key: cord-1004213-2aja7og2
authors: Perez-Nieto, Orlando R.; Escarraman-Martinez, Diego; Guerrero-Gutierrez, Manuel A.; Zamarron-Lopez, Eder I.; Mancilla-Galindo, Javier; Kammar-García, Ashuin; Martinez-Camacho, Miguel A.; Deloya-Tomás, Ernesto; Sanchez-Diaz, Jesús S.; Macías-García, Luis A.; Soriano-Orozco, Raúl; Cruz-Sánchez, Gabriel; Salmeron-Gonzalez, José D.; Toledo-Rivera, Marco A.; Mata-Maqueda, Ivette; Morgado-Villaseñor, Luis A.; Martinez-Mazariegos, Jenner J.; Ramirez, Raymundo Flores; Medina-Estrada, Josue L.; Ñamendys-Silva, Silvio A.
title: Awake prone positioning and oxygen therapy in patients with COVID-19: The APRONOX study
date: 2021-07-15
journal: Eur Respir J
DOI: 10.1183/13993003.00265-2021
sha: b4cb5cf81ded85043b644713afd93fb5ad8832bb
doc_id: 1004213
cord_uid: 2aja7og2

The awake prone position (AP) strategy for patients with acute respiratory distress syndrome (ARDS) is a safe, simple, and cost-effective technique used to improve hypoxemia. We aimed to evaluate intubation and mortality risk in patients with coronavirus disease (COVID-19) who underwent AP during hospitalisation. In this retrospective, multicentre observational study conducted between May 1 and June 12, 2020 in 27 hospitals in Mexico and Ecuador, non-intubated patients with COVID-19 managed with AP or supine positioning were included to evaluate intubation and mortality risk through logistic regression models; multivariable and centre adjustment, propensity score analyses, and E-values were calculated to limit confounding. This study was registered at https://clinicaltrials.gov/ct2/show/NCT04407468 827 non-intubated patients with COVID-19 in the AP (n=505) and supine (n=322) groups were included for analysis. Less patients in the AP group required endotracheal intubation (23.6% versus 40.4%) or died (20% versus 37.9%). AP was a protective factor for intubation even after multivariable adjustment (OR=0.39, 95%CI: 0.28–0.56, p<0.0001, E-value=2.01), which prevailed after propensity score analysis (OR=0.32, 95%CI: 0.21–0.49, p<0.0001, E-value=2.21), and mortality (adjusted OR=0.38, 95%CI: 0.25–0.57, p<0.0001, E-value=1.98). The main variables associated with intubation amongst AP patients were increasing age, lower baseline SpO(2)/FiO(2), and management with a non-rebreather mask. AP in hospitalised non-intubated patients with COVID-19 is associated with a lower risk of intubation and mortality.

The awake prone position (AP) in non-intubated patients with acute hypoxemic respiratory failure results in improved oxygenation, as demonstrated by an increase in arterial partial pressure of oxygen (PaO 2 ), peripheral arterial oxygen saturation (SpO 2 ), and PaO 2 /inspired oxygen fraction (PaO 2 /FiO 2 ), without deleterious effects on the level of partial arterial pressure of carbon dioxide (PaCO 2 ), pH, respiratory rate (RR), or haemodynamics [1, 2] . The physiological mechanism by which prone positioning is useful for ARDS is by increasing functional residual capacity, reducing dead space, reducing intrapulmonary shunts, increasing ventilation in areas dependent of gravity, and relieving the weight that the heart exerts over the lungs [3] .

The coronavirus disease (COVID-19) pandemic has unleashed a high global demand for respiratory support, a reason why AP in non-intubated patients has become popular and clinical interest has rapidly increased. AP combined with non-invasive ventilation (NIV) or high-flow nasal cannula (HFNC) in patients with moderate to severe acute respiratory distress syndrome (ARDS) [4, 5] and COVID-19 [6] [7] [8] has been shown to be safe and may prevent intubation. One further advantage of AP is that it allows patients to interact with their family during hospitalisation, thereby favouring humanisation of healthcare [9] . Nonetheless, few observational studies have evaluated AP against control groups (i.e. awake supine patients managed with NIV or HFNC) with conflicting findings [10] [11] [12] . Thus, the utility of AP remains to be further elucidated in larger observational or randomised studies.

In this multicentre retrospective observational study, we sought to evaluate intubation and mortality risk in conscious patients with COVID-19 who underwent AP during hospitalisation.

A multicentre retrospective cohort study was conducted with patients diagnosed with COVID-19 admitted to 27 hospitals in Mexico and Ecuador (Appendix 2) from the emergency department. The study was approved by the Health Services Research Committee of the State of Querétaro (registration number 1178/SESEQ-HGSJR/08-05-20) and all other participating centres. This study was prospectively registered in ClinicalTrials.gov (NCT04407468); STROBE recommendations were followed during the reporting of this study.

In each participating hospital centre, data collection was carried out by medical specialists in emergency medicine, respiratory medicine, anaesthesiology, and intensive care medicine, who collected information from patients' medical records. A separate group of physicians were appointed to review the data obtained and check for plausibility. In cases of doubt physicians in charge at each centre were contacted. All patients were followed-up during their entire inhospital stay, until discharge or in-hospital death.

Patients were deidentified by assigning them a code. All patients admitted to the emergency department during the period between 1 May and 12 June 2020 who met the following criteria were considered for inclusion in the study: [15] .

Awake, spontaneously breathing patients managed with non-invasive oxygen devices who were able to remain in the prone position for at least 2 continuous hours were considered as patients in the AP group (main exposure); those not meeting this criterion or in whom prone positioning was not attempted at all, were considered as the comparison group (awake supine). The primary outcome was successful orotracheal intubation for invasive mechanical ventilation and the secondary outcome was death during in-hospital follow-up. Factors associated with intubation amongst patients in the AP group were also evaluated.

The decision to place patients in the prone position and perform orotracheal intubation were based on individualised medical criteria and were not priorly defined or standardised. Patients were managed with low-flow nasal cannula, non-rebreather mask, or high-flow nasal cannula;

other non-invasive ventilation devices were either not used or unavailable across all centres.

Sample size was calculated to observe a 10% difference of the incidence of intubation based on that reported by Argenziano et al [16] . The calculated sample size was 309 subjects per group (Appendix 5). Convenience sampling for the original cohort was employed, with further propensity score-matched sampling performed to reduce bias.

The clinical and demographic characteristics of the patients were examined for all patients and for those in the AP or awake supine groups. Descriptive results for quantitative variables are presented as mean with standard deviation (SD) or median with interquartile range (IQR), and frequencies with percentage (%) for qualitative variables. Asymmetry and kurtosis were calculated for quantitative variables. Quantitative comparisons were performed with the independent-samples t-test; qualitative comparisons were done with chi-squared, chi-squared of trend, or Fisher's exact test. Baseline and post-AP SpO 2 /FiO 2 ratios were compared with the dependent-samples t-test. The PH-Covid19 mortality score was calculated as described in the original model development and validation study [17] .

To reduce the risk of bias due to unbalanced groups, propensity score analysis was performed through a logistic regression model adjusted for age, sex, the presence of 3 or more comorbidities, baseline SpO 2 /FiO 2 ratio, supplemental oxygen device, ICU attention, and treatment with systemic steroids, enoxaparin, tocilizumab, or ceftriaxone. Patients were matched in a 1:1 ratio according to the nearest-neighbour matching algorithm; changes in density functions are shown in Appendix 6. All inferential analyses were performed for all patients in the original cohort and for the propensity score-matched cohorts.

Distinct multivariable logistic regression analyses were performed to determine the risk of orotracheal intubation and mortality associated with AP. Variables included in the models were selected by the Enter method; adjustment variables were those which had a p value <0. Sub-analyses of intubation and mortality risk for patients who had a positive RT-PCR for SARS-CoV-2 (excluding patients in whom RT-PCR was not available but had a compatible CO-RADS study) were performed in the unmatched and propensity-score matched cohorts through logistic regression models; the size of effect was adjusted for the same variables as the main analyses.

E-values for the lower bound of the confidence intervals were calculated to determine the value at which an unmeasured confounding factor could potentially alter the observed effect of AP on the outcomes and drive them to a non-significant value [18] . Regression analyses were verified through residual analysis.

To determine the variability of the association between AP and intubation rates across different centres, multicentre adjustment was performed through generalized estimating equations (GEE); the centre with the lowest intubation rate throughout the entire study period was set as the reference. The main effect of every centre and AP were calculated in the same model, as well as their interaction within the model. 

Out of 932 patients identified across all 27 hospital centres, 827 patients were ultimately included for analysis ( Figure 1 ). Descriptive results for all patients are provided in Table 1 . The results of univariable logistic regression models for orotracheal intubation risk are provided in Table 3 , for both the unmatched and matched cohorts. The main risk factors identified were age, diabetes, arterial hypertension, obesity, heart disease, cancer, a baseline SpO 2 /FiO 2 <100 or between 100 and 199, and management with a non-rebreather mask. AP was a protective factor for orotracheal intubation even after multivariable adjustment ( Figure 2 .

After the search of the literature, 99 records were retrieved, of which only 9 studies [10] [11] [12] [19] [20] [21] [22] [23] [24] were observational comparison-group studies including both AP and supine patients, with sufficient information to calculate the overall risk of intubation, which are summarised alongside the APRONOX study in Figure 3 ; the funnel plot is provided as Appendix 9.

In this multicentre observational study, we aimed to evaluate the association between awake prone positioning and orotracheal intubation, as well as predictors of intubation amongst AP patients, and mortality in hospitalised patients with COVID-19. Even after multivariable adjustment and propensity score analyses, prone positioning in non-intubated patients was associated with lower intubation and mortality risk.

Patients in our cohort were younger (mean age 53.4 years) than those in other studies (56.0-65.8) [10] [11] [12] ; hospitalised patients with COVID-19 in Mexico have been reported to be young [25] . The prevalence of comorbidities in our study is similar to that reported in a population- The total time spent in the prone position during in-hospital stay in our study was 12 (IQR: [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] hours, which is considerable compared to a recent pilot randomised study which reported that self-proning patients spent only 1.6 (95%CI: 0.2-3.1) hours in the prone position in a 72-hour evaluation period [26] . Daily time spent in the prone position has been reported to be highly variable, with only 43% of patients achieving a daily dose of >6 hours in AP [27] .

The overall intubation rate in the APRONOX cohort was higher (30.1%) than that reported for hospitalised patients with COVID-19 in Mexico City (20.2%) [25] ; however, limited access to beds with ventilators in Mexico has been reported [28] . Intubation rates for patients in the unmatched AP (23.6%) and supine (40.4%) cohorts fall within those reported in previous studies (10-58% and 27.7-49%, respectively) [10] [11] [12] . AP in our study was associated with decreased intubation risk even after multivariable adjustment in both the unmatched and propensity-score matched cohorts, with an E-value of 2.01 and 2.21, respectively, which reflects that in order to drive this association to be non-significant, an unmeasured risk factor should have a lower-limit confidence interval that at least doubles the risk of the outcome between both groups. Out of all comorbidities, only diabetes and heart disease were associated with increased intubation risk after multivariable adjustment, however, diabetes was no longer a risk factor after propensity score analysis. A higher baseline SpO 2 /FiO 2 was associated with reduced intubation risk. The mortality rate reported in our study was 19.8%, comparable to 23.4% [12] and 27% [10] in other studies.

Regarding variables associated to intubation amongst AP patients, age, low SpO 2 /FiO 2 , and the use of a non-rebreather mask were the main variables associated. The distribution of risk for quantitative values of age show that the risk of intubation after AP is higher with increasing ages, whereas higher baseline SpO 2 /FiO 2 have the lowest risks.

AP has been presented as one the most cost-effective strategies to treat patients with COVID-19.

In countries with limited oxygen delivery devices, and a shortage of ventilators, AP could be used to avoid intubating patients with COVID-19 [29] . Nonetheless, conflicting evidence from observational studies for AP exists.

The supine position alters pulmonary function in patients with respiratory insufficiency due to the gravitational differences between dependent and non-dependent regions, resulting in a more negative pleural pressure (Ppl), increasing transpulmonary pressure (TPP) in non-dependent areas (more distension), and producing the opposite effect in dependent areas where Ppl is less negative and TPP is lower (less distension). Ventilation in the prone position causes even distribution of TPP, favouring uniform ventilation [30] . Approximately 45 years ago, prone positioning was shown to increase oxygenation in patients with respiratory insufficiency, primarily by improving the ventilation-perfusion ratio (V/Q) [31] .

Prone positioning has been evaluated in hospitalised patients with respiratory failure due to COVID-19, having observed improvements in SpO 2 and PaO 2 , decreased respiratory rate (RR), decreased need for intubation and possible reductions in mortality, in addition to being cost-free [8, [32] [33] [34] [35] . As summarised in Figure 4 , only three other studies to date have evaluated intubation risk among AP compared with AS. While Ferando et al. and Padrão et al. found no differences in intubation risk, Jagan et al found reduced intubation risk in AP patients [10] [11] [12] .

The APRONOX study is the largest study to date evaluating the effect of AP on intubation risk.

Regarding oxygenation modality, the use of a non-rebreather mask was associated with greater risk of intubation amongst all patients and within AP patients, whereas other oxygenation devices were not. There is documented evidence of the correlation between the oxygen saturation/fraction of inspired oxygen (SpO 2 /FiO 2 ) ratio and the partial pressure of oxygen/fraction of inspired oxygen (PaO 2 /FiO 2 ) ratio, with the advantage that the SpO 2 /FiO 2 ratio only relies on a pulse oximeter, with no need to perform a blood gas test, thereby highlighting the value of validated cost-effective strategies [14] .

Our study has the following limitations: 1) O 2 delivery devices were not standardised to a unique device, 2) the number of hours of AP varied between hospitals and patients, 3) no standardised criteria were established to consider intubation in patients requiring mechanical ventilation, 4) we were unable to asses which patients had do-not-intubate orders or other reasons for not performing intubation, 5) availability of laboratory studies was limited across centres and were thus not collected and analysed, 6) not all patients with a CO-RADS score >3

ultimately have a positive RT-PCR test [13] ; this limitation was partially addressed by subanalysing patients with a positive SARS-CoV-2 RT-PCR, 7) a measure of oxygenation comparable to post-prone SpO 2 /FiO 2 in AP patients was not collected for patients in the supine group, and 8) the length of stay of patients was not collected.

The strengths of our research include: 1) this is the largest study evaluating AP to date; 2) the large number of hospitals included; and 3) the fact that various O 2 delivery devices were employed may reflect that the benefits of AP are not necessarily unique to NIV or HFNC devices, which are costlier and not always available.

AP in spontaneously breathing patients with acute hypoxemic respiratory insufficiency may be a justifiable treatment modality, given the improvements in oxygenation and its physiological benefits, but the decision to intubate is based on the clinician's best judgement and intubation should not be delayed if under consideration. Close clinical evaluation of patients is key to avoid poor outcomes. Studies of AP are challenging and randomised controlled trials are warranted to *For this analysis, baseline SpO 2 /FiO 2 was studied as continuous variable, therefore, the range of odds ratios are different from others in the manuscript which consider baseline SpO 2 /FiO 2 as a categorical variable and use a category of reference to compare other categories.

95%CI: 95% confidence intervals; FiO2: Inspired oxygen fraction; SpO2: peripheral arterial oxygen saturation *Only patients in the propensity score-matched cohorts were included for the APRONOX study.

95%CI: 95% confidence intervals; M-H: Mantel-Haenszel [37] 322 patients in the awake supine group 

Intensive Care Unit. Hospital General San Juan del Rio, Querétaro, Mexico 2. Department of Anaesthesia. Hospital de Especialidades Centro Médico Nacional "LaRaza

Department of Critical Care Medicine. Instituto Nacional de Cancerología

Intensive Care Unit

Unidad de Investigación UNAM-INC, Instituto Nacional de Cardiología Ignacio Chávez

Intensive Care Unit. Hospital General de México

Intensive Care Unit. Hospital de Alta Especialidad IMSS

Intensive Care Unit. Hospital Vida Mejor ISSSTECH Tuxtla Gutiérrez, Chiapas, Mexico 18. Intensive Care Unit. Hospital de Especialidades "5 de Mayo

Response to the prone position in spontaneously breathing patients with hypoxemic respiratory failure

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Patient self-proning with high-flow nasal cannula improves oxygenation in COVID-19 pneumonia

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b: Model adjusted for age, sex [men], ICU attention, diabetes, systemic arterial hypertension, obesity, heart disease, pre-prone SpO 2 /FiO 2 ratio, supplemental oxygen delivery device, ceftriaxone, enoxaparin, tocilizumab, oseltamivir, and systemic steroids

Sample size was calculated to determine the difference between two independent proportions with the formula:at 95% (two-sided) was 1.96; at 90%, was 1.282; was 0.23 for the number of patients with oxygen therapy who were intubated during in-hospital stay, according to Argenziano MG, et al. 2020 . Considering a clinically significant reduction of 1'% in the incidence of orotracheal intubation, was estimated to be 0.13 for the number of patients in prone position intubated during in-hospital stay. P was the pondered measure of the two proportions, being equal to 0.18. Hence, the calculated sample size was 309 subjects per group. Calculations were performed with the G*Power v.3.1.9.7 software. Appendix 6. Density functions before and after propensity score matching of patients in the awake prone (treated) and awake supine (control) cohorts.

We searched MEDLINE and EMBASE through OVID, PubMed, BioRxiv and MedRxiv for research on COVID-19 published until 8 June 2021. We used the publicly available COVID-19 Living Evidence on COVID-19 dataset [32] . Search terms for the search strategy were: ('severe acute respiratory syndrome coronavirus 2' [supplementary concept] OR 'COVID-19' [supplementary concept] OR 'coronavirus' OR 'HCoV' OR 'nCoV' OR '2019 nCoV' OR 'covid' OR 'covid19' OR 'severe acute respiratory syndrome coronavirus 2' OR 'SARS-CoV-2' OR 'SARS-CoV 2' OR 'SARS coronavirus 2') AND (prone) AND (awake). The following filters were applied for study design: case series, case-control study, cohort study, trial, other, or unclassified. Studies were chosen regardless of language, provided an abstract in English was available, and if the study included and clearly differentiated patients undergoing awake prone positioning from those in awake supine position, as well as intubation rates for both groups.

Orotracheal intubation risk and mortality risk in patients with a positive SARS-CoV-2 test (excluding patients in whom diagnostic testing was not performed) managed with awake prone positioning, adjusted for confounding variables, in both the unmatched and the propensity-score matched cohort. 

PaO 2 : partial arterial pressure of oxygen, SpO 2 : peripheral arterial oxygen saturation, PaO 2 /FiO 2 : arterial partial pressure of oxygen /fraction of inspired oxygen, PaCO 2 : arterial partial pressure of carbon dioxide, RR: respiratory rate, NIV: non-invasive ventilation, HFNC: high-flow nasal cannula, ARDS: Acute respiratory distress syndrome, COVID-19: coronavirus disease, STROBE: Strengthening the Reporting of Observational studies in Epidemiology, AP: awake prone, CO-RADS: COVID-19 Reporting and Data System, IQR: interquartile range, SD: standard deviation, OR: odds ratio, CI: confidence interval, Ppl: pleural pressure, TPP: Transpulmonary pressure, V/Q: ventilation-perfusion.