Performance of the Rox index to predict High Flow Nasal Cannula failure in COVID-19 patients.

doi:10.21203/rs.3.rs-1727511/v1

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Performance of the Rox index to predict High Flow Nasal Cannula failure in COVID-19 patients.

https://doi.org/10.21203/rs.3.rs-1727511/v1

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Background

While High Flow Nasal Cannula (HFNC) use increased in COVID-19 hypoxic patients, the optimal timing of mechanical ventilation in COVID-19 is uncertain. We sought to evaluate the ROX index ([SpO2/FIO2]/breathing frequency) capacity to predict weaning from high-flow nasal cannula (HFNC) in COVID-19.

Methods

We performed a single-center, retrospective, observational study of subjects with respiratory failure from COVID-19 managed with HFNC. The ROX index was calculated at H 12 from HNFC and applied to predict HFNC failure. Subjects managed with HFNC were divided into two groups. And HFNC failure was defined as endotracheal intubation and invasive ventilation necessity in the first five days from admission. Standard statistical comparisons and regression analyses were used to evaluate the ROX index performance in prediction of HFNC failure.

Results

121 subjects with COVID-19 were managed with HFNC. 66 (55.5%) were successfully weaned from HFNC and 55 (45.5%) required intubation and mechanical ventilation. High mortality rates have been reported in the last group. Rox index < 2.8, a severe ARDS at admission and the occurrence of an acute cor pulmonale were independent risk factors of HFNC failure. The performance of a ROX index at H12 lower than 2,8 was significant (AUC = 0,621; 95% CI: 0,520-0,722) to predict a HFNC failure.:

Conclusion

In this retrospective review, HFNC success was associated to better clinical outcome. The ROX index was sensitive to predict HFNC failure and may allow better patient’s selection and earlier invasive mechanical ventilation initiation to optimize patient’s outcome.

COVID-19

high-flow nasal cannula

hypoxemic respiratory failure

Rox index

Since the emergence of the COVID-19 pandemic in December 2019 in Wuhan China [1] many changes have been adopted in the therapeutic guidelines especially those of ventilation modalities and respiratory support. An initial aggressive strategy with high levels of invasive mechanical ventilation (MV)[2] gave place to a less invasive strategies. These last strategies correspond to the High-flow nasal cannula (HFNC) oxygen therapy and non-invasive ventilation (NIV). The use of HFNC appears to be the most simple and appropriate alternative to manage this kind of hypoxic pneumonia [3].

Invasive MV in patients with COVID-19 acute respiratory distress syndrome (ARDS) is associated to a high level of complications such ventilator associated pneumonia (VAP), barotrauma and ventilator induced lung injury (VILI) [4]. The high mortality rates reported in this population may be due to the natural evolution of the viral infection and the severity of the ARDS, but the inherent part of the invasive mechanical ventilation can’t be neglected.

Non-invasive ventilatory strategies have been reported to reduce the need for endotracheal intubation and associated complications in patients with acute respiratory failure [5, 6] including those suffering from a SARS-CoV-2 infection [7].

Ventilatory strategies have not only to optimize pulmonary gas exchanges but also to protect the lung. This may not be respected in hypoxic patients with high respiratory neural drive. Spontaneous breathing effort are responsible of self-induced lung injury which is deleterious and associated to poor outcomes [8].

The optimal timing for the intubation in the management of COVID-19 ARDS is a matter of discuss in the absence of sensible reproduceable parameter to guide physicians.

ROX index is defined as the ratio of pulse oximetry/fraction of inspired oxygen (SpO₂/FiO₂) to respiratory rate (RR). It is known to predict the risk for intubation in patients with acute respiratory failure due to pneumonia [9].

This index has been subsequently applied to the use of HFNC in the treatment of hypoxic forms of COVID-19 [10, 11]. The aim of this study was to evaluate the validity of the ROX index in the critical COVID-19 patients managed with HFNC.

Study design and ethical status

This was a single-center, retrospective, observational study conducted at the medical ICU of the tertiary teaching hospital of la Rabta (Tunis, Tunisia). The study was approved by the Ethics Committee of the institutional review board of la Rabta hospital.

Study population

were recruited to the study, the first 121 consecutive patients, aged at least of 18 years, and admitted in our ICU for critical Covid-19 and managed with High Flow Nasal Cannula at admission. The initial respiratory support choice was left to the medical care giver The causative agent was confirmed by positive SARS-CoV-2 real-time polymerase chain reaction test from nasal swab samples, and/or a Covid-19 compatible chest CT scan. A critical Covid-19 was considered in the presence of a life-threatening condition such ARDS, hemodynamic failure, mental status deterioration, multiple organ dysfunction, etc.

Study procedure and assessed parameters

All patient’s records were thoroughly reviewed and several clinical and paraclinical parameters were recorded. Clinical data were age, sex, co-morbidities, severity scores, onset and nature of clinical features, type of oxygen therapy and MV use, specific management and the final issue. High Flow Nasal Cannula (HFNC) failure was defined as endotracheal intubation and invasive ventilation necessity in the first five days from admission. Rox index was calculated as the following formula: [ROX index = SpO₂/FiO₂/respiratory rate (RR)] and reported at H12 of the HFNC treatment initiation. The primary outcome was HFNCO failure. The second outcomes were mortality and the ICU length of stay.

Statistical analysis

The data were analyzed using the SPSS Base 20 statistical software package. Continuous data were expressed as mean ± standard deviation (SD) or median [IQR 25–75] according to the normality or not of the variables. Categorical variables were expressed as percentage. The ROC curve and logistic regression have been adopted to find the Cut Off value for the Rox index which have been compared according to the ventilation modality at day 5. The p value of less than 0.05 was considered statistically significant.

During the study period, 160 patients were admitted in the ICU for critical Covid-19. Among them, 121 patients have been managed by the HFNC. In our population 66 (54.5%) recovered without intubation and were weaned successfully from HFNC. HFNC failure was reported in 55 patients (45.5%). (Fig. 1).

The studied patients in the HNFC failure group (n = 55) have a median age of 59 years ± 15 and a sex ratio of 1.75 with 35 males. Patients in these group had an initial more severe clinical presentation with a median SOFA score at 4.4 ± 1.7. These patients were more hypoxic, 85.5% of them had a severe ARDS. No difference had been reported in the HFNC related complications between the two groups. Mortality was significantly higher in the failure group with p < 10^− 3 (Table 1).

Table 1

Baseline characteristics and outcome in the study groups according to the result of HNFC
		HFNC Failure group (n = 55)	HFNC Success group (n = 66)	P value
Clinical data
ROX index		3,14 ± 1,4	3,66 ± 0,9	0,022
Age		59 ± 11	53 ± 15	0,011
Sex-ratio (H/F)		35/20	38/28	0,57
Co-morbidities: -Arterial hypertension -Diabetes -Chronic respiratory failure		22 (40%) 23 (42%) 3 (5,5%)	17 (26%) 21 (32%) 2 (3%)	0,11 0,26 0,65
Obesity		7 (13%)	9 (13,6%)	1
Symptom’s time from admission		13 ± 5,5	12 ± 5,5	0,4
SOFA		4,4 ± 1,7	3,5 ± 1,4	0,003
Para-clinical data
TDM > 50%		16/26	20/43	0,32
P/F initial		87,5 ± 55	116 ± 62	0,002
SDRA severe		47 (85,5%)	38 (57,6%)	0,001
Acute cor pulmonale		27 (49%)	7 (10,6%)	< 10^− 3
ECMO		2 (3,6%)	0	0,2
HFNC Complications
Barotrauma		2 (3,6%)	1 (1,5%)	0,59
Nasal obstruction		6 (11%)	13 (19,7%)	0,16
Epistaxis		2 (3,6%)	3 (4,5%)	0,36
Outcome
Hospital length of stay	10,6 ± 5,9		10,6 ± 6,5	0,9
Mortality		52 (94,5%)	14 (21,2%)	< 10^− 3

The multi variable model analyses results are reported in (Table 2). The cut-off value of the Rox index was equal to 2,8. Thus, we showed that a Rox index < 2.8, a severe ARDS at admission and the occurrence of an acute cor pulmonale were independent risk factors of HFNC failure.

Table 2

Results of multivariate analyses to determine factors related to HFNC failure.
Studied factors	OR, 95% IC, p
ROX index < 2,8	12,9 [1,55–108], 0,018
Age (> 60 years)	1,02 [0,96 − 1,08], 0,49
SOFA (> 5)	0,66 [0,37 − 1,17], 0,15
Severe ARDS	14,9 [1,5-142], 0,019
Acute cor pulmonale	6,9 [1,21–39], 0,03
HFNC: High Flow Nasal Cannula, SOFA: Sepsis-related Organ Failure Assessment Score, ARDS: Acute Respiratory Distress Syndrome, OR: Odd Ratio CI: Confidence Interval.

To predict a HFNC failure, the performance of a ROX index at H12 lower than 2,8 was significant (AUC = 0,621; 95% CI: 0,520-0,722). Yet, the accuracy was moderately relevant with a sensitivity at 54,5%, a specificity at 70%, a positive predictive value at 64,7%, and a negative predictive value at 67% (Fig. 2).

Our study documents the clinical outcomes of 121 critical ill patients with COVID-19 related respiratory distress syndrome hospitalized in intensive care unit and initially managed with HFNC. Most of the baseline clinical characteristics were similar between the groups. The HFNC oxygenation failure was reported in 55 patients (45.5%). In this group, we showed a significant higher mortality (94,5% versus to 21.2%, p < 10^− 3). In the multi variable analysis, the independent factors of HNFC failure were age > 60 years, a SOFA score at admission > 5, the presence of severe ARDS, the acute pulmonary core and a ROX index < 2,8. A ROX index at H12 lower than 2,8 predicted the failure of this modality with a specificity at 70%.

The HFNC is based on a continuous flow of heated and humidified gas with FiO₂ up to 100% delivered to the patient through nasal cannula generating a mild positive end expiratory pressure (PEEP) effect, and upper airways dead space washout. Compared with standard oxygen, HFNCO decreases inspiratory effort, work of breathing and respiratory rate, improves comfort and oxygenation. Its benefits in patients with acute respiratory distress have been largely established [12]. This oxygenation technique has been widely adopted in the treatment of hypoxic COVID-19 patients with different clinical outcomes and a controversy regarding the timing for intubation [13].

While non-invasive oxygenation technique helps to ovoid invasive mechanical ventilation and related complications particularly ventilatory associated pneumonia, the spontaneous breathing efforts may be deleterious responsible of self-induced lung injury [8, 14, 15] .

In our series of critical ill patients, 54.5% were successfully managed with HFNC with a low mortality rate of 21%. The HFNC was a successful technic for COVID-19 patients management in several series [5, 7, 16] .

The HFNC failure and the invasive mechanical ventilation were almost synonyms of death. The mortality rate in this subgroup was 94.5%. This may be due to comorbidities and a more severe viral infection. Patients in the failure subgroup were more severe (SOFA 4.4 +/-1) and 85% of them were diagnosed with a severe acute respiratory distress syndrome at admission and a half of them had underlying cardiovascular affections.

The inherent part of the initial ventilatory support choice and the delayed intubation can’t be eliminated. In an observational study prior to the emergence of SARS-CoV-2, a delayed failure of HFNC was associated with high ICU mortality [17]. From were came the necessity of an accessible, sensible and reproduceable parameter to guide physicians.

Roca used the ROX index to predict the risk for intubation in those with pneumonia and acute respiratory failure (9).

Previous cohorts of hypoxic COVID-19 patients applied the ROX index to predict HFNC failure. The index was calculated in different times with different cut-off values [18, 19]. Chandel reported a retrospective series of 272 subjects with COVID-19 that were managed with HFNC and conclude that a ROX index > 3.0 at 2, 6, and 12 hours after initiation of HFNC was 85.3% sensitive for identifying subsequent HFNC success [20].

The meta-analysis of Prakash J, et al (that included eight cohort studies with 1301 patients) suggests that the ROX index has good discriminating power for prediction of HFNC failure in COVID-19 patients [21]. Indeed, the summary area under the curve was equal to 0.81 (95% CI, 0.77–0.84) with sensitivity of 0.70 (95% CI, 0.59–0.80) and specificity of 0.79 (95% CI, 0.67–0.88). The positive and negative likelihood ratio were 3.0 (95% CI, 2.2–5.3) and 0.37 (95% CI, 0.28–0.50) respectively, and was strongly associated with a promising predictive accuracy (Diagnostic odds ratio (DOR) 9, 95% CI, 5–16).

Herein, we selected a timing of 12 hours after HFNCO initiating to the cut-off and its relevance to predict HFNC failure.

Our results indicate that the index appears to be similarly applicable in COVID-19 related respiratory failure compared to the non-COVID-19 cohort in which it was previously evaluated.

We identified that a ROX index cut-off of 2.8 was useful in screening patients with high risk of HFNC failure with respectively a sensitivity and a specificity of 54.5% and 70%.

Strengths and Limitations

We estimate that we some add interesting data to the literature concerning the interest of the ROX index as HFNCO failure marker in COVID-19 critically ill patients with organ failure which contributed to better ventilatory support choice in this complex pathology. The relatively small and single-center design may be considered as limitations. Prospective trials with larger samples are required to further explore these important clinical questions.

Funding:

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Conflict of Interest:

The authors have no relevant financial or non-financial interests to disclose

Authors' contributions:

Literature research and study design were performed by Badis Tlili and Ahlem Trifi. Patient’s recruitment and data analysis were performed by Badis Tlili Asma Mehdi. Data collection and interpretation were performed by Cyrine Abdennebi, Foued Daly and Yosr Touil. The critical revisions of the manuscript were made by Sami Abdellatif and Salah Ben Salah. The first draft of the manuscript was written by Badis Tlili and Ahlem Trifi and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Ethics approval:

Ethical approval was granted by the Ethics Committee of the teaching hospital of la Rabta.

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No competing interests reported.

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Performance of the Rox index to predict High Flow Nasal Cannula failure in COVID-19 patients.

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