# Early prone positioning in acute respiratory distress syndrome related to COVID-19: a propensity score analysis from the multicentric cohort COVID-ICU network-the ProneCOVID study

Christophe Le Terrier, Florian Sigaud, Said Lebbah, Luc Desmedt, David Hajage, Claude Guérin, Jérôme Pugin, Steve Primmaz, Nicolas Terzi, Alain Mercat, et al.

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## To cite this version:

Christophe Le Terrier, Florian Sigaud, Said Lebbah, Luc Desmedt, David Hajage, et al. Early prone positioning in acute respiratory distress syndrome related to COVID-19: a propensity score analysis from the multicentric cohort COVID-ICU network-the ProneCOVID study. Critical Care, 2022, 26 (1), pp.71. 10.1186/s13054-022-03949-7. hal-04820973

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# Early prone positioning in acute respiratory distress syndrome related to COVID-19: a propensity score analysis from the multicentric cohort COVID-ICU network—the ProneCOVID study

Christophe Le Terrier¹, Florian Sigaud², Said Lebbah³, Luc Desmedt⁴, David Hajage³, Claude Guérin⁵,
Jérôme Pugin¹, Steve Primmaz¹, Nicolas Terzi²,⁶* and COVID-ICU Group on behalf of the REVA Network and
the COVID-ICU Investigators

## Abstract

**Background:** Delaying time to prone positioning (PP) may be associated with higher mortality in acute respiratory distress syndrome (ARDS) due to coronavirus disease 2019 (COVID-19). We evaluated the use and the impact of early PP on clinical outcomes in intubated patients hospitalized in intensive care units (ICUs) for COVID-19.

**Methods:** All intubated patients with ARDS due to COVID-19 were involved in a secondary analysis from a prospective multicenter cohort study of COVID-ICU network including 149 ICUs across France, Belgium and Switzerland. Patients were followed-up until Day-90. The primary outcome was survival at Day-60. Analysis used a Cox proportional hazard model including a propensity score.

**Results:** Among 2137 intubated patients, 1504 (70.4%) were placed in PP during their ICU stay and 491 (23%) during the first 24 h following ICU admission. One hundred and eighty-one patients (36.9%) of the early PP group had a PaO₂/FiO₂ ratio > 150 mmHg when prone positioning was initiated. Among non-early PP group patients, 1013 (47.4%) patients had finally been placed in PP within a median delay of 3 days after ICU admission. Day-60 mortality in non-early PP group was 34.2% versus 39.3% in the early PP group (p = 0.038). Day-28 and Day-90 mortality as well as the need for adjunctive therapies was more important in patients with early PP. After propensity score adjustment, no significant difference in survival at Day-60 was found between the two study groups (HR 1.34 [0.96–1.68], p = 0.09 and HR 1.19 [0.998–1.412], p = 0.053 in complete case analysis or in multiple imputation analysis, respectively).

**Conclusions:** In a large multicentric international cohort of intubated ICU patients with ARDS due to COVID-19, PP has been used frequently as a main treatment. In this study, our data failed to show a survival benefit associated with early PP started within 24 h after ICU admission compared to PP after day-1 for all COVID-19 patients requiring invasive mechanical ventilation regardless of their severity.

<footnote>*Correspondence: nterzi@chu-grenoble.fr
⁶ Medical Intensive Care Unit, Grenoble Alpes University Hospital, Avenue Maquis du Grésivaudan, 38700 La Tronche, France
Full list of author information is available at the end of the article
COVID-ICU Investigators are listed at the end of the manuscript</footnote>
**Keywords:** Acute respiratory distress syndrome, Intubation, COVID-19, Mortality, Prone position, Intensive care unit

**Introduction**

Since 2020, the world has been facing a global threat due to the COVID-19, overwhelming hospitals and intensive care units (ICUs) as never before. To date, the World Health Organization has reported 158 millions confirmed COVID-19 cases and more than 3 millions of deaths [1]. Patients infected by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and hospitalized for a severe pneumonia may develop acute respiratory distress syndrome (ARDS), which is associated with high mortality [2–4]. Therefore, an extensive burden brought upon the intensive care units (ICUs) to provide invasive mechanical ventilation and other advanced forms of life support [5].

Before the COVID-19 pandemic, the Proseva trial [6] demonstrated an improvement in survival from prone position (PP) used as cycles of more than 16 consecutive hrs in selected ARDS patients, i.e., those with a PaO₂/FIO₂ ratio < 150 mmHg after 12 to 24 h-stabilization period. Though experts recommended PP in this setting [7], in the daily practice the rate of use of PP was lower than expected [8]. Since the beginning of the COVID-19 pandemic, the surviving sepsis campaign (SSC) recommended PP in COVID-19 presenting with ARDS [9], a treatment widely adopted even though the level of evidence was similar as before the pandemic [4, 10]. In this recommendation, no timing to start prone position was proposed. Owing to the very large number of COVID-19-related ARDS treated with PP it was reported that an early application of PP [11, 12] and the response to PP in terms of oxygenation [13, 14] were both possibly associated with a better outcome. Even if some studies of patients report interesting results [11–14], the impact of early PP on mortality remains unclear in COVID-19 patients in the ICU.

The objective of the present ancillary study was to analyze the use of early PP in the ICU management of ARDS patient due to COVID-19 and to evaluate the impact of an early PP on survival, as well as on respiratory system mechanics and oxygenation, using a large international cohort of COVID-19 ARDS patients [4].

**Methods**

**Study design and patients**

This study was a secondary analysis of the COVID-ICU study [4]. COVID-ICU was a prospective, multicenter observational cohort study of 149 ICUs from 138 hospitals conducted across three European countries (France, Belgium and Switzerland). The ethical committees of

Switzerland (BASEC #: 2020-00704), of the French Intensive Care Society (CE-SRLF 20-23) and of Belgium (2020-294) approved this study and all patients or relatives had given their consent to be included in the COVID-ICU cohort. It recruited 4643 patients between February and May 2020 with 80% of patients receiving invasive mechanical ventilation during their ICU stay.

All consecutive patients over 16 year-old included from February 25, 2020, to May 4, 2020, in the COVID-ICU study with an available vital status at Day-90 were eligible. Patients who met the following criteria in the first 24 h after admission were included: intubated and mechanically ventilated, PaO₂/FiO₂ < 300 mmHg with PEEP > 5 cmH₂O and no therapeutic limitations. Laboratory confirmation for SARS-CoV-2 was defined as a positive result of real-time reverse transcriptase-polymerase chain reaction (RT-PCR) assay from either nasal or pharyngeal swabs, and/or lower respiratory tract aspirates. Patients without laboratory-confirmed COVID-19 were not included, even if they presented with a typical radiological pattern.

Patients were classified according to the fact that they had been subjected to PP at Day-1 or later. Day-1 was defined as the first day in ICU at 10 am following the COVID-ICU study. All patients placed in PP during their first day in ICU constituted the early PP group. All patients placed in PP after Day-1 or non-placed in PP during their ICU stay were categorized in the non-early prone position group. Patients placed in PP later in their ICU course were included in the non-early proning group to reduce the potential for immortal time bias and to emulate an intention-to-treat strategy of a randomized trial. Indication for invasive mechanical ventilation and mechanical ventilation settings was left to the discretion of the participating centers.

**Data collection**

A standardized electronic case report form was completed each day at 10 am by the study investigators. Baseline characteristics were collected at ICU admission: age, sex, body mass index (BMI), active smoking, Simplified Acute Physiology Score (SAPS) II score, Sequential Organ Failure Assessment (SOFA), treated hypertension, diabetes, long-term corticosteroids, immunodeficiency, Clinical Frailty Scale, the date of the first symptom and dates of the hospital and ICU admissions. All investigators were asked to provide the lowest arterial partial pressure of oxygen (PaO₂) at Day-1 after intubation and the corresponding fraction of oxygen inspired (FiO₂) to
calculate PaO₂/FiO₂ ratio and categorized according to the ARDS Berlin definition [15]. Static compliance was defined by dividing the tidal volume by the driving pressure. The driving pressure was calculated by subtracting plateau pressure from positive end-expiratory pressure (PEEP). All biological data were collected at ICU admission. Proved concurrent bacterial pneumonia was defined by a positive bacterial culture at ICU admission in either a bronchoalveolar lavage sample, or in a blind protected specimen brush distal, or in endotracheal aspirates. The main outcome was Day-60 survival. Secondary outcomes included Day-28 and Day-90 mortality, ventilator-free days until Day-28, extracorporeal membrane oxygenation (ECMO) requirement, extracorporeal CO₂ removal (ECCO₂R) requirement and inhaled nitric oxide. The ventilator-free days were computed as the number of days that a patient was alive and free of invasive ventilation, calculated from ICU admission until Day-28. Patients who died before Day-28 or received invasive ventilation for more than 28 days were considered to have 0 ventilator-free days [16]. The static compliance, the SOFA score and the PaO₂/FiO₂ ratio were also evaluated at Day-3, Day-5 and Day-7 as secondary outcomes.

## Statistical analysis

Characteristics of patients were described as counts and percentages for categorical variables, and as mean and standard deviation or median and interquartile range for quantitative variables. Categorical variables were compared by Chi-square or Fisher's exact test, and quantitative variables were compared by Student's t test or Wilcoxon's rank-sum test. Kaplan-Meier overall survival curves until Day-28, Day-60 and Day-90 were computed.

The primary endpoint was the Day-60 survival according to prone positioning at Day-1 of ICU stay. To assess prone positioning at Day-1 effect on Day-60 survival, we used a Cox proportional hazard model weighted on inverse probability of treatment weighting (IPTW) using propensity score (PS) defined as the predictive probability of prone positioning conditional on measured baseline covariates [17]. The variables used to estimate propensity score were: age, gender, clinical frailty scale, SOFA cardiovascular, SOFA renal, SOFA coagulation, SAPS II score, immunodepression, long-term corticosteroids, treated hypertension, diabetes, BMI, delay between first symptoms and ICU admission, bacterial coinfection, ICU admission period (March 29 or after vs. March 28 or before), PaO₂/FiO₂ ratio and static compliance. A multivariate logistic regression model was performed to estimate the PS for each patient. To assess the balance of measured covariates between treatment groups, we used the standardized mean differences before and after PS weighting

[18]. Then, a Cox proportional hazard model weighted on IPTW was performed to estimate the average treatment effect in the entire eligible population [17]. Hazard ratio and its 95% confidence interval were then estimated for the Day-60 mortality associated with prone positioning at Day-1. This analysis was performed on the complete cases data set, and a sensitivity analysis was performed using multiple imputations due to missing data. Imputation method, missing data were realized according to Vesin et al. [19]. Propional hazard assumption was assessed by inspecting the scaled Schoenfeld residuals and Harrel's test [20]. Multicollinearity was checked using variance inflation factor.

The secondary endpoints were: Day-28 survival, Day-90 survival, number of days free of mechanical ventilation up to Day-28, the need for extracorporeal life support, the need for inhaled nitric oxide, static compliance (at Day-3, 5 and 7), PaO₂/FiO₂ (at Day-3, 5 and 7) and SOFA score (Day-7, 21 and 28).

Subgroup analyses of mortality at Day-28, Day-60 and Day-90 were performed, according to PaO₂/FiO₂ at Day-1 (< or ≥ 150 mmHg) and time from ICU admission to the first prone position (< or ≥ 24 h). Subgroup analysis according to PaO₂/FiO₂ at Day-1 (< or ≥ 150 mmHg) also included a Cox proportional hazard model weighted on IPTW using propensity score to assess prone positioning at Day-1 effect on Day-60 survival.

All analyses were performed at a two-sided α level of 5% and conducted with R version 3.5.1 (R Foundation for Statistical Computing, Vienna, Austria).

## Results

### Characteristics of ICU patients

COVID-ICU study enrolled 4244 patients. In this secondary analysis, 2137 patients met the inclusion criteria and were involved (Fig. 1). The median [interquartile range] age was 63 [55-70] years, 1598 (75.1%) of patients were male, with a median BMI of 29 [26-33] kg/m². The median SAPS II, SOFA and Frailty score were 43 [32-56], 7 [4-10] and 2 [2-3] respectively. The main comorbidity was hypertension (49.9%), followed by diabetes (28.4%) and immunosuppression (7.3%). All patients were rapidly intubated after ICU admission with a median delay inferior to 3 h approximately. Regarding the ARDS severity at Day-1, the median static compliance was 32.8 [26.3-41.7] mL/cmH₂O, and the PaO₂/FiO₂ ratio was 145.7 [101.7-200] mmHg including 1106 (51.8%) patients with a ratio less than 150 mmHg. All other baseline characteristics of patients are summarized in Table 1.
<figure><img src="image_4.png" /><figcaption>**Fig. 1** Study flowchart. ICU intensive care unit, PaO₂ arterial partial pressure of oxygen, FiO₂ fraction inspired of oxygen, PEEP positive end-expiratory pressure</figcaption></figure>

## Prone position support

Among the 2137 patients analyzed, 1504 (70.4%) patients were subjected to prone positioning during the ICU stay with a median number of 4 [2–6] PP sessions and a median duration of 20 [16–32] h in the first 48 h.

At Day-1, 491 patients (23%) were placed in PP, constituting the early PP group. The distribution of patients per region is detailed in the Additional file 1: Table S1. Then, 1013 patients (47.4%) were prone after Day-1 with a median delay of 3 [2–5] days after ICU admission, and 633 (29.6%) were never subjected to PP. Those 1646 patients (77%) were classified as the non-early PP group. Characteristics of both groups at Day-1 are summarized in Table 1.

In the early PP group, patients were more obese (54.8% vs. 41.4%, *p* < 0.0001) and had a higher rate of treated hypertension (55.2% vs. 48.3%, *p* = 0.005). Median PaO₂/FiO₂ ratio was lower in the early PP group (128.3 [87.5–177.5] mmHg vs. 152.2 [107–205] mmHg, *p* < 0.0001) as well as the respiratory static compliance (30.7 [24.1–39.9] mL/cmH₂O vs. 33.6 [26.9–42] mL/cmH₂O, *p* = 0.001). In

the whole cohort, 181 (36.9%) patients of the early PP group had a PaO₂/FiO₂ ratio > 150 mmHg when placement in prone position was initiated. On the opposite, 796 (48.4%) patients with PaO₂/FiO₂ ratio < 150 mmHg at Day-1 were not placed in PP.

The median number of prone sessions was 3 [2–6] in the non-early PP group, with a median duration of 17 [16–23] h during the first 48 h versus 4 [2–7] number of prone sessions with a duration of 20 [16–32] h in the early PP group (*p* < 0.0001).

## Outcomes

### In the whole cohort

In unadjusted analysis, mortality at Day-28, Day-60 and Day-90 were 30.5%, 35.4% and 35.9%, respectively, in the complete cohort study. Mortality was significatively lower in the non-early PP group compared to the early PP group as shown in Table 2. More patients needed adjunctive therapies (ECMO, ECCO₂R, inhaled nitric oxide) in the early PP group. The static compliance, the PaO₂/FiO₂ ratio and the SOFA score at Day-3, Day-5 and Day-7
<table><caption>**Table 1** Demographic, clinical and ventilatory characteristics of patients according to their proning status at Day-1</caption><thead><tr><th>Variable</th><th>All patients (n = 2137)</th><th>Non-early prone position group (n = 1646)</th><th>Early prone position group (n = 491)</th><th>p</th></tr></thead><tbody><tr><td>Age (years), median (IQR)</td><td>63 (55-70)</td><td>63 (55-70)</td><td>63 (54-70)</td><td>0.393</td></tr><tr><td>Sex, n (%)</td><td></td><td></td><td></td><td></td></tr><tr><td>Men</td><td>1598 (75.1%)</td><td>1242 (75.7%)</td><td>356 (73.1%)</td><td>0.238</td></tr><tr><td>Women</td><td>529 (24.9%)</td><td>398 (24.3%)</td><td>131 (26.9%)</td><td></td></tr><tr><td>Body mass index (kg/m²), median (IQR)</td><td>29 (26-33)</td><td>28 (26-32)</td><td>30 (27-34)</td><td>&lt;0.0001</td></tr><tr><td>≥ 30 kg/m², n (%)</td><td>888 (44.4%)</td><td>636 (41.4%)</td><td>252 (54.8%)</td><td>&lt;0.0001</td></tr><tr><td>Comorbidities, n (%)</td><td></td><td></td><td></td><td></td></tr><tr><td>Active smokers</td><td>87 (4.2%)</td><td>68 (4.3%)</td><td>19 (4%)</td><td>0.791</td></tr><tr><td>Treated hypertension</td><td>1055 (49.9%)</td><td>786 (48.3%)</td><td>269 (55.2%)</td><td>0.005</td></tr><tr><td>Known diabetes</td><td>601 (28.4%)</td><td>446 (27.4%)</td><td>155 (31.9%)</td><td>0.053</td></tr><tr><td>Immunodeficiency</td><td>154 (7.3%)</td><td>120 (7.4%)</td><td>34 (7%)</td><td>0.788</td></tr><tr><td>Long-term corticosteroids</td><td>77 (3.7%)</td><td>66 (4.1%)</td><td>11 (2.3%)</td><td>0.064</td></tr><tr><td>SAPS II score, median (IQR)</td><td>43 (32-56)</td><td>42 (32-56)</td><td>44 (32-55)</td><td>0.702</td></tr><tr><td>SOFA score at ICU admission, median (IQR)</td><td>7 (4-10)</td><td>7 (4-10)</td><td>8 (5-10)</td><td>0.033</td></tr><tr><td>Clinical frailty score, median (IQR)</td><td>2 (2-3)</td><td>2 (2-3)</td><td>2 (2-3)</td><td>0.112</td></tr><tr><td>Time between first symptoms and ICU admission (days), median (IQR)</td><td>9 (6-12)</td><td>9 (6-12)</td><td>9 (6-11)</td><td>0.273</td></tr><tr><td>Time between ICU admission and invasive mechanical ventilation (hours), median (IQR)</td><td>2.7 (0.7-9.7)</td><td>3 (0.7-10.8)</td><td>1.8 (0.4-6.3)</td><td>0.001</td></tr><tr><td>Concomitant bacterial pneumonia, n (%)</td><td>130 (6.3%)</td><td>93 (5.8%)</td><td>37 (7.7%)</td><td>0.143</td></tr><tr><td>Respiratory support received in ICU before intubation at Day-1, n (%)</td><td></td><td></td><td></td><td></td></tr><tr><td>Oxygen therapy</td><td>220 (10.3%)</td><td>177 (10.8%)</td><td>43 (8.8%)</td><td>0.203</td></tr><tr><td>High-flow nasal cannula</td><td>143 (6.8%)</td><td>119 (7.3%)</td><td>24 (4.9%)</td><td>0.069</td></tr><tr><td>Non-invasive mechanical ventilation</td><td>61 (2.9%)</td><td>43 (2.3%)</td><td>18 (3.7%)</td><td>0.216</td></tr><tr><td>High-doses Corticosteroids using at Day-1 n (%)</td><td>227 (10.7%)</td><td>171 (10.5%)</td><td>56 (11.4%)</td><td>0.557</td></tr><tr><td>Invasive mechanical ventilation settings, median (IQR)</td><td></td><td></td><td></td><td></td></tr><tr><td>PaO<sub>2</sub>/FiO<sub>2</sub> (mmHg)</td><td>145.7 (101.7-200)</td><td>152.2 (107-205)</td><td>128.3 (87.5-177.5)</td><td>&lt;0.0001</td></tr><tr><td>Tidal volume (mL)</td><td>415 (375-450)</td><td>418 (380-450)</td><td>400 (370-440)</td><td>0.0035</td></tr><tr><td>Tidal volume, mL/kg PBW</td><td>6.1 (5.8-6.7)</td><td>6.1 (5.8-6.7)</td><td>6.1 (5.8-6.5)</td><td>0.1326</td></tr><tr><td>Set PEEP (cmH<sub>2</sub>O)</td><td>12 (10-14)</td><td>12 (10-14)</td><td>12 (10-14)</td><td>&lt;0.0001</td></tr><tr><td>Plateau pressure (cmH<sub>2</sub>O)</td><td>24 (21-27)</td><td>24 (21-27)</td><td>25 (22-28)</td><td>&lt;0.0001</td></tr><tr><td>Driving pressure<sup>1</sup> (cmH<sub>2</sub>O)</td><td>13 (10-17)</td><td>13 (10-17)</td><td>13.5 (11-17)</td><td>0.0345</td></tr><tr><td>Mechanical power<sup>2</sup> (J/min)</td><td>26.7 (18.9-35)</td><td>25.8 (18.4-33.6)</td><td>30.3 (21.1-39.1)</td><td>&lt;0.0001</td></tr><tr><td>Ventilatory ratio<sup>3</sup> (J/min)</td><td>1.7 (1.4-2.2)</td><td>1.7 (1.4-2.1)</td><td>1.9 (1.5-2.4)</td><td>&lt;0.0001</td></tr><tr><td>Static compliance<sup>4</sup> (mL/cmH<sub>2</sub>O)</td><td>32.8 (26.3-41.7)</td><td>33.6 (26.9-42)</td><td>30.7 (24.1-39.9)</td><td>0.001</td></tr><tr><td>Dynamic compliance<sup>5</sup> (mL/cmH<sub>2</sub>O)</td><td>16.7 (13.6-21)</td><td>17 (14.1-21.4)</td><td>15.2 (12.3-19.5)</td><td>&lt;0.0001</td></tr><tr><td>Blood gas, median (IQR)</td><td></td><td></td><td></td><td></td></tr><tr><td>pH</td><td>7.4 (7.3-7.4)</td><td>7.4 (7.3-7.4)</td><td>7.4 (7.3-7.4)</td><td>&lt;0.0001</td></tr><tr><td>PaCO<sub>2</sub> (mmHg)</td><td>43 (37-49)</td><td>42 (37-48)</td><td>45 (40-52)</td><td>&lt;0.0001</td></tr><tr><td>PaO<sub>2</sub>/FiO<sub>2</sub> (mmHg)</td><td>145.7 (101.7-200)</td><td>152.2 (107-205)</td><td>128.3 (87.5-177.5)</td><td>&lt;0.0001</td></tr><tr><td>&lt; 150 mmHg, n (%)</td><td>1106 (51.8%)</td><td>796 (48.4%)</td><td>310 (63.1%)</td><td>&lt;0.0001</td></tr><tr><td>HCO<sub>3</sub> (mmol/L)</td><td>25 (22-27)</td><td>24 (22-27)</td><td>25 (22-28)</td><td>0.001</td></tr><tr><td>Lactate (mmol/L)</td><td>1.3 (1-1.7)</td><td>1.3 (1-1.7)</td><td>1.3 (1-1.8)</td><td>0.012</td></tr><tr><td>Biology, median (IQR)</td><td></td><td></td><td></td><td></td></tr><tr><td>Lymphocyte count (× 10<sup>9</sup>/L)</td><td>0.8 (0.5-1.1)</td><td>0.8 (0.5-1.1)</td><td>0.8 (0.6-1.2)</td><td>0.294</td></tr><tr><td>Thrombocyte count (× 10<sup>9</sup>/L)</td><td>225 (167-292.5)</td><td>223 (165-291)</td><td>227 (170.2-296)</td><td>0.367</td></tr><tr><td>Total bilirubin (mg/dL)</td><td>0.58 (0.41-0.89)</td><td>0.58 (0.41-0.89)</td><td>0.58 (0.41-0.89)</td><td>0.245</td></tr><tr><td>Serum creatinine (mg/dL)</td><td>0.94 (0.71-1.39)</td><td>0.92 (0.7-1.38)</td><td>0.98 (0.74-1.46)</td><td>0.033</td></tr></tbody></table>
<table><caption>**Table 1 (continued)**</caption><thead><tr><th>Variable</th><th>All patients (n = 2137)</th><th>Non-early prone position group (n = 1646)</th><th>Early prone position group (n = 491)</th><th>p</th></tr></thead><tbody><tr><td>D-dimer (µg/L)</td><td>1913 (1100–4219)</td><td>1844 (1038.5–4212.2)</td><td>2220 (1237–4262)</td><td>0.158</td></tr><tr><td>CRP (mg/L)</td><td>186.4 (121.2–266.5)</td><td>180 (119–261.4)</td><td>202.4 (136.1–276)</td><td>0.021</td></tr><tr><td>Procalcitonin (ng/mL)</td><td>0.7 (0.3–2.2)</td><td>0.6 (0.3–2)</td><td>0.9 (0.4–2.9)</td><td>0.01</td></tr><tr><td>hsTroponine T (ng/L)</td><td>23 (12–63.2)</td><td>22 (11.3–58.6)</td><td>31.4 (14.1–95.2)</td><td>0.003</td></tr></tbody></table>

IQR interquartile range, SOFA sequential organ failure assessment, SAPS II simplified acute physiology score II, PaCO₂ arterial partial pressure in carbon dioxide, PaO₂ arterial partial pressure in oxygen, FiO₂ fraction inspired in oxygen, CRP C-reactive protein

<table><caption>**Table 2 Primary and secondary outcomes**</caption><thead><tr><th>Outcome</th><th>All patients (n = 2137)</th><th>No early prone position group (n = 1646)</th><th>Early prone position group (n = 491)</th><th>p</th></tr></thead><tbody><tr><td>Primary outcome</td><td></td><td></td><td></td><td></td></tr><tr><td>Mortality at Day-60, n (%)</td><td>756 (35.4%)</td><td>563 (34.2%)</td><td>193 (39.3%)</td><td>0.038</td></tr><tr><td>Secondary outcomes</td><td></td><td></td><td></td><td></td></tr><tr><td>Mortality, n (%)</td><td></td><td></td><td></td><td></td></tr><tr><td>At Day-28</td><td>652 (30.5%)</td><td>482 (29.3%)</td><td>170 (34.6%)</td><td>0.024</td></tr><tr><td>At Day-90</td><td>767 (35.9%)</td><td>574 (34.9%)</td><td>193 (39.3%)</td><td>0.072</td></tr><tr><td>Ventilatory-free days util Day-28, median (IQR)</td><td>6 (0–16)</td><td>7 (0–17)</td><td>0 (0–14)</td><td>&lt;0.001</td></tr><tr><td>Extracorporeal membrane oxygenation, n (%)</td><td>221 (10.4%)</td><td>151 (9.2%)</td><td>70 (14.3%)</td><td>0.001</td></tr><tr><td>Extracorporeal CO₂ removal, n (%)</td><td>10 (0.7%)</td><td>7 (0.7%)</td><td>3 (0.9%)</td><td>0.719</td></tr><tr><td>Inhaled nitric oxide, n (%)</td><td>412 (19.3%)</td><td>286 (17.4%)</td><td>126 (25.7%)</td><td>&lt;0.0001</td></tr><tr><td>Static compliance (mL/cmH₂O), median (IQR)</td><td></td><td></td><td></td><td></td></tr><tr><td>At Day-3</td><td>33.6 (25.7–42.5)</td><td>34.4 (26.7–43.6)</td><td>31.4 (23.4–40)</td><td>&lt;0.001</td></tr><tr><td>At Day-5</td><td>31.4 (24.3–40)</td><td>32.3 (24.7–40.8)</td><td>29.4 (22.6–39.7)</td><td>0.011</td></tr><tr><td>At Day-7</td><td>31 (22.9–40)</td><td>31.4 (23.3–40.4)</td><td>29.4 (22.1–38.8)</td><td>0.105</td></tr><tr><td>SOFA score, median (IQR)</td><td></td><td></td><td></td><td></td></tr><tr><td>At Day-7</td><td>9 (7–12)</td><td>9 (7–11)</td><td>10 (8–12)</td><td>0.002</td></tr><tr><td>At Day-21</td><td>8 (6.2–11)</td><td>8 (7–12)</td><td>8 (5–11)</td><td>0.638</td></tr><tr><td>At Day-28</td><td>8 (6.5–11)</td><td>8 (6–11)</td><td>9 (7–11)</td><td>0.905</td></tr><tr><td>PaO₂/FiO₂ ratio (mmHg), median (IQR)</td><td></td><td></td><td></td><td></td></tr><tr><td>At Day-3</td><td>158.3 (118.3–213.3)</td><td>162.9 (121.2–220)</td><td>148 (108.7–192.5)</td><td>&lt;0.0001</td></tr><tr><td>At Day-5</td><td>155 (113.3–205.5)</td><td>158.3 (115–208.6)</td><td>140 (106–191.4)</td><td>0.001</td></tr><tr><td>At Day-7</td><td>157.1 (114–205)</td><td>158.3 (116–209.3)</td><td>150 (104.4–187.5)</td><td>0.002</td></tr><tr><td>Number of prone sessions during ICU stay, median (IQR)</td><td>3 (2–6)</td><td>3 (2–6)</td><td>4 (2–7)</td><td>&lt;0.0001</td></tr><tr><td>Delay between ICU admission and 1st prone position, days, median (IQR)</td><td>2 [0–4]</td><td>3 [2–5]</td><td>0 [0–0]</td><td></td></tr></tbody></table>

IQR interquartile range, SOFA sequential organ failure assessment, PaO₂ arterial partial pressure in oxygen, FiO₂ fraction inspired in oxygen, ICU intensive care unit

were worse in the early PP group. In the whole cohort, ventilatory parameters did not improve during the first 7 days after ICU admission.

After propensity score adjustment, results were analyzed in both complete case analysis including 944 patients and in multiple imputation analysis with all

<footnote n="1">¹ Defined as plateau pressure—PEEP. If plateau pressure was missing, peak pressure was considered instead</footnote>

<footnote n="2">² Mechanical power (J/min) = 0.098 × tidal volume × respiratory rate × (peak pressure – 1/2 × driving pressure). If not specified, peak pressure was considered equal to plateau pressure</footnote>

<footnote n="3">³ Defined as (minute ventilation × PaCO₂) – (predicted bodyweight × 100 × 37.5)</footnote>

<footnote n="4">⁴ Normalized for ideal body weight. Defined as tidal volume/(Plateau pressure – PEEP)</footnote>

<footnote n="5">⁵ Normalized for ideal body weight. Defined as tidal volume/(Peak pressure – PEEP)</footnote>
baseline population of 2137 patients, supplied in the Additional file 1: Table S2. Baseline characteristics before and after weighted-propensity score analysis are provided in the Additional file 1: Table S3.

After weighting, no significant difference in Day-60 mortality was found between the two study groups, in both analysis (hazard ratio (HR) 1.34 [0.96–1.68], *p*=0.09 in complete case analysis and 1.19 [0.998–1.412], *p*=0.053 in multiple imputation analysis) as illustrated in Figs. 2 and 3. Mortality at Day-28 and Day-90 was also similar between the two study groups after weighted-propensity score analysis.

### In the subgroups

In the subgroups of ARDS patients according to their PaO₂/FiO₂ more or less than 150 at Day-1, mortality was higher in patients with PaO₂/FiO₂ less than 150 mmHg (Table 3).

Among the 1504 patients who received prone positioning during their ICU stay, an early PP was not associated with a reduction of mortality nor an increase in ventilator-free-days up to Day-28, as shown in Table 3. After propensity score adjustment in the subgroup of severely hypoxemic patients (PaO₂/FiO₂ ratio less than 150 mmHg) at Day-1, results were analyzed in both complete case analysis including 474 patients and in multiple imputation analysis with all baseline subgroup population of 1106 patients, supplied in the Additional file 1: Table S4. Subgroup baseline characteristics before and after weighted-propensity score analysis are provided in the Additional file 1: Table S5. After weighting, no significant difference in Day-60 mortality was found between

the non-early PP and the early PP groups, in both analysis (hazard ratio (HR) 1.12 [0.78–1.59], *p*=0.55 in complete case analysis and 1.13 [0.9–1.42], *p*=0.28 in multiple imputation analysis) as illustrated in Additional file 1: Figs. S3 and S4.

However, in the subgroup of non-severely hypoxemic patients (PaO₂/FiO₂ ratio more than 150 mmHg) at Day-1, an early PP seemed to be associated to higher Day-60 mortality with a significant difference between the two study groups in both analysis (hazard ratio (HR) 1.7 [1.05–2.77], *p*=0.03 in complete case analysis and 1.7 [1.16–2.47], *p*=0.006 in multiple imputation analysis) as illustrated in Additional file 1: Figs. S6 and S7.

### Discussion

In this secondary analysis of a multicenter observational cohort study, our results show that PP was widely used across European ICUs during the COVID-19 pandemic, with 70% of patients intubated at ICU admission placed in prone position during their ICU stay. This rate contrasts with the results of the Lung Safe study and Apronet studies published before this pandemic, reporting less than 15% use of PP in ARDS of all-causes worldwide [8, 21]. Interestingly, our study highlights that prone positioning was not always used according to international guidelines [7, 22]. As a result, a large proportion of patients (37%) was placed in PP despite a PaO₂/FiO₂ ratio higher than 150 mmHg. In addition, approximately 50% of patients were not placed in PP at Day-1 despite PaO₂/FiO₂ ratio lower than 150 mmHg. Those findings are consistent with results of previous studies [11, 12]. In a recent observational study, Mathews et al. reported

<figure><img src="image_5.png" /><figcaption>**Fig. 2** a Kaplan–Meier curves according to prone status in ICU at Day-1 before weighting adjustment in complete case population. b Kaplan–Meier curves according to prone status in ICU at Day-1 after weighting adjustment in complete case population. ICU intensive care unit</figcaption></figure>
a

Control, n = 721

HR [CI 95%] p value

Prone before weighting, n = 223 1.34 [1.04 - 1.72] 0.022

Prone after weighting, n = 223 1.27 [0.96 - 1.68] 0.090

b

Control, n = 1646

HR [CI 95%] p value

Prone before weighting, n = 491 1.22 [1.03 - 1.43] 0.019

Prone after weighting, n = 491 1.19 [0.998 - 1.412] 0.053

<figure><img src="image_6.png" /></figure>

<figure><img src="image_7.png" /><figcaption>**Fig. 3** a Forest plot: hazard ratio according to prone status in ICU at Day-1 before and after weighting in complete case population. **b** Hazard ratio according to prone status in ICU at Day-1 before and after weighting in baseline population. **ICU** intensive care unit, **HR** hazard ratio</figcaption></figure>

that 44% of intubated patients with a PaO₂/FiO₂ ratio less than 100 mmHg were not placed in PP during the first 2 days, and only 30% of patients experienced proning during their ICU stay [11]. In a large cohort study of more than 1000 patients, 21% of patients were not placed in PP despite a PaO₂/FiO₂ ratio of less than 100 mmHg [13]. Those results highlight the difficulty in this pandemic to properly apply international guidelines. Higher number of ICU beds and higher number of patients per physician or per nurse have previously been associated with a lower use of prone positioning [21]. The intervention of prone positioning in intubated patient requiring experimented staff to do it safely. Work overload, the deterioration of work conditions, the hiring of unexperienced staff and the reorganization of ICU care associated with this pandemic [23, 24] may have contributed

to an inadequate use of PP and may explain why patients had not been placed in PP or placed in PP disregarding international guidelines.

Our observational study failed to demonstrate an improvement of survival in intubated patients receiving an early PP at Day-1 compared to non-early PP. Our findings therefore contrast to those reported in another study in mechanically ventilated patients, in which early prone positioning in the first 2 days of ICU admission was associated with a survival benefit in COVID-19-related ARDS [11]. Several reasons may explain these discrepancies. First, definition of treatment group was different between studies. In our study, treatment groups were defined according to their PP status at Day-1 and not according to their PP status in the first 48 h after admission. In order to respect the validity of the propensity score using, our
<table><caption>**Table 3** Subgroups analysis</caption><thead><tr><th rowspan="2">Variable</th><th colspan="2">PaO<sub>2</sub>/FiO<sub>2</sub> ratio at Day-1</th><th rowspan="2">p</th></tr><tr><th>≥ 150 mmHg (n = 1031)</th><th>&lt; 150 mmHg (n = 1106)</th></tr></thead><tbody><tr><td>Mortality Day-28, n (%)</td><td>271 (26.3%)</td><td>381 (34.4%)</td><td>&lt; 0.0001</td></tr><tr><td>Mortality Day-60</td><td>312 (30.3%)</td><td>444 (40.1%)</td><td>&lt; 0.0001</td></tr><tr><td>Mortality Day-90</td><td>319 (30.9%)</td><td>448 (40.5%)</td><td>&lt; 0.0001</td></tr><tr><td>Invasive ventilation-free days up to Day-28 (days), median (IQR)</td><td>9 (0–18)</td><td>0 (0–14)</td><td>&lt; 0.0001</td></tr><tr><td colspan="4"><strong>Time between ICU admission and first prone session</strong></td></tr><tr><td></td><td>After 24 h (n = 1013)</td><td>Before 24 h (n = 491)</td><td></td></tr><tr><td>Mortality Day-28, n (%)</td><td>339 (33.5%)</td><td>170 (34.6%)</td><td>0.656</td></tr><tr><td>Mortality Day-60</td><td>403 (39.8%)</td><td>193 (39.3%)</td><td>0.86</td></tr><tr><td>Mortality Day-90</td><td>410 (40.5%)</td><td>193 (39.3%)</td><td>0.665</td></tr><tr><td>Invasive ventilation-free days up to Day-28 (days), median (IQR)</td><td>0 (0–13)</td><td>0 (0–14)</td><td>0.415</td></tr></tbody></table>

IQR interquartile range, PaO₂ arterial partial pressure in oxygen, FiO₂ fraction inspired in oxygen, ICU Intensive care unit

study was designed to analyze a potential survival benefit of prone positioning during the first 24 h of ICU admission. Although the median delay between ICU admission and the first prone positioning in the non-early PP group was 3 days, we could have failed to demonstrate a benefit because approximately 25% of patients in this group had been finally placed in PP during Day-2. Those patients would have been referred as PP group in Mathews et al. study [11]. Consequently, our results suggest no additional outcomes' improvement supporting very early PP during the first 24 h of ICU admission. Second, our study enrolled all intubated ARDS patients and more than a third of patients placed in PP had a PaO₂/FiO₂ ratio higher than 150 mmHg. The Proseva trial showed survival benefit with PP in moderate to severe selected patients with a PaO₂/FiO₂ ratio less than 150 mmHg with a PEEP ≥ 10 cmH₂O and FiO₂ ≥ 0.6 under standardized mechanical ventilation before inclusion [6]. Even if PP is supposed to limit the extent of lung injuries induced by ventilation in ARDS patients with various degrees of severity, the potential survival benefit in patients with PaO₂/FiO₂ ratio higher than 150 mmHg has not been demonstrated and remains unclear mainly due to under-powered previous studies [25]. Third, a large proportion of patients in the early PP group were placed in PP for less than 16 h in contrast to the Proseva trial showing a benefit in patient placed two time in prone position for at least 16 h during the first 2 days [6]. Similar to previous studies [26, 27], the short duration of PP session could also explain the absence of benefit of PP observed in the early PP group. Fourth, as previously described, the PaO₂/FiO₂ ratio is influenced by FiO₂ and the level of PEEP [28]. In this observational study, mechanical ventilation was not

standardized before blood gases analyses which was used to define PaO₂/FiO₂ ratio, which may have resulted in greater heterogeneity within groups. Finally, 660 patients were prone after 48 h of ICU admission, representing 43.8% of all prone patients in our cohort, and Guerin et al. found a survival benefit when using prone positioning early after endotracheal intubation (within 48 h) [6]. In Mathews et al.'s study a smaller proportion of patients (19.5%) was initiated on proning after 48 h of ICU admission [11], which might have contributed to greater difference in patient's care between groups and thus impact mortality. However, impact of timing of prone sessions initiation after endotracheal intubation has not been specifically studied yet and is scarcely described in other randomized control trials assessing proning in ARDS [29–31].

Prone position has been shown to improve blood oxygenation by homogenizing the distribution of pulmonary ventilation/perfusion ratios [32–35]; preventing ventilator induced lung injury by homogenizing the strain to lung tissue associated with mechanical ventilation on inflamed alveoli [36–38] and preserving systemic hemodynamics [39], particularly right ventricular function [40]. However, the clear response to the prone position has remained non-defined. Our results show that patients placed in PP at Day-1 did not improve their ventilatory parameters, including the static compliance and oxygenation during their ICU stay at least until Day-7. In a large cohort of intubated COVID-19 patients, Langer et al. found that prone positioning was associated with immediate oxygenation improvement without any increase of respiratory system compliance [13]. The lack of oxygenation improvement in our study
could be due to the timing of assessment of oxygenation. Indeed, we recorded blood gases results daily independently of patients proning status at that time and did not study blood gases evolution during and just after proning. This could be in line with results reported by Langer et al. showing a trend toward worsening of oxygenation after re-supination [13]. Our results considering the lack of improvement of static compliance are consistent with those of Langer et al. contrasting data on non-COVID-19-related ARDS which showed a reduction of driving pressure and plateau pressure when placed in prone position, suggesting better static compliance [35]. This difference of effect of PP on respiratory mechanics between COVID-19 and non-COVID-19-related ARDS possibly highlights different pathophysiologies [41]. Those lack of ventilatory parameters improvements could explain why the median duration of invasive mechanical ventilation in ARDS COVID-19 patients is approximately 12–13 days, longer than previously reported in all-causes ARDS patients included in Lung safe study [4, 20]. It might therefore also be possible that the follow-up of 7 days in our study did not allow us to show a potential ventilatory parameters benefits of prone position due to the short time of the follow-up. Moreover, we hypothesize that the main mechanism of the PP benefit in ARDS related to COVID-19 is the redistribution of pulmonary perfusion leading to higher ventilation perfusion ratios, rather than the recruitment, as reported by another study [12]. This pathophysiological rationale could explain why the mechanical property did not improve during the follow-up of our study.

This study has some limitations. First, only patients admitted in the first COVID wave have been enrolled in this research. Second, it is not a randomized controlled study. Although we used a propensity score adjusting on potential confounders, we cannot guarantee in this observational study that: (1) the standardization of mechanical ventilation at all centers was the same as that used in the positive randomized Proseva trial, (2) the PaO₂/FiO₂ ratio used by clinicians to initiate PP was calculated after a standardization of setting PEEP and FiO₂ level, as previously demonstrated as an important factor to define severity of ARDS patients [28, 42]. Third, despite of the propensity score weighting adjustment, it might be possible that patients in the early PP group were more severe at ICU admission and required a prone positioning earlier than patients in the non-early PP group, leading to confusion bias. Moreover, many patients were prone or not disregarded classical criteria for prone position suggesting that many additional factors (clinical, organizational, etc.) may have played a role in the decision to prone or not. However, those undetermined factors cannot be included in the analysis. Fourth, our study

design did not allow us to analyze outcomes in patients respecting the PP status in the first 48 h and after stabilization according the Proseva trial protocol, but only depending on the PP status at Day-1. This choice was made to limit the immortal bias that would result from comparing patients who were placed in PP after Day-1 to patients who did not initiate PP at all (patients placed in PP after Day-1 are part of this subgroup because they did not die earlier). Finally, some patients required up to 20 prone sessions leading to potential complications. Unfortunately, those data were not collected in this study.

## Conclusions

Our results suggest that ICUs across European countries have largely adopted prone positioning in ARDS patients due to COVID-19 regardless of their severity. In this observational study, our data failed to show a survival benefit associated with early prone positioning initiated during the first day of ICU admission compared to prone positioning initiation after Day-1 for all COVID-19 patients requiring invasive mechanical ventilation regardless of their severity. Further studies are needed to identify subgroups of patients with COVID-19-related ARDS who might benefit from early prone positioning.

## Abbreviations

COVID-19: Coronavirus disease 2019; PP: Prone position; ICU: Intensive care unit; ARDS: Acute respiratory distress syndrome; RT-PCR: Real-time reverse transcriptase-polymerase chain reaction; BMI: Body mass index; SOFA: Sequential Organ Failure Assessment; PaO₂: Arterial partial pressure of oxygen; FiO₂: Fraction inspired of oxygen; SAPS II: Simplified Acute Physiology Score II; PEEP: Positive end-expiratory pressure; ECMO: Extracorporeal membrane oxygenation; ECCO₂R: Extracorporeal CO₂ removal; IPTW: Inverse probability of treatment weighting; PS: Propensity score.

## Supplementary Information

The online version contains supplementary material available at https://doi.org/10.1186/s13054-022-03949-7.

**Additional file 1.** Additional information about the baseline characteristics and the statistical analysis (file format in .docx). **Additional Tables and Figures.** **Table S1.** Distribution of patients per region included in this study according to their prone position status at Day-1. **Table S2.** Descriptive analysis of baseline population included in propensity score analysis and complete case population. **Table S3.** Descriptive analysis of baseline characteristics before and after weighted-propensity score analysis. **Fig. S1.** Adjustment quality before and after propensity score analysis. **Table S4.** Descriptive subgroup analysis of baseline population with $P_aO_2/FiO_2$ ratio < 150 mmHg at Day-1 included in propensity score analysis and complete case population. **Table S5.** Descriptive subgroup analysis of baseline population characteristics with $P_aO_2/FiO_2$ ratio < 150 mmHg at Day-1 before and after weighted-propensity score analysis. **Fig. S2.** Adjustment quality before and after propensity score analysis in the subgroup of patients with $P_aO_2/FiO_2$ ratio < 150 mmHg at Day-1. **Fig. S3.** a Kaplan–Meier curves according to prone status in ICU at Day-1 before weighting adjustment in complete case subgroup population with $P_aO_2/FiO_2$ ratio < 150 mmHg. b Kaplan–Meier curves according to prone status in ICU at Day-1 after weighting adjustment in complete case subgroup population with $P_aO_2/FiO_2$ < 150 mmHg. **Fig. S4.** a Forest plot: Hazard
Ratio according to prone status in ICU at Day-1 before and after weighting in complete case subgroup population with $P_aO_2/F_0_2$ ratio < 150 mmHg.
**b** Hazard Ratio according to prone status in ICU at Day-1 before and after weighting in baseline subgroup population with $P_aO_2/F_0_2$ ratio < 150 mmHg. **Table S6.** Descriptive subgroup analysis of baseline population with $P_aO_2/F_0_2$ ratio > 150 mmHg included in propensity score analysis and complete case population. **Table S7.** Descriptive subgroup analysis of baseline population characteristics with $P_aO_2/F_0_2$ ratio > 150 mmHg at Day-1 before and after weighted-propensity score analysis. **Fig. S5.** Adjustment quality before and after propensity score analysis in the subgroup of patients with $P_aO_2/F_0_2$ ratio > 150 mmHg at Day-1. **Fig. S6.**
**a** Kaplan–Meier curves according to prone status in ICU at Day-1 before weighting adjustment in complete case subgroup population with $P_aO_2/F_0_2$ ratio > 150 mmHg. **b** Kaplan–Meier curves according to prone status in ICU at Day-1 after weighting adjustment in complete case subgroup population with $P_aO_2/F_0_2$ ratio > 150 mmHg. **Fig. S7.** a Forest plot: Hazard Ratio according to prone status in ICU at Day-1 before and after weighting in complete case subgroup population with $P_aO_2/F_0_2$ ratio > 150 mmHg. **b** Hazard Ratio according to prone status in ICU at Day-1 before and after weighting in baseline subgroup population with $P_aO_2/F_0_2$ ratio > 150 mmHg.

## Acknowledgements

We acknowledge all physicians and ICUs staff for taking care of all those patients. With contributions of the Clinical Research Center, University Hospital and Faculty of Medicine, Geneva (Isabelle Semac, Véronique Ménoni, Emmanuelle Lelong-Favre, Sophie Longchamp and Isabelle Mercier), we also acknowledge with gratitude all the French and Belgian clinical research centers, the medical students, the students of the Polytechnic University, and all the volunteers for their amazing help in data collection.

## Participating sites and COVID-ICU investigators

CHU Angers, Angers, France (Alain Mercat, Pierre Asfar, François Beloncle, Julien Demiselle), APHP—Hôpital Bicêtre, Le Kremlin-Bicêtre, France (Tai Pham, Arthur Pavot, Xavier Monnet, Christian Richard), APHP—Hôpital Pitié Salpêtrière, Paris, France (Alexandre Demoule, Martin Dres, Julien Mayaux, Alexandra Beurton), CHU Caen Normandie—Hôpital Côte de Nacre, Caen, France, Cédric Daubin, Richard Descamps, Aurélie Joret, Damien Du Cheyron), APHP—Hôpital Cochin, Paris, France (Frédéric Pene, Jean-Daniel Chiche, Mathieu Jozwiak, Paul Jaubert), APHP—Hôpital Tenon, Paris (France, Guillaume Voiriot, Muriel Fartoukh, Marion Teulier, Clarisse Blayau), CHRU de Brest—La Cavale Blanche, Brest, France (Erwen L’Her, Cécile Aubron, Laetitia Bodenes, Nicolas Ferrière), Centre Hospitalier de Cholet, Cholet, France (Johann Auchabe, Anthony Le Meur, Sylvain Pignal, Thierry Mazzoni), CHU Dijon Bourgogne, Dijon, France (Jean-Pierre Quenot, Pascal Andreu, Jean-Baptiste Roudau, Marie Labruyère), CHU Lille—Hôpital Roger Salengero, Lille, France (Saad Nseir, Sébastien Preau, Julien Poissy, Daniel Mathieu), Groupe Hospitalier Nord Essonne, Longjumeau, France (Sarah Benhamida, Rémi Paulet, Nicolas Roucaud, Martial Thyault), APHM—Hôpital Nord, Marseille, France (Florence Daviet, Sami Hraiech, Gabriel Parzy, Aude Sylvestre), Hôpital de Melun-Sénart, Melun, France (Sébastien Jochmans, Anne-Laure Bouilland, Mehran Monchi), Élément Militaire de Réanimation du SSA, Mulhouse, France (Marc Danguy des Déserts, Quentin Mathais, Gwendoline Rager, Pierre Pasquier), CHU Nantes—Hôpital Hotel Dieu, Nantes, France (Reignier Jean, Seguin Amélie, Garret Charlotte, Canet Emmanuel), CHU Nice—Hôpital Archet, Nice, France (Jean Dellamonicana, Clément Saccheri, Romain Lombardi, Yanis Kouchit), Centre Hospitalier d'Orléans, Orléans, France (Sophie Jacquier, Armelle Mathonnet, Mai-Ahn Nay, Isabelle Runge), Centre Hospitalier Universitaire de la Guadeloupe, Pointe-à-Pitre, France (Frédéric Martino, Laure Flurin, Amélie Rolle, Michel Carles), Hôpital de la Milétrie, Poitiers, France (Rémi Coudroy, Arnaud W Thille, Jean-Pierre Frat, Maeva Rodriguez), Centre Hospitalier Roanne, Roanne, France (Pascal Beuret, Audrey Tientcheu, Arthur Vincent, Florian Michelin), CHU Rouen—Hôpital Charles Nicolle, Rouen, France (Fabienne Tamion, Dorothée Carpentier, Déborah Boyer, Christophe Girault), CHRU Tours—Hôpital Bretonneau, Tours, France (Valérie Gissot, Stéphan Ehrmann, Charlotte Salmon Gandonniere, Djlali Elaroussi), Centre Hospitalier Bretagne Atlantique, Vannes, France (Agathe Delbove, Yannick Fedun, Julien Huntzinger, Eddy Lebas), CHU Liège, Liège, Belgique (Grâce Kisoka, Céline Grégoire, Stella Marchetta, Bernard Lambermont), Hospices Civils de

Lyon—Hôpital Edouard Herriot, Lyon, France (Laurent Argaud, Thomas Baudry, Pierre-Jean Bertrand, Auguste Dargent), Centre Hospitalier Du Mans, Le Mans, France (Christophe Guitton, Nicolas Chudeau, Mickaël Landais, Cédric Darreau), Centre Hospitalier de Versailles, Le Chesnay, France (Alexis Ferre, Antoine Gros, Guillaume Lacave, Fabrice Bruneel), Hôpital Foch, Suresnes, France (Mathilde Neuville, Jérôme Devaquet, Guillaume Tachon, Richard Gallot), Hôpital Claude Galien, Quincy sous Senart, France (Riad Chelha, Arnaud Galbois, Anne Gallot, Ludivine Chalumeau Lemoine), GHR Mulhouse Sud-Alsace, Mulhouse, France (Khdoun Kuteifan, Valentin Pointurier, Louise-Marie Jandeaux, Joy Mootien), APHP—Hôpital Antoine Béclère, Clamart, France (Charles Damoisel, Benjamin Sztrym), APHP—Hôpital Pitié-Salpêtrière, Paris, France (Matthieu Schmidt, Alain Combes, Juliette Chommeloux, Charles Edouard Luyt), Hôpital Intercommunal de Créteil, Créteil, France (Frédérique Schortgen, Leon Rusel, Camille Jung), Hospices Civils de Lyon—Hôpital Neurologique, Lyon, France (Florent Gobert), APHP—Hôpital Necker, Paris, France (Damien Vimpere, Lionel Lamhaut), Centre Hospitalier Public du Cotentin—Hôpital Pasteur, Cherbourg-en-coton, France (Bertrand Sauneuf, Liliane Charrrier, Julien Calus, Isabelle Desmeules), CHU Rennes—Hôpital du Pontchaillou, Rennes, France (Benoît Painvin, Jean-Marc Tadie), CHU Strasbourg—Hôpital Hautepierre, Strasbourg, France (Vincent Castelain, Baptiste Michard, Jean-Etienne Herbrecht, Mathieu Baldacini), APHP—Hôpital Pitié Salpêtrière, Paris, France (Nicolas Weiss, Sophie Demeret, Clémence Marois, Benjamin Rohaut), Centre Hospitalier Territorial Gaston-Bourret, Nouméa, France (Pierre-Henri Moury, Anne-Charlotte Savida, Emmanuel Couadau, Mathieu Série), Centre Hospitalier Compiègne-Noyon, Compiègne, France (Nica Alexandru), Groupe Hospitalier Saint-Joseph, Paris, France (Cédric Bruel, Candice Fontaine, Sonia Garrigou, Juliette Courtiade Mahler), Centre hospitalier mémorial de Saint-Lô, Saint-Lô, France (Maxime Leclerc, Michel Ramakers), Grand Hôpital de l'Est Francilien, Jossigny, France (Pierre Garçon, Nicole Massou, Ly Van Vong, Juliane Sen), Gustave Roussy, Villejuif, France (Nolwenn Lucas, Franck Chemouni, Annabelle Stoclin), Centre Hospitalier Intercommunal Robert Ballanger, Aulnay-sous-Bois, France (Alexandre Avenel, Henri Faure, Angélie Gentilhomme, Sylvie Ricome), Hospices Civiles de Lyon—Hôpital Edouard Herriot, Lyon, France (Paul Abraham, Céline Monard, Julien Textoris, Thomas Rimmele), Centre Hospitalier d'Avignon, Avignon, France (Florent Montini), Groupe Hospitalier Diaconesses—Croix Saint Simon, Paris, France (Gabriel Lejour, Thierry Lazard, Isabelle Etienney, Younes Kerroumi), CHU Clermont-Ferrand—Hôpital Gabriele Montpied, Clermont Ferrand, France (Claire Dupuis, Marine Bereiziat, Elisabeth Coupez, François Thouy), Hôpital d'Instruction des Armées Percy, Clamart, France (Clément Hoffmann, Nicolas Donat, Anne Chismert, Rose-Marie Blot), CHU Nancy—Hôpital Brabois, Vandoeuvre-les-Nancy, France (Antoine Kimmoun, Audrey Jacquot, Matthieu Mattei, Bruno Levy), Centre Hospitalier de Vichy, Vichy, France (Ramin Ravan, Loïc Dopeus, Jean-Mathias Liteaudon, Delphine Roux), Hôpital Pierre Bérégovoy, Nevers, France (Brice Rey, Radu Anghel, Deborah Schenesse, Vincent gevrey), Centre Hospitalier de Tarbes, Tarbes (Jemky Castanera, Philippe Petua, Benjamin Madeux), Hôpitaux Civils de Colmar—Hôpital Louis pasteur, Colmar, France (Otto Hartman), CHU Charleroi—Hôpital Marie Curie, Bruxelles, Belgique (Michael Piagnerelli, Anne Joosten, Cinderella Noel, Patrick Biston), Centre hospitalier de Verdun Saint Mihiel, Saint Mihiel, France (Thibaut Noel), CH Eure-Seine—Hôpital d'Evreux-Vernon, Evreux, France (Gurvan LE Bouar, Messabi Boukhanza, Elsa Demarest, Marie-France Bajolet), Hôpital René Dubos, Pontoise, France (Nathanaël Charrier, Audrey Quenet, Cécile Zylberfajn, Nicolas Dufour), APHP—Hôpital Lariboisière, Paris, France (Buno Mégarbane, Sébastien Voicu, Nicolas Deye, Isabelle Malissin), Centre Hospitalier de Saint-Brieuc, Saint-Brieuc, France (François Legay, Matthieu Debarre, Nicolas Barbarot, Pierre Fillatre), Polyclinique Bordeaux Nord Aquitaine, Bordeaux, France (Bertrand Delord, Thomas Laterrade, Tahar Saghi, Wilfried Pujol), HIA Sainte Anne, Toulon, France (Pierre Julien Cungi, Pierre Esnault, Mickael Cardinale), Grand Hôpital de l'Est Francilien, Meaux, France (Vivien Hong Tuan Ha, Grégory Fleury, Marie-Ange Brou, Daniel Zafimahazo), HIA Robert Picqué, Villenave d'Ornon, France (David Tran-Van, Patrick Avargues, Lisa Carenco), Centre Hospitalier Fontainebleau, Fontainebleau, France (Nicolas Robin, Alexandre Ouali, Lucie Houdou), Hôpital Universitaire de Genève, Genève, Suisse (Christophe Le Terrier, Noémie Suh, Steve Primmaz, Jérôme Pugin), APHP—Hôpital Beaujon, Clichy, France (Emmanuel Weiss, Tobias Gauss, Jean-Denis Moyer, Catherine Paugam Burtz), Groupe Hospitalier Bretagne Sud, Lorient, France (Béatrice La Combe, Rolland Smonig, Jade Violleau, Pauline Cailliez), Centre Hospitalier Intercommunal Toulon, La Seyne sur Mer, France (Jonathan Chelly), Centre Hospitalier de
Dieppe, Dieppe, France (Antoine Marchalot, Cécile Saladin, Christelle Bigot), CHU de Martinique, Fort-de-France, France (Pierre-Marie Fayolle, Jules Fatséas, Amr Ibrahim, Dabor Resiere), Hôpital Fondation Adolphe de Rothchild, Paris, France (Rabih Hage, Clémentine Cholot, Marie Cantier, Pierre Trouilier), APHP—Bichat Claude Bernard, Paris, France (Philippe Montravers, Brice Lortat-Jacob, Sebastien Tanaka, Alexy Tran Dinh), APHP—Hôpital Universitaire Paris Sud, Bicêtre, France (Jacques Duranteau, Anatole Harrois, Guillaume Dubreuil, Marie Werner), APHP—Hôpital Européen Georges Pompidou, Paris, France (Anne Godier, Sophie Hamada, Diane Zlotnik, Hélène Nougue), APHP, GHU Henri Mondor, Créteil, France (Armand Mekonto-Dessap, Guillaume Carteaux, Keyvan Razazi, Nicolas De Prost), APHP—Hôpitaux Universitaires Henri Mondor, Créteil, France (Nicolas Mongardon, Olivier Langeron, Eric Levesque, Arié Attias), APHP—Hôpital Lariboisière, Paris, France (Charles de Roquetaillade, Benjamin G. Chousterman, Alexandre Mebazaa, Etienne Gayat), APHP—Hôpital Saint-Antoine, Paris, France (Marc Garnier, Emmanuel Pardo, Lea Satre-Buisson, Christophe Gutton), APHP Hôpital Saint-Louis, Paris, France (Elise Yvin, Clémence Marcault, Elie Azoulay, Michael Darmon), APHP—Hôpital Saint-Antoine, Paris, France (Hafid Oit Aufella, Geoffroy Hariri, Tomas Urbina, Sandie Mazerand), APHP—Hôpital Raymond Pointcarré, Garches, France (Nicholas Heming, Francesca Santi, Pierre Moine, Djillali Annane), APHP—Hôpital Pitié Salpétrière, Paris, France (Adrien Bouglé, Edris Omar, Aymeric Lancelot, Emmanuelle Begot), Centre Hospitalier Victor Dupouy, Argenteuil, France (Gaétan Planteveve, Damien Contou, Hervé Mentec, Olivier Pajot), CHUToulouse—Hôpital Rangueil, Toulouse, France (Stanislas Faguer, Olivier Cointault, Laurence Lavayssiere, Marie-Béatrice Nogier), Centre Hospitalier de Poissy, Poissy, France (Matthieu Jamme, Claire Pichereau, Jan Hayon, Hervé Outin), APHP—Hôpital Saint-Louis, Paris, France (François Dépret, Maxime Coutrot, Maité Chaussard, Lucie Guillemet), Clinique du MontLégia, CHC Groupe-Santé, Liège, Belgique (Pierre Goffin, Romain Thouny, Julien Guntz, Laurent Jadot), CHU Saint-Denis, La Réunion, France (Romain Persichini), Centre Hospitalier de Tourcoing, Tourcoing, France (Vanessa Jean-Michel, Hugues Georges, Thomas Caulier), Centre Hospitalier Henri Mondor d'Aurillac, Aurillac, France (Gaël Pradel, Marie-Hélène Hausermann, Thi My Hue Nguyen-Valat, Michel Boudinaud), Centre Hospitalier Saint Joseph Saint Luc, Lyon, France (Emmanuel Vivier, Sylvène Rosseli, Gaël Bourdin, Christian Pommier) Centre Hospitalier de Polynésie Française, Polynésie, France (Marc Vinclair, Simon Poignant, Sandrine Mons), Ramsay Générale de Santé, Hôpital Privé Jacques Cartier, Massy, France (Wulfran Bougouin), Centre Hospitalier Alpes Léman, Contamine sur Arve, France (Franklin Bruna, Quentin Maestraggi, Christian Roth), Hospices Civils de Lyon—Hôpital de la Croix Rousse, Lyon, France (Laurent Bitker, François Dhelft, Justine Bonnet-Château, Mathilde Filippelli), Centre Cardiologique du Nord, Saint-Denis, France (Tristan Morichau-Beauchant, Stéphane Thierry, Charlotte Le Roy, Mélanie Saint Jouan), GHU—Hôpital Saint-Anne, Paris, France (Bruno Goncalves, Aurélien Mazeraud, Matthieu Daniel, Tarek Sharshar) CHR Metz—Hôpital Mercy, Metz, France (Cyril Cadoz, Rostane Gaci, Sébastien Gette, Guillaume Louis), APHP—Hôpital Paul Brouse, Villejuif, France (Sophe-Caroline Sacleux, Marie-Amélie Ordan), CHRU Nancy—Hôpital Central, Nancy, France (Aurélie Cravoisy, Marie Conrad, Guilhem Courte, Sébastien Gibot), Centre Hospitalier d'Ajaccio, Ajaccio, France (Younès Benzidi, Claudia Casella, Laurent Serpin, Jean-Lou Setti), Centre Hospitalier de Bourges, Bourges, France (Marie-Catherine Besse, Anna Bourreau), Centre hospitalier de la Côte Basque, Bayonne, France (Jérôme Pilot, Caroline Rivera, Camille Vinclair, Marie-Aline Robaux), Hospices Civils de Lyon—Hôpital de la Croix Rousse, Lyon, France (Chloé Achino, Marie-Charlotte Delignette, Tessa Mazard, Frédéric Aubrun), CH Saint-Malo, Saint-Malo, France (Bruno Bouchet, Aurélien Frérou, Laura Muller, Charlotte Quentin), Centre Hospitalier de Mulhouse, Mulhouse, France (Samuel Degoul), Centre Hospitalier de Briançon, Briançon, France (Xavier Stihle, Claude Sumian, Nicoletta Bergero, Bernard Lanaspre), CHU Nice, Hôpital Pasteur 2, Nice, France (Hervé Quintard, Eve Marie Maiziere), Centre Hospitalier des Pays de Morlaix, Morlaix, France (Pierre-Yves Egreteau, Guillaume Leloup, Florin Berteau, Marjolaine Cottrel), Centre Hospitalier Valence, Valence, France (Marie Bouteloup, Matthieu Jeannot, Quentin Blanc, Julien Saison), Centre Hospitalier Niort, Niort, France (Isabelle Geneau, Romaric Grenot, Abdel Ouchike, Pascal Hazera), APHP—Hôpital Pitié Salpétrière, Paris, France (Anne-Lyse Masse, Suela Demiri, Corinne Vezinet, Elodie Baron, Deborah Benchetrit, Antoine Monsel), Clinique du Val d'Or, Saint Cloud, France (Grégoire Trebbia, Emmanuelle Schaack, Raphaël Lepecq, Mathieu Bobet), Centre Hospitalier de Béthune, Béthune, France (Christophe Vinsonneau, Thibault Dekeyser, Quentin Delforge, Imen Rahmani), Groupe Hospitalier Intercommunal de la Haute-Saône, Vesoul, France (Bérengère Vivet, Jonathan Paillot, Lucie Hierle, Claire Chaignat, Sarah

Valette), Clinique Saint-Martin, Caen, France (Benoit Her, Jennifer Brunet), Ramsay Générale de Santé, Clinique Convert, Bourg en Bresse, France (Mathieu Page, Fabienne Boiste, Anthony Collin), Hôpital Victor Jousselin, Dreux, France (Florent Bavozet, Aude Garin, Mohamed Dlala, Kais Mhamdi), Centre Hospitalier de Troye, Troye, France, (Bassem Beilouny, Alexandra Lavalard, Severine Perez), CHU de ROUEN-Hôpital Charles Nicolle, Rouen, France (Benoit Veber, Pierre-Gildas Guitard, Philippe Gouin, Anna Lamaz), Centre Hospitalier Agen-Nérac, Agen, France (Fabienne Plouvier, Bertrand P Delaborde, Aïssa Kherchache, Amina Chaalal), APHP—Hôpital Louis Mourier, Colombes, France (Jean-Damien Ricard, Marc Amouretti, Santiago Freita-Ramos, Damien Roux), APHP—Hôpital Pitié-Salpétrière, Paris, France (Jean-Michel Constantin, Mona Assefi, Marine Lecore, Agathe Selves), Institut Mutualiste Montsouris, Paris, France (Florian Prevost, Christian Lamer, Ruiying Shi, Lyes Knani), CHU Besançon—Hôpital Jean Minjoz, Besançon, France, (Sébastien Pili Floury, Lucie Vettoretti), APHP—Hôpital Universitaire Robert-Debré, Paris, France (Michael Levy, Lucile Marsac, Stéphane Dauger, Sophie Guilmin-Crépon), CHU Besançon—Hôpital Jean Minjoz, Besançon, France, (Hadrien Winiszewski, Gael Piton, Thibaud Soumagne, Gilles Capellier); Médipôle Lyon-Villeurbanne, Vileurbanne, France, (Jean-Baptiste Putegnat, Frédérique Bayle, Maya Perrou, Ghyslaine Thao), APHP—Ambroise Paré, Boulogne-Billancourt, France (Guillaume Géri, Cyril Charron, Xavier Repessé, Antoine Vieillard-Baron), CHU Amiens Picardie, Amiens, France (Mathieu Guilbart, Pierre-Alexandre Roger, Sébastien Hinard, Pierre-Yves Macq), Hôpital Nord-Ouest, Villefranche-sur-Saône, France (Kevin Chaulier, Sylvie Goutte), CH de Chálons en Champagne, Chálons en Champagne, France (Patrick Chillet, Anais Pitta, Barbara Darjent, Amandine Bruneau), CHU Angers, Angers, France (Sigismond Lasocki, Maxime Leger, Soizic Gergaud, Pierre Lemarie), CHU Grenoble Alpes, Grenoble, France (Nicolas Terzi, Carole Schwebel, Anais Dartevel, Louis-Alexandre Galerneau), APHP—Hôpital Européen Georges Pompidou, Paris, France (Jean-Luc Diehl, Caroline Hauw-Berlemont, Nicolas Péron, Emmanuel Guérot), Hôpital Privé d'Antony, Antony, (Abolfazl Mohebbi Amoli, Michel Benhamou, Jean-Pierre Deyme, Olivier Andremont), Institut Arnault Tzanck, Saint Laurent du Var, France (Diane Lena, Julien Cady, Arnaud Caseruer, Arnaud De La Chapelle); Centre Hospitalier d'Angoulême, Angoulême, France (Christophe Cracco, Stéphane Rouleau, David Schnell); Centre Hospitalier de Cahors, Cahors, France (Camille Foucault), Centre hospitalier de Carcassonne, Carcassonne, France (Cécile Lory); CHU Nice—Hôpital L'Archet 2, Nice, France (Thibault Chapelle, Vincent Bruckert, Julie Garcia, Abdlazizah Sahraoui); Hôpital Privé du Vert Galant, Tremblay-en-France, France (Nathalie Abbosh, Caroline Bornstain, Pierre Pernet); Centre Hospitalier de Rambouillet, Rambouillet, France (Florent Poirson, Ahmed Pasem, Philippe Karoubi); Hopitaux du Léman, Thonon les Bains, France (Virginie Poupinel, Caroline Gauthier, François Bouniol, Philippe Feuchere), Centre Hospitalier Victor Jousselin, Dreux, France (Florent Bavozet, Anne Heron), Hôpital Sainte Camille, Brie sur Marne, France (Serge Carreira, Malo Emery, Anne Sophie Le Floch, Luana Giovannangeli), Hôpital d'instruction des armées Clermont-Tonnerre, Brest, France (Nicolas Herzog, Christophe Giacardi, Thibaut Baudic, Chloé Thill), APHP—Hôpital Pitié Salpétrière, Paris, France (Said Lebbah, Jessica Palmyre, Florence Tubach, David Hajage); APHP—Hôpital Avicenne, Bobigny, France (Nicolas Bonnet, Nathan Ebstein, Stéphane Gaudry, Yves Cohen); Groupement Hospitalier la Rochelle Ré Amis, La Rochelle, France (Julie Noublanche, Olivier Lesieur); Centre Hospitalier Intercommunal de Mont de Marsan et du Pays des Sources, Mont de Marsan, France (Arnaud Sément, Isabel Roca-Cerezo, Michel Pascal, Nesrine Sma); Centre Hospitalier Départemental de Vendée, La-Roche-Sur-Yon, France (Gwenhaël Colin, Jean-Claude Lacherade, Gauthier Bionz, Natacha Maquignneau); Pôle Anesthésie-Réanimation, CHU Grenoble (Pierre Bouzat, Michel Durand, Marie-Christine Hérault, Jean-Francois Payen).

## Authors' contributions

CLT and NT had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: CLT, SP and NT. Methodology: CLT, NT, SL, DH. Acquisition, analysis, or interpretation of data: CLT, FS, LD, SL, DH, JP, CG, NT. Drafting of the manuscript: CLT, LD, SP, NT. Critical revision of the manuscript for important intellectual content: JP, CG, DH, NT. Statistical analysis: SL, DH. Supervision: JP, NT. Obtained funding: CLT, JP. Administrative, technical, or material support: CLT, NT. All authors interpreted the data and critically revised the manuscript for important intellectual content and gave approval for the final version to be published. All authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part
of the work are appropriately investigated and resolved. The manuscript's guarantors (CLT and NT) affirm that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned have been explained. All authors read and approved the final manuscript.

## Funding

This study was funded by the AP-HP Foundation and its donators though the program "Alliance Tous Unis Contre le Virus", by the Clinical Research and Development Department, by the French Ministry of Health and by the foundation of the University hospitals of Geneva, Geneva, Switzerland. The Reseau European de recherche en Ventilation Artificielle (REVA) network received a 75,000 € research grant from Air Liquide Healthcare.

**Sponsor** The sponsor was Assistance Publique Hôpitaux de Paris (AP-HP).
**Role of the funder** The funder had no role in the design and conduct of the study, collection, management, analysis and interpretation of the data; preparation, review or approval of the manuscript; and decision to submit the manuscript for publication.

## Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

## Declarations

### Ethics approval and consent to participate

All patients or close relatives were informed that their data were included in the COVID-ICU cohort. Human research ethics committee approval for the study were the ethical committee of Geneva (BASEC #: 2020-00704), the ethical committee of the French Intensive Care Society (CE-SRLF 20-23) and the ethical committee of Belgium (2020-294) following our local regulations.

### Consent for publication

All patients or close relatives were informed that their data might be published.

### Competing interests

All authors declare no competing interests.

### Author details

¹Division of Intensive Care, Geneva University Hospitals and the University of Geneva Faculty of Medicine, Geneva, Switzerland. ²Medical Intensive Care Unit, Grenoble Alpes University Hospital, Grenoble, France. ³AP-HP, Département de Santé Publique, Centre de Pharmaco-épidémiologie, Paris, France. ⁴Medical Intensive Care Unit, Nantes Hôtel-Dieu University Hospital, Nantes, France. ⁵Division of Intensive Care, Edouard Herriot University Hospital, Lyon, France. ⁶Medical Intensive Care Unit, Grenoble Alpes University Hospital, Avenue Maquis du Grésivaudan, 38700 La Tronche, France.

Received: 13 September 2021 Accepted: 14 March 2022

Published online: 24 March 2022

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