SPICE III

Published

Shehabi Y, et al. "Early Sedation with Dexmedetomidine in Critically Ill Patients". The New England Journal of Medicine. 2019. 380(26):2506-2517.
PubMed • Full text • PDF • ClinicalTrials.gov

Clinical Question

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

Bottom Line

Among patients undergoing mechanical ventilation, primary use of dexmedetomidine as compared to usual care with other sedatives led to more adverse events without improving mortality.

Major Points

The newer sedative dexmedetomidine has desirable properties such as providing analgesia without depressing respiratory drive, may produce lighter sedation, and may cause delirium less frequently than other agents. Direct comparisons between sedation with dexmedetomidine versus other agents was lacking.

The Sedation Practice in Intensive Care Evaluation (SPICE III) study was a randomized, open-label trial enrolling 4,000 patients receiving mechanical ventilation. Patients were randomized to sedation with dexmedetomidine as the primary agent, versus usual care with other sedatives such as propofol and midazolam. The primary outcome of 90-day all-cause mortality was the same between groups at 29.1%. Patients in the dexmedetomidine group had high rates of supplemental sedative use, including propofol in 64%, and higher rates of adverse events including bradycardia, hypotension, and asystole. The number needed to harm to cause one serious adverse event with dexmedetomidine was 43.

The authors conclude that the early use of dexmedetomidine as a primary agent for sedation does not improve mortality and is associated with more toxicity compared with usual care. There are a number of criticisms for this trial including its open-label design. While this may have introduced bias in the results, attempting to blind multiple agents, including one dissolved in a lipid emulsion, would have been prohibitive.

Guidelines

PADIS Guidelines for Adult Patients in the ICU (2018, adapted)

• 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)
• Note, these guidelines were published prior to release of SPICE III

Design

• Multicenter, open-label, randomized, controlled trial
• N=4,000 mechanically ventilated patients
  • Dexmedetomidine (n=1,954)
  • Usual care (n=1,964)
• Setting: 74 ICUs in 8 countries
• Enrollment: 2013-2018
• Analysis: Modified intention-to-treat
• Primary outcome: 90-day mortality

Population

Inclusion Criteria

• Age ≥18 years
• 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

• Invasive ventilation in the ICU for longer than 12 hours before enrollment
• Suspected or proven acute primary brain injury
• ICU admission due to drug overdose or burn

Baseline Characteristics

From the dexmedetomidine group.

• Demographics: Age 61 years, 41% female, 27% surgical admission
• Patient level factors: APACHE II score 22, diabetes treated with insulin 10%, PF ratio 197, RASS score -4
• Admission diagnosis: Respiratory 40%, sepsis 16%, gastrointestinal 16%, cardiovascular 15%, trauma 4%, neurologic 1%, metabolic or endocrine 1%, renal disorder 1%, hematologic disorder 1%, MSK 3%, other 1%
• Anthropomorphics: Weight 82 kg
• Suspected or proven sepsis: 64%
• Time from eligibility to randomization: 5 hours

Interventions

Full protocol is available online.

• Eligible participants were randomized to a group
  • Dexmedetomidine - Infusion of dexmedetomidine 1-1.5 mcg/kg/h, with add-on propofol if needed. Midazolam to be avoided.
  • Usual care - Administration of propofol, midazolam, or both as determined by the treating clinician.
• Adequate analgesia as per treating physician
• Sedation to RASS goal -2 to +1 at all times in both groups

Outcomes

Comparisons are dexmedetomidine vs. usual care.

Primary Outcomes

90-day mortality

29.1% in both groups (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 vs. 23 days (difference 1.0, 95% CI 0.5 to 1.5)

Median no. of ventilator-free days

23 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%

Other Analyses

Protocol deviations

18.4% vs. 10.9%, P<0.0001

Subgroup Analysis

90 Day mortality by age, stratified by median age

Age ≤63.7: Risk difference (RD) 4.4 (0.8 to 7.9)

Age >63.7: RD -4.4 (-8.7 to -0.1)

No heterogeneity in other predefined subgroups.

Adverse Events

Detailed in the supplemental appendix in table S9Supplemental appendix.

≥1 adverse event

Any: 9.6% vs. 1.8%; P<0.0001

Serious adverse events: 2.7% vs. 0.4%; P<0.0001 (NNH=43)

Bradycardia

5.1% vs. 0.5%, P<0.001

Serious: 0.7% vs. 0.05%, P=0.001 (NNH=154)

Hypotension

2.7% vs. 0.5%, P<0.0001

Serious: 0.5% vs. 0.05%, P=0.006 (NNH=222)

Other

2.3% vs. 0.8%, P<0.0001

Serious: 0.82% vs. 0.15%, P=0.003 (NNH=149)

Asystole

0.7% vs. 0.1%, P=0.003 (NNH=167)

Uncontrolled agitation

2.3% vs. 3.9%, P=0.003 (NNT=62)

Criticisms

• Open-label design may have allowed treatment bias
• Patients indicated for deep sedation included in study analysis despite dexmedetomidine's inability to reach deeper sedation levels
• 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
• Adverse events not specified or collected systematically or adjudicated by the trial, reported independently by site investigators

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