Chan E. et al. Intravenous Droperidol or Olanzapine as an Adjunct to Midazolam for the Acutely Agitated Patient: A Multicenter Randomized, Double-Blind, Placebo-Controlled Clinical Trial. Ann Emerg Med. 2013; 61:72-81.  Patients commonly present to the ED in acutely agitated and hyper-aggressive states. Paranteral drug sedation may be required to manage these patients. Most studies have compared the use of benzodiazepines and antipsychotics in single arm studies against each other, but there is insufficient data analyzing combination therapy strategies for rapid sedation. This randomized, double-blinded, placebo-controlled, double-dummy, clinical trial sought to determine if combining an antipsychotic (olanzapine or droperidol) with midazolam shortened time to sedation. 

From 8/2009 to 3/2011, 336 patients receiving IV drug sedation for acute agitation were enrolled from three emergency departments. Patients were randomized to receive IV droperidol (5mg), olanzapine (5mg) or saline bolus (control). This was then followed by incremental IV midazolam boluses (2.5-5mg) until sedation (measured with a 6-point sedation score) was achieved. Outcomes of measure were time to sedation, need for rescue drugs, need for re-sedation and other adverse events (i.e. hypoxia, hypotension, seizures, etc.). 

The patients were randomized into the three treatment groups (olanzapine, droperidol, or saline-control group). The median times to sedation between the control-droperidol and control-olanzapine groups were 4 minutes and 5 minutes shorter, respectively, than time to sedation without these antipsychotics. Patients in both paranteral antipsychotic groups were found to be 1.6 times more likely to be sedated compared with the controls and these groups were less likely to require rescue drugs. There were no significant differences of adverse events or lengths of stay amongst the three groups. 

In summary, the authors conclude that combination antipsychotic/midazolam therapy for the acutely agitated ED patient provides more effective and faster time to adequate sedation than midazolam alone.

- Crum


Chestnut RM et al. A Trial of Intracranial Pressure Monitoring in Traumatic Brain Injury. N Engl J Med. 2012 367(26): 2471-81. This study was a multicenter, prospective, randomized, controlled trial to evaluate the efficacy of treatment based on intracranial pressure monitoring on improving the outcome in patients who have suffered a traumatic brain injury (TBI). A total of 324 patients aged 13 and over who were admitted to ICUs for TBI were randomly assigned to two treatment groups. One involving guideline based management where intracranial pressure monitoring was used with a goal of maintaining ICP at 20 mm of Hg or less, and two, into a treatment group where management was based entirely on imaging and clinical examination. Study centers were in Bolivia and Ecuador. Hospitals in South America were chosen for the study given that their standard ICU practice for the management of TBI typically follows an imaging and clinical examination approach. This thereby allowed for patient randomization into this treatment arm without deviating from the recognized standard of care. The primary outcome of interest was a composite of survival time, impaired consciousness and functional status evaluated at 3 and 6 months after injury. Neuropsychological status was also assessed at 6 months. The overall composite measure was assessed with 21 separate functional and cognitive status tools and patient scores were presented as a percentile (0 for poor performance, 100 for best performance). This study found that there was no difference between study groups where scores across the 21 separate evaluation measures were compared (56 in the ICP monitoring group and 53 in the imaging and exam group). Six month mortality was also unchanged (39% ICP monitoring versus 41% imaging and exam). A secondary outcome evaluating ICU length of stay showed similarity between groups (12 ICP monitoring versus 9 imaging and exam). In the ICP monitoring group there was found to be an increase in the number of days where brain-specific treatments (hypertonic saline and hyperventilation strategies) were used – 4.8 days versus 3.4 days in the imaging and exam group, p=0.002. This study has shown that ICP monitoring in the setting of TBI is not superior to an imaging and clinical exam strategy. This study is limited given that it was conducted in South America where other health system and pre-hospital factors could be confounding, such as less intensive pre-hospital resuscitation and delay in admission to the ICU setting. This may suggest that patients included in the study had less severe injuries and therefore a less aggressive approach is appropriate. However, the argument could also be made that these patients may have had secondary insult due to inadequate or less sophisticated pre-hospital care, thus resulting in a more severe injury. It is questionable whether this study result could be generalized into the North American patient population.