High-Flow Nasal Oxygen in Patients With COVID-19-Associated Acute Respiratory Failure

Ricard Mellado-Artigas; Bruno L. Ferreyro; Federico Angriman; Maria Hernandez-Sanz; Egoitz Arruti; Antoni Torres; Jesus Villar; Laurent Brochard; Carlos Ferrando


Crit Care. 2021;25(58) 

In This Article


In this multicentre observational cohort study of 122 matched, critically ill adult patients with COVID-19 associated acute hypoxemic respiratory failure, the use of HFNO was associated with an increase in VFDs and shorter ICU length of stay when compared to an early intubation strategy. No significant differences were evident in all cause in-hospital mortality.

The COVID-19 pandemic has unveiled the ongoing uncertainty and resulting discussions as to whether patients presenting with significant hypoxemia should undergo an early intubation strategy or whether, on the contrary, a conservative non-invasive approach could be offered.[39–41] Importantly, the benefits of the use of non-invasive oxygenation/ventilation strategies in the context of acute respiratory failure need to be balanced against the risk of treatment failure, given its potential association with worse clinical outcomes in non-COVID-19 populations.[6,7] The results of this analysis are consistent with other studies showing potential beneficial effects of HFNO in the context of COVID-19 associated acute respiratory failure[42] and reinforce recent evidence showing that HFNO was associated with a reduced risk of intubation in this patient population.[43]

To the best of our knowledge, this is the first study specifically comparing HFNO with an early intubation strategy. This study provides additional evidence that in a population with similar baseline characteristics and a potential to be randomized to any of these interventions, the use of HFNO may be associated with an increase in VFDs and shorter duration of ICU length of stay without any significant difference in mortality. Of note, on average, patients receiving early intubation in our cohort were sicker at baseline, as assessed by higher SOFA and APACHE II scores. However, matching achieved good balance in most of the covariates assessed and our results were robust to a variety of sensitivity analysis, including a secondary analysis in which adjustment by imbalanced variables was performed. Further, in the matched population, hypoxemia was profound despite the use of high FiO2 and the benefit spanned across the entire spectrum of PaO2/FiO2 values, as shown by our sensitivity analysis stratifying by oxygenation levels. This finding suggests that moderate-to-severely hypoxemic patients affected by COVID-19 may benefit from HFNO and that HFNO could potentially decrease the need and duration of mechanical ventilation and ICU length of stay without a negative impact in hospital mortality.

Several limitations need to be taken into account when interpreting the findings of our study. First, since treatment was not randomly allocated, both residual and unmeasured confounding are likely even after careful covariate adjustment. Nonetheless, the moderately robust E-value, together with a pre-planned emulation of a target trial increase the confidence in our study findings. Second, the use of VFDs as the primary outcome could be considered to favour upfront the HFNO group, given that a significant proportion of patients on HFNO was not subsequently intubated. As reported elsewhere, this endpoint encompasses both the time spent on mechanical ventilation as well as mortality and, for any given value in a population, both components should be provided to avoid misleading conclusions.[32] Given the similar mortality risk in both groups, the observed differences in VFDs between groups may be mostly driven by a reduction in the need for intubation among those initially treated with HFNO or, as previously stated, may also be due to unmeasured or residual confounding (e.g., patients who are sicker at baseline predominantly receive early invasive mechanical ventilation and have lower VFDs than those who have less severe disease and initially receive HFNO). Although an untestable assumption, our E-value and robustness to a variety of sensitivity analysis may point towards a potential causal effect rather than confounding as the main explanation for this finding. Explicitly, if both the HFNO and early invasive mechanical ventilation groups are considered comparable at baseline (e.g., regarding their initial severity), then the reduction in VFDs remains informative as it points towards a reduction in intubation as the likely mechanistic pathway—something that has been shown elsewhere in the broad population of critically ill patients with acute respiratory failure. Third, sample size was limited due to the inability to match a significant proportion of patients. This has to be understood in the context of populations differing significantly (the overall group of patients receiving early intubation was sicker) and the choice of very strict adjustment criteria to improve the precision of the estimates. In light of this fact, clinicians should keep in mind that the potential benefit of the treatment might be limited to patients with similar characteristics to the matched cohort (moderate-to-severe hypoxemic patients without concomitant non-pulmonary organ dysfunction) although two additional sensitivity analysis using the whole population also favoured HFNO. Fourth, missing information was present for several covariates of interest possibly resulting in both information bias and residual confounding. However, our multiple imputation-based results were consistent with the complete case analysis. Fifth, misclassification of relevant covariates and potential predictors is also likely. However, a concise operational manual was provided to all researchers at the study initiation, and two investigators checked for the accuracy of the data and unreliable values for all included patients. Sixth, criteria for intubation were not uniformly defined, and hence, the reported rate of failure and the effect of HFNO may not be generalizable to other settings with distinct clinical practice patterns. Sixth, code status at admission was not recorded and this might have impacted the rate of intubation in the conservative group. Indeed, despite achieving good balance between groups after matching, the presence of cancer was still more common in the conservative group. However, the mortality risk was similar across groups, our results were robust across sensitivity analysis adjusting for imbalanced covariates, and the intubation risk in the conservative group was 38%, which is in line with previous reports.[27] Finally, this study cannot offer any information regarding a potential increased risk of COVID-19 infection in healthcare professionals with HFNO use although studies have not been able to show an increase risk with this therapy.[44]