Presence of comorbidities alters management and worsens outcome of patients with acute respiratory distress syndrome: insights from the LUNG SAFE study

The impact of underlying comorbidities on the clinical presentation, management and outcomes in patients with ARDS is poorly understood and deserves further investigation. This knowledge gap is exacerbated by the fact that the evidence base for management of ARDS comes from clinical trials that frequently exclude these patients [1]. These trials have led to important clinical advances, including the recognition of the protective effects of lowered tidal volume [2], the role of prone positioning [3] and of muscle relaxants in early moderate–severe ARDS [4] among others.

A concern that has arisen is the generalizability of the findings of studies carried out in patients with no comorbidities, to the patient population with comorbidities, and the validity of these trials if only performed in a minority of the entire ARDS patient cohort. Furthermore, these concerns may limit the degree to which these interventions are applied to patients with significant underlying comorbidities [5].

Given the potential for important impact of comorbidities on the management and outcomes from ARDS, we wished to address these issues in this secondary analysis of the LUNG SAFE patient cohort. Briefly, LUNG SAFE was an international, multicentre, prospective cohort study of patients undergoing invasive or non-invasive ventilation, conducted during 4 consecutive weeks in the winter of 2014 in a convenience sample of 459 ICUs from 50 countries across 5 continents, that recruited 3,022 patients that fulfilled ARDS criteria [6].

Our primary objective, in this secondary LUNG SAFE analysis, was to determine the frequency, and impact of comorbidities on the management and ICU survival of patients with ARDS. Secondary outcomes included determination of the impact of these comorbidities on ventilatory management, the development of organ failures, and on end-of-life care.

This is a sub-study of the LUNG-SAFE study, an international, multicenter, prospective cohort study of patients receiving invasive or non-invasive ventilation, and the detailed methods and protocol have been published elsewhere [6]. The study, led by the European Society of Intensive Care Medicine (ESICM), was endorsed by multiple national societies/networks (Additional file 1: Appendix S1). All participating ICUs obtained ethics committee approval, and either patient consent or ethics committee waiver of consent. National coordinators and site investigators (Additional file 1: Appendix S1) were responsible for obtaining ethics committee approval and for ensuring data integrity and validity.

Of 4,499 patients that developed acute hypoxic respiratory failure (AHRF), 2,813 patients developed ARDS within the first 2 days of developing AHRF, of which 1692 (60.1%) had at least 1 major comorbidity (Fig. 1, Table 1). Of these, 1087 (64%) had one major comorbidity, 423 (25%) had two major comorbidities, while 182 (11%) had three or more major comorbidities. The order of frequency of comorbid conditions was chronic respiratory impairment (n = 631, 22.4%), diabetes (n = 613, 21.8%) immune incompetence (n = 584, 20.8%), chronic renal failure (n = 286, 10.2%), congestive heart failure (n = 290, 10.3%), and chronic liver failure (n = 112, 4%) (Fig. 1, Table 1).

The frequency and impact of underlying comorbidities on the clinical presentation, management and outcomes in patients with ARDS remain incompletely understood. We report that in the LUNG SAFE patient cohort, a large and geographically diverse cohort of ‘real world’ patient with ARDS, most patients had at least one significant comorbidity. We further found that patients with comorbidities were managed differently, being less likely to receive higher intensity modalities of organ support and adjunctive therapies. Patients with comorbidities experienced differences in end-of-life care and were more likely to die in the ICU and in hospital. These findings raise concerns regarding the management and outcomes of these patients and suggest that enhancing the care of these patients must be a priority for future clinical studies.

Critically ill ARDS patients with comorbidities were older and were more frequently admitted with acute medical condition. Geo-economic differences existed in comorbidity profiles, with a higher frequency of chronic renal failure, chronic liver failure, immune incompetence and diabetes in patients from high-income countries outside Europe. Of interest, ARDS was less likely to be recognized in patients with comorbidities, especially chronic respiratory impairment, congestive heart failure or immune incompetence. Overall, patients with comorbidities had less severe ARDS, and there were potentially important differences in the pattern of extrapulmonary organ injury.

The presence of comorbidities in our study population had a major impact on the management of ARDS patients. Patients with underlying comorbidities were managed more frequently with non-invasive ventilation, they received less adjunctive measures including NMBs, prone positioning and ECMO, regardless of their level of evidence [10], raising the concern of a potential bias towards less aggressive treatment of patients with comorbidities. It should be acknowledged that patients with comorbidities may have more contra-indications to the use of these management strategies, and/or the treating clinician may consider that these approaches may not be suitable for specific patients. Factors such as clinician recognition of ARDS at baseline, the use of invasive mechanical ventilation, greater ARDS severity (i.e., a lower PF ratio), a higher peak inspiratory and positive end-expiratory pressure were all independently associated with the use of adjunctive measures within 28-day follow-up. Furthermore, among all comorbidities immune incompetence and diabetes were independent predictors of using ARDS adjuncts during ICU stay.

The fact that ARDS patients with significant underling comorbidities are frequently excluded from interventional clinical trials, particularly trials of novel investigative medicinal products, has raised concerns regarding the generalizability of the findings of these studies. These concerns were first raised by Azoulay et al., in their study of the impact of comorbidities in a French cohort of patients with ARDS [11], where 51% of their cohort had significant comorbidities. Our findings confirm and extend their findings, demonstrating that the majority of patients in this global ARDS cohort had comorbidities that may have led to their being excluded from a clinical trial of an intervention for ARDS. Furthermore, clinician concerns regarding the generalizability of findings from ARDS trials of novel therapeutics to patients with underlying comorbidities may contribute to the differences seen in patient management.

The differences between cohorts of ARDS patients with and without comorbidities, in terms of their demographic profile, and the clinical pattern of ARDS, raises the possibility that patients with significant comorbidities may respond differently to these management strategies. These concerns are underlined by the findings that patients with different ARDS subphenotypes appear to respond differently to PEEP and to statin therapy [12, 13], while patients with different patterns of ARDS may respond differently to ventilation strategies [14]. These issues underline the need for additional studies focused on this patient population to develop the evidence base for their management.

ARDS patients with comorbidities had worse outcomes than those with no comorbidities. Specifically, these patients had less ventilator-free days, while ICU and hospital mortality was higher in this cohort. ICU survival in patients with no comorbidities at 73% compares favorably with outcomes from recent clinical trials [15, 16] and provides a ‘real world’ benchmark for outcomes in control populations in studies focused on this cohort. In contrast, ICU survival decreased to 61% in patients with at least 1 significant comorbidity.

The presence of even 1 major comorbidity increased the risk of death, there further increase in the risk of death with a greater number of comorbidities present. Specific comorbidities, including congestive heart failure, chronic liver failure and immune incompetence were each independent predictors of ICU mortality, while both chronic liver failure and immune incompetence were independently associated with hospital mortality. The presence of 1 or more comorbidities was associated with a higher proportion of limitation of life-sustaining measures compared to patients without comorbidities. Both chronic liver failure and immune incompetence were both independently associated with more decisions regarding end-of-life care. Of interest, we observed that a higher number of beds per physician (i.e., an index of resource ‘strain’) and location in a high-income European ICU were both positive predictors of a higher decision to limit treatment.

This study has several limitations. Our patient cohort, while large and geographically diverse, may not be representative of actual clinical practice in ICUs across the globe. We did not have access to the source data for the patients in the enrolling ICUs, and it is possible that not all patients with ARDS in participating centers were enrolled. However, enrollment of patients with ARDS from participating ICUs met expectations based on their recorded 2013 admission rates, while data from lower recruiting ICUs were not different from that from higher enrolling ICUs, suggesting the absence of reporting biases. We instituted a robust data quality control program in which all centers were requested to verify data that appeared inconsistent or erroneous. While we have adjusted our analyses to account for known measured confounders, the possibility remains that some of our findings may arise from unmeasured or residual confounding. Moreover, we cannot make causal inferences for the associations seen, given the observational nature of our study. It should be acknowledged that the LUNG SAFE study unveiled that a significant proportion of patients did not receive protective mechanical ventilation, PEEP levels stratified by ARDS severity [6] and widely available adjuncts such as neuromuscular blockade and prone position [10] despite guidelines recommendations [17, 18]. This may imply that the relationship between comorbidities and outcome (i.e., mortality and limitation of life-sustaining measures) may differ as compared to cohort of ARDS patients treated according to the ARDS guidelines. The lack of information regarding the use of non-pulmonary organ supports should be considered as a limitation of the study.

Furthermore, as the patient inclusion period was before the pandemic era, the findings of the present study may not apply to patients with COVID-19 ARDS.