Key study points:
1. Administration of IV droperidol or olanzapine as an adjunct to midazolam is an effective method of sedation that not associated with any increased risk of adverse events.
2. Olanzapine appears to be safe when administered intravenously as a 5mg dose for acute agitation.
3. IV droperidol does not appear to be associated with prolonged QTc intervals.
Primer: Agitation, a common symptom of patients seen in the ED, is often medically managed with pharmacological interventions of the benzodiazepine or neuroleptic drug classes. While several studies have compared the efficacy of these two pharmacological classes to each other, there has not been published research comparing the use of a sedative monotherapy to a combination regimen. This study strived to compare the efficacy and safety of two neuroleptics (droperidol 5mg and olanzapine 5mg) as an adjunct to midazolam in the management of highly agitated emergency department patients.
This [multi-center, randomized, double-blinded, controlled trial] study: Conducted in 3 large emergency departments in Australia and New Zealand between August 2009 and March 2011, this study looked at patients aged 18-65 who required parenteral drug sedation for acute agitation. Patients that had sensitivity to or contraindications against the use of any of the three intravenous drugs (midazolam, droperidol, and olanzapine), who had recently received sedatives, or who were pregnant or undergoing acute alcohol withdrawal were excluded. 336 patients were randomized to one of three groups: 1) control group (placebo-droperidol + placebo-olanzapine bolus), 2) droperidol group (droperidol 5mg + placebo-olanzapine bolus) or 3) olanzapine group (droperidol-placebo + olanzapine 5mg bolus). After the initial bolus, 2.5mg or 5mg of midazolam (for patients weighing <50kg or >50kg, respectively) was given, followed by more midazolam in incremental doses as needed to reach adequate sedation (defined as a sedation score less than or equal to 2).
Comparing several outcome measures, the authors found:
– Time needed to reach adequate sedation was significantly shorter for the droperidol and olanzapine groups than for the control groups, with a median difference in time to sedation being 4 minutes (CI: 1-6 min) shorter for droperidol and 5 minutes (CI: 1-6 min) shorter for olanzapine.
– The proportion of patients sedated after 10 minutes was significantly higher in the active drug groups compared to the control group, with 17.4% (CI: 3.8-30.9%) more of the droperidol group and 19.2% (CI: 5.6-32.8%) more of the olanzapine group sedated than the control group at this time point.
– The control group required a higher median cumulative dose (10 mg) than the active drug groups (5 mg) to achieve initial sedation.
– More patients in the control group required additional sedation within 60 minutes of initially achieving adequate sedation, and during the time period between 60 minutes after achieving adequate sedation and their ED discharge.
– The rate of adverse events, length of ED stay, and disposition destination were not different between the three groups.
In sum: The authors of this study conclude that combination sedative regimens (droperidol+midazolam and olanzapine+midazolam) are more effective than midazolam monotherapy in treating acutely agitated patients. Combination therapies not only allow shorter time to sedation, but they require lower proportions of sedative drugs to reach sedation and a lesser need for re-sedation without presenting a higher adverse risk profile. In fact, the midazolam-only group experienced higher rates of adverse events, a finding which the authors attributed to the higher doses needed to reach and maintain adequate sedation in this group. This is the first randomized, double-blinded clinical trial comparing monotherapy to combination therapy in the treatment of acute agitation in ED patients and is also the first published clinical study supporting the use of IV olanzapine.
Written by M.K.