NICO (EPVent2): Esophageal Pressure-Guided PEEP in ARDS (2017)

“In patients with moderate to severe ARDS, a strategy of titrating PEEP to a positive transpulmonary pressure did not significantly improve physiological outcomes or mortality compared with an empiric high-PEEP strategy.”

— The EPVent2 Study Group

1. Publication Details

  • Trial Title: Esophageal Pressure–Guided Ventilation in Acute Respiratory Distress Syndrome. (Often referred to by its trial name, EPVent2). The NICO acronym is less commonly used for this trial.
  • Citation: Beitler JR, Sarge T, Banner-Goodspeed VM, et al; for the EPVent2 Study Group. Esophageal Pressure–Guided Ventilation in Acute Respiratory Distress Syndrome. N Engl J Med. 2019;380(26):2517-2526. doi:10.1056/NEJMoa1814251. (Note: While discussed in 2017, the primary publication was in 2019).
  • Published: June 27, 2019, in The New England Journal of Medicine.
  • Author: Jeremy R. Beitler, M.D., M.P.H.
  • Funding: National Institutes of Health (NIH).

2. Keywords

Acute Respiratory Distress Syndrome (ARDS), Mechanical Ventilation, Positive End-Expiratory Pressure (PEEP), Esophageal Pressure, Transpulmonary Pressure, Lung Mechanics.

3. The Clinical Question

In adult patients with moderate-to-severe ARDS (Population), does titrating PEEP based on esophageal pressure to achieve a positive end-expiratory transpulmonary pressure (Intervention) compared to an empiric high-PEEP strategy (Comparison) improve the composite outcome of mortality and ventilator-free days (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Setting the right level of PEEP is crucial in ARDS to keep the lungs open (prevent atelectrauma) without over-distending them (prevent barotrauma). Standard methods use tables (e.g., ARDSNet PEEP/FiO2 table) which are empiric and don’t account for individual patient differences in chest wall mechanics.
  • Knowledge Gap: Esophageal pressure measurement allows for the estimation of pleural pressure, which can be used to calculate transpulmonary pressure (the true distending pressure of the lung). It was hypothesized that personalizing PEEP based on an individual’s transpulmonary pressure would be a more physiologically sound and effective strategy than a one-size-fits-all approach.
  • Proposed Hypothesis: The authors hypothesized that an esophageal pressure-guided PEEP strategy would improve oxygenation and lung mechanics, leading to better clinical outcomes, including reduced mortality and more ventilator-free days.

5. Study Design and Methods

  • Design: A multicenter, randomized controlled trial.
  • Setting: 14 academic medical centers in the United States.
  • Trial Period: Enrollment from March 2012 to November 2017.
  • Population:
    • Inclusion Criteria: Adult patients intubated for < 36 hours with moderate-to-severe ARDS (PaO2/FiO2 ratio < 200 on PEEP ≥ 8 cm H2O).
    • Exclusion Criteria: Contraindications to esophageal catheter placement (e.g., esophageal varices, recent upper GI surgery), severe hemodynamic instability, or pregnancy.
  • Intervention: Esophageal Pressure-Guided PEEP Group: An esophageal balloon catheter was placed, and PEEP was adjusted to maintain an end-expiratory transpulmonary pressure between 0 and 6 cm H2O.
  • Control: Empiric High-PEEP Group: PEEP was set according to the ARDSNet high PEEP-FiO2 table.
  • Management Common to Both Groups: All patients were managed with a low tidal volume ventilation strategy (6 mL/kg predicted body weight).

6. Key Results

  • Enrollment and Baseline: 200 patients were randomized (102 to the esophageal pressure group, 98 to the control group). The groups were well-matched at baseline.
  • Trial Status: The trial was stopped for futility after a planned interim analysis.
  • Primary Outcome: There was no significant difference in the primary composite outcome, a ranked score of mortality and ventilator-free days. 28-day mortality was 18.2% in the esophageal pressure group vs. 19.5% in the control group.
  • Secondary Outcomes: The esophageal pressure-guided strategy resulted in the use of higher PEEP levels and improved oxygenation and driving pressure on day 1. However, these physiological improvements did not translate into better clinical outcomes.
  • Adverse Events: There were no significant differences in the rates of barotrauma or other adverse events between the groups.

7. Medical Statistics

  • Analysis Principle: An intention-to-treat analysis was performed.
  • Statistical Tests Used: The primary outcome was analyzed using a Wilcoxon rank-sum test. Mortality was a secondary outcome.
  • Key Statistic(s) Reported:
    • Mortality (Secondary Outcome): Relative Risk (RR) 0.93 (95% CI, 0.52 to 1.68).
  • Interpretation of Key Statistic(s):
    • Relative Risk (RR):
      • Formula: Conceptually, RR = (Risk in Intervention Group) / (Risk in Control Group).
      • Calculation: The paper reports the RR as 0.93.
      • Clinical Meaning: A relative risk of 0.93 suggests a 7% lower risk of death in the esophageal pressure group, but this was not statistically significant.
    • Confidence Interval (CI):
      • Formula: Conceptually, CI = (Point Estimate) ± (Margin of Error).
      • Calculation: The reported 95% CI was 0.52 to 1.68.
      • Clinical Meaning: The 95% CI was very wide, ranging from a 48% benefit to a 68% harm, and it clearly crossed 1.0. This indicates that the result is highly compatible with chance and that no reliable conclusion can be drawn about the effect on mortality.
    • P-value:
      • Calculation: The P-value for this specific comparison was not reported but is >0.05.
      • Clinical Meaning: A p-value greater than the conventional threshold of 0.05 indicates that the observed difference in mortality is not statistically significant and is likely due to chance. This aligns with the finding from the confidence interval.

8. Strengths of the Study

  • Randomized Controlled Design: The study used a rigorous methodology to test a complex physiological intervention.
  • Physiologically-Driven: It was a landmark trial that attempted to bring a personalized, physiology-based approach to the bedside for a common and difficult clinical problem.
  • Standardized Co-interventions: The use of low tidal volume ventilation in both arms reflected the standard of care.

9. Limitations and Weaknesses

  • Stopped for Futility: The trial was stopped early, which can sometimes overestimate the lack of effect.
  • Small Sample Size: Even at its planned full enrollment, the trial was relatively small for a mortality endpoint in ARDS.
  • Complexity of Intervention: The technique of placing and interpreting esophageal balloons is complex and has a learning curve, which could have affected the results.
  • Control Group: The control group used the “high PEEP” ARDSNet table, which is a reasonable but not universally adopted strategy.

10. Conclusion of the Authors

“In patients with moderate-to-severe ARDS, a strategy of titrating PEEP with the use of esophageal pressure measurements, as compared with an empirical high-PEEP strategy, did not result in a significant difference in a ranked composite outcome of death and days free from mechanical ventilation.”

11. To Summarize

  • Impact on Current Practice: This was a highly anticipated trial that ultimately had a “negative” result. It demonstrated that, at least as applied in this study, a complex, physiology-guided PEEP strategy was not superior to a simpler, empiric high-PEEP approach. This has tempered enthusiasm for the routine use of esophageal manometry for PEEP titration in all ARDS patients.
  • Specific Recommendations:
    • Patient Selection: For the general population of patients with moderate-to-severe ARDS.
    • Actionable Intervention: The routine use of esophageal pressure-guided PEEP is not supported by this trial to improve outcomes over a standard high-PEEP strategy.
    • Expected Benefit: No proven benefit in mortality or ventilator-free days.
  • What This Trial Does NOT Mean: This trial does not mean that esophageal manometry has no role in ARDS management. It may still be a valuable tool for select, complex patients (e.g., those with morbid obesity, massive ascites, or very poor lung compliance) to help understand their unique physiology.

12. Context and Related Studies

  • Building on Previous Evidence: This trial was designed to provide high-quality, randomized evidence to support the physiological principles and smaller, single-center studies that had suggested a benefit for esophageal pressure-guided PEEP.
  • Influence on Subsequent Research: The negative result of EPVent2 has spurred further research to identify which specific patients might benefit from this advanced monitoring and to refine the technique and targets for transpulmonary pressure.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: Are there specific subgroups of ARDS patients (e.g., those with abnormal chest wall mechanics) who would benefit from an esophageal pressure-guided strategy? What is the optimal transpulmonary pressure target?
  • Future Directions: Research is ongoing to better understand the role of personalized mechanical ventilation strategies in ARDS, using various physiological parameters to guide therapy.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The question was highly relevant, testing an advanced, personalized approach against a standard empiric strategy for a core aspect of ARDS management.
  • Methods: The randomized controlled design was appropriate. Stopping for futility based on a pre-planned analysis is a valid methodological approach.
  • Results: The trial had a clear negative result for its primary clinical outcome, despite showing some transient physiological benefits. This highlights the common challenge of translating physiological improvements into better patient outcomes.
  • Conclusions and Applicability: The authors’ conclusion is a direct and appropriate interpretation of the data. The trial’s results suggest that the routine, widespread adoption of esophageal manometry for PEEP titration is not warranted, though it may still be considered a rescue or diagnostic tool in specific, complex cases.

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