Article Text

Original research
High-flow nasal oxygen versus conventional oxygen therapy in patients with COVID-19 pneumonia and mild hypoxaemia: a randomised controlled trial
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  1. Claudia Crimi1,
  2. Alberto Noto2,
  3. Fabiana Madotto3,
  4. Mariachiara Ippolito4,5,
  5. Santi Nolasco6,
  6. Raffaele Campisi1,
  7. Stefano De Vuono7,
  8. Giuseppe Fiorentino8,
  9. Ioannis Pantazopoulos9,
  10. Athanasios Chalkias10,11,
  11. Alessandro Libra1,6,
  12. Alessio Mattei12,
  13. Raffaele Scala13,
  14. Enrico M Clini14,
  15. Begum Ergan15,
  16. Manel Lujan16,
  17. Joao Carlos Winck17,18,
  18. Antonino Giarratano4,5,
  19. Annalisa Carlucci19,20,
  20. Cesare Gregoretti4,21,
  21. Paolo Groff7,
  22. Andrea Cortegiani4,5
  23. on behalf of the COVID-HIGH Investigators
    1. 1Respiratory Medicine Unit, Policlinico “G. Rodolico-San Marco” University Hospital, Catania, Italy
    2. 2Department of Human Pathology of the Adult and Evolutive Age “Gaetano Barresi”, Division of Anesthesia and Intensive Care, University of Messina, Policlinico “G. Martino”, Messina, Italy
    3. 3Value-Based Healthcare Unit, IRCCS MultiMedica, Sesto San Giovanni, Milan, Italy
    4. 4Department of Surgical, Oncological and Oral Science (Di.Chir.On.S.), University of Palermo, Palermo, Italy
    5. 5Department of Anesthesia, Intensive Care and Emergency, University Hospital Policlinico Paolo Giaccone, Palermo, Italy
    6. 6Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
    7. 7Emergency Department, “S. Maria della Misericordia” Hospital, Perugia, Italy
    8. 8UOC Fisiopatologia e Riabilitazione Respiratoria, AO dei Colli, Naples, Italy
    9. 9Department of Emergency Medicine, Faculty of Medicine, University of Thessaly, Larisa, Greece
    10. 10Department of Anesthesiology, Faculty of Medicine, University of Thessaly, Larisa, Greece
    11. 11Outcomes Research Consortium, Cleveland, Ohio, USA
    12. 12Cardio-Thoracic Department, AOU Città della Salute e della Scienza, Molinette Hospital, Turin, Italy
    13. 13Pulmonology and Respiratory Intensive Care Unit, S. Donato Hospital, Arezzo, Italy
    14. 14Respiratory Diseases Unit, Department of Medical and Surgical Sciences, University Hospital of Modena, University of Modena Reggio Emilia, Modena, Italy
    15. 15Department of Pulmonary and Critical Care, Dokuz Eylul University, İzmir, Turkey
    16. 16Pneumology Service, CIBERES, Hospital de Sabadell, Barcelona, Spain
    17. 17Department of Medicine, Faculty of Medicine, University of Porto, Porto, Portugal
    18. 18Centro De Reabilitação Do Norte, Centro Hospitalar de Vila Nova de Gaia/Espinho, Vila Nova De Gaia, Portugal
    19. 19Department of Medicina e Chirurgia, Università Insubria Varese-Como, Varese, Italy
    20. 20Pulmonary Rehabilitation Unit, Istituti Clinici Scientifici Maugeri, Pavia, Italy
    21. 21Fondazione ‘Giglio’, Cefalù, Palermo, Italy
    1. Correspondence to Prof. Andrea Cortegiani, Department of Surgical, Oncological and Oral Science (Di.Chir.On.S.), University of Palermo, Via del vespro 129, 90127, Palermo, Italy; andrea.cortegiani{at}unipa.it

    Abstract

    Rationale In patients with COVID-19 pneumonia and mild hypoxaemia, the clinical benefit of high-flow nasal oxygen (HFNO) remains unclear. We aimed to examine whether HFNO compared with conventional oxygen therapy (COT) could prevent escalation of respiratory support in this patient population.

    Methods In this multicentre, randomised, parallel-group, open-label trial, patients with COVID-19 pneumonia and peripheral oxygen saturation (SpO2) ≤92% who required oxygen therapy were randomised to HFNO or COT. The primary outcome was the rate of escalation of respiratory support (ie, continuous positive airway pressure, non-invasive ventilation or invasive mechanical ventilation) within 28 days. Among secondary outcomes, clinical recovery was defined as the improvement in oxygenation (SpO2 ≥96% with fractional inspired oxygen (FiO2) ≤30% or partial pressure of arterial carbon dioxide/FiO2 ratio >300 mm Hg).

    Results Among 364 randomised patients, 55 (30.3%) of 181 patients assigned to HFNO and 70 (38.6%) of 181 patients assigned to COT underwent escalation of respiratory support, with no significant difference between groups (absolute risk difference −8.2% (95% CI −18% to +1.4%); RR 0.79 (95% CI 0.59 to 1.05); p=0.09). There was no significant difference in clinical recovery (69.1% vs 60.8%; absolute risk difference 8.2% (95% CI −1.5% to +18.0%), RR 1.14 (95% CI 0.98 to 1.32)), intensive care unit admission (7.7% vs 11.0%, absolute risk difference −3.3% (95% CI −9.3% to +2.6%)), and in hospital length of stay (11 (IQR 8–17) vs 11 (IQR 7–20) days, absolute risk difference −1.0% (95% CI −3.1% to +1.1%)).

    Conclusions Among patients with COVID-19 pneumonia and mild hypoxaemia, the use of HFNO did not significantly reduce the likelihood of escalation of respiratory support.

    Trial registration number NCT04655638.

    • COVID-19
    • Critical Care
    • Pneumonia

    Data availability statement

    Data are available on reasonable request.

    This article is made freely available for personal use in accordance with BMJ’s website terms and conditions for the duration of the covid-19 pandemic or until otherwise determined by BMJ. You may use, download and print the article for any lawful, non-commercial purpose (including text and data mining) provided that all copyright notices and trade marks are retained.

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    WHAT IS ALREADY KNOWN ON THIS TOPIC

    • High-flow nasal oxygen has been widely used worldwide in patients with COVID-19-associated respiratory failure with the aim of reducing the need for invasive mechanical ventilation even without rigorous clinical research proving its benefits in this patient population. No studies evaluating the effects of high-flow nasal oxygen on hospitalised patients with COVID-19 pneumonia and mild hypoxaemia were identified.

    WHAT THIS STUDY ADDS

    • The COVID-HIGH trial is the first multicentre randomised controlled trial to report results on the use of high-flow nasal oxygen in hospitalised patients with COVID-19 pneumonia and mild hypoxaemia. We found no significant difference on the rate of escalation of respiratory support within 28 days between patients randomised to high-flow nasal oxygen compared with conventional oxygen therapy in this patient population. Secondary clinical outcomes such as the likelihood of clinical recovery, the time to the first escalation of respiratory support, admission to intensive care unit, and mortality at 28 days and 60 days, were concordant with the primary outcome.

    HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE AND/OR POLICY

    • The pathophysiological effects of high-flow nasal oxygen are unlikely to significantly affect the clinical course of COVID-19 pneumonia-related mild hypoxaemia compared with conventional oxygen therapy. Thus, in this patient population, high-flow nasal oxygen should not be used as routine strategy for oxygen supplementation.

    Introduction

    Almost 80% of hospitalised patients with COVID-19 need oxygen therapy,1 and up to one-third develop severe pneumonia2 that may require non-invasive respiratory support or invasive mechanical ventilation (IMV).3 4

    In patients with moderate-to-severe acute hypoxaemic respiratory failure, high-flow nasal oxygen (HFNO) has been promoted as an effective means of improving oxygenation and decreasing escalation of respiratory support and intubation when compared with conventional oxygen therapy (COT).5 6 In non-COVID-19-related acute hypoxaemic respiratory failure, international guidelines recommend using HFNO as the first-line respiratory support intervention with moderate certainty of evidence.7 8

    HFNO has been used extensively in patients with COVID-19.9 10 The potential benefits of HFNO in this population include the ability to match inspiratory demand, thus reducing inspiratory resistance, delivery of humidified warm gas mixture with a stable fraction of inspired oxygen (FiO2), preservation of mucociliary function and dead space wash-out.11 HFNO can also improve respiratory mechanics12 and end-expiratory lung volume13 and reduce respiratory rate and inspiratory effort.14 Therefore, these effects may theoretically prevent the progression of lung damage.15 Recently, a trial conducted in patients with severe COVID-19 demonstrated that HFNO compared with COT reduced the need for IMV and time to clinical recovery.16 In hospitalised patients with COVID-19 pneumonia and mild hypoxaemia, whether HFNO provides similar advantages over COT remains unclear.

    The COVID-HIGH multicentre trial was designed to test the hypothesis that in hospitalised patients with COVID-19 pneumonia and mild hypoxaemia, treatment with HFNO compared with COT decreases the likelihood of escalation of respiratory support within 28 days.

    Methods

    Study design

    We conducted this investigator-initiated, open-label, parallel-group randomised controlled trial (the COVID-HIGH trial) at 27 centres in 6 countries (Italy, Greece, Spain, Portugal, Poland, Turkey). A complete list of the participating sites is available in online supplemental eTable 1. Patients underwent screening and randomisation between 10 February 2021 and 26 August 2021. The trial was overseen by an oversight committee comprised of independent clinicians with no competing interests.

    Patients

    Eligibility criteria were hospital admission <48 hours in any department managing patients with COVID-19 pneumonia; age ≥18 years old; positive PCR test confirming SARS-CoV-2 infection; clinical signs of acute respiratory infection and radiological evidence of pneumonia; peripheral oxygen saturation (SpO2) ≤92% or arterial partial pressure of oxygen to fraction of inspired oxygen (arterial oxygen tension (PaO2)/FiO2) ratio <300 in room air and need for oxygen therapy17 according to clinical judgement, at screening.

    Exclusion criteria included respiratory rate ≥28 breaths/min and/or severe dyspnoea and/or use of accessory muscles; PaO2/FiO2 ratio ≤200; need for immediate intubation, continuous positive airway pressure (CPAP) or non-invasive ventilation (NIV) according to clinical judgement; patients already on CPAP/NIV or HFNO at study screening; septic shock; evidence of multiorgan failure; Glasgow Coma Scale <13; neuromuscular disease; presence of partial pressure of arterial carbon dioxide (PaCO2) >45 mm Hg (if blood gas available) or history of chronic hypercapnia. Patients already on long-term oxygen therapy and/or home NIV/CPAP or with limitation of care based on patients’ or physicians’ decision or with the inability to comprehend the study content and give consent were also excluded. Written informed consent was obtained from all patients or surrogates.

    Randomisation and masking

    Eligible patients were randomly assigned to a 1:1 ratio to either HFNO or COT throughout their hospitalisation or until reaching the termination criteria. A predefined list with permutation blocks having a fixed size of 4 was created by a statistician using SAS software (PROC PLAN). Block size was concealed. Randomisation was implemented using a web-based electronic system incorporated in the electronic case report form to ensure allocation concealment. Study data were collected, managed and stored using the Research Electronic Data Capture18 tool hosted at the University of Messina, Italy. The investigators of the study centres entered baseline variables and outcomes data into the electronic case report form from day 1 to 28 and on the 28-day and 60-day follow-up period. Blinding of patients and healthcare staff was not possible.

    Procedures

    Other than the randomly allocated interventions, all patients received treatments in accordance with the clinical judgement of treating physicians, local protocols and routine clinical practice. The randomly allocated treatments were started within 15 min of randomisation. In the intervention group, HFNO was delivered by any available device able to deliver it. The initial flow rate was set at 40 L/min and increased as required up to 60 L/min, according to patient tolerance. The temperature was set from 37°C to 31°C according to patient comfort. A surgical mask was placed over the HFNO cannula.19 In the control group, oxygen was delivered preferably by a Venturi mask, but any other device was allowed, and a table of conversion for FiO2 was provided. FiO2 and oxygen flow were titrated to maintain SpO2 between 92% and 96%20 in both groups.

    The criterion for weaning off study interventions was patients’ clinical recovery, defined as the improvement in oxygenation with the ability to maintain SpO2 ≥96% with FiO2 ≤30% or PaO2/FiO2 ratio >300 mm Hg. Any change from COT to HFNO (or vice versa) was considered a protocol violation.

    Predefined criteria for considering the escalation of respiratory support to CPAP, NIV or IMV were the presence of SpO2 ≤92% despite COT or HFNO or PaO2/FiO2 ratio ≤180 mm Hg with FiO2 ≥50%, and at least one of the following: respiratory rate ≥28 breaths/min, severe dyspnoea, signs of increased work of breathing (eg, use of accessory muscles). The type of respiratory support chosen for escalation was selected by treating physicians based on their clinical judgement. Escalation of respiratory support could be performed in the hospital ward where the patient was admitted or after being transferred to the intensive care unit (ICU).

    Outcomes

    The primary outcome was the rate of escalation of respiratory support to CPAP, NIV or IMV within 28 days of randomisation.

    The secondary outcomes included the rate of clinical recovery, time to the escalation of respiratory support, type of respiratory support as the first-line escalation therapy by day 28, admission to ICU, hospital and ICU length of stay, dyspnoea score (range, 0 (no dyspnoea) to 10 (severe dyspnoea)), patient comfort score (range, 0 (severe discomfort) to 10 (perfect comfort)), SpO2/FiO2 ratio divided by Respiratory Rate (ROX index), National Early Warning Score 2, mortality at 28 and 60 days, and in-hospital, days free from CPAP/NIV/IMV, oxygen free days, treatment intolerance. No blinding of adjudication was performed for outcome assessments.

    Prespecified subgroup analyses were performed on the primary outcome according to time from symptoms onset to hospital admission (<5 vs ≥5 days), time from hospitalisation to enrolment (<6 vs ≥6 hours), age (<65 vs ≥65 years old), comorbidities (<1 vs ≥1) and respiratory rate at randomisation (<25 bpm vs ≥25 bpm).

    Statistical analysis

    We calculated that 346 patients would need to be enrolled for the trial to have an 80% power to show a 15% absolute reduction in the proportion of patients with the escalation of respiratory support (primary outcome) in the HFNO group at a two-sided α level of 5%, assuming that 55% in the COT group would need escalation.10 As compensation for a possible drop-out rate of 5%, the final study population included 182 subjects in each group, for a total of 364 subjects enrolled in the study.

    Scheduled interim analyses were performed after the enrolment of the first 122 and 243 patients considering the Haybittle-Peto boundary, p value threshold of 0.001. Interim analyses were reviewed by the trial oversight committee. No specific (mandatory) stopping rules were defined.

    Analysis was based on intention to treat, that is, all patients were analysed in the group they had been allocated, with no exclusions after randomisation other than for withdrawn consent.

    The effect size of the dichotomous primary outcome was measured using the risk ratio (RR) of escalation in the intervention versus control arm. Asymptotic normal distribution of RRs was assumed for estimating CI (Wald method). A mixed-effects logistic regression model was used to evaluate a possible centre effect on the primary outcome. OR and 95% CI were estimated as a relative measure of this effect, considering the variable ‘centre’ as a random intercept. Survival analysis was conducted to evaluate the probability of escalation of respiratory support during the study period and time-to-event, considering death and clinical recovery as competing risks. Cumulative incidence of escalation of respiratory support was estimated in each study group and compared using the Grey test. The effect size was described with the HR (95% CI), using the Fine and Gray subdistribution hazard function. The effect on the primary outcome was also evaluated in each predefined subgroup using the Gail and Simon test to assess qualitative interaction between study treatments and stratification variables.

    For dichotomous secondary outcomes, we reported the effect size as described for the primary outcome. For continuous secondary outcomes, the mean difference between groups (and 95% CI) was assessed to evaluate the treatment effect. Differences between treatment groups were assessed each day using unpaired Student’s t-test or unpaired Wilcoxon rank-sum test according to data distribution.

    A post hoc generalised linear model with log link and binomial distribution (log-binomial regression model) was performed using treatment (HFNO-COT) as independent variable and each variable used for subgroups analyses and sex, due to the predominance of male in our study cohort.

    All statistical tests of significance were two sided (α of 0.05). Analyses were performed using R software V.4.0.3 (R Foundation for Statistical Computing, Vienna, Austria) and SAS V.9.4 software (SAS Institute). The trial was prospectively registered with ClinicalTrials.gov on 7 December 2020 (NCT04655638) and no changes were made thereafter.

    Results

    Between 10 February 2021 and 26 August 2021, 1866 patients were screened, and 364 were randomised (182 received HFNO and 182 received COT; figure 1). Of the 364 participants, 2 withdrew consent for the use of data (one in each group), and 362 patients (mean age, 59 years (SD 14); 131 (36%) women) (online supplemental eTable 2) were included in the final analysis (n=181 in each group) (figure 1). Data for the primary outcome and the subsequent follow-up were obtained for all patients. The final 60-day follow-up date was 25 October 2021. Baseline characteristics and cointerventions were evenly distributed between groups (table 1 and online supplemental eTable 3).

    Figure 1

    Trial profile. aNo need for oxygen: SpO2 >92% or PaO2/FiO2 >300 in room air or no need for oxygen therapy according to clinical judgement, at screening. COT, conventional oxygen therapy; CPAP, continuous positive airway pressure; GCS, Glasgow Coma Scale; FiO2, fraction of inspired oxygen; HFNO, high-flow nasal oxygen; LTOT, long-term oxygen therapy; NIV, non-invasive ventilation; PaCO2, partial pressure of arterial carbon dioxide; PaO2, partial pressure of arterial oxygen; SpO2, peripheral oxygen saturation.

    Table 1

    Baseline characteristics of the intention-to-treat population

    At randomisation, mean SpO2 was 89% (SD 2) and mean respiratory rate was 21 breaths/min (SD 3) in both groups. The median dyspnoea score was 2 (IQR 2–3) and 3 (IQR 2–3) in the HFNO and COT groups, respectively. The mean Charlson Comorbidity Index21 was 2.2 (SD 2) in both groups (table 1). Median time from symptoms onset to hospital admission was 7 days (IQR 4–9) and 6 days (IQR 4–8), and the median time from hospital admission to randomisation was 8 hours (IQR 0–21) and 6 hours (IQR 0–22) in the HFNO and COT group, respectively (table 1).

    All patients in the intervention group received continuous HFNO starting immediately after randomisation, with a mean flow of 51 L/min (SD 9), mean temperature of 32°C (SD 1) and mean FiO2 of 45% (SD 16). In the COT group, mean FiO2 was 42% (SD 14). All the other characteristics of the interventions are described in online supplemental eTable 4. The median treatment duration was 4 days (IQR 2–7) in the HFNO group and 3 days (IQR 1–6) in the COT group. In twenty-eight patients (8%), there were protocol violations as the assigned intervention was changed at least once (n=2 in the HFNO group; n=26 in the COT group) (online supplemental eTable 4).

    Interim analyses were performed as planned and yielded p values of 0.059 and 0.12, respectively, for the primary outcome. As there was also no evidence of harm, the trial was continued.

    By day 28 after randomisation, 55 of 181 patients (30.3%) randomised to HFNO and 70 of 181 patients (38.6%) randomised to COT received escalation of respiratory support with no significant difference between groups (absolute risk difference −8.2% (95% CI −18% to +1.4%); RR 0.79 (95% CI 0.59 to 1.05); p=0.09) (table 2). Competing risk analysis of the cumulative incidence of escalation of respiratory support within 28 days according to the intervention showed no significant difference (HR 0.75 (95% CI 0.54 to 1.0); p=0.09) (figure 2). There was no significant centre effect on the primary outcome (OR 0.64 (95% CI 0.40 to 1.03)).

    Figure 2

    Cumulative incidence of escalation of respiratory support, according to the original assigned intervention.

    Table 2

    Primary and key secondary outcomes

    There was no significant difference between HFNO and COT in clinical recovery (69.1% vs 60.8%; absolute risk difference 8.2% (95% CI −1.5% to +18.0%), HR 1.14 (95% CI 0.98 to 1.32)), time to the first escalation of respiratory support (2 (IQR 1–3) vs 2 (IQR 1–3) days, mean difference −0.2 days (95% CI −1.2 to +0.7)), ICU admission (7.7% vs 11.0%, absolute risk difference −3.3% (95% CI −9.3% to +2.6%)) and median hospital length of stay (11 (IQR 8–17) vs 11 (IQR 7–20) days, absolute risk difference −1.0% (95% CI −3.1% to +1.1%)). There was no significant difference in the proportion of patients who received CPAP, NIV or IMV as the first-line strategy for escalation of respiratory support (table 2). Mortality was not significantly different between groups neither within 28 days (7.7% vs 7.2%; absolute risk difference +0.5% (95% CI −4.8% to +5.9%)), nor within 60 days (8.3% vs 8.3%; absolute risk difference +0% (95% CI −5.6% to +5.6%)). A statistically significant difference in median dyspnoea score on the first time point at 2 hours and on days 3, 4 and 5 was found in the HFNO group compare to COT (online supplemental eFigure1). Respiratory rate and comfort score were not significantly different between groups at any time points (online supplemental eFigure1–3). None of the other secondary outcomes differed significantly between the two groups (online supplemental eTable 5).

    Prespecified exploratory subgroup analyses showed no qualitative interaction between study interventions and subgroups. However, the risk of escalation of respiratory support may be more pronounced among patients younger than 65 years old (22.5% vs 37.5%; RR 0.60 (95% CI 0.39 to 0.91)) and among patients whose duration of symptoms prior to hospital admission was ≥5 days (29.0% vs 42.5%; RR 0.68 (95% CI 0.49 to 0.95)) (figure 3, online supplemental eTable 6). In the post hoc generalised linear model with log link and binomial distribution, there was no credible effect of the variable used in the subgroups analyses and sex on the associations between study intervention and the occurrence of the primary outcome (online supplemental eTable 7).

    Figure 3

    Primary outcome in predefined subgroups of patients, according to the original assigned intervention. Square sides of data markers are proportional to subgroup sizes. Error bars indicate 95% CIs. The Gail and Simon test for interaction was used. COT, conventional oxygen therapy; HFNO, high-flow nasal oxygen; SPO2, peripheral oxygen saturation.

    Discussion

    This randomised controlled trial found no significant reduction in the escalation of respiratory support with HFNO compared with COT. These results suggest that pathophysiological effects of HFNO are unlikely to significantly affect the clinical course of COVID-19 pneumonia-related mild hypoxaemia compared with COT. However, these considerations should be seen in light of a lower than expected event rate and its contribution to the not significant difference in the primary outcome, also taking into account the minimum clinically important difference used for sample size calculation.

    HFNO can deliver more stable oxygen supplementation compared with COT, and it can provide several beneficial effects in terms of oxygenation, respiratory mechanics and patient’s effort.22 23 Thus, it is generally considered a form of non-invasive respiratory support.24 HFNO has been extensively used worldwide for respiratory support of patients with COVID-19 during the pandemic,9 even outside the ICUs,25 considering the shortage of intensive care beds and the relative ease of use.26 However, national and international organisations recommendations relating to the use of HFNO are inconsistent.27 Unprecedented demands for hospital resources and particularly oxygen requirements during the pandemic have led to oxygen shortages in many centres worldwide.28 HFNO requires a high amount of oxygen,29 especially in hypoxaemic patients who require high FiO2 and flows and, in a pandemic context, a judicious administration of oxygen should be considered. In the HFNO group, a lower proportion of patients underwent escalation of respiratory support and a higher proportion had clinical recovery. Thus, a small but clinically significant improvement associated with HFNO use cannot be excluded. However, considering the higher oxygen consumption and the inherent infection control concerns with HFNO,30 a substantial clear benefit would be required to support HFNO, which is lacking.

    Our trial hypothesis was based on the uncertainty of whether the overall effects of HFNO would provide significant clinical benefits in terms of risk for clinical deterioration compared with standard oxygen in the mild stage of COVID-19 pneumonia-related hypoxaemia. The RECOVERY-RS multicentre trial showed no difference between HFNO and COT for the composite primary outcome of intubation or mortality within 30 days (44.3% HFNO vs 45.1% COT, unadjusted OR 0.97 (95% CI 0.73 to 1.29), p=0.83) in COVID-19 patients.31 Although our results were in line with these data, our patient population and trial design differed significantly from RECOVERY-RS.31 The RECOVERY-RS recruited more severe patients with COVID-19 pneumonia-related hypoxaemia, with a SpO2 ≤94% despite receiving a FiO2 of at least 40%. Differently from our design, CPAP was one of the RECOVERY-RS study arms.31 A recent trial conducted in three centres in Colombia demonstrated that HFNO significantly reduced the risk of intubation (HR 0.62 (95% CI 0.39 to 0.96); p=0.03) and time to clinical recovery (HR 1.39 (95% CI 1.00 to 1.92); p=0.047) in patients with severe COVID-19 (FiO2 <200). The results of these trials suggest that the clinical benefit of HFNO over COT may differ according to the severity of COVID-19 pneumonia-related hypoxaemia.16

    To the best of our knowledge, this is the first trial evaluating HFNO compared with COT in patients with COVID-19 pneumonia-related mild hypoxaemia with the aim of reducing the likelihood of escalation of respiratory support. No patients were lost to follow-up, and the analysis was performed by intention to treat. The participation of 27 centres in 6 countries with different logistic characteristics confers external validity to our results.

    The trial has limitations. Due to the nature of the study interventions, blinding was not possible. However, clinical criteria used to decide on the escalation of respiratory support were standardised. Nonetheless, we acknowledge that subjectivity in clinical judgement could not be excluded. It is possible that, in selected cases, clinicians may have considered HFNO as a form of respiratory support and been less likely to escalate to CPAP/NIV compared with COT. Therefore, this may partly explain the higher rate of protocol violations observed in the COT group. The study was designed to detect an absolute difference of 15% (equal to a relative difference of 27%) for the primary outcome, considering an event rate of 55% in the control group that was the most likely at the time of trial design.10 However, the event rate was lower than expected (40% vs 55%). Therefore, the trial is underpowered to detect the hypothesised difference since it has a 60% of power for detecting a relative difference of 27%. By contrast, the study shows a power of 80% for detecting a relative difference of 35%, that corresponds to an absolute difference of 14%. These considerations suggest that a clinically meaningful benefit from HFNO in this patient population could not be definitely ruled out. In our cohort, 64% of patients were males and this may limit the generalisability of our finding towards the whole patient population. However, the adjusted RR for sex showed no significant effect on the association between occurrence of the primary outcome and study interventions. Due to the multinational and multicentre nature of the study, different surges of the pandemic may have had different indirect consequences on the level of care at the study sites. We did not register data on SARS-CoV-2 variants and the vaccination status of the participants. Finally, the results of the subgroup analyses should be considered exploratory as positive findings may be attributed to repeated testing.

    Conclusions

    The COVID-HIGH trial showed that HFNO did not significantly decrease the escalation of respiratory support compared with COT among hospitalised patients with COVID-19 pneumonia with mild hypoxaemia.

    Data availability statement

    Data are available on reasonable request.

    Ethics statements

    Patient consent for publication

    Ethics approval

    The study protocol was approved by the Ethics Committee of the coordinating centre (Comitato Etico Catania 1, 01/2021/PO, 25/01/2021) and all participating sites before patient inclusion. The study was performed in accordance with Good Clinical Practice guidelines and ethical principles of the Declaration of Helsinki.

    Acknowledgments

    We thank Professor Sharon Einav and Prof. Nicolino Ambrosino for their invaluable contribution and assistance for this trial and for their commitment as members of the Trial Oversight Committee. None mentioned herein were compensated.

    References

    Supplementary materials

    • Supplementary Data

      This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

    Footnotes

    • Twitter @Crimillina, @nolascos91, @chiccoclini, @AndCorteg

    • Collaborators COVID-HIGH trial collaborators: Drs. Sokol Berisha, Patrizia Pierini, Maria Rita Taliani, Francesco Balducci, Pasquale Cianci, Alessandra Lignani from Emergency Department, Santa Maria della Misericordia Hospital, Perugia, Italy; Drs. Pasquale Imitazione, Angela Mirizzi, Anna Annunziata, Antonietta Coppola, Francesca Simioli, Antonella Marotta from UOC Fisiopatologia e Riabilitazione Respiratoria AO dei Colli, Naples, Italy; Drs. Konstantinos Gourgoulianis, Athanasios Pagonis from Department of Emergency Medicine, Faculty of Medicine, University of Thessaly, Larissa, Greece; Drs. Eleni Laou, Konstantinos Tourlakopoulos from Department of Anesthesiology, Faculty of Medicine, University of Thessaly, Larisa, Greece; Drs. Ada Vancheri, Nicola Ciancio, Pietro Impellizzeri, Rossella Intravaia from Respiratory Medicine Unit, Policlinico ‘G. Rodolico-San Marco’ University Hospital, Catania, Italy; Drs. Ernesto Crisafulli, Giulia Sartori from Respiratory Medicine Unit, Department of Medicine, University of Verona, Verona, Italy; Drs. Valentina Musella, Leonello Fuso, Luciana Paladini, Gabriele Valli from UOC Malattie Apparato Respiratorio ed Endoscopia Bronchiale, AO San Giovanni, Roma, Italy; Drs. José Pedro Boléo-Tomé, Énia Ornelas, Miguel Filipe Guia from Pulmonology Department, Hospital Prof. Doutor Fernando Fonseca, Amadora, Portugal; Drs. Chiara Chiappero, Marco Bardessono, Mauro Mangiapia from Cardio-Thoracic Department, AOU Città della Salute e della Scienza, Molinette Hospital, Turin, Italy; Drs. Margherita Marelli, Cinzia Gambarini, Dania Mazzola, Giuditta Riganti from UO Pneumologia ASST-Settelaghi, Varese, Italy; Drs. Alberto Perboni, Sara Demichelis, Massimo Comune, Giulia Rovere from Pulmonology Department; San Luigi Gonzaga Hospital, Orbassano (TO), Italy; Drs. Luca Guidelli, Giacomo Ghinassi, Nicoletta Golfi from Pulmonology and Respiratory Intensive Care Unit, S. Donato Hospital, Arezzo, Italy; Drs. Antonella Spacone, Antonietta Esposito, Giorgia Rapacchiale from Respiratory Medicine Unit, General Hospital, Pescara, Italy; Drs. Antonio Voza, Carlo Fedeli, Sara Sauro from Dipartimento di Medicina d’Urgenza, Istituto Clinico Humanitas Research Hospital, Milano, Italy; Drs. Gianfilippo Gangitano, Ilaria Gessaroli, Davide Francia from AUSL Romagna, Emergency Department, Infermi Hospital, Rimini; Drs. Pablo Flórez, Cristina Lalmolda from Pneumology Service, Hospital de Sabadell, Spain, CIBERES; Drs. Valentina Pinelli, Stefania Artioli, Massimiliano Meazza from Division of Pneumology, Ospedale San Bartolomeo, Sarzana, La Spezia, Italy; Drs. Donato Lacedonia, Giulia Scioscia, Marcello Stomaci from Department of Medical and Surgical Sciences, ‘Policlinico Riuniti’ University Hospital, University of Foggia, Italy; Drs. Silvia Marani, Mara Bozzoli from Medicina Interna, Ospedale Ramazzini, Carpi, Ausl Modena, Italy; Dr. Mehmet Nuri Yakar from Dokuz Eylul University, Department of Pulmonary and Critical Care, İzmir, Turkey; Drs. Elisiana Carpagnano, Valentina Di Lecce from Institute of Respiratory Disease, Department of Basic Medical Science, Neuroscience, and Sense Organs, University of Bari ‘Aldo Moro’, Bari, Italy; Drs. Erika Zanardi, Monica Trentin from Aulss 7 Pedemontana, Ospedale Santorso, Santorso (VI), Italia; Drs. Szymon Skoczyński, Aleksandra Oraczewska from Department of Pneumonology, Faculty of Medical Sciences in Katowice, Medical University of Silesia - Katowice, Poland; Drs. Marco Contoli, Brunilda Marku from Respiratory Section, Department of Translational Medicine, University of Ferrara, Italy; Drs. Paola Noto, Eugenia Di Fazio from Emergency Medicine Unit, AOU Policlinico ‘G. Rodolico-San Marco’ University Hospital, Catania, Italy; Drs. Pierachille Santus, Dejan Radovanovic from Division of Respiratory Diseases, Ospedale Luigi Sacco, ASST Fatebenefratelli-Sacco, Department of Biomedical and Clinical Sciences (DIBIC), University of Milan, Italy; Dr. Luigi Marino, U.O. Pneumotisiologia, Ospedale di Vittorio Veneto, ULSS 2 Marca Trevigiana, Vittorio Veneto, Treviso, Italy.

    • Contributors PG, ACo and CC contributed to the concept and design of the trial. CC, ACh, FM, MI and SN wrote the first draft. FM performed the statistical analysis. All authors contributed to the data analysis and interpretation, critical revision of the publication, and final approval to submit. ACo, CC, AN and FM accessed and verified the data in this study and take responsibility for the integrity of the data and the accuracy of the data analysis. ACo and CC are responsable for the overall content as the guarantors. The COVID-HIGH trial collaborators consist of local investigators who were responsible for participant recruitment and local ethical board approval.

    • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

    • Competing interests ACh, AG and CG declare a patent, in association with the University of Palermo—Italy (No 102019000020532—Italian Ministry of Economic Development), not discussed in the present study. ACa received honoraria for lectures or consultancies from Breas, Philips (outside the submitted work). CC received honoraria for lectures from Philips, Resmed (outside the submitted work). CG received honoraria for lectures or consultancies from Vivisol, Philips, Mindray, Air Liquide (outside the submitted work). JCW received honoraria for lectures from Vitalaire, Nippon Gases, Philips, Breas and Armstrong Medical (outside the submitted work). The remaining authors declared no competing interests.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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