A second look at the EPVent-2 trial: What else does it tell us

Author: Caroline Brown, Reviewer: Jean-Michel Arnal, Munir Karjaghli, Süha Demiracka, Thomas Reimer, Alysson Silva Carvalho

In order to improve survival in ARDS patients, it is important to limit the extent of mechanical injury to the lung from invasive ventilation (1).

Takeaway messages:

  • Using esophageal pressure as a guide to adjust PEEP to achieve non-negative transpulmonary pressure may enable more individual titration, reducing atelectrauma while limiting overdistension.
  • The EPVent-2 trial compared the effect of PEEP titration using an esophageal balloon with management using an empirical high PEEP-FiO2 strategy and found no significant difference in terms of death or ventilator-free days.
  • A subsequent re-analysis of the data investigated whether multiorgan failure at baseline and lung mechanics may modify and thus account for the variation in the treatment effect of Pes-guided PEEP.
  • Results showed a significant association between the severity of multiorgan dysfunction at baseline and the treatment effect in terms of 60-day mortality.

Approaches include use of lower tidal volumes and limited driving pressure (2, 3), the benefits of which have been clearly demonstrated, and titration of positive end-expiratory pressure (PEEP), whereby such a PEEP strategy should balance the benefits of lung recruitment with the risks of overdistension (4). The evidence here is less clear: Studies using PEEP-FiO2 tables based on oxygenation (5) or targeting a recruitment strategy (6) have demonstrated no significant treatment effect on mortality, thus suggesting an individual response to a PEEP strategy.

What did the EPVent-2 trial find?

The use of esophageal pressure (Pes) – an estimate of pleural pressure – as a guide may help more precise, individual PEEP titration to reduce atelectrauma while still limiting overdistension. It enables us to separate lung from chest wall mechanics, identify the lung’s propensity to recruit/derecruit, and estimate global lung stress (7, 8, 9, 10). The EPVent-2 trial addressed the question of whether PEEP titration using an esophageal balloon was superior to an empirical high PEEP–FiO2 strategy in terms of outcomes in patients with moderate to severe ARDS. The investigators found no significant difference in terms of either death or ventilator-free days between the Pes-guided PEEP group and the empirical high PEEP–FiO2 group (11).

What was behind the re-analysis?

In a recent secondary analysis (12), the authors re-analyzed the data to evaluate the role of both multiorgan failure and lung mechanics in modifying the treatment effect. They hypothesized that firstly, the variation in the treatment effect of Pes-guided PEEP might be associated with the severity of multiorgan dysfunction at baseline and secondly, PEEP titrated to end-expiratory transpulmonary pressure (PL; PL = airway – pleural pressure) near 0 cmH2O would be associated with greater survival.

The analysis included all 200 patients enrolled in the EPVent-2 trial. The risk of death at baseline due to multiorgan dysfunction and chronic morbidities was quantified using the Acute Physiology and Chronic Health Evaluation II (APACHE-II) score. The median value was 27.5; values below the median were classified as low APACHE-II scores and those above as high APACHE-II scores. APACHE-II scores were distributed evenly between the two groups ((Pes-guided vs. empirical high PEEP: 27.0 ± 7.7 vs. 27.7 ± 7.4; P = 0.35). The median baseline risk of death by day 60 was 36.6% (interquartile range, 29.0–43.0%) in the Pes-guided PEEP group and 37.6% (31.9–44.3%) for the empirical high PEEP group (P = 0.34).

The role of multiorgan failure at baseline

Results of the primary analysis for 60-day mortality showed a significant association between the effect of Pes-guided PEEP and the severity of illness at baseline. Among patients with a low APACHE-II score, 60-day mortality was 20% in the Pes-guided PEEP group and 39.6% in the empirical high PEEP group. In patients with high APACHE-II scores however, the effect seemed to be reversed. Mortality at 60 days in those patients with more severe multiorgan dysfunction at baseline was higher with Pes-guided PEEP than with empirical high PEEP. This association for mortality remained consistent across all analyses performed, regardless of which modeling technique was used and even when the APACHE-II score was replaced by the Sequential Organ Failure Assessment (SOFA) score.

The authors offer two potential explanations for these findings. Firstly, that individual PEEP titration is more likely to benefit severe ARDS patients who are primarily at risk of dying due to lung injury as opposed to multiorgan failure. In patients with severe multiorgan failure, the greater risk of hemodynamic instability due to tidal overdistension may outweigh the lung-protective benefit. Secondly, end-inspiratory PL was significantly higher for two of the first three days in the subgroup of patients with high APACHE-II scores assigned to Pes-guided PEEP. As higher end-inspiratory PL indicates tidal hyperinflation, this may explain the poorer outcomes in those patients.

In terms of secondary outcomes, namely ventilator-free and shock-free days, data showed a similar association. The treatment effect of Pes-guided PEEP was dependent on overall illness severity at baseline and in patients with low APACHE-II scores, Pes-guided PEEP was associated with more ventilator- and shock-free days than empirical high PEEP. In contrast to the primary outcome, however, this association did not withstand post hoc sensitivity analyses.

End-expiratory transpulmonary pressure and survival 

The second important finding of this study was the association between survival and the proximity of end-expiratory transpulmonary pressure to 0 cmH2O. In all patients, regardless of the treatment group or the APACHE-II score, mortality was lowest when PEEP was titrated to end-expiratory PL near 0 cmH2O. Instead of a linear association between end-expiratory PL and mortality, the authors found that values between +2 and -2 cmH2O were associated with greater survival, while values outside this range in either direction were shown separately to be associated with lower survival. This association remained statistically significant even when end-inspiratory PL was taken into account. Values within this protective range were also associated with more ventilator- and shock-free days.

Also of interest was the narrower range of values for end-expiratory PL in the Pes-guided PEEP group for each of the first 4 days, which may indicate more precise PEEP titration to PL. In addition, end-expiratory PL was closer to 0 cmH2O in the Pes-guided PEEP group, despite this not being a specific target of that strategy.

What is next?

These findings – although stemming from a re-analysis not specified in the original trial protocol – demonstrate that further investigation is needed in prospective trials to evaluate PEEP titration to an end-expiratory PL near 0 cmH2O, while taking into account heterogeneity of multiorgan dysfunction at baseline.

They also remind us of the importance of considering the hemodynamic condition when selecting PEEP, and suggest that PEEP should be set to target an end-expiratory PL near 0 cmH2O. Therefore, we should be careful about using high PEEP in patients with severe shock, especially where the chosen PEEP results in end-expiratory PL much greater than 0 cmH2O.

The HAMILTON-G5/S1 and HAMILTON-C6 ventilators offer an auxiliary port for connecting the esophageal catheter pressure line*. The clinician can then display the waveform for absolute values of esophageal and transpulmonary pressure.

* Not all features or ventilators available in all markets


  1. Slutsky AS, Ranieri VM. Ventilator-induced lung injury. N Engl J Med. 2013;369(22):2126-2136.
  2. Amato MB, Barbas CS, Medeiros DM, et al. Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome. N Engl J Med. 1998;338(6):347-354.
  3. Brower RG, Matthay MA, Morris A, Schoenfeld D, Thompson BT, Wheeler A; Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med. 2000;342(18):1301-1308.
  4. Madahar P, Talmor D, Beitler JR. Transpulmonary pressure–guided ventilation to attenuate atelectrauma and hyperinflation in acute lung injury. Am J Respir Crit Care Med 2021;203:934–937.
  5. Brower RG, Lanken PN, MacIntyre N, Matthay MA, Morris A, Ancukiewicz M, Schoenfeld D, Thompson BT; National Heart, Lung, and Blood Institute ARDS Clinical Trials Network. Higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome. N Engl J Med. 2004 Jul 22;351(4):327-36.
  6. Mercat A, Richard JC, Vielle B, Jaber S, Osman D, Diehl JL, Lefrant JY, Prat G, Richecoeur J, Nieszkowska A, Gervais C, Baudot J, Bouadma L, Brochard L; Expiratory Pressure (Express) Study Group. Positive end-expiratory pressure setting in adults with acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. JAMA. 2008 Feb 13;299(6):646-55.
  7. Chiumello D, Carlesso E, Cadringher P, Caironi P, Valenza F, Polli F, et al. Lung stress and strain during mechanical ventilation for acute respiratory distress syndrome. Am J Respir Crit Care Med 2008;178:346–355.
  8. Beitler JR,Majumdar R, Hubmayr RD,Malhotra A, Thompson BT,Owens RL, et al. Volume delivered during recruitment maneuver predicts lung stress in acute respiratory distress syndrome. Crit CareMed 2016;44:91–99.
  9. Loring SH, O’Donnell CR, Behazin N, Malhotra A, Sarge T, Ritz R, et al. Esophageal pressures in acute lung injury: do they represent artifact or useful information about transpulmonary pressure, chest wall mechanics, and lung stress? J Appl Physiol (1985) 2010;108:515–522.
  10. Talmor D, Sarge T, O’Donnell CR, Ritz R, Malhotra A, Lisbon A, et al. Esophageal and transpulmonary pressures in acute respiratory failure. Crit Care Med 2006;34:1389–1394.
  11. Beitler JR, Sarge T, Banner-Goodspeed VM, Gong MN, Cook D, Novack V, et al.; EPVent-2 Study Group. 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. JAMA 2019;321:846–857.
  12. Sarge T, Baedorf-Kassis E, Banner-Goodspeed V, Novack V, Loring SH, Gong MN, Cook D, Talmor D, Beitler JR; EPVent-2 Study Group. 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. Am J Respir Crit Care Med. 2021 Nov 15;204(10):1153-1163.


Related Articles

epvent-2, pes, esophageal pressure, peep, titration, transpulmonary pressure, multiorgan failure, lung mechanics, peep-guided titration, peep-fio2

Date of Printing: 30.06.2022
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Date of Printing: 30.06.2022
The content of this Knowledge Base is intended for informational purposes only. Medin Medical AG provides no warranty with respect to the information contained in this Knowledge Base and reliance on any part of this information is solely at your own risk. For detailed instructions on operating your Medin Medical device, please refer to the official Medin Medical Operator’s Manual for the respective device.