Running title: NAVA may reduce weaning duration from mechanical ventilation A randomized controlled trial to compare Neurally adjusted ventilatory assist versus pressure support ventilation in patients difficult to wean from mechanical ventilation Ling Liu1, Xiaoting Xu1, Qin Sun1, Yue Yu1, Feiping Xia1, Jianfeng Xie1, Yi Yang1, Leo Heunks2*, Haibo Qiu1* Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, 210009, Jiangsu, China 2Amsterdam UMC, location VUmc, Amsterdam, the Netherlands *Joint corresponding authors

Study designs Prospective Randomized controlled trial One general ICU, From October 2011 to September 2017 Clinicaltrials.gov (NCT01280773) The protocol was approved by Institutional Ethics Committee of Zhongda hospital (Approval Number: 2010ZDLL018.0) Patient Patients receiving acute invasive mechanical ventilation for more than 24h were eligible when meeting all the following criteria Failing the initial spontaneous breathing trial (SBT) or re-intubated within 48 h after the first extubation able to sustain PSV more than 1h with inspiratory support ≤ 15 cmH2O, hemodynamic stable (heart rate < 140 beats/min, no vasopressors required or ≤ 5 μg.kg-1.min-1 dopamine/ dobutamine, or ≤ 0.2 μg.kg-1.min-1 norepinephrine), Maintain light sedation (RASS ≥ -2) during day time

Ventilation strategies Hypothesis We reasoned that a ventilator mode that improves patient ventilator interaction and delivers proportional support most likely improves weaning outcome in patients difficult to wean from mechanical ventilation. Ventilation strategies PSV support level was set to obtain a Vt of 6–8 ml/kg. PBW flow-trigger- 1 L/min cycle off -30 % NAVA NAVA level was titrated to obtain a Vt of 6–8 ml/kg. PBW EAdi trigger-0.5 μV cycles off -70 % of peak EAdi FiO2 and PEEP were set by the physician in charge to maintain the SpO2 ≥ 90%

Materials and methods Weaning protocol Daily screen at 9:00 AM Patients were screened once daily for possible SBT from the first day after randomization (day 1) A 30-minute SBT CPAP of 5 cm H2O or PSV with inspiratory pressure of 7 cmH2O and 5 cmH2O of PEEP Failed Success Patients were screened once daily (9.00 am) by investigators for possible SBT from the first day after randomization (day 1). Cough was evaluated by placing a white card about 1.5 cm away from the end of the endotracheal tube and asking the patient to cough (3 to 4 times). Adequate cough was considered if wetness appeared on the card [13]. Patien Reconnected and ventilated in either NAVA or PSV mode No Restore to ventilation settings before SBT Adequate cough Yes Extubation Decisions related to tracheostomy, post-extubation NIV and reintubation were made by clinical team.

Primary outcome The percentage of patients who were never weaned from mechanical ventilation was 17% (8/47) in NAVA group and 33% (17/52) in PSV group (P = 0.073)   PSV (n=52) NAVA (n=47) P Primary outcome Duration of weaning in weaned patient a, days 4.1(1.1-7.7) 2.4 (1.1-5.3) 0.041 Duration of weaning in all patients b, days 7.4 (2.0-26.5) 3.0 (1.2-7.9) 0.003

Conclusions Secondary outcomes   PSV (n=52) NAVA (n=47) P other outcomes Invasive ventilator-free days, day 28 21 (0-26) 25 (20-27) 0.034 Ventilator-free days, day 7 0 (0-5.0) 4.0 (0-5.8) 0.061 Ventilator-free days, day 14 6.6 (0-12.0) 11.0 (6.0-12.8) 0.011 Ventilator-free days, day 28 21.0 (0-26.0) 25.0 (20.0-27.0) 0.041 Length of stay in ICU, days 27 (13-40) 19(12-32) 0.330 Length of stay in ICU in survivors, days 19 (10-33) 24 (12-35) 0.326 Length of stay in hospital, days 32 (19-58) 29 (19-44) 0.491 Length of stay in hospital in survivors, days 30 (17-44) 35 (26-47) 0.424 ICU mortality, n (%) 17 (32.7) 8 (17.0) 0.073 28 day mortality, n (%) 14 (26.9) 14 (29.8) 0.752 Hospital mortality, n (%) 25 (48.1) 16 (34.0) 0.157 Conclusions In patients who were difficult to wean, NAVA decreased duration of weaning and increase ventilator-free days. NAVA which improved patient-ventilator asynchrony, is safe, feasible and effective during weaning.