Criteria abstracted from The Users' Guide to Medical Literature, from the Health Information Research Unit and Clinical Epidemiology and Biostatistics, McMaster University

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Article Reviewed:

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Comparison of intranasal midazolam with intravenous diazepam for treating febrile seizures in children: prospective randomised study

Lahat E, Goldman M, Barr J, Bistritzer T, Berkovitch M.

Br Med J 2000;321:83-86 [full-text]

Reviewed by Al Torres, MD , University of Illinois College of Medicine at Peoria

Review posted May 23, 2001

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I. What is being studied?:

The study objective:

To compare the safety and efficacy of midazolam given intranasally with diazepam given intravenously in the treatment of children with febrile seizures lasting greater than 10 minutes.

The study design:

Prospective, randomized study.

The patients included:

44 children, aged 6 months to 5 years with febrile seizures lasting at least 10 minutes.

The patients excluded:

Nine children (5 in the midazolam group, 4 in the diazepam group) were excluded for spontaneous cessation of seizure

The interventions compared:

Intranasal midazolam (0.2 mg/kg) and intravenous diazepam (0.3 mg/kg).

The outcomes evaluated:

Time from arrival at hospital to cessation of seizures was primary outcome. Secondary outcomes included time from arrival at hospital to treatment and time from treatment to cessation of seizures. Clear declaration of the outcomes was only made in the structured abstract.

Successful treatment was defined as seizure control within 10 minutes of treatment. Treatment failure was defined as seizures lasting longer than 10 minutes after receiving treatment. Adverse effects included the development of respiratory distress or bradycardia.

II. Are the results of the study valid?

Primary questions:

1. Was the assignment of patients to treatments randomized?

Yes. Randomization was performed a priori with a random number table by a pharmacist not involved in the execution of the study. Treatment allocations were sealed in opaque envelopes and the investigators were blinded from these allocations.

2. Were all patients who entered the trial properly accounted for and attributed at its conclusion?

Was followup complete?

Yes. Fifty-three children were enrolled, nine children did not receive treatment, and 44 completed the trial.

Were patients analyzed in the groups to which they were randomized?

No. The nine children whose seizures spontaneously stopped prior to receiving treatment were not included in an intention-to-treat analysis. However, with equal numbers in both groups, it seems unlikely that including these patients would have altered the results of the study.

Secondary questions:

3. Were patients, health workers, and study personnel "blind" to treatment?

Unclear. The investigators do not state whether they were present during the administration of the intranasal midazolam or whether the intravenous diazepam patients received intranasal placebo. The investigators do not state whether they were present during the administration of intranasal midazolam or intravenous diazepam; or whether intranasal or intravenous placebos were given. It is unlikely they were blinded to treatment.

4. Were the groups similar at the start of the trial?

Yes. The two groups were similar in age, gender, history of previous seizures, and precipitating factors.

5. Aside from the experimental intervention, were the groups treated equally?

Maybe. All patients received supplemental oxygen. Two patients with recurrent seizures, one in each group, failed to respond to midazolam and/or diazepam but responded to intravenous phenobarbital. The investigators do not describe in their methods section any protocol for how patients with recurrent seizures (seizure that initially stops but recurs within 60 minutes) would be treated. In the results section they say that for each occasion of recurrent seizure the patients were re-randomized to midazolam or diazepam. Four children were randomized 3 times. Does this mean that some patients randomized to intranasal midazolam for their first seizure were then randomized to diazepam for the subsequent seizure? This is very unclear.

III. What were the results?

1. How large was the treatment effect?

Both agents were equally effective stopping seizure activity in these patients. 23 of 26 (88%) of the intranasal midazolam patients and 24 of 26 (92%) of the intravenous diazepam patients ceased seizing. The absolute risk reduction of ceasing seizure activity with intravenous diazepam versus intranasal midazolam was only 4%.

Statistically significant differences were found between groups in length of time from hospital arrival to giving the drug, length of time from giving drug to cessation of seizure, and length of time from hospital arrival to cessation of seizure.

Duration of time intervals in minutes for giving drug, seizure control, and response to treatment in study groups. Reported as mean (SD) [95% CI]

	Midazolam	Diazepam
Time to giving drug after arrival to hospital	3.5 (1.8) [3.5, 3.7]	5.5 (2.0) [5.3, 5.7]
Time of cessation of seizure after drug	3.1 (2.2) [2.9, 3.3]	2.5 (1.9) [2.4, 2.6]
Time to cessation of seizure after arrival	6.1 (3.6) [6.3, 6.7]	8.0 (4.1) [7.9, 8.3]

p < 0.001 for all groups

In the accompanying editorial, the reviewer points out that despite the lack of a placebo, the "survival" curves for midazolam and diazepam in Figure 2 would have overlapped if there truly was no difference between the two agents and the seizures were going to stop anyway. (1)

2. How precise was the estimate of the treatment effect?

The 95% confidence interval for the absolute risk reduction of ceasing seizure activity with intravenous diazepam versus intranasal midazolam is -12 to 20%. This wide interval contains 0 suggesting neither treatment is more effective than the other. The 95% confidence intervals for the time periods for giving drug, seizure control, and response to treatment are listed in the table above. Please note none of the confidence intervals for time to giving drug after arrival to hospital and time to cessation of seizure after arrival between the two groups overlap, which suggests that these differences did not occur by chance.

IV. Will the results help me in caring for my patients?

1. Can the results be applied to my patient care?

Yes. Although a reduction of 2 minutes of seizure activity seen with intranasal midazolam may not be clinically significant, these data do suggest that intranasal midazolam is as effective as intravenous diazepam. This study was limited to patients with febrile seizures and not patients with epilepsy so the results cannot be generalized to the latter group. The ease of administration and safety of intranasal midazolam administration (see below) make this delivery route an attractive alternate to rectal diazepam for clinic and possibly home treatment of febrile seizures.

2. Were all clinically important outcomes considered?

Yes. The outcomes may have not been as good if the investigators had selected to treat seizures of longer duration or in children with epilepsy having breakthrough seizures. Further investigation under these conditions is warranted.

3. Are the likely treatment benefits worth the potential harms and costs?

Maybe. The investigators did not find any difference in adverse effects between the two groups but did not state whether the sample size had the power to detect a difference. Certainly with so few patients in the study they might well miss complications with low occurrence rates. The investigators did not discuss cost differences but there is certainly appeal to not having to place an intravenous line in a child that is actively seizing, especially in a non-hospital setting.

References

1. . Koren G. Intranasal midazolam for febrile seizures. A step forward in treating a common and distressing condition. Br Med J 2000; 321:64-65. [full-text]

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