J. JuschtenP. R. TuinmanT. GuoN. P. JuffermansM. J. SchultzS. A. LoerA. R.J. GirbesH. J. de GroothLeiden Academic Centre for Drug ResearchOLVGMahidol UniversityNuffield Department of MedicineVrije Universiteit AmsterdamUniversiteit van Amsterdam2022-08-042022-08-042021-04-01Intensive Care Medicine. Vol.47, No.4 (2021), 422-43414321238034246422-s2.0-85102386532https://repository.li.mahidol.ac.th/handle/123456789/78316Purpose: Most randomized controlled trials (RCTs) in patients with acute respiratory distress syndrome (ARDS) revealed indeterminate or conflicting study results. We aimed to systematically evaluate between-trial heterogeneity in reporting standards and trial outcome. Methods: A systematic review of RCTs published between 2000 and 2019 was performed including adult ARDS patients receiving lung-protective ventilation. A random-effects meta-regression model was applied to quantify heterogeneity (non-random variability) and to evaluate trial and patient characteristics as sources of heterogeneity. Results: In total, 67 RCTs were included. The 28-day control-group mortality rate ranged from 10 to 67% with large non-random heterogeneity (I2 = 88%, p < 0.0001). Reported baseline patient characteristics explained some of the outcome heterogeneity, but only six trials (9%) reported all four independently predictive variables (mean age, mean lung injury score, mean plateau pressure and mean arterial pH). The 28-day control group mortality adjusted for patient characteristics (i.e. the residual heterogeneity) ranged from 18 to 45%. Trials with significant benefit in the primary outcome reported a higher control group mortality than trials with an indeterminate outcome or harm (mean 28-day control group mortality: 44% vs. 28%; p = 0.001). Conclusion: Among ARDS RCTs in the lung-protective ventilation era, there was large variability in the description of baseline characteristics and significant unexplainable heterogeneity in 28-day control group mortality. These findings signify problems with the generalizability of ARDS research and underline the urgent need for standardized reporting of trial and baseline characteristics.Mahidol UniversityMedicineReviewSCOPUS10.1007/s00134-021-06370-w