Baseline PaO2/FiO2 at the time of ARDS diagnosis failed to identify subgroups of patients with distinct lung injury severity For peer review only

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1 Baseline PaO/FiO at the time of ARDS diagnosis failed to identify subgroups of patients with distinct lung injury severity Journal: BMJ Open Manuscript ID: bmjopen-0-00 Article Type: Research Date Submitted by the Author: 0-Oct-0 Complete List of Authors: Villar, Jesús; Instituto de Salud Carlos III, CIBER de Enfermedades Respiratorias; Hospital Universitario Dr. Negrin, Research Unit Blanco, Jesús; Instituto de Salud Carlos III, CIBER de Enfermedades Respiratorias; Hospital Universitario Rio Hortega, Intensive Care Unit del Campo, Rafael; Hospital General de Ciudad Real, Intensive Care Unit Andaluz-Ojeda, David; Hospital Clínico Universitario de Valladolid, Intensive Care Unit Díaz-Domínguez, Francisco; Hospital Universitario General de León, Intensive Care Unit Muriel, Arturo; Hospital Universitario Rio Hortega, Intensive Care Unit Córcoles, Virgilio; Complejo Hospitalario Universitario de Albacete, Intensive Care Unit Suárez-Sipmann, Fernando; Uppsala University Hospital, Department of Anesthesiology and Critical Care; Instituto de Salud Carlos III, CIBER de Enfermedades Respiratorias Tarancón, Concepción; Hospital Virgen de la Concha, Intensive Care Unit González-Higueras, Elena; Hospital Virgen de la Luz, Intensive Care Unit López, Julia; Hospital Universitario La Paz, Intensive Care Unit Blanch, Lluis; Instituto de Salud Carlos III, CIBER de Enfermedades Respiratorias; Corporació Sanitaria Parc taulí, Critical Care Center Fernández, Rosa; Instituto de Salud Carlos III, CIBER de Enfermedades Respiratorias; Hospital Universitario Dr. Negrin, Multidisciplinary Organ Dysfunction Evaluation Research Network Kacmarek, Robert; Massachusetts General Hospital, Department of Respiratory Care; Harvard University, Department of Anesthesiology <b>primary Subject Heading</b>: Intensive care Secondary Subject Heading: Respiratory medicine Keywords: Adult intensive & critical care < ANAESTHETICS, Adult thoracic medicine < THORACIC MEDICINE, RESPIRATORY MEDICINE (see Thoracic Medicine) - BMJ Open: first published as 0./bmjopen-0-00 on March 0. Downloaded from on January 0 by guest. Protected by copyright.

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3 Page of Baseline PaO /FiO at the time of ARDS diagnosis failed to identify subgroups of patients with distinct lung injury severity Running title: Failure of ARDS stratification at disease onset, Jesús Villar,, Jesús Blanco, Rafael del Campo, David Andaluz-Ojeda, Francisco J. Díaz- Domínguez, Arturo Muriel, Virgilio Córcoles,, Fernando Suárez-Sipmann, Concepción Tarancón, 0 Elena González-Higueras, Julia López,, Lluis Blanch,, Rosa Lidia Fernández,, Robert M. Kacmarek, for the Spanish Initiative for Epidemiology, Stratification & Therapies for ARDS (SIESTA) Network* From () CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain; () Multidisciplinary Organ Dysfunction Evaluation Research Network, Research Unit, Hospital Universitario Dr. Negrín, Las Palmas, Spain; () Intensive Care Unit, Hospital Universitario Río Hortega, Valladolid, Spain; () Intensive Care Unit, Hospital General de Ciudad Real, Ciudad Real, Spain; () Intensive Care Unit, Hospital Clínico Universitario de Valladolid, Valladolid, Spain; () Intensive Care Unit, Hospital Universitario General de León, León, Spain; () Intensive Care Unit, Complejo Hospitalario Universitario de Albacete, Albacete, Spain; () Department of Surgical Sciences, Anesthesiology & Critical Care, Hedenstierna Laboratory, Uppsala University Hospital, Sweden; () Intensive Care Unit, Hospital Virgen de la Concha, Zamora, Spain; (0) Intensive Care Unit, Hospital Virgen de la Luz, Cuenca, Spain; () Intensive Care Unit, Hospital Universitario La Paz, Madrid, Spain; () Critical Care Center, Corporació Sanitaria Parc Taulí, Sabadell, Spain; () Department of Respiratory Care, Massachusetts General Hospital, Boston, Massachusetts, USA; () Department of Anesthesiology, Harvard University, Boston, Massachusetts, USA. (*) Additional investigators (collaborators) from the SIESTA Network are listed in the Appendix. Corresponding author Jesús Villar, MD, PhD Hospital Universitario Dr. Negrin. Barranco de la Ballena s/n, th floor, South wing. 00 Las Palmas de Gran Canaria. SPAIN. Tel: +() - Fax: +() - jesus.villar@gmail.com Key words: acute respiratory distress syndrome, positive end-expiratory pressure, standard ventilator settings, stratification, classification, risk assessment. Abstract word count: 0 Main Text word count:, - BMJ Open: first published as 0./bmjopen-0-00 on March 0. Downloaded from on January 0 by guest. Protected by copyright.

4 Page of BMJ Open ABSTRACT Introduction: A recent update of the definition of the acute respiratory distress syndrome (ARDS) proposed an empirical classification based on PaO /FiO values at ARDS onset. Since the proposal did not mandate PaO /FiO calculation under standardized ventilator settings, we hypothesized that a stratification based on baseline PaO /FiO would not provide accurate assessment of lung injury severity. Methods: We analyzed data from consecutive patients included in two observational cohort studies with moderate (00<PaO /FiO 00) and severe (PaO /FiO 00) ARDS. Patients were ventilated using a low-tidal volume strategy with positive end-expiratory pressure (PEEP) cmh O. We examined physiologic and ventilator parameters in association with the PaO /FiO at ARDS onset and hours later under a standardized ventilator setting. At hours, patients were reclassified as severe, moderate, mild (00<PaO /FiO 00) ARDS, and non-ards (PaO /FiO >00). Outcomes of interest included group severity and hospital mortality. Results: Overall hospital mortality was.%. At ARDS onset, patients had a PaO /FiO 00 but only.% of them met severe ARDS criteria after hours of usual care. Classification using baseline PaO /FiO did not identify ARDS patients with distinct lung injury severity. When assessed under standardized ventilator settings, most patients (.%) were reclassified as moderate, mild, and non ARDS, while lung severity and hospital mortality changed markedly with every PaO /FiO category (p=.0e-). Conclusions: Baseline PaO /FiO failed to identify subgroups of patients with distinct lung injury severity. Assessment of oxygenation defect under standardized ventilator settings at hours after ARDS onset represents a better method for optimizing risk stratification of ARDS patients. - BMJ Open: first published as 0./bmjopen-0-00 on March 0. Downloaded from on January 0 by guest. Protected by copyright.

5 Page of STRENGTHS OF THIS STUDY. This study demonstrated that baseline PaO /FiO failed to identify subgroups of ARDS patients with distinct characteristics of lung injury severity, as defined by several physiologic and lung mechanics parameters.. This study suggests that appropriate risk stratification of ARDS patients is a two-step process (first meeting the ARDS criteria, then reassessment of PaO /FiO ratio at hours under a standardized ventilator setting.. These findings have potential implications for guiding therapy and for future design of clinical trials. - BMJ Open: first published as 0./bmjopen-0-00 on March 0. Downloaded from on January 0 by guest. Protected by copyright.

6 Page of BMJ Open INTRODUCTION The acute respiratory distress syndrome (ARDS) is an inflammatory process of the lungs resulting in increased permeability and subsequent interstitial and alveolar protein-rich edema.[] ARDS is characterized by severe hypoxemia, reduced lung compliance, and bilateral radiographic pulmonary infiltrates.[,] ARDS patients require mechanical ventilation (MV) with positive endexpiratory pressure (PEEP) for decreasing work of breathing and improving oxygenation. Current hospital mortality approximates 0-0% in major epidemiological series.[,] Since diagnosis is based on a combination of clinical, radiographic and physiologic criteria, these criteria allow the inclusion of a heterogeneous group of patients. The original description of ARDS was incapable of identifying a uniform group of patients.[] A precise definition is crucial since the effects on outcome of MV and adjunctive techniques depend on the degree of lung injury.[] In, an American-European Consensus Conference (AECC)[] formalized the diagnostic criteria for ARDS and acute lung injury (ALI) but these definitions have been challenged over the years.[,] In 0, a proposal for updating the ARDS definition (the Berlin criteria) was published.[0] Three PaO /FiO cut-off values recorded at ARDS onset: severe ( 00 mmhg), moderate (>00-00), and mild (>00-00) were proposed. By considering only patients who were on PEEP cmh O at the time of study enrollment, the panel found that hospital mortality increased with every stage of PaO /FiO severity. Since the Berlin criteria, similar to the AECC criteria, did not mandate the assessment of hypoxemia under standardized ventilator conditions, we hypothesized that baseline PaO /FiO values recorded at ARDS onset would not provide accurate assessment of ARDS severity. To test our hypothesis, we sought to characterize consecutive ARDS patients, most of them enrolled in two published multicenter observational studies,[,] using the Berlin criteria at ARDS onset and reassessed after hours of routine care based on the responses of PaO under standardized levels of PEEP and FiO. - BMJ Open: first published as 0./bmjopen-0-00 on March 0. Downloaded from on January 0 by guest. Protected by copyright.

7 Page of METHODS Data were derived from patients included in two independent, multicenter, observational cohorts that enrolled consecutive patients from 00 to 00 and from 00 to 00 in a network of Spanish intensive care units (ICUs), into a Natural History, Epidemiology, and Stratification of ARDS Study, as described previously.[,] The study was conducted in accordance with the amended Declaration of Helsinki and approved by the Ethics Committees at the coordinating centers [Hospital Universitario NS de Candelaria, Tenerife, Spain (#00/), Hospital Universitario Dr. Negrín, Las Palmas, Spain (#00/0), and Hospital Virgen de La Luz, Cuenca, Spain (#00/0)]. Study subjects Patients meeting criteria for ARDS using the AECC definition[] were considered for enrollment in the parent studies.[,] Since all patients were on PEEP at study entry, they also met the recent Berlin criteria for moderate and severe ARDS.[0] Although patient care was not strictly protocolized, physicians were asked to follow current standards for critical care management. For ventilatory management, it was recommended that patients be ventilated with a tidal volume (VT) of - ml/kg predicted body weight (PBW), at a ventilatory rate to maintain PaCO at -0 mmhg, a plateau pressure <0 cmh O, and PEEP and FiO combinations to maintain PaO >0 mmhg or SpO >0%. During the enrollment period, none of the patients were included in any other clinical trial or managed with prone ventilation, high frequency ventilation, or extracorporeal life support. For the present study, onset of ARDS was defined as the day and time in which the patient first met ARDS criteria. Demographics, arterial blood gases, radiographic, hemodynamic, and ventilator data were collected at study entry, at hours, at days,,, and last day of MV. Organ failure was documented daily. Patients were followed-up until hospital death or discharge. Approximately hours after meeting moderate/severe ARDS criteria, oxygenation was assessed under the following standardized ventilator settings: VT= ml/kg PBW, PEEP=0 cmh O and FiO =0.. When patients required PEEP>0 or FiO >0. and could not tolerate a decrease in PEEP or FiO for maintaining the oxygenation target, a set of rules for setting PEEP and FiO were applied only during - BMJ Open: first published as 0./bmjopen-0-00 on March 0. Downloaded from on January 0 by guest. Protected by copyright.

8 Page of BMJ Open the standardized setting assessment (Table ). At other times, the PEEP and FiO levels were up to the discretion of the managing clinician. Blood gases were obtained 0 min after the setting adjustment. Based on the PaO /FiO ratio at study entry, patients were categorized as moderate or severe ARDS according to the Berlin criteria. Based on PaO /FiO values at hours under standardized ventilator settings, patients were reclassified into four groups: severe ARDS (PaO /FiO 00 mmhg), moderate ARDS (00<PaO /FiO 00), mild ARDS (00<PaO /FiO 00), and non-ards (PaO /FiO >00). Outcome data We sought to determine whether the use of the baseline PaO /FiO for stratifying patients at ARDS onset results in the identification of subgroups of patients with a distinct degree of lung injury. We also examined whether patients categorized as severe ARDS based on their baseline PaO /FiO could evolve to less severe forms of lung injury after hours of usual care. In addition, we determined whether the stratification of patients using standardized ventilator settings could identify groups of patients for each PaO /FiO category with different lung injury severity score,[] ventilator-free days (VFDs), extrapulmonary organ failures included in the SOFA scale,[] hospital mortality, and cause of death (pulmonary/non-pulmonary). Statistical analysis Data are expressed as percentage, mean±sd, or median and interquartile range (IQR). Differences between categorical variables were analyzed by χ or Fisher s exact tests. For continuous variables, data were analyzed using the t-test, analysis of variance (ANOVA), Mann-Witney or the Kruskall-Wallis tests, depending on their distribution and number of variables. To assess the agreement of patient classification between baseline (Berlin criteria) and the stratification at hours under standardized ventilator settings, the Cohen s kappa coefficient (κ) was calculated for severe and moderate ARDS. A p-value <0.0 was considered statistically significant (two-tailed). All statistical analyses were conducted using SPSS v BMJ Open: first published as 0./bmjopen-0-00 on March 0. Downloaded from on January 0 by guest. Protected by copyright.

9 Page of RESULTS Although the published parent studies enrolled patients, the present study included additional patients that had been enrolled at the time of finalization of both observational periods and were followed-up until hospital discharge. Thus, the present analysis included a total of ARDS patients with complete data. Baseline characteristics of patients are displayed in Table. Pneumonia, sepsis and trauma were the most common causes of ARDS. No significant differences were found in ventilation and oxygenation parameters at study entry between survivors and non-survivors, although non-survivors were older, had a higher APACHE II score and more organ dysfunctions (Table ). The overall hospital mortality was.% (%CI:.-.%). At study entry, most patients (0/,.%) had a baseline PaO /FiO >00 mmhg but their FiO and PEEP levels varied widely ranging from 0. to.0 and from to 0 cmh O, respectively. Although patients initially categorized as severe ARDS had a higher overall hospital mortality than patients classified as moderate ARDS: / (.%, %CI:.-.%) vs. 0/0 (.%, %CI: 0.-.%) (p=0.00), there were no statistical differences in the number of pulmonary deaths between severe and moderate ARDS: / (.0%) vs. /0.%), respectively (p=0.). Of note, there were no significant differences in lung injury score, PEEP, VT, number of failing organs, and VFDs between severe and moderate ARDS when patients were classified using baseline PaO /FiO (Table ). Despite patients had a PaO /FiO 00 mmhg at ARDS onset, only.% of them maintained the PaO /FiO 00 mmhg when assessed at hours under standardized ventilator settings (Figure ). Most patients diagnosed as severe ARDS by the Berlin criteria (0/,.%) were reclassified as moderate, mild and non-ards when assessed after h of routine care. Only (.%) patients could not have their PEEP or FiO level decreased to 0 cmh O and 0. at the time of assessment, and their assignment was based on the PaO /FiO value under the clinicianselected PEEP and FiO settings. Cohen s kappa analysis showed a very high disagreement between patient s classification using Berlin criteria and assessment at h: κ=0.0 for moderate ARDS and - BMJ Open: first published as 0./bmjopen-0-00 on March 0. Downloaded from on January 0 by guest. Protected by copyright.

10 Page of BMJ Open κ=0. for severe ARDS. Of note,.% (/) of patients categorized as severe or moderate ARDS progressed with usual care to mild ARDS or non-ards, while.% (/0) of patients categorized as moderate ARDS by Berlin criteria progressed to severe ARDS within h. Significant differences for lung injury score, PEEP, plateau pressure, number of failing organs, and VFDs were found in each category (Table ). Patients who evolved to non-ards were significantly younger than the other categories. Hospital mortality decreased. to.-fold with every stage of PaO /FiO severity. The lower the PaO /FiO category, the higher the hospital mortality: /0 (%, %CI.-.%) vs. 0/ (.%, %CI.-.%) vs. /0 (.%, %CI.-.%) vs. / (.%, %CI.-0%) for severe, moderate, mild and non-ards categories, respectively (p=.0e- ). When using assessment at h, the number of pulmonary deaths in each subgroup increased with every increasing stage of PaO /FiO severity: 0% (0/) vs..% (/) vs..% (/0) vs. 0.% (/), for non-ards and for mild, moderate, and severe ARDS, respectively (p for trend <0.000). - BMJ Open: first published as 0./bmjopen-0-00 on March 0. Downloaded from on January 0 by guest. Protected by copyright.

11 Page 0 of DISCUSSION Our present investigation in a large population of consecutive patients with moderate and severe ARDS who were managed with a low tidal volume strategy in the context of two observational studies revealed that: (i) the value of PaO /FiO ratio at the time of ARDS diagnosis failed to identify homogeneous subgroups of lung injured patients, and (ii) a standardized method based on preset PEEP and FiO levels is more precise in assessing risk stratification of severity and outcome of ARDS. Our study suggests that patients within an identical PaO /FiO range at baseline may not have similar degrees of lung injury or prognosis. If assessment of ARDS severity is of crucial importance, it should be appropriate to set standardized rules for quantifying the severity of lung injury. The Berlin proposal of using the value of PaO /FiO at the time of ARDS onset does not mandate standardization of PEEP and FiO levels. The baseline PaO /FiO is generally calculated under a wide range of applied PEEP and FiO and can be easily manipulated by changing PEEP and FiO. Thus, if the measurement of PaO is not standardized, the calculated PaO /FiO may mask the severity of the underlying lung pathology in a substantial proportion of patients. Although baseline PEEP could not predict outcome,[,]baseline FiO does predict mortality.[,] The key issue unmasked by our analyses is that many patients with severe lung disease evolve with usual care to less severe forms of lung injury within hours while others evolve to more severe forms of ARDS, as clearly demonstrated by the lack of concordance between the Berlin criteria and data at hours. Our findings have implications for clinical trials design and patient enrollment. Acute lung injury has a range of severity from mild pulmonary insult to full blown ARDS. The assessment of PaO /FiO at hours after ARDS diagnosis on standardized ventilator settings can be used to insure a more homogeneous distribution of patients by disease severity. As our data suggest, the use of the Berlin criteria is inadequate for enrolling patients with similar degree of lung injury into clinical trials. The use of baseline PaO /FiO for fast enrollment into therapeutic clinical trials may be responsible for patient selection bias as a treatment that might benefit a subgroup of ARDS patients is also tested - BMJ Open: first published as 0./bmjopen-0-00 on March 0. Downloaded from on January 0 by guest. Protected by copyright.

12 Page of BMJ Open in patients who are unresponsive to the experimental treatment. Some clinicians are concerned about a mandatory waiting period for reassessment of oxygenation before enrolling ARDS patients into clinical trials.[] However, all trials performed to date in ARDS have enrolled patients within - h of ARDS onset[-]and up to days after meeting the AECC criteria.[,] If patients in a trial have a low risk of the condition that the intervention is hypothesized to prevent, the trial will not demonstrate the efficacy of the intervention, regardless of the trial size.[] Stratification of enrolled patients can reduce the necessary sample size, since it makes larger treatment effects easier to detect.[] That could explain why only one randomized controlled trial in ARDS patients has been positive[] since the publication of the ARDSnet trial. In that study, only patients with a PaO /FiO threshold that persisted after - hours under a specific level of PEEP and FiO were enrolled. Recent high-frequency ventilation trialshave been either ineffective or worse than usual care,[,] potentially due to a patient selection bias: both trials enrolled patients based on baseline PaO /FiO. These trials support the importance of PaO /FiO assessment after hours of making the initial diagnosis of ARDS. If severe ARDS is characterized by profound hypoxemia that responds to traditional management, our findings demonstrated that a high rate of misclassification occurred because patients were not reassessed after hours of usual care when many patients responded to a stepwise escalation of traditional therapies. If patients are identified as severe ARDS by the Berlin criteria only, 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 hours of usual care a high percentage of patients have milder forms of ARDS. We would recommend attempting to enrol patients who met the Berlin definition at ARDS onset but only randomizing those patients who sustained the desired level of injury at hours after onset while on standardized ventilator settings. In an attempt to validate the modification of the AECC ARDS definition by the Berlin criteria, Hernu et al[0] and Caser et al[] found that neither definition was able to identify homogeneous groups with different levels of lung injury based on non-standardized baseline PaO /FiO values. Those studies reported that the Berlin criteria were incapable of separating patients into distinct BMJ Open: first published as 0./bmjopen-0-00 on March 0. Downloaded from on January 0 by guest. Protected by copyright.

13 Page of categories of severity with significantly different mortalities. Furthermore, a recent autopsy study revealed that the Berlin criteria did not correlate with the presence of diffuse alveolar damage in more than 0% of patients categorized as moderate and severe ARDS.[] However, this correlation improved significantly only when patients met PaO /FiO criteria beyond h of persistence of ARDS criteria. Despite that changes in the applied FiO and PEEP induces profound variations in PaO /FiO,[,] by leaving the assessment of PaO /FiO criteria essentially unchanged, the AECC definition and the Berlin criteria are essentially identical.[,] The requirement of a minimum PEEP level of cmh O has no impact on the definition[] since it is hard to conceive that an ARDS patient would be managed with PEEP< cmh O.[] There is a limitation to this study. Although we did not enroll patients with mild ARDS under the Berlin criteria (PaO /FiO >00), we do not believe that the exclusion of these patients weakens our results. Patients meeting criteria for mild ARDS constitutes a very heterogeneous group of patients that are usually underdiagnosed, representing a case-mix in which many of them do not require endotracheal intubation and invasive MV. Also, since PaO /FiO values in patients under noninvasive MV are not comparable with those on conventional MV, it is not clear whether patients meeting criteria for mild ARDS on noninvasive ventilation would meet those criteria after intubation and conventional MV. However, we are confident that no patients with mild ARDS were excluded during our observational periods if they moved to a more severe category, although we do not have data on the precise number of these patients. In conclusion, the stratification of ARDS patients based on the value of PaO /FiO ratio at the time of ARDS diagnosis, as proposed by the Berlin criteria, is not useful for assessing severity of lung injury and for enrolling appropriate ARDS patients into clinical trials. Assessment of ARDS should be a two-step process. The initial assessment at ARDS onset followed by a second assessment at hours under standardized ventilator settings represents a better method for optimizing risk stratification of ARDS patients. Since there is no biomarker that identifies patients as having ARDS nor identifies the severity of illness, we must continue to search for methods to better define and stratify ARDS. - BMJ Open: first published as 0./bmjopen-0-00 on March 0. Downloaded from on January 0 by guest. Protected by copyright.

14 Page of BMJ Open ACKNOWLEDGMENTS Contributors: JV and RMK contributed to the initial study concept and design. JB, RD, DAO, FJDD, AM, VC, FSS, CT, EGH, JL, LB, and RLF contributed to the final study design. JB, RD, DAO, FJDD, AM, VC, FSS, CT, EGH, JL, and LB contributed with data collection. JV, RLF, and RMK analyzed and interpreted the data. RLF and JV performed the statistical analysis. JV and RMK drafted the article and all other authors critically revised it for important intellectual content. JV and RLF had full access to all the data in the study, and take responsibility for the integrity of the data and the accuracy of the data analyses. All authors gave final approval of the manuscript version to be published. Funding: JV obtained grants from the Instituto de Salud Carlos III, Madrid, Spain (PI 0/0, PI0/0, CB0/0/0) and Asociación Científica Pulmón y Ventilación Mecánica, Las Palmas, Spain. All researchers are independent of the funding bodies. The funding bodies had no role in the study design; in the data collection, analysis and interpretation of data; in the writing of the manuscript; and in the decision to submit the manuscript for publication. Competing interest: Jesús Villar has received research grants from Maquet. Robert Kacmarek is a consultant for Covidien and has received honorarium from Maquet for lecturing. None of the other authors has financial or personal relationships or affiliations to report that could directly influence the content of this work and manuscript. Ethical approval: This study was approved by the Ethics Committees for Clinical Research of Hospital Universitario NS de Candelaria (Tenerife, Spain), Hospital Universitario Dr. Negrín (Las Palmas de Gran Canaria, Spain), and Hospital Virgen de La Luz (Cuenca, Spain), and all other institutional review boards of participating study sites. Data Sharing: No additional data are available. - BMJ Open: first published as 0./bmjopen-0-00 on March 0. Downloaded from on January 0 by guest. Protected by copyright.

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17 Page of Mercat A, Richard JC, Vielle B, et al. Positive end-expiratory pressure setting in adults with acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. JAMA 00;:-.. Mancebo J, Fernández R, Blanch L, et al. A multicenter trial of prolonged prone ventilation in severe acute respiratory distress syndrome. Am J Respir Crit Care Med 00;:-.. Peek GJ, Mugford M, Tiruvoipati R, et al. Efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR): a multicentre randomised controlled trial. Lancet 00;:-.. Villar J, Kacmarek RM, Guérin C. Clinical trials in patients with the acute respiratory distress syndrome: burn after reading. Intensive Care Med 0;0:00-.. Eichler HG, Pétavy F, Pignatti F, et al. Access to patient-level trial data -A boon to drug developers. N Engl J Med 0;:-.. Guérin C, Reignier J, Richard JC, et al. Prone positioning in severe acute respiratory distress syndrome. N Engl J Med 0;:-.. Young D, Lamb SF, Shah S, et al. High-frequency oscillation for acute respiratory distress syndrome. N Engl J Med 0;:0-.. Ferguson ND, Cook DJ, Guyatt GH, et al. High-frequency oscillation in early acute respiratory distress syndrome. N Engl J Med 0;: Hernu R, Wallet F, Thiollière F, et al. 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 0;:-0.. 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, patients. Crit Care Med 0;:-.. Thille AW, Esteban A, Fernández-Segoviano P, et al. Comparison of the Berlin definition for acute respiratory distress syndrome with autopsy. Am J Respir Crit Care Med 0;: BMJ Open: first published as 0./bmjopen-0-00 on March 0. Downloaded from on January 0 by guest. Protected by copyright.

18 Page of BMJ Open Karbing DS, Kjaergaard S, Smith BW, et al. Variation in the PaO /FiO ratio with FiO : mathematical and experimental description, and clinical relevance. Crit Care 00;:R.. Phillips CR. The Berlin definition: real change or the emperor s new clothes? Crit Care 0;:. - BMJ Open: first published as 0./bmjopen-0-00 on March 0. Downloaded from on January 0 by guest. Protected by copyright.

19 Page of APPENDIX Additional list of investigators in the Spanish Initiative for Epidemiology, Stratification and Therapies for ARDS (SIESTA) Network: José López, Demetrio Carriedo, Ana María Domínguez (Hospital General de León, León); Javier Belda, Gerardo Aguilar, Francisco Martí, Armando Maruenda (Hospital Clínico de Valencia, Valencia); José M. Añón, María J. Bruscas (Hospital Virgen de la Luz, Cuenca); Iñaki Saralegui (Hospital Santiago Apóstol, Vitoria); Santiago Lubillo, Lina Pérez-Méndez (Hospital Universitario N.S. de Candelaria, Tenerife); Dario Toral (Hospital Universitario de Octubre, Madrid); Miguel A. Romera (Hospital Universitario Puerta de Hierro, Madrid); Antonio Santos-Bouza (Hospitales Universitarios de Santiago, Santiago de Compostela); Eli Zavala, Ramón Adalia (Hospital Clinic, Barcelona); Frutos del Nogal (Hospital Severo Ochoa, Madrid); Luís Ramos (Hospital General de La Palma, La Palma); Gumersindo González-Díaz, Antonia López-Martínez (Hospital Morales Meseguer, Murcia); Santiago Macías, Noelia Lázaro (Hospital General de Segovia, Segovia); Francisco Gandía, David Andaluz, Laura Parra (Hospital Clínico Universitario de Valladolid, Valladolid); Javier Collado, José I. Alonso (Hospital Río Carrión, Palencia); Antonio Álvarez (Hospital Virgen de la Concha, Zamora); Noelia Albalá, Ángel Rodríguez-Encinas (Hospital Clínico de Salamanca, Salamanca); Raúl Sánchez, Fabiola Tena (Hospital General de Soria, Soria); Alberto Indarte, María E. Perea (Hospital General Yagüe, Burgos); Fernando Mosteiro (Complejo Hospitalario Universitario de La Coruña, La Coruña); Eleuterio Merayo (Complejo Hospitalario de Orense, Orense); Alfonso Ambrós (Hospital General de Ciudad Real, Ciudad Real); José Manuel Gutiérrez (Complejo Hospitalario Universitario de Albacete, Albacete); Francisca Prieto (Hospital Santa Bárbara, Puertollano, Ciudad Real); Ricardo Fernández, José Ignacio Lozano (Hospital de Hellín, Albacete); Antonio García, Carmen Martín (Hospital La Mancha Centro, Alcázar de San Juan, Ciudad Real); Lluís Blanch, Gemma Gomá, Gisela Gili (Corporació Sanitaria Parc Taulí, Sabadell, Barcelona); Jesús Villar, Rosa Lidia Fernández (Hospital Universitario Dr. Negrin, Las Palmas de Gran Canaria); Robert M. Kacmarek (Massachusetts General Hospital, Boston, MA, USA). - BMJ Open: first published as 0./bmjopen-0-00 on March 0. Downloaded from on January 0 by guest. Protected by copyright.

20 Page of BMJ Open Table. Rules for setting PEEP and FiO during assessment on standardized settings at hours of ARDS diagnosis. PEEP level before changing cmh O PEEP setting for assessment to standardized settings 0 cmh O 0 cmh O >0 and < cmh O Set at 0 cmh O, unless SpO <%. Then returned to previous level. Maintain current level and assess. FiO level before changing FiO setting for assessment to standardized settings 0. >0. and 0. Set at 0., unless SpO <%. Then, returned to previous level. >0. 0. Maintain current level and assess. ARDS: acute respiratory distress syndrome; PEEP: positive end-expiratory pressure - BMJ Open: first published as 0./bmjopen-0-00 on March 0. Downloaded from on January 0 by guest. Protected by copyright.

21 Page 0 of TABLE. Demographics, physiologic and clinical parameters at study entry in patients with moderate/severe acute respiratory distress syndrome (ARDS). Variable Values Age, yrs, median (IQR) (0-0) APACHE II score ± Lung injury score. ± 0. Tidal volume, ml/kg PBW. ±. PEEP, cmh O ± Plateau pressure, cmh O. ± FiO 0. ± 0. PaO /FiO, mmhg ± PaCO, mmhg ± Causes of ARDS, n (%) Pneumonia Sepsis Trauma Aspiration pneumonia Others (.) (0.) 0 (.) 0 (.) (.) Number of organ failure. ±. Hospital mortality, n (%) 0 (.) IQR: interquartile range; PEEP: positive end-expiratory pressure; PBW: predicted body weight. - BMJ Open: first published as 0./bmjopen-0-00 on March 0. Downloaded from on January 0 by guest. Protected by copyright.

22 Page of BMJ Open TABLE. Baseline characteristics of survivors and non-survivors with the acute respiratory distress syndrome (ARDS). Variables Survivors Values Non-survivors N= N=0 p-value APACHE II ± ± <0.000 Age, yrs, median (IQR) (-) (0-) <0.000 Gender, number males/females / / NS VT, ml/kg PBW, mean±sd. ±.. ±. NS Plateau pressure, cmh O, mean±sd ± ± NS PEEP, cmh O, mean±sd ± ± NS FiO, mean±sd 0. ± ± 0.0 NS PaO /FiO, mean±sd 0 ± ± NS No. Organ failure, mean±sd. ±.0. ± Causes of ARDS Pulmonary Non-pulmonary IQR: interquartile range; PBW: predicted body weight; PEEP: positive end-expiratory pressure; PBW: predicted body weight; SD: standard deviation; VT: tidal volume NS BMJ Open: first published as 0./bmjopen-0-00 on March 0. Downloaded from on January 0 by guest. Protected by copyright.

23 Page of TABLE. Demographics, physiological and clinical parameters of patients with the acute respiratory distress syndrome (ARDS) categorized by the Berlin criteria (baseline PaO /FiO ). Parameters patients with moderate and severe ARDS (Berlin criteria) Severe n= Moderate n=0 p-value Age, yr, median (IQR) (-) (-) NS Lung injury score.0±0..±0. NS PEEP, cmh O 0± ± NS V T, ml/kg PBW.±..±. NS Pplat, cmh O ±.± <0.0 FiO 0.±0. 0.±0. <0.000 PaO /FiO, mmhg ± ± <0.000 No. organ failures.±..±. NS VFDs, days.± ± NS Hospital mortality, n (%) (.) 0 (.) 0.00 Pulmonary deaths, n (%) () (.) 0. IQR: interquartile range; MV: mechanical ventilation; NS: non-significant; PBW: predicted body weight; Pplat: plateau pressure; VFDs: ventilator-free days. - BMJ Open: first published as 0./bmjopen-0-00 on March 0. Downloaded from on January 0 by guest. Protected by copyright.

24 Page of BMJ Open TABLE. Demographics, physiological and clinical parameters of patients with the acute respiratory distress syndrome (ARDS) at hours of ARDS onset after being categorized by assessment of PaO /FiO on PEEP 0 cmh O with FiO 0.. Parameters Classification at h under standardized ventilator settings severe n=0 moderate n= mild n=0 Non ARDS p n= Age, yr, median (IQR) (-) (-) (-0) (-) 0.0 Lung injury score.±0..0±0..±0..±0. <0.000 PEEP, cmh O ± ± 0± ± <0.000 VT, ml/kg PBW.0±..0±..±..±. NS Pplat, cmh O ± ± ± ± <0.000 FiO 0.±0.0 0.±0. 0.±0. 0.±0.0 <0.000 PaO /FiO, mmhg ± ± ± ±0 <0.000 No. organ failure.±..±..±..0±. <0.000 VFDs, days ± ± ± ± <0.000 Hospital mortality, n (%) () 0 (.) (.) (.) < Pulmonary deaths, n (%) (0.) (.) (.) 0 (0) <0.000 IQR: interquartile range; MV: mechanical ventilation; NS: non-significant; PBW: predicted body weight; Pplat: Plateau pressure; VFDs: ventilator-free days. - BMJ Open: first published as 0./bmjopen-0-00 on March 0. Downloaded from on January 0 by guest. Protected by copyright.

25 Page of FIGURE LEGEND FIGURE : Flow diagram of the study. AECC: American-European Consensus Conference; ARDS: acute respiratory distress syndrome. PaO /FiO : ratio of arterial partial pressure of oxygen to fraction of inspired oxygen; PEEP: positive end-expiratory pressure. - BMJ Open: first published as 0./bmjopen-0-00 on March 0. Downloaded from on January 0 by guest. Protected by copyright.

26 Page of BMJ Open Flow diagram of the study. xmm (00 x 00 DPI) - BMJ Open: first published as 0./bmjopen-0-00 on March 0. Downloaded from on January 0 by guest. Protected by copyright.

27 Page of APPENDIX Additional list of investigators in the Spanish Initiative for Epidemiology, Stratification and Therapies for ARDS (SIESTA) Network: José López, Demetrio Carriedo, Ana María Domínguez (Hospital General de León, León); Javier Belda, Gerardo Aguilar, Francisco Martí, Armando Maruenda (Hospital Clínico de Valencia, Valencia); José M. Añón, María J. Bruscas (Hospital Virgen de la Luz, Cuenca); Iñaki Saralegui (Hospital Santiago Apóstol, Vitoria); Santiago Lubillo, Lina Pérez-Méndez (Hospital Universitario N.S. de Candelaria, Tenerife); Dario Toral (Hospital Universitario de Octubre, Madrid); Miguel A. Romera (Hospital Universitario Puerta de Hierro, Madrid); Antonio Santos-Bouza (Hospitales Universitarios de Santiago, Santiago de Compostela); Eli Zavala, Ramón Adalia (Hospital Clinic, Barcelona); Frutos del Nogal (Hospital Severo Ochoa, Madrid); Luís Ramos (Hospital General de La Palma, La Palma); Gumersindo González-Díaz, Antonia López-Martínez (Hospital Morales Meseguer, Murcia); Santiago Macías, Noelia Lázaro (Hospital General de Segovia, Segovia); Francisco Gandía, David Andaluz, Laura Parra (Hospital Clínico Universitario de Valladolid, Valladolid); Javier Collado, José I. Alonso (Hospital Río Carrión, Palencia); Antonio Álvarez (Hospital Virgen de la Concha, Zamora); Noelia Albalá, Ángel Rodríguez-Encinas (Hospital Clínico de Salamanca, Salamanca); Raúl Sánchez, Fabiola Tena (Hospital General de Soria, Soria); Alberto Indarte, María E. Perea (Hospital General Yagüe, Burgos); Fernando Mosteiro (Complejo Hospitalario Universitario de La Coruña, La Coruña); Eleuterio Merayo (Complejo Hospitalario de Orense, Orense); Alfonso Ambrós (Hospital General de Ciudad Real, Ciudad Real); José Manuel Gutiérrez (Complejo Hospitalario Universitario de Albacete, Albacete); Francisca Prieto (Hospital Santa Bárbara, Puertollano, Ciudad Real); Ricardo Fernández, José Ignacio Lozano (Hospital de Hellín, Albacete); Antonio García, Carmen Martín (Hospital La Mancha Centro, Alcázar de San Juan, Ciudad Real); Lluís Blanch, Gemma Gomá, Gisela Gili (Corporació Sanitaria Parc Taulí, Sabadell, Barcelona); Jesús Villar, Rosa Lidia Fernández (Hospital Universitario Dr. Negrin, Las Palmas de Gran Canaria); Robert M. Kacmarek (Massachusetts General Hospital, Boston, MA, USA). - BMJ Open: first published as 0./bmjopen-0-00 on March 0. Downloaded from on January 0 by guest. Protected by copyright.

28 Page of BMJ Open STROBE Statement Checklist of items that should be included in reports of cohort studies Baseline PaO /FiO at the time of ARDS diagnosis failed to identify subgroups of patients with distinct lung injury severity Item No Recommendation Title and abstract (a) Indicate the study s design with a commonly used term in the title or the abstract Introduction (Page ) (b) Provide in the abstract an informative and balanced summary of what was done and what was found (Page ) Background/rationale Explain the scientific background and rationale for the investigation being reported (page ) Objectives State specific objectives, including any prespecified hypotheses (page ) Methods Study design Present key elements of study design early in the paper (pages & ) Setting Describe the setting, locations, and relevant dates, including periods of recruitment, exposure, follow-up, and data collection (page ) Participants (a) Give the eligibility criteria, and the sources and methods of selection of participants. Describe methods of follow-up (page ) (b) For matched studies, give matching criteria and number of exposed and unexposed (not applicable) Variables Clearly define all outcomes, exposures, predictors, potential confounders, and effect Data sources/ measurement modifiers. Give diagnostic criteria, if applicable (page ) * For each variable of interest, give sources of data and details of methods of assessment (measurement). Describe comparability of assessment methods if there is more than one group (pages & ) Bias Describe any efforts to address potential sources of bias (page ) Study size 0 Explain how the study size was arrived at (not applicable) Quantitative variables Explain how quantitative variables were handled in the analyses. If applicable, describe which groupings were chosen and why (pages & ) Statistical methods (a) Describe all statistical methods, including those used to control for confounding Results (page ) (b) Describe any methods used to examine subgroups and interactions (page ) (c) Explain how missing data were addressed (not applicable) (d) If applicable, explain how loss to follow-up was addressed (e) Describe any sensitivity analyses (page ) Participants * (a) Report numbers of individuals at each stage of study eg numbers potentially eligible, examined for eligibility, confirmed eligible, included in the study, completing follow-up, and analysed (pages & ) (b) Give reasons for non-participation at each stage (not applicable) (c) Consider use of a flow diagram (Figure ) Descriptive data * (a) Give characteristics of study participants (eg demographic, clinical, social) and information on exposures and potential confounders (pages & ) (b) Indicate number of participants with missing data for each variable of interest (not applicable) (c) Summarise follow-up time (eg, average and total amount) (pages & ) - BMJ Open: first published as 0./bmjopen-0-00 on March 0. Downloaded from on January 0 by guest. Protected by copyright.

29 Page of Outcome data * Report numbers of outcome events or summary measures over time (pages & ) Main results (a) Give unadjusted estimates and, if applicable, confounder-adjusted estimates and their precision (eg, % confidence interval) (pages & ). Make clear which confounders were adjusted for and why they were included (not applicable) (b) Report category boundaries when continuous variables were categorized (Tables) (c) If relevant, consider translating estimates of relative risk into absolute risk for a meaningful time period Other analyses Report other analyses done eg analyses of subgroups and interactions, and sensitivity analyses (pages & ) Discussion Key results Summarise key results with reference to study objectives (page ) Limitations Discuss limitations of the study, taking into account sources of potential bias or imprecision. Discuss both direction and magnitude of any potential bias (page ) Interpretation 0 Give a cautious overall interpretation of results considering objectives, limitations, multiplicity of analyses, results from similar studies, and other relevant evidence (pages, 0, ) Generalisability Discuss the generalisability (external validity) of the study results (pages 0,) Other information Funding Give the source of funding and the role of the funders for the present study and, if applicable, for the original study on which the present article is based (acknowledgments page) *Give information separately for exposed and unexposed groups (not applicable). - BMJ Open: first published as 0./bmjopen-0-00 on March 0. Downloaded from on January 0 by guest. Protected by copyright.