Table 1.

Selected enrichment strategies used or proposed for ARDS clinical trials. Reprinted with permission of the American Thoracic Society. Copyright © 2022 American Thoracic Society. All rights reserved. Cite: Martin TR, Zemans RL, Ware LB, Schmidt EP, Riches DWH, Bastarache L, Calfee CS, Desai TJ, Herold S, Hough CL, Looney MR, Matthay MA, Meyer N, Parikh SM, Stevens T, Thompson BT. New Insights into Clinical and Mechanistic Heterogeneity of the Acute Respiratory Distress Syndrome: Summary of the Aspen Lung Conference 2021. Am J Respir Cell Mol Biol. 2022 Sep;67(3):284–308. Doi: 10.1165/rcmb.2022-0089WS. PMID: 35679511; PMCID: PMC9447141. The American Journal of Respiratory Cell and Molecular Biology is an official journal of the American Thoracic Society.

Trial/Author	Enrichment Strategy	Intervention	Findings/Rationale
ACURASYS, Papazian [22] ROSE, PETAL Network [14]	ARDS Severity PF < 120–150 P/F < 120	Early neuromuscular blockade	ACURASYS demonstrated higher placebo mortality in, and benefits limited to, the P/F < 120 subsets (prognostic and predictive enrichment, respectively). Did not replicate in ROSE.
PROSEVA, Guerin [12]	ARDS Severity P/F < 150	Prone positioning	Large treatment effect in moderate to severe ARDS concordant with prior metanalyses suggesting predictive enrichment.
LASRS, Steinberg [23]	ARDS for 7–28 d	Methylprednisolone	Attempted to enrich for a steroid-responsive phase of ARDS (fibro-proliferation). Late steroids (>14 d) may be harmful.
Willson [24] Spragg [25]	Direct vs. indirect	Surfactant replacement	Benefit with pediatric direct lung injury. Did not replicate in adults.
Constantin [26]	Focal vs. diffuse ARDS	Personalized ventilator strategy; higher VT and lower PEEP for focal vs. lower VT and higher PEEP for diffuse ARDS	No difference in mortality; high rates of misclassification and higher mortality if a strategy is applied to the incorrect subgroup.
Calfee [27]	Trauma vs non-trauma	Reduce heterogeneity by studying traumatic ARDS separately	Lower mortality is not explained by baseline clinical factors; biomarker profiles suggest the differing extent of epithelial and endothelial injury.
Villar [28] Goligher [29]	Evaluate stability on standardized ventilator settings Assess physiologic responsiveness during a run-in period	Enroll only persistent ARDS Randomize to higher vs. lower PEEP in responders only	Reevaluation after 24 h enriches for higher mortality. Analysis of PEEP responsiveness in RCTs suggests a potential for predictive and prognostic enrichment.
Gattinoni [30] Goligher [31,32]	Match lung-protective intervention to physiology to optimize benefit/risk	Assess for recruitability or lung weight (CT) ECCO2R for subset likely to have a ≥5 cm H2O drop in driving pressure Titration of tidal volume to elastance	Modeling and observational data suggest potential for both prognostic and predictive enrichment.
Calfee [33]	ARDS subclass	Simvastatin for Class 2 (“Hyperinflammatory”) ARDS (see text)	Post hoc analysis of RCT demonstrates mortality benefit limited to Class 2 ARDS.
Lai [34] Sinha [35]	Markers of dysregulated coagulation, high dead space fraction or ventilatory ratio, and RV function by cardiac ultrasound	Anticoagulants or pulmonary vascular targeted therapies	Identify subsets with or at risk for microvascular thrombi, vascular remodeling, pulmonary hypertension, or adverse outcomes.

Definition of abbreviations: ACURASYS = ARDS et Curarisation Systematique; ARDS = acute respiratory distress syndrome; ECCO₂R = extracorporeal CO₂ Removal; LASRS = Late Steroid Rescue Study; PEEP = positive end-expiratory pressure; PETAL = Prevention and Early Treatment of Acute Lung Injury; PROSEVA = Proning Severe ARDS Patients; RCT = Randomized Clinical Trial; ROSE = Reevaluation of Systemic Early Neuromuscular Blockade; V_T = tidal volume.