NONSEDA: No Sedation in Mechanically Ventilated Patients (2010)

“Our results challenge the widespread practice of sedating all hemodynamically stable patients during mechanical ventilation.”

  • The NONSEDA Investigators

1. Publication Details

  • Trial Title: A protocol of no sedation for critically ill patients receiving mechanical ventilation: a randomised trial
  • Citation: Strøm T, Martinussen T, Toft P. A protocol of no sedation for critically ill patients receiving mechanical ventilation: a randomised trial. Lancet. 2010;375(9713):475-480. DOI: 10.1016/S0140-6736(09)62072-9
  • Published: February 6, 2010, in The Lancet
  • Author: Thomas Strøm, M.D.
  • Funding: The Danish Society of Anesthesiology and Intensive Care Medicine and others.

2. Keywords

  • Sedation, No Sedation, Mechanical Ventilation, Delirium, Analgesia-First, Randomized Controlled Trial

3. The Clinical Question

  • In critically ill adult patients requiring mechanical ventilation (Population), does a strategy of no sedation (with analgesia as needed) (Intervention) compared to a strategy of sedation with daily interruption (Comparison) increase the number of ventilator-free days at 28 days (Outcome)?

4. Background and Rationale

  • Existing Knowledge: The paradigm of ICU sedation had shifted from deep, continuous sedation towards lighter sedation with daily interruptions, based on landmark trials like Kress et al. (2000) and the ABC trial (2008). This was known to improve outcomes.
  • Knowledge Gap: While lighter sedation was proven to be better than deep sedation, it was a radical and unanswered question whether a strategy of providing no sedation at all (relying solely on analgesia and patient communication) would be a safe and even more effective approach to liberating patients from the ventilator.
  • Proposed Hypothesis: The authors hypothesized that a protocol of no sedation would be superior to a protocol of sedation with daily interruption in increasing the number of ventilator-free days.

5. Study Design and Methods

  • Design: A single-center, prospective, randomized, open-label, controlled trial (used to test the effectiveness of interventions).
  • Setting: A single medical-surgical intensive care unit (ICU) in Denmark.
  • Trial Period: Enrollment ran from February 2007 to August 2008.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) who were expected to require mechanical ventilation for more than 24 hours.
    • Exclusion Criteria: Included patients with severe neurologic injury (GCS < 9 without sedation), those requiring deep sedation for medical reasons (e.g., status epilepticus, severe ARDS), and those with a history of psychosis.
  • Intervention: A “no sedation” strategy. Patients received no sedative infusions. Pain was treated with intermittent boluses of morphine, and patients were kept calm and comfortable through frequent reassurance and communication.
  • Control: A “sedation” strategy. Patients received a continuous infusion of propofol (or midazolam if needed for >72 hours) with a daily interruption (spontaneous awakening trial).
  • Management Common to Both Groups: All patients received intermittent morphine for analgesia. Weaning was protocolized in both groups.
  • Power and Sample Size: The authors calculated that a sample size of 140 patients would be required to have 80% power to detect a 5-day difference in ventilator-free days. (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 number of ventilator-free days in a 28-day period.
    • Secondary Outcomes: Included length of ICU and hospital stay, and the incidence of agitated delirium.

6. Key Results

  • Enrollment and Baseline: 140 patients were randomized (70 to no sedation and 70 to sedation). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: Patients in the no-sedation group had a significantly higher number of ventilator-free days: a median of 13.8 days in the no-sedation group vs. 9.6 days in the sedation group (p=0.02).
  • Secondary Outcomes: The length of stay in the ICU and in the hospital was significantly shorter in the no-sedation group. There was no significant difference in the incidence of agitated delirium between the groups.
  • Adverse Events: There was no significant difference in the rate of accidental extubation. One patient in the no-sedation group had a brief episode of ventilator-associated distress that resolved with morphine.

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 number of ventilator-free days between the two groups.
  • Key Statistic(s) Reported: The key statistics were the median values for the primary outcome and the associated P-value.
  • Interpretation of Key Statistic(s):
    • P-value: The p-value of 0.02 for the primary outcome is below the 0.05 threshold, indicating that the observed difference in ventilator-free days is statistically significant and 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 number of ventilator-free days was 4.2 days longer in the no-sedation group. This represents a large, clinically meaningful benefit.
  • 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.
  • Novelty: The trial tested a radical and paradigm-shifting hypothesis.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was unblinded, which is a significant limitation that introduces a risk of performance bias. The high level of nursing attention and communication in the no-sedation group may have been a key component of the benefit, independent of the lack of sedatives.
  • External Validity (Generalizability): The single-center design is a major limitation. The study was conducted in a Danish ICU with a very high nurse-to-patient ratio, and this strategy may not be feasible or safe in ICUs with lower staffing levels. The study also had very strict exclusion criteria, meaning the findings do not apply to a large proportion of ICU patients (e.g., those with severe ARDS or brain injury).
  • Other: The trial was relatively small.

10. Conclusion of the Authors

  • The authors concluded that a protocol of no sedation for critically ill patients is associated with a shorter duration of mechanical ventilation and a shorter ICU and hospital stay.

11. To Summarize

  • Impact on Current Practice: This was a landmark trial that took the “less is more” sedation paradigm to its logical extreme. While it has not led to the widespread adoption of a strict “no sedation” policy, it has been profoundly influential in reinforcing the safety and benefits of an “analgesia-first” sedation strategy that prioritizes pain control and aims for the lightest possible level of sedation.
  • Specific Recommendations:
    • Patient Selection: For a select group of hemodynamically stable, mechanically ventilated adult patients without severe ARDS or brain injury.
    • Actionable Intervention: The results support a strategy that prioritizes analgesia and minimizes or avoids the use of sedative infusions.
    • Expected Benefit: This strategy can be expected to reduce the duration of mechanical ventilation and ICU stay.
  • What This Trial Does NOT Mean: This trial does NOT mean that sedation is never necessary. Many patients, particularly those with severe ARDS, status asthmaticus, or high ICP, require deep sedation.
  • Implementation Caveats: The success of a no-sedation or light-sedation strategy is highly dependent on a culture of excellent nursing care, frequent patient communication, and a robust analgesia plan.

12. Context and Related Studies

  • Building on Previous Evidence: The NONSEDA trial (2010) was the next logical step after the Kress et al. (2000) and ABC trial (2008) had established the benefit of lighter sedation and daily interruptions.
  • Influence on Subsequent Research: The definitive positive result of this trial has been a cornerstone of the evidence supporting an “analgesia-first” or “analgosedation” approach, which is now a key recommendation in international sedation guidelines (e.g., the PADIS guidelines).

13. Unresolved Questions & Future Directions

  • Unresolved Questions: The key unresolved question is whether the remarkable findings of this single-center trial are replicable in a large, multicenter setting with more diverse patient populations and staffing models.
  • Future Directions: Future research is focused on identifying which specific patients are the best candidates for a no-sedation strategy and on the long-term psychological outcomes of being awake and aware during mechanical ventilation.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant and innovative, challenging a fundamental paradigm of ICU care.
  • Methods: The randomized controlled trial design was appropriate. However, the single-center, unblinded design and the highly selected patient population are major methodological limitations that significantly reduce the external validity of the findings.
  • 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 their data. However, the applicability of the findings is limited by the study’s significant methodological weaknesses. While it has not led to a universal “no sedation” policy, the trial has been profoundly influential in shifting the culture of ICU care towards lighter sedation and an analgesia-first approach.

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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