By Elaine Chen, MD

Assistant Professor, Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Section of Palliative Medicine, Rush University Medical Center, Chicago

Dr. Chen reports no financial relationships relevant to this field of study.

SYNOPSIS: Low-dose nocturnal dexmedetomidine infusion was shown to prevent delirium in critically ill patients.

SOURCE: Skrobik Y, Duprey MS, Hill NS, Devlin JW. Low-dose nocturnal dexmedetomidine prevents ICU delirium: A randomized, placebo-controlled trial. Am J Respir Crit Care Med 2018;197:1147-1156.

Delirium in the ICU is common and associated with numerous adverse outcomes. The goal is to minimize delirium, but no agents have shown efficacy in preventing or treating delirium in critically ill adults. Dexmedetomidine has been associated with less delirium than midazolam and propofol. Very low-dose nocturnal dexmedetomidine has been shown to improve sleep quality and efficacy. Skrobik et al hypothesized that nocturnal dexmedetomidine would prevent delirium and improve sleep during ICU admission.

The authors conducted a randomized, double blind, placebo-controlled trial in ICUs in two institutions. Both institutions already had well-established pain, sedation, and delirium assessment practices. One hundred patients were enrolled between 2013 and 2016, with 50 in each arm. Eligible patients could consent, received intermittent or continuous sedatives, and were expected to require at least 48 hours of ICU care without meeting exclusion criteria. Patients were randomized to receive nocturnal dexmedetomidine or placebo in a 1:1 ratio. The study drug was administered from 9:30 p.m. to 6:15 a.m. each night, all sedatives were decreased to half, and infusions were titrated by protocol to a target Richmond Agitation Sedation Scale of -1.

The main study outcome was the number of patients who remained delirium-free during critical illness. Taking dexmedetomidine at night was associated with a higher proportion of patients who stayed delirium-free during the stay in the ICU vs. placebo (P = 0.006). In the dexmedetomidine group, 80% of patients remained free of delirium compared with 54% in the placebo group, with an absolute risk reduction (RR) of 26% (RR, 0.44; 95% confidence interval, 0.23-0.82) during their ICU stay. Additionally, patients in the dexmedetomidine group logged fewer total days of coma (P = 0.009), received a lower average dose of propofol (P < 0.001), and took fentanyl at a lower rate (76% vs. 94%; P = 0.02). The Leicester sleep evaluation questionnaire did not reveal significant differences in sleep quality. There were no differences in antipsychotic or oral analgesic use, duration of mechanical ventilation, length of stay, ICU or hospital mortality, or frequency of bradycardia or hypotension.

The authors concluded that nocturnal administration of low-dose dexmedetomidine in critically ill adults can help prevent ICU delirium and reduce days spent with coma and overall opiate requirements.

COMMENTARY

The Skrobik et al study provides useful information. Other investigators failed to identify a safe and effective pharmacologic strategy to either prevent or treat delirium in critically ill adults. In fact, the REDUCE trial showed that haloperidol, commonly used to treat ICU delirium, did not prevent delirium.1 The complex interplay between critical illness, delirium, cerebral perfusion, medications, and sleep makes study of this topic difficult. Prevention and treatment are difficult to distinguish, as many investigators enroll both delirious and nondelirious patients. In this study, patients who were delirious at the time of screening were excluded, thus ensuring that prevention was studied, but limiting generalizability to patients with early-onset delirium.2

Additionally, sleep was evaluated by self-report rather than with polysomnography, the objective gold standard. It is unclear why the dexmedetomidine group received less fentanyl and whether this is related to prevention of delirium. As nocturnal dexmedetomidine was studied, it is unclear whether continuous infusion would affect delirium prevention. Limiting the drug to nocturnal-only administration potentially could limit side effects and cost, but also might limit benefit. Long-term outcomes such as cognitive impairment also should be studied.

The Skrobik et al study results offer exciting potential for the future of delirium management in the ICU. However, these results do not change practice yet. This article is hypothesis-generating and leads to more questions than answers. The use of dexmedetomidine has increased over the past few years in our critically ill patients. I suspect its use will continue to increase.

Notably, this study was sponsored by Hospira Canada, the manufacturer of dexmedetomidine. Two authors were the first and second authors in the new clinical practice guidelines for the prevention and management of pain, agitation/sedation, delirium, immobility, and sleep disruption in critically ill adult patients that were published in Critical Care Medicine in September 2018. Those guidelines do not yet recommend pharmacologic modalities for preventing delirium.3 I look forward to future advances in delirium management and the potential varying uses of dexmedetomidine.

REFERENCES

  1. van den Boogaard M, Slooter AJC, Brüggemann RJM, et al. Effect of haloperidol on survival among critically ill adults with a high risk of delirium: The REDUCE randomized clinical trial. JAMA 2018;319:680-690.
  2. Nuzzo E, Girard TD. The Sandman in the ICU: A novel use of dexmedetomidine? Am J Respir Crit Care Med 2018;197:1098-1099.
  3. Devlin JW, Skrobik Y, Gélinas C, et al. Executive summary: Clinical practice guidelines for the prevention and management of pain, agitation/sedation, delirium, immobility, and sleep disruption in adult patients in the ICU. Crit Care Med 2018;46:1532-1548.