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N Engl J Med. 2019 Nov 28;381(22):2103-2113. doi: 10.1056/NEJMoa1905795.

Randomized Trial of Three Anticonvulsant Medications for Status Epilepticus.

Collaborators (237)

Kapur J, Gray E, Gunter S, Fansler A, Silbergleit R, Barsan W, Stevenson V, Bengelink E, Harney D, Speers M, Black J, Fisher N, Harsh D, Ramakrishnan A, Harris L, Bozeman N, Spiteri A, Palesch Y, Elm J, Meinzer C, Tillman H, Zhao W, Pauls Q, Arnaud C, Dillon CR, Riley J, Alford T, Conner C, Underwood E, Chamberlain J, Shreve K, Dayan P, Kuppermann N, Denninghoff K, Stanley R, Ruddy R, Lerner EB, Dean JM, Casper C, Nigrovic L, Schalick W, Nelson D, Thomas B, Shinnar S, Lowenstein D, Cock H, Fountain N, Cloyd J, Coles L, Sathe A, Janis S, Conwit R, Hartman A, Fureman B, Trinka E, Treiman D, Bleck T, Wright D, Ratcliff J, Hall A, Williams A, Okada P, Lee A, Truesdale N, Simon H, Stanley N, Babcock L, Chan S, Naresh M, Robinson V, Holsti M, Hwang J, Carlston K, Dela Cruz M, Harbour T, Karki R, Humphries R, Mims T, Short J, Cohen DM, Nowakowski A, Lin C, Fisher Kenny E, Jones E, Ottman M, Steele D, Merck LH, Ryan E, Basso K, D'Urso L, Gentile N, Isenberg D, Reimer H, Sayoc Kalugdan V, Hemphill C, Yi Madhok D, Duncan J, Randazzo D, Brown K, Thomas B, Nauman G, Ledda M, Gillen S, Grant V, Quinn J, Visweswaran A, Mann R, Vance C, Nishijima DK, Pimenta K, Rogers AJ, Herzog N, Bennett J, Eisenhart C, Adeoye O, McMullan J, Foreman B, Keegan S, Thomas D, Wagner D, Biros M, Driver B, Hendrickson A, Stang J, Lewandowski C, Miller J, Chaudhry K, Berry S, Warden C, Blake R, Cook JNB, Sabolick E, Selman A, Kissman K, Moore M, Huff JS, Becker L, Claassen J, Velazquez A, Falo C, Coralic Z, Grupp-Phelan J, Baren J, Ellison A, Woodford A, Samba I, Kittick M, Hickey RW, Azrak R, Riviello R, Massey J, Bonacquisti L, Levine S, Motov S, Fromm C, Hossain R, Likourezos A, Pushkar I, Terndrup T, Khaliqdina S, Hill M, Peterson B, Terwilliger A, Holm J, Wicklund K, Wewerka S, Welch R, Pearson C, Kumar VA, Ayaz F, Bhuiyan S, Mika VH, Rubalcava D, Mondragon J, Gonzalez V, Khalil M, Morgan L, Jones F, Dishman L, Neuro TH, Erickson F, Staugaitis A, Lawyer C, Miller K, Callaway C, Urban A, DiFiore S, Adams P, Baum B, Hart K, Parker S, Nomura J, Davis B, Aufderheide T, Emmrich A, Mena M, Labinski J, Ogedegbe C, McCarthy D, Villot-Santiago A, Goldstein J, Rosenthal ES, Cohen A, Mei Su C, Tirrell G, Howell M, Lumba A, Quayle K, Chinta S, Robinson D, Henry T, Hendrickson M, Nerheim D, Jaton E, Merck L, Biney B, Gibson C, Dahlmeier E, Blackburn K, Vqughan-Ogunlus O, Zehtabchi S, Sinert R, Petty B, Kwok M, Peery B, Ochs J, Suarez L, Youngquist S, Carlson M, Gilles N, Weingast S, Stern B, Hopp J, Ganley V, Ornato J, Hogan C, Payne A.

Author information

From the Department of Neurology, University of Virginia, Charlottesville (J.K., N.F.); the Data Coordination Unit, Department of Public Health Sciences, Medical University of South Carolina, Charleston (J.E., C.M.); the Division of Emergency Medicine, Children's National Medical Center, Washington, DC (J.M.C.); the Department of Emergency Medicine, University of Michigan, Ann Arbor (W.B., R.S.); the College of Pharmacy, Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis (J.C.); the Department of Neurology, University of California, San Francisco, San Francisco (D.L.); the Departments of Neurology and Pediatrics, Albert Einstein College of Medicine, Montefiore Medical Center, New York (S.S.); the National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD (R.C.); St. George's University of London and St. George's University Hospitals NHS Foundation Trust, London (H.C.); and ConfluenceStat (J.T.C.) and the University of Central Florida College of Medicine (J.T.C.) - both in Orlando.



The choice of drugs for patients with status epilepticus that is refractory to treatment with benzodiazepines has not been thoroughly studied.


In a randomized, blinded, adaptive trial, we compared the efficacy and safety of three intravenous anticonvulsive agents - levetiracetam, fosphenytoin, and valproate - in children and adults with convulsive status epilepticus that was unresponsive to treatment with benzodiazepines. The primary outcome was absence of clinically evident seizures and improvement in the level of consciousness by 60 minutes after the start of drug infusion, without additional anticonvulsant medication. The posterior probabilities that each drug was the most or least effective were calculated. Safety outcomes included life-threatening hypotension or cardiac arrhythmia, endotracheal intubation, seizure recurrence, and death.


A total of 384 patients were enrolled and randomly assigned to receive levetiracetam (145 patients), fosphenytoin (118), or valproate (121). Reenrollment of patients with a second episode of status epilepticus accounted for 16 additional instances of randomization. In accordance with a prespecified stopping rule for futility of finding one drug to be superior or inferior, a planned interim analysis led to the trial being stopped. Of the enrolled patients, 10% were determined to have had psychogenic seizures. The primary outcome of cessation of status epilepticus and improvement in the level of consciousness at 60 minutes occurred in 68 patients assigned to levetiracetam (47%; 95% credible interval, 39 to 55), 53 patients assigned to fosphenytoin (45%; 95% credible interval, 36 to 54), and 56 patients assigned to valproate (46%; 95% credible interval, 38 to 55). The posterior probability that each drug was the most effective was 0.41, 0.24, and 0.35, respectively. Numerically more episodes of hypotension and intubation occurred in the fosphenytoin group and more deaths occurred in the levetiracetam group than in the other groups, but these differences were not significant.


In the context of benzodiazepine-refractory convulsive status epilepticus, the anticonvulsant drugs levetiracetam, fosphenytoin, and valproate each led to seizure cessation and improved alertness by 60 minutes in approximately half the patients, and the three drugs were associated with similar incidences of adverse events. (Funded by the National Institute of Neurological Disorders and Stroke; ESETT number, NCT01960075.).

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