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 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.
Table 1.
The resultant changes in ventilator/ECMO settings and blood gas analysis before and after PP
| Variables | Before prone position | After prone position | P value |
|---|---|---|---|
| Mechanical ventilation settings | |||
| Tidal volume (mL/kg) | 2.4 (1.8–2.9) | 2.4 (1.8–2.7) | 0.42 |
| RR (breaths/min) | 20 (16–25) | 19 (16–25) | 0.87 |
| Plateau airway pressure (cmH2O) | 28 (26–32) | 29 (28–32) | 0.43 |
| PEEP (cmH2O) | 14 (12–18) | 16 (12–20) | 0.36 |
| Respiratory system compliance (mL/cmH2O) | 18.6 (13.7–25.9) | 17.9 (12.8–26.5) | 0.92 |
| Driving pressure (cmH2O) | 14.5 (12–16.5) | 14.5 (11–16) | 0.56 |
| Inspired fraction of oxygen (%) | 70 (60–100) | 67.5 (52.5–95) | 0.16 |
| ECMO settings | |||
| ECMO blood flow (L/min) | 6.2 (6–6.7) | 6 (5.8–6.7) | 0.41 |
| Sweep gas flow (L/min) | 7 (6–8.5) | 7 (6.8–9) | 0.15 |
| FDO2 (%) | 100 (80–100) | 100 (80–100) | 0.56 |
| Gas analysis | |||
| PaO2 (mmHg) | 64 (51–78) | 82 (66–109) | 0.007 |
| PaO2/FiO2 (mmHg) | 84 (73–108) | 112 (83–157) | 0.002 |
| PaCO2 (mmHg) | 44 (41–46) | 42 (36–49) | 0.27 |
| pH | 7.38 (7.35–7.43) | 7.38 (7.34–7.42) | 0.47 |
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
Table 2.
Pre-ECMO characteristics, ventilator/ECMO settings, and outcomes
| All patients (n = 25) | Prone ECMO (n = 14) | Supine ECMO (n = 11) | P value | |
|---|---|---|---|---|
| Age (years) | 59 (49.5–63) | 59 (48–63) | 57 (48–66) | 0.82 |
| Male sex, n (%) | 22 (88) | 12 (85.7) | 10 (90.9) | 1 |
| Body mass index (kg/m2) | 32 (28.4–37.5) | 31.5 (28–38) | 33.6 (28.4–37.6) | 0.86 |
| Comorbidities | ||||
| Any, n (%) | 6 (24) | 3 (21.4) | 3 (27.3) | 1 |
| Hypertension, n (%) | 12 (48) | 6 (42.8) | 6 (54.5) | 0.7 |
| Diabetes, n (%) | 10 (40) | 5 (35.7) | 5 (45.4) | 0.7 |
| SAPS II | 60 (40–65) | 59.5 (46–62) | 61 (38–80) | 0.39 |
| Delay symptoms-ECMO (days) | 16 (11–18) | 15 (11–20) | 16 (10–16) | 0.94 |
| Delay mechanical ventilation-ECMO (days) | 7 (4–10) | 6.5 (4–10) | 7 (4–13) | 0.99 |
| Chest imaging (X-rays or CT) | ||||
| Consolidation, n (%) | 14 (56%) | 11 (78.6) | 3 (27.3) | 0.02 |
| Ground glass opacity, n (%) | 25 (100) | 14 (100) | 11 (100) | – |
| Bilateral infiltration, n (%) | 25 (100) | 14 (100) | 11 (100) | – |
| PaO2/FiO2 ratio before ECMO (mmHg) | 84 (69–98) | 84 (67–96) | 87 (66–102) | 0.77 |
| Prone position before ECMO, n (%) | 25 (100) | 14 (100) | 11 (100) | – |
| Neuromuscular blockers, n (%) | 25 (100) | 14 (100) | 11 (100) | – |
| iNO before ECMO, n (%) | 21 (84) | 12 (85.7) | 9 (81.8) | 1 |
| Corticosteroids, n (%) | 4 (16) | 1 (7.1) | 3 (27.3) | 0.29 |
| MV and ECMO settings the first day of ECMO | ||||
| Tidal volume (mL/kg) | 2.6 (1.9–2.9) | 2.4 (1.7–3.1) | 2.6 (2.1–2.8) | 0.71 |
| Plateau airway pressure (cmH2O) | 26 (23–29) | 26 (25–29) | 26 (21–29) | 0.52 |
| PEEP (cmH2O) | 14 (11–20) | 14 (12–20) | 14 (10–20) | 0.47 |
| Driving pressure (cmH2O) | 10 (9–13) | 11 (10–14) | 9 (8–12) | 0.44 |
| Respiratory rate (cycles/min) | 14 (12–18) | 18 (13–25) | 12 (12–14) | 0.006 |
| Respiratory system compliance (mL/cmH2O) | 25 (15–32) | 24 (14–30) | 28 (18–33) | 0.36 |
| Inspired fraction of oxygen (%) | 50 (50–80) | 55 (50–72.5) | 50 (40–80) | 0.53 |
| ECMO blood flow (L/min) | 5.9 (5–6.3) | 5.8 (5.2–6.7) | 5.9 (4.9–6) | 0.31 |
| Sweep gas flow (L/min) | 5 (4–6) | 5.5 (4.5–6.2) | 4 (3.5–5) | 0.04 |
| Membrane lung fraction of oxygen (%) | 100 (80–100) | 100 (80–100) | 100 (90–100) | 0.38 |
| Outcomes | ||||
| ECMO weaning, n (%) | 11 (44) | 3 (21.4) | 8 (72.7) | 0.02 |
| ECMO duration (days) | 10 (5–13) | 11 (6–13) | 6 (3–12) | 0.28 |
| 28-day mortality, n (%) | 14 (56) | 11 (78.6) | 3 (27.3) | 0.02 |
| Discharged alive from ICU, n (%) | 10 (40) | 2 (14.3) | 8 (72.7) | 0.005 |
| Still in ICU, n (%) | 1 (4) | 1 (7.1) | 0 | 1 |
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
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.
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 Boddaert1 (Pauline.boddaert@chru-lille.fr), Arthur Durand1 (Arthur.durand@chru-lille.fr), Ahmed El Kalioubie1 (Ahmed.elkalioubie@chru-lille.fr), Patrick Girardie1 (Patrick.girardie@chru-lille.fr), Marion Houard1 (Marion.houard@chru-lille.fr), Geoffrey Ledoux1 (Geoffrey.ledoux@chru-lille.fr), Anne Sophie Moreau1 (Annesophie.moreau@chru-lille.fr), Christopher Niles1 (Christopher.niles@chru-lille.fr), Saad Nseir1 (Saad.nseir@chru-lille.fr), Thierry Onimus1 (Thierry.onimus@chru-lille.fr), Aurelia Toussaint1 (Aurelia.toussaint@chru-lille.fr), Sebastien Préau1 (Sebastien.preau@chru-lille.fr), Laurent Robriquet1 (Laurent.robriquet@chru-lille.fr), Anahita Rouze1 (Anahita.rouze@chru-lille.fr), Arthur Simonnet1 (Arthur.simonnet@chru-lille.fr), Sophie Six1 (Sophie.six@chru-lille.fr), Morgan Caplan1 (morgan.caplan@chru-lille.fr), Julien Goutay1 (julien.goutay@chru-lille.fr), Emmanuelle Jaillette1 (emmanuelle.jaillette@chru-lille.fr), Erika Parmentier-Decrucq1 (erika.decrucq@chru-lille.fr), Raphael Favory1 (raphael.favory@chru-lille.fr), Daniel Mathieu1 (daniel.mathieu@chru-lille.fr), Guillaume Degouy (Guillaume.degouy@chru-lille.fr), Mouhamed Moussa2 (Mouhamed.MOUSSA@CHRU-LILLE.FR)
1Pôle de Réanimation, CHU Lille, University of Lille, F-59000 Lille, France
2Service d’Anesthésie-Réanimation Cardio-Vasculaire, CHU Lille, University of Lille, F-59000 Lille, France
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
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.
Footnotes
Publisher’s Note
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Contributor Information
Thibault Duburcq, Email: thibault.duburcq@chru-lille.fr.
on behalf of the Lille Intensive Care COVID-19 group:
Pauline Boddaert, Arthur Durand, Ahmed El Kalioubie, Patrick Girardie, Marion Houard, Geoffrey Ledoux, Anne Sophie Moreau, Christopher Niles, Saad Nseir, Thierry Onimus, Aurelia Toussaint, Sebastien Préau, Laurent Robriquet, Anahita Rouze, Arthur Simonnet, Sophie Six, Morgan Caplan, Julien Goutay, Emmanuelle Jaillette, Erika Parmentier-Decrucq, Raphael Favory, Daniel Mathieu, Guillaume Degouy, and Mouhamed Moussa
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Associated Data
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Data Availability Statement
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.