1. 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, , Jiangsu, China
2Amsterdam UMC, location VUmc, Amsterdam, the Netherlands
*Joint corresponding authors

2. Study designs
Prospective Randomized controlled trial
One general ICU, From October 2011 to September 2017
Clinicaltrials.gov (NCT )
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

3. 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%

4. 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.

5. 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( )
2.4 ( )
0.041
Duration of weaning in all patients b, days
7.4 ( )
3.0 ( )
0.003

6. 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 ( )
0.011
Ventilator-free days, day 28
21.0 (0-26.0)
25.0 ( )
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.