Study design

This single-center, prospective, nonblinded RCT and equivalent RCT that compared NIPPV (intervention group) and HFNC (control group) after extubation was conducted between January 2017 and December 2020 at the respiratory care center (RCC) of Shin Kong Wu Ho-Su Memorial Hospital in Taipei, Taiwan. The study was approved by the Institutional Review Board of Shin Kong Wu Ho-Su Memorial Hospital (IRB number: 20160901R), and written informed consent was obtained from all the participants or their relatives. The trial was registered at (NCT04564859 25/09/2020).


Patients aged more than 20 years who were ready for extubation, had received mechanical ventilation for more than 6 h per day for at least 14 consecutive days, and who had been transferred from the ICU to the RCC were immediately enrolled into this study. The exclusion criteria for this study were tracheostomy, do-not-intubate status, pregnancy, neuromuscular diseases, and unplanned extubation.

In Taiwan, an integrated delivery system was launched to reduce the average length of ICU stay and improve the quality of care of patients with PMV37. Patients receiving mechanical ventilation are transferred to subacute care facilities, such as RCC or respiratory care ward, on the basis of the number days for which they have been receiving mechanical ventilation and their clinical status37.


The clinical weaning protocol involved a daily evaluation of weaning readiness up to the time of extubation, and the readiness was determined on the basis of the following criteria: recovery from the precipitating illness; respiratory measures of PaO2/FiO2 > 150 with FiO2 ≤ 0.4, PEEP < 8 cmH2O, and pH > 7.35; the absence of electrocardiographic signs of myocardial ischemia; no requirement for vasoactive drugs or a requirement for only low-dose dopamine (< 5 µg/kg/min; heart rate < 140 b/min, hemoglobin > 8 g/dL, temperature < 38 °C); no need for sedatives; the presence of a respiratory stimulus; and appropriate spontaneous cough. Patients who met these criteria underwent a spontaneous breathing trial with either T-piece or pressure support of 6–8 cmH2O for 30 to 120 min according to the patient’s condition. The following factors indicated respiratory failure: a respiratory rate > 35 b/min, SpO2 < 92%, exhaled tidal volume < 4 mL/kg, heart rate > 140 b/min or 25% above baseline or < 60 b/min, blood pressure increased to 40 mm Hg above the baseline, worsening agitation, and anxiety or discomfort despite reassurance.

After undergoing extubation, each patient was randomly assigned to the HFNC and NIPPV groups (in a 1:1 ratio) and received noninvasive respiratory support (NRS) administered using their assigned method. Randomization was achieved through the use of a website ( Each group assignment was provided in a consecutively numbered, sealed, opaque envelope. The patients in the HFNC group received continuous flow of oxygen through a nasal cannula (Optiflow, Fisher & Paykel Healthcare, Auckland, New Zealand) with a high-flow oxygen system (Airvo2, Fisher & Paykel Healthcare, Auckland, New Zealand). The initial flow rate was set to 50 L/min with subsequent adjustments to maintain adequate gas exchange. To provide adequate airway humidity, the gas temperature was set to 34 °C or 37 °C according to each patient’s airway secretion condition. NIPPV was delivered using a Trilogy 202 ventilator (Philips Respironics, Murraysville, PA, USA) with a facemask (Mirage Quattro, ResMed, Sydney, Australia). The inspiratory pressure and end-expiratory pressure were set to 12–16 and 4–6 cmH2O, respectively, to maintain a tidal volume of 6–10 mL/kg.

NRS weaning protocol

All participants were screened for weaning readiness daily according to the following criteria: (1) pH value of ≥ 7.35; (2) oxygen saturation (SpO2) of > 90% at a fraction of inspired oxygen (FiO2) of ≤ 0.5; (3) respiratory rate of ≤ 25 breaths/min; (4) heart rate of ≤ 120 beats/min; (5) systolic blood pressure of ≥ 90 mmHg; and (6) no signs of respiratory distress, such as agitation, diaphoresis, paradoxical respiration, accessory muscle recruitment, or anxiety.

Failure criteria

Postextubation respiratory failure was defined as follows: (1) lack of improvement in pH or in the partial pressure of carbon dioxide (PaCO2) under NRS; (2) decrease in SpO2 to ≤ 85% despite FiO2 of ≥ 0.5; (3) persistent or worsening signs of respiratory muscle fatigue; (4) copious secretions that could not be adequately cleared; (5) changes in mental status; (6) acute upper airway obstruction; and (7) hemodynamic instability. Patients who fulfilled these criteria were considered to be reintubated. The final decision to reintubate was made by the treating physician.

Outcome measurement

The primary outcome was reintubation within 72 h after extubation. The secondary outcomes were reintubation within 7 days of extubation, changes in physiological parameters and arterial blood gas analysis results, time to liberation from NRS, duration of respiratory support, length of RCC and hospital stay, ventilator-free days at 28-day and 90-day mortality. Successful liberation from NRS was defined as the time point at which a patient was alive and free of NRS (HFNC or NIPPV) for more than 48 h.

Statistical analysis

The primary outcome of this study was the reintubation rate. We assumed the reintubation rates of the HFNC and NIPPV groups to be 50% and 10%, respectively. A sample size of 20 for each group was required to achieve an alpha level of 5% (two tailed) and power of 80%. Sample size calculation was conducted using G*Power, version (University of Kiel, Kiel, Germany). The clinical characteristics and outcomes of the patients in the NIPPV and HFNC groups were compared using Fisher’s exact test (for categorical variables) or an independent-samples t test (for continuous variables). The number of high-risk factors for reintubation in each group is expressed as a median with an interquartile range, and the numbers were compared using a Mann–Whitney U test. The cumulative incidence of reintubation and mortality within 90 days was estimated using the Kaplan–Meier method, and a log-rank test was used to compare the groups. Finally, the preextubation-to-postextubation changes in the physiological parameters of the NIPPV and HFNC groups were compared using a generalized estimating equation (GEE). The link function was identity, the distribution was normal, and the working correlation matrix was exchangeable. The robust standard error was used in the GEE model to test the intercept, main effects of time (preextubation vs. postextubation) and group, and the interaction effect between time and group. In addition, preextubation-to-postextubation changes within each group were tested using the contrast within the GEE model. All the tests were two-tailed, and a P value of < 0.05 was considered statistically significant. Statistical analyses were conducted using IBM SPSS (version 25.0 for Windows, Chicago, IL, USA).

Ethics approval and consent to participate

We conducted the trial in accordance with good clinical practice guidelines and the Declaration of Helsinki. The study was approved by local institutional review committees (IRB number: 20160901R). Informed written consent was obtained from all participants.

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