Brochard et al: Noninvasive Ventilation for COPD Exacerbations (1995)

“We conclude that, in selected patients with acute exacerbations of chronic obstructive pulmonary disease, noninvasive ventilation can reduce the need for endotracheal intubation and decrease in-hospital mortality.”

  • Adapted from Brochard L, et al.

1. Publication Details

  • Trial Title: Noninvasive Ventilation for Acute Exacerbations of Chronic Obstructive Pulmonary Disease
  • Citation: Brochard L, Mancebo J, Wysocki M, et al. Noninvasive ventilation for acute exacerbations of chronic obstructive pulmonary disease. N Engl J Med. 1995;333(13):817-822. DOI: 10.1056/NEJM199509283331301.
  • Published: September 28, 1995, in The New England Journal of Medicine
  • Author: Laurent Brochard, M.D.
  • Funding: French Ministry of Health and others.

2. Keywords

  • Chronic Obstructive Pulmonary Disease (COPD), Acute Exacerbation of COPD, Noninvasive Ventilation (NIV), Mechanical Ventilation, Respiratory Failure, Randomized Controlled Trial

3. The Clinical Question

  • In adult patients with acute exacerbations of COPD and acute hypercapnic respiratory failure (Population), does the addition of noninvasive ventilation (NIV) to standard medical therapy (Intervention) compared to standard medical therapy alone (Comparison) reduce the need for endotracheal intubation (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Acute exacerbations of COPD are a leading cause of hospitalization and mortality. Standard treatment consisted of oxygen, bronchodilators, and corticosteroids, but a significant proportion of patients failed this therapy and required invasive mechanical ventilation, which is associated with high morbidity.
  • Knowledge Gap: Noninvasive ventilation (NIV) was emerging as a promising technique to support breathing without the need for an endotracheal tube. It was unknown if NIV could be an effective and safe therapy to prevent the need for intubation in patients with severe COPD exacerbations.
  • Proposed Hypothesis: The authors hypothesized that the early use of NIV would be superior to standard medical therapy in reducing the rate of endotracheal intubation in patients with acute exacerbations of COPD.

5. Study Design and Methods

  • Design: A multicenter, prospective, randomized, controlled trial (used to test the effectiveness of interventions).
  • Setting: 7 intensive care units (ICUs) in France, Spain, and Argentina.
  • Trial Period: Enrollment period not explicitly stated in the publication.
  • Population:
    • Inclusion Criteria: Adult patients with a history of COPD who presented with an acute exacerbation and moderate to severe respiratory acidosis (pH 7.25-7.35, PaCO2 > 45 mm Hg) and a respiratory rate > 25 breaths/min.
    • Exclusion Criteria: Included an immediate need for intubation (e.g., cardiac arrest, coma), facial trauma, or recent upper airway surgery.
  • Intervention: Patients received noninvasive ventilation via a face mask, in addition to standard medical therapy.
  • Control: Patients received standard medical therapy alone, which consisted of supplemental oxygen via a Venturi mask, bronchodilators, and corticosteroids.
  • Management Common to Both Groups: All patients received a standardized regimen of medical therapies. The criteria for intubation were pre-specified and the same for both groups.
  • Power and Sample Size: The authors calculated that a sample size of 84 patients would be required to have 80% power to detect a 30% absolute risk reduction in the intubation 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 need for endotracheal intubation.
    • Secondary Outcomes: Included in-hospital mortality, length of hospital stay, and the incidence of complications.

6. Key Results

  • Enrollment and Baseline: 85 patients were randomized (43 to NIV and 42 to standard therapy). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: The need for endotracheal intubation was dramatically and significantly lower in the NIV group. 11 of 43 patients (26%) in the NIV group required intubation, compared with 31 of 42 patients (74%) in the standard-therapy group (p<0.001).
  • Secondary Outcomes: In-hospital mortality was also significantly lower in the NIV group (9% vs. 29%; p=0.02). Patients in the NIV group had a significantly shorter length of hospital stay.
  • Adverse Events: The incidence of major complications was significantly lower in the NIV group.

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 intubation between the two groups.
  • Key Statistic(s) Reported: The key statistics were the absolute rates of the primary outcome and the associated P-value.
  • Interpretation of Key Statistic(s):
    • P-value: The p-value of <0.001 for the primary outcome is extremely low, indicating that the observed difference in intubation rates 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:
    • Absolute Risk Reduction (ARR):
      • Formula: ARR = (Risk in Control Group) – (Risk in Intervention Group)
      • Calculation: ARR = 74% – 26% = 48%.
      • Clinical Meaning: For every 100 patients with a severe COPD exacerbation treated with NIV, 48 were saved from needing endotracheal intubation.
    • Number Needed to Treat (NNT):
      • Formula: NNT = 1 / ARR
      • Calculation: NNT = 1 / 0.48 = 2.1, which is rounded down to 2.
      • Clinical Meaning: You would only need to treat 2 patients with NIV to prevent one additional intubation.
  • Subgroup Analyses: Not a major feature of this publication.

8. Strengths of the Study

  • Study Design and Conduct: The multicenter, randomized, controlled design provided a high level of evidence for a novel therapy.
  • Generalizability: The inclusion of 7 centers in 3 different countries increases the applicability of the findings.
  • Statistical Power: The study was adequately powered and found a very large, significant effect.
  • Patient-Centered Outcomes: The study focused on the crucial outcomes of intubation, mortality, and length of stay.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was unblinded, which is an unavoidable limitation for this type of intervention and introduces a risk of performance bias.
  • External Validity (Generalizability): The study population was a select group of patients with hypercapnic respiratory failure due to COPD, and the results do not apply to patients with other causes of respiratory failure (e.g., hypoxemic failure from pneumonia).
  • Other: The trial was relatively small by modern standards.

10. Conclusion of the Authors

  • The authors concluded that in patients with acute exacerbations of COPD, the early use of noninvasive ventilation can reduce the need for endotracheal intubation, decrease the rate of complications, and shorten the hospital stay.

11. To Summarize

  • Impact on Current Practice: This was a profoundly practice-changing trial. It provided the first definitive, high-quality evidence that NIV was a life-saving intervention for severe COPD exacerbations, establishing it as a new standard of care.
  • Specific Recommendations:
    • Patient Selection: For adult patients with acute exacerbations of COPD who have moderate to severe hypercapnic respiratory failure.
    • Actionable Intervention: Initiate noninvasive ventilation early.
    • Expected Benefit: This intervention has a very large effect, with an NNT of only 2 to prevent one intubation.
  • What This Trial Does NOT Mean: This trial does NOT mean that NIV is a magic bullet for all forms of respiratory failure. Its benefit is most clearly established in the hypercapnic population.
  • Implementation Caveats: The success of NIV requires careful patient selection, appropriate equipment, and skilled staff who can manage the interface and monitor for failure.

12. Context and Related Studies

  • Building on Previous Evidence: The Brochard et al. trial (1995) was the landmark study that provided the definitive evidence for a practice that had been explored in smaller, less conclusive studies.
  • Influence on Subsequent Research: The definitive positive result of this trial led to the widespread adoption of NIV as a first-line therapy for severe COPD exacerbations worldwide. It also spurred a great deal of research into the use of NIV for other conditions, such as cardiogenic pulmonary edema and post-extubation respiratory failure.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: This trial definitively answered its primary question.
  • Future Directions: Subsequent research has focused on refining the use of NIV, including comparing different interfaces (e.g., helmet vs. face mask) and on identifying which patients are most likely to fail NIV and require early intubation.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, testing a novel, less invasive therapy for a very common and life-threatening condition.
  • Methods: The multicenter RCT design was appropriate and robust. The main methodological weakness is the open-label design, but the primary outcome of intubation is objective and unlikely to be biased.
  • Results: The study reported a very large and both statistically and clinically significant benefit for the intervention (NNT of 2). The finding was consistent across multiple important outcomes, including mortality and length of stay.
  • Conclusions and Applicability: The authors’ conclusion is strongly supported by the data. The trial is a landmark in respiratory and critical care medicine that established a new standard of care. Its findings are highly applicable to the management of severe COPD exacerbations in most hospital settings.

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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