Advertisement

Intensive Care Medicine

, Volume 42, Issue 5, pp 648–650 | Cite as

The Berlin definition met our needs: no

  • Jesús Villar
  • Lina Pérez-Méndez
  • Robert M. Kacmarek
Editorial

“It’s far more important to know what person the disease has than what disease the person has.”—Hippocrates.

Introduction

According to the European Telecommunications Standards Institute [1], standardization provides a solid foundation upon which to develop new technologies and to enhance existing practices. Adherence to standards helps improve safety, reduce costs, ensure reliability, encourage innovation, increase awareness of technical developments, and provide the foundation for new options. Developing standards for defining disease processes improves quality in health care [2]. However, although definitions are an essential component of medical progress, they need to be continuously refined as new knowledge is accrued.

The acute respiratory distress syndrome (ARDS) cannot be diagnosed or described by any single laboratory test and is not associated with or caused by any single etiology. Although there is a general agreement on the criteria on which to base a definition for ARDS (severe hypoxemia, bilateral pulmonary infiltrates, decreased pulmonary compliance, and a risk factor in the setting in which cardiogenic pulmonary edema is excluded), the specific ranges and conditions under which to evaluate the hypoxemia vary among clinicians and researchers. Since no biomarker has yet been described that is specific for ARDS, it is plausible that ARDS prevalence is overestimated, since many patients with acute hypoxemic respiratory failure from other diseases with bilateral pulmonary infiltrates could be incorrectly diagnosed as having ARDS [3, 4]. Misdiagnosis can also occur if clinicians consider qualifying PaO2 values resulting from acute events unrelated to the disease process (such as patient–ventilator asynchrony, endotracheal tube obstruction, pneumothorax, or hemodynamic instability), instead of considering only PaO2 values while patients are clinically stable. Today, the term ARDS is used with greater care than previously, since several patients from the first clinical report [5] would not be diagnosed as having ARDS.

Searching for a satisfactory ARDS definition

The original description of ARDS proved to be incapable of identifying a uniform group of patients in terms of severity and prognosis. From a therapeutic point of view, we need a rigorous stratification of lung injury severity since the intensity and modality of ventilatory support and adjunctive therapies should differ depending on the degree of hypoxemia. From the research perspective, a precise definition helps to standardize studies on etiology, pathophysiology and treatment [6], improves our ability to compare data among studies and centers, and helps in evaluating the natural history, incidence, and prognosis of ARDS [7].

In 1994, an American-European Consensus Conference (AECC) [8] formalized the criteria for the diagnosis of ARDS by quantifying lung damage based on PaO2/FiO2 ratio, regardless of applied FiO2 and positive end-expiratory pressure (PEEP):ARDS (PaO2/FiO2 ≤ 200 mmHg) and “acute lung injury” (300 ≥ PaO2/FiO2 > 200). This definition was challenged by Villar et al. [7, 9, 10], when they demonstrated that the PaO2 response to standardized ventilatory settings (which included a specific level of PEEP and FiO2) allowed the separation of ARDS patients into several groups with different severity and outcome. They observed that: (1) about half of the patients were improperly classified, and (2) ARDS patients could be uniformly stratified according to their response to a PEEP-FiO2 trial. Their findings illustrated the problems of trying to compare the results of clinical trials, since most trials have used different ARDS definitions and enrolled patients with different levels of lung dysfunction [11].

The Berlin definition does not resolve the problems with the AECC definition

Patients can easily meet the AECC PaO2/FiO2 criteria because of a lack of PEEP and FiO2 requirements. In 2012, the Berlin definition [12, 13] attempted—but failed—to address this limitation by classifying patients into three categories based on thresholds for baseline PaO2/FiO2 on PEEP ≥ 5 cmH2O regardless of FiO2: mild (300 ≥ PaO2/FiO2 > 200), moderate (200 < PaO2/FiO2 > 100), and severe (PaO2/FiO2 ≤100). There are no data that link a particular baseline PaO2/FiO2 to predictable structural changes in the alveolar–capillary membrane. Two recent studies [14, 15] showed that the use of non-standardized baseline PaO2/FiO2 were incapable of separating patients into distinct categories of severity with significantly different mortalities. An autopsy study revealed that the Berlin criteria did not correlate with the presence of diffuse alveolar damage in more than 50 % of patients categorized as moderate and severe ARDS [16]. However, this correlation improved significantly only when patients met PaO2/FiO2 criteria beyond 24 h of persistent ARDS. The requirement of a minimum PEEP of 5 cmH2O has essentially no impact on the definition, since it is hard to conceive a patient with hypoxemic respiratory failure on PEEP <5 cmH2O. Also, it is well established that changes in PEEP and FiO2 alter the PaO2/FiO2 in lung-injured patients. If assessment of ARDS severity is of crucial importance, it should be mandatory to set standard rules for quantifying the degree of lung injury. If PaO2 measurements are not standardized, the calculated PaO2/FiO2 may mask the severity of the underlying lung pathology in a substantial proportion of patients. By only adding a PEEP ≥5 cmH2O to the assessment of PaO2/FiO2, the AECC and the Berlin definitions are essentially identical.

The success of personalized medicine [17] depends on the development of diagnostic tests that can accurately identify and stratify appropriate patients for a given therapy. The use of non-standardized criteria to enroll patients into clinical trials may negatively impact the outcome of the trial and potentially harm patients. If PaO2/FiO2 ratio is used to select patients for a trial, a standard validated method should be applied at the time of trial initiation to insure that patients within an identical baseline PaO2/FiO2 range have similar degrees of lung injury and prognosis. Otherwise, it becomes difficult—if not impossible—to interpret trial results [11]. Villar et al. [18] studied 478 patients with moderate and severe ARDS and examined the PaO2/FiO2 at ARDS onset, after 24 h of usual care, and at 24 h under standardized ventilator settings. Their standardized model outperformed the Berlin criteria and non-standardized PaO2/FiO2 at 24 h. More than 60 % of patients with severe ARDS according to Berlin criteria were reclassified as moderate, mild or non-ARDS after 24 h of usual care, while hospital mortality changed significantly with every PaO2/FiO2 category under the standardized method. If patients are identified as severe ARDS by the Berlin criteria, they could be forced to receive highly invasive and aggressive therapies that provide no benefit (useless) or could be harmful (worse than usual care), since after 24 h of routine care a high percentage evolve to milder forms of ARDS.

In conclusion, the stratification of ARDS patients as proposed by the Berlin criteria is useless for assessing severity of lung injury and could be harmful for enrolling patients into clinical trials. Current data support the need for a new standardized method for evaluating oxygenation criteria (Table 1).
Table 1

Proposal of a two-step process for appropriate assessment of hypoxemia for the diagnosis of acute respiratory distress syndrome (ARDS)

Parameters

Values

A known predisposing factor

Radiographic bilateral pulmonary infiltrates consistent with bilateral alveolar edema

Heart failure or fluid overload must be excluded as a cause of pulmonary edema

No clinical (or ecocardiographic or hemodynamic) signs of heart failure

Hypoxemia (assessed by PaO2/FiO2), mmHg

1st step (ARDS onset): PaO2/FiO2 ≤300 on PEEP ≥5 cmH2O

2nd step (reassessment at 24 h on PEEP ≥10 and FiO2 ≥0.5)a:

Severe ARDS: PaO2/FiO2 ≤100

Moderate ARDS: 100 < PaO2/FiO2 ≤ 200

Mild ARDS: 200 < PaO2/FiO2 ≤ 300

Non-ARDS: PaO2/FiO2 >300

Specific biomarker(s) of lung injury

Specific threshold values (easy to measure in blood, exhaled air, or any other biological sample)

aSee Ref. [18] for rules for setting PEEP and FiO2 during assessment on standardized settings at 24 h of ARDS diagnosis

Notes

Acknowledgments

This work was supported in part by Instituto de Salud Carlos III (CB06/06/1088, PI13/0119) and Asociación Científica Pulmón y Ventilación Mecánica. The funders had no role in the content, decision to publish, or preparation of the manuscript.

Compliance with ethical standards

Conflicts of interest

JV has received research grants from Maquet. RMK has received research grants from Venner Medical and Covidien, and is a consultant for Covidien and Orange Med Inc. LPM declared no competing interest in relation to the content of this manuscript.

References

  1. 1.
  2. 2.
    Segouin C, Hodges B, Brechat PH (2005) Globalization in health care: is international standardization of quality a step toward outsourcing? Int J Qual Health Care 17:277–279CrossRefPubMedGoogle Scholar
  3. 3.
    Guérin C, Thompson T, Brower R (2015) The ten diseases that look like ARDS. Intensive Care Med 41:1099–1102CrossRefPubMedGoogle Scholar
  4. 4.
    Gibelin A, Parrot A, Maitre B, Brun-Buisson C, Mekontso Dessap A, Fartoukh M, de Prost N (2015) Acute respiratory distress syndrome mimickers lacking common risk factors of the Berlin definition. Intensive Care Med 42:164–172. doi: 10.1007/s00134-015-4064-y CrossRefPubMedGoogle Scholar
  5. 5.
    Ashbaugh DG, Bigelow DB, Petty TL, Levine BE (1967) Acute respiratory distress in adults. Lancet 2:319–323CrossRefPubMedGoogle Scholar
  6. 6.
    Villar J, Kacmarek RM, Pérez-Méndez L, Aguirre-Jaime A, The ARIES Network (2006) A high positive end-expiratory pressure, low tidal volume ventilatory strategy improves outcome in persistent acute respiratory distress syndrome: a randomized, controlled trial. Crit Care Med 34:1311–1318CrossRefPubMedGoogle Scholar
  7. 7.
    Villar J, Pérez-Méndez L, Kacmarek RM (1999) Current definitions of acute lung injury and the acute respiratory distress syndrome do not reflect their true severity and outcome. Intensive Care Med 25:930–935CrossRefPubMedGoogle Scholar
  8. 8.
    Bernard GR, Artigas A, Brigham KL, Carlet J, Falke K, Hudson L, et al (1994) The American-European Consensus Conference on ARDS. Am J Respir Crit Care Med 149:818-824Google Scholar
  9. 9.
    Villar J, Pérez-Méndez L, Blanco J, Añón JM, Blanch L, Belda J, Santos-Bouza A, Fernández RL, Kacmarek RM, The SIESTA Network (2013) A universal definition of ARDS: the PaO2/FiO2 ratio under a standard ventilatory setting. A prospective, multicenter validation study. Intensive Care Med 39:583–592CrossRefPubMedGoogle Scholar
  10. 10.
    Villar J, Pérez-Méndez L, López J, Belda J, Blanco J, Saralegui I, Suárez-Sipmann F, López J, Lubillo S, Kacmarek RM, Network HELP (2007) An early PEEP/FiO2 trial identifies different degrees of lung injury in patients with acute respiratory distress syndrome. Am J Respir Crit Care Med 176:795–804CrossRefPubMedGoogle Scholar
  11. 11.
    Villar J, Kacmarek RM, Guerin C (2014) Clinical trials in patients with the acute respiratory syndrome: burn after reading. Intensive Care Med 40:900–902CrossRefPubMedGoogle Scholar
  12. 12.
    The ARDS Definition Task Force (2012) Acute respiratory distress syndrome: the Berlin definition. JAMA 307:2526–2533Google Scholar
  13. 13.
    Ferguson ND, Fan E, Camporota L, Antonelli M, Anzueto A, Beale R, Brochard L, Brower R et al (2012) The Berlin definition of ARDS: an expanded rationale, justification, and supplementary material. Intensive Care Med 38:1573–1582CrossRefPubMedGoogle Scholar
  14. 14.
    Hernu R, Wallet F, Thiollière F, Martin O, Richard JC, Schmitt Z, Wallon G, Delannoy B, Rimmelé T, Démaret C et al (2013) An attempt to validate the modification of the American-European consensus definition of acute lung injury/acute respiratory distress syndrome by the Berlin definition in a university hospital. Intensive Care Med 39:2161–217015CrossRefPubMedGoogle Scholar
  15. 15.
    Caser EB, Zandonade E, Pereira E, Gama AM, Barbas CS (2014) 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 42:574–582CrossRefPubMedGoogle Scholar
  16. 16.
    Thille AW, Esteban A, Fernández-Segoviano P, Rodriguez JM, Aramburu JA, Peñuelas O, Cortés-Puch I, Cardinal-Fernández P, Lorente JA, Frutos-Vivar F (2013) Comparison of the Berlin definition for acute respiratory distress syndrome with autopsy. Am J Respir Crit Care Med 187:761–767CrossRefPubMedGoogle Scholar
  17. 17.
    Woodcock J (2010) Assessing the clinical utility of diagnostics used in drug therapy. Clin Pharmacol Ther 88:765–773CrossRefPubMedGoogle Scholar
  18. 18.
    Villar J, Blanco J, del Campo R, Andaluz-Ojeda D, Díaz-Dominguez FJ, Muriel A, Córcoles V, Suárez-Sipmann F, Tarancón C, González-Higueras E, López L, Blanch L, Pérez-Méndez L, Fernández RL, Kacmarek RM, SIESTA Network (2015) Assessment of PaO2/FiO2 for stratification of patients with moderate and severe acute respiratory distress syndrome. BMJ Open 5:e006812CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg and ESICM 2016

Authors and Affiliations

  • Jesús Villar
    • 1
    • 2
    • 3
  • Lina Pérez-Méndez
    • 1
    • 4
  • Robert M. Kacmarek
    • 5
    • 6
  1. 1.CIBER de Enfermedades RespiratoriasInstituto de Salud Carlos IIIMadridSpain
  2. 2.Multidisciplinary Organ Dysfunction Evaluation Research Network (MODERN), Research UnitHospital Universitario Dr. NegrinLas Palmas de Gran CanariaSpain
  3. 3.Keenan Research Center for Biomedical Science at the Li Ka Shing Knowledge InstituteSt Michael’s HospitalTorontoCanada
  4. 4.Research UnitHospital Universitario N.S. de CandelariaSanta Cruz de TenerifeSpain
  5. 5.Department of Respiratory CareMassachusetts General HospitalBostonUSA
  6. 6.Department of Anesthesiology and Critical CareHarvard UniversityBostonUSA

Personalised recommendations