Tianyi Ai,Mingli Zhu,Zhiyun Zhang,Zhangjun Tan,Zhiqiang Shi,Hui Li,Shuyi Zhang,Xianyuan Zhao,Yulong Yao,Wen Li,Yuan Gao
MODIFIED RESPIRATORY RATE OXYGENATION INDEX: AN EARLY WARNING INDEX FOR THE NEED OF INTUBATION IN COVID-19 PATIENTS WITH HIGH-FLOW NASAL CANNULA THERAPY
COVID-19,HFNC,mROX index
Background High-flow nasal cannula oxygen therapy (HFNC) is recommended for patients with COVID-19. However, the increasing use of HFNC brings a risk of delayed intubation. The optimal timing of switching from HFNC to invasive mechanical ventilation (IMV) remains unclear. An effective predictor is needed to assist in deciding on the timing of intubation. Respiratory rate and oxygenation (ROX) index, defined as (SpO2/FiO2) / respiratory rate, has already shown good diagnostic accuracy. Modified ROX (mROX) index, defined as (PaO2 /FiO2) / respiratory rate, might be better than the ROX index in predicting HFNC failure. Objective The aim was to evaluate the predictive value of mROX for HFNC failure in patients with COVID-19. Methods Severe or critical patients with COVID-19 treated with HFNC were enrolled in two clinical centers. Laboratory indicators, respiratory parameters, and mROX index at 0 h and 2 h after initial HFNC were collected. Based on the need for IMV after HFNC initiation, the patients were divided into an HFNC failure group and an HFNC success group. The predictive value of mROX index for IMV was evaluated by the area under the receiver operating characteristic curve (AUROC) and logistic regression analysis. We performed Kaplan–Meier survival analysis using the log-rank test. Results Sixty patients with COVID-19 (mean ± SD age, 62.8 ± 14.1 years; 42 patients were male) receiving HFNC were evaluated, including 18 critical and 42 severe cases. A total of 33 patients had hypertension; 14 had diabetes; 17 had chronic cardiac disease; 11 had chronic lung disease; 13 had chronic kidney disease; and 17 had a history of stroke. The AUROC of mROX index at 2 h was superior to that of other respiratory parameters to predict the need for IMV (0.959; p < 0.001). At the mROX index cutoff point of 4.45, predicting HFNC failure reached the optimal threshold, with specificity of 94% and sensitivity of 92%. Logistic regression analysis showed that 2-h mROX index < 4.45 was a protective factor for IMV (odd radio 0.18; 95% CI 0.05–0.64; p = 0.008). In the HFNC failure group, the median time from HFNC to IMV was 22.5 h. The 28-day mortality of the late intubation patients (≥ 22.5 h) was higher than that of the early intubation patients (< 22.5 h) (53.8% vs. 8.3%; p = 0.023). Conclusions mROX at 2 h is a good early warning index of the need for IMV in patients with COVID-19 after HFNC initiation. Early intubation may lead to better survival in patients with 2-h mROX index < 4.45.
MODIFIED RESPIRATORY RATE OXYGENATION INDEX: AN EARLY WARNING INDEX FOR THE NEED OF INTUBATION IN COVID-19 PATIENTS WITH HIGH-FLOW NASAL CANNULA THERAPY

High-flow nasal cannula oxygen therapy (HFNC) is recommended for patients with COVID-19. However, the increasing use of HFNC brings a risk of delayed intubation. The optimal timing of switching from HFNC to invasive mechanical ventilation (IMV) remains unclear. An effective predictor is needed to assist in deciding on the timing of intubation. Respiratory rate and oxygenation (ROX) index, defined as (SpO2/FiO2) / respiratory rate, has already shown good diagnostic accuracy. Modified ROX (mROX) index, defined as (PaO2 /FiO2) / respiratory rate, might be better than the ROX index in predicting HFNC failure.

The aim was to evaluate the predictive value of mROX for HFNC failure in patients with COVID-19.

Severe or critical patients with COVID-19 treated with HFNC were enrolled in two clinical centers. Laboratory indicators, respiratory parameters, and mROX index at 0 h and 2 h after initial HFNC were collected. Based on the need for IMV after HFNC initiation, the patients were divided into an HFNC failure group and an HFNC success group. The predictive value of mROX index for IMV was evaluated by the area under the receiver operating characteristic curve (AUROC) and logistic regression analysis. We performed Kaplan–Meier survival analysis using the log-rank test.

Sixty patients with COVID-19 (mean ± SD age, 62.8 ± 14.1 years; 42 patients were male) receiving HFNC were evaluated, including 18 critical and 42 severe cases. A total of 33 patients had hypertension; 14 had diabetes; 17 had chronic cardiac disease; 11 had chronic lung disease; 13 had chronic kidney disease; and 17 had a history of stroke. The AUROC of mROX index at 2 h was superior to that of other respiratory parameters to predict the need for IMV (0.959; p < 0.001). At the mROX index cutoff point of 4.45, predicting HFNC failure reached the optimal threshold, with specificity of 94% and sensitivity of 92%. Logistic regression analysis showed that 2-h mROX index < 4.45 was a protective factor for IMV (odd radio 0.18; 95% CI 0.05–0.64; p = 0.008). In the HFNC failure group, the median time from HFNC to IMV was 22.5 h. The 28-day mortality of the late intubation patients (≥ 22.5 h) was higher than that of the early intubation patients (< 22.5 h) (53.8% vs. 8.3%; p = 0.023).

mROX at 2 h is a good early warning index of the need for IMV in patients with COVID-19 after HFNC initiation. Early intubation may lead to better survival in patients with 2-h mROX index < 4.45.

SARS-CoV-2 is a virus that mainly causes an acute infection of the respiratory tract. COVID-19 developed to a pandemic in March 2020 (1,2). Although most of the patients with confirmed COVID-19 and mild to moderate symptoms could recover quickly without any special treatment, the prevalence of acute hypoxic respiratory failure (AHRF) in patients with COVID-19 was approximately 19% (3). Multiple studies have found that high-flow nasal cannula (HFNC) plays an important role in managing AHRF (4, 5, 6). Previous studies have demonstrated the relationship between HFNC and improvements in oxygenation, lung mechanics, and tolerance (7, 8, 9). Successful HFNC is associated with a lower short-term mortality rate in immunocompromised patients with acute respiratory failure, more ventilator-free days, and a lower risk for intubation in severe respiratory failure patients (10,11). For adults with COVID-19 and AHRF, the Surviving Sepsis Campaign (SSC) has also suggested using HFNC over conventional oxygen therapy (12). However, the increasing use of HFNC brings a risk of delayed intubation in other causes of AHRF, such as bacterial pneumonia (13). This is the most important concern because previous studies have found that patients with failed noninvasive ventilator management of AHRF have a worse clinical outcome (14,15). The optimal timing of switching from HFNC to invasive mechanical ventilation (IMV) remains unclear. This may lead to considerable differences among clinicians in terms of the timing of intubation, which could affect patient outcomes. ROX index, defined as the ratio of SpO2/FiO2 and respiratory rate (RR), has a higher diagnostic accuracy than each of the two variables separately (16). Previous studies in patients with AHRF have found that patients with a lower ROX index after HFNC therapy were more likely to be intubated (17, 18, 19). Furthermore, on the basis of the research of Roca et al., who evaluated the capability of ROX index to predict failure of HFNC therapy, Karim et al. proposed that modified ROX (mROX) index, defined as PaO2 / (FiO2 · RR), might be better than ROX index in predicting HFNC failure (16,20). Specifically, the fall of SpO2 and PaO2 is not linear, and the ratios SpO2/FiO2 and PaO2/FiO2 are close when patients receive low-concentration oxygen therapy, but the correlation between the two becomes worse at higher oxygen inhalation concentrations (21,22).ROX index, a traditional prediction index, has been applied and studied adequately, but its abovementioned drawbacks are also obvious. Unfortunately, Karim et al. only put forward a theoretical hypothesis without testing it. With the limited available data from clinical trials, the predictive value of mROX for the need for IMV is still unknown. In this retrospective cohort study, we aimed to determine the predictive value of mROX index for the need to switch to IMV in patients with severe COVID-19 after HFNC therapy initiation.

This retrospective study was performed in patients with severe or critical COVID-19 treated with HFNC who were admitted to the intensive care unit (ICU; a traditional general ICU) of Shanghai Clinical Center from February 1 to April 30, 2020, and Shanghai Hospital from April 7 to June 7, 2022, China. Patients younger than 18 years and patients with an indication for immediate intubation were excluded. Patients with hypercapnic respiratory failure (pH < 7.2 and partial pressure of carbon dioxide in arterial blood (PaCO2) > 45 mm Hg) were placed on nasal intermittent positive pressure ventilation (NIPPV) instead of HFNC and thus were excluded. Invasive ventilation was initiated when hypercapnia continued to worsen (PaCO2 > 70 mm Hg) or was combined with hypoxemia (SpO2 < 92%). Patients with do-not-resuscitate orders were excluded. Sixty subjects (mean ± SD age, 62.8 ± 14.1 years; 42 were male) receiving HFNC were evaluated. HFNC failure was defined as the need for intubation for IMV. The permission statement to use clinical information regarding infectious diseases was sent to all of the patients or their close relatives (Supplementary Material). The patients were divided into the HFNC failure (intubation) group or the HFNC success (no intubation) group on the basis of need for intubation (HFNC to IMV conversion). This study was approved by University, School of Medicine, Hospital Ethics Committee (KY-2020-059).

HFNC was applied continuously via large-bore binasal prongs with Airvo 2 (Optiflow; Fisher & Paykel Healthcare).

Demographic characteristics, Sequential Organ Failure Assessment (SOFA), Acute Physiology and Chronic Health Evaluation (APACHE) II, clinical symptoms, laboratory testing (i.e., white blood cell count, lymphocyte count, C-reactive protein, interleukin-6, D-dimer, liver enzymes, and renal function parameters), respiratory variables, and blood gas analyses were collected at admission to the ICU. Arterial blood gas analysis by means of bedside testing (point-of-care testing) was conducted at 0 h and 2 h after HFNC initiation, which is the standard operation procedure in our department. We determined PaO2, FiO2, and RR, and then calculated mROX. All data collection and recording were performed by physicians within the medical team.

Severe cases were those meeting one of the following criteria: dyspnea, respiratory frequency ≥ 30 breaths/min; blood oxygen saturation < 93%; partial pressure of arterial oxygen to fraction of inspired oxygen ratio (P/F ratio) < 300; and lung infiltrates > 50% within 24 to 48 h (21). Critical cases were those meeting one of the following criteria: respiratory failure, septic shock, and multiple organ dysfunction or failure (23).

Data were presented as percentage, mean ± SD, or median (quartile [Q] 1, Q3), as appropriate. For categorical data, χ2 test was performed. Continuous data were compared using Student's t-test. Mann–Whitney U test was used for data that did not comply with normal distribution. Normal distribution was verified by Kolmogorov–Smirnov test. Receiver operating characteristic curve (ROC) analysis was performed to assess the accuracy of different variables for correctly classifying patients who would succeed or fail on HFNC, and the area under the receiver operating characteristic curve (AUROC) was calculated. The optimal threshold of continuous variables was chosen to maximize the sum of sensitivity and specificity according to the cutoff value described in the ROC curve analysis. We performed a logistic regression model incorporating all factors associated with HFCN failure in univariate analysis (univariate p < 0.05) to identify independent predictors of IMV. We performed Kaplan–Meier survival analysis using the log-rank test. A p value < 0.05 was considered statistically significant. We used SPSS software, version 20.0 (SPSS) for all analyses. The dependent variable was IMV (HFNC failure); independent variables were demographic data, respiratory parameters, and laboratory variables.

A total of 33 patients (55%) had hypertension; 14 patients (23.3%) had diabetes; 17 patients (28.3%) had chronic cardiac disease, including coronary heart disease and atrial fibrillation; 11 patients (18.3%) had chronic lung disease, such as chronic bronchitis and tuberculosis; 13 patients (21.7%) had chronic kidney disease; and 17 patients (28.3%) had a history of stroke. The median (Q1, Q3) duration from symptom onset to hospital admission was 4 (1,8) days, and the median (Q1, Q3) time from hospital admission to HFNC was 75 (6.25, 172.5) h. In all of the patients, mean ± SD SOFA score was 5.95 ± 1.21 and APACHE II was 8.95 ± 1.42 (Table 1 ). There were 25 patients in the HFNC failure group and 35 patients in the HFNC success group.

There was no significant difference in respiratory parameters, including RR, SPO2, PaO2, P/F ratio, ROX index, and mROX index, between the two groups at the 0-h point (Table 1). SpO2 (91.05% ± 5.22% vs. 95.71% ± 4.23%; p < 0.001), PaO2 (70.36 ± 15.45 mm Hg vs. 96.79 ± 34.68 mm Hg; p < 0.001), P/F ratio (107.45 ± 30.08 vs. 194 ± 65.14; p < 0.001), ROX index (3.00 ± 0.60 vs. 4.14 ± 0.73; p < 0.001), and mROX index (3.52 ± 1.06 vs. 8.36 ± 3.16; p < 0.001) at 2 h after HFNC initiation were significantly lower in the HFNC failure group than in the HFNC success group. The RR was significantly higher in the HFNC failure group than in the HFNC success group (31.52 ± 6.33 breaths/min vs. 23.8 ± 4.22 breaths/min; p < 0.001) at 2 h after HFNC initiation. Patients had a significantly higher lymphocyte count at admission to the ICU in the HFNC failure group than in the HFNC success group (median [Q1, Q3] 0.47 [0.35, 0.64] vs. 0.81 [0.57, 1.31]; p = 0.002). No significant difference in other laboratory results was found between the two groups (Table 1).

The median treatment duration of HFNC was 22.5 h in the HFNC failure group (patients who eventually switched to IMV). We divided patients from this group into the early intubation group (< 22.5 h) and the late intubation group (≥ 22.5 h) according to the mean time. Seven patients (53.8%) died within 28 days in the late group and only 1 patient (8.3%) died in the early group (log-rank test, p = 0.023; Figure 2).

When using respiratory parameters to predict the need for IMV, the AUROC of mROX index was superior to that of the other respiratory parameters (0.959; p < 0.001) (Figure 1 ). At the mROX index cutoff point of 4.45, the specificity (94%) and sensitivity (92%) reached the best combination. Logistic regression analysis showed that a higher mROX index was a strong protective factor against IMV (odds ratio 0.18; 95% CI 0.05–0.64; p = 0.008). When mROX index increased by 1, the risk of IMV decreased by 82% (Table 2 ).

As a pandemic disease, SARS-CoV-2 infection quickly spread across the world in early 2020. The Omicron variant of SARS-CoV-2 has been reported in Shanghai, China, since March 2022. Recent data indicated a 19% prevalence of severe or critical cases, and in 26.3% of these cases the patients were critically ill (3). We reported that 41.7% of adult patients with severe cases of COVID-19 had received IMV in the ICUs of two clinical centers in 2020 and 2022. From the available literature data, the risk factor associated with a critical illness or ICU admission is age older than 60 years (3,24,25). We reported that the mean ± SD age of patients with severe COVID-19 was 62.8 ± 14.1 years and patients from the HFNC failure group were older. Pre-existing comorbidities were more common among patients with severe COVID-19 disease in China, according to the Chinese Center for Disease Control and Prevention (3). Our data indicated that at baseline 55% of patients had hypertension; 23.3% of patients had diabetes; 28.3% of patients had chronic cardiac disease, including coronary heart disease and atrial fibrillation; 18.3% patients had chronic lung disease, such as chronic obstructive pulmonary disease and tuberculosis; 21.7% patients had chronic kidney disease; and 28.3% patients had stroke history. Almost all patients had one or more comorbidities. The SSC suggested using HFNC over conventional oxygen therapy for adults with COVID-19 and AHRF (12). HFNC has been an important approach to treating acute respiratory failure for the past 2 decades, and its use has been growing gradually (26,27). The major challenge of using HFNC for managing patients with AHRF is to avoid delayed intubation when necessary. All patients receiving HFNC should be monitored closely and cared for in a setting where intubation can be facilitated in the event of decompensation (28,29). There are many respiratory criteria (e.g., oxygenation and respiratory rate) associated with HFNC failure, but none of them have been strong positive predictors of HFNC outcomes (30,31). Recently, a systematic review reported ROX index as a good predictor of HFNC failure in patients with COVID-19 with AHRF (32). Although ROX index is a good parameter to predict HFNC failure, our previous study found that mROX index could be a more suitable predictor of HFNC therapy outcomes at the early phase in patients with AHRF, which is comparable with the findings of Karim et al., who stated that the mROX index might be better than ROX (18,20,33). First, SpO2/FiO2 is consistent with PaO2/FiO2 when a patient is receiving low concentrations of supplemental oxygen, but the consistency of their relationship is still unclear at FiO2 of 100%. Second, the correlation between SpO2/FiO2 and PaO2/FiO2 is not linear (34). Third, the ascent of SpO2 and PaO2 is not linear (21). Moreover, SpO2 in critically ill patients, such as those in shock, could not precisely reflect oxygenation because of the peripheral low perfusion. PaO2 value obtained from blood gas analysis could provide more predictability or accuracy. Therefore, SpO2 was continuously monitored by oxygen saturation detector in our ICU, but it was not recorded in the predefined interval post HFNC for study analysis. In the present study, we used mROX index to evaluate its value in predicting HFNC failure at 2 h after the initiation of HFNC therapy in patients with COVID-19. The mROX index < 4.45 may indicate HFNC failure. We found that this parameter was an early warning index of the need for intubation after HFNC therapy in patients with severe COVID-19. To avoid delayed intubation, we suggest that when the mROX index in a patient with COVID-19 is lower than 4.45 at 2 h after HFNC initiation, intubation should be considered as early as possible. Using the mROX index to predict HFNC failure can help clinicians to make a timely judgment to switch from HFNC to IMV. Optimizing the timing of intubation can improve the prognosis of these patients. Patients with possible progression usually require advanced oxygen therapy. Patients usually have certain compensations for hypoxia (except for cases with lung interstitial changes), when the body compensates for the lack of oxygen by increasing respiratory efforts first, which causes PSILI (patient self-inflicted lung injury) later, so the need for further respiratory support may not be accurately determined the first time, or a short-term follow-up is required (35). It is essential to evaluate the effectiveness of relevant treatment and the need for advanced treatment over time. However, in clinical practice, we found that in the emergency stage, early HFNC or other advanced oxygen therapy has two advantages. First, it can give high-risk patients early advanced respiratory support to avoid respiratory complications, such as exorbitant transpulmonary pressure and lung injury caused by vigorous respiratory efforts (36). Second, patients needing invasive ventilation could be screened quickly, and delayed intubation could be avoided. Guidelines on the management of critically ill adults with COVID-19 recommend early intubation with dynamic monitoring of the respiratory status (37). Moreover, intensive care management of COVID-19 suggests reserving the use of HFNC or NIPPV for mild hypoxemia and adopting a low threshold for intubation (38). Therefore, it is of great clinical significance to apply advanced oxygen therapy and early screening of high-risk patients with invasive ventilation through mROX in the emergency stage. Our data indicated that the duration of HFNC therapy was approximately 15.5 h in patients with HFNC failure who eventually switched to IMV. This indicates that the time of making a decision for intubation may be up to 16 h or earlier after the patient receives HFNC. Thus, a strong predictor for early evaluation and early intervention is urgently needed. Patients with delayed IMV showed higher 28-day mortality, which is consistent with previous studies, so optimizing the timing of intubation may improve the prognosis of these patients. mROX index may predict invasive ventilation and provide a certain basis for the need for early endotracheal intubation in the prehospital emergency period. In this study, patients with hypercapnic respiratory failure were placed on NIPPV instead of HFNC, and these patients were excluded. Both HFNC and NIPPV can be chosen for noninvasive ventilation support (37). NIPPV is more suitable for hypercapnic respiratory failure in patients with chronic obstructive pulmonary disease and COVID-19, but it could also cause lung injury by means of high transpulmonary pressures (39). HFNC is recommended for acute hypoxemic respiratory failure (40,41). In addition, HFNC may be better tolerated in patients with hypoxemic respiratory failure, is more conducive to the elimination of airway secretions, and can avoid gastrointestinal flatulence and other discomfort caused by positive pressure ventilation. Noninvasive ventilation approaches, including helmet noninvasive ventilation, HFNC, and NIPPV, are the most important therapeutic measures for patients with COVID-19, and the optimal choice should be based on the patient's specific conditions and tolerance.

There were some limitations in this study. First, this was a retrospective study with a small sample size. Second, we did not monitor ROX index at different time points, so the variation of ROX index was unknown, which may affect the prediction value. Larger sample size, prospective studies, and controlled trials should be performed further to address the questions that remained unanswered.

mROX is a good early warning index of the need for intubation in patients with severe COVID-19 after HFNC initiation. Delayed IMV in patients with a lower mROX at 2 h may lead to higher 28-day mortality, but further studies are needed to clarify the reasons for this observation.

None of the authors have any conflict of interest to declare.