Pharmacologic interventions to prevent or treat delirium have been elusive. Antipsychotic drugs have sometimes been touted to be successful but the evidence has not been very convincing. A meta-analysis of antipsychotic treatment in patients with delirium (Kishi 2015) suggested that second generation antipsychotics have a benefit for the treatment of delirium with regard to efficacy and safety compared with haloperidol but emphasized that further study using larger samples is required. But another recent systematic review and meta-analysis found that current evidence does not support the use of antipsychotics for prevention or treatment of delirium (Neufeld 2016). Those authors found antipsychotic use was not associated with reduction in delirium incidence, change in delirium duration, severity, or hospital or ICU length of stay.
For several years now there has been interest in the use of dexmedetomidine, an α2-adrenoreceptor agonist, as a sedation agent in the ICU because it might be associated with less delirium. In our February 10, 2009 Patient Safety Tip of the Week Sedation in the ICU: The Dexmedetomidine Study we discussed the SEDCOM (Safety and Efficacy of Dexmedetomidine Compared With Midazolam) Study, which concluded that dexmedetomidine was as effective as midazolam at keeping patients in the desired sedation range and was associated with a reduced prevalence of delirium and reduced time to extubation (Riker 2009). However, we urged caution in interpreting the conclusions of that study because of several methodological and other concerns outlined in our column. We again discussed dexmedetomidine in our June 16, 2015 Patient Safety Tip of the Week Updates on Delirium.
Now another study has addressed the use of dexmedetomidine in intubated ICU patients with delirium (Reade 2016). The Dexmedetomidine to Lessen ICU Agitation (DahLIA) study was a double-blind, placebo-controlled, parallel-group randomized clinical trial in 15 ICUs in Australia and New Zealand. Subjects were ICU patients who were deemed to be ready for extubation except that they had delirium. Dexmedetomidine increased ventilator-free hours at 7 days compared with placebo (median, 144.8 hours vs 127.5 hours, respectively). Among several secondary outcome measures they also found that dexmedetomidine reduced time to extubation (median, 21.9 hours vs 44.3 hours with placebo), and accelerated resolution of delirium (median, 23.3 hours vs 40.0 hours).
Again, this sounds encouraging, particularly since our pharmacologic armamentarium for managing delirium is so limited. Yet there are again some red flags that urge us to be cautious in recommending widespread use of dexmedetomidine. First of all, this study applies only to a very select group of patients those who were already well enough to be being considered for extubation except for their delirium. The authors note that they screened 21,500 patients to recruit just the 74 patients randomized in the study! That small sample size (actually only 71 patients after 3 withdrawals for various reasons). Even more importantly, the study was terminated before its planned recruitment of 96 patients. Studies with early termination typically show more exaggerated effect sizes. Early termination was apparently done because the funding source ceased funding beyond the originally defined period. The authors note that the funding source had no role in the design of the study and had no access to study data during the study, and the authors performed sensitivity analyses suggesting the abbreviated sample size was unlikely to alter the primary conclusion. Nevertheless, such occurrences always raise our hype radar or spin radar (see our February 16, 2010 Patient Safety Tip of the Week ).
So while we are somewhat encouraged by the results of the DahLIA study, were not yet ready to jump on the dexmedetomidine bandwagon for more widespread use. Remember, this was a very narrow patient population and it would be premature to extrapolate the results to patients with delirium earlier in their ICU course (i.e. before they were deemed otherwise ready for extubation). The good news, though, is that the dexmedetomidine seemed to be well tolerated in this study and adverse events were rare. We therefore look forward to further studies on the use of dexmedetomidine for either prevention or treatment of delirium.
Some of our prior columns on delirium assessment and management:
· October 21, 2008 Preventing Delirium
· October 14, 2008 Managing Delirium
· February 10, 2009 Sedation in the ICU: The Dexmedetomidine Study
· March 31, 2009 Screening Patients for Risk of Delirium
· June 23, 2009 More on Delirium in the ICU
· January 26, 2010 Preventing Postoperative Delirium
· August 31, 2010
· September 2011 Modified HELP Helps Outcomes in Elderly Undergoing Abdominal Surgery
· December 2010 The ABCDE Bundle
· February 28, 2012 AACN Practice Alert on Delirium in Critical Care
· April 3, 2012 New Risk for Postoperative Delirium: Obstructive Sleep Apnea
· August 7, 2012 Cognition, Post-Op Delirium, and Post-Op Outcomes
· September 2013 Disappointing Results in Delirium
· October 29, 2013 PAD: The Pain, Agitation, and Delirium Care Bundle
· February 2014 New Studies on Delirium
· March 25, 2014 Melatonin and Delirium
· May 2014 New Delirium Severity Score
· August 2014 A New Rapid Screen for Delirium in the Elderly
· August 2014 Delirium in Pediatrics
· November 2014 The 3D-CAM for Delirium
· June 16, 2015 Updates on Delirium
· October 2015 Predicting Delirium
· April 2016
Kishi T, Hirota T, Matsunaga S, Iwata N. Antipsychotic medications for the treatment of delirium: a systematic review and meta-analysis of randomised controlled trials. J Neurol Neurosurg Psychiatry 2015; Published online first September 4, 2015
Neufeld KJ, Yue J, Robinson TN, et al. Antipsychotic Medication for Prevention and Treatment of Delirium in Hospitalized Adults: A Systematic Review and Meta-Analysis. Journal of the American Geriatrics Society 2016; published online 23 March 2016
Riker RR, Shehabi Y, Bokesch PM, et al for the SEDCOM (Safety and Efficacy of Dexmedetomidine Compared With Midazolam) Study Group. Dexmedetomidine vs Midazolam for Sedation of Critically Ill Patients. A Randomized Trial. JAMA. 2009; 301(5):489-499. Published online February 2, 2009
Reade MC, Eastwood GM, Bellomo R, et al. Effect of Dexmedetomidine Added to Standard Care on Ventilator-Free Time in Patients With Agitated Delirium: A Randomized Clinical Trial. JAMA 2016; Published online March 15, 2016