Overall, 34,734 VA-ECMO patients were queried from the 2012-2021 ELSO database. Of those, 1,693 patients were later converted to different modes of ECMO, and thus excluded from analysis, resulting in 33,041 patients. 20,297 had complete mortality data, of which 12,327 were from 2018-2021 (Additional File 1). Table 1 summarizes the variables related to patient demographics, ECMO, and mortality. Among the patients with complete mortality data, 96% (n=19,389) had no stroke, 3% (n=659) developed ischemic strokes, 1% (n=287) developed hemorrhagic strokes, and 0.2% (n=38) developed both ischemic and hemorrhagic strokes during ECMO support. The median detection timing was 3.04 days for ischemic strokes and 3.79 days for hemorrhagic strokes since ECMO cannulation. The 90-day mortality was higher for patients with ischemic strokes than those without (65% vs 36% respectively, p<0.0001, c2 test). Similarly, the 90-day mortality was higher for patients with hemorrhagic strokes than those without (72% vs 37% respectively, p<0.0001, c2 test). Many ECMO-related variables were found to be significantly different between patients with ischemic or hemorrhagic stroke and those without (Table 1). Notably, patients who developed ischemic stroke experienced more on-ECMO complications, compared to those without, including longer duration of ECMO support (6.17 vs 4.75 days respectively, p<0.0001, t-test), more neurosurgical interventions (1% vs 0.07% respectively, p<0.0001, c2 test), and more cardiac arrhythmias (20% vs 11% respectively, p<0.0001, c2 test). This was similar to patients who developed hemorrhagic strokes, compared to those without, including longer duration of ECMO support (6.33 vs 4.79 days respectively, p<0.0001, t-test), more neurosurgical interventions (4% vs 0.04% respectively, p<0.0001, c2 test), and more gastrointestinal hemorrhage (9% vs 3% respectively, p<0.0001, c2 test).
Table 1: Patient demographics and ECMO variables for ECMO-associated ischemic stroke and hemorrhagic stroke
Variable
|
Ischemic
Stroke (n=659)
|
No Ischemic Stroke (n=19,638)
|
p
|
|
Hemorrhagic Stroke (n=287)
|
No Hemorrhagic Stroke (n=20,010)
|
p
|
Age (years)
|
58.1 (46.4-65.4)
|
57.5 (45.3-66.2)
|
0.61
|
|
57.9 (46.1-65.6)
|
57.5 (45.3-66.2)
|
0.82
|
Female
|
234 (36%)f
|
6,310 (32%)g
|
0.09
|
|
114 (40%)h
|
6,430 (32%)i
|
0.01
|
Total Center Volume
|
123 (56-234)
|
123 (55-225)
|
0.31
|
|
127 (61-237)
|
123 (55-225)
|
0.25
|
Year of ECMO
|
|
|
|
|
|
|
|
2012
|
20 (3%)
|
581 (3%)
|
0.35
|
|
10 (3%)
|
591 (3%)
|
0.17
|
2013
|
25 (4%)
|
718 (4%)
|
|
16 (6%)
|
727 (4%)
|
|
2014
|
27 (4%)
|
1,001 (5%)
|
|
12 (4%)
|
1,016 (5%)
|
|
2015
|
51 (8%)
|
1,352 (7%)
|
|
15 (5%)
|
1,388 (7%)
|
|
2016
|
55 (8%)
|
1,716 (9%)
|
|
21 (7%)
|
1,750 (9%)
|
|
2017
|
59 (9%)
|
2,365 (12%)
|
|
24 (8%)
|
2,400 (12%)
|
|
2018
|
100 (15%)
|
2,726 (14%)
|
|
34 (12%)
|
2,792 (14%)
|
|
2019
|
123 (19%)
|
3,249 (17%)
|
|
55 (19%)
|
3,317 (17%)
|
|
2020
|
96 (15%)
|
2,975 (15%)
|
|
51 (18%)
|
3,020 (15%)
|
|
2021
|
103 (16%)
|
2,955 (15%)
|
|
49 (17%)
|
3,009 (15%)
|
|
Pre-ECMO ABG
|
|
|
|
|
|
|
|
pH (2012-2016)a
|
7.25 (7.12-7.35)f
|
7.30 (7.19-7.39)g
|
0.002
|
|
7.25 (7.13-7.32)h
|
7.30 (7.19-7.39)i
|
0.004
|
pH (2017-2021)b
|
7.28 (7.17-7.37)f
|
7.30 (7.21-7.39)g
|
<0.001
|
|
7.29 (7.20-7.36)h
|
7.30 (7.21-7.39)i
|
0.04
|
PaO2 (2012-2016)a
|
95 (59-216)f
|
96 (64-197)g
|
0.35
|
|
97 (68-159)h
|
96 (64-197)i
|
0.32
|
PaO2 (2017-2021)b
|
100 (68-254)f
|
116 (74-232)g
|
0.63
|
|
107 (76-218)h
|
116 (74-233)i
|
0.25
|
ABG at 24 hours
|
|
|
|
|
|
|
|
pH (2012-2017)c
|
7.42 (7.38-7.45)f
|
7.42 (7.38-7.47)g
|
0.50
|
|
7.41 (7.36-7.45)h
|
7.42 (7.38-7.47)i
|
0.18
|
pH (2018-2021)d
|
7.43 (7.37-7.47)f
|
7.43 (7.38-7.47)g
|
0.29
|
|
7.43 (7.39-7.48)h
|
7.43 (7.38-7.47)i
|
0.09
|
PaO2 (2012-2017)c
|
149 (92-254)f
|
143 (94-238)g
|
0.62
|
|
157 (91-299)h
|
143 (94-238)i
|
0.15
|
PaO2 (2018-2021)d
|
132 (88-270)f
|
134 (91-222)g
|
0.08
|
|
129 (86-207))h
|
134 (91-224)i
|
0.81
|
Days on ECMO Support
|
6.17 (3.71-10.04)
|
4.75 (2.71-7.67)
|
<0.001
|
|
6.33 (3.71-10.81)
|
4.79 (2.71-7.71)
|
<0.001
|
Timing of Stroke (days)
(2018-2021)
|
3.04 (1.29-6.29)f
|
N/A
|
N/A
|
|
3.79 (1.25-6.88)
|
N/A
|
N/A
|
Mortality
|
|
|
|
|
|
|
|
90-day Mortality
|
427 (65%)
|
7,123 (36%)
|
<0.001
|
|
206 (72%)
|
7,344 (37%)
|
<0.001
|
30-day Mortality
|
411 (62%)
|
6,339 (32%)
|
<0.001
|
|
195 (68%)
|
6,555 (33%)
|
<0.001
|
ECMO Complications
|
|
|
|
Cardiac Arrhythmia
|
129 (20%)
|
2,112 (11%)
|
<0.001
|
|
52 (18%)
|
2,189 (11%)
|
<0.001
|
CPB
|
166 (25%)
|
4,172 (21%)
|
0.02
|
|
54 (19%)
|
4,284 (21%)
|
0.32
|
GI Hemorrhage
|
48 (7%)
|
601 (3%)
|
<0.001
|
|
27 (9%)
|
622 (3%)
|
<0.001
|
Hemolysis (Mod-Sev)
|
22 (3%)
|
261 (1%)
|
<0.001
|
|
7 (2%)
|
276 (1%)
|
0.21
|
Neurosurgical Int
(2018-2021)e
|
5 (1%)
|
8 (0.07%)
|
<0.001
|
|
8 (4%)
|
5 (0.04%)
|
<0.001
|
Pump Failure
|
7 (1%)
|
100 (0.5%)
|
0.10
|
|
4 (1%)
|
103 (0.5%)
|
0.10
|
RRT
|
237 (36%)
|
4,509 (23%)
|
<0.001
|
|
94 (33%)
|
4,652 (23%)
|
<0.001
|
All data are presented as n (%) for categorical variables, and median (interquartile range) for continuous variables.
Abbreviations: a: “worst” values; b: “closest” value to ECMO start time; c: “best” values; d: “closest” value to 24-hours of ECMO; e: Used sample size of patients in years 2018-2021 as denominator; f: Missing values for variables in the “Ischemic Stroke” group: Sex (n=3), pre-ECMO pH (n=175), pre-ECMO PaO2 (n=188), 24-hour-pH (n=43), 24-hour-PaO2 (n=53), timing of stroke (n=9); g: Missing values for variables in the “No Ischemic Stroke” group: Sex (n=176), pre-EMCO pH (n=4,995), pre-EMCO PaO2 (n=5,584), 24-hour-pH (n=2,644), 24-hour-PaO2 (n=3,247); h: Missing values for variables in the “Hemorrhagic Stroke” group: pH (n=65), PaO2 (n=70), 24h-pH (n=30), 24h-PaO2 (n=34); i: Missing values for variables in the “No Hemorrhagic Stroke” group: Sex (n=179), pH (n=5,105), PaO2 (n=5,702), 24h-pH (n=2,657), 24h-PaO2 (n=3,266); ABG: arterial blood gas; CPB: cardiopulmonary bypass; ECMO: extracorporeal membrane oxygenation; GI: gastrointestinal; Int: intervention; Mod: moderate; N/A: not applicable; RRT: renal replacement therapy; Sev: severe
Trend of VA-ECMO associated ischemic stroke, hemorrhagic stroke, and mortality
Fig. 1a shows the trend of VA-ECMO cases submitted to the ELSO registry database. The number of cases has generally increased during the past decade, from 1,034 cases in 2012 to 4,737 cases in 2021, corresponding to a roughly 1.18 times increase per year (p<0.0001, Poisson regression). Fig. 1b depicts the temporal trends of the reported incidence of ischemic and hemorrhagic strokes. The incidence of hemorrhagic stroke did not change overall between 2012 and 2021 (p=0.41, Cochran-Armitage). However, the incidence of ischemic stroke increased (p=0.002, Cochran-Armitage), with the number of cases increasing roughly 1.21 times per year (p<0.0001, Poisson regression). Fig. 1c and Additional File 2 illustrate the temporal trends of 90-day and 30-day mortality, respectively. The overall 90-day mortality declined (p<0.0001, Cochran-Armitage) by 1.78% per year between 2012 and 2021 (p=0.0003, Poisson regression). Similarly, 90-day mortality of patients without strokes also declined (p<0.0001, Cochran-Armitage) by 2.02% per year (p<0.0001, Poisson regression). In contrast, 90-day mortality of patients with hemorrhagic stroke did not significantly change over time (p=0.85). While the 90-day mortality of patients with ischemic stroke showed a potential trend towards increased mortality over time, this did not reach statistical significance (p=0.053).
Association of ELSO center volume and incidence of ischemic stroke, hemorrhagic stroke, or mortality
Fig. 2 and Additional File 3 demonstrate the associations between the total case volume of each ELSO center and its incidence of strokes or mortality. The total case volumes of each center ranged from 1 to 646. Univariable logistic regression revealed that for each additional 100 cases of VA-ECMO that an ELSO center has experienced, the incidences of strokes increased by 3.93% for ischemic stroke (p=0.022), 5.83% for hemorrhagic stroke (p=0.022), and 3.67% for any strokes (p=0.011). In contrast, the 90-day mortality decreased by 9.07% (p<0.0001) per each additional 100 cases of VA-ECMO at an ELSO center. This statistical significance for total center volume became even greater in the multivariable logistic regression models for 90-day and 30-day mortality (Table 2, Additional File 4).
Table 2: Logistic Regression of Variables Associated with 90-day Mortality^
|
Odds ratio
|
95% CI
|
p-value
|
Age
|
1.04
|
[1.03-1.04]
|
<1×10-4
|
Female
|
1.07
|
[0.96-1.19]
|
0.20
|
Total Center Volume
|
0.998
|
[0.997-0.999]
|
<1×10-4
|
Pre-ECMO ABG
|
pH
|
2.19×10-10
|
[9.79×10-24-3.01×103]
|
0.15
|
PaO2
|
1.00
|
[0.9991-1.000]
|
0.36
|
ABG at 24 hours of ECMO support
|
pH
|
1.81×10-10
|
[1.51×10-23-1.34×103]
|
0.14
|
PaO2
|
1.001
|
[1.001-1.002]
|
<1×10-4
|
Pre-ECMO pH × 24h-pHa
|
17.69
|
[0.30-1.12×103]
|
0.17
|
Pre-ECMO PaO2 × 24h-PaO2b
|
1.00
|
[1.00-1.00]
|
0.54
|
ECMO Duration (days)
|
1.02
|
[1.01-1.03]
|
<1×10-4
|
ECMO Complications
|
Cardiac Arrhythmia
|
1.08
|
[0.93-1.25]
|
0.30
|
Cardiopulmonary Bypass
|
1.04
|
|
0.50
|
Gastrointestinal Hemorrhage
|
1.71
|
[1.32-2.22]
|
<1×10-4
|
Hemolysis (Moderate-Severe)
|
1.37
|
[1.01-1.84]
|
0.04
|
Hemorrhagic Stroke
|
3.99
|
[2.60-6.28]
|
<1×10-4
|
Ischemic Stroke
|
3.29
|
[2.52-4.33]
|
<1×10-4
|
Neurosurgical Intervention
|
1.94
|
[0.51-8.14]
|
0.33
|
Pump Failure
|
1.15
|
[0.57-2.30]
|
0.69
|
Renal Replacement Therapy
|
2.02
|
[1.81-2.26]
|
<1×10-4
|
Ischemic Stroke × Hemorrhagic Strokec
|
0.17
|
[0.06-0.47]
|
5.76×10-4
|
Abbreviations: ^:12,327 cases with complete mortality data from 2018-2021; a: interaction term between pre-ECMO pH and 24 hour pH; b: interaction term between pre-ECMO PaO2 and 24 hour PaO2; c: interaction term between ischemic stroke and hemorrhagic stroke; ABG: arterial blood gas; CI: confidence interval; ECMO: extracorporeal membrane oxygenation
Ischemic and hemorrhage stroke as risk factors for mortality
Fig. 3 and Additional File 5 show the overall survival curves and hazard functions of VA-ECMO patients with or without strokes. Median 90-day survival times were significantly different between patients who developed strokes and those who did not: 8.54 vs 67.17 days in the presence or absence of ischemic stroke respectively (p<0.0001, log-rank test); 4.00 vs 66.20 days in the presence or absence of hemorrhagic stroke respectively (p<0.0001, log-rank test); and 7.00 vs 68.80 days in the presence or absence of any stroke respectively (p<0.0001, log-rank test).
The multivariable logistic regression models for 90-day and 30-day mortality revealed numerous, significantly associated variables (Table 2, Additional File 4). In particular, the odds of 90-day mortality were higher for patients with ischemic stroke than those without (odds ratio=3.29, p<0.0001, logistic regression). This was also similar to the case of 90-day mortality of patients with hemorrhagic stroke compared to those without (odds ratio=3.99, p<0.0001, logistic regression).