Agitation and aggression are common problems in Emergency Department as well as in acute psychiatric units. Injectable medications, either benzodiazepines or antipsychotics are often required to control these conditions. Practice vary much in different countries. Combination therapy for rapid sedation (especially by the intravenous route) is common practice in the Emergency Dept setting in Australia.Most ED clinicians prefer IV Midazolam. IV Droperidol or IV Olanzapine is also used. Haloperidol Midazolam combination is not much used now a days.
Droperidol have a black box warning due to prolonged QT and is use has disappeared/declined in many countries.
Most studies in this area have compared one class of drug to other though combination treatment is a common practice. Most trials exploring the use of combination therapy have been undertaken in non-ED settings.
This multi centre placebo controlled double blind study by Chan et al compared the efficacy and safety of intravenous Droperidol or Olanzapine boluses as an adjunct to Midazolam with Midazolam monotherapy as a sedating agent for the management of acute agitation in the ED setting.Obvious reversible cause for agitation (eg, hypotension, hypoxia, hypoglycemia); known pregnancy; and acute alcohol withdrawal were the exclusion criteria.
336 patients were randomized to one of 3 groups :
Control group: placebo for Olanzapine and placebo for Droperidol PLUS IV Midazolam
Droperidol group: Droperidol 5mg plus placebo for Olanzapine PLUS IV Midazolam
Olanzapine group: 5mg Olanzapine plus placebo for Droperidol PLUS IV Midazolam
Midazolam was administered after the others were given. (2.5 mg or 5 mg for estimated weights of less than 50 kg and above 50 kg, respectively) This was further followed by incremental doses of midazolam until adequate sedation was achieved.
The primary outcomes were time to achieve adequate sedation for the first time (from administration of the study drugs to adequate sedation) and the proportion of patients adequately sedated at 5 and 10 minutes after study drug administration.Sedation was measured with a 6-point, validated sedation scale.Adequate sedation was defined as a score less than or equal to 2.
1.The times to adequate sedation for the droperidol and olanzapine groups were significantly shorter than that for the control group.
2.The proportions of patients sedated at 5 minutes after study drug administration were similar across the 3 groups.
3.at 10 minutes, there were significantly more patients sedated in the droperidol and olanzapine groups.The hazard ratios were 1.61 (95% CI 1.23 to 2.11) and 1.66 (95% CI 1.27 to 2.17), respectively
4.The numbers of patients who experienced adverse events were similar among the groups.
5.The groups did not differ in median ED length of stay.
6.The median QTc intervals did not differ between groups: control 444 msec (interquartile range [IQR] 425 to 461 msec), droperidol 441 msec (IQR 421 to 460 msec), and olanzapine 448 msec (IQR 426 to 462 msec). Two patients had a QTc interval greater than or equal to 500 msec, 1 in the control group (500 msec) and 1 in the olanzapine group (512 msec).Neither patient experienced an adverse event related to the prolonged QTc.
The need for parenteral sedation was decided by the doctor.Selection bias may have occurred as a result of this.Iedation scale’s interpretation is potentially subject to observer bias.it is not known whether intravenous Olanzapine 5 mg is equivalent to intravenous Droperidol 5 mg.The suitability of the intravenous route depends on the clinical setting and the resources available.
Drug combination regimens (droperidol-midazolam and olanzapine- midazolam) were significantly more efficacious than midazolam monotherapy in achieving rapid and adequate sedation.Intravenous olanzapine appeared safe when used at the 5 mg dose and concurrently with other sedating drugs.(This probably is the first study of IV olanzapine). It also supports previous findings of superiority of droperidol in achieving rapid sedation. At the dose administered in this study (5 mg), intravenous droperidol does not appear to affect the QTc interval.
Please note that Droperidol was removed from clinical use in UK in 2001.IV Olanzapine is not licensed or available in UK.
Summary of the article:
Chan EW, Taylor DM, Knott JC, Phillips GA, Castle DJ, Kong DC. Ann Emerg Med. 2012 Sep 12 (E pub ahead of print)