Effect of Titrating Positive End-Expiratory Pressure (PEEP) With an Esophageal Pressure-Guided Strategy vs an Empirical High PEEP-Fio2 Strategy on Death and Days Free From Mechanical Ventilation Among Patients With Acute Respiratory Distress Syndrome: A Randomized Clinical Trial

Abstract

Importance: Adjusting positive end-expiratory pressure (PEEP) to offset pleural pressure might attenuate lung injury and improve patient outcomes in acute respiratory distress syndrome (ARDS).

Objective: To determine whether PEEP titration guided by esophageal pressure (PES), an estimate of pleural pressure, was more effective than empirical high PEEP-fraction of inspired oxygen (Fio2) in moderate to severe ARDS.

Design, setting, and participants: Phase 2 randomized clinical trial conducted at 14 hospitals in North America. Two hundred mechanically ventilated patients aged 16 years and older with moderate to severe ARDS (Pao2:Fio2 ≤200 mm Hg) were enrolled between October 31, 2012, and September 14, 2017; long-term follow-up was completed July 30, 2018.

Interventions: Participants were randomized to PES-guided PEEP (n = 102) or empirical high PEEP-Fio2 (n = 98). All participants received low tidal volumes.

Main outcomes and measures: The primary outcome was a ranked composite score incorporating death and days free from mechanical ventilation among survivors through day 28. Prespecified secondary outcomes included 28-day mortality, days free from mechanical ventilation among survivors, and need for rescue therapy.

Results: Two hundred patients were enrolled (mean [SD] age, 56 [16] years; 46% female) and completed 28-day follow-up. The primary composite end point was not significantly different between treatment groups (probability of more favorable outcome with PES-guided PEEP: 49.6% [95% CI, 41.7% to 57.5%]; P = .92). At 28 days, 33 of 102 patients (32.4%) assigned to PES-guided PEEP and 30 of 98 patients (30.6%) assigned to empirical PEEP-Fio2 died (risk difference, 1.7% [95% CI, -11.1% to 14.6%]; P = .88). Days free from mechanical ventilation among survivors was not significantly different (median [interquartile range]: 22 [15-24] vs 21 [16.5-24] days; median difference, 0 [95% CI, -1 to 2] days; P = .85). Patients assigned to PES-guided PEEP were significantly less likely to receive rescue therapy (4/102 [3.9%] vs 12/98 [12.2%]; risk difference, -8.3% [95% CI, -15.8% to -0.8%]; P = .04). None of the 7 other prespecified secondary clinical end points were significantly different. Adverse events included gross barotrauma, which occurred in 6 patients with PES-guided PEEP and 5 patients with empirical PEEP-Fio2.

Conclusions and relevance: Among patients with moderate to severe ARDS, PES-guided PEEP, compared with empirical high PEEP-Fio2, resulted in no significant difference in death and days free from mechanical ventilation. These findings do not support PES-guided PEEP titration in ARDS.

Trial registration: ClinicalTrials.gov Identifier NCT01681225.

Conflict of interest statement

Conflict of Interest Disclosures: All authors reported receiving support from the National Heart, Lung, and Blood Institute to conduct this trial. Ms Banner-Goodspeed reported receiving grants from the Department of Defense. Dr Gong reported receiving grants from the Agency for Healthcare and Research Quality outside the submitted work. Dr Novack reported receiving personal fees from CardioMed Consultants outside the submitted work. Dr Talmor reported receiving speaking fees and grant funds from Hamilton Medical outside the submitted work.

Figures

Figure 1.. Screening, Enrollment, Randomization, and Follow-up of Study Participants

ARDS indicates acute respiratory distress syndrome. aDetailed eligibility criteria are provided in the eAppendix in Supplement 2. The sum of reasons excluded exceeds the total number of patients excluded because some patients met multiple exclusion criteria. bThe initial protocol excluded liver transplant recipients. This exclusion was removed in a protocol amendment during the trial. cOther reasons eligible patients were not approached for consent include death prior to approach (n = 2), extubation prior to approach (n = 1), local site exclusion for pregnancy (n = 1), and reason not reported (n = 1).

Figure 2.. Respiratory Physiological Measures From Baseline Through Day 7

Boxes represent median and interquartile range. Whiskers extend 1.5 times the interquartile range beyond the first and third quartiles per the conventional Tukey method. Circles beyond the whiskers represent outliers. Diamonds represent mean values. Day 0 denotes baseline preintervention values. The number of patients with available respiratory physiological data decreases over successive study days due to deaths and discontinuation of invasive mechanical ventilation. Transpulmonary pressure (PL) equals airway pressure minus pleural pressure. Airway driving pressure equals plateau pressure minus positive end-expiratory pressure (PEEP). Transpulmonary driving pressure equals end-inspiratory PL minus end-expiratory PL. Fio2 indicates fraction of inspired oxygen; Pao2, partial pressure of arterial oxygen; and PES, esophageal pressure.

Figure 3.. Kaplan-Meier Survival Analysis Through Day 60

Fio2 indicates fraction of inspired oxygen; PEEP, positive end-expiratory pressure; and PES, esophageal pressure.