By Samuel Nadler, MD, PhD

Critical Care, Pulmonary Medicine, The Polyclinic Center, Seattle; Clinical Instructor, University of Washington, Seattle

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

SYNOPSIS: The choice of dexmedetomidine or propofol over midazolam may improve outcomes in patients mechanically ventilated for three or more days.

SOURCE: Klompas M, Li L, Szumita P, et al. Associations between different sedatives and ventilator-associated events, length of stay, and mortality in patients who were mechanically ventilated. Chest 2016;149:1373-1379.

It’s common to treat critically ill patients on mechanical ventilation with sedative medications. Limited data exist to direct which sedatives are most appropriate to maintain patient comfort yet facilitate timely extubation and minimize adverse events. Previously, benzodiazepine infusions were most common. More recently, propofol and dexmedetomidine have supplanted benzodiazepine, based largely on two studies published in 2009 and 2012.1,2

Klompas et al examined how these recommendations generalize into routine practice. This is a retrospective study of 9,603 patients in a single academic center between July 2006 and December 2013. The inclusion criteria specified patients on mechanical ventilation for three or more days. Outcomes studied included time to extubation, time to hospital discharge, ventilator associated events (VAEs), and mortality. Proportional subdistribution hazard models were used to estimate the effect of sedative exposure on these outcomes.

Over the specified time period, researchers identified 86,714 ventilator days. The combination of benzodiazepines and propofol (42%) was the most common sedation method, followed by benzodiazepines alone (21%), propofol alone (12%), and the combination of benzodiazepines, propofol, and dexmedetomidine (10%). Clinicians used dexmedetomidine alone in 0.3% of ventilator days, most commonly in the cardiac surgery ICU. Compared with regimens without benzodiazepines, there was a significantly higher risk of VAEs in patients on midazolam (hazard ratio [HR], 1.4; 95% confidence interval [CI], 1.1-1.7; P = 0.002). Compared with regimens without propofol, patients on propofol experienced a higher risk of VAEs (HR, 1.3; 95% CI, 1.1-1.6; P = 0.003), infection-related, ventilator-associated complications (IVACs) (HR, 1.6; 95% CI, 1.2-2.2; P = 0.0009), and possible or probable pneumonias (HR, 1.5; 95% CI, 1.0-2.2; P = 0.003). Direct comparisons of single agents did not reveal statistically significant HRs, although there was a trend toward decreased events in patients on dexmedetomidine. Overall, patients on dexmedetomidine were more likely to be extubated (HR, 2.05; 95% CI, 1.77-2.38; P < 0.0001) when compared to patients on regimens without dexmedetomidine and in single-agent comparisons. There were no differences in hospital discharges and mortality among different regimens.

COMMENTARY

This study represents a huge, albeit retrospective, cohort study of the effects of various sedative agents on patient outcomes in the ICU. It focuses on patients on prolonged mechanical ventilation, specifically three or more days. The use of proportional sub-distribution hazard models can correct for known confounding variables but cannot eliminate bias in this study.

It is important to note that investigators conducted this study using data on patients admitted between 2006 and 2013. Although efforts were made to correct hazard risks based on year of admission, the bulk of patients were admitted before most practitioners had transitioned away from the use of benzodiazepines. The SEDCOM and MIDEX/PRODEX trials were published in 2009 and 2012, respectively.1,2 This is evident by the many patients on propofol and benzodiazepines and benzodiazepine-only regimens. Relatively few patients were on dexmedetomidine only or regimens including dexmedetomidine. Thus, this study may not represent contemporary practice patterns in the ICU.

There were significant differences in the type of ICU using each sedative. The greatest proportion of dexmedetomidine was used in the cardiac surgery (57%) and thoracic surgery (16%) units. While hazard risk adjustments were made for this confounding variable, these patients clearly are different from patients in medical units, which may bias results.

Ultimately, base the decision on which sedatives to use on relative risks and benefits. This study suggested dexmedetomidine-based sedation strategies might facilitate extubation and reduce VAEs and IVACs. However, this did not translate into shorter length of stay or hospital mortality. Greater rates of bradyarrhythmias have been noted with dexmedetomidine. Although Klompas et al did not address depth of sedation in this study, the SEDCOM and MIDEX/PRODEX trials did, and it may lead to improved patient arousability and ability to communicate with dexmedetomidine. This study did not address the cost-effectiveness of these regimens, as dexmedetomidine can be much more expensive than other agents. Thus, while the Klompas et al study hints that dexmedetomidine-based regimens may have benefits, one must consider the many other factors not examined in this study in choosing sedatives for patients on mechanical ventilation in the ICU.

REFERENCES

  1. Riker RR, Shehabi Y, Bokesch PM, et al. Dexmedetomidine vs midazolam for sedation of critically ill patients. JAMA 2009;301:489-499.
  2. Jokob SM, Ruokonen E, Grounds RM, et al. Dexmedetomidine vs midazolam or propofol for sedation during prolonged mechanical ventilation. JAMA 2012;307:1151-1160.