# Prone positioning under VV-ECMO in SARS-CoV-2-induced acute respiratory distress syndrome

Bruno Garcia, Nicolas Cousin, Claire Bourel, Mercedes Jourdain, Julien Poissy, Thibault Duburcq

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Bruno Garcia, Nicolas Cousin, Claire Bourel, Mercedes Jourdain, Julien Poissy, et al. Prone positioning under VV-ECMO in SARS-CoV-2-induced acute respiratory distress syndrome. Critical Care, 2020, 24, pp.428. 10.1186/s13054-020-03162-4. hal-03283645

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RESEARCH LETTER

Open Access

Prone positioning under VV-ECMO in SARS-CoV-2-induced acute respiratory distress syndrome

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Bruno Garcia¹, Nicolas Cousin¹, Claire Bourel¹, Mercé Jourdain¹,², Julien Poissy¹,³, Thibault Duburcq¹* ID and on behalf of the Lille Intensive Care COVID-19 group

**Keywords:** COVID-19, Prone positioning, ECMO, Refractory hypoxemia

**Background**

Infection due to severe acute respiratory coronavirus 2 (SARS-CoV-2) may lead to an atypical acute respiratory distress syndrome (ARDS) [1], requiring in the most severe cases veno-venous extracorporeal membrane oxygenation (VV-ECMO). The management of persistent severe hypoxemia under VV-ECMO requires a multi-step clinical approach including prone positioning (PP), which could improve oxygenation [2].

**Methods**

We performed a retrospective study of patients with SARS-CoV-2-induced ARDS submitted to PP during VV-ECMO. We aimed to describe mechanical ventilation parameters and gas exchanges before and after PP. We assess the safety of PP and compare patients with PP under ECMO (prone ECMO group) to those maintained in the supine position (supine ECMO group). Patients were treated in accordance with the recommendation guidelines on ARDS [3]. During VV-ECMO, PP was considered in case of severe hypoxemia (PaO₂/FiO₂ ratio below 80 mmHg) despite FDO₂ and FiO₂ both at 100% and in case of extensive lung consolidation (ECL) on chest imaging (> 50% of lung volume).

**Results**

We enrolled 208 COVID-19 patients. Among the 125 patients with ARDS, 25 (20%) required VV-ECMO, and 14 (56%) were placed at least once in PP for a total of 24 procedures with a median duration of 16 (15–17) h. The delay from ECMO implantation therapy to PP was 1.5 days [1–3]. The resultant changes in ventilator/ECMO settings and blood gas analysis before and after PP are displayed in Table 1. The median PaO₂/FiO₂ ratio improvement after PP was 28% [2–36]. High responders (increase PaO₂/FiO₂ ratio > 20%) were 62.5%, moderate-responders (increase PaO₂/FiO₂ < 20%) were 16.7%, and non-responders (decrease PaO₂/FiO₂) were 20.8%. We did not observe any major safety concerns but only pressure sores after 6 procedures, three minor

<footnote>* Correspondence: thibault.duburcq@chru-lille.fr
¹CHU Lille, Pôle de réanimation, F-59000 Lille, France
Full list of author information is available at the end of the article</footnote>
<table><caption>**Table 1** The resultant changes in ventilator/ECMO settings and blood gas analysis before and after PP</caption><thead><tr><th>Variables</th><th>Before prone position</th><th>After prone position</th><th>P value</th></tr></thead><tbody><tr><td><strong>Mechanical ventilation settings</strong></td><td></td><td></td><td></td></tr><tr><td>Tidal volume (mL/kg)</td><td>2.4 (1.8-2.9)</td><td>2.4 (1.8-2.7)</td><td>0.42</td></tr><tr><td>RR (breaths/min)</td><td>20 (16-25)</td><td>19 (16-25)</td><td>0.87</td></tr><tr><td>Plateau airway pressure (cmH<sub>2</sub>O)</td><td>28 (26-32)</td><td>29 (28-32)</td><td>0.43</td></tr><tr><td>PEEP (cmH<sub>2</sub>O)</td><td>14 (12-18)</td><td>16 (12-20)</td><td>0.36</td></tr><tr><td>Respiratory system compliance (mL/cmH<sub>2</sub>O)</td><td>18.6 (13.7-25.9)</td><td>17.9 (12.8-26.5)</td><td>0.92</td></tr><tr><td>Driving pressure (cmH<sub>2</sub>O)</td><td>14.5 (12-16.5)</td><td>14.5 (11-16)</td><td>0.56</td></tr><tr><td>Inspired fraction of oxygen (%)</td><td>70 (60-100)</td><td>67.5 (52.5-95)</td><td>0.16</td></tr><tr><td><strong>ECMO settings</strong></td><td></td><td></td><td></td></tr><tr><td>ECMO blood flow (L/min)</td><td>6.2 (6-6.7)</td><td>6 (5.8-6.7)</td><td>0.41</td></tr><tr><td>Sweep gas flow (L/min)</td><td>7 (6-8.5)</td><td>7 (6.8-9)</td><td>0.15</td></tr><tr><td>FDO<sub>2</sub> (%)</td><td>100 (80-100)</td><td>100 (80-100)</td><td>0.56</td></tr><tr><td><strong>Gas analysis</strong></td><td></td><td></td><td></td></tr><tr><td>PaO<sub>2</sub> (mmHg)</td><td>64 (51-78)</td><td>82 (66-109)</td><td><strong>0.007</strong></td></tr><tr><td>PaO<sub>2</sub>/FiO<sub>2</sub> (mmHg)</td><td>84 (73-108)</td><td>112 (83-157)</td><td><strong>0.002</strong></td></tr><tr><td>PaCO<sub>2</sub> (mmHg)</td><td>44 (41-46)</td><td>42 (36-49)</td><td>0.27</td></tr><tr><td>pH</td><td>7.38 (7.35-7.43)</td><td>7.38 (7.34-7.42)</td><td>0.47</td></tr></tbody></table>

Data are expressed as number (%) or median [IQR]. Analyses were performed with the GraphPad Prism 6 software (San Diego, CA). All tests were two-tailed, with α level at 0.05. The comparisons before vs. after prone position were realized by Wilcoxon matched-pairs signed-rank test
RR respiratory rate, PEEP positive end-expiratory pressure, FiO₂ fraction of inspired oxygen, PaCO₂ arterial partial pressure of carbon dioxide, PaO₂ arterial partial pressure of oxygen, FDO₂ fraction on oxygen delivered in the sweep gas, ECMO extracorporeal membrane oxygenation

hemorrhages at the injection cannula, and three moderate drops in VV-ECMO flow requiring fluid resuscitation. Pre-ECMO characteristics, ventilator/ECMO settings, and outcomes are exposed in Table 2. Patients in the prone ECMO group were less likely to be weaned from ECMO, and 28-day mortality rate was significantly higher.

## Discussion

We report that during VV-ECMO, PP improved oxygenation without a change in respiratory system compliance and PaCO₂ at constant levels of minute ventilation and sweep gas flow. This does not suggest lung recruitment by PP but rather an optimization of ventilation and perfusion matching. Three explanations could be advanced for the mortality rate in the prone ECMO group (78.6%). First, prone ECMO patients may be more severe than supine ECMO patients. As described by Gattinoni et al., worsening patients progress from type 1 to type 2 (higher percentage of non-aerated tissue) [1], which is associated with a higher mortality rate [4]. Prone ECMO patients had much more consolidations, obviously because ECL was the main indication to be prone

(n = 10/14). Furthermore, prone ECMO patients need a higher respiratory rate for a higher sweep gas flow suggesting that they may be exposed to a higher mechanical power, and they possibly had also a higher dead space. Second, postmortem biopsies, performed in 6 patients with ECL in the prone ECMO group, found a fibrin exudative presence both in the alveolar spaces and bronchioles followed by a fibroblastic phase [5] and raise the question of the use of corticosteroids (only one patient in the prone ECMO group). Third, as already described by Zeng et al. [6], more than half (8/11) of the patients died from septic shock and multiple organ failure, for which ECMO may be useless.

## Conclusion

Prone positioning under VV-ECMO improves oxygenation in SARS-CoV-2-induced ARDS without compromising the safety of the patients. The high mortality rate in prone ECMO patients may be explained by the greater illness severity and the lack of an immunomodulatory therapy such as corticosteroids.
<table><caption>**Table 2** Pre-ECMO characteristics, ventilator/ECMO settings, and outcomes</caption><thead><tr><th></th><th>All patients (n = 25)</th><th>Prone ECMO (n = 14)</th><th>Supine ECMO (n = 11)</th><th>P value</th></tr></thead><tbody><tr><td>Age (years)</td><td>59 (49.5–63)</td><td>59 (48–63)</td><td>57 (48–66)</td><td>0.82</td></tr><tr><td>Male sex, n (%)</td><td>22 (88)</td><td>12 (85.7)</td><td>10 (90.9)</td><td>1</td></tr><tr><td>Body mass index (kg/m²)</td><td>32 (28.4–37.5)</td><td>31.5 (28–38)</td><td>33.6 (28.4–37.6)</td><td>0.86</td></tr><tr><td>Comorbidities</td><td></td><td></td><td></td><td></td></tr><tr><td>Any, n (%)</td><td>6 (24)</td><td>3 (21.4)</td><td>3 (27.3)</td><td>1</td></tr><tr><td>Hypertension, n (%)</td><td>12 (48)</td><td>6 (42.8)</td><td>6 (54.5)</td><td>0.7</td></tr><tr><td>Diabetes, n (%)</td><td>10 (40)</td><td>5 (35.7)</td><td>5 (45.4)</td><td>0.7</td></tr><tr><td>SAPS II</td><td>60 (40–65)</td><td>59.5 (46–62)</td><td>61 (38–80)</td><td>0.39</td></tr><tr><td>Delay symptoms-ECMO (days)</td><td>16 (11–18)</td><td>15 (11–20)</td><td>16 (10–16)</td><td>0.94</td></tr><tr><td>Delay mechanical ventilation-ECMO (days)</td><td>7 (4–10)</td><td>6.5 (4–10)</td><td>7 (4–13)</td><td>0.99</td></tr><tr><td>Chest imaging (X-rays or CT)</td><td></td><td></td><td></td><td></td></tr><tr><td>Consolidation, n (%)</td><td>14 (56%)</td><td>11 (78.6)</td><td>3 (27.3)</td><td><strong>0.02</strong></td></tr><tr><td>Ground glass opacity, n (%)</td><td>25 (100)</td><td>14 (100)</td><td>11 (100)</td><td>–</td></tr><tr><td>Bilateral infiltration, n (%)</td><td>25 (100)</td><td>14 (100)</td><td>11 (100)</td><td>–</td></tr><tr><td>PaO₂/FiO₂ ratio before ECMO (mmHg)</td><td>84 (69–98)</td><td>84 (67–96)</td><td>87 (66–102)</td><td>0.77</td></tr><tr><td>Prone position before ECMO, n (%)</td><td>25 (100)</td><td>14 (100)</td><td>11 (100)</td><td>–</td></tr><tr><td>Neuromuscular blockers, n (%)</td><td>25 (100)</td><td>14 (100)</td><td>11 (100)</td><td>–</td></tr><tr><td>iNO before ECMO, n (%)</td><td>21 (84)</td><td>12 (85.7)</td><td>9 (81.8)</td><td>1</td></tr><tr><td>Corticosteroids, n (%)</td><td>4 (16)</td><td>1 (7.1)</td><td>3 (27.3)</td><td>0.29</td></tr><tr><td>MV and ECMO settings the first day of ECMO</td><td></td><td></td><td></td><td></td></tr><tr><td>Tidal volume (mL/kg)</td><td>2.6 (1.9–2.9)</td><td>2.4 (1.7–3.1)</td><td>2.6 (2.1–2.8)</td><td>0.71</td></tr><tr><td>Plateau airway pressure (cmH₂O)</td><td>26 (23–29)</td><td>26 (25–29)</td><td>26 (21–29)</td><td>0.52</td></tr><tr><td>PEEP (cmH₂O)</td><td>14 (11–20)</td><td>14 (12–20)</td><td>14 (10–20)</td><td>0.47</td></tr><tr><td>Driving pressure (cmH₂O)</td><td>10 (9–13)</td><td>11 (10–14)</td><td>9 (8–12)</td><td>0.44</td></tr><tr><td>Respiratory rate (cycles/min)</td><td>14 (12–18)</td><td>18 (13–25)</td><td>12 (12–14)</td><td><strong>0.006</strong></td></tr><tr><td>Respiratory system compliance (mL/cmH₂O)</td><td>25 (15–32)</td><td>24 (14–30)</td><td>28 (18–33)</td><td>0.36</td></tr><tr><td>Inspired fraction of oxygen (%)</td><td>50 (50–80)</td><td>55 (50–72.5)</td><td>50 (40–80)</td><td>0.53</td></tr><tr><td>ECMO blood flow (L/min)</td><td>5.9 (5–6.3)</td><td>5.8 (5.2–6.7)</td><td>5.9 (4.9–6)</td><td>0.31</td></tr><tr><td>Sweep gas flow (L/min)</td><td>5 (4–6)</td><td>5.5 (4.5–6.2)</td><td>4 (3.5–5)</td><td><strong>0.04</strong></td></tr><tr><td>Membrane lung fraction of oxygen (%)</td><td>100 (80–100)</td><td>100 (80–100)</td><td>100 (90–100)</td><td>0.38</td></tr><tr><td>Outcomes</td><td></td><td></td><td></td><td></td></tr><tr><td>ECMO weaning, n (%)</td><td>11 (44)</td><td>3 (21.4)</td><td>8 (72.7)</td><td><strong>0.02</strong></td></tr><tr><td>ECMO duration (days)</td><td>10 (5–13)</td><td>11 (6–13)</td><td>6 (3–12)</td><td>0.28</td></tr><tr><td>28-day mortality, n (%)</td><td>14 (56)</td><td>11 (78.6)</td><td>3 (27.3)</td><td><strong>0.02</strong></td></tr><tr><td>Discharged alive from ICU, n (%)</td><td>10 (40)</td><td>2 (14.3)</td><td>8 (72.7)</td><td><strong>0.005</strong></td></tr><tr><td>Still in ICU, n (%)</td><td>1 (4)</td><td>1 (7.1)</td><td>0</td><td>1</td></tr></tbody></table>

Data are expressed as number (%) or median [IQR]. Analyses were performed with the GraphPad Prism 6 software (San Diego, CA). All tests were two-tailed, with α level at 0.05. To compare the prone ECMO group to the supine ECMO group, we used the non-parametric Mann-Whitney test for continuous variables and the exact Fisher test for categorical ones

SAPS II Simplified Acute Physiology Score, IQR interquartile range, CT computed tomography, PaO₂ arterial partial pressure of oxygen, FiO₂ fraction of inspired oxygen, PEEP positive end-expiratory pressure, ECMO extracorporeal membrane oxygenation, ICU intensive care unit
**Abbreviations**

ARDS: Acute respiratory distress syndrome; ICU: Intensive care unit; PP: Prone positioning; VV-ECMO: Veno-venous extracorporeal membrane oxygenation; SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2; FiO₂: Fraction of inspired oxygen; PaO₂: Arterial partial pressure of oxygen; FDO₂: Fraction on oxygen delivered in the sweep gas; ECL: Extensive lung consolidation

**Acknowledgements**

The authors are indebted to thank the whole members of the Lille Intensive Care COVID-19 Group and the entire nursing staff of the intensive care unit of the "Roger Salengro Hospital" of the "Centre Hospitalier Universitaire de Lille."

Lille Intensive Care COVID-19 group:
Pauline Boddaert<fnref n="1" /> (Pauline.boddaert@chru-lille.fr), Arthur Durand<fnref n="1" /> (Arthur.durand@chru-lille.fr), Ahmed El Kalioubie<fnref n="1" /> (Ahmed.elkalioubie@chru-lille.fr), Patrick Girardie<fnref n="1" /> (Patrick.girardie@chru-lille.fr), Marion Houard<fnref n="1" /> (Marion.houard@chru-lille.fr), Geoffrey Ledoux<fnref n="1" /> (Geoffrey.ledoux@chru-lille.fr), Anne Sophie Moreau<fnref n="1" /> (Annesophie.moreau@chru-lille.fr), Christopher Niles<fnref n="1" /> (Christopher.niles@chru-lille.fr), Saad Nseir<fnref n="1" /> (Saad.nseir@chru-lille.fr), Thierry Onimus<fnref n="1" /> (Thierry.onimus@chru-lille.fr), Aurelia Toussaint<fnref n="1" /> (Aurelia.toussaint@chru-lille.fr), Sebastien Préau<fnref n="1" /> (Sebastien.preau@chru-lille.fr), Laurent Robriquet<fnref n="1" /> (Laurent.robriquet@chru-lille.fr), Anahita Rouze<fnref n="1" /> (Anahita rouze@chru-lille.fr), Arthur Simonnet<fnref n="1" /> (Arthur.simonnet@chru-lille.fr), Sophie Six<fnref n="1" /> (Sophie.six@chru-lille.fr), Morgan Caplan<fnref n="1" /> (morgan.caplan@chru-lille.fr), Julien Goutay<fnref n="1" /> (Julien.goutay@chru-lille.fr), Emmanuelle Jaillette<fnref n="1" /> (emmanuelle.jaillette@chru-lille.fr), Erika Parmentier-Decrucq<fnref n="1" /> (erika.decrucq@chru-lille.fr), Raphael Favory<fnref n="1" /> (raphael.favory@chru-lille.fr), Daniel Mathieu<fnref n="1" /> (daniel.mathieu@chru-lille.fr), Guillaume Degouy (Guillaume.degouy@chru-lille.fr), Mouhamed Moussa<fnref n="2" /> (Mouhamed.MOUSSA@CHRU-LILLE.FR)

**Authors' contributions**

B.G and T.D. conceived the study. B.G, C.B., and N.C. collected the data. T.D. conducted the data analysis. B.G and T.D. drafted the manuscript. M.J. and J.P. revised the draft of the manuscript. All authors read and approved the final manuscript.

**Funding**

This study was supported by the French government through the Programme Investissement d'Avenir (I-SITE ULNE / ANR-16-IDEX-0004 ULNE) managed by the Agence Nationale de la Recherche ("PHYSIO COVID" and "PREDICT" projects)

**Availability of data and materials**

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

**Ethics approval and consent to participate**

French institutional authority for personal data protection (National Commission for Information Technology and Freedom, registration no DEC20-086) and ethics committee (ID-CRB 2020-A00763-36) approved the study.

**Consent for publication**

Not applicable

**Competing interests**

The authors declare that they have no competing interests.

**Author details**

Received: 1 July 2020 Accepted: 9 July 2020

Published online: 14 July 2020

**References**

1. Gattinoni L, Chiumello D, Rossi S. COVID-19 pneumonia: ARDS or not? Crit Care. 2020;24(1):154.

2. Kimmoun A, Roche S, Bridey C, Vanhuyse F, Fay R, Girerd N, Mandry D, Levy B. Prolonged prone positioning under VV-ECMO is safe and improves oxygenation and respiratory compliance. Ann Intensive Care. 2015;5(1):35.

3. Papazian L, Aubron C, Brochard L, Chiche J-D, Combes A, Dreyfuss D, Forel JM, Guérin C, Jaber S, Mekontso-Dessap A, et al. Formal guidelines: management of acute respiratory distress syndrome. Ann Intensive Care. 2019;9:69.

4. Yuan M, Yin W, Tao Z, Tan W, Hu Y. Association of radiologic findings with mortality of patients infected with 2019 novel coronavirus in Wuhan, China. PloS One. 2020;15(3):e0230548.

5. Copin M-C, Parmentier E, Duburcq T, Poissy J, Mathieu D, Lille COVID-19 ICU and Anatomopathology Group. Time to consider histologic pattern of lung injury to treat critically ill patients with COVID-19 infection. Intensive Care Med. 2020.46(6):1124-1126.

6. Zeng Y, Cai Z, Xianyu Y, Yang BX, Song T, Yan Q. Prognosis when using extracorporeal membrane oxygenation (ECMO) for critically ill COVID-19 patients in China: a retrospective case series. Crit Care. 2020;24(1):148.

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<footnote n="1">¹Pôle de Réanimation, CHU Lille, University of Lille, F-59000 Lille, France</footnote>

<footnote n="2">²Service d'Anesthésie-Réanimation Cardio-Vasculaire, CHU Lille, University of Lille, F-59000 Lille, France</footnote>

<footnote n="1">¹CHU Lille, Pôle de réanimation, F-59000 Lille, France. ²Univ. Lille, Inserm Pasteur Lille, Inserm U1190 EGID, F-59000 Lille, France. ³Univ. Lille, Inserm U1285, CNRS, UMR 8576 - Unité de Glycobiologie Structurale et Fonctionnelle, F-59000 Lille, France.</footnote>