SPICE III

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Shehabi Y. "Early Sedation with Dexmedetomidine in Critically Ill Patients". NEJM. 2019. ePub ahead of print:.
PubMedClinicalTrials.gov

Clinical Question

In critically ill adult patients undergoing mechanical ventilation, does the use of dexemedetomidine as the primary sedative as compared to usual care with other sedatives, lead to improvements in mortality.

Bottom Line

Dexmedetomidine should be reserved for select patients, its use as the primary sedative led to similar mortality but required more rescue sedatives and led to more adverse events than the usual care.

Major Points

Dexmedetomidine, a second generation clonidine, is the most recent sedative to be developed. While it has many desirable properties, including providing some analgesia and not depression the respiratory drive, it also may not provide as deep of a sedation as previous sedatives. There has also been some research that suggests the dexmedetomidine may have less association with delirium or may be used for prevention Nocturnal Dexmedetomidine for Delirium Prevention.

In this trial, enrolling 4000 patients across 74 intensive care units in 8 countries outside of North America between 2013 and 2018, they assessed the use of dexmedetomidine as the primary sedative during mechanical ventilation, as compared to usual care with other sedatives. Their analysis included a modified intention-to-treat model including 3904 patients with a primary outcome of 90 day all-cause mortality. Across both groups, there was no difference with a 29.1% vs. 29.1% (95% CI −2.9 to 2.8) mortality rate.

Dexemdetomidine was generally insufficient to maintain sedation score targets and additional sedation was required, however, the 11% of the usual care group was also exposed to the drug. There was also more adverse effects seen with the dexmedetomidine group, seeing significantly more bradycardia, hypotention, and asystole than with the usual care. Interestingly in the subgroup analysis, patients above the median age (63.7 years) had a lower mortality rate with dexmedetomidine. There are a number of criticisms for this trial, the first is the open-label design. This may have introduced bias in the results but attempting to blind multiple agents, including one dissolved in a lipid emulsion, would have been prohibitive. Sleep was assess subjectively via questionnaire, and none of the other aspects of care were assessed, all of which may have introduced some bias.

Guidelines

Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption (PADIS) in Adult Patients in the ICU, 2018, Adapted [1]:

Prevention of Delirium: Recommend against the use of pharmacological agents (haloperidol, dexmedetomidine, HMG-CoA reductase inhibitors, ketamine) to prevent delirium (conditional recommendation, very low to low quality of evidence)

Design

  • Multicenter, open-label, randomized, control trial
  • N=4000
    • Dexmedetomidine (n=1954)
    • Usual Care (n=1964)
  • Setting: 74 ICUs in 8 countries (Australia, Ireland, Italy, Malaysia, New Zealand, Saudi Arabia, Switzerland, and the UK)
  • Enrollment: November 2013 - February 2018
  • Analysis: modified intention-to-treat
  • Primary Outcome: 90 day mortality

Population

Inclusion Criteria

  • receiving mechanical ventilation through an endotracheal tube,
  • expected to receive ventilatory support beyond the next full calendar day
  • receiving sedatives for safety and comfort

Exclusion Criteria

  • age < 18 years
  • invasive ventilation in the ICU for longer than 12 hours before enrollment
  • suspected or proven acute primary brain injury

Baseline Characteristics

‘'Dexmedetomidine Group displayed

  • Demographics: mean age 62 years, 40% female, 27% operative admission,
  • Physiologic parameters: mean APACHE II score 22, diabetes treated with insulin 9.5%,
  • Admission diagnosis: Respiratory 40%, Sepsis 16%, Gastrointestinal 16%,cardiovascular 15%, trauma 4%, neurologic 1.3%, metabolic or endocrine 1.3%, renal disorder 1%, hematologic disorder 0.6%, MSK 3.2%, other 0.9%
  • Anthropomorphics: Weight 82kg
  • Labs: suspected or proven sepsis 64%

Interventions

  • Adequate analgesia as per treating physician
  • Sedation to RASS goal -2 to +1
    • Dexmedetomidine 1 mcg/kg/h (max 1.5 mug/kg/h)
    • Usual sedation care (propofol, midazolam, or other sedatives)

Outcomes

Comparisons are dexemetomidine vs. usual care.

Primary Outcomes

90 day all-cause mortality
29.1% vs. 29.1% (OR 1.00, Difference 0, 95% CI −2.9 to 2.8) P = 0.98

Secondary Outcomes

180 day mortality
31.5% vs. 31.3% (OR 1.01, Difference 0.1, 95% CI -2.8 to 3.1)
Institutional dependency at 180 days
6.7% vs. 7.0% (OR 0.96, Difference -0.3, 95% CI -2.1 to 1.5)
Mean score on Short IQCODE at 180 days
3.14 vs. 3.08 (Difference 0.06, 95% CI 0.02 to 0.11)
Mean score on the EQ-5D-3L questionnaire
69.8 vs. 70.2 (Difference -0.4, 95% CI -2.2 vs. 1.3)
Median no. of days free from coma or delirium
24 days vs. 23 days (Difference 1.0, 95% CI 0.5 to 1.5)
Median no. of ventilator-free days
23 days vs. 22 days (Difference 1.0, 95% CI 0.4 to 1.6)
Attainment of target RASS within the the first two days of randomization
-2 to +1 = 56.6% vs. 51.8%
-5 to -3 = 40.0% vs. 45.6%
Use of additional sedatives to maintain sedation level
Propofol = 64.7% vs. 60.1%
Midazolam = 2.9% vs. 11.9%
Both Propofol and Midazolam = 6.9% vs. 20.0%
Dexmedetomidine = 97.8% vs. 11.5%
Fentanyl = 78.5% vs. 80.7%

Subgroup Analysis

Median Age 63.7, mortality
above 63.7 favoured dexmedetomidine, significance could not be determined
All other pre-defined subgroups were non-significant

Adverse Events

Bradycardia
5.1% vs. 0.5%, P < 0.001
Serious Bradycardia
0.7% vs. 0.05%, P = 0.001
Hypotention
2.7% vs. 0.5%, P < 0.0001
Serious Hypotention
0.5% vs. 0.05%, P = 0.006
Asystole
0.7% vs. 0.1%, P = 0.003
Uncontrolled Agitation
2.3% vs. 3.9%, P = 0.003

Criticisms

  • Open-label design may have allowed treatment bias
  • Daily sedation vacation was not mandated by the trial
  • Other aspects of critical care was not assessed and may have introduced confounders in the outcomes
  • Sleep was assessed by subjective patient questionnaires instead of polysomnography

Funding

  • Funded by:
    • National Health and Medical Research Council of Australia
    • Health Research Council of New Zealand,
    • Institut Jantung Negara Foundation of Malaysia
  • Pfizer and Orion Pharma supplied dexmedetomidine

Further Reading

  1. Devlin JW 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.