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Background: Monitoring respiratory effort and drive during mechanical ventilation is needed to deliver lung and diaphragm protection. Esophageal pressure (∆P ES ) is the gold standard measure of respiratory effort but is not routinely available. Airway occlusion pressure in the first 100 ms of the breath (P0.1) is a readily available surrogate for both respiratory effort and drive but is only modestly correlated with ∆P ES in children. We sought to identify risk factors for P0.1 over or underestimating ∆P ES in ventilated children., Methods: Secondary analysis of physiological data from children and young adults enrolled in a randomized controlled trial testing lung and diaphragm protective ventilation in pediatric acute respiratory distress syndrome (PARDS) (NCT03266016). ∆P ES (∆P ES-REAL ), P0.1 and predicted ∆P ES (∆P ES-PRED  = 5.91*P0.1) were measured daily to identify phenotypes based upon the level of respiratory effort and drive: one passive (no spontaneous breathing), three where ∆P ES-REAL and ∆P ES-PRED were aligned (low, normal, and high effort and drive), two where ∆P ES-REAL and ∆P ES-PRED were mismatched (high underestimated effort, and overestimated effort). Logistic regression models were used to identify factors associated with each mismatch phenotype (High underestimated effort, or overestimated effort) as compared to all other spontaneous breathing phenotypes., Results: We analyzed 953 patient days (222 patients). ∆P ES-REAL and ∆P ES-PRED were aligned in 536 (77%) of the active patient days. High underestimated effort (n = 119 (12%)) was associated with higher airway resistance (adjusted OR 5.62 (95%CI 2.58, 12.26) per log unit increase, p < 0.001), higher tidal volume (adjusted OR 1.53 (95%CI 1.04, 2.24) per cubic unit increase, p = 0.03), higher opioid use (adjusted OR 2.4 (95%CI 1.12, 5.13, p = 0.024), and lower set ventilator rate (adjusted OR 0.96 (95%CI 0.93, 0.99), p = 0.005). Overestimated effort was rare (n = 37 (4%)) and associated with higher alveolar dead space (adjusted OR 1.05 (95%CI 1.01, 1.09), p = 0.007) and lower respiratory resistance (adjusted OR 0.32 (95%CI 0.13, 0.81), p = 0.017)., Conclusions: In patients with PARDS, P0.1 commonly underestimated high respiratory effort particularly with high airway resistance, high tidal volume, and high doses of opioids. Future studies are needed to investigate the impact of measures of respiratory effort, drive, and the presence of a mismatch phenotype on clinical outcome., Trial Registration: NCT03266016; August 23, 2017., (© 2024. The Author(s).)