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Response to PEEP in COVID-19 ARDS patients with and without extracorporeal membrane oxygenation. A multicenter case–control computed tomography study

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Background PEEP selection in severe COVID-19 patients under extracorporeal membrane oxygenation (ECMO) is challenging as no study has assessed the alveolar recruitability in this setting. The aim of the study was to compare lung recruitability and the impact of PEEP on lung aeration in moderate and severe ARDS patients with or without ECMO, using computed tomography (CT). Methods We conducted a two-center prospective observational case–control study in adult COVID-19-related patients who had an indication for CT within 72 h of ARDS onset in non-ECMO patients or within 72 h after ECMO onset. Ninety-nine patients were included, of whom 24 had severe ARDS under ECMO, 59 severe ARDS without ECMO and 16 moderate ARDS. Results Non-inflated lung at PEEP 5 cmH 2 O was significantly greater in ECMO than in non-ECMO patients. Recruitment induced by increasing PEEP from 5 to 15 cmH 2 O was not significantly different between ECMO and non-ECMO patients, while PEEP-induced hyperinflation was significantly lower in the ECMO group and virtually nonexistent. The median [IQR] fraction of recruitable lung mass between PEEP 5 and 15 cmH 2 O was 6 [4–10]%. Total superimposed pressure at PEEP 5 cmH 2 O was significantly higher in ECMO patients and amounted to 12 [11–13] cmH 2 O. The hyperinflation-to-recruitment ratio (i.e., a trade-off index of the adverse effects and benefits of PEEP) was significantly lower in ECMO patients and was lower than one in 23 (96%) ECMO patients, 41 (69%) severe non-ECMO patients and 8 (50%) moderate ARDS patients. Compliance of the aerated lung at PEEP 5 cmH 2 O corrected for PEEP-induced recruitment (C BABY LUNG ) was significantly lower in ECMO patients than in non-ECMO patients and was linearly related to the logarithm of the hyperinflation-to-recruitment ratio. Conclusions Lung recruitability of COVID-19 pneumonia is not significantly different between ECMO and non-ECMO patients, with substantial interindividual variations. The balance between hyperinflation and recruitment induced by PEEP increase from 5 to 15 cmH 2 O appears favorable in virtually all ECMO patients, while this PEEP level is required to counteract compressive forces leading to lung collapse. C BABY LUNG is significantly lower in ECMO patients, independently of lung recruitability.
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Richardetal. Critical Care (2022) 26:195
https://doi.org/10.1186/s13054-022-04076-z
RESEARCH
Response toPEEP inCOVID-19 ARDS
patients withandwithout extracorporeal
membrane oxygenation. Amulticenter case–
control computed tomography study
Jean‑Christophe Richard1,2,3*, Florian Sigaud4, Maxime Gaillet1, Maciej Orkisz2, Sam Bayat5,6, Emmanuel Roux2,
Touria Ahaouari5, Eduardo Davila2, Loic Boussel2,7, Gilbert Ferretti8, Hodane Yonis1, Mehdi Mezidi1,3,
William Danjou1, Alwin Bazzani1, Francois Dhelft1,3, Laure Folliet1, Mehdi Girard1, Matteo Pozzi9,
Nicolas Terzi4,10 and Laurent Bitker1,2,3
Abstract
Background: PEEP selection in severe COVID‑19 patients under extracorporeal membrane oxygenation (ECMO) is
challenging as no study has assessed the alveolar recruitability in this setting. The aim of the study was to compare
lung recruitability and the impact of PEEP on lung aeration in moderate and severe ARDS patients with or without
ECMO, using computed tomography (CT).
Methods: We conducted a two‑center prospective observational case–control study in adult COVID‑19‑related
patients who had an indication for CT within 72 h of ARDS onset in non‑ECMO patients or within 72 h after ECMO
onset. Ninety‑nine patients were included, of whom 24 had severe ARDS under ECMO, 59 severe ARDS without ECMO
and 16 moderate ARDS.
Results: Non‑inflated lung at PEEP 5 cmH2O was significantly greater in ECMO than in non‑ECMO patients. Recruit‑
ment induced by increasing PEEP from 5 to 15 cmH2O was not significantly different between ECMO and non‑ECMO
patients, while PEEP‑induced hyperinflation was significantly lower in the ECMO group and virtually nonexistent.
The median [IQR] fraction of recruitable lung mass between PEEP 5 and 15 cmH2O was 6 [4–10]%. Total superim‑
posed pressure at PEEP 5 cmH2O was significantly higher in ECMO patients and amounted to 12 [11–13] cmH2O. The
hyperinflation‑to‑recruitment ratio (i.e., a trade‑off index of the adverse effects and benefits of PEEP) was significantly
lower in ECMO patients and was lower than one in 23 (96%) ECMO patients, 41 (69%) severe non‑ECMO patients
and 8 (50%) moderate ARDS patients. Compliance of the aerated lung at PEEP 5 cmH2O corrected for PEEP‑induced
recruitment (CBABY LUNG) was significantly lower in ECMO patients than in non‑ECMO patients and was linearly related
to the logarithm of the hyperinflation‑to‑recruitment ratio.
Conclusions: Lung recruitability of COVID‑19 pneumonia is not significantly different between ECMO and non‑
ECMO patients, with substantial interindividual variations. The balance between hyperinflation and recruitment
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Open Access
*Correspondence: j‑christophe.richard@chu‑lyon.fr
1 Service de Médecine Intensive Réanimation, Hôpital de la Croix Rousse,
Hospices Civils de Lyon, 103 Grande Rue de la Croix Rousse, 69004 Lyon,
France
Full list of author information is available at the end of the article
Page 2 of 13
Richardetal. Critical Care (2022) 26:195
Background
Lung recruitability of COVID-19 acute respiratory dis-
tress syndrome (ARDS) remains to date a matter of
debate, as conflicting results have been reported using
several techniques derived from change in respiratory
mechanics and/or gas exchange in response to positive
end-expiratory pressure (PEEP) increase [15]. Various
factors may explain the heterogeneity of literature reports
regarding recruitability of COVID-19 ARDS: time from
ARDS onset, ARDS severity, reliability of these methods
to compute recruitment, ventilatory management before
evaluation, body mass index (BMI), among others. Fur-
thermore, COVID-19 ARDS lungs may be intrinsically
less recruitable than “classical” ARDS, as non-aerated
lung regions in COVID-19 patients may represent alve-
olar spaces substituted by fibrosis, cellular debris and
necrotic tissue rather than atelectasis [6].
Two small studies have been published so far using
computed tomography (CT) in the context of COVID-19
ARDS and provided conflicting results [7, 8]. One study
performed during the later phase of the disease identified
most patients as being non-recruiters by PEEP [7], while
median recruitability in the other study [8] performed
within 72 h of ARDS onset was substantially higher than
in non-COVID ARDS historical studies [9].
No study has assessed to date the recruitability of
severe COVID-19 ARDS under veno-venous extra-
corporeal membrane oxygenation (ECMO). In non-
COVID-19 ARDS patients, median lung recruitability
was substantially higher in 47 patients under ECMO
[10] than in the seminal study of Gattinoni performed
on non-ECMO ARDS patients [9], suggesting that higher
PEEP levels should be beneficial in ARDS patients under
ECMO. Whether these results apply to COVID-19
ARDS patients under ECMO remains to date unknown,
as well as optimal PEEP level in this subset of patients.
We hypothesized that lung recruitability is influenced
by time from ARDS onset and may be lower in ECMO
patients cannulated more than 72 h after ARDS onset.
Furthermore, we hypothesized that compliance of the
baby lung (i.e., aerated lung at PEEP 5 cmH2O) may
explain poor lung recruitability, as it may be an early
marker of fibrosis.
e primary aim of the study was to compare lung
recruitability assessed with CT in moderate and severe
ARDS patients with or without ECMO. e secondary
aim of the study was to identify the mechanisms underly-
ing lung recruitability in COVID-19 ARDS.
Methods
Study design andsetting
e study is a multicenter prospective observational
case–control study, performed in 2 intensive care units
located in university hospitals, and was conducted in
accordance with the amended declaration of Helsinki.
e study was approved by a local independent ethics
committee (Comité Scientifique et Ethique des Hospices
Civils de Lyon, 20_194) and complied to the STROBE
criteria for observational studies [11]. Patients were
enrolled between November 1, 2020, and June 16, 2021,
in center#1 and between November 1, 2020, and Decem-
ber 31, 2021, in center#2. Consent for data utilization was
sought from the patients or their representative, and fol-
low-up lasted 90days. e primary endpoint of the study
was the amount of recruitable lung between PEEP 5 and
15 cmH2O on CT.
Patients andprotocol
Eligible participants were ARDS patients [12] aged
18years or older, under invasive mechanical ventilation,
who had a COVID-19 pneumonia with a positive SARS-
CoV-2 reverse transcription polymerase chain reaction,
and an indication for CT.
Exclusion criteria were ARDS onset > 72 h in non-
ECMO patients, ECMO onset > 72h, contra-indication
to transport to the imaging facility (ratio of oxygen arte-
rial partial pressure to inspired oxygen fraction (PaO2/
FiO2) < 60 Torr, mean arterial pressure < 65 mmHg , or
intracranial hypertension), chronic obstructive pulmo-
nary disease, pneumothorax or bronchopleural fistula,
previous inclusion in the present study, the presence of
intrathoracic metallic devices, pregnancy, patient under
a legal protective measure, and refusal to participate by
patient and/or relative.
Non-ECMO patients were ventilated with a tidal vol-
ume (VT) of 4 to 6mL.kg1 of predicted body weight
(PBW) to keep plateau pressure (PPlat,rs) below 30
cmH2O, with recommendation to use a PEEP-FiO2 table
to adjust PEEP [13]. ECMO patients were ventilated with
a VT of 1mL.kg1 PBW, with PEEP adjusted to target a
PPlat,rs approximating 20–22 cmH2O.
induced by PEEP increase from 5 to 15 cmH2O appears favorable in virtually all ECMO patients, while this PEEP level is
required to counteract compressive forces leading to lung collapse. CBABY LUNG is significantly lower in ECMO patients,
independently of lung recruitability.
Keywords: ARDS, Computed tomography, ECMO, PEEP, COVID‑19
Page 3 of 13
Richardetal. Critical Care (2022) 26:195
Respiratory measurements and arterial blood gas
analysis were performed at least 1h after adjustment of
ventilatory settings. Patients were then transferred to the
imaging facility using a transport ventilator (MONNAL
T60—Air Liquide Medical Systems, Antony, France) with
unchanged ventilatory settings. e endotracheal tube
was transiently occluded with a Kocher clamp during
ventilator change to avoid derecruitment.
Data analysis
Total PEEP (PEEPtot,rs) and PPlat,rs were measured at the
end of 3-s end-expiratory and end-inspiratory pauses.
Airway driving pressure (ΔPrs) was computed as PPlat,rs
minus PEEPtot,rs. Elastance of the respiratory system was
computed as ΔPrs divided by VT.
Low-dose CT acquisitions were performed in the
supine position with an iCT 256 Ingenuity CT (Philips
Healthcare, Eindhoven, e Netherlands), or a GE
Optima CT scan (GE Medical Systems, Milwaukee, USA)
using the following settings: voltage 140 kVP, slice thick-
ness 1mm, and matrix size 512 × 512. Field of view, pixel
size, and mAs were adapted for each patient. Lung scan-
ning was performed from apex to base during end-expir-
atory and end-inspiratory pauses at the PEEP level set
by the clinician (CTExpi-Inspi), and during end-expiratory
pauses at PEEP 15 and 5 cmH2O (CTPEEP5-15). Lack of
respiratory efforts during the pauses was visually checked
on the ventilator pressure–time curves. Image recon-
struction was performed using a smooth filter (kernel B).
e lungs were interactively segmented with a CreaTools-
based software [14], excluding pleural effusions, hilar and
mediastinal structures. Segmented lung volumes were
analyzed using MATLAB (MathWorks, Natick, MA).
Voxel tissue and gas fraction were computed as previ-
ously described [15]. Tissue and gas volumes were com-
puted as the product of their respective fractions times
voxel volume times number of voxels in segmented lung
volume, respectively.
Lung parenchyma was classified into four compart-
ments, according to CT number: non-inflated (density
between + 100 and 100 Hounsfield units (HU)), poorly
inflated (density between 101 and 500 HU), nor-
mally inflated (density between 501 and 900 HU),
and hyperinflated tissue (density 901 HU).
Total lung weight and weight of each compartment
were estimated using lung tissue volume, assuming a tis-
sue density of 1g.mL1 [16].
VT was assessed on CT (VTCT) by subtracting the vol-
ume of gas at end-inspiration and at end-expiration in
segmented lungs.
e amount of recruitable lung between PEEP 5 and
15 cmH2O (∆PEEP5-15-induced recruitment) was com-
puted as the weight of the non-inflated compartment at
PEEP 5 cmH2O minus its weight at PEEP 15 cmH2O,
and standardized to total lung weight.
Tidal recruitment of the non-inflated compartment
was defined as the weight of the non-inflated compart-
ment at end-expiration minus its weight at end-inspira-
tion [17], and standardized to total lung weight.
Change in lung aerated volume induced by PEEP
change from 5 to 15 cmH2O (PEEPvolume) was com-
puted as the difference in the total volume of gas within
the lungs between PEEP 15 and 5 cmH2O.
e hyperinflation-to-recruitment ratio was com-
puted as the difference between hyperinflated compart-
ment total volume at PEEP 15 minus its value at PEEP
5 cmH2O, over the difference between non-inflated
compartment total volume at PEEP 5 minus its value at
PEEP 15 cmH2O [8].
Tidal hyperinflation was computed as the volume
of the hyperinflated compartment at end-inspiration
minus its volume at end-expiration [17], and standard-
ized to predicted body weight.
e total superimposed pressure in the most dorsal
parts of the lung was computed as previously described
[18].
e lung inhomogeneity extent was measured by
comparing the inflation of neighboring lung regions
as previously described [19, 20] and was defined as the
percentage of lung volume presenting an inflation ratio
of neighboring regions greater than 1.61 (i.e., the 95th
percentile of a control population) [19].
We finally developed a method to estimate elas-
tic properties of the already aerated lung at PEEP 5
cmH2O with CT (CBABY LUNG, Additional file1). Classi-
cal computation of compliance between PEEP 5 and 15
cmH2O (i.e., change in lung aerated volume divided by
change in PEEP) overestimates CBABY LUNG as recruited
alveoli account partly for the change in aeration. As
recruitment assessed by CT is computed as the differ-
ence in non-aerated lung compartment weight between
PEEP levels, a computation of recruited aerated volume
(RecAer vol) from recruited lung weight was performed
using the methodology proposed by Paula and cowork-
ers [21], assuming that recruitable alveoli would remain
aerated at PEEP 5 cmH2O and have equilibrated to a
level of expansion equivalent to that of other already
open alveoli at PEEP 5 [21]. CBABY LUNG between PEEP
5 and 15 cmH2O was finally computed as: (PEEPvolume
RecAer vol)/∆PEEP (i.e., 10 cmH2O).
A quality control was performed on both couples of
CT images (CTExpi-Inspi, CTPEEP5-15). Images couples
with segmented lung weight differing by more than 5%
were excluded. CTExpi-Inspi, in which VTCT differed from
VT set on the ventilator by more than 60mL were also
excluded (Additional file2).
Page 4 of 13
Richardetal. Critical Care (2022) 26:195
Statistical analysis
Statistical analysis was performed using R version 4.1.1
[22] with packages multcomp [23], lme4 [24], lmerTest
[25], and interactions [26]. A p value 0.05 was chosen
for statistical significance.
Data were expressed as count (percentage) or median
[interquartile range] and compared between groups
with the Fisher’s exact test for categorical variables and
ANOVA for continuous variables. Multiple compari-
sons between groups were made using the Holm–Sidak
procedure. Comparisons of variables involving the same
individual were made with linear mixed models, using
patient as a random effect.
Multivariate analyses were performed using linear
models, by incorporating variables with p v alues < 0.2 in
univariate analysis and stepwise backward selection.
Estimation of sample size was not computed as the
study is exploratory, and data collection stopped with the
control of COVID-19 fifth wave in our geographic area.
Missing data were not imputed owing to the low rate
of missingness for variables included in the multivariate
models (Additional file3).
Results
Flowchart of the study is presented in Additional file2.
Ninety-nine patients were included, of whom 24 were
severe ARDS under ECMO, 59 severe ARDS with-
out ECMO and 16 moderate ARDS. ree non-ECMO
patients with delay between ARDS onset > 72 h (4 to
6 days after ARDS onset) were erroneously included
and remained in the analysis. Patients’ characteristics
at inclusion are reported in Table 1, and respiratory
mechanics and blood gas data are presented in Table2.
Lung CT parameters atPEEP 5 cmH2O
CT images obtained in 4 representative ECMO and
non-ECMO patients are provided in Fig.1. Lung weight
assessed on CT was not significantly different between
groups (Fig. 2). Non-inflated lung at PEEP 5 cmH2O
was significantly greater in ECMO than in non-ECMO
patients (Fig.2), and in severe ARDS non-ECMO patients
vs. moderate ARDS patients. End-expiratory aerated
lung volume (EELV) at PEEP 5 cmH2O was significantly
lower in ECMO patients. Total superimposed pressure at
PEEP 5 cmH2O (Fig.3, left panel) was significantly higher
Table 1 Patient characteristics
Values are median [1st quartile–3rd quartile] or count (percentage)
a p < 0.05 vs. moderate ARDS without ECMO. b p < 0.05 vs. severe ARDS without ECMO, c p < 0.05 between groups
ARDS acute respiratory distress syndrome, BMI body mass index, CT computed tomography, ECMO extracorporeal membrane oxygenation, ICU intensive care unit, IMV
invasive mechanical ventilation, iNO inhaled nitric oxide, NMBA neuromuscular blocking agents, no number, RRT renal replacement therapy, SAPS2 Simplied Acute
Physiology Score
Variables Whole
dataset(n = 99) Moderate ARDS without
ECMO (n = 16) Severe ARDS without
ECMO (n = 59) Severe ARDS
on ECMO
(n = 24)
Sex male—no. (%) 75 (76%) 14 (88%) 42 (71%) 19 (79%)
Age—yr 62 [54–71] 61 [55–70] 66 [57–73] 57 [50–61]b
BMI—kg.m230 [26–37] 29 [25–32] 30 [26–37] 32 [27–39]
Delay between hospital admission and CT—day 5 [3–8] 5 [3–6] 4 [3–7] 10 [6–12] b
Delay between ICU admission and CT—day 3 [1–6] 3 [1–5] 2 [1–3] 7 [5–8]a,b
Delay between ARDS onset and CT—day 1 [1–3] 1 [1, 2] 1 [1, 2] 5 [3–7] a,b
Delay between IMV onset and CT—day 1 [1–3] 1 [1, 2] 1 [1, 2] 5 [3–7] a,b
SAPS 2 at ICU admission 39 [30–45] 41 [28–45] 40 [31–47] 36 [30–42]
SOFA score at inclusion 7 [5–8] 6 [5–7] 7 [4–8] 7 [5–9]
Prone position in the 24 h preceding CT—no. (%) 81 (82%) 14 (88%) 46 (78%) 21 (88%)
iNO in the 24 h preceding CT—no. (%) 19 (19%) 0 (0%) 12 (20%) 7 (29%)
NMBA in the 24 h preceding CT—no. (%) 96 (96%) 15 (94%) 57 (97%) 24 (100%)
RRT in the 24 h preceding CT—no. (%) 4 (4%) 1 (6%) 2 (3%) 1 (4%)
Inotropes in the 24 h preceding CT—no. (%) 1 (1%) 0 (0%) 1 (2%) 0 (0%)
Vasopressor in the 24 h preceding CT—no. (%) 67 (68%) 13 (81%) 37 (63%) 17 (71%)
ICU mortality—no. (%) c49 (49%) 3 (19%) 32 (54%) 14 (58%)
Day‑90 mortality—no. (%) c48 (49%) 3 (19%) 32 (55%) 13 (54%)
Ventilator‑free days at day 90—day 0 [0–71] 59 [13–83] 0 [0–70] 0 [0–56]
ICU length of stay—day 25 [16–40] 24 [13–45] 23 [16–36] 36 [21–48]
Hospital length of stay—day 37 [23–58] 44 [28–78] 35 [21–49] 41 [29–59]
Page 5 of 13
Richardetal. Critical Care (2022) 26:195
in ECMO patients (12 [11-13] cmH2O), as compared
to both moderate (10 [8-11] cmH2O) and severe non-
ECMO patients (9 [7-13] cmH2O).
Lung recruitability
Left panel of Fig.4 shows the frequency distribution of
patients according to lung recruitability between PEEP 5
and 15 cmH2O. e median amount of recruitable lung
between PEEP 5 and 15 cmH2O was 6 [4-10]%, and was
not significantly different between groups. PEEPvolume
was significantly lower in ECMO patients, while ∆PEEP5-
15-induced hyperinflation was significantly lower in the
ECMO group and virtually inexistent (Fig. 2). A sensi-
tivity analysis excluding the 3 patients with exclusion
criteria yielded identical results (Additional file 4). e
hyperinflation-to-recruitment ratio (a trade-off index of
the adverse effects and benefits of PEEP increase from 5
to 15 cmH2O) was significantly lower in ECMO patients,
as compared to both severe non-ECMO ARDS patients
and moderate ARDS patients (Fig. 3, right panel).
is ratio was lower than 1 in 8 (50%) moderate ARDS
patients, 41 (69%) severe non-ECMO patients, and in 23
(96%) ECMO patients, i.e., virtually all ECMO patients
responded to PEEP 15 cmH2O by recruited volume out-
weighing hyperinflation volume.
Multivariate analysis identified poorly inflated lung
at PEEP5, EELV at PEEP5 and the interaction of ECMO
status and delay between ARDS onset and CT as inde-
pendent predictors of ∆PEEP5-15-induced recruitment
(Additional file5 and 6). ∆PEEP5-15-induced recruitment
significantly decreased over time from ARDS onset in
non-ECMO patients, but not in ECMO patients (Fig.5).
Tidal hyperination andtidal recruitment
e frequency distribution of patients according to tidal
hyperinflation is reported in Fig. 4 (right panel). Tidal
hyperinflation amounted to 0.3 [0.1–1.0] mL.kg1 PBW.
Tidal hyperinflation greater than 1mL.kg1 PBW was
observed in 19 (25%) non-ECMO patients and 0 (0%)
ECMO patients. As expected, tidal hyperinflation was
significantly lower in ECMO patients, while tidal recruit-
ment was significantly higher in non-ECMO severe
ARDS patients (Fig.2).
Lung inhomogeneity
e extent of lung inhomogeneity decreased significantly
from PEEP 5 to PEEP 15 cmH2O in non-ECMO patients,
but not in ECMO patients (Fig. 6), with substantial
interindividual variations. Lung inhomogeneity extent
decreased between PEEP5 and 15 cmH2O in 94% of
moderate ARDS patients, 97% of severe ARDS patients,
and 62% of severe ECMO patients.
Compliance oftheaerated lung atPEEP 5 cmH2O
CBABY LUNG was significantly lower in ECMO patients
than in both severe ARDS patients without ECMO and
Table 2 Respiratory mechanics and arterial blood gas
Values are median [1st quartile–3rd quartile], a p < 0.05 vs. moderate ARDS without ECMO. b p < 0.05 vs. severe ARDS without ECMO
ARDS acute respiratory distress syndrome, ΔPrs, driving pressure of the respiratory system, ECMO extracorporeal membrane oxygenation, Ers elastance of the
respiratory system, FiO2 inspired fraction of oxygen, FmO2, ECMO membrane oxygen fraction, PaCO2 carbon dioxide partial pressure in arterial blood, PaO2 oxygen
partial pressure in arterial blood, PBW predicted body weight, PEEP positive end-expiratory pressure, PEEPtot,rs total PEEP of the respiratory system, Ppeak peak airway
pressure, Pplat,rs plateau pressure of the respiratory system, RR respiratory rate, VT tidal volume
Variables Whole dataset (n = 99) Moderate ARDS without
ECMO (n = 16) Severe ARDS without
ECMO (n = 59) Severe ARDS on
ECMO (n = 24)
PEEP—cmH2O 10 [5–14] 9 [5–10] 10 [5–10] 15 [13–15] a,b
VT—mL.kg1 PBW 5.9 [3.9–6.0] 6.0 [5.9–6.0] 6.0 [5.9–6.0] 1.0 [1.0–1.0] a,b
RR—min122 [16–28] 23 [20–28] 25 [22–29] 5 [5–10] a,b
PEEPtot,rs—cmH2O 10 [7–15] 9 [6–10] 10 [6–11] 15 [14–15] a,b
Pplat,rs—cmH2O 20 [17–22] 18 [17–24] 20 [16–23] 20 [19–21]
Ppeak—cmH2O 29 [25–35] 30 [28–34] 32 [27–37] 22 [21–24] a,b
ΔPrs—cmH2O 9 [7–12] 10 [9–13] 10 [9–12] 5 [3–8] a,b
Ers—cmH2O. L133 [25–44] 29 [22–37] 28 [23–35] 70 [53–95] a,b
pH 7.38 [7.32–7.44] 7.37 [7.33–7.42] 7.37 [7.31–7.41] 7.46 [7.39–7.47] a,b
PaO2—To rr 72 [65–80] 78 [67–89] 74 [66–80] 69 [62–74] a
FiO2 or FmO2 – % 90 [60–100] 50 [44–53] 90 [65–100] a100 [80–100] a
PaCO2Torr 49 [41–54] 42 [37–51] 50 [43–58] 49 [41–51]
Bicarbonates—mmol.L128 [24–32] 26 [22–28] 27 [24–31] 32 [29–34] a,b
Lactate—mmol.L11.7 [1.3–2.2] 1.5 [1.3–1.9] 1.6 [1.3–2.2] 1.9 [1.6–2.4]
Page 6 of 13
Richardetal. Critical Care (2022) 26:195
moderate ARDS (Fig.7, left panel). CBABY LUNG was lin-
early related to the logarithm of the hyperinflation-to-
recruitment ratio (Fig.7, right panel).
Multivariate analysis identified BMI, ECMO, and EELV
at PEEP 5 cmH2O as independent variables significantly
associated with CBABY LUNG (Additional file 7), while
CBABY LUNG was not independently associated with lung
recruitability (Additional file5 and 6).
Discussion
e main findings of the study are the following: 1—lung
recruitability between PEEP 5 and 15 cmH2O was not
significantly different between categories of ARDS sever-
ity, 2—the trade-off between hyperinflation and recruit-
ment induced by a PEEP change from 5 to 15 cmH2O was
favorable in virtually all ECMO patients, 3—compliance
of the aerated lung at PEEP 5 was significantly lower in
ECMO patients, independently of lung recruitability, and
may be a protective factor against PEEP-induced hyper-
inflation under ECMO.
Patient characteristics at inclusion were similar in
the present study and in the largest French epidemio-
logical study on critically ill adults with COVID-19 [27].
ECMO patients were older in the present study than in
the ELSO [28] and the Paris–Sorbonne University Hos-
pital Network [29] registries, but with similar BMI.
However, PEEP level under ECMO was higher (15 vs 10
and 12 cmH2O, respectively), while VT, ΔPrs, and PPlat,rs
were substantially lower in the present study [28, 29]. In
non-ECMO-patients, the amount of non-aerated lung at
PEEP 5 cmH2O was similar in the present study and in 3
previous studies on COVID-19 patients under mechani-
cal ventilation (approximately 40%) [5, 7, 8]. On the other
hand, median lung recruitability between PEEP 5 and
15 cmH2O was substantially lower in the present study
as compared to the study by Protti etal. (6% vs. 11% of
lung weight) [8], with a relatively similar CT protocol and
delay between ARDS onset and CT. In addition to dif-
ferences between pre-intubation management and case-
mix, this may be explained by CT acquisition at higher
PEEP levels (10 and 20 cmH2O, respectively) in some
Fig. 1 CT images acquired at the mid‑chest level in 4 representative patients. ECMO patients are presented in the uppermost quadrants, while
non‑ECMO patients are presented in the lowermost quadrants. Patients with ∆PEEP5–15‑induced recruitment below the median value of the
whole population (deemed as low recruiters) are presented in the leftmost quadrants, while patients with PEEP5–15‑induced recruitment above
the median value of the whole population (deemed as high recruiters) are presented in the rightmost quadrants. In each quadrant, the upper two
images were acquired at PEEP 5 cmH2O (one raw CT image on the left and one quantitative parametric CT on the right), and the lower two were
acquired at PEEP 15 cmH2O. The color code used for parametric images is provided in the figure legend. CT, computed tomography, ∆PEEP5–
15‑induced recruitment, amount of recruitable lung between PEEP 5 and 15 cmH2O, ECMO, extracorporeal membrane oxygenation, PEEP, positive
end‑expiratory pressure
Page 7 of 13
Richardetal. Critical Care (2022) 26:195
Fig. 2 CT parameters as a function of ARDS severity a, p < 0.05 vs. severe ARDS with ECMO, b, p < 0.05 vs. severe ARDS without ECMO. ARDS, acute
respiratory distress syndrome, ∆PEEP5‑15, change in PEEP from 5 to 15 cmH2O, PEEPvolume, change in lung aeration induced by PEEP change from 5 to
15 cmH2O, ECMO, extracorporeal membrane oxygenation, EELV, end‑expiratory lung volume, MODERATE, moderate ARDS, PBW, predicted body
weight, PEEP, positive end‑expiratory pressure, SEVERE, severe ARDS without ECMO, SEVERE ECMO, severe ARDS under ECMO
Fig. 3 Total superimposed pressure at PEEP 5cmH2O and hyperinflation‑to‑recruitment ratio as a function of ARDS severity. The total superimposed
pressure is the hydrostatic pressure superimposed in the most dorsal level of the lungs, computed with CT, assuming that pressure is transmitted
through the lung parenchyma as in a fluid. Data points are individual values in each lung for total superimposed pressure and individual values
in the whole lung for hyperinflation‑to‑recruitment ratio. a, p < 0.05 vs severe ARDS under ECMO.ARDS, acute respiratory distress syndrome, CT,
computed tomography, ECMO, extracorporeal membrane oxygenation, MODERATE, moderate ARDS, PEEP, positive end‑expiratory pressure,
SEVERE, severe ARDS without ECMO, SEVERE ECMO, severe ARDS under ECMO
Page 8 of 13
Richardetal. Critical Care (2022) 26:195
obese patients in the latter study. In ECMO patients, the
amount of non-aerated lung at PEEP 5 cmH2O was simi-
lar in our study and in non-COVID-19 ECMO patients
(approximately 80%) [10].
An important finding of our study is that the delay
from ARDS onset is an important confounding factor of
lung recruitability and that lung recruitability decreases
as early as during the first 3days after ARDS onset. Sur-
prisingly, this effect was not identified in ECMO patients
and the following potential reasons may be hypothesized
to explain this finding: patient selection for ECMO eligi-
bility, lower sample size of the ECMO subgroup, benefi-
cial impact of fluid administration required to maintain
ECMO flow on lung recruitability, or preventive effect
of ECMO on fibrotic changes potentially involved in the
progressive loss of recruitability observed under standard
ventilation [30], although this remains speculative.
To date, there is no undisputable threshold defining low
or high recruiter patients with CT. Most studies defined
high recruiters as patients with an amount of recruited
lung between 5 and 45 cmH2O above the median value
of the population [9, 10]. As approximately 50% of the
recruitment between PEEP 5 and 45 cmH2O is achieved
between PEEP 5 and 15 cmH2O [8, 9], and as the thresh-
old defining high recruiter amounted to 10% of total
lung weight in the seminal study by Gattinoni and cow-
orkers [9], it can be speculated that the 6% median lung
recruitment value identified in our study suggests that
COVID-19 and non-COVID-19 ARDS are roughly simi-
lar regarding lung recruitability. Remarkably, recruitabil-
ity was similar among categories of ARDS severity in our
study, despite a stepwise increase in non-inflated lung
compartment as severity increases, in striking contrast
with Gattinoni’s study [9], suggesting that the underlying
mechanisms responsible for lung consolidation are dif-
ferent between COVID-19 and non-COVID-19 ARDS.
However, we failed to relate decreased compliance of the
aerated lung to poor lung recruitability, suggesting that
the mechanical characteristics of the aerated and non-
aerated lung may be unrelated.
Another striking result of the present study is that the
balance between hyperinflation and recruitment induced
by a PEEP increase from 5 to 15 cmH2O is favorable in
virtually all ECMO patients, as opposed to COVID-19
ARDS patients without ECMO. Interestingly, most of
the patients included in large ECMO cohort studies on
COVID-19 ARDS were ventilated with substantially
lower PEEP levels [28, 29]. Our results suggests that the
lower compliance of the aerated lung at PEEP 5 cmH2O
during ECMO (a consequence of lower EELV) may pre-
vent occurrence of PEEP-induced hyperinflation (Figs.2
and 7). Hyperinflation may have nonetheless been unde-
tected in ECMO patients as it may occur at a level below
the resolution of CT, or since the decrease in CT density
Fig. 4 Distribution of patients according to recruitability between PEEP 5 and 15 cmH2O or tidal hyperinflation. Vertical bar is the median amount
of recruitable lung. ECMO, severe acute respiratory distress syndrome (ARDS) patients under extracorporeal membrane oxygenation, moderate,
moderate ARDS, severe, severe ARDS without ECMO, PBW, predicted body weight
Page 9 of 13
Richardetal. Critical Care (2022) 26:195
Fig. 5 Relationship between ∆PEEP5‑15‑induced recruitment and delay between ARDS onset and CT, according to ECMO status. Each point is partial
residuals of the multivariate model with ∆PEEP5–15‑induced recruitment as the dependent variable, and the following independent variables: EELV
at PEEP 5 cmH2O, poorly inflated lung at PEEP5 and the interaction between ECMO status × delay between CT and ARDS onset. Lines are regression
lines according to ECMO status. Shadowed areas are 95% confidence interval for each regression line. ARDS, acute respiratory distress syndrome, CT,
computed tomography, ECMO, extracorporeal membrane oxygenation, ∆PEEP5‑15‑induced recruitment, amount of recruitable lung between PEEP 5
and 15 cmH2O, EELV, end‑expiratory lung volume, NS, non‑statistically significant, PEEP, positive end‑expiratory pressure
Fig. 6 Lung inhomogeneities and PEEP. The extent of lung inhomogeneity of the individual patients with moderate ARDS (left panel), severe ARDS
without ECMO (middle panel), and severe ARDS with ECMO (right panel) is reported at PEEP 5 (red circles) and 15 cmH2O (blue circles) * p < 0.05
between PEEP 5 and 15 cm H2O of the same category of severity. Lung inhomogeneities are registered to the following patent: WO 2013/088336,
and agreement to use this patent for research purposes was obtained from the owner (Fondazione IRCCS Ca’ Granda Ospedale Maggiore
Policlinico). ARDS, acute respiratory distress syndrome, ECMO, extracorporeal membrane oxygenation, MODERATE, moderate ARDS, PEEP, positive
end‑expiratory pressure, SEVERE, severe ARDS without ECMO, SEVERE ECMO, severe ARDS under ECMO.
Page 10 of 13
Richardetal. Critical Care (2022) 26:195
due to hyperinflation can be masked by the increased tis-
sue mass in severe ARDS [31]. Hyperinflation was hence
not detected during PEEP increase from 5 to 45 cmH2O
in a previous study on ECMO patients [10]. Furthermore,
we cannot exclude that overdistension without hyper-
inflation occurred at the interface between non-aerated
and aerated lung units in some patients (see below) [19,
20]. Finally, the impact of reduced lung compliance on
overdistension occurrence during PEEP increase in
ECMO patients remains unknown.
A beneficial impact of PEEP increase on lung inho-
mogeneity extent was only identified in non-ECMO
patients. As lung inhomogeneities act as stress raisers,
this suggests that the energy load was more evenly dis-
tributed within the lung parenchyma at PEEP 15 in this
subgroup of patients. is effect was not observed in
ECMO patients, although with substantial interindivid-
ual variations, as was previously observed in non-COVID
ARDS [20]. Moreover, PEEP increase was expected to be
detrimental on stress raisers in 38% of ECMO patients,
favoring individualization of PEEP settings.
Some limitations of the present study should be
acknowledged. First, potentially recruitable lung at
PEEP 45 cmH2O was not assessed, as this PEEP level
was deemed excessive by our team [32] and others in
COVID-19 ARDS [7] and higher PEEP levels may have
led to different results. ECMO patients were studied
a median of 4days later than non-ECMO patients, and
this delay may have impacted lung recruitability under
ECMO, although this effect was ruled out by our multi-
variate analysis (Additional file6, Fig.5). Occurrence of
complete airway closure [1] was not assessed in the pre-
sent study, and this effect may have biased measurement
of CBABY LUNG. Approximately 70% of the screened popu-
lation (i.e., patients with COVID-19 pneumonia under
invasive mechanical ventilation) lacked eligibility crite-
ria, mostly because a CT was performed before inten-
sive care admission, and the study population may be a
biased subset of the initial population. Variable selection
for multivariate analysis was performed on the basis of
bivariable association, and this may have increased the
risks of detecting spurious statistical associations [33].
Finally, the observational design of the study precludes
any firm conclusion to be drawn regarding optimal venti-
lation settings in ARDS COVID-19 patients.
Nevertheless, the study has the following strengths.
Lung evaluation was performed using CT, i.e., the refer-
ence method to perform a quantitative analysis of lung
aeration and recruitment [15, 31, 34]. External validity of
the study is expected to be good owing to the low rate of
screen failure despite the context of pandemics, the sub-
stantial sample size for a CT study, and the multicenter
design. Furthermore, the study is the first to assess lung
recruitability in both ECMO and non-ECMO patients,
in a homogeneous time frame (i.e., at the early phase of
ARDS), thus minimizing potential confounding effects
related to ventilator-induced lung injury or ventilator-
associated pneumonia.
Fig. 7 Compliance of the aerated lung at PEEP 5 cmH2O (CBABY LUNG). Left panel: CBABY LUNG as a function of ARDS severity. Right panel. Relationship
between hyperinflation‑to‑recruitment ratio and CBABY LUNG as a function of ECMO status. Circles are individual datapoints. Black line is the regression
line on the whole population. a, p < 0.05 vs severe ARDS under ECMO. ARDS, acute respiratory distress syndrome, ECMO, extracorporeal membrane
oxygenation, MODERATE, moderate ARDS, PEEP, positive end‑expiratory pressure, SEVERE, severe ARDS without ECMO, SEVERE ECMO, severe ARDS
under ECMO
Page 11 of 13
Richardetal. Critical Care (2022) 26:195
According to our results, a PEEP level around 13–15
cmH2O is required to overcome the superimposed
hydrostatic pressure and prevent alveolar collapse in the
majority of COVID-19 ARDS patients under ECMO.
Higher PEEP levels may be required in patients with
elevated chest wall to respiratory system elastance ratio,
such as superobese patients, as part of this pressure level
may be dissipated in the chest wall. In addition, a PEEP
level of 15 cmH2O is associated with a favorable balance
ratio between hyperinflation and recruitment induced by
PEEP in virtually all COVID-19 ECMO patients. How-
ever, this PEEP level may be detrimental on stress raisers
in a subset of ECMO patients favoring individualization
of PEEP setting. Furthermore, the rationale for high PEEP
use in patients under ECMO may be questionable as it
relies on a putative protective effect on derecruitment
related to the use of ultra-low tidal volume, while it may
overdistend the lung, alter hemodynamics or increase
the mechanical power transmitted to the lung from the
ventilator. Finally, lung recruitability should be reassessed
early in the course of COVID-19 ARDS without ECMO,
as it decreases sharply over time.
Conclusion
Lung recruitability of COVID-19 pneumonia is not sig-
nificantly different among categories of ARDS sever-
ity, with substantial interindividual variations favoring
individualization of PEEP setting. e balance between
hyperinflation and recruitment induced by PEEP increase
from 5 to 15 cmH2O appears to be favorable in virtually
all ECMO patients, although lung inhomogeneities act-
ing as stress raisers were not significantly improved by
PEEP increase in this group of patients. A PEEP level
of 12–15 cmH2O is required to counteract compressive
forces leading to lung collapse in most ECMO patients.
In non-ECMO patients, lung recruitability decreases
steadily during the first 3days after ARDS onset and jus-
tifies reevaluation of the PEEP setting on a daily basis.
Abbreviations
ARDS: Acute respiratory distress syndrome; BMI: Body mass index; CBABY LUNG:
Compliance of the aerated lung at PEEP 5 cmH2O, corrected for PEEP‑induced
recruited aerated volume; CT: Computed tomography; CTExpi‑Inspi: CT acquired
during end‑expiratory and end‑inspiratory pauses at the PEEP level set by the
clinician; CTPEEP5‑15: CT acquired during end‑expiratory pauses at PEEP 5 and
15 cmH2O; ∆PEEP5‑15: Change in PEEP from 5 to 15 cmH2O; ΔPrs: Airway driving
pressure; ECMO: Extracorporeal membrane oxygenation; EELV: End‑expiratory
aerated lung volume; FiO2: Inspired oxygen fraction; HU: Hounsfield units;
PaO2/FiO2: Ratio of oxygen arterial partial pressure to inspired oxygen fraction;
PBW: Predicted body weight; PEEP: Positive end‑expiratory pressure; PEEPtot,rs:
Total PEEP of the respiratory system; PEEPvolume: Change in lung aerated
volume induced by PEEP change from 5 to 15 cmH2O; PPlat,rs: Plateau pressure
of the respiratory system; RecAer vol: Recruited aerated volume between PEEP5
and 15 cmH2O; VT: Tidal volume; VTCT: Tidal volume was assessed on CT.
Supplementary Information
The online version contains supplementary material available at https:// doi.
org/ 10. 1186/ s13054‑ 022‑ 04076‑z.
Additional le1: Computation of compliance of the already aerated lung
at PEEP 5 (CBABY LUNG)
Additional le2: Flow chart of the study
Additional le3: Missing data per variable
Additional le4: Sensitivity analysis
Additional le5: Univariate analysis of variables associated with lung
recruitment
Additional le6: Multivariate analysis of variables associated with PEEP‑
induced lung recruitment
Additional le7: Univariate and multivariate analyses of variables associ‑
ated with CBABY LUNG
Acknowledgements
The authors wish to thank Loredana Baboi for her help with inclusion of the
patients in the study and data acquisition. The authors also wish to thank the
following residents for their help with patient transport to the imaging facility:
Hugo Dumargne, Claire Guerin, Mathilde Legros, Anaelle Romagny, Hippolyte
Lequain, Maxime Billon, Alexandre Pinede, Bastien Berger, Mathieu Chivot,
Alexandre Berland, Thomas Foddis, Mathieu Sadoul, Gabriel Sarciron, Amaury
Gaussiome, Ali Chour, Vincent Alcazer, Martin Deslais, Caroline Abou‑Zeid,
Amaury Berrou, Camille Chaffard, Victor Dechaene, Florian Genty, Malik Haou‑
tar, Julien Perrone, Benjamin Pequignot, and Louis Auffray. The authors wish
to thank the intensive care unit nurses for their help with patients transport to
the imaging facility, and patients and their relatives for agreeing to participate
in the study. The authors wish to thank the radiology technicians for their help
in organizing and acquiring the CT scans
Author contributions
JCR and LBitker made substantial contributions to study design, to data
acquisition, study analysis, and interpretation of data, drafted the manuscript,
approved the version to be published, and agreed 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.
FS, MO, SB, ER, LBoussel, and NT made substantial contributions to study
design, data acquisition, study analysis, and interpretation of data, revised the
manuscript critically for important intellectual content, approved the version
to be published, and agreed 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. MGaillet, TA, GF, HY, MM, WD,
AB, FD, LF, and MGirard made substantial contributions to data acquisition,
study analysis, and interpretation of data, revised the manuscript critically
for important intellectual content, approved the version to be published,
and agreed 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. ED made substantial contributions
to study analysis and interpretation of data, revised the manuscript critically
for important intellectual content, approved the version to be published,
and agreed 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. MP made substantial contribu‑
tions to interpretation of data, revised the manuscript critically for important
intellectual content, approved the version to be published, and agreed 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. All authors have read and approved the final manuscript.
Funding
The study was funded by the Hospices Civils de Lyon. The funding body did
not take part in the design of the study, nor in data collection, analysis, or
interpretation, and was not involved in writing the manuscript.
Page 12 of 13
Richardetal. Critical Care (2022) 26:195
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
The authors state that the study has been approved by a local independent
ethics committee (Comité Scientifique et Ethique des Hospices Civils de Lyon,
20_194). Consent for data utilization was sought from the patients or their
representative.
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Author details
1 Service de Médecine Intensive Réanimation, Hôpital de la Croix Rousse, Hos‑
pices Civils de Lyon, 103 Grande Rue de la Croix Rousse, 69004 Lyon, France.
2 INSA‑Lyon, CNRS, INSERM, CREATIS UMR 5220, Univ Lyon, Université Claude
Bernard Lyon 1, U1294 Villeurbanne, France. 3 Université de Lyon, Université
Claude Bernard Lyon 1, Villeurbanne, France. 4 Service de Médecine‑Intensive
Réanimation, CHU Grenoble‑Alpes, Grenoble, France. 5 Synchrotron Radiation
for Biomedicine Laboratory (STROBE), INSERM UA07, Univ. Grenoble Alpes,
Grenoble, France. 6 Department of Pulmonology and Physiology, Grenoble
University Hospital, Grenoble, France. 7 Ser vice de Radiologie, Hôpital De La
Croix Rousse, Hospices Civils de Lyon, Lyon, France. 8 Grenoble, France Service
de Radiologie Diagnostique Et Interventionnelle, Université Grenoble Alpes,
CHU Grenoble‑Alpes, Grenoble, France. 9 Service de Chirurgie Cardiaque,
Hôpital Louis Pradel, Hospices Civils de Lyon, Lyon, France. 10 INSERM, U1042,
University Grenoble Alpes, HP2 Grenoble, France.
Received: 28 April 2022 Accepted: 27 June 2022
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Lung recruitment assessed by respiratory mechanics and computed
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the relationship? Am J Respir Crit Care Med. 2016;193(11):1254–63.
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Comparisons of histopathological features and microbiological findings between decedents with respiratory symptoms due to SARS-CoV-2 infection or other causes, in settings with high prevalence of HIV and Mycobacterium tuberculosis (MTB) infections have not been reported. Deaths associated with a positive ante-mortem SARS-CoV-2 PCR test and/or respiratory disease symptoms at Chris Hani Baragwanath Academic Hospital in Soweto, South Africa from 15th April to 2nd November 2020, during the first wave of the South African COVID-19 epidemic, were investigated. Deceased adult patients had post-mortem minimally-invasive tissue sampling (MITS) performed to investigate for SARS-CoV-2 infection and molecular detection of putative pathogens on blood and lung samples, and histopathology examination of lung, liver and heart tissue. During the study period MITS were done in patients displaying symptoms of respiratory disease including 75 COVID-19-related deaths (COVID+) and 42 non-COVID-19-related deaths (COVID-). The prevalence of HIV-infection was lower in COVID+ (27%) than in the COVID- (64%), MTB detection was also less common among COVID+ (3% vs 13%). Lung histopathology findings showed differences between COVID+ and COVID- in the severity of the morphological appearance of Type-II pneumocytes, alveolar injury and repair initiated by SARS-CoV-2 infection. In the liver necrotising granulomatous inflammation was more common among COVID+. No differences were found in heart analyses. The prevalence of bacterial co-infections was higher in COVID+. Most indicators of respiratory distress syndrome were undifferentiated between COVID+ and COVID- except for Type-II pneumocytes. HIV or MTB infection does not appear in these data to have a meaningful correspondence with COVID-related deaths.
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Background International guidelines suggest using a higher (>10 cmH2O) positive end-expiratory pressure (PEEP) in patients with moderate-to-severe acute respiratory distress syndrome (ARDS) due to the novel coronavirus disease (COVID-19). However, even if oxygenation generally improves with a higher PEEP, compliance and arterial carbon dioxide tension (PaCO2) frequently do not, as if recruitment was small. Research question Is the potential for lung recruitment small in patients with early ARDS due to COVID-19? Study design and methods Forty patients with ARDS due to COVID-19 were studied in the supine position within three days of endotracheal intubation. They all underwent a PEEP trial, where oxygenation, compliance, and PaCO2 were measured with 5, 10, and 15 cmH2O of PEEP and all other ventilatory settings unchanged. Twenty underwent a whole-lung static computed tomography at 5 and 45 cmH2O, and the other twenty at 5 and 15 cmH2O of airway pressure. Recruitment and hyperinflation were defined as a decrease in the volume of the non-aerated (density above -100 HU) and an increase in the volume of the over-aerated (density below -900 HU) lung compartments, respectively. Results From 5 to 15 cmH2O, oxygenation improved in thirty-six (90%) patients but compliance only in eleven (28%) and PaCO2 only in fourteen (35%). From 5 to 45 cmH2O, recruitment was 351 (161-462) ml and hyperinflation 465 (220-681) ml. From 5 to 15 cmH2O, recruitment was 168 (110-202) ml and hyperinflation 121 (63-270) ml. Hyperinflation variably developed in all patients and exceeded recruitment in more than half of them. Interpretation Patients with early ARDS due to COVID-19, ventilated in the supine position, present with a large potential for lung recruitment. Even so, their compliance and PaCO2 do not generally improve with a higher PEEP, possibly due to hyperinflation.
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Background There is a paucity of data concerning the optimal ventilator management in patients with COVID-19 pneumonia; particularly, the optimal levels of positive-end expiratory pressure (PEEP) are unknown. We aimed to investigate the effects of two levels of PEEP on alveolar recruitment in critically ill patients with severe COVID-19 pneumonia. Methods A single-center cohort study was conducted in a 39-bed intensive care unit at a university-affiliated hospital in Genoa, Italy. Chest computed tomography (CT) was performed to quantify aeration at 8 and 16 cmH 2 O PEEP. The primary endpoint was the amount of alveolar recruitment, defined as the change in the non-aerated compartment at the two PEEP levels on CT scan. Results Forty-two patients were included in this analysis. Alveolar recruitment was median [interquartile range] 2.7 [0.7–4.5] % of lung weight and was not associated with excess lung weight, PaO 2 /FiO 2 ratio, respiratory system compliance, inflammatory and thrombophilia markers. Patients in the upper quartile of recruitment (recruiters), compared to non-recruiters, had comparable clinical characteristics, lung weight and gas volume. Alveolar recruitment was not different in patients with lower versus higher respiratory system compliance. In a subgroup of 20 patients with available gas exchange data, increasing PEEP decreased respiratory system compliance (median difference, MD − 9 ml/cmH 2 O, 95% CI from − 12 to − 6 ml/cmH 2 O, p < 0.001) and the ventilatory ratio (MD − 0.1, 95% CI from − 0.3 to − 0.1, p = 0.003), increased PaO 2 with FiO 2 = 0.5 (MD 24 mmHg, 95% CI from 12 to 51 mmHg, p < 0.001), but did not change PaO 2 with FiO 2 = 1.0 (MD 7 mmHg, 95% CI from − 12 to 49 mmHg, p = 0.313). Moreover, alveolar recruitment was not correlated with improvement of oxygenation or venous admixture. Conclusions In patients with severe COVID-19 pneumonia, higher PEEP resulted in limited alveolar recruitment. These findings suggest limiting PEEP strictly to the values necessary to maintain oxygenation, thus avoiding the use of higher PEEP levels.
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Background: Patients with coronavirus disease 2019 (COVID-19) may develop severe acute respiratory distress syndrome (ARDS). The aim of the study was to explore the lung recruitability, individualized positive end-expiratory pressure (PEEP), and prone position in COVID-19-associated severe ARDS. Methods: Twenty patients who met the inclusion criteria were studied retrospectively (PaO 2 /FiO 2 68.0 ± 10.3 mmHg). The patients were ventilated under volume-controlled mode with tidal volume of 6 mL/kg predicted body weight. The lung recruitability was assessed via the improvement of PaO 2 , PaCO 2 , and static respiratory system compliance (C stat ) from low to high PEEP (5–15 cmH 2 O). Patients were considered recruitable if two out of three parameters improved. Subsequently, PEEP was titrated according to the best C stat . The patients were turned to prone position for further 18–20 h. Results: For recruitability assessment, average value of PaO 2 was slightly improved at PEEP 15 cmH 2 O (68.0 ± 10.3 vs. 69.7 ± 7.9 mmHg, baseline vs. PEEP 15 cmH 2 O; p = 0.31). However, both PaCO 2 and C stat worsened (PaCO 2 : 72.5 ± 7.1 vs. 75.1 ± 9.0 mmHg; p < 0.01. C stat : 17.5 ± 3.5 vs. 16.6 ± 3.9 ml/cmH 2 O; p = 0.05). Only four patients (20%) were considered lung recruitable. Individually titrated PEEP was higher than the baseline PEEP (8.0 ± 2.1 cmH 2 O vs. 5 cmH 2 O, p < 0.001). After 18–20 h of prone positioning, investigated parameters were significantly improved compared to the baseline (PaO 2 : 82.4 ± 15.5 mmHg. PaCO 2 : 67.2 ± 6.4 mmHg. C stat : 20.6 ± 4.4 ml/cmH 2 O. All p < 0.001 vs. baseline). Conclusions: Lung recruitability was very low in COVID-19-associated severe ARDS. Individually titrated PEEP and prone positioning might improve lung mechanics and blood gasses.
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Purpose: To describe acute respiratory distress syndrome (ARDS) severity, ventilation management, and the outcomes of ICU patients with laboratory-confirmed COVID-19 and to determine risk factors of 90-day mortality post-ICU admission. Methods: COVID-ICU is a multi-center, prospective cohort study conducted in 138 hospitals in France, Belgium, and Switzerland. Demographic, clinical, respiratory support, adjunctive interventions, ICU length-of-stay, and survival data were collected. Results: From February 25 to May 4, 2020, 4643 patients (median [IQR] age 63 [54-71] years and SAPS II 37 [28-50]) were admitted in ICU, with day-90 post-ICU admission status available for 4244. On ICU admission, standard oxygen therapy, high-flow oxygen, and non-invasive ventilation were applied to 29%, 19%, and 6% patients, respectively. 2635 (63%) patients were intubated during the first 24 h whereas overall 3376 (80%) received invasive mechanical ventilation (MV) at one point during their ICU stay. Median (IQR) positive end-expiratory and plateau pressures were 12 (10-14) cmH2O, and 24 (21-27) cmH2O, respectively. The mechanical power transmitted by the MV to the lung was 26.5 (18.6-34.9) J/min. Paralyzing agents and prone position were applied to 88% and 70% of patients intubated at Day-1, respectively. Pulmonary embolism and ventilator-associated pneumonia were diagnosed in 207 (9%) and 1209 (58%) of these patients. On day 90, 1298/4244 (31%) patients had died. Among patients who received invasive or non-invasive ventilation on the day of ICU admission, day-90 mortality increased with the severity of ARDS at ICU admission (30%, 34%, and 50% for mild, moderate, and severe ARDS, respectively) and decreased from 42 to 25% over the study period. Early independent predictors of 90-day mortality were older age, immunosuppression, severe obesity, diabetes, higher renal and cardiovascular SOFA score components, lower PaO2/FiO2 ratio and a shorter time between first symptoms and ICU admission. Conclusion: Among more than 4000 critically ill patients with COVID-19 admitted to our ICUs, 90-day mortality was 31% and decreased from 42 to 25% over the study period. Mortality was higher in older, diabetic, obese and severe ARDS patients.
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Purpose: To investigate whether COVID-19-ARDS differs from all-cause ARDS. Methods: Thirty-two consecutive, mechanically ventilated COVID-19-ARDS patients were compared to two historical ARDS sub-populations 1:1 matched for PaO2/FiO2 or for compliance of the respiratory system. Gas exchange, hemodynamics and respiratory mechanics were recorded at 5 and 15 cmH2O PEEP. CT scan variables were measured at 5 cmH2O PEEP. Results: Anthropometric characteristics were similar in COVID-19-ARDS, PaO2/FiO2-matched-ARDS and Compliance-matched-ARDS. The PaO2/FiO2-matched-ARDS and COVID-19-ARDS populations (both with PaO2/FiO2 106 ± 59 mmHg) had different respiratory system compliances (Crs) (39 ± 11 vs 49.9 ± 15.4 ml/cmH2O, p = 0.03). The Compliance-matched-ARDS and COVID-19-ARDS had similar Crs (50.1 ± 15.7 and 49.9 ± 15.4 ml/cmH2O, respectively) but significantly lower PaO2/FiO2 for the same Crs (160 ± 62 vs 106.5 ± 59.6 mmHg, p < 0.001). The three populations had similar lung weights but COVID-19-ARDS had significantly higher lung gas volume (PaO2/FiO2-matched-ARDS 930 ± 644 ml, COVID-19-ARDS 1670 ± 791 ml and Compliance-matched-ARDS 1301 ± 627 ml, p < 0.05). The venous admixture was significantly related to the non-aerated tissue in PaO2/FiO2-matched-ARDS and Compliance-matched-ARDS (p < 0.001) but unrelated in COVID-19-ARDS (p = 0.75), suggesting that hypoxemia was not only due to the extent of non-aerated tissue. Increasing PEEP from 5 to 15 cmH2O improved oxygenation in all groups. However, while lung mechanics and dead space improved in PaO2/FiO2-matched-ARDS, suggesting recruitment as primary mechanism, they remained unmodified or worsened in COVID-19-ARDS and Compliance-matched-ARDS, suggesting lower recruitment potential and/or blood flow redistribution. Conclusions: COVID-19-ARDS is a subset of ARDS characterized overall by higher compliance and lung gas volume for a given PaO2/FiO2, at least when considered within the timeframe of our study.
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Background Patients with COVID-19 who develop severe acute respiratory distress syndrome (ARDS) can have symptoms that rapidly evolve to profound hypoxaemia and death. The efficacy of extracorporeal membrane oxygenation (ECMO) for patients with severe ARDS in the context of COVID-19 is unclear. We aimed to establish the clinical characteristics and outcomes of patients with respiratory failure and COVID-19 treated with ECMO. Methods This retrospective cohort study was done in the Paris–Sorbonne University Hospital Network, comprising five intensive care units (ICUs) and included patients who received ECMO for COVID-19 associated ARDS. Patient demographics and daily pre-ECMO and on-ECMO data and outcomes were collected. Possible outcomes over time were categorised into four different states (states 1–4): on ECMO, in the ICU and weaned off ECMO, alive and out of ICU, or death. Daily probabilities of occupation in each state and of transitions between these states until day 90 post-ECMO onset were estimated with use of a multi-state Cox model stratified for each possible transition. Follow-up was right-censored on July 10, 2020. Findings From March 8 to May 2, 2020, 492 patients with COVID-19 were treated in our ICUs. Complete day-60 follow-up was available for 83 patients (median age 49 [IQR 41–56] years and 61 [73%] men) who received ECMO. Pre-ECMO, 78 (94%) patients had been prone-positioned; their median driving pressure was 18 (IQR 16–21) cm H2O and PaO2/FiO2 was 60 (54–68) mm Hg. At 60 days post-ECMO initiation, the estimated probabilities of occupation in each state were 6% (95% CI 3–14) for state 1, 18% (11–28) for state 2, 45% (35–56) for state 3, and 31% (22–42) for state 4. 35 (42%) patients had major bleeding and four (5%) had a haemorrhagic stroke. 30 patients died. Interpretation The estimated 60-day survival of ECMO-rescued patients with COVID-19 was similar to that of studies published in the past 2 years on ECMO for severe ARDS. If another COVID-19 outbreak occurs, ECMO should be considered for patients developing refractory respiratory failure despite optimised care. Funding None.
Article
Background: Multiple major health organisations recommend the use of extracorporeal membrane oxygenation (ECMO) support for COVID-19-related acute hypoxaemic respiratory failure. However, initial reports of ECMO use in patients with COVID-19 described very high mortality and there have been no large, international cohort studies of ECMO for COVID-19 reported to date. Methods: We used data from the Extracorporeal Life Support Organization (ELSO) Registry to characterise the epidemiology, hospital course, and outcomes of patients aged 16 years or older with confirmed COVID-19 who had ECMO support initiated between Jan 16 and May 1, 2020, at 213 hospitals in 36 countries. The primary outcome was in-hospital death in a time-to-event analysis assessed at 90 days after ECMO initiation. We applied a multivariable Cox model to examine whether patient and hospital factors were associated with in-hospital mortality. Findings: Data for 1035 patients with COVID-19 who received ECMO support were included in this study. Of these, 67 (6%) remained hospitalised, 311 (30%) were discharged home or to an acute rehabilitation centre, 101 (10%) were discharged to a long-term acute care centre or unspecified location, 176 (17%) were discharged to another hospital, and 380 (37%) died. The estimated cumulative incidence of in-hospital mortality 90 days after the initiation of ECMO was 37·4% (95% CI 34·4-40·4). Mortality was 39% (380 of 968) in patients with a final disposition of death or hospital discharge. The use of ECMO for circulatory support was independently associated with higher in-hospital mortality (hazard ratio 1·89, 95% CI 1·20-2·97). In the subset of patients with COVID-19 receiving respiratory (venovenous) ECMO and characterised as having acute respiratory distress syndrome, the estimated cumulative incidence of in-hospital mortality 90 days after the initiation of ECMO was 38·0% (95% CI 34·6-41·5). Interpretation: In patients with COVID-19 who received ECMO, both estimated mortality 90 days after ECMO and mortality in those with a final disposition of death or discharge were less than 40%. These data from 213 hospitals worldwide provide a generalisable estimate of ECMO mortality in the setting of COVID-19. Funding: None.
Chapter
Acute respiratory distress syndrome (ARDS) is a critical impairment of the lung function, which occurs – among others – in severe cases of patients with Covid-19. Its therapeutic management is based on mechanical ventilation, but this may aggravate the patient’s condition if the settings are not adapted to the actual lung state. Computed tomography images allow for assessing the lung ventilation with fine spatial resolution, but their quantitative analysis is hampered by the contrast loss due to the disease. This article describes software developed to assist the clinicians in this analysis by implementing semi-automatic algorithms as well as interactive tools. The focus is the assessment of the cyclic hyperinflation, which may lead to ventilator-induced lung injury. For this purpose aerated parts of the lungs were segmented in twenty ARDS patients, half with Covid-19. The results were in very good agreement with manual segmentation performed by experts: (5.1 ml) mean difference in measured cyclic hyperinflation.
Article
Purpose The aim of this study was to assess whether the computed tomography (CT) features of COVID-19 (COVID+) ARDS differ from those of non-COVID-19 (COVID−) ARDS patients. Materials and methods The study is a single-center prospective observational study performed on adults with ARDS onset ≤72 h and a PaO2/FiO2 ≤ 200 mmHg. CT scans were acquired at PEEP set using a PEEP-FiO2 table with VT adjusted to 6 ml/kg predicted body weight. Results 22 patients were included, of whom 13 presented with COVID-19 ARDS. Lung weight was significantly higher in COVID− patients, but all COVID+ patients presented supranormal lung weight values. Noninflated lung tissue was significantly higher in COVID− patients (36 ± 14% vs. 26 ± 15% of total lung weight at end-expiration, p < 0.01). Tidal recruitment was significantly higher in COVID− patients (20 ± 12 vs. 9 ± 11% of VT, p < 0.05). Lung density histograms of 5 COVID+ patients with high elastance (type H) were similar to those of COVID− patients, while those of the 8 COVID+ patients with normal elastance (type L) displayed higher aerated lung fraction.