Skip to main content

Concerns about LUNG-SAFE: response to the letter to the Editor of Critical Care by Bellani et al.

We appreciate the opportunity to respond to the letter by Bellani et al. regarding our commentary on LUNG-SAFE. They expressed concern regarding the four potential biases we raised about their study.

First, we were concerned with the use of the Berlin Criteria to classify patients with ARDS. They indicated that there was no need to validate these criteria. However, these criteria were developed by consensus and have never been validated. All attempts to validate the criteria have failed, indicating that the criteria could not identify patients based on severity with increasing mortality [1, 2].

Second, we indicated that patients with ARDS need to meet the criteria for at least 24 hours. We have demonstrated previously that patients classified as severe ARDS at onset may not even meet the criteria for mild ARDS 24 hours later [3, 4]. There is no evidence which would indicate that the severe, lung inflammatory response that is a hallmark of ARDS on autopsy [5] resolves within a 24-hour period. Without longitudinal data meeting ARDS criteria, it is highly likely that many of these patients simply developed atelectasis.

Third, we agree the authors did not directly state that the incidence of ARDS they identified was over a full 1-year period. However, the implication presented, we believe, would lead the naïve reader to easily interpret these data as implying a global incidence of ARDS.

Finally, the authors state that “nonrecruiting sites” were eliminated. We interpreted this as sites without ARDS patients during the 4-week study period. This is a finding we consider highly plausible but to be adding bias if they were eliminated. We did not even consider that 207 ICUs would be eliminated because there were no mechanically ventilated patients in those ICUs during the 4-week winter study period. A total of 666 ICUs registered to be part of the study but only patients from 459 ICUs were included.

We commend the authors on performing a very difficult and enlightening study but have ongoing concerns with the utility of the Berlin Criteria as the definition for ARDS. The continued failure for validating these criteria may provide the medical community with a highly inflated perception of the incidence of ARDS. We believe the data indicate that a definition with a more precise, standardized ventilator setting requiring criteria to be present over a longitudinal period would provide a much more accurate indication of the incidence of ARDS.



Acute respiratory distress syndrome


Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure


  1. Hernu R, Wallet F, Thiollirer F, et al. An attempt to validate the modification of the American European consensus definition of the acute lung injury/acute respiratory distress syndrome by the Berlin Definition in a university hospital. Intensive Care Med. 2013;39:2161–70.

    Article  CAS  PubMed  Google Scholar 

  2. Caser EB, Zandonade E, Pereira E, et al. Impact of distinct definitions of acute lung injury on its incidence and outcomes in Brazilian ICUs: prospective evaluation of 7,133 patients. Crit Care Med. 2014;42:574–82.

    Article  PubMed  Google Scholar 

  3. Villar J, Pérez-Méndez L, López J, et al. An early PEEP/FIO2 trial identifies different degrees of lung injury in patients with different degrees of lung injury. Am J Respir Crit Care Med. 2007;176:795–804.

    Article  PubMed  Google Scholar 

  4. Villar J, Perez-Mendez L, Blanco J, et al. A universal definition of ARDS: the PaO2/FIO2 ratio under standard ventilator settings—a prospective multicenter validation study. Intensive Care Med. 2013;39:583–92.

    Article  CAS  PubMed  Google Scholar 

  5. Tomashefski Jr JF. Pulmonary pathology of acute respiratory distress syndrome. Clin Chest Med. 2000;21:435–66.

    Article  PubMed  Google Scholar 

Download references


Not applicable.


Not applicable.

Availability of supporting data

Not applicable.

Authors’ contributions

JV and RMK are both responsible for writing, revising, and submitting this letter. Both authors read and approved the final manuscript.

Competing interests

The authors declare that they have no competing interests.

Consent for publication

Not applicable.

Ethics approval and consent to participate

Not applicable.

Author information

Authors and Affiliations


Corresponding authors

Correspondence to Jesús Villar or Robert M. Kacmarek.

Rights and permissions

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated.

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Villar, J., Kacmarek, R.M. Concerns about LUNG-SAFE: response to the letter to the Editor of Critical Care by Bellani et al.. Crit Care 20, 296 (2016).

Download citation

  • Published:

  • DOI: