Summary: High flow nasal therapy versus noninvasive ventilation as initial ventilatory strategy in COPD exacerbation: a multicenter non inferiority randomized trial.

Topic: Primary Support

Cortegiani et al.High flow nasal therapy versus noninvasive ventilation as initial ventilatory strategy in COPD exacerbation: a multicenter non inferiority randomized trial.Crit Care (2020) 24:692.https://doi.org/10.1186/s13054-020-03409-0

Cortegiani and colleagues conducted a multicenter, non-inferiority randomized trial comparing high flow nasal therapy (HFNT) and noninvasive ventilation (NIV) in nine centers in Italy to evaluate the short-term effect of HFNT versus NIV in patients with mild-to-moderate acute exacerbation of chronic obstructive pulmonary disease (AECOPD). The investigators hypothesized that HFNT is non-inferior to NIV on CO2 clearance after 2 h of treatment. In this trial, the investigators found that HFNT was statistically non-inferior to NIV as initial ventilatory support in decreasing PaCO2 after 2 h of treatment in patients with mild-to-moderate AECOPD, considering a non-inferiority margin of 10 mmHg. However, 32% of patients receiving HFNT required NIV by 6 h.

The study enrolled adult patients > 18 years old, with a diagnosis of COPD exacerbation according to GOLD criteria admitted for a mild-to-moderate acute hypercapnic respiratory failure, with an arterial pH between 7.25 and 7.35 and a PaCO2 ≥ 55 mmHg. Exclusion criteria included received HFNT or NIV before the study enrolment and long-term domiciliary NIV among other criteria.

In the intervention group, patients received HFNT (Optiflow and MR850 or AIRVO™ 2, Fisher & Paykel Healthcare, Auckland, New Zealand), initially set at 60 L/min. In the control group, patients received NIV through a total full-face or oro-nasal mask. The ventilator was set in Pressure Support Ventilation (PSV) mode, with a PEEP titrated between 3 and 5 cm H2O. The inspiratory pressure was titrated to achieve a measured or estimated expiratory tidal volume equal to 6–8 mL kg−1 of ideal body weight.

The primary endpoint was the mean difference of PaCO2 to evaluate the non-inferiority of HFNT to NIV from baseline to 2 h after the randomization. Main secondary endpoints were non-inferiority of HFNT to NIV in reducing PaCO2 at 6 h in the per-protocol and intention-to-treat analysis and rate of treatment changes.

By 2 h, six patients in the HFNT group had switched to NIV (n = 5 worsening/no improvement of respiratory failure; n = 1 intolerance to the intervention) while one patient switched to HFNT (intolerance to the intervention) and one to IMV in the NIV group (worsening of respiratory failure). By 6 h, seven patients had switched to NIV (worsening/no improvement of respiratory failure), one to IMV (worsening of respiratory failure) in the HFNT group.

As regards to the primary outcome, absolute PaCO2 difference was 2.7 mmHg (1-sided 95% CI) and HFNT was non-inferior to NIV since the upper boundary of 95% CI did not reach the non-inferiority margin of 10 mmHg (p = 0.0003). Both treatments had a significant effect on PaCO2 reduction over time (time effect, p < 0.0001) and trends were similar between groups. Similar results were found in both per-protocol at 6 h and intention-to-treat analysis. By 6h, 32% of patients treated with HFNT were switched to NIV, even if patients had a slightly lower severity of illness than those in the NIV group. In addition, patients randomized to HFNT worsened the oxygenation during the 6 h, and those who subsequently underwent NIV during hospitalization had a longer length of NIV than those originally allocated to the NIV group.

HFNT group
NIV group
p value
Per protocol 2 hr
At baseline ( T0)74.0 +/- 13.572.2 +/- 13.30.5845
At 2 hrs ( T2h )67.2 +/- 16.462.7 +/- 13.50.1933
After 6 hrs ( T6h )64.5 +/- 15.857.9 +/- 12.20.0630
ΔT2h − T0− 6.8 mmHg (± 8.7)− 9.5 mmHg (± 8.5) 0.4040
ΔT6h − T0− 9.5 ± 13.0− 14.3 ± 11.10.0962
Δ difference in PaCO2 values between timepoints
Absolute PaCO2 difference was 2.7 mmHg (1-sided 95% CI 6.1), (p = 0.0003)

The authors suggest one study limitation was related to the design as a non-inferiority trial with a primary physiologic outcome, leaving uncertainty on stronger patient-related outcomes. In addition, due to the study design, the variables associated with the need for escalation of treatments cannot be adequately evaluated. The authors note that although they found lower baseline oxygenation in HFNT patients who escalated the treatment to NIV or IMV after 6 h compared to patients who did not switch, further studies should assess predictors for HFNT success in this patient population. Finally, this study was not a blinded study.

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