Non-invasive respiratory support (NIRS) such as non-invasive ventilation (NIV) or High-Flow Nasal Cannula (HFNC), is commonly used in acute hypoxemic respiratory failure (AHRF), a common complication of many diseases with a mortality of up to 45%.1 Its utilization has been shown to avoid the need for intubation improving clinical outcomes in selected patients but without clear benefits in mortality rates.2–4. The use of NIRS may directly reduce the complications associated with endotracheal intubation and invasive mechanical ventilation (IMV).5–11 However, approximately 37.5% of patients treated with NIRS still require endotracheal intubation.1,7,12–14

Although NIV was the only NIRS strategy available and used for AHRF for many years, in 2015, Frat et al. published a landmark paper supporting the role of HFNC in the management of AHRF, and its use rapidly increased over the years. They showed that its use was associated with lower mortality, more ventilator-free days, and a lower risk for intubation in subsets of severe hypoxemic patients.15–17. Currently, combined use of NIRS strategies has been described. In this regard, Frat et al. used HFNC as a rest tool to increase NIV tolerability, and Wang et al. used sequential HFNC and NIV in the post-extubation period.18,19 However, there is limited data regarding the specific switches performed in patients with AHRF (NIRS patterns) and their association with clinical outcomes.

Despite the significant benefits of NIRS, some studies have shown that patients who fail NIRS as the initial therapy for AHRF present worse outcomes. This has been convincingly demonstrated with NIV, especially in patients treated for pneumonia, but also with HFNC.20–22. The latest European Respiratory Society (ERS)/American Thoracic Society (ATS) guidelines for non-invasive AHRF management23 and the ERS guideline for the management of severe community-acquired pneumonia24 did not provide formal recommendation to follow when NIRS techniques fail and there are no specific standardized criteria for NIRS failure that can be used in clinical practice or research studies. In this context, two scales have been described and validated to predict NIRS failure, ROX index for HFNC and HACOR score for NIV.25,26 However, they are not commonly used in daily clinical practice due to their high specificity to be useful since they do not usually anticipate clinical criteria in predicting failure. Lack of recommendations in the national or international guidelines and the low usability of the available scales could lead to an uncontrolled use of NIRS, including multiple NIRS switches that could delay intubation, worsening the outcomes of some patients.27–29 In this sense, it has been described the imperative need to monitor the patient's clinical trend towards improvement, stagnation or deterioration during the initial use of NIV (NIV-trial), to avoid delaying endotracheal intubation, as it can lead to increased mortality.27–29 However, specific criteria to define the failure of a NIV-trial have not been established yet.

The aim of this study was to describe the pattern of combined NIRS use (HFNC and NIV), determining the reasons for switching NIRS and evaluating the association of specific NIRS switching strategies with clinical outcomes in patients with AHRF.

In this study we evaluated the combined use of NIRS (HFNC and NIV) in patients admitted to the ICU due to AHRF, determining the reasons for switching NIRS and evaluating the association of controlled strategies with clinical outcomes in these patients. The key findings of our study are as follows: 1) combined NIRS strategies is used in 32.5% of patients with AHRF needing NIRS; 2) clinical worsening is the main reason for switching from HFNC to NIV which is associated with higher rates of NIRS failure; in contrast, the main reason for switching from NIV to HFNC is clinical respiratory improvement, with a lower rate of NIRS failure; 3) following controlled NIRS switching strategies when combined NIRS is used, could be related with better outcomes.

Very few studies have been published on NIRS switches. Moreover, they do not discuss the impact of NIRS switch as a management strategy for AHRF, but rather as a rest tool for NIV (using HFNC during resting periods) or they analyze switches in different scenarios such as COVID-19 pandemics31 or during the weaning phase of mechanical ventilation in the post-extubation period.18,19 Recently, Marin-Corral et al.31 have published a Spanish multicentric study including 3889 COVID-19 patients describing the use of initial NIRS (HFNC or NIV) and their subsequent changes.31 Their results showed that 43% of critically ill COVID-19 patients initially underwent NIRS, 75% of them HFNC and 25% NIV. Moreover, among those severe patients who underwent NIRS due to COVID-19 AHRF, 11% were on combined NIRS strategies, being slightly more frequent the switch from HFNC to NIV (52.8%) than NIV to HFNC (47.2%). However, there are important limitations that do not allow us to compare these results. Importantly, in the COVID-19 scenario pandemic overload meant that decisions had to be made based on resource availability, including switches of NIRS strategy in order to reserve IMV for refractory cases. In this context, further research will be needed to evaluate the impact of pandemic in the future habits on the management of these patients in our environment.

Our study shows that the main reason for switching from HFNC to NIV is the clinical worsening of the patient, leading to an escalation in respiratory support. This is consistent with findings in the literature.32–35 Studies comparing HFNC with NIV have shown improved oxygenation with NIV but no reduction in work of breathing, as indicated by respiratory rate or inspiratory effort.15,36,37 Therefore, it would make sense to switch from HFNC to NIV during AHRF to improve hypoxemia. However, as there is not always an improvement in work of breathing (WOB) with NIV, it is logical that the failure rate of NIV is quite high. This may be because a significant percentage of patients experience a transient improvement in oxygenation without sufficient mechanical support, leading to a lack of improvement in respiratory mechanics.

High failure NIRS rates in patients switching from HFNC to NIV due to clinical worsening could suggest not recommending this strategy when HFNC fails. However, a different scenario arises when a NIV trial is performed as a controlled monitoring of NIRS in these patients. As previously described by Tomii et al., patients who undergo a NIV trial during AHRF of various causes, instead of proceeding directly to IMV, have a higher survival rate compared to those who do not undergo a NIV trial.38 Additionally, delayed intubation resulting from any NIRS intervention is known to be associated with increased mortality.6,39–41 In our study we retrospectively inferred those patients that could be treated following or not a controlled NIRS strategy based on NIV-trial criteria. In agreement with previous findings, our results suggest that a NIV trial after switching from HFNC therapy could be related with better outcomes decreasing the mortality rates in these patients undergoing both NIRS therapies. Therefore, based on our data, in those patients initially treated with HFNC who need switching to NIV, we recommend establishing thorough monitoring of the patient during the first 4−6 h of NIV use (to perform a NIV-trial). If clinical improvement does not occur during this period, it should be considered the endotracheal intubation and initiation of IMV to avoid unnecessary delays that could increase mortality.

Our results also show that the switch from NIV to HFNC is associated with clinical improvement in the patient, making it a potential therapeutic de-escalation. Despite HFNC providing lower oxygenation than NIV, in the context of clinical improvement and therefore improved oxygenation, a de-escalation to HFNC makes sense. Furthermore, it is widely recognized in the literature that HFNC is better tolerated than NIV.42 Therefore, once a patient improves with NIV and has lower oxygen requirements, transitioning to HFNC can increase comfort and tolerance to NIRS.3 In a different scenario, if the patient deteriorates while already on HFNC after NIV, and is switched back to NIV, the outcomes are not as favorable. In this situation, based on our results, the failure rate of NIV increases; and both ICU and hospital mortality also tend to increase. No specific recommendations can be made based on our findings; however, according to the results of the NIV-trial, applying NIV under strict supervision could be considered a valid therapeutic option.

This study has several limitations that should be acknowledged. First, it is a retrospective, single center study with a small sample size. It should be noted that although the study was retrospective, all the data analyzed were transferred directly and prospectively to the data management system of our ICU, and all the patients were treated by a homogeneous medical staff team. Then, all patients included in this study were thoroughly and comprehensively analyzed throughout their entire course, with detailed hourly assessments from their arrival at the ICU until their discharge, transfer, or death. Therefore, despite being retrospective, the detailed hourly analysis of each patient was specific and meticulous. Second, our patients did not undergo a prospective NIV trial; instead, it was inferred based on extensive and detailed clinical data collected after initiation of NIV and the clinician’s approach to the indication for initiation IMV. Third, the guidelines on respiratory failure, including guidelines on acute hypercapnic respiratory failure, do not provide specific details about the characteristics of an NIV trial. They only specify that if NIV fails, it should be discontinued and that the trial should be of short duration (without specifying the time). In this regard we have used the clinical criteria most used in previous studies where a NIV trial was used.23,43

In conclusion, this study demonstrates that NIRS combination is used in real life and that both switches’ strategies, HFNC to NIV and NIV to HFNC are common in AHRF transitioning from HFNC to NIV is suggested as a therapeutic escalation and in this context performance of a NIV-trial could be beneficial. Conversely, switching from NIV to HFNC is suggested as a de-escalation strategy that is deemed safe if there is no evidence of NIRS failure. Further research is needed to elucidate the impact of the NIRS switch strategy in patients with AHRF.

FJPG, JMC and JRM conceived and designed the study.

FJPG, JMC, AC, PPT, LP, JRB and MCG contributed to patient recruitment.

FJPG, JMC, OF, MIR and JRM made important intellectual contributions and actively participated in the interpretation of the data.

FJP and JMC wrote the paper.

AC, PPT, LP, OF and MIR made contributions to the writing and conceptual presentation of the results.

All authors contributed to critical examination of the paper for important intellectual content and approval of the final manuscript.

JRM: grants and non-financial support from Fisher & Paykel, personal fees from Dextro.

None of the other authors have any conflicts of interest to declare.

No funding was received for this study.

No funding was received for this study.

The institutional review board of PSMAR approved the original study (IRB Ref 2020/9050).