The Berlin definition of ARDS: An expanded rationale, justification, and supplementary material
University of Toronto1, Guy's and St Thomas' NHS Foundation Trust2, Catholic University of the Sacred Heart3, University of Texas at Austin4, University of Geneva5, Johns Hopkins University6, University of Milan7, St George’s University Hospitals NHS Foundation Trust8, Université libre de Bruxelles9, Harvard University10, University of Turin11
TL;DR: This panel addressed some of the limitations of the prior ARDS definition by incorporating current data, physiologic concepts, and clinical trials results to develop the Berlin definition, which should facilitate case recognition and better match treatment options to severity in both research trials and clinical practice.
Abstract: Our objective was to revise the definition of acute respiratory distress syndrome (ARDS) using a conceptual model incorporating reliability and validity, and a novel iterative approach with formal evaluation of the definition. The European Society of Intensive Care Medicine identified three chairs with broad expertise in ARDS who selected the participants and created the agenda. After 2 days of consensus discussions a draft definition was developed, which then underwent empiric evaluation followed by consensus revision. The Berlin Definition of ARDS maintains a link to prior definitions with diagnostic criteria of timing, chest imaging, origin of edema, and hypoxemia. Patients may have ARDS if the onset is within 1 week of a known clinical insult or new/worsening respiratory symptoms. For the bilateral opacities on chest radiograph criterion, a reference set of chest radiographs has been developed to enhance inter-observer reliability. The pulmonary artery wedge pressure criterion for hydrostatic edema was removed, and illustrative vignettes were created to guide judgments about the primary cause of respiratory failure. If no risk factor for ARDS is apparent, however, objective evaluation (e.g., echocardiography) is required to help rule out hydrostatic edema. A minimum level of positive end-expiratory pressure and mutually exclusive PaO2/FiO2 thresholds were chosen for the different levels of ARDS severity (mild, moderate, severe) to better categorize patients with different outcomes and potential responses to therapy. This panel addressed some of the limitations of the prior ARDS definition by incorporating current data, physiologic concepts, and clinical trials results to develop the Berlin definition, which should facilitate case recognition and better match treatment options to severity in both research trials and clinical practice.
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TL;DR: In patients with nonhypercapnic acute hypoxemic respiratory failure, treatment with high-flow oxygen, standard oxygen, or noninvasive ventilation did not result in significantly different intubation rates, and there was a significant difference in favor of high- flow oxygen in 90-day mortality.
Abstract: BACKGROUND Whether noninvasive ventilation should be administered in patients with acute hypoxemic respiratory failure is debated. Therapy with high-flow oxygen through a nasal cannula may offer an alternative in patients with hypoxemia. METHODS We performed a multicenter, open-label trial in which we randomly assigned patients without hypercapnia who had acute hypoxemic respiratory failure and a ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen of 300 mm Hg or less to high-flow oxygen therapy, standard oxygen therapy delivered through a face mask, or noninvasive positive-pressure ventilation. The primary outcome was the proportion of patients intubated at day 28; secondary outcomes included all-cause mortality in the intensive care unit and at 90 days and the number of ventilator-free days at day 28. RESULTS A total of 310 patients were included in the analyses. The intubation rate (primary outcome) was 38% (40 of 106 patients) in the high-flow–oxygen group, 47% (44 of 94) in the standard group, and 50% (55 of 110) in the noninvasive-ventilation group (P = 0.18 for all comparisons). The number of ventilator-free days at day 28 was significantly higher in the high-flow–oxygen group (24±8 days, vs. 22±10 in the standard-oxygen group and 19±12 in the noninvasive-ventilation group; P = 0.02 for all comparisons). The hazard ratio for death at 90 days was 2.01 (95% confidence interval [CI], 1.01 to 3.99) with standard oxygen versus high-flow oxygen (P = 0.046) and 2.50 (95% CI, 1.31 to 4.78) with noninvasive ventilation versus high-flow oxygen (P = 0.006). CONCLUSIONS In patients with nonhypercapnic acute hypoxemic respiratory failure, treatment with high-flow oxygen, standard oxygen, or noninvasive ventilation did not result in significantly different intubation rates. There was a significant difference in favor of high-flow oxygen in 90-day mortality. (Funded by the Programme Hospitalier de Recherche Clinique Interregional 2010 of the French Ministry of Health; FLORALI ClinicalTrials.gov number, NCT01320384.)
1,571 citations
Additional excerpts
...Refractory hypoxemia 5/13 (38) 6/22 (27) 8/31 (26) 0....
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TL;DR: The peer-reviewed and preprint literature pertaining to cardiovascular considerations related to COVID-19 are reviewed to highlight gaps in knowledge that require further study pertinent to patients, health care workers, and health systems.
1,484 citations
Cites methods from "The Berlin definition of ARDS: An e..."
...However, if these tests are unclear and there remains concern for mixed presentation, pulmonary artery catheterization should be considered in select cases to assess filling pressures, cardiac output, and to guide clinical decision-making, given the different management approaches for ARDS and cardiogenic shock....
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...With severe respiratory infection and hypoxia, especially in the setting of severe infection and ARDS due to COVID-19, it is likely that a number of patients will develop such injury....
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...In severe cases, COVID-19 may present as pneumonia, the acute respiratory distress syndrome (ARDS), with or without both distributive and cardiogenic shock, to which elderly populations with preexisting medical comorbidities are the most vulnerable (1,6,19,20)....
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...Right heart failure and associated pulmonary hypertension should be also considered, in particular in the context of severe parenchymal lung disease and ARDS....
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...ACE = angiotensin converting enzyme ARDS = acute respiratory distress syndrome COVID-19 = coronavirus disease 2019 CV = cardiovascular CVD: cardiovascular disease ECMO = extracorporeal membrane oxygenation ICU = intensive care unit SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2...
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TL;DR: High proportion of severe to critical cases and high fatality rate were observed in the elderly COVID-19 patients and close monitoring and timely treatment should be performed for the elderly patients at high risk.
941 citations
Cites background from "The Berlin definition of ARDS: An e..."
...shorter than that in the survival group (5 (3-8) vs....
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...Shorter length of stay was found for the dead compared with the survivors (5 (3-8) vs....
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TL;DR: The Berlin definition of acute respiratory distress syndrome addressed limitations of the American-European Consensus Conference definition, but poor reliability of some criteria may contribute to underrecognition by clinicians.
Abstract: Importance Acute respiratory distress syndrome (ARDS) is a life-threatening form of respiratory failure that affects approximately 200 000 patients each year in the United States, resulting in nearly 75 000 deaths annually. Globally, ARDS accounts for 10% of intensive care unit admissions, representing more than 3 million patients with ARDS annually. Objective To review advances in diagnosis and treatment of ARDS over the last 5 years. Evidence Review We searched MEDLINE, EMBASE, and the Cochrane Database of Systematic Reviews from 2012 to 2017 focusing on randomized clinical trials, meta-analyses, systematic reviews, and clinical practice guidelines. Articles were identified for full text review with manual review of bibliographies generating additional references. Findings After screening 1662 citations, 31 articles detailing major advances in the diagnosis or treatment of ARDS were selected. The Berlin definition proposed 3 categories of ARDS based on the severity of hypoxemia: mild (200 mm Hg 2 /Fio 2 ≤300 mm Hg), moderate (100 mm Hg 2 /Fio 2 ≤200 mm Hg), and severe (Pao 2 /Fio 2 ≤100 mm Hg), along with explicit criteria related to timing of the syndrome’s onset, origin of edema, and the chest radiograph findings. The Berlin definition has significantly greater predictive validity for mortality than the prior American-European Consensus Conference definition. Clinician interpretation of the origin of edema and chest radiograph criteria may be less reliable in making a diagnosis of ARDS. The cornerstone of management remains mechanical ventilation, with a goal to minimize ventilator-induced lung injury (VILI). Aspirin was not effective in preventing ARDS in patients at high-risk for the syndrome. Adjunctive interventions to further minimize VILI, such as prone positioning in patients with a Pao 2 /Fio 2 ratio less than 150 mm Hg, were associated with a significant mortality benefit whereas others (eg, extracorporeal carbon dioxide removal) remain experimental. Pharmacologic therapies such as β 2 agonists, statins, and keratinocyte growth factor, which targeted pathophysiologic alterations in ARDS, were not beneficial and demonstrated possible harm. Recent guidelines on mechanical ventilation in ARDS provide evidence-based recommendations related to 6 interventions, including low tidal volume and inspiratory pressure ventilation, prone positioning, high-frequency oscillatory ventilation, higher vs lower positive end-expiratory pressure, lung recruitment maneuvers, and extracorporeal membrane oxygenation. Conclusions and Relevance The Berlin definition of acute respiratory distress syndrome addressed limitations of the American-European Consensus Conference definition, but poor reliability of some criteria may contribute to underrecognition by clinicians. No pharmacologic treatments aimed at the underlying pathology have been shown to be effective, and management remains supportive with lung-protective mechanical ventilation. Guidelines on mechanical ventilation in patients with acute respiratory distress syndrome can assist clinicians in delivering evidence-based interventions that may lead to improved outcomes.
873 citations
Cites background from "The Berlin definition of ARDS: An e..."
...or congestive heart failure as the primary cause for the respiratory failure (Table 1).(8) ARDS acute respiratory distress...
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...A reference set of chest radiographswas includedto illustrate findings thatmaybeconsistent, inconsistent, or equivocal for the diagnosis of ARDS.(8) Despite a more precise definition of the radiographic findings that should be used to diagnose ARDS and the inclusion of sample radiographs, interobserver reliability of the chest radiograph criterion remains suboptimal and is not improvedwith structured training or education....
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TL;DR: In this preliminary study of patients with sepsis and ARDS, a 96-hour infusion of vitamin C compared with placebo did not significantly improve organ dysfunction scores or alter markers of inflammation and vascular injury.
Abstract: Importance Experimental data suggest that intravenous vitamin C may attenuate inflammation and vascular injury associated with sepsis and acute respiratory distress syndrome (ARDS). Objective To determine the effect of intravenous vitamin C infusion on organ failure scores and biological markers of inflammation and vascular injury in patients with sepsis and ARDS. Design, Setting, and Participants The CITRIS-ALI trial was a randomized, double-blind, placebo-controlled, multicenter trial conducted in 7 medical intensive care units in the United States, enrolling patients (N = 167) with sepsis and ARDS present for less than 24 hours. The study was conducted from September 2014 to November 2017, and final follow-up was January 2018. Interventions Patients were randomly assigned to receive intravenous infusion of vitamin C (50 mg/kg in dextrose 5% in water, n = 84) or placebo (dextrose 5% in water only, n = 83) every 6 hours for 96 hours. Main Outcomes and Measures The primary outcomes were change in organ failure as assessed by a modified Sequential Organ Failure Assessment score (range, 0-20, with higher scores indicating more dysfunction) from baseline to 96 hours, and plasma biomarkers of inflammation (C-reactive protein levels) and vascular injury (thrombomodulin levels) measured at 0, 48, 96, and 168 hours. Results Among 167 randomized patients (mean [SD] age, 54.8 years [16.7]; 90 men [54%]), 103 (62%) completed the study to day 60. There were no significant differences between the vitamin C and placebo groups in the primary end points of change in mean modified Sequential Organ Failure Assessment score from baseline to 96 hours (from 9.8 to 6.8 in the vitamin C group [3 points] and from 10.3 to 6.8 in the placebo group [3.5 points]; difference, −0.10; 95% CI, −1.23 to 1.03;P = .86) or in C-reactive protein levels (54.1 vs 46.1 μg/mL; difference, 7.94 μg/mL; 95% CI, −8.2 to 24.11;P = .33) and thrombomodulin levels (14.5 vs 13.8 ng/mL; difference, 0.69 ng/mL; 95% CI, −2.8 to 4.2;P = .70) at 168 hours. Conclusions and Relevance In this preliminary study of patients with sepsis and ARDS, a 96-hour infusion of vitamin C compared with placebo did not significantly improve organ dysfunction scores or alter markers of inflammation and vascular injury. Further research is needed to evaluate the potential role of vitamin C for other outcomes in sepsis and ARDS. Trial Registration ClinicalTrials.gov Identifier:NCT02106975
548 citations
Cites background from "The Berlin definition of ARDS: An e..."
...At 168 hours, median was 46 μM [IQR, 19-66] for vitamin C vs 29 μM for placebo [12-39], P < ....
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...At 96 hours, median was 169 μM [IQR, 87-412] for vitamin C vs 26 μM for placebo [9-41], P < ....
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...At 48 hours, median was 166 μM [IQR, 88-376] for vitamin C vs 23 μM for placebo [9-37], P < ....
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References
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TL;DR: In patients with acute lung injury and the acute respiratory distress syndrome, mechanical ventilation with a lower tidal volume than is traditionally used results in decreased mortality and increases the number of days without ventilator use.
Abstract: Background Traditional approaches to mechanical ventilation use tidal volumes of 10 to 15 ml per kilogram of body weight and may cause stretch-induced lung injury in patients with acute lung injury and the acute respiratory distress syndrome. We therefore conducted a trial to determine whether ventilation with lower tidal volumes would improve the clinical outcomes in these patients. Methods Patients with acute lung injury and the acute respiratory distress syndrome were enrolled in a multicenter, randomized trial. The trial compared traditional ventilation treatment, which involved an initial tidal volume of 12 ml per kilogram of predicted body weight and an airway pressure measured after a 0.5-second pause at the end of inspiration (plateau pressure) of 50 cm of water or less, with ventilation with a lower tidal volume, which involved an initial tidal volume of 6 ml per kilogram of predicted body weight and a plateau pressure of 30 cm of water or less. The primary outcomes were death before a patient was discharged home and was breathing without assistance and the number of days without ventilator use from day 1 to day 28. Results The trial was stopped after the enrollment of 861 patients because mortality was lower in the group treated with lower tidal volumes than in the group treated with traditional tidal volumes (31.0 percent vs. 39.8 percent, P=0.007), and the number of days without ventilator use during the first 28 days after randomization was greater in this group (mean [+/-SD], 12+/-11 vs. 10+/-11; P=0.007). The mean tidal volumes on days 1 to 3 were 6.2+/-0.8 and 11.8+/-0.8 ml per kilogram of predicted body weight (P Conclusions In patients with acute lung injury and the acute respiratory distress syndrome, mechanical ventilation with a lower tidal volume than is traditionally used results in decreased mortality and increases the number of days without ventilator use.
11,028 citations
TL;DR: The updated and revised Berlin Definition for ARDS addresses a number of the limitations of the AECC definition and may serve as a model to create more accurate, evidence-based, critical illness syndrome definitions and to better inform clinical care, research, and health services planning.
Abstract: The acute respiratory distress syndrome (ARDS) was defined in 1994 by the American-European Consensus Conference (AECC); since then, issues regarding the reliability and validity of this definition have emerged. Using a consensus process, a panel of experts convened in 2011 (an initiative of the European Society of Intensive Care Medicine endorsed by the American Thoracic Society and the Society of Critical Care Medicine) developed the Berlin Definition, focusing on feasibility, reliability, validity, and objective evaluation of its performance. A draft definition proposed 3 mutually exclusive categories of ARDS based on degree of hypoxemia: mild (200 mm Hg < PaO2/FIO2 ≤ 300 mm Hg), moderate (100 mm Hg < PaO2/FIO2 ≤ 200 mm Hg), and severe (PaO2/FIO2 ≤ 100 mm Hg) and 4 ancillary variables for severe ARDS: radiographic severity, respiratory system compliance (≤40 mL/cm H2O), positive end-expiratory pressure (≥10 cm H2O), and corrected expired volume per minute (≥10 L/min). The draft Berlin Definition was empirically evaluated using patient-level meta-analysis of 4188 patients with ARDS from 4 multicenter clinical data sets and 269 patients with ARDS from 3 single-center data sets containing physiologic information. The 4 ancillary variables did not contribute to the predictive validity of severe ARDS for mortality and were removed from the definition. Using the Berlin Definition, stages of mild, moderate, and severe ARDS were associated with increased mortality (27%; 95% CI, 24%-30%; 32%; 95% CI, 29%-34%; and 45%; 95% CI, 42%-48%, respectively; P < .001) and increased median duration of mechanical ventilation in survivors (5 days; interquartile [IQR], 2-11; 7 days; IQR, 4-14; and 9 days; IQR, 5-17, respectively; P < .001). Compared with the AECC definition, the final Berlin Definition had better predictive validity for mortality, with an area under the receiver operating curve of 0.577 (95% CI, 0.561-0.593) vs 0.536 (95% CI, 0.520-0.553; P < .001). This updated and revised Berlin Definition for ARDS addresses a number of the limitations of the AECC definition. The approach of combining consensus discussions with empirical evaluation may serve as a model to create more accurate, evidence-based, critical illness syndrome definitions and to better inform clinical care, research, and health services planning.
7,731 citations
TL;DR: The acute respiratory distress syndrome (ARDS), a process of nonhydrostatic pulmonary edema and hypoxemia associated with a variety of etiologies, carries a high morbidity, mortality, and financial cost.
Abstract: The acute respiratory distress syndrome (ARDS), a process of nonhydrostatic pulmonary edema and hypoxemia associated with a variety of etiologies, carries a high morbidity, mortality (10 to 90%), and financial cost. The reported annual incidence in the United States is 150,000 cases, but this figure has been challenged, and it may be different in Europe. Part of the reason for these uncertainties are the heterogeneity of diseases underlying ARDS and the lack of uniform definitions for ARDS. Thus, those who wish to know the true incidence and outcome of this clinical syndrome are stymied. The American-European Consensus Committee on ARDS was formed to focus on these issues and on the pathophysiologic mechanisms of the process. It was felt that international coordination between North America and Europe in clinical studies of ARDS was becoming increasingly important in order to address the recent plethora of potential therapeutic agents for the prevention and treatment of ARDS.
6,233 citations
"The Berlin definition of ARDS: An e..." refers background in this paper
...was achieved when the American-European Consensus Conference (AECC) published a definition [2, 3]....
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...The panel had originally proposed a requirement of PEEP C10 cm H2O as a criterion for the severe ARDS group, but this was subsequently dropped as it did not improve predictive validity for mortality within the group of patients with PaO2/FiO2 B100 [22]....
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...Additional physiological measurements Plateau pressure (as measured after an end-inspiratory pause) reflects the combined effects of tidal volume, PEEP, and the compliance of the respiratory system and is associated with mortality [31]....
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...These patients had severe hypoxemia that was refractory to supplemental oxygen, but which in some cases was responsive to the application of positive endexpiratory pressure (PEEP)....
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...Static respiratory system compliance (i.e., the change in lung volume for a given driving pressure defined as tidal volume divided by plateau pressure minus PEEP) reflects the degree of lung volume loss....
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TL;DR: Positive end-expiratory pressure was most helpful in combating atelectasis and hypoxaemia and Corticosteroids appeared to have value in the treatment of patients with fat-embolism and possibly viral pneumonia.
3,706 citations
"The Berlin definition of ARDS: An e..." refers background in this paper
...The first definition of acute respiratory distress syndrome (ARDS) dates to Ashbaugh and colleagues in 1967 when they described 12 patients with severe acute respiratory failure [1]....
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TL;DR: It is estimated that each year in the United States there are 190,600 cases of acute lung injury, which are associated with 74,500 deaths and 3.6 million hospital days, considerably higher than previous reports have suggested.
Abstract: BACKGROUND Acute lung injury is a critical illness syndrome consisting of acute hypoxemic respiratory failure with bilateral pulmonary infiltrates that are not attributed to left atrial hypertension. Despite recent advances in our understanding of the mechanism and treatment of acute lung injury, its incidence and outcomes in the United States have been unclear. METHODS We conducted a prospective, population-based, cohort study in 21 hospitals in and around King County, Washington, from April 1999 through July 2000, using a validated screening protocol to identify patients who met the consensus criteria for acute lung injury. RESULTS A total of 1113 King County residents undergoing mechanical ventilation met the criteria for acute lung injury and were 15 years of age or older. On the basis of this figure, the crude incidence of acute lung injury was 78.9 per 100,000 person-years and the age-adjusted incidence was 86.2 per 100,000 person-years. The in-hospital mortality rate was 38.5 percent. The incidence of acute lung injury increased with age from 16 per 100,000 person-years for those 15 through 19 years of age to 306 per 100,000 person-years for those 75 through 84 years of age. Mortality increased with age from 24 percent for patients 15 through 19 years of age to 60 percent for patients 85 years of age or older (P<0.001). We estimate that each year in the United States there are 190,600 cases of acute lung injury, which are associated with 74,500 deaths and 3.6 million hospital days. CONCLUSIONS Acute lung injury has a substantial impact on public health, with an incidence in the United States that is considerably higher than previous reports have suggested.
3,358 citations