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

Villar, Jesús; Martínez, Domingo; Mosteiro, Fernando; Ambrós, Alfonso; Añón, J.M.; Ferrando, Carlos; Soler, Juan Alfonso; Montiel, Raquel; Vidal, Ánxela; Conesa-Cayuela, Luís A; Blanco, Jesús; Arrojo, Regina; Solano, Rosario; Capilla, L; Campo, Rafael Del; Civantos, Belén; Fernández, María M.; Aldecoa, César; Parra, Laura; Gutiérrez, Andrea; Martínez-Jiménez, Chanel; González-Martín, Jesús María; Fernandez, R.; Kacmarek, Robert M.; Stratification,

doi:10.1097/ccm.0000000000003022

Cited by 29 publications

(27 citation statements)

References 37 publications

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“…Fourth, since participating investigators were asked to estimate duration of MV regardless of their probability for survival, it is plausible that they underestimated the true severity of the underlying disease and the likelihood for successful weaning and survival. Fifth, most patients died in the ICU, and the most common causes of death were similar to those from patients with severe acute respiratory failure [30], a scenario that was not anticipated in our trial design. Sixth, the strict inclusion/exclusion criteria for enrolling patients could have biased our results toward excluding difficult-to-wean patients ventilated for more than 5 days.…”

Section: Discussionmentioning

confidence: 84%

Neurally adjusted ventilatory assist in acute respiratory failure: a randomized controlled trial

et al. 2020

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We hypothesized that neurally adjusted ventilatory assist (NAVA) compared to conventional lung-protective mechanical ventilation (MV) decreases duration of MV and mortality in patients with acute respiratory failure (ARF). Methods: We carried out a multicenter, randomized, controlled trial in patients with ARF from several etiologies. Intubated patients ventilated for ≤ 5 days expected to require MV for ≥ 72 h and able to breathe spontaneously were eligible for enrollment. Eligible patients were randomly assigned based on balanced treatment assignments with a computerized randomization allocation sequence to two ventilatory strategies: (1) lung-protective MV (control group), and (2) lung-protective MV with NAVA (NAVA group). Allocation concealment was maintained at all sites during the trial. Primary outcome was the number of ventilator-free days (VFDs) at 28 days. Secondary outcome was all-cause hospital mortality. All analyses were done according to the intention-to-treat principle. Results: Between March 2014 and October 2019, we enrolled 306 patients and randomly assigned 153 patients to the NAVA group and 153 to the control group. Median VFDs were higher in the NAVA than in the control group (22 vs. 18 days; between-group difference 4 days; 95% confidence interval [CI] 0 to 8 days; p = 0.016). At hospital discharge, 39 (25.5%) patients in the NAVA group and 47 (30.7%) patients in the control group had died (between-group difference − 5.2%, 95% CI − 15.2 to 4.8, p = 0.31). Other clinical, physiological or safety outcomes did not differ significantly between the trial groups. Conclusion: NAVA decreased duration of MV although it did not improve survival in ventilated patients with ARF.

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Section: Discussionmentioning

confidence: 84%

Neurally adjusted ventilatory assist in acute respiratory failure: a randomized controlled trial

et al. 2020

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“…However, for decades, it has been clear that refractory hypoxemia accounts for only a small fraction of deaths in ARDS [7,8]. A recent study showed the majority of deaths of ICU patients with ARDS were not directly related to lung damage [9]. Thus, it has been challenging to determine what proportion of mortality is attributable to ARDS itself (and therefore a potential target for ARDS-focused clinical trials), and what proportion is driven by the underlying ARDS risk factor, comorbidities, or a combination of the two.…”

Section: Introductionmentioning

confidence: 99%

Acute respiratory distress syndrome-attributable mortality in critically ill patients with sepsis

et al. 2020

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Previous studies assessing impact of acute respiratory distress syndrome (ARDS) on mortality have shown conflicting results. We sought to assess the independent association of ARDS with in-hospital mortality among intensive care unit (ICU) patients with sepsis. Methods: We studied two prospective sepsis cohorts drawn from the Early Assessment of Renal and Lung Injury (EARLI; n = 474) and Validating Acute Lung Injury markers for Diagnosis (VALID; n = 337) cohorts. ARDS was defined by Berlin criteria. We used logistic regression to compare in-hospital mortality in patients with and without ARDS, controlling for baseline severity of illness. We also estimated attributable mortality, adjusted for illness severity by stratification. Results: ARDS occurred in 195 EARLI patients (41%) and 99 VALID patients (29%). ARDS was independently associated with risk of hospital death in multivariate analysis, even after controlling for severity of illness, as measured by APACHE II (odds ratio [OR] 1.65 (95% confidence interval [CI] 1.02, 2.67), p = 0.04 in EARLI; OR 2.12 (CI 1.16, 3.92), p = 0.02 in VALID). Patients with severe ARDS (P/F < 100) primarily drove this relationship. The attributable mortality of ARDS was 27% (CI 14%, 37%) in EARLI and 37% (CI 10%, 51%) in VALID. ARDS was independently associated with ICU mortality, hospital length of stay (LOS), ICU LOS, and ventilator-free days. Conclusions: Development of ARDS among ICU patients with sepsis confers increased risk of ICU and in-hospital mortality in addition to other important outcomes. Clinical trials targeting patients with severe ARDS will be best poised to detect measurable differences in these outcomes.

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“…In pediatric ARDS (PARDS), mortality rates are half of adult rates (3–6). Studies examining the epidemiology of cause of death in adults demonstrate that refractory hypoxemia is uncommon (7, 8), and that the majority of non-survivors die from multisystem organ failure (MSOF) or due to poor neurologic prognosis. This has relevance because interventions that target hypoxemia, such as inhaled nitric oxide (9), exogenous surfactant (10), and fluid-conservative therapy (11), have not improved mortality.…”

Section: Introductionmentioning

confidence: 99%

Epidemiology of Cause of Death in Pediatric Acute Respiratory Distress Syndrome

Dowell

Parvathaneni

Thomas

et al. 2018

Critical Care Medicine

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In pediatric acute respiratory distress syndrome, early deaths were due primarily to neurologic failure, whereas later deaths were more commonly due to multisystem organ failure. Deaths from neurologic causes accounted for a substantial portion of nonsurvivors. Refractory hypoxemia accounted for only a minority of deaths. Our study highlights limitations associated with using death as an endpoint in therapeutic pediatric acute respiratory distress syndrome trials.

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

Abstract: 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.

Cited by 29 publications

References 37 publications

Neurally adjusted ventilatory assist in acute respiratory failure: a randomized controlled trial

Neurally adjusted ventilatory assist in acute respiratory failure: a randomized controlled trial

Acute respiratory distress syndrome-attributable mortality in critically ill patients with sepsis

Epidemiology of Cause of Death in Pediatric Acute Respiratory Distress Syndrome

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