Esteban et al: Noninvasive Ventilation for Postextubation Respiratory Failure (2004)

“We conclude that noninvasive positive-pressure ventilation is not an effective treatment for unselected patients who have respiratory failure after extubation and that its use may delay required reintubation.”

  • Andrés Esteban, M.D., Ph.D., et al.

1. Publication Details

  • Trial Title: Noninvasive Positive-Pressure Ventilation for Respiratory Failure after Extubation
  • Citation: Esteban A, Frutos-Vivar F, Ferguson ND, et al. Noninvasive positive-pressure ventilation for respiratory failure after extubation. N Engl J Med. 2004;350(24):2452-2460. DOI: 10.1056/NEJMoa032736
  • Published: June 10, 2004, in The New England Journal of Medicine
  • Author: Andrés Esteban, M.D., Ph.D.
  • Funding: Spanish Ministry of Health and others.

2. Keywords

  • Noninvasive Ventilation (NIV), Postextubation Respiratory Failure, Weaning, Mechanical Ventilation, Reintubation, Randomized Controlled Trial

3. The Clinical Question

  • In adult ICU patients who develop respiratory failure after extubation (Population), does the use of noninvasive positive-pressure ventilation (NIV) (Intervention) compared to standard medical therapy (Comparison) reduce the need for reintubation (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Reintubation after planned extubation is associated with a very high mortality rate. Noninvasive ventilation (NIV) had shown promise in preventing the need for intubation in other forms of respiratory failure (e.g., COPD exacerbations) by reducing the work of breathing and improving gas exchange.
  • Knowledge Gap: It was unknown if NIV could be used as a “rescue” therapy to prevent reintubation in the general population of ICU patients who develop respiratory failure after being liberated from mechanical ventilation.
  • Proposed Hypothesis: The authors hypothesized that the use of NIV would be superior to standard medical therapy in reducing the rate of reintubation among patients with postextubation respiratory failure.

5. Study Design and Methods

  • Design: A multicenter, prospective, randomized, controlled trial (used to test the effectiveness of interventions).
  • Setting: 8 intensive care units (ICUs) in Spain.
  • Trial Period: Enrollment ran from October 1999 to March 2003.
  • Population:
    • Inclusion Criteria: Adult patients who developed respiratory failure within 48 hours of a planned extubation. Respiratory failure was defined by specific clinical and blood gas criteria.
    • Exclusion Criteria: Included patients with upper-airway obstruction, copious secretions, or hemodynamic instability.
  • Intervention: Patients received noninvasive positive-pressure ventilation (NIV) via a face mask.
  • Control: Patients received standard medical therapy, which included oxygen therapy via a Venturi mask and other supportive care.
  • Management Common to Both Groups: In both groups, the decision to reintubate was based on pre-specified criteria of worsening respiratory distress or clinical instability.
  • Power and Sample Size: The authors calculated that a sample size of 106 patients would be required to have 80% power to detect a 25% absolute risk reduction in the reintubation rate. (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 rate of reintubation.
    • Secondary Outcomes: Included ICU mortality, length of ICU stay, and serious complications.

6. Key Results

  • Enrollment and Baseline: 106 patients were randomized (52 to NIV and 54 to standard therapy). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: There was no significant difference in the primary outcome. The reintubation rate was identical in both groups: 25 of 52 patients (48%) in the NIV group were reintubated, compared with 26 of 54 patients (48%) in the standard-therapy group.
  • Secondary Outcomes: ICU mortality was significantly higher in the NIV group: 13 of 52 patients (25%) died, compared with 5 of 54 patients (9%) in the standard-therapy group (p=0.048).
  • Adverse Events: The primary adverse event was death, which was more common in the NIV group. A key finding was that the time from the onset of respiratory failure to reintubation was significantly longer in the NIV group (median, 12 hours vs. 2.5 hours).

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 chi-square test.
  • Primary Outcome Analysis: The primary outcome was a comparison of the proportions of patients who required reintubation between the two groups.
  • Key Statistic(s) Reported: The key statistics were the absolute rates of reintubation and mortality, with their associated P-values.
  • Interpretation of Key Statistic(s):
    • P-value: The p-value for the primary outcome was not reported but was stated as not significant. The p-value of 0.048 for ICU mortality is below the 0.05 threshold, indicating a statistically significant difference in this secondary outcome (a result is conventionally considered statistically significant if the p-value is less than 0.05).
  • Clinical Impact Measures (for ICU mortality):
    • Absolute Risk Increase (ARI):
      • Formula: ARI = (Risk in Intervention Group) – (Risk in Control Group)
      • Calculation: ARI = 25% – 9% = 16%.
      • Clinical Meaning: For every 100 patients treated with rescue NIV, about 16 additional deaths occurred.
    • Number Needed to Harm (NNH):
      • Formula: NNH = 1 / ARI
      • Calculation: NNH = 1 / 0.16 = 6.25, which is rounded down to 6.
      • Clinical Meaning: You would only need to treat 6 patients with rescue NIV to cause one additional death.
  • Subgroup Analyses: Not a major feature of this publication.

8. Strengths of the Study

  • Study Design and Conduct: The multicenter, randomized, controlled design provided high-quality evidence on an important clinical question.
  • Generalizability: The inclusion of 8 different ICUs increases the applicability of the findings.
  • Statistical Power: The study was adequately powered for its primary outcome.
  • Patient-Centered Outcomes: The study focused on the crucial outcomes of reintubation and mortality.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was unblinded, which introduces a risk of performance bias.
  • External Validity (Generalizability): The study population was a heterogeneous group of ICU patients. The findings may not apply to specific subgroups who are known to benefit from NIV, such as those with COPD exacerbations.
  • Other: The trial was relatively small.

10. Conclusion of the Authors

  • The authors concluded that in an unselected group of patients with respiratory failure after extubation, NIV does not prevent the need for reintubation and may be associated with increased mortality.

11. To Summarize

  • Impact on Current Practice: This was a landmark, practice-changing trial. It provided strong evidence that the routine use of NIV as a “rescue” therapy for all-comers with postextubation respiratory failure is not effective and may be harmful.
  • Specific Recommendations:
    • Patient Selection: For the general population of adult ICU patients who develop respiratory failure after extubation.
    • Actionable Intervention: Do not routinely use NIV as a rescue therapy.
    • Expected Benefit: Avoiding this therapy prevents one additional death for every 6 patients treated.
  • What This Trial Does NOT Mean: This trial does NOT mean that NIV has no role in the ICU. Its findings are specific to the treatment of established postextubation respiratory failure in an unselected population. It does not apply to the prevention of respiratory failure in high-risk patients or its use in specific conditions like COPD.
  • Implementation Caveats: The key takeaway is that using NIV may dangerously delay necessary reintubation. If a patient has failed extubation, they should be promptly reintubated unless they have a specific condition known to respond well to NIV.

12. Context and Related Studies

  • Building on Previous Evidence: The Esteban et al. trial (2004) was designed to test whether the known benefits of NIV in other settings would translate to the postextubation period.
  • Influence on Subsequent Research: The definitive negative result of this trial was highly influential. It led to a crucial shift in research and clinical practice, distinguishing between the prophylactic use of NIV in high-risk patients (which has since been shown to be beneficial) and the rescue use of NIV for established failure (which this trial showed to be ineffective or harmful).

13. Unresolved Questions & Future Directions

  • Unresolved Questions: This trial did not address the role of NIV in specific subgroups, such as patients with hypercapnic respiratory failure due to COPD.
  • Future Directions: Subsequent research has focused on identifying the specific high-risk patient groups who benefit from prophylactic NIV immediately after extubation to prevent respiratory failure from developing in the first place.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, addressing a common and high-stakes clinical problem.
  • Methods: The multicenter RCT design was appropriate. The main methodological weakness is the open-label design. The inclusion of a heterogeneous ICU population is a key factor in interpreting the results.
  • Results: The study reported a clear neutral finding for its primary outcome but a statistically significant and clinically important increase in harm (mortality) as a secondary outcome. The finding that NIV delayed reintubation provides a plausible mechanism for this harm.
  • Conclusions and Applicability: The authors’ conclusion is a direct and fair reflection of the data. The trial is a classic example of how an intervention that seems physiologically plausible can be ineffective and even harmful when tested in a rigorous trial. Its findings are broadly applicable and have been instrumental in shaping modern weaning guidelines.

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.
Scroll to Top