Extracorporeal membrane oxygenation for life-threatening asthma refractory to mechanical ventilation: analysis of the Extracorporeal Life Support Organization registry
Yeo et al. Critical Care
Extracorporeal membrane oxygenation for life-threatening asthma refractory to mechanical ventilation: analysis of the Extracorporeal Life Support Organization registry
Hye Ju Yeo 0 1
Dohyung Kim 0 2
Doosoo Jeon 0 1
Yun Seong Kim 0 1
Peter Rycus 3
Woo Hyun Cho 0 1
0 Research Institute for Convergence of Biomedical Science and Technology Pusan National University Yangsan Hospital , Yangsan , Republic of Korea
1 Department of Pulmonology and Critical Care Medicine, Pusan National University Yangsan Hospital , Geumo-ro 20, Beomeo-ri, Mulgeum-eup, Yangsan-si, Gyeongsangnam-do 50612 , Republic of Korea
2 Department of Thoracic and Cardiovascular Surgery, Pusan National University Yangsan Hospital , Yangsan , Republic of Korea
3 Extracorporeal Life Support Organization (ELSO) , Ann Arbor, MI , USA
Background: The use of extracorporeal membrane oxygenation (ECMO) in cases of near-fatal asthma (NFA) has increased, but the benefits and potential complications of this therapy have yet to be fully investigated. Methods: Cases were extracted from the Extracorporeal Life Support Organization Registry between March 1992 and March 2016. All patients with a diagnosis of asthma (according to the International Classification of Diseases 9th edition), who also received ECMO, were extracted. Exclusion criteria included patients who underwent multiple courses of ECMO; those who received ECMO for cardiopulmonary resuscitation or cardiac dysfunction; and those with another primary diagnosis, such as sepsis. We analyzed survival to hospital discharge, complications, and clinical factors associated with in-hospital mortality, in patients with severe life-threatening NFA requiring ECMO support. Results: In total 272 patients were included. The mean time spent on ECMO was 176.4 hours. Ventilator settings, including rate, fraction of inspired oxygen (FiO2), peak inspiratory pressure (PIP), and mean airway pressure, significantly improved after ECMO initiation (rate (breaths/min), 19.0 vs. 11.3, p < 0.001; FiO2 (%), 81.2 vs. 48.8, p < 0.001; PIP (cmH2O), 38.2 vs. 25.0, p < 0.001; mean airway pressure (cmH2O): 21.4 vs. 14.2, p < 0.001). In particular, driving pressure was significantly decreased after ECMO support (29.5 vs. 16.8 cmH2O, p < 0.001). The weaning success rate was 86.7%, and the rate of survival to hospital discharge was 83.5%. The total complication rate was 65.1%, with hemorrhagic complications being the most common (28.3%). Other complications included renal (26.8%), cardiovascular (26.1%), mechanical (24.6%), metabolic (22.4%), infection (16.5%), neurologic (4.8%), and limb ischemia (2.6%). Of the hemorrhagic complications, cannulation site hemorrhage was the most common (13.6%). Using multivariate logistic regression analysis, it was found that hemorrhage was associated with increased in-hospital mortality (odds ratio, 2.97; 95% confidence interval, 1.07-8.24; p = 0.036). Hemorrhage-induced death occurred in four patients (1.5%). The most common reason for death was organ failure (37.8%). (Continued on next page)
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Conclusions: ECMO can provide adequate gas exchange and prevent lung injury induced by mechanical ventilation,
and may be an effective bridging strategy to avoid aggressive ventilation in refractory NFA. However, careful management
is required to avoid complications.
Near-fatal asthma (NFA) is a life-threatening condition
caused by acute respiratory failure, and is the most severe
clinical presentation of asthma [
]. Although there are
no specific diagnostic criteria for NFA, it is characterized
by cardiorespiratory arrest, hypercapnia, acidemia, and the
need for intubation and mechanical ventilation . NFA
can progress to fatal asthma, and the mortality rate varies
widely across countries. In 2015, there were 3615 deaths
from asthma in the USA [
]. Despite recent advances in
treatment, the mortality rate for asthma has not changed
significantly. It may be that much of the current asthma
mortality is due to unpredictable deaths in the context of
]. Globally, nearly 30% of NFA cases result in
significant morbidity and mortality [
protective mechanical ventilation with rescue therapy,
including neuromuscular blockade, has been the mainstay
treatment for NFA. However, technical advances in
extracorporeal membrane oxygenation (ECMO) have made it a
promising alternative therapy in the treatment of
lifethreatening NFA [
ECMO can provide adequate gas exchange during
acute respiratory failure, and can help prevent lung
injury induced by aggressive mechanical ventilation. Using
data from the multicenter Extracorporeal Life Support
Organization (ELSO) Registry, a previous study showed
that ECMO support improved survival in patients with
status asthmaticus to a greater degree than in other
respiratory conditions [
]. However, this study included a
small number of cases. The low incidence of NFA may
preclude large-scale, prospective randomized trials on
the effectiveness of ECMO in this context. Nevertheless,
an increasing number of reports suggest ECMO may be
an effective rescue therapy for NFA [
Despite the potential benefits of ECMO in NFA,
concerns remain about complications. In general,
complications are the primary factor limiting the effectiveness of
ECMO in many diseases. Evidence supporting ECMO use
in NFA is lacking, and questions about the safety and
effectiveness of ECMO in NFA remain unanswered. In this
study, we reviewed data from the ELSO Registry
collected between March 1992 and March 2016. Our
aim was to investigate survival to hospital discharge,
complications, and clinical factors associated with
inhospital mortality, in patients with severe
lifethreatening NFA requiring ECMO support.
The ELSO Registry is a worldwide voluntary registry.
Currently, data are reported from 350 international
ECMO centers. Data are collected using a standardized
form, and include patient demographics, pre-ECMO
ventilator settings, pre-ECMO arterial blood gas analysis
(ABGA), post-ECMO ventilator settings, ECMO
complications, and survival to hospital discharge [
pressure (ΔP) was calculated as ventilator-measured
plateau pressure minus applied positive end-expiratory
pressure (PEEP). Diagnostic information is reported using the
International Classification of Diseases 9th edition (ICD-9)
codes, and indications for ECMO application are
categorized as cardiac, respiratory, or extracorporeal
cardiopulmonary resuscitation (ECPR). The study was approved by
the Institutional Review Board (IRB) of Pusan National
University Yangsan Hospital (IRB no.05-2017-066).
Informed consent was not sought due to the retrospective
nature of the study.
Between March 1992 and March 2016, 24,147 adults aged
over 18 years were registered in the ELSO database. All
cases of ECMO use in the context of an ICD-9 diagnosis
of asthma were extracted (N = 568). Patients receiving
ECMO support for ECPR or cardiac dysfunction were
excluded according to the support type (ECPR, cardiac, or
respiratory), and multiple ECMO courses were excluded.
To discriminate between asthma and other non-asthmatic
respiratory ECMO cases, patients with other primary
diagnoses were also excluded. For example, a patient with
asthma who received ECMO for sepsis was excluded, as
sepsis was the primary indication for therapy. In total, 272
patients were included in the NFA group (Fig. 1).
Data were reported as mean values with standard
deviations for normally distributed data, or frequencies with
proportions for categorical data. We compared the
demographics, pre-ECMO and post-ECMO values, and ECMO
complications between survivors and non-survivors
among patients with NFA. Student’s t test was used for
continuous data and the Fisher’s exact or Pearson’s
chisquare test was used for categorical data. Pre-ECMO and
post-ECMO ventilator settings were compared using the
paired t test.
Binary logistic regression analysis was used to identify
predictors of in-hospital mortality. Significant and
borderline values (≤0.05) were entered into stepwise
backward multivariable logistic regression, including age as
the continuous covariate, to estimate factors associated
with mortality prior to hospital discharge. Two-way
interaction terms were tested between the remaining
significant variables. A p value <0.05 was considered
significant. Age, pre-ECMO ventilator settings,
preECMO ABGA, post-ECMO ventilator settings, and
ECMO complications were used as predictors.
Baseline patient characteristics
Among the 24,147 adult patients in the ELSO registry,
568 patients had a diagnosis of asthma according to the
ICD-9 code (2.4%). Of these, 272 patients met the
criteria for inclusion in the study. The use of ECMO for
NFA in adults has been growing rapidly since 1992
(Additional file 1). The baseline clinical characteristics of
the patients are presented in Table 1. Mean age was
36.2 years (range, 18–83 years). Mean body weight was
88.0 kg and. 39.7% of the patients were men. Pre-ECMO
ABGA showed hypercapnic acidosis with mean pH of
7.1, mean partial pressure of carbon dioxide of
80.5 mmHg, and mean partial pressure of arterial
oxygen/mean fraction of inspired oxygen (FiO2) ratio of
153.7. The mean values of the ventilator settings were
relatively high. Prior to ECMO initiation, the mean peak
inspiratory pressure (PIP) was 38.2 cmH2O; mean airway
pressure was 21.4 cmH2O; mean PEEP was 8.3 cmH2O;
mean FiO2 was 81.2%; and mean driving pressure was
Venovenous ECMO was the most common mode used
(93.9%, Table 2). Double lumen cannulation was used in
43.5% of patients. The mean duration of ECMO support
was 176.4 hours, and 63.2% (163/258) of patients were
weaned off of ECMO within 7 days. Improvement was
characterized using the best ventilator settings occurring
within 24 hours of ECMO initiation. Mean FiO2 was
48.8%; mean PIP was 25.0 cmH2O; the mean of the mean
airway pressures was 14.2 cmH2O; and the average driving
pressure was 16.8 cmH2O. Respiration rate, FiO2, PIP, and
mean airway pressure significantly decreased within
24 hours of ECMO initiation (rate (breaths/min), 19.0 vs.
11.3, p < 0.001; FiO2 (%), 81.2 vs. 48.8, p < 0.001; PIP
(cmH2O), 38.2 vs. 25.0, p < 0.001; mean airway pressure
(cmH2O), 21.4 vs. 14.2, p < 0.001). In particular, driving
pressure was significantly decreased after ECMO support
(29.5 vs. 16.8 cmH2O, p < 0.001, Fig. 2).
Complications and in-hospital mortality
In-hospital complications are shown in Table 3 and
Additional file 2. Complications occurred in 177 patients
(65.1%). Hemorrhagic complications were the most
common (28.3%, 77/272). Other complications included
renal (26.8%, 73/272), cardiovascular (26.1%, 71/272),
mechanical (24.6%, 67/272), and metabolic (22.4%, 61/
272) complications, culture-proven infection (16.5%, 45/
272), neurologic complications (4.8%, 13/272), and limb
ischemia (2.6%, 7/272). Among the hemorrhagic
complications, cannulation-site hemorrhage was the most
common (13.6%, 37/272). Other hemorrhagic complications
included surgical-site hemorrhage (8.5%), pulmonary
hemorrhage (5.1%) and gastrointestinal hemorrhage
(2.6%). There were four deaths due to hemorrhage
Overall, the rate of weaning success was 86.7% (234/
272) and the rate of survival to discharge was 83.5%
(227/272). Among non-survivors, 15.6% (7/45) died after
ECMO weaning. The most common reason for death
was organ failure (37.8%, 17/45; Additional file 2).
Differences between survivors and non-survivors
Baseline ECMO patient profiles were significantly
different between survivors and non-survivors (Table 1). The
mean age was lower in survivors (34.7 vs. 43.4, p = 0.001),
as was the mean pH (7.1 vs. 7.2, p = 0.045). Saturation was
higher in survivors (92.3 vs. 85.2, p = 0.030). In addition,
PEEP was lower in survivors (7.8 vs. 11.5, p = 0.002).
ECMO duration and ventilator settings after ECMO
initiation were significantly different between survivors and
non-survivors (Table 2). The mean duration of ECMO
was shorter in survivors (161.6 vs. 257.2, p = 0.035). The
values of rate, FiO2, PIP, and driving pressure after ECMO
initiation were lower in survivors (rate (breaths/min), 11.1
vs. 12.7, p = 0.043; FiO2 (%), 47.4 vs. 57.4, p = 0.025; PIP
Values are shown as number (%) or mean ± SD
ECMO extracorporeal membrane oxygenation, GI gastrointestinal
N = 227
(cmH2O), 24.3 vs. 29.7, p < 0.001; driving pressure
(cmH2O), 16.2 vs. 21.1, p = 0.002).
The complication rate was higher in non-survivors
(60.8 vs. 86.7, p = 0.001; Table 3). The rate of mechanical
complications was also higher in non-survivors (21.1 vs.
42.2, p = 0.003), especially the rate of oxygenator failure
(3.1 vs. 15.6, p = 0.001) and clots (0.4 vs. 8.9, p = 0.042).
The rate of hemorrhage in general (22.9 vs. 55.6, p =
0.001), the rate of cannulation-site hemorrhage (11.0 vs.
26.7, p = 0.005), and the rate of pulmonary hemorrhage
(3.1 vs. 15.6, p = 0.001) were higher in non-survivors.
Among neurologic complications, the rates of brain
death (1.3 vs. 6.7, p = 0.026), cerebral infarction (0.9 vs.
13.3, p < 0.001), and cerebral hemorrhage (3.1 vs. 11.1, p
= 0.017) were higher in non-survivors. In addition, renal
complications occurred more often in non-survivors
(24.2% vs. 40%, p = 0.029), especially the rate of dialysis
(17.2 vs. 40, p = 0.013).
Factors associated with in-hospital mortality
Univariate and multivariate analyses were performed to
investigate the possible predictors of in-hospital mortality
in the study population (Table 4). In the univariate
analysis, age (odds ratio (OR), 1.05, 95% confidence interval
(CI), 1.02–1.07, p < 0.001), mechanical complication (OR,
2.73, 95% CI, 1.39–5.34, p = 0.003), hemorrhage (OR, 4.21,
95% CI 2.16–8.18, p < 0.001), dialysis on ECMO (OR,
2.41, 95% CI, 1.19–4.90, p = 0.015), pre-ECMO PEEP (OR,
1.10, 95% CI, 1.03–1.18, p = 0.003), pre-ECMO pH (OR,
7.57, 95% CI, 1.04–55.29, p = 0.046), post-ECMO FiO2
(OR, 1.02, 95% CI, 1.01–1.04, p = 0.006), post-ECMO PIP
(OR, 1.08, 95% CI, 1.03–1.14, p = 0.001), and post-ECMO
driving pressure (OR, 1.08, 95% CI, 1.03–1.13, p = 0.003)
were associated with increased in-hospital mortality. Among
hemorrhagic complications, cannulation-site hemorrhage
(OR, 2.94, 95% CI, 1.35–6.41, p = 0.007), central nervous
system hemorrhage (OR, 3.93, 95% CI, 1.19–12.99, p =
0.025), and pulmonary hemorrhage (OR, 5.79, 95% CI,
1.92–17.44, p = 0.002) were associated with increased
In the multivariate logistic regression model, age (OR,
1.05, 95% CI, 1.01–1.08, p = 0.012), bleeding (OR, 2.97,
95% CI, 1.07–8.24, p = 0.036), pre-ECMO PEEP (OR,
1.10, 95% CI, 1.01–1.20, p = 0.027), post-ECMO FiO2
(O,: 1.03, 95% CI, 1.00–1.05, p = 0.034), and post-ECMO
driving pressure (OR, 1.08, 95% CI, 1.02–1.15, p = 0.011)
were associated with increased in-hospital mortality.
To our knowledge, this is the largest study of patients
who have received ECMO for NFA refractory to
mechanical ventilation. In this study, ventilator settings
significantly improved after ECMO initiation to allow
protective ventilation. Overall survival to hospital
discharge was 83.5%, which was favorable compared to the
ECMO outcome of other types of respiratory failure.
Otherwise, ECMO complication was still common, even
though it was mostly not serious. The total complication
rate was 65.1%, with hemorrhagic complications being
the most common (28.3%). Although bleeding was
associated with increased in-hospital mortality, fatal bleeding
only occurred in 1.5% of cases and most other
complications were not fatal. Therefore, ECMO may be an
effective treatment to prevent ventilator-induced lung injury
in NFA refractory to mechanical ventilation. In addition,
careful monitoring is required to detect and manage
complications early and reduce their impact.
The mortality rate of patients with asthma is decreasing,
but remains significant [
]. While mechanical
ventilation is a potentially life-saving intervention, a large
proportion of the morbidity and mortality seen in patients with
asthma may be related to the mechanical ventilation itself
OR Odds ratio, CI confidential interval, ECMO extracorporeal membrane oxygenation, PEEP positive end-expiratory pressure, FiO2 fraction of inspired oxygen
saturation, PIP peak inspiratory pressure
aThe worst values in the previous 6 h were collected
bThe best values in the last 24 h were collected
rather than to disease progression [
]. Regardless of
the mode of ventilation selected, mechanical ventilation in
NFA should aim to avoid barotrauma, minimize dynamic
hyperinflation, maintain adequate oxygenation, and allow
some degree of permissive hypercapnia until
bronchodilators and steroids improve airflow [
]. However, this
strategy may be impossible in patients with severe NFA. A new
therapeutic approach is needed to reduce lung damage in
patients with severe NFA requiring treatment with maximal
Traditionally, overt hypercapnic acidosis in patients with
acute severe asthma is significantly associated with higher
rates of invasive ventilation; this leads to longer hospital
stays, more complications, and a higher mortality rate
]. In general, it is recommended that a moderate degree
of hypercarbia and respiratory acidosis be tolerated in
NFA, and that airway pressure be limited by using low
respiratory rates and low tidal volumes [
hypercapnea can recover rapidly once effective treatment has
begun and hypoxemia is corrected. However, in severe
cases with extreme airway obstruction, hypoxemia cannot
be corrected despite maximal use of the mechanical
ventilator. Death can occur as a result of asphyxia due to
extreme airflow limitation and resulting hypoxia.
Despite limited data about physiologic and ventilator
parameters, ventilator settings after ECMO initiation
significantly improved, particularly driving pressure and PIP.
Driving pressure is considered to be a reasonable surrogate
for transpulmonary pressure, and high transpulmonary
pressure can cause lung injury or gross barotrauma [
]. The high PIP seen before ECMO initiation may reflect
possible dynamic hyperinflation, which can result in
cardiovascular instability and barotrauma to the lung. Our results
suggest that ECMO significantly improves gas exchange,
despite a lower PIP and lower driving pressure. Therefore,
the use of ECMO in NFA may reduce ventilator-induced
lung injury and oxygen toxicity by allowing for decreased
ventilator settings. In NFA, the time to restoration of airway
patency and reactivity following conventional treatment is
highly variable, and clinicians cannot predict when
bronchospasm will resolve. ECMO should be considered
before refractory NFA causes barotrauma and volutrauma.
In particular, the ventilation/perfusion mismatch produced
by increased airway resistance and airflow limitation may
facilitate severe hypoxemia in NFA. Therefore, ECMO
could be considered in patients with persistent signs of
deterioration including severe hypoxemia, acidosis, and
hemodynamic instability, despite maximal mechanical
Complications were common, even though the rates
were lower than in previous studies [
]. However, the
total complication rate included all minor complications,
even those unrelated to ECMO, such as hyperglycemia.
Hemorrhage was the most common complication,
particularly at the cannulation site. In general,
cannulation-site hemorrhage is less lethal, and easier to
manage than bleeding at other sites. Overall, there were
few fatal complications and only four patients died due
to hemorrhage (1.5%, Additional file 2). The
hemorrhagic complications of ECMO support are
known to significantly impact patient survival and
quality of life [
]. In this study, hemorrhage was
independently associated with increased in-hospital mortality.
Maintaining the balance between hemostasis and
anticoagulation is difficult, and it remains a major challenge
during ECMO [
]. Unfortunately, the ELSO
Registry did not include information about anticoagulation
management. Clinicians should assess patient risk
factors for ECMO-related hemorrhage, and actively take
steps to correct them. In selected cases, termination of
ECMO support may be required to prevent hemorrhage.
Fortunately, ECMO stabilzes platelet function and the
risk of hemorrhage is low in the early period of
]. Furthermore, there is a recent trend toward
conservative anticoagulation strategies to decrease
complications due to hemorrhage [
]. Considering the
reversibility of airflow obstruction in asthma, ECMO can
be safely used in these patients for a short period of
time. However, careful management is required to
balance the risks and benefits. The need for ECMO support
should be reassessed when hemorrhagic complications
are likely to be fatal.
This study had several limitations. First, we analyzed
data voluntarily submitted by various international
centers; these data may be susceptible to information bias,
reporting bias, and uncontrolled confounding factors.
Second, we defined patients with NFA as those with a
primary ICD-9 diagnosis code of asthma. This may limit
the applicability of these results to certain cases. Third,
the ABGA values following ECMO initiation were not
always present in this dataset, and as such their
improvement could not be assessed as a secondary
outcome. Furthermore, many of the baseline ventilator
settings in this dataset did not adhere to the generally
recommended criteria [
]. In these cases, refractory
airway obstruction and unstable blood gas profiles might
be related to suboptimal ventilator strategies. While this
registry may not be representative of all cases, the
strength of this study was that cases were extracted from
a relatively large, international dataset. The data are also
contemporary and reflect the current status of ECMO
use in NFA. A further strength of the study was that the
detailed complication profiles are present in the ELSO
data. Because asthma is a reversible disease, it is
important to know the complications associated with
therapeutic interventions. This analysis provides important
and current information to guide a rapid increase in the
use of ECMO in NFA.
The management of NFA remains a significant problem
in critical care. Mechanical ventilation of patients with
NFA is challenging, and high ventilator settings may
cause lung injury and hemodynamic instability
secondary to barotrauma and dynamic hyperinflation. As NFA
is ultimately reversible, clinicians should actively
consider ECMO to both provide adequate gas exchange and
prevent lung injury. In this study, ECMO provided full
respiratory support in patients with NFA, and its use
resulted in acceptable survival to hospital discharge.
However, ECMO-related complications are common. To
encourage the use of ECMO as a rescue therapy,
understanding and reducing ECMO-related complications
should be a priority. The use of ECMO to reduce
ventilator-induced lung injury may reduce overall NFA
mortality worldwide. Further clinical research into the
use of ECMO in this context is needed.
Additional file 1: Figure S1. This graph shows the increasing trend in
extracorporeal membrane oxygenation use in adults with near-fatal
asthma. (TIF 80 kb)
Additional file 2: Table S1. Complications. Table S2. Reason for
extracorporeal membrane oxygenation discontinuation and mortality.
(DOC 80 kb)
ABGA: Arterial blood gas analysis; ECMO: Extracorporeal membrane
oxygenation; ECPR: Extracorporeal cardiopulmonary resuscitation;
ELSO: Extracorporeal Life Support Organization; FiO2: Fraction of inspired
oxygen; ICD-9: International Classification of Diseases 9th edition; NFA:
Nearfatal asthma; PEEP: Positive end-expiratory pressure; PIP: Peak inspiratory
pressure; VV: Venovenous
We truly appreciate Peter Rycus, MPH. who had contributed in the
acquisition of data from Extracorporeal Life Support Organization (ELSO)
No funding to declare.
Availability of data and materials
Study concept and design: YHJ, CWH, KDH. Acquisition of data: PR. Analysis
and interpretation of data: YHJ, CWH. Writing of the manuscript: YHJ, CWH.
Critical revision of the manuscript: JD, CWH, KYS. Support for data collection:
KDH. Approval of final manuscript and agreement of submission: all authors.
Consent for publication
Ethics approval and consent to participate
The study was approved by the Institutional Review Board of Pusan National
University Yangsan Hospital (IRB no.05-2017-066). Informed consent was not
sought due to the retrospective nature of the study.
The authors declare that they have no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
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