By Drayton Hammond, PharmD, MBA, BCPS, BCCCP

Clinical Pharmacy Specialist, Adult Critical Care, Rush University Medical Center, Chicago

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

SYNOPSIS: When the early use of continuous infusion dexmedetomidine was compared to usual care for sedation in mechanically ventilated critically ill adults, there was no difference in 90-day mortality. Dexmedetomidine may not be an ideal sedative for mechanically ventilated critically ill adults requiring deeper sedation, although its use may result in greater ventilator-free, coma-free, or delirium-free days.

SOURCE: Shehabi Y, Howe BD, Bellomo R, et al. Early sedation with dexmedetomidine in critically ill patients. N Engl J Med 2019;380:2506-2517.

In mechanically ventilated critically ill adults, pain assessment and management are vital components to high-quality care.1 In patients for whom pain is being adequately managed but agitation develops, intravenous sedatives such as propofol and dexmedetomidine may be used to achieve a degree of sedation that supports safe and effective mechanical ventilation. Previous trials with dexmedetomidine routinely have had a benzodiazepine-centric comparator arm.2-4 Although a large trial comparing dexmedetomidine and propofol was conducted and found predominately similar outcomes between groups, except for reduced ventilation time and agitation in the dexmedetomidine group, a detailed investigation into other intermediate- and long-term patient-centered outcomes between these sedatives had not been performed. The SPICE III trial was performed to investigate these outcomes in a methodical manner with the largest sample size to date.5

A randomized, open-label trial was conducted in 74 intensive care units in eight countries.5 Mechanically ventilated adults receiving sedatives who were expected to continue ventilatory support for at least one additional day were randomized within 4.6 hours (interquartile range [IQR], 1.8-8.7 hours) to a continuous infusion of dexmedetomidine initiated at 1 mcg/kg/hour or usual care (e.g., continuous infusions of propofol and/or midazolam). Rescue sedative use was allowed in both groups, although benzodiazepines were discouraged. Adequate analgesia was provided as determined by treating clinicians, and light sedation was targeted unless the treating clinician deemed this practice unsafe or contraindicated (e.g., receipt of neuromuscular blockade during acute respiratory distress syndrome). Other supportive care, including use of ABCDEF bundle components, was institution-specific.

At the time of randomization, approximately 80% of patients were receiving propofol and 80% of patients were receiving fentanyl or morphine. Almost all patients in the intervention group received dexmedetomidine infusions during the intervention period (97.7%), and one-ninth (11.5%) of patients in the usual care group received dexmedetomidine. A surprisingly high number of patients (50-60%) had a clinical indication for deep sedation during the first two days of treatment post-randomization, which led to patients receiving adjunctive sedative agents in the dexmedetomidine group (64.7% received propofol, 2.9% midazolam, 6.9% for both agents). Although many patients in both groups (78.5% vs. 80.7%) received fentanyl infusions, the average daily dosage was 800-1,000 mcg (equivalent to 33-42 mcg/hour.

The primary outcome, 90-day all-cause mortality, was similar between the dexmedetomidine and usual care groups (29.1% vs. 29.1%, mean difference 0.0 percentage points, 95% confidence interval [CI], -2.9 to 2.8). The only pre-specified subgroup for which a 90-day mortality difference was found was based on median age; patients younger than 63.7 years experienced mortality less frequently with usual care, while older patients experienced mortality less frequently with dexmedetomidine. Patients in the dexmedetomidine group experienced a greater median number of coma- or delirium-free days (24 vs. 23, adjusted risk difference 1.0 days, 95% CI, 0.5-1.5) and ventilator-free days (23 vs. 22, adjusted risk difference 1.0, 95% CI, 0.4-1.6).

COMMENTARY

When the early use of continuous infusion dexmedetomidine was compared to usual care (most commonly propofol) for sedation in mechanically ventilated critically ill adults, there was no difference in 90-day mortality. Compared to patients enrolled in the PRODEX trial,4 those in the SPICE III trial more frequently required deeper sedation based on clinicians’ assessments and preferences.5 This difference in desired sedation depth may explain the frequent use of adjunctive propofol in the dexmedetomidine group. However, the relatively low doses of opioid analgesics in both groups may have masked unmet patient needs for adequate pain management, which is a practice counter to guideline recommendations, but often is observed in practice.1 The inclusion of patients who needed deeper sedation was likely unavoidable by trial investigators because of the early patient enrollment and represents a population that is unlikely to benefit from a sedative strategy primarily focused on dexmedetomidine, which is particularly emphasized by 35% of patients receiving a neuromuscular blocking agent that should be accompanied with a RASS of -4 to -5 (well beyond the target RASS of -2 to +1).

For those patients in whom dexmedetomidine is administered, caution should be provided for concomitant propofol use. This combination therapy is not used routinely in practice, so clinician and nurse experience with sedative titration and achievement of target RASS in a patient receiving both therapies may have driven the higher complication rate, particularly hypotension and bradycardia, in the dexmedetomidine group compared to the usual care group.6 Additionally, the starting dexmedetomidine dosage of 1 mcg/kg/hour, which far exceeds a usual starting dosage of
0.2-0.4 mcg/kg/hour, could explain some of the adverse effects observed. The observed difference in mortality when patients were stratified by age warrants further consideration by clinicians and researchers, as this may be a spurious finding or one with a pathophysiological basis previously unappreciated. Dexmedetomidine may not be an ideal sedative for mechanically ventilated critically ill adults requiring deeper sedation, although its use may result in a greater number of mechanical ventilation-free and coma-free or delirium-free days.

REFERENCES

  1. Devlin JW, Skrobik Y, Gélinas C, et al. 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:e825-e873.
  2. Pandharipande PP, Pun BT, Herr DL, 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. Riker RR, Shehabi Y, Bokesch PM, et al. Dexmedetomidine vs midazolam for sedation of critically ill patients: A randomized trial. JAMA 2009;301:489-499.
  4. Jakob SM, Ruokonen E, Grounds RM, et al. Dexmedetomidine vs midazolam or propofol for sedation during prolonged mechanical ventilation: Two randomized controlled trials. JAMA 2012;307:1151-1160.
  5. Shehabi Y, Howe BD, Bellomo R, et al; ANZICS Clinical Trials Group and the SPICE III Investigators. Early sedation with dexmedetomidine in critically ill patients. N Engl J Med 2019;380:2506-2517.
  6. Lonardo NW, Mone MC, Nirula R, et al. Propofol is associated with favorable outcomes compared with benzodiazepines in ventilated intensive care unit patients. Am J Respir Crit Care Med 2014;189:1383-1394.