Kress et al: Daily Interruption of Sedative Infusions (2000)

“We conclude that daily interruption of sedative-drug infusions in critically ill patients receiving mechanical ventilation decreases the duration of mechanical ventilation and the length of stay in the intensive care unit.”

  • John P. Kress, M.D., et al.

1. Publication Details

  • Trial Title: Daily Interruption of Sedative Infusions in Critically Ill Patients Undergoing Mechanical Ventilation
  • Citation: Kress JP, Pohlman AS, O’Connor MF, Hall JB. Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation. N Engl J Med. 2000;342(20):1471-1477. DOI: 10.1056/NEJM200005183422002
  • Published: May 18, 2000, in The New England Journal of Medicine
  • Author: John P. Kress, M.D.
  • Funding: The Parker B. Francis Foundation.

2. Keywords

  • Sedation, Daily Sedation Interruption, Spontaneous Awakening Trial (SAT), Mechanical Ventilation, Weaning, Critical Care, Randomized Controlled Trial

3. The Clinical Question

  • In critically ill adult patients requiring mechanical ventilation and continuous sedative infusions (Population), does a strategy of daily interruption of sedation (Intervention) compared to standard, uninterrupted sedation (Comparison) reduce the duration of mechanical ventilation (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Continuous intravenous sedation was a cornerstone of care for mechanically ventilated patients to ensure comfort and safety. However, it was recognized that over-sedation was common and could lead to prolonged mechanical ventilation, increased complications, and a longer ICU stay due to the unpredictable accumulation of sedative drugs.
  • Knowledge Gap: It was unknown if a strategy of actively and routinely interrupting sedation on a daily basis would be a safe and effective way to reduce the total dose of sedatives, shorten the duration of ventilation, and improve outcomes.
  • Proposed Hypothesis: The authors hypothesized that a strategy of daily interruption of sedative infusions would be superior to standard uninterrupted sedation in reducing the duration of mechanical ventilation and ICU length of stay.

5. Study Design and Methods

  • Design: A single-center, prospective, randomized, controlled trial (used to test the effectiveness of interventions).
  • Setting: A single medical intensive care unit (ICU) at a university hospital in the United States.
  • Trial Period: Enrollment ran from May 1997 to October 1998.
  • Population:
    • Inclusion Criteria: Adult patients who were receiving mechanical ventilation and continuous infusions of sedative drugs (midazolam or propofol).
    • Exclusion Criteria: Included patients with acute, severe neurologic injury, those receiving neuromuscular blockers, and those requiring deep sedation for control of intracranial pressure.
  • Intervention: The “interruption” group. Sedative infusions were stopped each morning and held until the patient was awake and able to follow commands, or became agitated or distressed, at which point the infusions were restarted at half the previous rate.
  • Control: The “standard therapy” group. Sedative infusions were continued at a level deemed appropriate by the clinical team, with no protocol for daily interruption.
  • Management Common to Both Groups: All patients were managed by the same clinical teams. The choice of sedative agent was at the discretion of the treating physician.
  • Power and Sample Size: The authors calculated that a sample size of 128 patients would be required to have 80% power to detect a 2-day difference in the duration of mechanical ventilation. (Power is a study’s ability to find a real difference between treatments if one truly exists; 80% is the standard accepted level for clinical trials).
  • Outcomes:
    • Primary Outcome: The duration of mechanical ventilation.
    • Secondary Outcomes: Included length of stay in the ICU and hospital, total dose of sedative medications, and the incidence of complications.

6. Key Results

  • Enrollment and Baseline: 128 patients were randomized (68 to the interruption group and 60 to the control group). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: The median duration of mechanical ventilation was significantly shorter in the interruption group: 4.9 days in the interruption group vs. 7.3 days in the control group (p=0.004).
  • Secondary Outcomes: The median length of stay in the ICU was also significantly shorter in the interruption group (6.4 days vs. 9.9 days; p=0.02). Patients in the interruption group received lower total doses of sedative medications.
  • Adverse Events: There was no significant difference in the rate of complications, including self-extubation or the need for reintubation, between the two groups.

7. Medical Statistics

  • Analysis Principle: The trial was analyzed using an intention-to-treat principle.
  • Statistical Tests Used: The primary outcome was analyzed using a Wilcoxon rank-sum test.
  • Primary Outcome Analysis: The primary outcome was a comparison of the median duration of mechanical ventilation between the two groups.
  • Key Statistic(s) Reported: The key statistics were the median durations of mechanical ventilation and ICU stay, with their associated P-values.
  • Interpretation of Key Statistic(s):
    • P-value: The p-value of 0.004 for the primary outcome is well below the 0.05 threshold, indicating that the observed difference in ventilation duration is highly statistically significant and very unlikely to be due to chance (a result is conventionally considered statistically significant if the p-value is less than 0.05).
  • Clinical Impact Measures:
    • Difference in Medians: The median duration of mechanical ventilation was 2.4 days shorter in the interruption group. The median ICU length of stay was 3.5 days shorter. These represent large, clinically meaningful benefits.
  • Subgroup Analyses: Not a major feature of this publication.

8. Strengths of the Study

  • Study Design and Conduct: The randomized, controlled design provided a high level of evidence for a novel management strategy.
  • Patient-Centered Outcomes: The study focused on highly relevant outcomes like duration of ventilation and length of stay.
  • Pragmatic Intervention: The intervention of a daily “sedation vacation” is a simple, low-cost, and easily implementable strategy.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was unblinded, which is a significant limitation that introduces a risk of performance bias, as clinicians’ knowledge of the intervention could have influenced their decisions about weaning and extubation.
  • External Validity (Generalizability): The single-center design is a major limitation, as the results may not be applicable to other centers with different patient populations, staffing models, or baseline sedation practices.
  • Other: The study was relatively small.

10. Conclusion of the Authors

  • The authors concluded that a strategy of daily interruption of sedative infusions in critically ill patients receiving mechanical ventilation reduces the duration of mechanical ventilation and the length of stay in the ICU without increasing the incidence of complications.

11. To Summarize

  • Impact on Current Practice: This was a landmark, practice-changing trial that provided the first strong evidence to challenge the prevailing culture of deep, continuous sedation in the ICU. It introduced the concept of the “spontaneous awakening trial” or “sedation vacation” as a new standard of care.
  • Specific Recommendations:
    • Patient Selection: For the broad population of adult ICU patients requiring mechanical ventilation and continuous sedation.
    • Actionable Intervention: Implement a daily protocol to interrupt sedative infusions until the patient is awake and responsive.
    • Expected Benefit: This strategy can be expected to reduce the duration of mechanical ventilation and ICU stay by several days.
  • What This Trial Does NOT Mean: This trial does NOT mean that all patients must be awakened every day. The protocol included safety screens to exclude patients for whom awakening would be dangerous (e.g., those with high ICP or severe respiratory failure).
  • Implementation Caveats: The success of this strategy requires a multidisciplinary team approach and a culture that prioritizes light sedation and early liberation from the ventilator.

12. Context and Related Studies

  • Building on Previous Evidence: The Kress et al. trial (2000) was a pioneering study that provided the first high-quality evidence for a “less is more” approach to sedation.
  • Influence on Subsequent Research: The definitive positive result of this trial was a major catalyst for a paradigm shift in ICU sedation. It directly led to the design of the ABC trial (2008), which paired the spontaneous awakening trial with a spontaneous breathing trial, and was a foundational component of the now-ubiquitous ABCDEF bundle for ICU care.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: This trial did not determine the optimal sedative agents to use with a daily interruption strategy.
  • Future Directions: The entire subsequent field of research into light sedation, sedation protocols, and the management of pain, agitation, and delirium in the ICU can be seen as the future direction that followed from this seminal study.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant and innovative, challenging a long-standing and potentially harmful dogma of ICU care.
  • Methods: The randomized controlled trial design was appropriate. The main methodological weaknesses are the single-center, unblinded design, which limits generalizability and introduces a risk of performance bias.
  • Results: The study reported a large and both statistically and clinically significant benefit for the intervention across multiple important patient-centered outcomes.
  • Conclusions and Applicability: The authors’ conclusion is strongly supported by the data. Despite its limitations, this trial was profoundly influential because it introduced a simple, low-cost, and highly effective new standard of care. Its findings have been replicated and built upon in subsequent multicenter trials and are now a cornerstone of modern ICU practice.

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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