the recommended infusion rate and dosages. An infusion rate of 50 mg/min was reported to be safe for young patients. For old patients and patients with a cardiovascular co-morbidity, a slower infusion rate was recommended with a careful follow-up of heart rhythm and blood pressure. No cardiovascular adverse effect was reported in oral phenytoin overdoses except one case with a very high serum phenytoin level and hypoalbuminemia. Phenytoin is an effective and well tolerated drug in the treatment of epilepsy. Intravenous phenytoin is safe when given at recommended infusion rates and doses.


Epilepsy Phenytoin Cardiovascular adverse effects Arrhythmia Death 


Compliance with ethical standards

Conflicts of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.


  1. 1.
    Glauser T, Ben-Menachem E, Bourgeois B, Cnaan A, Guerreiro C, Kälviäinen R, Mattson R, French JA, Perucca E, Tomson T (2013) Updated ILAE evidence review of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia 54:551–563CrossRefPubMedGoogle Scholar
  2. 2.
    Meierkord H, Boon P, Engelsen B, Göcke K, Shorvon S, Tinuper P, Holtkamp M (2010) EFNS guideline on the management of status epilepticus in adults. Eur J Neurol 17:348–355CrossRefPubMedGoogle Scholar
  3. 3.
    Zoneraich S, Zoneraich O, Siegel J (1976) Sudden death following intravenous sodium diphenylhydantoin. Am Heart J 91:375–377CrossRefPubMedGoogle Scholar
  4. 4.
    Goldschlager AW, Karliner JS (1967) Ventricular standstill after intravenous diphenylhydantoin. Am Heart J 74:410–412CrossRefPubMedGoogle Scholar
  5. 5.
    Russell MA, Bousvaros G (1968) Fatal results from diphenylhydantoin administered intravenously. JAMA 206:2118–2119CrossRefPubMedGoogle Scholar
  6. 6.
    Unger AH, Sklaroff HJ (1967) Fatalities following intravenous use of sodium diphenylhydantoin for cardiac arrhythmias. Report of two cases. JAMA 200:335–336CrossRefPubMedGoogle Scholar
  7. 7.
    Gellerman GL, Martinez C (1967) Fatal ventricular fibrillation following intravenous sodium diphenylhydantoin therapy. JAMA 200:337–338CrossRefPubMedGoogle Scholar
  8. 8.
    Agarwal P, Kumar N, Chandra R, Gupta G, Antony AR, Garg N (2007) Randomized study of intravenous valproate and phenytoin in status epilepticus. Seizure 16:527–532CrossRefPubMedGoogle Scholar
  9. 9.
    Kellinghaus C, Berning S, Stögbauer F (2014) Intravenous lacosamide or phenytoin for treatment of refractory status epilepticus. Acta Neurol Scand 129:294–299CrossRefPubMedGoogle Scholar
  10. 10.
    Rudis MI, Touchette DR, Swadron SP, Chiu AP, Orlinsky M (2004) Cost-effectiveness of oral phenytoin, intravenous phenytoin, and intravenous fosphenytoin in the emergency department. Ann Emerg Med 43:386–387CrossRefPubMedGoogle Scholar
  11. 11.
    Szaflarski JP, Sangha KS, Lindsell CJ, Shutter LA (2010) Prospective, randomized, single-blinded comparative trial of intravenous levetiracetam versus phenytoin for seizure prophylaxis. Neurocrit Care 12:165–172CrossRefPubMedGoogle Scholar
  12. 12.
    Aaronson PM, Belgado BS, Spillane JP, Kunisaki TA (2011) Evaluation of intramuscular fosphenytoin vs intravenous phenytoin loading in the ED. Am J Emerg Med 29:983–989CrossRefPubMedGoogle Scholar
  13. 13.
    Marchetti A, Magar R, Fischer J, Sloan E, Fischer P (1996) A pharmacoeconomic evaluation of intravenous fosphenytoin (Cerebyx@) versus intravenous phenytoin (Dilantin@) in hospital emergency departments. Clin Ther 18:953–966CrossRefPubMedGoogle Scholar
  14. 14.
    Rai A, Aggarwal A, Mittal H, Sharma S (2011) Comparative efficacy and safety of intravenous valproate and phenytoin in children. Pediatr Neurol 45:300–304CrossRefPubMedGoogle Scholar
  15. 15.
    Chitsaz A, Mehvari J, Salari M, Gholami F, Najafi M-R (2013) A comparative assessment the efficacy of intravenous infusion of sodium valproate and phenytoin in the treatment of status epilepticus. Int J Prev Med 4:S216–S221PubMedPubMedCentralGoogle Scholar
  16. 16.
    Misra UK, Kalita J, Patel R (2006) Sodium valproate vs phenytoin in status epilepticus: a pilot study. Neurology 67:340–342CrossRefPubMedGoogle Scholar
  17. 17.
    Gilad R, Izkovitz N, Dabby R, Rapoport A, Sadeh M, Weller B, Lampl Y (2008) Treatment of status epilepticus and acute repetitive seizures with i.v. valproic acid vs phenytoin. Acta Neurol Scand 118:296–300CrossRefPubMedGoogle Scholar
  18. 18.
    Kern K, Schebesch KM, Schlaier J, Hansen E, Feigl GC, Brawanski AT, Lange M (2012) Levetiracetam compared to phenytoin for the prevention of postoperative seizures after craniotomy for intracranial tumours in patients without epilepsy. J Clin Neurosci 19:99–100CrossRefPubMedGoogle Scholar
  19. 19.
    Fuller KL, Wang YY, Cook MJ, Murphy MA, D’Souza WJ (2013) Tolerability, safety, and side effects of levetiracetam versus phenytoin in intravenous and total prophylactic regimen among craniotomy patients: a prospective randomized study. Epilepsia 54:45–57CrossRefPubMedGoogle Scholar
  20. 20.
    Treiman DM, Meyers PD, Walton NY et al (1998) A comparison of four treatments for generalized convulsive status epilepticus. Veterans affairs status epilepticus cooperative study group. N Engl J Med 339:792–798CrossRefPubMedGoogle Scholar
  21. 21.
    Esplin DW (1957) Effects of diphenylhydantoin on synaptic transmission in cat spinal cord and stellate ganglion. J Pharmacol Exp Ther 120:301–323PubMedGoogle Scholar
  22. 22.
    Francis J, Burnham WM (1992) [3H]Phenytoin identifies a novel anticonvulsant-binding domain on voltage-dependent sodium channels. Mol Pharmacol 42:1097–1103PubMedGoogle Scholar
  23. 23.
    Dill WA, Glazko AJ, Kazenko A, Wolf LM (1956) Studies on 5, 5′-diphenylhydantoin (dilantin) in animals and man. J Pharmacol Exp Ther 118:270–279PubMedGoogle Scholar
  24. 24.
    Wilder BJ, Ramsay RE (1976) Oral and intramuscular phenytoin. Clin Pharmacol Ther 19:360–364CrossRefPubMedGoogle Scholar
  25. 25.
    Swadron SP, Rudis MI, Azimian K, Beringer P, Fort D, Orlinsky M (2004) A comparison of phenytoin-loading techniques in the emergency department. Acad Emerg Med 11:244–252CrossRefPubMedGoogle Scholar
  26. 26.
    Ratanakorn D, Kaojarern S, Phuapradit P, Mokkhavesa C (1997) Single oral loading dose of phenytoin: a pharmacokinetics study. J Neurol Sci 147:89–92CrossRefPubMedGoogle Scholar
  27. 27.
    Morita DA GT (2006) Phenytoin and fosphenytoin. In: Wyllie Elaine (ed) Treat. Epilepsie, 4th edn. Lippincott Williams & Wilkins, Philadelphia, pp 785–803Google Scholar
  28. 28.
    Craig S (2005) Phenytoin poisoning. Neurocrit Care 3:161–170CrossRefPubMedGoogle Scholar
  29. 29.
    Zaccara G, Tion C, Perucca E (2014) Seminar in epileptology interactions between antiepileptic drugs, and between antiepileptic drugs and other drugs. Epileptic Disord Epileptic Disord Epileptic Disord 16:409–432PubMedGoogle Scholar
  30. 30.
    Bivins BA, Rapp RP, Griffen WO, Blouin R, Bustrack J (1978) Dopamine-phenytoin interaction. A cause of hypotension in the critically ill. Arch Surg 113:245–249CrossRefPubMedGoogle Scholar
  31. 31.
    York RC, Coleridge ST (1988) Cardiopulmonary arrest following intravenous phenytoin loading. Am J Emerg Med 6:255–259CrossRefPubMedGoogle Scholar
  32. 32.
    Conn RD, Kennedy JW, Blackmon JR (1967) The hemodynamic effects of diphenylhydantoin. Am Heart J 73:500–505CrossRefPubMedGoogle Scholar
  33. 33.
    Cranford RE, Leppik IE, Patrick B, Anderson CB, Kostick B (1978) Intravenous phenytoin: clinical and pharmacokinetic aspects. Neurology 28:874–880CrossRefPubMedGoogle Scholar
  34. 34.
    Louis S, Kutt H, McDowell F (1967) The cardiocirculatory changes caused by intravenous dilantin and its solvent. Am Heart J 74:523–529CrossRefPubMedGoogle Scholar
  35. 35.
    Al-Khudhairi D, Whitwam JG (1986) Autonomic reflexes and the cardiovascular effects of propylene glycol. Br J Anaesth 58:897–902CrossRefPubMedGoogle Scholar
  36. 36.
    Conn RD (1965) Diphenylhydantoin sodium in cardiac arrythmias. N Engl J Med 272:277–282CrossRefPubMedGoogle Scholar
  37. 37.
    Karliner JS (1967) Intravenous diphenylhydantoin sodium (Dilantin) in cardiac arrhythmias. Dis Chest 51:256–269CrossRefPubMedGoogle Scholar
  38. 38.
    Rosen M, Lisak R, Rubin IL (1967) Diphenylhydantoin in cardiac arrhythmias. Am J Cardiol 20:674–678CrossRefPubMedGoogle Scholar
  39. 39.
    Carducci B, Hedges JR, Beal JC, Levy RC, Martin M (1984) Emergency phenytoin loading by constant intravenous infusion. Ann Emerg Med 13:1027–1031CrossRefPubMedGoogle Scholar
  40. 40.
    Donovan PJ, Cline D (1991) Phenytoin administration by constant intravenous infusion: selective rates of administration. Ann Emerg Med 20:139–142CrossRefPubMedGoogle Scholar
  41. 41.
    McWilliam PK (1958) Intravenous phenytoin sodium in continuous convulsions in children. Lancet 2:1147–1149CrossRefPubMedGoogle Scholar
  42. 42.
    Tiamkao S, Sawanyawisuth K, Chancharoen A (2013) The efficacy of intravenous sodium valproate and phenytoin as the first-line treatment in status epilepticus: a comparison study. BMC Neurol 13:98CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Hawcutt DB, Sampath S, Timmis A, Newland V, Newland P, Appleton R (2011) Serum phenytoin concentrations in paediatric patients following intravenous loading. Arch Dis Child 96:883–884CrossRefPubMedGoogle Scholar
  44. 44.
    Piper JD, Hawcutt DB, Verghese GK, Spinty S, Newland P, Appleton R, Hey A (2014) Phenytoin dosing and serum concentrations in paediatric patients requiring 20 mg/kg intravenous loading. Arch Dis Child 99:585–586CrossRefPubMedGoogle Scholar
  45. 45.
    Martinelli EF, Mühlebach SF (2003) Rapid i.v. loading with phenytoin with subsequent dose adaptation using non-steady-state serum levels and a Bayesian forecasting computer program to predict maintenance doses. J Clin Pharm Ther 28:385–393CrossRefPubMedGoogle Scholar
  46. 46.
    Handley AJ (1970) Phenytoin tolerance tests. Br Med J 3:203–204CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Schmidt H, Belleza J, Dougherty Lynn White JM, Robin Lammers M (1995) Adverse Effects associated with phenytoin administration. Acad Emerg Med 2:758–759CrossRefPubMedGoogle Scholar
  48. 48.
    Wallis W, Kutt H, McDowell F (2001) Intravenous diphenylhydantoin in treatment of acute repetitive seizures. 1968. Neurology 57:S49–S61PubMedGoogle Scholar
  49. 49.
    Slater RM, Smith WD, Patrick J, Mawer GE, Wilcox FL, Donnai P, Richardson T, D’Souza SW, Anderton JM (1987) Phenytoin infusion in severe pre-eclampsia. Lancet 1:1417–1421CrossRefPubMedGoogle Scholar
  50. 50.
    Chance JF (1991) Emergency department treatment of alcohol withdrawal seizures with phenytoin. Ann Emerg Med 20:520–522CrossRefPubMedGoogle Scholar
  51. 51.
    Appleton RE, Gill A (2003) Adverse events associated with intravenous phenytoin in children: a prospective study. Seizure 12:369–372CrossRefPubMedGoogle Scholar
  52. 52.
    Salem RB, Wilder BJ, Yost RL, Doering PL, Lee C (1981) Rapid infusion of phenytoin sodium loading doses. Am J Hosp Pharm 38:354–357PubMedGoogle Scholar
  53. 53.
    De Santis A, Villani R, Sinisi M, Stocchetti N, Perucca E (2002) Add-on phenytoin fails to prevent early seizures after surgery for supratentorial brain tumors: a randomized controlled study. Epilepsia 43:175–182CrossRefPubMedGoogle Scholar
  54. 54.
    Lee ST, Lui TN, Chang CN, Cheng WC, Wang DJ, Heimburger RF, Lin CG (1989) Prophylactic anticonvulsants for prevention of immediate and early postcraniotomy seizures. Surg Neurol 31:361–364CrossRefPubMedGoogle Scholar
  55. 55.
    Young B, Rapp RP, Norton JA, Haack D, Walsh JW (1983) Failure of prophylactically administered phenytoin to prevent post-traumatic seizures in children. Childs Brain 10:185–192PubMedGoogle Scholar
  56. 56.
    Evers ML, Izhar A, Aqil A (1997) Cardiac monitoring after phenytoin overdose. Hear Lung J Acute Crit Care 26:325–328CrossRefGoogle Scholar
  57. 57.
    Curtis DL, Piibe R, Ellenhorn MJ, Wasserberger J, Ordog G (1989) Phenytoin toxicity: a review of 94 cases. Vet Hum Toxicol 31:164–165PubMedGoogle Scholar
  58. 58.
    Wyte CD, Berk WA (1991) Severe oral phenytoin overdose does not cause cardiovascular morbidity. Ann Emerg Med 20:508–512CrossRefPubMedGoogle Scholar
  59. 59.
    Earnest MP, Marx JA, Drury LR (1983) Complications of intravenous phenytoin for acute treatment of seizures. Recommendations for usage. JAMA 249:762–765CrossRefPubMedGoogle Scholar
  60. 60.
    DeToledo JC, Lowe MR, Rabinstein A, Villaviza N (2001) Cardiac arrest after fast intravenous infusion of phenytoin mistaken for fosphenytoin. Epilepsia 42:288CrossRefPubMedGoogle Scholar
  61. 61.
    Randazzo DN, Ciccone A, Schweitzer P, Winters SL (1995) Complete atrioventricular block with ventricular asystole following infusion of intravenous phenytoin. J Electrocardiol 28:157–159CrossRefPubMedGoogle Scholar
  62. 62.
    Berry JM, Kowalski A, Fletcher SA (1999) Sudden asystole during craniotomy: unrecognized phenytoin toxicity. J Neurosurg Anesthesiol 11:42–45CrossRefPubMedGoogle Scholar
  63. 63.
    Lu C-H, Su C-M, Kung C-T, Wang Y-C (2009) Life-threatening cardiotoxicity due to chronic oral phenytoin overdose. Neurol India 57:200CrossRefPubMedGoogle Scholar
  64. 64.
    Gugler R, Manion CV, Azarnoff DL (1976) Phenytoin: pharmacokinetics and bioavailability. Clin Pharmacol Ther 19:135–142CrossRefPubMedGoogle Scholar
  65. 65.
    Meek PD, Davis SN, Collins DM, Gidal BE (2015) Guidelines for nonemergency use of parenteral phenytoin products. Arc Intern Med 159:2639–2644CrossRefGoogle Scholar
  66. 66.
    Binder L, Trujillo J, Parker D, Guetter A (1996) Association of intravenous phenytoin toxicity with demographic, clinical, and dosing parameters. Am J Emerg Med 14:398–401CrossRefPubMedGoogle Scholar
  67. 67.
    Prasad K, Al-Roomi K, Krishnan PR, Sequeira R (2005) Anticonvulsant therapy for status epilepticus. Cochrane Database Syst Rev. doi: 10.1002/14651858.CD003723 Google Scholar
  68. 68.
    Siebert WJ, McGavigan AD (2013) Requirement for cardiac telemetry during intravenous phenytoin infusion: guideline fact or guideline fiction? Intern Med J 43:7–17CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  1. 1.Department of Neurology, Epilepsy CenterUniversity of MunichMunichGermany
  2. 2.Neurology DepartmentTrakya University Medical FacultyEdirneTurkey

Personalised recommendations