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Intensive Care Medicine

, Volume 42, Issue 5, pp 643–647 | Cite as

The Berlin definition met our needs: yes

  • Lorenzo Del Sorbo
  • V. Marco Ranieri
  • Niall D. Ferguson
Editorial

Introduction

A specific clinical definition for acute respiratory distress syndrome (ARDS) is needed to inform clinicians about specific therapies or prognosis, and to facilitate investigators in developing reproducible research [1].

Prior definitions of ARDS

Like other syndromic illnesses such as depression or sepsis, a challenge in defining ARDS is the lack of a reference gold standard for its diagnosis. However, the definition can still be evaluated on the basis of feasibility, reliability, and other forms of validity [1]. In this way, the definition of ARDS has evolved over time with progressive refinements.

In 1967, the first widely accepted description of ARDS was published describing a case-series of 12 patients that developed a common pattern of respiratory failure stemming from a variety of insults. “Respiratory-distress syndrome” was clinically characterized by the acute onset of severe dyspnea, tachypnea, cyanosis refractory to oxygen, loss of compliance, and infiltration on the chest radiographs [2]. Informal definitions such as this were used for more than two decades until the Murray Lung Injury Score was published in 1988 [3], followed shortly thereafter in 1994 by the American-European Consensus Conference (AECC) definition of ARDS [4]. The AECC definition allowed knowledge on ARDS to remarkably increase, facilitating the completion of seminal epidemiological [5] and clinical [6, 7] studies. The AECC defined ARDS by the presence of the following four criteria: (1) acute onset; (2) hypoxemia, as indicated by the ratio of partial pressure of arterial oxygen to fraction of inspired oxygen [PaO2/FiO2] ≤200 mmHg; (3) bilateral infiltrates on frontal chest radiograph; (4) absence of left atrial hypertension. ARDS was considered the more severe form of an overarching entity called acute lung injury (ALI), defined by the same criteria, but with less severe hypoxemia (PaO2/FiO2 ≤300 mmHg) [4].

Issues with the AECC definition of ARDS

Despite its utility, it became apparent that the AECC definition also had limitations. These included imprecision in the exact time frame of ‘acute onset’; variation in the PaO2/FiO2 ratio according to FiO2 and mechanical ventilation settings; poor interobserver reliability of the chest radiographs interpretation; and the frequent misclassification of left atrial hypertension. In addition, the term ALI was often misused to indicate only less severe patients with PaO2/FiO2 200–300 mmHg, instead of being used to define the overall syndrome. Because of these concerns and others, the European Society of Intensive Care Medicine convened an international expert panel in 2011 in Berlin to develop a new definition of ARDS.

The Berlin definition of ARDS

According to the Berlin definition, ARDS is a form of acute diffuse lung injury occurring in patients with a predisposing risk factor, meeting the following criteria: (1) onset within 1 week of a known clinical insult or new/worsening respiratory symptoms; (2) presence of bilateral opacities on the chest radiographs, not fully explained by effusions, lobar/lung collapse, or nodules; (3) diagnosis of respiratory failure not fully explained by cardiac failure or fluid overload, with the need for objective assessment (e.g., echocardiography) to exclude hydrostatic edema if no risk factor is present; (4) presence of hypoxemia, defined by PaO2/FiO2 measured with a minimum requirement for PEEP of ≥5 cmH2O (or non-invasive continuous positive airway pressure ≥5 cmH2O for mild ARDS) and identifying three mutually exclusive categories of severity: mild with 200 mmHg < PaO2/FiO2 ≤ 300 mmHg, moderate with 100 mmHg < PaO2/FiO2 ≤ 200 mmHg, severe with PaO2/FiO2 ≤ 100 mmHg [8, 9].

Advances with the Berlin definition of ARDS

Several important issues were addressed in this new definition. The often misused term ALI was removed. A specific timing of onset was defined. The need for a predisposing risk factor was incorporated. The exclusion criterion based on the presence of hydrostatic edema was redefined. The radiological criteria were reformulated. The requirement of a minimum PEEP to establish the severity of hypoxemia according to PaO2/FiO2 was introduced. Moreover, the three mutually exclusive categories of mild, moderate, and severe ARDS were validated, as they were associated with increasingly severe disease using mortality, ventilator-free days, and the duration of mechanical ventilation as outcomes in survivors. Furthermore, the draft definition underwent testing and revision using predictive validity for mortality as a standard. This process resulted in a final definition that was simpler to use but had similar predictive validity and better distribution among categories [8, 10]. Finally, the reliability of the definition was addressed by the publication of a reference set of vignettes and chest radiographs to facilitate consistency in the interpretation [9].

Criticisms of the Berlin definition of ARDS

Criticisms have been raised about the Berlin definition. In particular, it has been shown that the measurement of PaO2/FiO2 using predefined ventilator settings after 24 h from the initial assessment would improve the stratification of the ARDS severity [11]. However, this approach could delay enrollment in clinical trials or delivery of beneficial treatments and also negates much observational research. Moreover, it has been suggested that adding compliance normalized to ideal body weight to the criteria would improve the risk stratification within each subcategory of severity [12]. These and other criteria including biomarkers, extravascular lung water, and CT scans were considered and rejected during definition development because of a lack of association data, impact on feasibility, or both. Only more observational data will allow further refinements of the definition of ARDS with the aim of retaining feasibility and improving its reliability and validity.

Uptake of the Berlin definition of ARDS

The uptake of the Berlin definition has been impressive. Initiated by the European Society of Intensive Care Medicine, the process was endorsed by the American Thoracic Society and the Society of Critical Care Medicine. Since its publication in 2012 it has been cited more the 1500 times and is the subject of more than 150 articles on PubMed. Furthermore, the Pediatric Acute Lung Injury Consensus Conference used the Berlin criteria for the development of the pediatric ARDS definition [13, 14]. Finally, the Berlin definition is used in a remarkable number of ongoing clinical trials in ARDS (Table 1).
Table 1

Title of the ongoing randomized clinical trials on ARDS, diagnosed according to the Berlin definition, the sponsor and the identification number

Sponsor

Title of the clinical study

Identification number

Athersys Limited Cell Therapy Catapult

A phase 1/2 study to assess MultiStem® therapy in acute respiratory distress syndrome (MUST-ARDS)

NCT02611609

University Hospital, Clermont-Ferrand

Predictive values of plasma soluble RAGE levels and RAGE polymorphisms for the onset of acute respiratory distress syndrome in critically Ill patients (PrediRAGE)

NCT02070536

Faron Pharmaceuticals Ltd

Efficacy and safety of FP-1201-lyo (interferon beta-1a) in patients having acute respiratory distress syndrome (ARDS) (INTEREST)

NCT02622724

University Hospital, Clermont-Ferrand

Impact of fluid resuscitation therapy on pulmonary edema as measured by alveolar fluid clearance in patients with acute respiratory distress syndrome (ARDS) (IROCA)

NCT01763853

Michael A. Matthay, University of California, San Francisco

Human mesenchymal stem cells for acute respiratory distress syndrome (START)

NCT01775774

Centre Hospitalier Universitaire de Besancon

Echocardiography predictive of the inefficacy and/or of the unsafeness of recruitment maneuvers in patients with acute respiratory distress syndrome (RV STAR)

NCT01768949

Groupe Hospitalier Pitie-Salpetriere

Low-flow CO2 removal for mild to moderate ARDS with PRISMALUNG

NCT02606240

National Taiwan University Hospital

Risk factors of postoperative acute lung injury following liver transplantation

NCT02412800

Xiangya Hospital of Central South University

Discovery of new early detection biomarkers of acute respiratory distress syndrome (ARDS)

NCT02625064

University Hospital Regensburg

Surviving ARDS: the influence of quality of care and individual patient characteristics on quality of life (DACAPO)

NCT02637011

University Hospital, Clermont-Ferrand

Effects of sevoflurane on gas exchange and inflammation in patients with ARDS (SEGA study) (SEGA)

NCT02166853

Australian and New Zealand Intensive Care Research Centre

A multi-centre trial of an open lung strategy including permissive hypercapnia, alveolar recruitment and low airway pressure in patients with acute respiratory distress syndrome (PHARLAP)

NCT01667146

Ling Liu, Southeast University, China

Standardized application of high frequency oscillatory ventilation in the acute respiratory distress syndrome (ARDS)

NCT01677130

Shaoxing Second Hospital

Adipose-derived mesenchymal stem cells in acute respiratory distress syndrome

NCT01902082

Assistance Publique—Hôpitaux de Paris

Validation of the percentage of alveolar fibrocyte as biomarker during ARDS (IFRA2)

NCT01854424

St. Michael’s Hospital, Toronto

Respiratory mechanics registry for ARDS patients

NCT02623192

West China Hospital

Airway pressure release ventilation (APRV) protocol early used in acute respiratory distress syndrome

NCT02639364

Central Hospital, Nancy, France

Assessment of right ventricular 2D-strain in acute respiratory distress syndrome (ARDStrain)

NCT02638844

Corporacion Parc Tauli

Preventive strategies in acute respiratory distress syndrome (ARDS) (EPALI)

NCT02070666

University Hospital, Clermont-Ferrand

A role for RAGE/TXNIP/Inflammasome axis in alveolar macrophage activation during ARDS (RIAMA): a proof-of-concept clinical study

NCT02545621

University of Minnesota

Diaphragm ultrasound vs transpulmonary pressure to set PEEP in ARDS

NCT02463773

Zhongda Hospital

The influence of tidal volume to lung strain

NCT01864668

St. Michael’s Hospital, Toronto

Validation of a simple approach to estimate alveolar recruitability in ARDS patients

NCT02457741

Charite University, Berlin, Germany

Measuring energy expenditure in ECMO (extracorporeal membrane oxygenation) patients (MEEP)

NCT01992237

University of Athens

Physiological study of low-frequency HFO/HFO-TGI and high-frequency HFO

NCT02027129

RWTH Aachen University

Hemodynamic and cardiac effects of individualized PEEP titration using esophageal pressure measurements in ARDS patients (ENCODE)

NCT02617914

University Hospital Freiburg

Extravascular lung water and pulmonary vascular permeability after minimally invasive cardiac surgery

NCT02155387

Peking Union Medical College Hospital

Lung alveolar recruitment and individualized PEEP setting in patients with ARDS

NCT02361398

University Hospital, Toulouse

Alveolar recruitment maneuvers, intracerebral hemodynamic and oxygenation (M’RHICO)

NCT02574169

Capital Medical University

Effect of increased positive end-expiratory pressure on intracranial pressure in different respiratory mechanic in acute respiratory distress syndrome

NCT02670733

University of Toronto

Esophageal pressure-guided optimal PEEP/mPaw in CMV and HFOV: the EPOCH study (EPOCH)

NCT02342756

Centre Hospitalier Universitaire de Nice

Strain and blood inflammatory markers as prognostic tools for ARDS AMIS (ARDS-markers of inflammation-strain) (AMIS)

NCT02003326

University of Turin, Italy

Protective ventilatory strategy in severe acute brain injury (PROLABI)

NCT01690819

Technische Universität München

Extracorporeal lung assist device in acute lung impairment (EXODUS)

NCT02550600

National University Health System, Singapore

Ultra-protective pulmonary ventilation supported by low flow ECCO2R for severe ARDS (U-Protect)

NCT02252094

European Society of Intensive Care Medicine

Strategy of ultraprotective lung ventilation with extracorporeal CO2 removal for new-onset moderate to severe ARDS (SUPERNOVA)

NCT02282657

Hospices Civils de Lyon

Validation of digital chest-X-ray (CXR) to assess lung recruitment in ARDS (RECRUTEX)

NCT02081105

Beth Israel Deaconess Medical Center

EPVent 2—a phase II study of mechanical ventilation directed by transpulmonary pressures (EPVent2)

NCT01681225

Hospital Universitari Vall d’Hebron Research Institute

The role of IL33/ST2 axis in ARDS patients

NCT02492204

Children’s Hospital Boston

Titration of PEEP during mechanical ventilation in patients with ARDS using electrical impedance tomography

NCT02596178

University of Toronto

Strategies for optimal lung ventilation in ECMO for ARDS: the SOLVE ARDS study (SOLVE ARDS)

NCT01990456

Ruijin Hospital

Effect of early mechanical ventilation to severe acute pancreatitis

NCT01992224

Academisch Medisch Centrum—Universiteit van Amsterdam

Protective ventilation in patients without ARDS (PReVENT-NL)

NCT02153294

The source of the identification number and title is ClinicalTrials.gov

Conclusion

The Berlin definition of ARDS shows qualitative improvements in a number of definition metrics, and better suits the needs of critical care clinicians and investigators as demonstrated by its immediate and wide uptake.

Notes

Compliance with ethical standards

Conflicts of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

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Copyright information

© Springer-Verlag Berlin Heidelberg and ESICM 2016

Authors and Affiliations

  • Lorenzo Del Sorbo
    • 1
    • 2
  • V. Marco Ranieri
    • 3
  • Niall D. Ferguson
    • 1
    • 2
    • 4
  1. 1.Department of Medicine, Division of Respirology and Critical Care Medicine, Toronto General Research Institute, Toronto General HospitalUniversity Health Network and Mount Sinai HospitalTorontoCanada
  2. 2.University of TorontoTorontoCanada
  3. 3.Dipartimento di Anestesia e Rianimazione, Ospedale Policlinico Umberto IUniversità La Sapienza di RomaRomeItaly
  4. 4.Interdepartmental Division of Critical Care Medicine, Departments of Medicine and Physiology and Institute for Health Policy, Management and EvaluationUniversity of TorontoTorontoCanada

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