High-flow nasal oxygen cannula vs. noninvasive mechanical ventilation to prevent reintubation in sepsis: a randomized controlled trial

This study was a prospective, randomised, unblinded clinical trial at two medical ICU in Siriraj Hospital, Mahidol University, Bangkok, Thailand between October 1, 2017 and October 31, 2019. The protocol was approved by the Siriraj Institutional Review Board (certificate of approval no. Si212/2017) and was conducted under the ethical principles of the Declaration of Helsinki. Prior informed consent for participation was obtained from patients or their legal guardians if the patient was unable to provide consent. All participant screening and enrolment procedures were performed by the coinvestigators (Fig. 1). The outcome evaluation data analysis was conducted by the principal investigator and a statistician, both of whom were blinded to the patient’s treatment group. The trial was funded by the Siriraj-Critical-Care-Research-Funding. The funder had no role in the study design, data analysis, or outcome assessment.

All patients aged 18 years or older who were admitted to the medical ICU, intubated, and ventilated for at least 48 h were assessed for eligibility. Those who met the diagnostic criteria of sepsis or septic shock according to the Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock 2016(SEPSIS-3) [1] and then recovered from their critical condition were eligible for enrolment. Patients who underwent tracheostomy or unplanned extubation, and those who signed a “do not resuscitate” order were excluded. We classified acute respiratory failure requiring intubation into four categories based on the underlying pathophysiology. The categories were type 1) acute hypoxic respiratory failure, type 2) acute hypercapnic respiratory failure, type 3) acute respiratory failure caused by perioperative atelectasis, and type 4) acute respiratory failure during shock or hypoperfusion [27].

After obtaining informed consent, we performed daily assessments of the patients’ weaning readiness in accordance with a standard weaning protocol. Weaning readiness was defined according to the following criteria: (i) recovery from the current critical illness (temperature < 38 °C, mean arterial blood pressure ≥ 65 mmHg without vasoactive drugs or only low doses of dopamine [< 5 μg/kg/min] or norepinephrine [< 0.05 μg/kg/min], and heart rate < 120 beats/minute); (ii) rapid shallow breathing index < 105 breaths/min/L; (iii) partial pressure of oxygen in arterial blood to fraction of inspired oxygen (PaO₂:FiO₂ ratio) > 150 with FiO₂ ≤ 0.4, positive end expiratory pressure (PEEP) < 8 cmH₂O, and arterial pH > 7.35; (iv) no symptoms and electrocardiographic signs of active myocardial ischaemia; (v) haemoglobin level > 7 g/dL; and (vi) Richmond Agitation-Sedation Scale (RASS) score ≥ − 1 without neuromuscular blocking agent use in the last 12 h. Patients who fulfilled these criteria for weaning readiness underwent a spontaneous breathing trial with either a T-piece or pressure support of 8 cmH₂O in accordance with their attending physicians’ judgement, for at least 30 min. Patients were considered to have failed the spontaneous breathing trial if they developed agitation, altered mental status, cyanosis, respiratory rate > 35 breaths/minutes, oxygen saturation < 90%, PaCO₂ > 50 mmHg or a more than 8 mmHg increase from baseline value, heart rate > 140 beats/minute, systolic arterial pressure > 180 mmHg or an increase of more than 20% from baseline value, systolic arterial pressure < 90 mmHg, or evidence of new-onset cardiac arrhythmias.

All patients who passed the spontaneous breathing trial were prepared for extubation and randomly assigned in a 1:1 ratio to receive either HFNC or NIV. Randomisation was performed using a computer-generated randomisation table derived from www.​randomization.​com. This process was performed by the principal investigator (S.T.). The device assignments were placed in concealed envelopes, which were labelled with a sequential number. The other investigators, the patients, the patients’ relatives, the attending physicians, and the nurses were all blinded to the study assignment. The concealed envelope was opened after the patient was enrolled with a signed informed consent.

After extubation, the patient underwent HFNC or NIV depending on the results of randomisation. For the HFNC group, a High-flow: Optiflow® system was used. The device setting was started at an oxygen flow rate of 30 L/min at a temperature of 37 °C. The flow rate was titrated by 5 L/min every 10 min to achieve patient demand while maintaining arterial blood pH > 7.35 and PaCO₂ < 60 mmHg. The maximum flow rate was not more than 50 L/min. The fraction of inspired oxygen (FiO₂) was started at 40% and adjusted to maintain the patient’s oxygen saturation at 92% or more. The HFNC device was continuously applied to the patient for 24 h. If the patient remained clinically stable, the setting was reduced according to the patients' status.

For the NIV group, a Drager Carina noninvasive ventilator with a full facemask interface was used. The NIV interface size was selected to cover the patient’s mouth and nose to minimize air leakage. The NIV interface was hand held by a physician while adjusting the NIV pressure setting for 10 to 15 min. Once the patient was familiar with NIV assistance, a strapped mask was applied that was tight enough to minimize air leakage while avoiding patient discomfort. The bilevel positive airway pressure (BiPAP) mode was used beginning with an inspiratory positive pressure (P_inp) of 8 cmH₂O and expiratory positive pressure (P_exp) of 5 cmH₂O. The FiO₂ was started at 40% and adjusted to maintain the patient’s oxygen saturation at 92% or more. The P_inp was titrated by 2 cmH₂O every 10 min to achieve patient demand while maintaining arterial blood pH > 7.35 and PaCO₂ < 60 mmHg. The maximum P_inp was limited to 20 cmH₂O. The device was continuously applied to the patient for 24 h, except during airway secretion clearance. If the patient remained clinically stable for 24 h, the duration and setting of NIV use was reduced according to the patient’s status. Standard intensive care unit monitoring, including electrocardiography, oxygen saturation, and exhaled PaCO₂, were continuously performed. Arterial blood gas analysis was performed 1 h after applying the device.

The primary outcome of this study was the rate of reintubation at 72 h after planned extubation. Reintubation was performed if patients developed one of the following conditions: (i) respiratory or cardiac arrest, (ii) respiratory pauses with loss of consciousness or gasping for air, (iii) Glasglow coma score < 8, (iv) massive aspiration or persistent inability to remove respiratory secretions, (v) heart rate < 50 or > 140 beats/minute with signs of poor tissue perfusion, (vi) severe hemodynamic instability unresponsive to treatment, (vii) extubation failure unresponsive to treatment for 30 min, and (viii) reintubation because of other reasons, such as urgent surgery. The reintubation was performed by the patient’s attending physician. The definition of extubation failure included (1) respiratory rate > 35 breaths/minute, (2) oxygen saturation < 90% or PaO₂ < 80 mmHg despite receiving FiO₂ > 50%, (3) respiratory acidosis with pH < 7.35 or PaCO₂ > 50 mmHg or an increase of 20% from baseline. Patients with these findings were treated with the assigned device adjusted to its upper limit of the protocol. If the extubation failure did not improve, the patient was switched to the other device as the rescue therapy. We limited rescue therapy to 30 min under close observation. Patients who continued to deteriorate after changing the device were reintubated. Patients who required reintubation or died before reintubation were also described as extubation failure. The secondary outcomes were reintubation rates at 7 days, at 28 days after extubation, rate of extubation failure at 72 h, ICU mortality rate, hospital mortality rate, and the 28-day mortality rate.

From our experience with critically ill medical patients on NIV, we observed that 40% experienced extubation failure [28]. We hypothesized that HFNC would reduce the reintubation rate by an absolute 20% reduction. Enrolment of at least 102 participants per group would provide at least 90% power to detect a difference of 20% in the primary outcome between the two groups at a two-sided alpha error of 0.05.

Continuous variables were presented using either mean (standard deviation) or median (range) and analysed by t test or Wilcoxon rank-sum test, when suitable. Categorical variables were presented using frequency and percentage. Chi-squared test or Fisher’s exact test was used as appropriate. The primary and secondary outcomes were analysed by Chi-squared test and presented as relative risk with a 95% confidence interval (CI). The Kaplan–Meier curve was used to assess time from extubation to reintubation, followed by a comparison using the log-rank test at 72 h. For mortality analysis, the 28-day mortality was calculated from the date of extubation. All primary and secondary outcome analyses were based on the intention-to-treat principle and a P value < 0.05 was considered statistically significant. Data were analysed using SPSS Statistics version 18 (SPSS.Inc., Chicago, IL). This study was registered on the ClinicalTrials.gov database (identification number: NCT03246893).