Impact of differences in acute respiratory distress syndrome randomised controlled trial inclusion and exclusion criteria: systematic review and meta-analysis

Abstract

Background: Control-arm mortality varies between acute respiratory distress syndrome (ARDS) RCTs. Methods: We systematically reviewed ARDS RCTs that commenced recruitment after publication of the AmericaneEuropean Consensus (AECC) definition (MEDLINE, Embase, and Cochrane central register of controlled trials; January 1994 to October 2020). We assessed concordance of RCT inclusion criteria to ARDS consensus definitions and whether exclusion criteria are strongly or poorly justified. We estimated the proportion of between-trial difference in control-arm 28-day mortality explained by the inclusion criteria and RCT design characteristics using meta-regression. Results: A literature search identified 43 709 records. One hundred and fifty ARDS RCTs were included; 146/150 (97.3%) RCTs defined ARDS inclusion criteria using AECC/Berlin definitions. Deviations from consensus definitions, primarily aimed at improving ARDS diagnostic certainty, frequently related to duration of hypoxaemia (117/146; 80.1%). Exclusion criteria could be grouped by rationale for selection into strongly or poorly justified criteria. Common poorly justified exclusions included pregnancy related, age, and comorbidities (infectious/immunosuppression, hepatic, renal, and human immunodeficiency virus/acquired immunodeficiency syndrome). Control-arm 28-day mortality varied between ARDS RCTs (mean: 29.8% [95% confidence interval: 27.0e32.7%; I 2 ¼88.8%; t 2 ¼0.02; P<0.01]), and differed significantly between RCTs with different PaO 2 :FiO 2 ratio inclusion thresholds (26.6e39.9 kPa vs <26.6 kPa; P<0.01). In a metaregression model, inclusion criteria and RCT design characteristics accounted for 30.6% of between-trial difference (P<0.01). Conclusions: In most ARDS RCTs, consensus definitions are modified to use as inclusion criteria. Between-RCT mortality differences are mostly explained by the PaO 2 :FiO 2 ratio threshold within the consensus definitions. An exclusion criteria framework can be applied when designing and reporting exclusion criteria in future ARDS RCTs.

Association of platelet count with all‐cause mortality from acute respiratory distress syndrome: A cohort study

“…The database contains a total of 58,976 critically ill patients and patients with ARDS age of 18 years or older were eligible for enrollment. The following symptoms were included in the Berlin criteria 24 , 25 : acute onset, arterial partial pressure of oxygen (PaO 2 )/fraction of inspired oxygen (FiO 2 ) <300 mmHg, positive end‐expiratory pressure ≥5 cm H 2 O, and on the first day of admission, the absence of heart failure and the presence of bilateral infiltrates on chest radiograph. The exclusion criteria of the patients from the current study included the following conditions: (1) no platelet count measurement during ICU hospitalization; (2) hematologic disease such as leukemia and myelodysplastic syndrome; (3) ICU hospital stay <48 h; and (4) missing >5% individual data.…”

ARDS subphenotypes: searching for Rorschach among the roentgenograms?

“…Globally, ARDS remains clinically underrecognized, with an acute hospital mortality of 46% in patients with severe ARDS 3 . Further, after more than 150 randomised controlled trials (RCTs) 4 , we do not have a single drug proven to benefit patients with ARDS. Notably, the histopathological hallmark of ARDS, diffuse alveolar damage (DAD) 1 , is only found in half of the patients, and is difficult to ascertain during acute illness 5 .…”

Repair of acute respiratory distress syndrome by stromal cell administration (REALIST) trial: A phase 1 trial

“…This is towards the upper range of mortality previously been reported in this population [4] . In a systematic review and meta-analysis of control arm mortality in randomised controlled trials in ARDS, when the inclusion criteria included a PF ratio consistent with moderate to severe ARDS, the control arm mean mortality rate was 35·1% [5] . The mortality rate in this phase 1 study is consistent with the baseline severity of illness.…”

“…Acute respiratory distress syndrome (ARDS) is characterised by hypoxaemia and bilateral radiographic opacities [1] . The mortality burden is high, between 35 and 45%, and there is considerable physical and psychological morbidity in survivors [2] , [3] , [4] , [5] . ARDS is driven by immune activation and cytokine release with loss of integrity of the epithelial-endothelial interface resulting in alveolar and interstitial oedema, loss of pulmonary compliance, and impaired gas exchange [6] .…”