Extracorporeal Membrane Oxygenation for Coronavirus Disease 2019-Induced Acute Respiratory Distress Syndrome: A Multicenter Descriptive Study

Abstract

Objectives:
Severe acute respiratory distress syndrome is complicated with coronavirus disease 2019 and extracorporeal membrane oxygenation support may be necessary in severe cases. This study is to summarize the clinical features, extracorporeal membrane oxygenation characteristics, and outcomes of patients with severe acute respiratory syndrome coronavirus 2 pneumonia received extracorporeal membrane oxygenation.

Design:
Descriptive study from two hospitals.

Setting:
The ICUs from university hospitals.

Patients:
Patients with severe acute respiratory syndrome coronavirus 2 pneumonia received mechanical ventilation, including those underwent extracorporeal membrane oxygenation from Zhongnan Hospital of Wuhan University and Wuhan Pulmonary Hospital from January 8, 2020, to March 31, 2020.

Interventions:
None.

Measurements and main results:
Clinical records, laboratory results, ventilator parameters, and extracorporeal membrane oxygenation-related data were abstracted from the medical records. One-hundred twenty-nine critically ill patients with severe acute respiratory syndrome coronavirus 2 pneumonia were admitted to ICU of the two referral hospitals. Fifty-nine patients received mechanical ventilation and 21 of them received extracorporeal membrane oxygenation support (fourteen from Zhongnan hospital and seven from Wuhan pulmonary hospital). Compared to mechanical ventilation patients without extracorporeal membrane oxygenation support, there was a tendency of decline in mortality but with no significant difference (no-extracorporeal membrane oxygenation group 24/38 [63.2%] vs extracorporeal membrane oxygenation group 12/21 [57.1%]; p = 0.782). For those patients with extracorporeal membrane oxygenation, 12 patients died and nine survived by April 7, 2020. Among extracorporeal membrane oxygenation patients, the PaCO2 prior to extracorporeal membrane oxygenation was lower (54.40 mm Hg [29.20-57.50 mm Hg] vs 63.20 mm Hg [55.40-72.12 mm Hg]; p = 0.006), and pH prior to extracorporeal membrane oxygenation was higher (7.38 [7.28-7.48] vs 7.23 [7.16-7.33]; p = 0.023) in survivors than nonsurvivors.

Conclusions:
Extracorporeal membrane oxygenation might be an effective salvage treatment for patients with severe acute respiratory syndrome coronavirus 2 pneumonia associated with severe acute respiratory distress syndrome. Severe CO2 retention and acidosis prior to extracorporeal membrane oxygenation indicated a poor prognosis.

Full text

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Critical Care Medicine www.ccmjournal.org 1289
Objectives: Severe acute respiratory distress syndrome is com-
plicated with coronavirus disease 2019 and extracorporeal mem-
brane oxygenation support may be necessary in severe cases.
This study is to summarize the clinical features, extracorporeal
membrane oxygenation characteristics, and outcomes of patients
with severe acute respiratory syndrome coronavirus 2 pneumonia
received extracorporeal membrane oxygenation.
Design: Descriptive study from two hospitals.
Setting: The ICUs from university hospitals.
Patients: Patients with severe acute respiratory syndrome coro-
navirus 2 pneumonia received mechanical ventilation, including
those underwent extracorporeal membrane oxygenation from
Zhongnan Hospital of Wuhan University and Wuhan Pulmonary
Hospital from January 8, 2020, to March 31, 2020.
Interventions: None.
Measurements and Main Results: Clinical records, laboratory
results, ventilator parameters, and extracorporeal membrane oxy-
genation-related data were abstracted from the medical records.
One-hundred twenty-nine critically ill patients with severe acute
respiratory syndrome coronavirus 2 pneumonia were admitted to
ICU of the two referral hospitals. Fifty-nine patients received me-
chanical ventilation and 21 of them received extracorporeal mem-
brane oxygenation support (fourteen from Zhongnan hospital and
seven from Wuhan pulmonary hospital). Compared to mechanical
ventilation patients without extracorporeal membrane oxygenation
support, there was a tendency of decline in mortality but with no
significant difference (no-extracorporeal membrane oxygenation
group 24/38 [63.2%] vs extracorporeal membrane oxygenation
group 12/21 [57.1%]; p = 0.782). For those patients with extracor-
poreal membrane oxygenation, 12 patients died and nine survived
by April 7, 2020. Among extracorporeal membrane oxygenation
patients, the Paco2 prior to extracorporeal membrane oxygenation
was lower (54.40 mm Hg [29.20–57.50 mm Hg] vs 63.20 mm Hg
[55.40–72.12 mm Hg]; p = 0.006), and pH prior to extracorpo-
real membrane oxygenation was higher (7.38 [7.28–7.48] vs 7.23
[7.16–7.33]; p = 0.023) in survivors than nonsurvivors.
Conclusions: Extracorporeal membrane oxygenation might be an
effective salvage treatment for patients with severe acute respira-
tory syndrome coronavirus 2 pneumonia associated with severe
acute respiratory distress syndrome. Severe Co2 retention and ac-
idosis prior to extracorporeal membrane oxygenation indicated a
poor prognosis. (Crit Care Med 2020; 48:1289–1295)
Key Words: acute respiratory distress syndrome; coronavirus
disease 2019; extracorporeal membrane oxygenation
The coronavirus virus disease 2019 (COVID-19),
occurred in Wuhan, China, in December 2019 and sub-
sequently caused an ongoing outbreak from Wuhan,
now spread globally. According to the National Health Com-
mission of the People’s Republic of China, the COVID-19
patients in Wuhan had more severe disease in comparison with
other regions of China. The recent report demonstrated that
the rate of critical illness among patients infected with severe
acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was
about 26%, and critically ill patients had mortality about 61.5%
(1, 2). Most COVID-19 patients usually develop severe pneu-
monia and have a high risk of acute respiratory distress syn-
drome (ARDS) (3). Patients with ARDS have a mortality rate
DOI: 10.1097/CCM.0000000000004447
*See also p. 1389.
1Department of Critical Care Medicine, Zhongnan Hospital of Wuhan Uni-
versity, Wuhan, Hubei, China.
2Department of Critical Care Medicine, Wuhan Pulmonary Hospital,
Wuhan, Hubei, China.
3Department of Emergency Medicine, Zhongnan Hospital of Wuhan Uni-
versity, Wuhan, Hubei, China.
4Department of Critical Care Medicine, Northern Jiangsu People’s Hos-
pital, Yangzhou, Jiangsu Province, China.
5Department of Respiratory and Critical Care Medicine, Beijing Institute of
Respiratory Medicine, Beijing Chao-Yang Hospital, Capital Medical Uni-
versity, Beijing, China.
Copyright © 2020 by the Society of Critical Care Medicine and Wolters
Kluwer Health, Inc. All Rights Reserved.
Extracorporeal Membrane Oxygenation for
Coronavirus Disease 2019-Induced Acute
Respiratory Distress Syndrome: A Multicenter
Descriptive Study*
Xiao Yang, MD1; Shuhan Cai, MD1; Yun Luo, MD1; Fangfang Zhu, MD1; Ming Hu, MD2; Yan Zhao, MD3;
Ruiqiang Zheng, MD4; Xuyan Li, MD5; Bo Hu, MD1; Zhiyong Peng, MD1

Copyright © 2020 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
Yang et al
1290 www.ccmjournal.org September 2020 • Volume 48 • Number 9
of near 50% (4). In a recently published study from Wuhan, the
28-day mortality of mechanical ventilation (MV) COVID-19
patients was 81% (2). Extracorporeal membrane oxygenation
(ECMO) can support gas exchange for patients with ARDS.
ECMO was found to be an effective management choice dur-
ing influenza A (H1N1) outbreaks in 2009 (5–8). However, it
remains unclear whether ECMO is effective in treating SARS-
CoV-2 pneumonia associated ARDS. Thus, in this study, we
aimed to present the clinical characteristics, ECMO-related
variables, and outcomes from patients who received ECMO
support for COVID-19-related ARDS.
MATERIALS AND METHODS
Design, Setting, and Patients
The institutional ethics boards of Zhongnan Hospital of
Wuhan University (number 2020020) and Wuhan Pulmonary
Hospital (number 2020020) approved this case-series. Patients
or families provided informed consent for data analysis with
anonymized individual data.
We screened all consecutive adult ICU admissions with
SARS-CoV-2 related moderate to severe ARDS in Zhongnan
Hospital of Wuhan University and Wuhan Pulmonary Hospital
from January 8, 2020, to March 31, 2020. The diagnose of
SARS-CoV-2 pneumonia was confirmed by both chest scan
and real-time reverse transcription-polymerase chain reaction
assays, according to the World Health Organization Interim
Guidelines (9). The diagnosis of ARDS was defined based on
the Berlin definition (3). We included patients who were intu-
bated and ventilated including those receiving ECMO support
in the final analysis.
Data Collection
The medical records of patients were analyzed by the research
team of the Department of Critical Care Medicine, Zhongnan
Hospital of Wuhan University. We collected demographics,
medical history, underlying comorbidities, laboratory find-
ings, imaging studies, vital signs, medications, need for con-
tinuous renal replacement therapy (CRRT), ventilator settings
(e.g., mode, positive end-expiratory pressure [PEEP], plateau
pressure [Pplat], Fio2, static compliance), ECMO-related in-
formation (i.e., duration time, flow, gas flow, fraction of ox-
ygen), and outcomes from the medical records. The research
coordinators or clinicians obtained relevant data using a priori
designed case report forms.
Oxygenation Therapy, Respiratory Support Strategy,
and ECMO Protocol
All enrolled patients had a diagnosis of ARDS. For patients
with Pao2/Fio2 ratio was about 200–300, nasal cannula and
mask oxygen therapy are recommended. If patients were
not resolved, high-flow nasal cannula (HFNC) or noninva-
sive ventilation (NIV) should be initiated. Within the first 2
hours of the HFNC or NIV, if the patient’s Pao2/Fio2 was still
less than 150 mm Hg, or respiratory rate (RR) was still more
than 30 times per minute with the tidal volume over 9 mL/kg,
invasive MV should be considered. MV should be performed
with lung-protective strategy. Prone positioning should be
continued for at least 12 hours daily. Lung recruitment is not
applied routinely unless indicated and PEEP would be usually
set at 5–10 mm Hg.
When the optimal lung-protective strategy and prone po-
sition were both proved to be ineffective, patients would be
considered to initiate ECMO if any one of these criteria was
met: 1) Pao2/Fio2 less than 50 mm Hg over 3 hours; 2) Pao2/
Fio2 less than 80 mm Hg over 6 hours; 3) arterial blood gas pH
less than 7.25 and Paco2 greater than 60 mm Hg over 6 hours,
as well as RR greater than 35 breaths per minute; 4) RR greater
than 35 breaths per minute, arterial blood gas pH less than 7.2,
and Pplat greater than 30 cm H2O; and 5) complicated with
cardiogenic shock or cardiac arrest.
During ECMO, the blood flow and oxygen flow were set
according to the pulse oxygen saturation and blood gas test,
to maintain the Pao2 60–80 mm Hg and the Paco2 35–45 mm
Hg. When the ECMO started, the ventilation strategy would
be supper lung-protective strategy. Pressure controlled ventila-
tion would be preferred, while the settings would be no more
than pressure controlled 15 cm H2O, PEEP 5–10 cm H2O, res-
piratory rate 8–10 breaths per minute, and Fio2 less than 40%,
even if the tide volume less than 4 mL/kg.
All the patients accepted heparin continuous IV infusion
according to activated clotting time (ACT) of the whole blood
and activated partial thromboplastin time (APTT) test. The
goal ACT was 160–200 seconds while keeping APTT no more
than two times of the upper limit of normal. If the patient had
high risk of bleeding, the goal ACT turned to be 130–160 sec-
onds, and we would give the transfusion of blood products if
necessary.
Statistical Analysis
We summarized the data to frequency (percentages) for cat-
egorical variables and medians and interquartile ranges for
continuous variables. We used chi-square test for categorical
and Wilcoxon-Mann-Whitney U test for continuous variables.
Statistical analyses were performed using IBM SPSS 26 Version
software (IBM, Armonk, NY). p value of less than 0.05 was
regarded statistical significantly.
RESULTS
General Characteristics of the Whole Ventilated
Patients
From January 8, 2020, to March 31, 2020, 129 critically ill
patients with SARS-CoV-2 pneumonia were admitted to the
ICUs of the two ECMO referral hospitals and 59 patients re-
ceived MV. Table 1 summarizes the general characteristics of
patients who received MV. In the whole cohort, 21 (35.6%)
individuals received ECMO therapy, seven from Wuhan Pul-
monary hospital and 14 from Zhongnan Hospital of Wuhan
University. The whole patients had a median age of 65.50
years (56.75–76.00 yr), and median body mass index of 23.15
(21.13–24.27), with 40 (67.8%) of them being male. The

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Clinical Investigations
Critical Care Medicine www.ccmjournal.org 1291
lymphocytes count was 0.55 (0.28–0.80) and lactic dehydro-
genase was 506.00 U/L (421.00–755.00 U/L).
Compared to ventilated patients without ECMO therapy
(MV only group), patients with ECMO (MV with ECMO
group) had a significant younger age (58.50 yr [42.75–67.25
yr] vs 70.50 yr [61.75–79.25 yr]; p = 0.066). Two groups had
the similar Acute Physiology and Chronic Health Evaluation II
score (17.00 [11.25–24.75] vs 16.50 [12.00–23.00]; p = 0.413),
Sequential Organ Failure Assessment score (6.50 [4.00–8.00]
vs 6.50 [5.00–9.00]; p = 0.897), and the duration between
symptoms and initiation of MV (14.00 d [11.00–19.00 d] vs
15.00 d [11.00–21.50 d]; p = 0.534). Compared to MV only
group, although the MV with ECMO group had an elevated
tendency in Murray Lung Injury Score (LIS) (3.59 [3.31–4.00]
vs 3.00 [2.67–3.33]; p = 0.124), and had a shorten tendency
in the duration between hospitalization and initiation of MV
(2.00 d [0–7.50 d] vs 6.00 d [2.50–9.00 d]; p = 0.138), there
were no significant difference between two groups. By April 7,
2020, nine of 21 patients survived in MV with ECMO group,
and 14 of 38 patients survived in MV only group (57.1% vs
63.2%; p = 0.782).
Laboratory Tests of Patients With ECMO Therapy
From laboratory tests (Table 2), the majority of patients with
ECMO therapy had leukocytosis with the WBC count of
12.29 × 109/L (7.94–18.04 × 109/L). Although the lymphocytes
counts were relatively low at 0.70 × 109/L (0.51–1.10 × 109/L).
Included patients had a normal coagulation status, with a me-
dian of partial thromboplastin time (14.85 s [13.73–17.40 s]),
APTT (32.05 s [29.73–36.98 s]) but with an elevated d-dimer
(359.00 mg/L [105.75.00–2,952.50 mg/L]). Liver injury was also
common, characterized by elevated alanine aminotransferase
(49.50 U/L [18.50–75.00 U/L]), aspartate aminotransferase
(51.00 U/L [31.75–115.500 U/L]), and bilirubin (13.92 μmol/L
[9.63–19.83 μmol/L]). The creatinine level was normal, with
a median of 70.70 μmol/L (58.65–107.35 μmol/L). The level
of hypersensitive troponin I was 30.00 ng/mL (5.03–126.00 ng/
mL). However, survivors had a significant lower creatinine
than nonsurvivors prior to ECMO (61.10 μmol/L [54.70–95.08
μmol/L] vs 82.95 μmol/L [70.55–157.13 μmol/L]; p = 0.027).
Lung Functions Before ECMO
Nineteen patients (90.4%) received neuromuscular block-
ers, and 12 (57.1%) underwent prone positioning be-
fore administration of ECMO. Table 3 presents the lung
functions of patients who underwent ECMO prior to in-
itiation. The median of LIS was 3.59 (3.31–4.00) (3.33
[3.25–3.67] in survivors, and 4.00 [3.33–4.00] in nonsur-
vivors; p = 0.211) before initiation of ECMO. Survivors
tended to have a shorter duration of onset of illness be-
fore ECMO than nonsurvivors (15.00 d [12.50–20.50 d] vs
18.00 d [14.75–21.75 d]; p = 0.382). Meanwhile, the dura-
tion of MV before ECMO seemed to be shorter in survivors
than in nonsurvivors, but with no significant difference
TABLE 1. General Characteristics of Patients With Invasive Mechanical Ventilation
Demographic and Clinical Data Total
(n = 59) IMV Only
(n = 38)
IMV + Extracorporeal
Membrane
Oxygenation (n = 21) p
Gender: male, n (%) 40 (67.8) 28 (73.7) 12 (57.1) 0.248
Age, yr 65.50 (56.75–76.00) 70.50 (61.75–79.25) 58.50 (42.75–67.25) 0.066
Body mass index 23.15 (21.13–24.27) 22.23 (20.11–23.82) 23.66 (22.52–26.59) 0.792
Acute Physiology and Chronic Health
Evaluation II score 16.50 (12.00–23.00) 16.50 (12.00–23.00) 17.00 (11.25–24.75) 0.413
Sequential Organ Failure Assessment score 6.50 (4.75–8.00) 6.50 (5.00–9.00) 6.50 (4.00–8.00) 0.897
Lung Injury Score 3.25 (2.75–3.50) 3.00 (2.67–3.33) 3.59 (3.31–4.00) 0.124
Duration of onset of symptoms to MV, d 15.00 (11.00–19.00) 15.00 (11.00–21.50) 14.00 (11.00–19.00) 0.534
Duration of hospitalization to MV, d 4.00 (1.00–9.00) 6.00 (2.50–9.00) 2.00 (0–7.50) 0.138
Positive end-expiratory pressure, cm H2O 10.00 (8.00–10.00) 10.00 (8.00–10.00) 10.00 (10.00–11.00) 0.175
Prone position, n (%) 41 (69.5) 25 (67.6) 16 (76.2) 0.594
Lymphocytes number (×109/L) 0.55 (0.28–0.80) 0.47 (0.24–0.73) 0.69 (0.45–1.11) 0.142
Lactic dehydrogenase (U/L) 506.00 (421.00–755.00) 482.00 (423.00–600.00) 625.00 (346.50–889.80) 0.653
Acute kidney injury, n (%) 23 (41.8) 15 (39.5) 8 (47.1) 0.768
Outcome: death, n (%) 36 (61) 24 (63.2) 12 (57.1) 0.782
IMV = invasive mechanical ventilation, MV = mechanical ventilation.
Data reported as median (interquartile range).
p values: survivors vs nonsurvivors.

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Yang et al
1292 www.ccmjournal.org September 2020 • Volume 48 • Number 9
(20.00 hr [2.00–63.00 hr] vs 43.00 hr [12.25–109.00 hr];
p = 0.277). The Pao2/Fio2 was low (60.0 [55.60–72.00]),
and Co2 retention occurred in all patients (Paco2, 56.00 mm
Hg [54.00–64.00 mm Hg]). Paco2 was higher in nonsurvi-
vors when compared with survivors (63.20 cm H2O [55.40–
72.12 cm H2O] vs 54.40 cm H2O [29.20–57.50 cm H2O];
p = 0.006). Accordingly, nonsurvivors were more acidosis
than survivors with pH (nonsurvivors 7.23 [7.16–7.33] vs
survivors 7.38 [7.28–7.48]; p = 0.023). The static compliance
was similar in survivors (20.0 mL/cm H2O [15.50–28.00 mL/
cm H2O]) and nonsurvivors (18.00 mL/cm H2O [16.25–
23.00 mL/cm H2O]). Serum lactate was mildly elevated with
a median of 1.80 mmol/L (1.50–3.10 mmol/L) (1.60 mmol/L
[1.35–2.55 mmol/L] in survivors vs 2.25 mmol/L [1.70–3.60
mmol/L] in nonsurvivors; p = 0.211).
ECMO Initiation and Related Variables
The average running time of ECMO was 218.0 hours (142.5–
594.0 hr) (193.0 hr [106.0–576.5 hr] in survivors vs 419.3 hr
[202.5–629.0 hr] in nonsurvivors; p = 0.382). All patients
started an ECMO flow rate at 1,500 revolutions per minute
(rpm) and maintained at 4 L/min. All nonsurvivors had a
continued need of high-flow rates. After ECMO initiation,
the Paco2 was reduced to normal range in both survivors and
nonsurvivors. This was regardless of the Paco2 level prior to
ECMO initiation. The sweep flow in the survivors decreased
gradually, while it remained high among nonsurvivors. During
ECMO support, nonsurvivors remained with no significant
higher lactate concentrations than survivors (Fig. 1).
Outcomes and Complications With ECMO
At the end of April 7, 2020, among the 21 ECMO patients, there
were 12 patients died. Nine patients weaned from ECMO suc-
cessfully, six of which had been discharged. The crude mortality
rate from ECMO therapy was 57.1%. Among the patients who
died, one patient experienced bradycardia, which led to car-
diac arrest. This patient did not have any evidence of bleeding
or volume depletion based on ultrasonography examination.
Six patients died of persistently worsening lung consolidation
that was difficult to reverse and got secondary lung infections
with multiple drug-resistant bacteria. Three patients died of
septic shock from uncontrolled bloodstream infection by mul-
tiple drug-resistant Acinetobacter baumannii. One patient had
heart arrest before initiation of ECMO and complicated with
brain death. One patient died of cerebral hemorrhage who had
a stroke history before.
Bradycardia occurred in five patients (23.8%). Except for
one patient, the other four patients responded to medical
therapy promptly. Three of the patients presented with enlarged
right or left ventricular accompanied by low contractility.
TABLE 2. Laboratory Tests of Patients With Extracorporeal Membrane Oxygenation
Therapy
Laboratory Data Total (n = 21) Survivors (n = 9) Nonsurvivors (n = 12) p
Leukocyte (×109/L) 12.29 (7.94–18.04) 12.29 (4.25–17.28) 12.23 (7.94–20.96) 0.573
Lymphocyte (×109/L) 0.70 (0.51–1.10) 0.67 (0.49–0.85) 0.78 (0.46–1.23) 0.536
Neutrophil, % 87.80 (82.70–94.03) 87.80 (76.03–93.63) 87.80 (83.81–95.00) 0.515
Lymphocyte, % 7.10 (3.46–10.90) 7.35 (3.37–18.00) 7.10 (3.20–10.74) 0.696
Monocyte, % 4.77 (2.25–6.30) 4.95 (2.53–6.68) 4.47 (2.08–6.05) 0.515
Platelets (×109/L) 202.50 (163.00–216.25) 205.0 (180.75–219.50) 194.50 (125.50–219.50) 0.762
Partial thromboplastin time (s) 14.85 (13.73–17.40) 14.40 (13.20–16.25) 15.95 (13.80–17.45) 0.360
Active partial thromboplastin time (s) 32.05 (29.73–36.98) 30.90 (29.58–32.53) 34.15 (29.70–47.90) 0.173
d-dimer (mg/L) 359.00 (105.75–2,952.50) 1,258.0 (193.25–3,577.50) 175.50 (68.78–2,901.0) 0.408
Creatine kinase (U/L) 96.00 (46.75–415.50) 100.50 (63.00–2,322.75) 96.00 (38.75–415.50) 0.515
MB isoenzyme of creatine kinase (U/L) 22.00 (12.05–52.00) 22.50 (12.00–62.00) 19.00 (10.82–49.75) 0.762
Alanine aminotransferase (U/L) 49.50 (18.50–75.00) 71.00 (41.00–130.25) 32.00 (14.00–64.50) 0.055
Aspartate aminotransferase (U/L) 51.00 (31.75–115.50) 112.00 (36.50–293.25) 38.00 (27.25–70.50) 0.101
Bilirubin (μmol/L) 13.92 (9.63–19.83) 13.92 (8.58–19.60) 13.97 (10.00–23.65) 0.633
Blood urea nitrogen (mmol/L) 6.38 (4.78–9.19) 9.01 (5.09–11.74) 5.68 (4.74–7.48) 0.146
Creatinine (μmol/L) 70.70 (58.65–107.35) 82.95 (70.55–157.13) 61.10 (54.70–95.08) 0.027
Troponin I (pg/mL) 30.00 (5.03–126.00) 25.00 (10.63–88.50) 30.00 (2.04–269.23) 1.000
Procalcitonin (ng/mL) 0.19 (0.06–1.48) 0.36 (0.06–3.53) 0.19 (0.07–1.39) 0.897
Data reported as median (interquartile range).
p values: survivors vs nonsurvivors.

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Clinical Investigations
Critical Care Medicine www.ccmjournal.org 1293
Hemorrhagic complications occurred in three patients, which
manifested as insertion catheter site bleeding (two patients)
and intracerebral hemorrhage (one patient). In the cohort of
patients requiring ECMO, nine patients received vasopressors,
and eight developed acute kidney injury and required CRRT.
DISCUSSION
To our knowledge, this is the first study to summarize the
characteristics of patients with SARS-CoV-2 pneumonia who
developed ARDS and treated with ECMO. In this study, the
mortality rate was 57.1%. All included patients had severe
ARDS with a median of Pao2/Fio2 ratio of 60.00 (55.60–72.00).
Our study provides a more optimistic view as we showed using
ECMO as an option for salvage therapy of COVID-19 could be
associated with lower mortality.
By April 7, the COVID-19 had already involved 1,263,219
patients and resulted in 71,235 deaths globally. Thus, it is
critical to have a protocolized and effective strategy to treat
these patients, particularly among those who become criti-
cally ill. A recent report with a focus on critically ill patients
with confirmed SARS-CoV-2 infection from Jinyintan
Hospital (Wuhan) demonstrated considerable mortality
(81%) within mechanically ventilated patients (2). However,
the death rate among patients who received ECMO was
not reported. Similar to SARS-CoV-2, patients with severe
ARDS associated with influenza A (H1N1) pneumonia when
treated with ECMO have lower mortality of 30–40% (5–8).
Indeed, the Conventional ventilation or Extracorporeal
membrane oxygenation for Severe Adult Respiratory failure
(CESAR) study (10) suggested that ECMO could be regarded
as rescue therapy for patients with severe ARDS. Also, in the
Extracorporeal membrane Oxygenation for severe acute res-
piratory distress (EOLIA) trial (11), the patient has received
ECMO had lower mortality when compared with conven-
tional study by 11%.
The timing of ECMO initiation is still disputed. It has been
suggested to initiate ECMO when Pao2/Fio2 ratio less than
50 mm Hg for greater than 3 hours, or Pao2/Fio2 ratio less than
80 mm Hg for greater than 6 hours, or pH less than 7.25 with
Paco2 greater than or equal to 60 mm Hg in arterial blood gas
for greater than 6 hours, with the RR greater than 35 breaths/
min and MV settings adjusted to keep a Pplat of less than or
equal to 32 cm H2O (12). During the H1N1 outbreak, the Pao2/
Fio2 ratio of less than 70 mm Hg for at least 2 hours and Pplat
greater than 30 cm H2O, or Pao2/Fio2 ratio of less than 100 mm
Hg associated with Pplat greater than 35 cm H2O, or respi-
ratory acidosis with pH less than or equal to 7.15 treatment
with ECMO was considered (5). However, our observations
indicated that earlier initiation of ECMO (evaluated by the
length of MV before ECMO initiation) maybe associated with
improved outcomes. The majority of patients who developed
severe ARDS with SARS-CoV-2 pneumonia had delayed treat-
ment and deteriorated rapidly. We considered ECMO should
be implemented as soon as possible when the Pao2/Fio2 ratio
was less than 80 mm Hg despite being on lung-protective MV
strategy and prone positioning.
In our study, ventilated patients had a bad compliance with
a median 18.00 mL/cm H2O (16.50–24.00 mL/cm H2O) prior
to ECMO. Compliance less than 20 mL/cm H2O was reported
to be a prognostic factor of death on venovenous ECMO (12,
13). We noted that patients with more severe Co2 retention
tended to have a worse prognosis. In a previous study, higher
Figure 1. Dynamic changes tendency in extracorporeal membrane oxygenation (ECMO) variables and arterial blood gas variables between survivors and
nonsurvivors. ECMO variables including blood flow (L/min) and creep flow (L/min), arterial blood gas variables including lactate levels, and Paco2 level.
Data expressed as median (range).

Copyright © 2020 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
Yang et al
1294 www.ccmjournal.org September 2020 • Volume 48 • Number 9
Pco2 was associated with worse prognosis (14). Also in the
study by Nuckton et al (15), the elevated Co2 likely reflects
ARDS severity and increased dead space fraction. Thus, we
speculated that patients with higher Pco2 for a period might
need ECMO support. Besides, acidosis and elevated creatinine
prior to ECMO was also associated with poor outcomes.
When the ECMO pump started, many patients developed
bradycardia with or without hypotension. We speculated
that multiple factors led to such observation. Most patients
were severely hypoxemic before ECMO initiation. Following
ECMO initiation, receiving highly oxygenated blood could
have resulted in ischemia-reperfusion injury and excessive in-
flammatory response. Patients with hemodynamic instability
before ECMO initiation had a higher risk of bradycardia. So
we suggested that the ECMO pump rotation should increase
slowly from 1,500 rpm to the target rotation with a rate of
500 rpm elevation in every 10 minutes.
Bleeding and thromboembolic events are reported as the
most frequent causes of death (16). In our observation, bleed-
ing occurred in the early phase of ECMO therapy in three
patients. Bleeding resolved by compression, suturing, and re-
quired transfusion. More contemporary ECMO circuitry with
higher biocompatibility (17) have markedly contributed to
an overall reduction in the need for anticoagulation. Our low
prevalence of bleeding may be explained by careful manage-
ment of the anticoagulation regimen, along with the recruit-
ment of highly experienced teams.
Our study has several limitations inherent to all retrospec-
tive studies. First, the power of the study is limited by the small
size of our cohort. Therefore, type 2 errors could have led to
missing statistical significant differences. Second, we did not
adjust for the multiple confounding factors simultaneously;
as such, identified risk factors like time to ECMO needed, are
likely accounting for ARDS severity and Co2 retention. Third,
several data related to the ECMO and mechanical ventilator
settings were not available. Last, our observation period was
short and further outcomes about these patients may be re-
quired for complete analysis.
In conclusion, ECMO might be an effective salvage treat-
ment for patients with SARS-CoV-2 pneumonia associated
with severe ARDS. Severe Co2 retention and acidosis prior to
ECMO indicated a poor prognosis.
ACKNOWLEDGMENTS
We would like to thank the staff of the Department of Critical
Care Medicine of Wuhan Pulmonary Hospital, who contrib-
uted to this study by collecting the required data in the hospital
data system.
Drs. Yang and Cai contributed equally to the first authorship.
This work was supported by the National Natural Science Foundation
(grants 81772046 and 81971816 to Dr. Peng) and the Special Project
for Significant New Drug Research and Development in the Major Na-
tional Science and Technology Projects of China (2020ZX09201007 to
Dr. Peng).
Dr. Zhao received support for article research from Hubei Clinical Re-
search Center for Emergency and Resuscitation, Hubei Emergency and
Critical Mobile Extracorporeal Membrane Oxygenation (ECMO) Support
Center, and the Emergency and Critical Care Mobile ECMO Support
Center of Zhongnan Hospital of Wuhan University. Dr. Peng received sup-
port for article research from the Chinese National Natural Science Foun-
dation. The remaining authors have disclosed that they do not have any
potential conflicts of interest.
For information regarding this article, E-mail: pengzy5@hotmail.com; hob-
bier1979@163.com
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TABLE 3. Variables of Lung Function Prior to Extracorporeal Membrane Oxygenation
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ECMO = extracorporeal membrane oxygenation.
Data reported as median (interquartile range).
p values: survivors vs nonsurvivors.

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