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Abstract & Commentary
Source: Alldredge BK, 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.
In this randomized, double-blind study, the authors attempted to determine the safety and efficacy of lorazepam and diazepam for out-of-hospital status epilepticus when administered by emergency medical service (EMS) paramedics. Adults with prolonged (lasting five minutes or more) or repetitive, generalized convulsive seizures received intravenous diazepam (5 mg), lorazepam (2 mg), or placebo. An identical second injection was given if seizures recurred or continued four minutes or more after the first injection. Patients were excluded if they had a pulse less than 60 beats per minute, a systolic blood pressure less than 100 mmHg, second- or third-degree atrioventricular block, sustained ventricular tachyarrythmia, asthma or chronic obstructive pulmonary disease, a history of long-term use of benzodiazepines, or sensitivity to benzodiazepines.
Of the 205 patients enrolled, 66 received lorazepam, 68 received diazepam, and 71 received placebo. Status epilepticus had been terminated on arrival to the emergency department (ED) in more patients treated with lorazepam (59%) or diazepam (43%) than patients given placebo (21%) (P = 0.001). After adjustment for covariates, the odds ratio for termination of status epilepticus by the time of arrival in the lorazepam group as compared with the placebo group was 4.8 (95% CI, 1.9-13.0). The odds ratio was 1.9 (95% CI, 0.8-4.4) in the lorazepam group as compared with the diazepam group, and 2.3 (95% CI, 1.0-5.9) in the diazepam group as compared with the placebo group. The rates of out-of-hospital respiratory or circulatory complications (such as manually assisted ventilation or intubation) after the study treatment was administered were 11% for the lorazepam group, 10% for the diazepam group, and 22.5% for the placebo group (P = 0.08). Most of these complications were transient and noted at the time of ED arrival; similar numbers of complications were seen in each group.
Of the 66 patients examined in the lorazepam group, 32 (48%) received two doses for a total of 4 mg. Of the 68 patients in the diazepam group, 27 (39%) received two doses for a total of 10 mg. There were noticeable differences in the study groups for causes of status epilepticus, but they did not reach statistical significance. Also, the randomization did not evenly disperse ethnic groups and race among the three study groups.
Finally, the authors’ power calculations determined that the study had the power to detect a 25% difference between each study arm. The authors concluded that benzodiazepines are safe and effective when administered by paramedics for out-of-hospital status epilepticus in adults and that lorazepam is likely to be a better therapy than diazepam.
Commentary by Richard J. Hamilton, MD, FAAEM, ABMT
Why is there such interest in the safety of benzodiazepines for status epilepticus? In spite of the intuitive notion that administering benzodiazepines to terminate a seizure is good practice, no study has demonstrated any particular benefit to the patient. Furthermore, studies have suggested that lorazepam distributes in the central nervous system more effectively than other benzodiazepines, imparting with its use a theoretical advantage to patients with status epilepticus or prolonged seizures.
These untested notions have been examined in this paper, but not without an obvious bias favoring lorazepam. The equivalent of 2 mg of lorazepam is 10 mg of diazepam, not 5 mg. It is interesting to me that the authors do not discuss or statistically analyze the finding that lorazepam patients received a second dose of drug slightly more often. In addition, if the power analysis concludes that the study can detect only a 25% difference in response rates, then clearly no conclusion can be drawn from the 17% difference between the two study drugs at this mismatched dose.
However, I commend the authors on an arduous and rewarding study and wish to underscore their truly important findings. They successfully demonstrate that benzodiazepines reduce out-of-hospital cardiorespiratory complications of status epilecticus and are safe to use in the field. Many EMS interventions that appear intuitive have failed to produce tangible benefit when studied closely. It is rewarding to find that field care makes a difference. I would encourage everyone to consider stocking a benzodiazepine in EMS units. In fact, diazepam may be a better drug for field use because it requires no refrigeration. In any case, it’s not the drug that’s important; the correct dose of any benzodiazepine in status epilepticus is the dose that works!
(Dr. Hamilton, Associate Professor of Emergency Medicine, Program Director, Emergency Medicine, MCP Hahnemann University, Philadelphia, Pa., is on the Editorial Board of Emergency Medicine Alert.)