The transition from control modes to spontaneous modes is ubiquitous for mechanically ventilated patients yet there is little data describing the changes and patterns that occur to breathing during this transition for patients on ECMO. We identified high fidelity data among a diverse cohort of 419 mechanically ventilated patients on ECMO. We examined every ventilator change, describing the differences in >30,000 sets of original ventilator observations, focused around the time of transition from control modes to spontaneous modes. We performed multivariate regression with mixed effects, clustered by patient, to examine changes in ventilator characteristics within patients, including a subset among patients with low compliance (<30 milliliters (mL)/centimeters water (cmH2O)). We found that during the transition to spontaneous modes among patients with low compliance, patients exhibited greater tidal volumes (471 mL (364,585) vs. 425 mL (320,527); p < 0.0001), higher respiratory rate (23 breaths per minute (bpm) (18,28) vs. 18 bpm (14,23); p = 0.003), greater mechanical power (elastic component) (0.08 mL/(cmH2O × minute) (0.05,0.12) vs. 0.05 mL/(cmH2O × minute) (0.02,0.09); p < 0.0001) (range 0 to 1.4), and lower positive end expiratory pressure (PEEP) (6 cmH2O (5,8) vs. 10 cmH2O (8,11); p < 0.0001). For patients on control modes, the combination of increased tidal volume and increased respiratory rate was temporally associated with significantly low partial pressure of arterial oxygen (PaO2)/fraction of inspired oxygen (FiO2) ratio (p < 0.0001). These changes in ventilator parameters warrant prospective study, as they may be associated with worsened lung injury. [ABSTRACT FROM AUTHOR]