In December 2019, a series of pneumonia cases of unknown cause emerged in Wuhan (Hubei), China, whose clinical presentation was like viral pneumonia.1 The disease was named COVID-19. In March 2020, the WHO declared a pandemic due to the exponential increase in SARS-CoV-2 infections.2 Since then, healthcare systems around the world have been compromised because about 5% of patients develop critical illness secondary to acute respiratory distress syndrome (ARDS) and have to be admitted to high complexity units for respiratory support.3–6

Prepandemic studies have considered invasive mechanical ventilation (IMV) to be the first therapeutic option for patients in moderate or severe stages of ARDS.7,8 However, the “ICU overwhelming” circumstance during the pandemic9,10 led to a search being made for therapeutic alternatives, such as non invasive respiratory support (NIRS), given the possibility of preventing IMV in some individuals. These therapies are effective in many cases and offer added benefits, such as reducing not only IMV-related complications, including nosocomial infections, myopathy in critically ill patients and delirium,11 but also hospital stays and costs.12 These NIRS cases include high-flow nasal cannula (HFNC) and positive airway pressure (PAP) therapy either with continuous positive airway pressure (CPAP) or non invasive ventilation (NIV).

No consensus has been reached by different scientific societies about the most suitable NIRS for patients with ARDS due to COVID-19.13 A recent study demonstrated reduced tracheal intubation and lower mortality rates in patients with acute respiratory hypoxemic failure (ARHF) treated with CPAP compared to conventional oxygen therapy.14 This could be due to the ability to recruit alveoli and improve respiratory mechanics.15 In contrast, no differences appear between HFNC and conventional oxygen therapy.14 However, in patients who poorly adapt to and/or are intolerant to PAP, increased transpulmonary pressure and the occurrence of patient self-induced lung injury (P-SILI) may increase failure rates16 and result in increased mortality due to delayed IMV.8 For CPAP, prolonged periods of use and delivered pressure may be associated with poorer outcomes.17

Studies in post-extubation patients treated with HFNC+NIV combination have shown a lowering NIRS failure rate. This outcome is attributed to the benefits of positive pressure by allowing breaks with HNFC, which increases patient comfort by maintaining both peripheral oxygen saturation and respiratory rates stable compared to conventional oxygen therapy.18 To date, there is no evidence for the usefulness of this strategy in patients with ARDS.

In this context, we propose that the combined use of therapies, understood as treatment with HFNC plus positive pressure sessions with CPAP, can be a useful tool in the non invasive management of patients with ARDS secondary to SARS-CoV-2. Despite the theoretical benefits, a priori the profile of a patient requiring such treatment has not yet been described, nor has the ideal time to initiate it. For this reason, our main objective was to study the benefits of administering this combined therapy in the first 24h after admission to intermediate respiratory care units (IRCUs).

In this cohort study of patients with ARDS due to COVID-19, applying HFNC+CPAP in the first 24h of NIRS onset was associated with a significant reduction in endotracheal intubation and 30-day mortality compared to delayed onset. The EHC presented a significant reduction in hospital admission days and NIRS duration and an increase in tolerance to CPAP.

Several publications refer to HFNC+CPAP as an alternative for patients with COVID-19 and AHRF,13,20,23 but information on its effectiveness is scarce. Based on rotating HFNC with CPAP, the study by Colaianni-Alfonso et al.,24 recently reported an ETI rate of 41.6% and a mortality rate of 20.8%, similar to other published studies that applied different NIRS strategies.25 However, the lower mortality recorded in our series, especially in the EHC group, is remarkable. Studies with a similar sample size to ours, such as Kurtz et al.,26 Wang et al.,27 Bellani et al.21 or Franco et al.,20 describe mortality to be 22%, 63%, 38% and 30%, respectively. A possible explanation may lie in reduced P-SILI development, although in the absence of mechanisms to measure variables such as esophageal pressure, the possible decrease in P-SILI is a hypothesis and never a statement. Weaver et al.28 used a simulation model of patients with distress and NIV to demonstrate that an increase in both the RR and tidal volume (VT) can generate potential lung damage due to increases in pleural pressure, transpulmonary pressure and driving pressure. In the early treated patients, the RR lowered more and SpO2/FiO2 increased more on the days following combined therapy onset, which could serve as a surrogate variable for diminished respiratory drive. Tonelli et al.29 demonstrated that decreased respiratory drive lowers the likelihood of developing P-SILI and predicted the success of NIRS. Finally, in patients with COVID-19 with respiratory failure, Schifino et al. observed a reduction in RR and transesophageal pressure swings, a reliable assessment of respiratory effort, with HFNC compared to conventional oxygen,30 which would support the use of HFNC in CPAP breaks.

When analyzing mortality in patients undergoing ETI for IMV, the EHC group presented a significantly lower mortality rate than the DHC group (31.6% vs. 68.4%; p=0.01). Perhaps this was once again due to lesser P-SILI development before tracheal intubation, and it probably improved mechanics and response to treatment during IMV. Although between-group differences in NIRS duration could be considered a confounder for mortality by meaning an increased delay in ETI, it was not identified as a risk factor for mortality in the multivariate analysis.

No studies have demonstrated the usefulness of HFNC+CPAP for lowering the ETI rate in patients with de novo AHRF. Thille et al.31 demonstrated reduced reintubation after extubation in subjects treated with HFNC+NIV compared to HFNC alone. This was partly attributed to the combination of the benefits of PAP with diminished work of breathing during NIV rests with HFNC. Despite the different setting, it would seem that the stability of respiratory mechanics in PAP breaks is critical for lowering the risk of ETI in patients undergoing NIRS.

Moreover, CPAP break with HFNC can not only decrease the number of adverse ventilation-related events, but can also be applied for feeding and hydration, physiotherapy sessions, communication with family members, etc. Spoletini et al.18 demonstrated increased comfort and tolerability of the NIV combination with breaks of HFNC compared to breaks of standard oxygen. Significantly fewer adverse events, such as dry nose and mouth, eye irritation and difficulty eating, were observed in the HFNC group. CPAP intolerance in our cohort, understood as the need to discontinue CPAP due to adverse effects (flow or pressure was too strong, breathlessness, coughing, etc.), was almost twice in the DHC despite the median use of more than 5 days in both groups. We consider that early PAP usage in a stable situation can help to get used to the interface with better pressures than upon initiation in response to clinical deterioration.

This study has several limitations. First, due to its observational character, we can only show associations and not causality. In addition, there is no control group because the health care collapse limited the development of more robust clinical studies. Selection bias may limit data interpretation. However, we found that the two groups were homogeneous in the main predictors of severity with a similar disease process, and they received the same treatment and respiratory support, with HFNC+CPAP onset only at different times. To reduce the influence of confounders, we developed a multivariate model to mitigate the effect on the results. Second, its single-center nature limits the results being extrapolated. Additionally, the availability of devices may be a constraint for performing this NIRS strategy in other centers. Third, as no information on vaccination status was collected during the study period, it is impossible to assess the influence on the results. Finally, the treatment protocol in the IRCU does not allow comparisons to be made to CPAP or HFNC in monotherapy. So, it is impossible to reach conclusions about the superiority of therapies. However, our study also has its strengths. First, as far as we know, this is the largest cohort study to date of patients with ARDS by COVID-19 treated with a combination of respiratory therapies. Second, despite the widespread use of HFNC+CPAP in clinical practice and it being mentioned in many publications, our results for the relevant variables, such as mortality or orotracheal intubation, have not yet been reported. Third, our results may help to develop more scientific strength studies to demonstrate the potential usefulness of this strategy in non-COVID ARDS.

In patients with ARDS secondary to COVID-19, the HFNC+CPAP combination in the first 24h was associated with a significant reduction in ETI and 30-day mortality rates compared to initiation on the following days. Future studies that compare HFNC+CPAP to CPAP or HFNC in monotherapy to treat ARDS would be welcomed.

JT and PL had the idea for and designed the study, had full access to all data in the study and take full responsibility for data integrity and data analysis accuracy. JT, JGR, AN, LJD, JNL and PL drafted the paper. JGR and AN contributed to the statistical analysis. All the authors contributed to data acquisition, data analysis or data interpretation, and reviewed and approved the final version.

JTT, PL, JGR, LJD, JNL and ANL equally contributed.

This work was supported by University of Castilla-La Mancha intramural fundings.

Jose Rafael Teran-Tinedo declares a Madrid Society of Pneumology Young Researchers Grant 2020; funds from Air Liquide Healthcare for registration in the National Congress of the Spanish Society of Pneumology and Thoracic Surgery 2021; funds from Bial for registration in the European Respiratory Congress 2021 and 2022; funds from PharmaMar for secondary researcher in NEPTUNO clinical trial to evaluate utility of plitidepsin in COVID-19 patients. The payments were made to all the researchers; funds from GlaxoSmithKline (GSK) for Secondary researcher in OSCAR clinical trial to evaluate utility of otilimab in COVID-19 patients. The payments were made to all the researchers.

Miguel Lorente-González is a Secondary researcher in NEPTUNO clinical trial to evaluate utility of plitidepsin in COVID-19 patients. PharmaMar payments were made to all the researchers. He also declares payment from Gilead Sciences for a session at his hospital about the use of remdesivir in COVID-19 and registration in the XVII Regional Congress of the Madrilenian Society of Pneumology and Thoracic Surgery (NeumoMadrid) in May 2022.

Annette Zevallos-Villegas is a Secondary researcher in NEPTUNO clinical trial to evaluate utility of plitidepsin in COVID-19 patients. PharmaMar payments were made to all the researchers.

Eduardo Cano-Sanz is a Secondary researcher in NEPTUNO clinical trial to evaluate utility of plitidepsin in COVID-19 patients. PharmaMar payments were made to all the researchers.

Joaquín Hernández-Núñez is a Secondary researcher in NEPTUNO clinical trial to evaluate utility of plitidepsin in COVID-19 patients. PharmaMar payments were made to all the researchers.

Luis Puente Maestu funds from GSK for investigation and educational grants (institution); funds from MSD for sponsored study (no direct money); funds from Palex for investigation grant (institution); funds for Astra sponsored study (no direct money)

María Ángeles Ortega-Fraile is a Secondary researcher in NEPTUNO clinical trial to evaluate utility of plitidepsin in COVID-19 patients. PharmaMar payments were made to all the researchers.

Pedro Landete declares support for educational activities from Linde Healthcare, Bial, Boehringer Ingelheim, Air Liquide, GSK, FAES Farma and Novartis; payment from PharmaMar for expert investigation support; payment from Boehringer Ingelheim for registration for congress, travel and hotel; is on the PharmaMar Advisory board; funding from Phillips/Cardiva formedical writing at his institution.

All other authors have nothing to declare.