Pediatrics
Does adjunctive midazolam reduce recovery agitation after ketamine sedation for pediatric procedures? A randomized, double-blind, placebo-controlled trial

Presented at the California Chapter of the American College of Emergency Physicians Scientific Assembly, San Diego, CA, June 1999.
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Abstract

Study objective: Despite widespread use of adjunctive benzodiazepines during ketamine sedation, their efficacy in reducing recovery agitation in children has never been studied. We wished to characterize the nature and severity of recovery agitation after ketamine sedation in children treated in the emergency department and to determine whether the addition of adjunctive midazolam reduces the magnitude of such recovery agitation. Methods: The study was a randomized, double-blind, clinical trial of adjunctive midazolam versus placebo during ketamine sedation. We enrolled 104 children aged 12 months to 15 years (median age, 6 years) at a combined university medical center and children’s hospital. Subjects received either intravenous midazolam (0.05 mg/kg up to 2 mg) or placebo after intravenous administration of a ketamine loading dose (1.5 mg/kg). Treating physicians and nurses independently noted the presence of crying, hallucinations, and nightmares during recovery and graded recovery agitation by using a 100-mm visual analog scale. Preprocedure agitation and external stimulation during recovery were also graded. The time from ketamine injection until each subject met the recovery criteria was recorded. Results: Fifty-three subjects received midazolam, and 51 received placebo. Potentially confounding variables were similar between the groups. Sedation efficacy, adverse effects, and recovery time were also similar between groups. Interobserver agreement between physician and nurse assessments was substantial. Median physician assessment of recovery agitation was 4 mm (interquartile range, 2 to 19) in the midazolam group and 5 mm (interquartile range, 3 to 14) in the placebo group (difference –1; 95% confidence interval –3 to 2; P =.705). Recovery agitation was moderately correlated with preprocedure agitation (ρ=0.486) but not with external stimulation during recovery (ρ=0.147). Conclusion: Recovery agitation is common but generally of very low magnitude after ketamine sedation in children in the ED. We observed a median physician rating of 5 mm on a 100-mm visual analog scale, a score that we believe to be clinically insignificant. The degree of recovery agitation after ketamine sedation is significantly related to the degree of preprocedure agitation. In this study, concurrent midazolam did not diminish such agitation and had no measurably beneficial effect. Use of adjunctive benzodiazepines in pediatric ketamine sedation appears unnecessary. [Sherwin TS, Green SM, Khan A, Chapman DS, Dannenberg B. Does adjunctive midazolam reduce recovery agitation after ketamine sedation for pediatric procedures? A randomized, double-blind, placebo-controlled trial. Ann Emerg Med .March 2000;35:229-238.]

Section snippets

INTRODUCTION

Ketamine has been established as a safe and effective sedative for painful emergency department pediatric procedures.1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 The widespread acceptance of ketamine as an ED sedative may be limited by physician apprehension regarding recovery agitation. Ketamine can induce dreaming and hallucinations during recovery, and unpleasant reactions and nightmares have limited its use in adults. Children, however, are less prone to unpleasant recovery reactions and display

MATERIALS AND METHODS

The study was performed in the ED of a combined university medical center and children’s hospital with a yearly census of 44,000. We selected children aged 12 months to 15 years for ketamine sedation if they required short painful procedures (especially procedures in which immobilization was required) or examinations likely to produce emotional distress. We attempted to enroll consecutive children treated by 6 physicians, all of whom were faculty or fellows in pediatric emergency medicine. We

RESULTS

Participant flow is shown in Figure 1.

. Participant flow.

Interobserver agreement between treating physicians and nurses was substantial across all assessments (Table 1).

. Physician-nurse interrater reliability (n=104).

Empty CellPhysician RatingNurse RatingInterobserver Agreement
Presedation agitation, median (IQR)7 (0–22)6 (1–34.5)Spearman ρ=0.621 SD of differences=16
Recovery agitation, median (IQR)5 (2–17)6.5 (1–20.5)Spearman ρ=0.640 SD of differences=15
External stimulation, median (IQR)33.5 (13–44.5)42

DISCUSSION

This is the first study evaluating the use of adjunctive benzodiazepines during pediatric ketamine sedation. We found no evidence of benefit with adjunctive midazolam in improvement of recovery agitation, character, or duration or in the efficacy of sedation itself. The CIs for each of these comparisons (Table 3) demonstrate that our study had sufficient power to exclude clinically important differences. Thus our results do not support the common practice of benzodiazepine prophylaxis for

Acknowledgements

We thank our ED nurses for their invaluable assistance in patient monitoring and parental education; Norman Hamada, PharmD, for his assistance in preparing the study vials; and Arit Mbagwu, MD, and Thomas K Denmark, MD, for their help in enrolling study subjects. We thank James Li, MD, and William Wittlake, MD, for their review of the manuscript and many helpful suggestions.

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