American Thoracic Society International Conference
American Thoracic Society International Conference
May 20, 2019
3 min read

Early sedation with dexmedetomidine fails to lower mortality vs. usual care: SPICE III

You've successfully added to your alerts. You will receive an email when new content is published.

Click Here to Manage Email Alerts

We were unable to process your request. Please try again later. If you continue to have this issue please contact

DALLAS — Critically ill patients undergoing mechanical ventilation in the ICU who received early sedation with dexmedetomidine as the primary or sole agent had a similar rate of mortality at 90 days compared with patients who received usual care, and were likely to require supplemental sedatives, researchers reported at the American Thoracic Society International Conference.

The open-label, randomized, controlled SPICE III trial enrolled 4,000 critically ill patients who were receiving ventilatory support in the ICU for less than 12 hours and were expected to continue ventilation for at least 1 day. Patients were randomly assigned to dexmedetomidine (Precedex, Pfizer) at a starting dose of 1 µg/kg of body weight without a loading dose or usual care consisting of propofol, midazolam or other sedatives to achieve target sedation scores on the Richmond Agitation and Sedation Scale (RASS) ranging from –2 to +1. As dexmedetomidine takes time to work, use of low-dose propofol was allowed if RASS was outside the target range, Yahya Shehabi, PhD, MBBS, professor and program medical director for critical care, Monash Health, Melbourne, Australia, said during his presentation of the data.

At 90 days, the primary outcome — death from any cause — occurred in 29.1% of patients in both treatment groups, according to a modified intention-to-treat analysis of 3,904 patients (P = .98). There was also no difference in the rate of death from any cause at 90 days when the researchers looked at subgroups of patients with or without sepsis and by country, cause of death or discharge destination.

“Overall, when dexmedetomidine is used as a primary sedative agent, it does have some modest benefits compared to propofol or midazolam,” Shehabi said.
Source: Adobe Stock

Further, 1,910 patients who received the early dexmedetomidine required supplemental sedatives to achieve the target level of sedation: propofol was used in 64%, midazolam in 3% and both in 7% during the first 2 days after randomization to dexmedetomidine.

There was a benefit in the dexmedetomidine group, in that median number of days free from coma or delirium and median number of days free from ventilation were 1 day higher compared with usual care.

Other secondary outcomes including mortality at 180 days, institutional dependence at 180 days, Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) score and European Quality of Life 5-Dimensions 3-Level (EQ-5D-3L) questionnaire revealed no difference between the groups.

Overall rates of adverse events and serious adverse events were higher among patients assigned dexmedetomidine. The most common serious adverse events were bradycardia (0.7% vs. 0.5%; P = .001), hypotension (0.5% vs. 0.5%; P = .006) and prolonged sinus arrest (0.7% vs. 0.1%; P = .003).


A finding worth further investigation emerged from a subgroup analysis of treatment effect by age, according to Shehabi. Patients older than the median age of 63.7 years had lower mortality and those younger than the median age had higher mortality. This remained significant after adjustment for multiplicity, he said.

The SPICE III trial was conducted at 74 ICUs in eight countries worldwide. Mean age was 61 years and two-thirds were men.

Overall, 98% of patients assigned dexmedetomidine received the agent for a median duration of 2.56 days and 98% of patients assigned usual care with propofol or midazolam received the agents for a median duration of 2.67 days and 1.51 days, respectively. In the usual-care group, propofol was used in 60%, midazolam in 11.9% and both in 20%. Fentanyl was used in 78% of the dexmedetomidine group and 81% of the usual-care group.

In the first 2 days after randomization, 56.6% of patients assigned dexmedetomidine had RASS scores in the target range of light sedation vs. 51.8% of patients assigned usual care. RASS scores in the deep-sedation range were observed in 40% of those assigned dexmedetomidine vs. 45.6% assigned usual care.

Taken in context, Shehabi said the results of the SPICE III provide several important insights.

“Overall, when dexmedetomidine is used as a primary sedative agent, it does have some modest benefits compared to propofol or midazolam,” he said. “So, when we choose a sedation strategy for ventilated patients who are critically ill, in younger patients the use of dexmedetomidine early as a primary sedative agent should be carefully considered, especially in the first 4 to 5 years. In older patients who are requiring sedation, the early use of dexmedetomidine as a primary sedative agent needs urgent evaluation.” – by Katie Kalvaitis


Shehabi Y. JAMA and The New England Journal of Medicine Discussion on the Edge: Reports of Recently Published Critical Care Research. Presented at: American Thoracic Society International Conference; May 17-22, 2019; Dallas.

Shehabi Y, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1904710.

Disclosures: The SPICE III trial was funded by the National Health and Medical Research Council of Australia and others. Shehabi reports receiving grants from The National Health and Medical Research Council of Australia, nonfinancial support from Orion Pharma and Pfizer during the conduct of the study. Please see the study for all other authors’ relevant financial disclosures.