By Betty Tran, MD, MSc

Assistant Professor of Medicine, Pulmonary and Critical Care Medicine, Rush University Medical Center, Chicago

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

SYNOPSIS: In patients with sepsis requiring mechanical ventilation, use of dexmedetomidine compared with no dexmedetomidine did not result in an improvement in 28-day mortality or ventilator-free days.

SOURCE: Kawazoe Y, et al. Effect of dexmedetomidine on mortality and ventilator-free days in patients requiring mechanical ventilation with sepsis: A randomized clinical trial. JAMA 2017;317:1321-1328.

There is increasing interest in the use of dexmedetomidine, a selective alpha2-adrenergic agonist, as a sedative agent in the ICU compared to traditional gamma-aminobutyric acid (GABA) receptor antagonists such as benzodiazepines and propofol. Although dexmedetomidine can produce side effects such as hypotension and bradycardia, which may limit its use in septic patients, a prior subgroup analysis reported less brain dysfunction and 28-day mortality in septic patients receiving dexmedetomidine.1 In the Dexmedetomidine for Sepsis in ICU Randomized Evaluation (DESIRE) trial conducted in eight ICUs in Japan between 2013 and 2016, Kawazoe et al hypothesized that a sedation strategy using dexmedetomidine would improve 28-day mortality and ventilator-free days in patients with sepsis requiring mechanical ventilation.

Inclusion criteria were ≥ 20 years of age, sepsis (defined as exhibiting at least two out of four systemic inflammatory response syndrome [SIRS] criteria due to infection; acute pancreatitis patients were included), and use mechanical ventilation (invasive and non-invasive) for at least 24 hours. Patients were excluded if they had severe chronic liver disease (Child B or C), acute myocardial infarction or heart failure (NYHA 4), drug or alcohol dependence, psychological or severe cognitive dysfunction, were pregnant or lactating, or were allergic to dexmedetomidine. This was an investigator-initiated, open-label trial; patients were randomized to receive sedation with dexmedetomidine or a sedation strategy without it (control group). Patients in the control group received sedatives such as propofol, midazolam, and analgesia without dexmedetomidine. For both groups, sedation targets were a Richmond Agitation-Sedation Scale (RASS) score of 0 during the day and -2 at night, and there were standardized protocols in place for enteral feeding as well ventilator weaning. The co-primary outcomes were 28-day mortality and ventilator-free days. A total of 201 mechanically ventilated patients with sepsis were randomized either to the dexmedetomidine group (n = 100) or the control group (n = 101); notably, six patients in the control group received dexmedetomidine during ventilation at the discretion of the attending physician. The cumulative incidence of death at 28 days was 22.8% in the dexmedetomidine group, compared to 30.8% in the control group (hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.38-1.22; P = 0.20). There was no difference in the number of ventilator-free days between the two groups, (6 [interquartile range, 3-11] vs. 6 [interquartile range, 3-11] days; P = 0.64). Regarding secondary outcomes, the dexmedetomidine group had higher rates of well-controlled sedation (patient’s number of days in which RASS scores were between -3 and +1 throughout day/total number of patients in ICU, calculated for each day) compared to the control group (range, 17-58% vs. 20-39%; P = 0.01). They also had lower median levels of C-reactive protein. Other secondary outcomes (including length of ICU and hospital stays, rate of delirium and coma-free days) and lab values (including disseminated intravascular coagulation and procalcitonin) were not significantly different between the two groups. In a prespecified subgroup analysis of patients with Acute Physiology and Chronic Health Evaluation (APACHE) II scores of ≥ 23, the dexmedetomidine group had lower hospital mortality (HR, 0.39; 95% CI, 0.16-0.91; P = 0.03).

COMMENTARY

Based on its mechanisms of action, there has been much interest in the use of dexmedetomidine in the ICU. Because its sedative effects are mediated through non-GABA pathways, it is thought to be less delirium-inducing and generate a more natural sleep cycle.2,3 It is observed to have anti-inflammatory properties by promoting macrophage phagocytosis and bactericidal killing and reducing levels of TNF-alpha, IL-1beta, and IL-6 in patients with sepsis.4 It also can attenuate sympathetic hyperdynamic responses, which theoretically can translate to myocardial protection.5 Whether these physiologic observations translate to significant clinical outcomes has been the subject of interest in recent studies. In patients requiring sedation for invasive mechanical ventilation in general, dexmedetomidine is associated with less delirium and a shorter time on the ventilator when compared with midazolam but not propofol.6,7 Patients receiving dexmedetomidine had enhanced arousability and ability to communicate pain, which may have contributed to earlier mobilization, extubation, and recovery. No significant differences were observed in ICU or hospital lengths of stay or mortality in these randomized trials.6,7 In contrast, a previous subgroup analysis of the Maximizing Efficacy of Targeted Sedation and Reducing Neurological Dysfunction trial found that use of dexmedetomidine was associated with lower 28-day mortality (16% vs. 41%; HR, 0.3; 95% CI, 0.1-0.9; P = 0.03) compared to midazolam, but only in patients with sepsis.1 However, caution should be used in interpreting these findings, as this was a subgroup analysis of a larger study and, as such, had small numbers, was not powered to examine specific outcomes, and was subject to serious confounding given its lack of randomization. Indeed, results of the currently reported randomized trial have not supported a clear benefit regarding mortality with the use of dexmedetomidine. Whether these results are related to lack of power, heterogeneity of the comparison group (the control group could receive either propofol or a benzodiazepine), or other reasons is unclear and remains to be addressed based on future studies.

REFERENCES

  1. Pandharipande PP, et al. Effect of dexmedetomidine versus lorazepam on outcome in patients with sepsis: An a priori-designed analysis of the MENDS randomized controlled trial. Crit Care 2010;14:R38.
  2. Pandharipande PP, et al. Effect of sedation with dexmedetomidine vs lorazepam on acute brain dysfunction in mechanically ventilated patients: The MENDS randomized controlled trial. JAMA 2007;298:2644-2653.
  3. Nelson LE, et al. The alpha2-adrenoceptor agonist dexmedetomidine converges on an endogenous sleep-promoting pathway to exert its sedative effects. Anesthesiology 2003;98:428-436.
  4. MacLaren R. Immunosedation: A consideration for sepsis. Crit Care 2009;13:191.
  5. Zamani MM, et al. Survival benefits of dexmedetomidine used for sedating septic patients in intensive care setting: A systematic review. J Crit Care 2016;32:93-100.
  6. Riker RR, et al. for the SEDCOM (Safety and Efficacy of Dexmedetomidine Compared with Midazolam) Study Group. JAMA 2009;301:489-499.
  7. Jakob SM, et al. Dexmedetomidine vs midazolam or propofol for sedation during prolonged mechanical ventilation: Two randomized controlled trials. JAMA 2012;307:1151-1160.