In this retrospective observational study of a prospectively collected 44 patients with AHRF from COVID-19, we found that 66% of patients receiving HFNC required EI. Moreover, we found that high SOFA and low ROX index were associated with HFNC failure.
Very few observational studies have looked at HFNC use in COVID-19 patients. Retrospective observational studies report a HFNC failure rate to range between 32–72% [13–16, 20]. The high variability in the reported HFNC failure rates might be attributed to several possible explanations. For instance, the definition of failure was not standardized in all studies, some defined failure as the need for NIV or EI [7, 8], while others defined failure as the need for EI or death [16, 20]. Furthermore, the threshold for intubation varies among ICU physicians as there is no consensus on how to determine HFNC or NIV failure. In addition, hypoxemia, disease intensity, and other baseline characteristics of patients varied between the studies.
Our observational study confirmed the observation of previous studies, where mortality was found to be higher in cases of HFNC treatment failure than in cases of success (34% versus 0%). Thus, clinicians treating hypoxemic COVID-19 patients should identify patients who are likely to benefit from HFNC treatment. Roca et al. found that the ROX index predicts HFNC failure in patients with AHRF secondary to pneumonia . They reported that a ROX of ≥ 4.88 measured after HFNC therapy at 2, 6, and 12 hours was associated with a lower risk of HFNC failure . However, the ROX index has not yet been validated in hypoxemic COVID-19 patients. In our study, we measured the ROX index prior to HFNC and at 2, 6, 12, 18, and 24 hours after HFNC treatment. The results showed a significant difference in the probability of success with the cutoff of 4.88 at 2, 6, 12, and 18 hours. After adjustment for other confounders, the ROX index and SOFA score were still strong predictors of HFNC treatment failure. In terms of the baseline characteristics upon ICU admission, the prevalence of hypertension, chronic kidney disease, and asthma was higher in patients with HFNC failure. However, the PaO2/FiO2 ratio at baseline was found to be higher in successful HFNC cases than in failed HFNC cases.
Similarly, another study included 62 patients with COVID-19-related AHRF, which showed that a ROX index measured after 4 hours of HFNC was significantly associated with HFNC success and low risk of EI . Our study adds to the existing knowledge by showing the potential utility of the previously established cutoff of ROX index for monitoring HFNC treatment in COVID-19-related AHRF. Another study showed that PaO2/FiO2 ≤ 100 mm Hg at ICU admission was a significant predictor of HFNC failure . The study by Wang et al.14 showed that none of the patients with PaO2/FiO2 > 200 mm Hg had HFNC failure compared to 63% failure in patients with low PaO2/FiO2 (≤ 200 mm Hg). Additionally, the RR was found to decrease significantly after 1–2 hours of HFNC in the successful cases .
Another retrospective study of 109 patients who were treated with HFNC, found that chronic obstructive pulmonary disease, high SOFA score at ICU admission, and high white blood cell count were predictors of HFNC failure . Interestingly, after adjusting for possible confounding variables, longer duration from ICU admission to EI was not associated with increased mortality in their cohort. A multicenter retrospective study included 43 patients treated with HFNC reported success with HFNC in 53.5% of the patients, while 46.5% needed EI or died . While the overall hospital mortality of that cohort was 32.9%, the hospital mortality rate for failed HFNC was 65%. Male sex and low SpO2 at admission were independent predictors of HFNC failure in the multivariate regression model . The accuracy of multiple monitoring parameters in predicting HFNC failure in COVID-19-related AHRF was assessed in one study, where RR ≥ 26/min after half an hour of HFNC application was associated with a higher risk of HFNC failure. However, the study was limited by small sample size (32 patients) and high SpO2 (100%) observed in a third of their cohort, which could participate in decreasing the contribution of SpO2/FiO2 in the diagnostic accuracy of ROX .
Ferrando et al. have examined the use of HFNC with awake prone positioning versus HFNC alone, in which they reported that out of the entire cohort, 82 patients (41%) required EI . They observed that awake prone positioning combined with HFNC did not reduce the EI rate compared to HFNC alone, with no significant difference in neither ICU LOS nor 28-day mortality rate . Nevertheless, these findings need to be confirmed with the currently ongoing multiple randomized controlled trials. Although this study has shown that awake prone positioning does not affect intubation and mortality rates, HFNC may remain an effective modality of respiratory support in which 117 patients (59%) of 199 patients on HFNC did not require EI and mechanical ventilation.
Most recently, a prospective multicenter study that involved 293 patients has reported 53% HFNC failure rate, in which half of the patients did not require mechanical ventilation . Moreover, they found that a high ROX index (per point increase) at 6 hours to be significantly associated with HFNC success cases (adjusted HR, 0.42; 95% CI [0.33–0.54]; p < 0.001). However, the mortality in patients who failed HFNC treatment was very high (92%) . This considerably high rate is inconsistent with neither previous studies nor the current study findings, which might be attributed to several reasons, including resource-constrained setting, the majority (64%) of their cohort were admitted to the ward in a non-critical care environment, and limited access to ICU expertise . Besides, there was a significant difference between the admitting settings of the two groups, where 45% of successfully treated patients were admitted to ICU setting compared to only 28% of the failed HFNC cases were treated in ICU setting (p = 0.004) . Although this study adds a great value to the current literature, it was aimed to assess the impact of HFNC in a resource-constrained setting; thus, it does not reflect the actual rate of HFNC failure mortality in an ICU care setting with optimal monitoring.
These findings indicate that with the application of appropriate selection criteria, a significant number of patients with COVID-19-related AHRF could avoid EI. Yet, HFNC therapy should not be provided to patients at a high risk of failure due to increased mortality in this particular group of patients.
This study has several strengths. First, it is one of the very few studies that investigated the use of HFNC in AHRF due to COVID-19, which can be a useful and safe intervention for appropriately selected patients in a pandemic situation. In addition, consecutive sampling, duplicate data collection, and quality monitoring are important strengthening points. The study looked at many different possible predictors of success and failure of HFNC treatment that can help physicians and respiratory therapists to select patients with the best chance of success and not delay EI when necessary. Another strengthening point is the adherence of the treating team with guidelines issued by the Saudi Critical Care Society and Survival Sepsis Campaign, in which there was no major changes or variations in patients management throughout the study period [17, 18].
However, this study also has several limitations. The observational nature of the study, lack of a control arm, plus a small sample size are important limiting factors in terms of clinical outcomes. Furthermore, since this was a single-center study, the generalizability of the results is limited. Further prospective randomized studies with a controlled arm are needed to confirm the results of this study.