By Kathryn Radigan, MD, MSc

Attending Physician, Division of Pulmonary and Critical Care, Stroger Hospital of Cook County, Chicago

Dr. Radigan reports no financial relationships relevant to this field of study.

SYNOPSIS: A multicenter, randomized clinical trial of 641 adults deemed ready for weaning after at least 24 hours of mechanical ventilation revealed that the use of high-flow nasal oxygen (HFNO) with noninvasive ventilation immediately after extubation significantly decreased the risk of reintubation compared to HFNO alone in mechanically ventilated patients who were at high risk of extubation failure.

SOURCE: Thille AW, Muller G, Gacouin A, et al. Effect of postextubation high-flow nasal oxygen with noninvasive ventilation vs high-flow nasal oxygen alone on reintubation among patients at high risk of extubation failure: A randomized clinical trial. JAMA 2019;322:1465-1475.

Thille and colleagues conducted a multicenter, randomized clinical trial in 30 intensive care units (ICUs) in France between April 2017 and January 2018. The study involved 641 patients who were intubated more than 24 hours in the ICU, were ready for extubation after a successful spontaneous breathing trial, and were deemed high risk for extubation failure (i.e., > 65 years of age or with underlying cardiac or respiratory disease). Participants were randomly assigned to high-flow nasal oxygen (HFNO) alone (n = 306) or HFNO with noninvasive ventilation (NIV) (n = 342) immediately after extubation. Underlying chronic cardiac diseases included left ventricular dysfunction (left ventricular ejection fraction < 45%), history of cardiogenic pulmonary edema, ischemic heart disease, or permanent atrial fibrillation. Underlying chronic lung diseases included chronic obstructive pulmonary disease, obesity-hypoventilation syndrome, or restrictive pulmonary disease. Exclusion criteria included long-term treatment with NIV at home, contraindication to NIV, underlying neuromuscular disease, traumatic brain injury leading to intubation, patients with unplanned extubation (accidental or self-extubation), or patients with a do-not-reintubate order at the time of extubation.

Patients in the control group were treated continuously with HFNO for at least 48 hours with a flow of 50 L/min and fraction of inspired oxygen (FiO2) adjusted to maintain an oxygen saturation (SpO2) of at least 92%. Patients in the NIV intervention group were treated with NIV immediately after extubation, with a minimal duration of at least 12 hours per day during the 48 hours after extubation and specific attention to adherence at night. When the patient was not on NIV, HFNO was delivered. Both groups were treated for a minimum of 48 hours.

In terms of the primary outcome, on day 7, the reintubation rate was 11.8% (95% confidence interval [CI], 8.4% to 15.2%) in the NIV/HFNO group vs. 18.2% (95% CI, 13.9% to 22.6%) in the HFNO-only group (difference, −6.4%; 95% CI, −12.0% to −0.9%; P = 0.02). As for secondary outcomes, the proportion of patients with post-extubation respiratory failure at day 7 was significantly lower in the NIV/HFNO group (21% vs. 29%; P = 0.01), and reintubation rates up until ICU discharge also were lower in this group (12% vs. 20%; P = 0.009) compared to the HFNO-only group. However, ICU mortality rates were not significantly different: 6% in the NIV/HFNO group vs. 9% in the HFNO group (P = 0.25).


Successful liberation from mechanical ventilation on the first attempt without the need for reintubation is important. Approximately 10% to 15% of all patients extubated will fail, with higher numbers for those at particularly increased risk.1 In these patients at particularly increased risk, the mortality is 25% to 50%.2 To reduce risk, the most recent international practice guidelines published in 2017 made a conditional recommendation (low certainty of evidence) to use NIV to prevent post-extubation respiratory failure for high-risk patients, but recommended against NIV in low-risk patients and in those who develop post-extubation respiratory failure.3 Shortly before this recommendation, Hernández and colleagues revealed that HFNO prevents post-extubation respiratory failure and reintubation in the critically ill, specifically those patients at low risk of reintubation.4 Six months later, the same group showed that HFNO therapy was not inferior to NIV for preventing reintubation and post-extubation respiratory failure in high-risk patients.5 Of course, the question of whether NIV plus HFNO was better than HFNO alone sparks an interesting clinical question, especially since the clinical evidence supporting NIV was not profound. In this study, Thille and colleagues found that NIV with HFNO reduced the risk of reintubation at seven days post-extubation, but also up until ICU discharge.

The study’s protocol for administering NIV and HFNO was significant in the amount of time patients spent on NIV. Patients assigned to the NIV intervention group were started on NIV immediately after extubation. The first session lasted at least four hours, with a minimal duration of at least 12 hours per day during the 48 hours following extubation, with continuous application of NIV throughout the entire night period. The NIV/HFNO group was successful in maintaining a mean of 13 hours of NIV time within the first 24 hours. NIV was delivered with an ICU ventilator with NIV mode or a dedicated bilevel ventilator in pressure support (PS) mode with a minimal PS of 5 cm H2O targeting a tidal volume of 6-8 mL/kg of predicted body weight, a positive end-expiratory pressure (PEEP) level of 5-10 cm H2O, and an FiO2 targeted to SpO2 ≥ 92%. When NIV was not in use, HFNO was delivered as within the control group. Both groups continued for at least 48 hours, but the treatment was continued until there were no signs of respiratory failure. Although the control group was only supposed to receive HFNO, it is important to note that 20 out of 70 patients who experienced post-extubation respiratory failure also received NIV as a rescue therapy for a mean of seven hours. Ten of these patients needed reintubation.

The real secret to this study was how the investigators achieved high adherence to the protocol, with only 6% of patients not tolerating NIV. One may question whether the high adherence was the result of the use of HFNO during the off time. The NIV/HFNO group benefits from both delivery systems. NIV assists ventilation by providing pressurized oxygenated gas to the airways through a tight-fitting facial mask. Although NIV is effective in offsetting the load of acute illness, it also may be poorly tolerated because of discomfort or claustrophobia, inadequate secretion clearance, and poor synchrony as a result of high respiratory rate and minute ventilation in patients with acute respiratory failure. This often leads to high inspiratory and expiratory pressures and predisposes the patient to increased air leaks and the need for a tighter fit, leading to more discomfort. The ability to offset this with HFNO, which is more comfortable because the high flow rates are closer to the patient’s flow rate, is a great alternative.6 The HFNO system also can flush out anatomical dead space in the nasopharynx and upper airway and keep secretions moist, promoting mobilization. Even patients with hypercapnia in addition to hypoxemia may benefit from the combination of upper airway CO2 clearance and decreased CO2 production from reduced metabolic demand. The balance between NIV’s ability to offset the load of acute illness with the comforts and benefits of HFNO likely led to the successful outcomes and optimal NIV adherence.

Interestingly, there was no significant interaction between partial pressure of carbon dioxide (PaCO2) at enrollment and treatment group with respect to reintubation (P = 0.25). The number of patients with elevated PaCO2 was evenly distributed between the NIV/HFNO and HFNO groups. Patients with PaCO2 > 45 mmHg before extubation had a significantly lower reintubation rate at day 7 with NIV/HFNO than with HFNO alone (8% vs. 21%; P = 0.049). The findings at seven days are not surprising, especially since there are data showing that prophylactic NIV in hypercapnic patients resulted in lower rates of respiratory failure and mortality after extubation.7

This study supports the use of NIV with HFNO immediately after extubation because it significantly decreased the risk of reintubation compared HFNO alone in patients who were mechanically ventilated and at high risk of extubation failure. This finding was most profound for hypercapnic patients, and appropriate clinical judgment should be used decide which patients within the high-risk, non-hypercapnic group will benefit the most. In the future, it would be interesting to explore the differences in outcomes between patients with chronic cardiac vs. pulmonary disease and aim for larger randomized controlled trials that could evaluate mortality as a primary outcome.


  1. Thille AW, Richard JC, Brochard L. The decision to extubate in the intensive care unit. Am J Respir Crit Care Med 2013;187:1294-1302.
  2. Thille AW, Boissier F, Ben Ghezala H, et al. Risk factors for and prediction by caregivers of extubation failure in ICU patients: A prospective study. Crit Care Med 2015;43:613-620.
  3. Rochwerg B, Brochard L, Elliott MW, et al. Official ERS/ATS clinical practice guidelines: Noninvasive ventilation for acute respiratory failure. Eur Respir J 2017;50:1602426.
  4. Hernàndez G, Vaquero C, Gonzalez P, et al. Effect of postextubation high-flow nasal cannula vs conventional oxygen therapy on reintubation in low-risk patients: A randomized clinical trial. JAMA 2016;315:1354-1361.
  5. Hernàndez G, Vaquero C, Colinas L, et al. Effect of postextubation high-flow nasal cannula vs noninvasive ventilation on reintubation and postextubation respiratory failure in high-risk patients: A randomized clinical trial. JAMA 2016;316:1565-1574.
  6. Drake MG. High-flow nasal cannula oxygen in adults: An evidence-based assessment. Ann Am Thorac Soc 2018;15:145-155.
  7. Ferrer M, Sellares J, Valencia M, et al. Non-invasive ventilation after extubation in hypercapnic patients with chronic respiratory disorders: Randomised controlled trial. Lancet 2009;374:1082-1088.