SLEAP: Sedation Interruption vs. Protocolized Sedation (2012)

“For mechanically ventilated adults managed with protocolized sedation, the addition of daily sedation interruption did not reduce the duration of mechanical ventilation or ICU stay.”

— The SLEAP Investigators

1. Publication Details

  • Trial Title: Daily Sedation Interruption in Mechanically Ventilated Critically Ill Patients Cared for With a Sedation Protocol: A Randomized Controlled Trial.
  • Citation: Mehta S, Burry L, Cook D, et al; for the SLEAP Investigators and the Canadian Critical Care Trials Group. Daily sedation interruption in mechanically ventilated critically ill patients cared for with a sedation protocol: a randomized controlled trial. JAMA. 2012;308(19):1985-1992. doi:10.1001/jama.2012.13872.
  • Published: November 21, 2012, in The Journal of the American Medical Association (JAMA).
  • Author: Sangeeta Mehta, M.D.
  • Funding: Canadian Institutes of Health Research.

2. Keywords

Sedation, Daily Sedation Interruption, Spontaneous Awakening Trial, Mechanical Ventilation, Protocolized Sedation, Critical Illness, Benzodiazepines.

3. The Clinical Question

In critically ill, mechanically ventilated adults managed with protocol-directed sedation (Population), does the addition of daily sedation interruption (Intervention) compared to protocol-directed sedation alone (Comparison) reduce the time to successful extubation (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Both nurse-driven protocolized sedation (PS) and daily sedation interruption (DI), also known as spontaneous awakening trials (SATs), were known as individual strategies to minimize over-sedation and shorten the duration of mechanical ventilation.
  • Knowledge Gap: It was unknown whether combining these two effective strategies would provide an additive benefit, or if one strategy was redundant in the presence of the other. Specifically, if a protocol already aims for light sedation, it was unclear if a daily “hard stop” of infusions was still necessary or beneficial.
  • Proposed Hypothesis: The authors hypothesized that combining protocolized sedation with daily interruption would result in a shorter duration of mechanical ventilation compared to protocolized sedation alone.

5. Study Design and Methods

  • Design: A multicenter, randomized, unblinded, controlled trial.
  • Setting: 16 medical and surgical ICUs in Canada and the United States.
  • Trial Period: Enrollment from January 2008 to July 2011.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) expected to require mechanical ventilation for at least 48 hours and for whom a continuous sedative/opioid infusion was initiated.
    • Exclusion Criteria: Admission after cardiac arrest, traumatic brain injury, ongoing neuromuscular blockade, or lack of commitment to aggressive treatment.
  • Intervention: Protocolized sedation (targeting a light level of sedation using a validated scale) plus a daily interruption of continuous opioid and benzodiazepine infusions.
  • Control: Protocolized sedation alone, targeting the same light level of sedation.
  • Management Common to Both Groups: Both groups were managed with a nurse-driven sedation protocol targeting a Sedation-Agitation Scale (SAS) score of 3-4 or a Richmond Agitation-Sedation Scale (RASS) score of -3 to 0. Sedation was primarily with benzodiazepines (midazolam or lorazepam) and opioids (fentanyl or morphine).
  • Power and Sample Size: The trial was powered to detect a 2-day difference in the median time to extubation, requiring 430 patients.
  • Outcomes:
    • Primary Outcome: Time to successful extubation.
    • Secondary Outcomes: Duration of ICU and hospital stay, doses of sedatives and opioids, incidence of delirium, unintentional device removal, and nurse workload.

6. Key Results

  • Enrollment and Baseline: 430 patients were randomized (214 to interruption, 209 to control). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: There was no significant difference in the median time to successful extubation between the interruption and control groups (7 days vs 7 days; Hazard Ratio 1.08, 95% CI 0.86-1.35; P=.52).
  • Secondary Outcomes: There were no significant differences in ICU or hospital length of stay, or in the rates of delirium or unintentional endotracheal tube removal. The daily interruption group received significantly higher daily doses of midazolam and fentanyl and required more bolus doses. Nurse workload was rated as significantly higher in the interruption group.
  • Adverse Events: The rate of unintentional device removal was similar in both groups (4.7% vs 5.8%).

7. Medical Statistics

  • Analysis Principle: An intention-to-treat analysis was performed.
  • Statistical Tests Used: The primary outcome was analyzed using a Cox proportional-hazards model.
  • Primary Outcome Analysis: Time to successful extubation was compared between the two groups.
  • Key Statistic(s) Reported: Hazard Ratio for time to extubation: 1.08 (95% CI, 0.86 to 1.35; P=.52).
  • Interpretation of Key Statistic(s):
    • Hazard Ratio (HR): An HR of 1.08 suggests a slight (8%) but non-significant increase in the rate of extubation in the interruption group.
    • Confidence Interval (CI): The 95% CI broadly crosses 1.0 (from a 14% decrease to a 35% increase in the extubation rate), indicating no statistically significant difference.
    • P-value: The p-value of 0.52 confirms the lack of a statistically significant difference between the strategies.
  • Clinical Impact Measures: Not applicable as no benefit was shown for the primary outcome.
  • Subgroup Analyses: No significant benefit was found in any pre-specified subgroups.

8. Strengths of the Study

  • Study Design and Conduct: This was a large, multicenter randomized trial that addressed a highly relevant clinical question about combining two established “best practices.”
  • Generalizability: The inclusion of 16 diverse medical and surgical ICUs increases the external validity of the findings.
  • Pragmatic Design: The study was designed to reflect real-world practice without dedicated research nurses, which enhances its applicability.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was unblinded, which is a potential source of bias. There was some protocol non-adherence, with interruptions missed in the intervention group and some interruptions occurring in the control group, which would bias the results toward the null.
  • External Validity (Generalizability): The sedation strategy was primarily based on benzodiazepines, the use of which has declined in favor of agents like propofol and dexmedetomidine since the trial was conducted.
  • Other: The control group was managed with a high-quality sedation protocol targeting light sedation, which may have minimized the potential additional benefit of the daily interruption strategy.

10. Conclusion of the Authors

“For mechanically ventilated adults managed with protocolized sedation, the addition of daily sedation interruption did not reduce the duration of mechanical ventilation or ICU stay.”

11. To Summarize

  • Impact on Current Practice: This was a landmark trial that provided crucial nuance to ICU sedation management. It demonstrated that if an ICU is already successfully using a protocol to achieve and maintain light levels of sedation, the addition of a mandatory daily interruption may not provide further benefit and could increase drug consumption and nursing workload. It shifted the focus from the specific method (DI) to the overall goal (achieving light sedation).
  • Specific Recommendations:
    • Patient Selection: For mechanically ventilated adult patients receiving continuous sedation.
    • Actionable Intervention: The priority should be to implement a reliable system (like a nurse-driven protocol) to target a light level of sedation. Adding daily interruption to this may be redundant.
    • Expected Benefit: No additional benefit in ventilation time or ICU stay was demonstrated by adding DI to an effective sedation protocol.
  • What This Trial Does NOT Mean: This trial does NOT mean that daily sedation interruption is ineffective. The original Kress et al. (2000) trial showed a clear benefit of DI compared to a strategy of no protocol and deep sedation. SLEAP’s findings apply only when comparing DI to an already effective light sedation protocol.
  • Implementation Caveats: The key to good sedation practice is having a system to regularly assess and titrate sedation to the lightest possible level, whether through a protocol, daily interruptions, or both.

12. Context and Related Studies

  • Building on Previous Evidence: This trial was a direct follow-up to the landmark study by Kress et al. (NEJM 2000), which established the benefit of daily interruption compared to usual (deep sedation) care. SLEAP asked the next logical question: is interruption still beneficial if “usual care” is now a high-quality protocol targeting light sedation?
  • Influence on Subsequent Research: The results of SLEAP have influenced sedation guidelines, emphasizing the overall goal of targeted light sedation. It helped solidify the components of the “ABCDEF Bundle,” where Spontaneous Awakening Trials (SATs) and Spontaneous Breathing Trials (SBTs) are paired, but underscores that the “A” (Assess, Prevent, and Manage Pain) and overall sedation titration are foundational.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: Would these results hold true for sedation strategies based primarily on propofol or dexmedetomidine instead of benzodiazepines?
  • Future Directions: Research continues to focus on optimizing sedation, including the use of newer agents, minimizing sedation entirely in some patients, and better integrating pain, agitation, and delirium management.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The question was highly relevant and pragmatic, testing whether two beneficial strategies had an additive effect.
  • Methods: The multicenter RCT design was robust. The choice of a strong comparator (protocolized light sedation) was a key feature and likely explains the neutral result.
  • Results: The trial had a clear negative finding for its primary outcome. The secondary findings of increased drug use and nursing workload in the interruption group are important for clinical practice.
  • Conclusions and Applicability: The authors’ conclusion is well-supported. The trial is highly applicable and provides a crucial lesson: the benefit of an intervention (like DI) depends heavily on the quality of the control group’s care. It suggests that achieving a state of light sedation is the key objective, and the specific method used to get there may be less important.

16. Disclaimer and Contact

This summary is provided by the Academic Committee of ESBICM (ACE) to facilitate the understanding of this study; readers are advised to refer to the original trial document for a deeper understanding. If you find any information incorrect, or missing, or it needs an update or have a request for a specific critical care trial summary, kindly write to us at academics[at]esbicm.org.

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