Introduction
High-flow nasal cannula (HFNC) is a modality of non-invasive respiratory support that has been used worldwide in different acute settings. Recently, ERS clinical practice guidelines were published to provide recommendations to define the utility of HFNC. They suggest a trial of non-invasive ventilation (NIV) prior to use HFNC in patients with chronic obstructive pulmonary disease (COPD) and acute hypercapnic respiratory failure, pointing out the lack of strong evidence in favor to HFNC compared to the high certainty evidence for the use of NIV in this population [1].

Xia and coworkers [2] performed a multicenter randomized controlled trial among 16 chinese tertiary hospital to compared conventional oxygen therapy (COT) and HFNC in acute COPD exacerbation (AECOPD) patients with not acidotic hypercapnia (inclusion criteria: pH ≥ 7.35, PaCO2 > 45 mmHg).

Methods
Patients were randomized to receive HFNC or COT in a 1:1 ratio. The primary outcome was the need for intubation expressed with predetermined criteria (see main text).  The secondary outcomes were: the rate of treatment failure, occurred in case of patient’s intolerance, need for intubation or need for NIV (pH < 7.35, severe dyspnea, respiratory muscle fatigue or increase work of breathing or PaO2 < 50 mmHg), daily duration of HFNC and COT treatment during the first week, proportion of patients upgraded to NIV, actual intubation rate, length of hospital stay (HLOS) and costs, mortality rate in the hospital and at day 90 and the readmission rate due to AECOPD at day 90. Exploratory outcomes were blood gas and BORG dyspnea periodically measured after randomization. More than 1200 patients were screened from July 2017 to December 2020, 330 of which were included in the final analysis, matching the calculated sample-size. 158 patients were randomized to HFNC group: initial flow was 25 l/minutes, and it was increased to patient’s maximum tolerance, while FiO2 was adjusted to obtain a SpO2 value of 90-95%. Oxygen flow rate administered by nasal cannulae in the COT group was set to reach the same SpO2 values.

Study population
Median age was 70 in the HFNC group versus 69 in the COT group, and the median APACHE II score was 10 in both groups. Median FEV1%predicted was approximately 32% in both groups. In the HFNC group, the median values of CO2 (mmHg), pH and HCO3- (mmol/l) were 50.4, 7.40 and 31.3 respectively. In the COT group, the median values of CO2 (mmHg), pH and HCO3- (mmol/l) were 51.7, 7.40 and 31.8 respectively.

Results

• No statistical difference was found in the primary outcome between the two groups: 2.5% (n=4) patients reached the intubation criteria in the HFNC group, while 0.6 (1%) in the COT group.
• The rate of treatment failure was similar in both groups (15,8% vs 14,4% in HFNC and COT respectively). Interestingly, the most common reason for treatment failure in the HFNC group was patients’ intolerance. Conversely, 72% of treatment failure in the COT group was due to need for NIV.
• No statistical difference was found in the proportion of patients upgraded to NIV between the two groups (9,5% vs 12,8%).
• Only one death was registered in the COT group, while no death was reported in the HFNC group.
• Compared with the COT group, patients in the HFNC group had a significantly higher HLOS (9 days vs 8 days, p = 0.021) and a higher hospital cost (p = 0.006).
• No significant difference between the two groups were found in blood gas values and dyspnea.

Strength of this study 

-      This is the first randomized control trial comparing HFNC versus COT in acute exacerbated COPD without respiratory acidosis. In this group of patients ERS/ATS guidelines suggest not to use NIV, but medical therapy and, when needed, standard oxygen therapy targeted to a saturation of 88-92% [3].

-      The outcomes criteria are defined in detail and no decisions were taken independently from the study protocol by clinicians.

Weakness of this study

-      Patient’s adherence. Author reported that the median duration of HFNC treatment was 45 hours in the first three days after randomization and 82 hours during the first week after randomization compared to 52 and 111 hours in the COT group respectively (p = 0.027, p = 0.005 respectively; see additional table E2). This means that both the treatments were not performed continuously during daytime, but HFNC was more discontinued than COT. 

-      HFNC settings and gas exchange outcomes. Median HFNC flow was 30 l/min according to the patient’s tolerance. Authors reported that no significant changes were obtained in the HFNC in the first 72 hours of treatment, in contrast to previous studies, in which the flow rates were higher [4, 5].

-      A low intubation rate. Authors underline that the primary outcome rate was lower than expected, resulting in an underpowering of the study to show a statistical difference between the two treatment groups [6]. According to the author's discussion, this low intubation rate may be related to the improvement of non-invasive ventilation strategy. In fact, when NIV criteria were reached (NIV criteria are reported above), patients were promptly treated with NIV, avoiding intubation.

-      Mortality. Only one death was registered, in the COT group, developing a ventilator acquired pneumonia after intubation. This mortality rate could seem low for the population that has a median APACHE II of 10 [7].

Conclusions

 The study shows no statistical differences between HFNC and COT in avoiding intubation. In addition, the study suggests that there is no difference between patients treated with NIV after a failure of HFNC or COT. Authors concluded pointing out that the next studies should focus on patients with AECOPD and respiratory acidosis.

The study also showed that the proportion of patients upgraded to NIV (secondary outcome) was similar between the two groups.  A desirable goal of HFNC could be preventing acidosis and consequently avoiding upgrade to NIV in patients hospitalized with AECOPD and mild hypercapnia: it would be interesting to draw a RCT comparing HFNC and COT with a primary outcome focused to the patient’s need for NIV.

References

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