Correspondence
Treatment of Out-of-Hospital Status Epilepticus
N Engl J Med 2001; 345:1913-1914December 27, 2001
- Article
To the Editor:
The article by Alldredge et al. (Aug. 30 issue)1 describes a randomized, controlled study of the prehospital use of benzodiazepines for patients with status epilepticus. I am concerned by the inclusion of a placebo group and by the approval of this study by the institutional review boards. Did this study really provide clinical equipoise? Assuming that the paramedics and physicians are appropriately trained, would the authors or members of the institutional review boards wish to have benzodiazepines withheld in the prehospital setting if they were in status epilepticus?
1 ReferencesRobert K. Knopp, M.D.
Regions Hospital, St. Paul, MN 55101
knopp003@gold.tc. umn. edu 1
Alldredge BK ,Gelb AM ,Isaacs SM , et al. A comparison of lorazepam, diazepam, and placebo for the treatment of out-of-hospital status epilepticus. N Engl J Med 2001;345:631-637
Full Text | Web of Science | Medline
To the Editor:
Alldredge et al. attempt to equate nonequivalent doses of pharmacologically different benzodiazepines by comparing lorazepam (2 or 4 mg) and diazepam (5 or 10 mg). More patients in the study also received two doses of lorazepam than received two doses of diazepam (48 percent vs. 40 percent). No significant difference is shown between the two groups, yet the authors still conclude that lorazepam is “likely to be a better therapy.” Since the equivalent anticonvulsant doses of the two benzodiazepines are unknown, could it be that too little diazepam was given? We believe that the findings simply reflect the dose–response curves for the two agents. Higher doses of diazepam (10 and 20 mg) could have produced results that were equal to or even better than those with lorazepam, probably without a significantly increased risk of complications.
The use of benzodiazepines may be relatively new in some prehospital settings, but research studies should not exclude patients from receiving potentially lifesaving therapy. The extremely broad exclusion criteria seem unjustified. What treatment did the patients who were not enrolled receive? It is surprising that patients in status epilepticus are still being transported to hospitals without receiving any prior mandatory pharmacologic intervention.
Mark Su, M.D.
New York City Poison Control Center, New York, NY 10016Adam Chodosh, B.S.
Albert Einstein College of Medicine, Bronx, NY 10461Lewis S. Nelson, M.D.
New York City Poison Control Center, New York, NY 10016Author/Editor Response
The authors reply:
To the Editor: We appreciate Dr. Knopp's concern about the use of a placebo in our study of the out-of-hospital treatment of status epilepticus. Our rationale for including a placebo group relates to the potential drug-related risks of the administration of intravenous lorazepam and diazepam and to the nonhospital environment in which these treatments were given. These topics are addressed in our report and in the accompanying editorial by Valenzuela and Copass.1 As investigators, we regularly asked ourselves the same question posed by Knopp, since our primary concern throughout the study was the safety and well-being of our patients. The trial would not have been carried out if we, along with the expert advisors who oversaw the study and the reviewing agencies, had thought that the benefits of one approach to the care of patients were clearly superior to those of any other.
Su and colleagues question whether the doses of lorazepam and diazepam that we studied (a maximum of 4 mg and 10 mg, respectively) were not equally potent in terms of their therapeutic and toxic effects. This issue cannot be adequately addressed on the basis of available clinical data. The doses of each agent that we used were similar (though not identical) to those used in previous randomized studies of the inhospital use of lorazepam and diazepam for status epilepticus.2,3 These studies demonstrated that lorazepam was more efficacious, and the rates of adverse events were nearly identical for the two drugs — results similar to ours. Our preference for lorazepam is based on these results and on the fact that lorazepam has a longer duration of antiseizure effect.4 Though not addressed in our study, this advantage may be particularly important when there is a prolonged interval between the treatment of a patient by a paramedic and the arrival of the patient at an emergency department.
Patients who met the criteria for status epilepticus during the trial but who were excluded from the study were treated according to the existing protocol for our emergency-medical-services system. The recommended treatment was 5 mg of diazepam by intravenous injection, and a second injection could be authorized by the base-hospital physician. This treatment was administered to patients only during generalized tonic–clonic seizure activity. Diazepam was not administered if the seizures were witnessed by paramedics but stopped spontaneously. As discussed above, we believe that treatment with lorazepam or no drug would have also been reasonable prehospital therapies for these patients during the trial.
4 ReferencesBrian K. Alldredge, Pharm.D.
University of California, San Francisco, CA 94143Daniel H. Lowenstein, M.D.
Harvard Medical School, Boston, MA 02115
daniel_lowenstein@hms.harvard. edu 1
Valenzuela TD ,Copass MK . Clinical research on out-of-hospital emergency care. N Engl J Med 2001;345:689-690
Full Text | Web of Science | Medline2
Leppik IE ,Derivan AT ,Homan RW ,Walker J ,Ramsay RE ,Patrick B . Double-blind study of lorazepam and diazepam in status epilepticus. JAMA 1983;249:1452-1454
CrossRef | Web of Science | Medline3
Andermann F ,Cendes F ,Reiher J , et al. A prospective double-blind study of the effects of intravenously administered lorazepam and diazepam in the treatment of status epilepticus. Epilepsia 1992;33:Suppl 3:3-3 abstract.
CrossRef4
Lowenstein DH ,Alldredge BK . Status epilepticus. N Engl J Med 1998;338:970-976
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