Influence of Clinical Factors and Exclusion Criteria on Mortality in ARDS Observational Studies and Randomized Controlled Trials

Abstract

ARDS has a high mortality in the acute setting, with long-term disability among disease survivors. In 1967, David Ashbaugh and colleagues first described the clinical features of ARDS, which were notably similar to the infantile respiratory distress syndrome. Half a century later, ARDS remains underrecognized and is associated with high mortality rates. Valuable insights from observational studies fail to demonstrate a mortality benefit in randomized controlled trials (RCTs). In the absence of a pharmacologic cure, supportive ventilator strategies limit rather than treat the ongoing lung injury. Interestingly, ARDS has higher mortality rates in observational studies compared to RCTs. Comparing mortality rates between ARDS studies and trials is problematic, partly due to varying time-points at which mortality is reported. Discerning the true mortality attributable to ARDS is also difficult. The diagnostic criteria for ARDS are mainly clinical and lack the objectivity of a laboratory test or biomarker. Nonetheless, these factors are common to both studies and trials, and fail to explain the higher mortality rate of ARDS observational studies. Disease heterogeneity and complex patient characteristics can also confound mortality estimation in ARDS. We therefore examined patient and trial factors that could influence mortality outcomes in ARDS observational studies and RCTs. Unlike RCTs, observational studies include ARDS subjects with severe comorbidities and those requesting limited care. Less stringent selection criteria could thereby contribute to high mortality rates in ARDS observational studies. In contrast, exclusion criteria in RCTs meticulously scrutinize patient characteristics, confining the type and number of eligible subjects. As a result, the task of identifying, consenting, and randomizing eligible patients within the enrollment window is challenging, further decreasing the number of subjects enrolled. Moreover, ARDS RCTs strictly adhere to lung-protective strategies, while ARDS observational studies continually demonstrate variable compliance. This review highlights the impact of patient- and trial-related factors on influencing mortality rates in ARDS observational studies and RCTs.

Mechanical stretch and LPS affect the proliferation, extracellular matrix remodeling and viscoelasticity of lung fibroblasts

“…The use of an ARDS-associated mechanical ventilator is a key treatment of patients with ARDS; however, it may cause ARDS-associated ventilator-induced lung injury and pulmonary fibrosis. A previous study indicated that have indicated that pulmonary fibrosis is closely related to mortality, prognosis and quality of life in patients with ARDS (12). However, to date, the cellular mechanisms of pulmonary fibrosis in patients with ARDS have remained to be clarified and the clinical prevention and treatment effects are not satisfactory.…”

Exosomes from endothelial progenitor cells improve outcomes of the lipopolysaccharide-induced acute lung injury

“…The acute respiratory distress syndrome (ARDS) is a complex and deadly disease characterized by inflammation and lung permeability leading to alveolar edema, hypoxemia, and organ failure [1, 2]. ARDS occurs in up to 10% of patients admitted to an intensive care unit with mortality rates ranging from 35 to 46% [3, 4]. To date, there are no approved pharmacological treatments for this syndrome.…”

Methodological management of end-of-life decision data in intensive care studies: A systematic review of 178 randomized control trials published in seven major journals

“…The first and most common method was to consider EOL decisions as non-inclusion criteria (99% of the 61 articles); however, this method of data management leads to questions regarding how representative the selected population is since not including approximately half of the patients dying in ICUs in some pathologies could potentially diminish the relevance of the results [7]. The second point is that not including patients affected by EOL decisions does not avoid the potential need for EOL decisions during the study or follow-up period.…”

“…Thus, the decision to withhold or withdraw treatment and other EOL decisions may greatly influence the immediate mortality rate and, therefore, could potentially modify the results of ICU studies, especially randomized controlled trials (RCTs), by over- or under-estimating mortality depending on how EOL decisions are considered in the study and/or in the analysis [7,8]. To the best of our knowledge, there is a lack of methodological guidance on how to correctly describe and manage data affected by EOL decisions.…”