To the Editor:
For patients with severe acute respiratory distress syndrome (ARDS), receipt of extracorporeal
membrane oxygenation (ECMO) (1) may improve survival. During the coronavirus disease
(COVID-19) pandemic, the number of patients with COVID-19 referred for ECMO has exceeded
the capacity of specialized centers to provide ECMO (2, 3). The outcomes of patients
with COVID-19 who are eligible to receive ECMO but do not because of limited health
system capacity have not been reported.
Methods
We analyzed prospectively collected clinical data from all consecutive patients with
severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection who were referred
for ECMO to a single center between January 1, 2021, and August 31, 2021. For all
referrals, a standardized case report form was used to record patient characteristics
(as listed in Table 1) and the result of a multidisciplinary committee’s determination
of whether the patient was eligible for ECMO.
Table 1.
Patient Characteristics at the Time of Extracorporeal Membrane Oxygenation Referral
and Clinical Outcomes
Characteristic
Overall (N = 90)
Capacity for ECMO (n = 35)
No Capacity for ECMO (n = 55)
P Value
Age, yr
40.0 (34.0–48.0)
40.0 (32.0–47.0)
41.0 (35.0–51.0)
0.07
Sex, F
25 (27.8)
10 (28.6)
15 (27.8)
0.89
Body mass index, kg/m2
35.0 (30.0–39.0)
35.0 (31.0–40.0)
34.0 (32.0–38.0)
0.40
Comorbidities
Hypertension
22 (24.4)
10 (28.6)
12 (21.8)
0.47
Diabetes mellitus
16 (17.8)
4 (11.4)
12 (22.2)
0.27
Hyperlipidemia
3 (3.3)
0 (0.0)
3 (5.5)
0.28
Asthma
5 (5.6)
5 (14.3)
0 (0.0)
0.004
Obstructive sleep apnea
3 (3.3)
2 (5.7)
1 (1.8)
0.32
Hypothyroidism
3 (3.3)
2 (5.7)
1 (1.8)
0.32
Other*
8 (8.9)
6 (17.1)
6 (10.9)
0.53
Pregnant or postpartum
4 (4.4)
2 (5.7)
2 (3.6)
0.64
Vasopressors
37 (41.1)
11 (31.4)
26 (47.3)
0.14
Acute kidney injury
24 (26.7)
9 (25.7)
15 (27.3)
0.87
Renal replacement therapy
7 (8.1)
3 (8.6)
4 (7.8)
>0.99
Duration of mechanical ventilation, d
2.0 (1.0–3.0)
1.0 (1.0–3.0)
2.0 (1.0–5.0)
0.03
Ventilator settings
Mode
0.63
Volume control
74 (92.5)
30 (91.9)
44 (93.6)
—
Pressure control
5 (6.3)
2 (6.1)
3 (6.4)
—
Airway pressure release ventilation
1 (1.3)
1 (3.0)
0 (0.0)
—
Respiratory rate
28.0 (24.0–32.0)
30.0 (26.0–32.0)
28.0 (22.0–32.0)
0.29
Vt, ml
410.0 (360.0–450.0)
400.0 (350.0–450.0)
430.0 (385.0–460.0)
0.20
Plateau pressure, cm H2O
33.0 (28.0–38.0)
34.5 (32.0–38.0)
29.0 (22.0–36.5)
0.08
Fi
O2
1.0 (1.0–1.0)
1.0 (1.0–1.0)
1.0 (1.0–1.0)
0.13
Positive end-expiratory pressure, cm H2O
14.0 (12.0–16.0)
15.5 (12.0–18.0)
14.0 (12.0–15.0)
0.07
Arterial blood gas
pH
7.31 (7.24–7.38)
7.30 (7.23–7.35)
7.31 (7.24–7.38)
0.62
Partial pressure of carbon dioxide, mm Hg
57.5 (46.0–68.5)
57.0 (45.0–66.0)
60.0 (47.0–69.0)
0.69
Partial pressure of oxygen, mm Hg
63.0 (54.0–72.0)
64.0 (57.0–72.0)
62.0 (53.0–70.0)
0.35
Adjunctive therapies
Neuromuscular blocking agent
81 (96.4)
34 (97.1)
47 (95.9)
>0.99
Prone positioning
46 (55.4)
20 (58.8)
26 (53.1)
0.60
Inhaled pulmonary vasodilators
12 (14.3)
8 (22.9)
4 (8.2)
0.11
Miles from referring to receiving hospital
165.0 (100.0–243.0)
163.0 (81.0–211.0)
171.0 (105.0–278.0)
0.28
Outcome
Died before hospital discharge
†
64 (71.1)
15 (42.9)
49 (89.1)
<0.001
Survived to hospital discharge
‡
23 (25.6)
18 (51.4)
5 (9.1)
<0.001
Remains alive in the hospital
§
3 (3.3)
2 (5.7)
1 (1.8)
0.07
Definition of abbreviations: ECMO = extracorporeal membrane oxygenation; IQR = interquartile
range.
Data are expressed as median (IQR) or frequency (percentage) unless otherwise indicated.
The Wilcoxon rank-sum test, Fisher’s exact test, or the Kruskal-Wallis test was used
to examine differences between groups when appropriate. Missingness in observations:
mode (n = 10), body mass index (n = 7), ventilator days (n = 2), receipt of renal
replacement therapy (n = 4), ventilator mode (n = 10), respiratory rate (n = 19),
Vt (n = 18), positive end-expiratory pressure (n = 10), pH (n = 6), PaCO2
(n = 8), PaO2
(n = 4), receipt of prone positioning (n = 7), receipt of neuromuscular blocking agent
(n = 6), and receipt of inhaled pulmonary vasodilator (n = 6).
*
Other comorbidities included (n = 1 for each) Asperger syndrome, polycystic ovarian
syndrome, and thyroid cancer status after thyroidectomy in the capacity for ECMO group
and chronic atrial fibrillation, congestive heart failure, osteoporosis, seizures,
and sickle cell disease in the no capacity for ECMO group.
†
Median time from referral for ECMO to death was 19.0 days (IQR, 7.0–47.0) among patients
for whom the capacity to provide ECMO was available and 7.0 days (IQR, 4.0–12.0) among
patients for whom capacity to provide ECMO was unavailable.
‡
Median time from referral for ECMO to discharge from the hospital alive was 36.0 days
(IQR, 0.0–72.0) among patients for whom the capacity to provide ECMO was available
and 32.0 days (IQR, 28.0–43.0) among patients for whom capacity to provide ECMO was
unavailable.
§
Median time from referral for ECMO to last follow-up among patients who remained alive
in the hospital was 40.0 days (IQR, 30.0–55.0) among patients for whom the capacity
to provide ECMO was available and 50.0 days (IQR, 50.0–50.0) among patients for whom
capacity to provide ECMO was unavailable.
Patients were considered medically eligible for ECMO 1) if criteria for sufficiently
severe ARDS, as defined by the EOLIA (Extracorporeal Membrane Oxygenation for Severe
Acute Respiratory Distress Syndrome) inclusion criteria, were present (1); 2) in the
absence of the absolute contraindications of age greater than 60 years, body mass
index greater than 55 kg/m2, duration of mechanical ventilation greater than 7 days,
irreversible neurologic injury, chronic lung disease, active malignancy, or advanced
multiple organ dysfunction; and 3) if they had three or fewer of the relative contraindications
of age greater than 50 years, body mass index greater than 45 kg/m2, presence of comorbidities,
duration of mechanical ventilation greater than 4 days, presence of acute kidney injury,
receipt of vasopressors, duration of hospitalization greater than 14 days, or greater
than 4 weeks since COVID-19 diagnosis (3, 4). Contraindications used to determine
eligibility were selected by the committee on the basis of published guidance (3),
published data on factors associated with death during ECMO for COVID-19 (4), and
investigator experience.
After a patient was determined to be medically eligible to receive ECMO, a separate
systematic assessment of the health system’s resources was performed to provide ECMO
with regard to equipment, personnel, and ICU bed availability. When health system
resources were not available, the patient was not transferred to an ECMO center and
did not receive ECMO. When health system resources were available, the patient was
transferred to an ECMO center. No waiting list was maintained, given the short eligibility
window for ECMO after tracheal intubation and the long average duration of ECMO support
for patients using existing ECMO resources. For patients transferred to the ECMO center
receiving the referral, the ECMO team performed cannulation at the referring facility
and transported patients while receiving ECMO. For patients who were transferred to
other regional ECMO centers, cannulation was performed after arrival at the receiving
facility.
All patients were followed until the time of death or hospital discharge by review
of electronic health records or by telephone. Among patients determined to be eligible
for ECMO, we compared those for whom health system capacity permitted transfer to
receive ECMO at a specialized center with those for whom health system capacity did
not permit transfer to receive ECMO with regard to the primary outcome of all-cause
in-hospital mortality using Cox proportional hazards regression analysis, adjusting
for patient age, the presence of acute kidney injury, and receipt of vasopressors.
To determine whether the relationship between the availability of resources to provide
ECMO and mortality was modified by changing COVID-19 outcomes over time, we tested
for interactions between ECMO availability and the date of each ECMO consult. To examine
whether hospital strain modified the relationship between the availability of resources
to provide ECMO and mortality, we tested for interactions between ECMO availability
and hospital strain, as represented by the 2-week average of COVID-19 hospitalizations
and deaths in the region over the study period (5).
Results
Among the 240 patients with COVID-19 referred for ECMO, 26 patients (10.8%) did not
complete the referral evaluation, 44 (18.3%) did not meet criteria for severity of
lung injury, 80 (33.3%) had one or more absolute contraindications or more than three
relative contraindications, and 90 patients (37.5%) were determined to be medically
eligible to receive ECMO and were included in this study. The median age of patients
was 40 years (interquartile range, 34–48), and 25 (27.8%) were female.
For 35 patients (38.9%), the health system capacity to provide ECMO at a specialized
center was available. Of these, 24 patients were cannulated at the referring hospital
and transferred to the ECMO center that received the referral, and 11 patients were
transferred to another regional ECMO center, of whom 8 were cannulated after arrival
and 3 died or developed a contraindication to ECMO after transfer but before cannulation.
For 55 patients (61.1%), the health system capacity to provide ECMO at a specialized
center was unavailable; none were transferred to an ECMO center, and none received
ECMO. Characteristics at the time of referral were similar between patients for whom
health system capacity permitted transfer to receive ECMO at a specialized center
and patients for whom health system capacity did not permit transfer to receive ECMO
(Table 1).
Death before hospital discharge occurred in 15 (42.9%) of the 35 patients for whom
health system capacity permitted transfer to receive ECMO at a specialized center
compared with 49 (89.1%) of the 55 patients for whom health system capacity did not
permit transfer to receive ECMO (adjusted hazard ratio, 0.23; 95% confidence interval,
0.12–0.43; P < 0.001) (Figure 1).
Figure 1.
Cumulative proportion of patients who died before hospital discharge. The cumulative
proportion of patients who died before hospital discharge is displayed for the 35
patients for whom the health system capacity to provide extracorporeal membrane oxygenation
(ECMO) at a specialized center was available (blue) and the 55 patients for whom the
health system capacity to provide ECMO was unavailable (red). Groups were compared
using Cox proportional hazards regression, adjusting for age, acute kidney injury,
and receipt of vasopressors. CI = confidence interval.
The effect on mortality of health system capacity to provide ECMO was not modified
by time as measured by date of ECMO consult (P value for interaction, 0.80) or by
hospital strain as measured by the 2-week average number of hospitalizations or deaths
in the state over the study period (P values for interaction, 0.87 and 0.99, respectively).
The results were similar in sensitivity analyses excluding days with multiple consults.
Discussion
In this cohort of adults with COVID-19, nearly 90% of patients who were eligible for
ECMO but did not receive it because of limited health system capacity died before
hospital discharge, despite young age and limited comorbidities. The benefits of a
life-support therapy can be difficult to estimate. Clinical trials of providing or
withholding a life-support therapy may be infeasible, unethical, or limited by selection
bias and crossover (1, 6). Periods when resource limitations determine which patients
receive life support therapy may act as a natural experiment and provide unique information
on the effect of the life support therapies on outcomes. The large difference in survival
associated with the availability of health system capacity to provide ECMO at a specialized
center in our study suggests that the benefit of ECMO for some patients with severe
ARDS because of COVID-19 may be greater than previously understood (1).
Like prior studies (6), this study cannot differentiate between the potential beneficial
effects of receiving ECMO and the effects of receiving care at a specialized ECMO
center. Unlike prior studies, however, no patients in this study who were transferred
to a specialized center survived without receiving ECMO. Moreover, 3 of the 11 patients
for whom transfer to a specialized center without cannulation was attempted died of
complications arising during transfer. Together, these suggest that the observed difference
in outcomes may be more likely to be attributable to receipt of ECMO than to transfer
to a specialized center without receiving ECMO. Regardless of whether ECMO itself
or care at a specialized center is primary, the observations that 1) lack of health
system capacity prevented more than half of eligible patients with COVID-19 from receiving
ECMO at a specialized center and 2) the risk of death among those who received ECMO
at a specialized center was approximately half that of those who did not may have
implications for resource allocation decisions by health systems and policy makers.
Additional limitations of this study include its small sample size, conduct in one
ECMO referral region, nonrandomized group allocation, and uncertainty of the final
outcome for three patients who remain alive and in the hospital.
In conclusion, among patients eligible for ECMO in one referral region, the health
system capacity to provide ECMO was available for less than half of patients. Mortality
was 90% when the health system capacity to provide ECMO was unavailable, compared
with 43% when capacity was available, despite both groups having young age and limited
comorbidities. These findings suggest that ECMO provides a significant mortality benefit
in the treatment of COVID-19 and that the inability to provide ECMO to all eligible
patients because of limited healthcare system resources may be causing potentially
preventable deaths.