Effect of Esophageal Pressure-guided Positive End-Expiratory Pressure on Survival from Acute Respiratory Distress Syndrome: A Risk-based and Mechanistic Reanalysis of the EPVent-2 Trial

Todd Sarge, Elias Baedorf-Kassis, Valerie Banner-Goodspeed, Victor Novack, Stephen H Loring, Michelle N Gong, Deborah Cook, Daniel Talmor, Jeremy R Beitler, EPVent-2 Study Group, Emily Fish, Sayuri Jinadasa, Ray Ritz, Joseph Previtera, Lawrence Lee, France Clarke, Tom Piraino, Joseph Levitt, Rosemary Vojnik, Pauline Park, Kristin Brierley, Carl Haas, Andrew Weirauch, Eddy Fan, Andrea Matte, R Scott Harris, Mamary Kone, Stephen Heard, Karen Longtine, François Lellouche, Pierre-Alexandre Bouchard, Lewis Rubinson, Jennifer Titus McGrain, Donald E G Griesdale, Denise Foster, Richard Oeckler, Amy Amsbaugh, Edgar Jimenez, Valerie Danesh, Arthur S Slutsky, Jesse Hall, Rolf D Hubmayr, Gordon Rubenfeld, David Schoenfeld, Todd Sarge, Elias Baedorf-Kassis, Valerie Banner-Goodspeed, Victor Novack, Stephen H Loring, Michelle N Gong, Deborah Cook, Daniel Talmor, Jeremy R Beitler, EPVent-2 Study Group, Emily Fish, Sayuri Jinadasa, Ray Ritz, Joseph Previtera, Lawrence Lee, France Clarke, Tom Piraino, Joseph Levitt, Rosemary Vojnik, Pauline Park, Kristin Brierley, Carl Haas, Andrew Weirauch, Eddy Fan, Andrea Matte, R Scott Harris, Mamary Kone, Stephen Heard, Karen Longtine, François Lellouche, Pierre-Alexandre Bouchard, Lewis Rubinson, Jennifer Titus McGrain, Donald E G Griesdale, Denise Foster, Richard Oeckler, Amy Amsbaugh, Edgar Jimenez, Valerie Danesh, Arthur S Slutsky, Jesse Hall, Rolf D Hubmayr, Gordon Rubenfeld, David Schoenfeld

Abstract

Rationale: In acute respiratory distress syndrome (ARDS), the effect of positive end-expiratory pressure (PEEP) may depend on the extent to which multiorgan dysfunction contributes to risk of death, and the precision with which PEEP is titrated to attenuate atelectrauma without exacerbating overdistension. Objectives: To evaluate whether multiorgan dysfunction and lung mechanics modified treatment effect in the EPVent-2 (Esophageal Pressure-guided Ventilation 2) trial, a multicenter trial of esophageal pressure (Pes)-guided PEEP versus empirical high PEEP in moderate to severe ARDS. Methods: This post hoc reanalysis of the EPVent-2 trial evaluated for heterogeneity of treatment effect on mortality by baseline multiorgan dysfunction, determined via Acute Physiology and Chronic Health Evaluation II (APACHE-II). It also evaluated whether PEEP titrated to end-expiratory transpulmonary pressure near 0 cm H2O was associated with survival. Measurements and Main Results: All 200 trial participants were included. Treatment effect on 60-day mortality differed by multiorgan dysfunction severity (P = 0.03 for interaction). Pes-guided PEEP was associated with lower mortality among patients with APACHE-II less than the median value (hazard ratio, 0.43; 95% confidence interval, 0.20-0.92) and may have had the opposite effect in patients with higher APACHE-II (hazard ratio, 1.69; 95% confidence interval, 0.93-3.05). Independent of treatment group or multiorgan dysfunction severity, mortality was lowest when PEEP titration achieved end-expiratory transpulmonary pressure near 0 cm H2O. Conclusions: The effect on survival of Pes-guided PEEP, compared with empirical high PEEP, differed by multiorgan dysfunction severity. Independent of multiorgan dysfunction, PEEP titrated to end-expiratory transpulmonary pressure closer to 0 cm H2O was associated with greater survival than more positive or negative values. These findings warrant prospective testing in a future trial.

Keywords: acute respiratory distress syndrome; mechanical ventilation; positive end-expiratory pressure; randomized controlled trial; ventilator-induced lung injury.

Figures

Figure 1.
Figure 1.
Kaplan-Meier survival analysis by randomly assigned treatment group, stratified by APACHE-II score. Low and high APACHE-II scores refer to patients with values less or greater than the median APACHE-II score, respectively. Median APACHE-II score was 27.5. APACHE-II = Acute Physiology and Chronic Health Evaluation II; PEEP = positive end-expiratory pressure; Pes = esophageal pressure.
Figure 2.
Figure 2.
Treatment effects by APACHE-II score. Odds ratio for mortality 1 indicates treatment effect favors Pes-guided PEEP. Effect estimates are reported from the overall study population or unadjusted subgroup logistic or Poisson models as indicated. *P value for interaction term. APACHE-II = Acute Physiology and Chronic Health Evaluation II; IQR = interquartile range; PEEP = positive end-expiratory pressure; Pes = esophageal pressure.
Figure 3.
Figure 3.
Cumulative distribution of ventilator-free days and shock-free days by treatment group, stratified by APACHE-II. APACHE-II = Acute Physiology and Chronic Health Evaluation II; PEEP = positive end-expiratory pressure; Pes = esophageal pressure.
Figure 4.
Figure 4.
End-expiratory and end-inspiratory Pl over time by treatment assignment. (A) Patients with an APACHE-II score less than median value. (B) Patients with an APACHE-II score greater than median value. Note the much narrower range of end-expiratory Pl values on each of the first 4 days on protocol with the Pes-guided PEEP strategy, indicative of more precise PEEP titration to Pl. Day 0 denotes baseline preintervention values. Once oxygenation improved and remained stable for 24 hours on minimum ventilator requirements, PEEP was weaned empirically without regard for Pl in either arm, partially contributing to the lower values observed on later study days. *Statistically significant difference between treatment groups in the absolute value of end-expiratory Pl (distance from 0 cm H2O) on that study day. #Statistically significant difference between treatment groups in PL at end-inspiration on that study day. APACHE-II = Acute Physiology and Chronic Health Evaluation II; PEEP = positive end-expiratory pressure; Pes = esophageal pressure; Pl = transpulmonary pressure.
Figure 5.
Figure 5.
Kaplan-Meier survival analysis by end-expiratory Pl. The average daily value of Pl from baseline through Day 3 was used for analyses. Pl data were missing in one patient, assigned to Pes-guided PEEP, in whom the esophageal balloon catheter could not be inserted successfully. PEEP = positive end-expiratory pressure; Pes = esophageal pressure; Pl = transpulmonary pressure.
Figure 6.
Figure 6.
Cumulative distribution of ventilator-free days and shock-free days by end-expiratory Pl. Pl data were missing in one patient, assigned to Pes-guided PEEP, in whom the esophageal balloon catheter could not be inserted successfully. PEEP = positive end-expiratory pressure; Pes = esophageal pressure; Pl = transpulmonary pressure.

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