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Is Overall Mortality the Right Composite Endpoint in Clinical Trials of Acute Respiratory Distress Syndrome?*

Villar, Jesús, MD, PhD, FCCM1,2; Martínez, Domingo, MD3; Mosteiro, Fernando, MD4; Ambrós, Alfonso, MD, PhD5; Añón, José M., MD, PhD1,6; Ferrando, Carlos, MD, PhD1,7; Soler, Juan A., MD, PhD3; Montiel, Raquel, MD8; Vidal, Anxela, MD9; Conesa-Cayuela, Luís A., MD3; Blanco, Jesús, MD, PhD1,10; Arrojo, Regina, MD4; Solano, Rosario, MD, PhD11; Capilla, Lucía, MD12; del Campo, Rafael, MD5; Civantos, Belén, MD6; Fernández, María Mar, MD, PhD13; Aldecoa, César, MD, PhD14; Parra, Laura, MD15; Gutiérrez, Andrea, MD7; Martínez-Jiménez, Chanel, MD16; González-Martín, Jesús M., PhD17; Fernández, Rosa L., MSc1,2; Kacmarek, Robert M., PhD, RTT18,19 for the Stratification and Outcome of Acute Respiratory Distress Syndrome (STANDARDS) Network

doi: 10.1097/CCM.0000000000003022
Clinical Investigations

Objectives: Overall mortality in patients with acute respiratory distress syndrome is a composite endpoint because it includes death from multiple causes. In most acute respiratory distress syndrome trials, it is unknown whether reported deaths are due to acute respiratory distress syndrome or the underlying disease, unrelated to the specific intervention tested. We investigated the causes of death after contracting acute respiratory distress syndrome in a large cohort.

Design: A secondary analysis from three prospective, multicenter, observational studies.

Setting: A network of multidisciplinary ICUs.

Patients: We studied 778 patients with moderate-to-severe acute respiratory distress syndrome treated with lung-protective ventilation.

Interventions: None.

Measurements and Main Results: We examined death in the ICU from individual causes. Overall ICU mortality was 38.8% (95% CI, 35.4–42.3). Causes of acute respiratory distress syndrome modified the risk of death. Twenty-three percent of deaths occurred from refractory hypoxemia due to nonresolving acute respiratory distress syndrome. Most patients died from causes unrelated to acute respiratory distress syndrome: 48.7% of nonsurvivors died from multisystem organ failure, and cancer or brain injury was involved in 37.1% of deaths. When quantifying the true burden of acute respiratory distress syndrome outcome, we identified 506 patients (65.0%) with one or more exclusion criteria for enrollment into current interventional trials. Overall ICU mortality of the “trial cohort” (21.3%) was markedly lower than the parent cohort (relative risk, 0.55; 95% CI, 0.43–0.70; p < 0.000001).

Conclusions: Most deaths in acute respiratory distress syndrome patients are not directly related to lung damage but to extrapulmonary multisystem organ failure. It would be challenging to prove that specific lung-directed therapies have an effect on overall survival.

1CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain.

2Research Unit, Hospital Universitario Dr. Negrín, Las Palmas de Gran Canaria, Spain.

3Intensive Care Unit, Hospital Universitario Virgen de Arrixaca, Murcia, Spain.

4Intensive Care Unit, Hospital Universitario de La Coruña, La Coruña, Spain.

5Intensive Care Unit, Hospital General de Ciudad Real, Ciudad Real, Spain.

6Intensive Care Unit, Hospital Universitario La Paz, IdiPAZ, Madrid, Spain.

7Department of Anesthesiology, Hospital Clínico Universitario de Valencia, Valencia, Spain.

8Intensive Care Unit, Hospital Universitario NS de Candelaria, Santa Cruz de Tenerife, Spain.

9Intensive Care Unit, Hospital Fundación Jiménez Díaz, Madrid, Spain.

10Intensive Care Unit, Hospital Universitario Río Hortega, Valladolid, Spain.

11Intensive Care Unit, Hospital Virgen de la Luz, Cuenca, Spain.

12Intensive Care Unit, Hospital Universitario Morales Meseguer, Murcia, Spain.

13Intensive Care Unit, Hospital Universitario Mutua de Terrasa, Terrasa, Barcelona, Spain.

14Department of Anesthesiology, Hospital Universitario Río Hortega, Valladolid, Spain.

15Intensive Care Unit, Hospital Clínico Universitario de Valladolid, Valladolid, Spain.

16Intensive Care Unit, Hospital del Bierzo, Ponferrada, León, Spain.

17Department of Biostatistics, Research Unit, Hospital Universitario Dr. Negrín, Las Palmas de Gran Canaria, Spain.

18Department of Respiratory Care, Massachusetts General Hospital, Boston, MA.

19Department of Anesthesia, Harvard University, Boston, MA.

*See also p. 1013.

This study is registered with (NCT00435110, NCT00736892, NCT02288949).

Drs. Villar and Kacmarek designed the original study. Drs. Martínez, Mosteiro, Ambrós, Añón, Ferrando, Soler, Montiel, Vidal, Conesa-Cayuela, Blanco, Arrojo, Solano, Capilla, del Campo, Civantos, Fernández, Aldecoa, Parra, Gutierrez, and Martínez-Jiménez enrolled patients and collected the data. Dr. Villar obtained funding for the study. Drs. Villar, Martínez, Mosteiro, Ambrós, Añón, Ferrando, Soler, Montiel, Vidal, Conesa-Cayuela, Blanco, Arrojo, Solano, Capilla, del Campo, Civantos, Fernández, Aldecoa, Parra, Gutierrez, Martínez-Jiménez, González-Martín, Ms. Fernández, and Kacmarek made substantial contributions to conception and design or acquisition of data or analysis and interpretation of data; drafting the article or revising it for important intellectual content; and approved the final version. Drs. Villar, Ms. Fernández, and Kacmarek wrote the first draft. Drs. Villar, González-Martín, Ms. Fernández, and Kacmarek performed and supervised data management and statistical analysis. Drs. Villar, González-Martín, and Ms. Fernández 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 analysis.

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Supported, in part, by Instituto de Salud Carlos III (CB06/06/1088, PI10/0393, PI13/0119, PI16/00049) and Asociación Científica Pulmón y Ventilación Mecánica. The funding agencies had no role in the study design, data collection and analysis, decision to publish, or preparation of the article.

Dr. Villar has received a research grant from Maquet. Dr. Kacmarek served as a consultant for Medtronic, Teleflex, and Orange Med and received research grants from Covidien and Venner Medical. The remaining authors have disclosed that they do not have any potential conflicts of interest.

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