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TRANSCRIPT
Online Data Supplement
Title: The ENCOURAGE mortality-risk score and
analysis of long-term outcomes after VA-ECMO for acute
myocardial infarction with cardiogenic shock
Grégoire Muller, MD; Erwan Flecher, MD, PhD; Guillaume Lebreton, MD, PhD;
Charles-Edouard Luyt, MD, PhD; Jean-Louis Trouillet, MD; Nicolas Bréchot, MD,
PhD; Matthieu Schmidt, MD, PhD; Ciro Mastroianni, MD, PhD; Jean Chastre, MD;
Pascal Leprince, MD, PhD; Amedeo Anselmi, MD and Alain Combes, MD, PhD*
From the Medical–Surgical Intensive Care Unit (G.M., C.-E.L., J.-L.T, N.B., J.C., A.C.), and
Cardiac Surgery Department (G.L., C.M., P.L.), INSERM UMRS 1166 iCAN, Institute of
Cardiometabolism and Nutrition, Hôpital de la Pitié–Salpêtrière, Assistance Publique–
Hôpitaux de Paris, Université Pierre et Marie Curie, Paris 6, 47, bd de l’Hôpital, 75651 Paris
Cedex 13, France. Thoracic and Cardio-Vascular Surgery Department (E.F., A.A.), Centre
Cardio-Pneumologique, Hôpital Universitaire Pontchaillou, 2, rue Henri-Le-Guilloux, 35000
Rennes, France.
*Corresponding author. Tel: +331.42.16.38.16; Fax: +33 1.42.16.38.17;
e-mail: [email protected]
Methods
Data collected at intensive care unit (ICU) admission
The following information was recorded retrospectively: age; sex; height, weight and body
mass index; underlying comorbidities; Simplified Acute Physiology Score II (SAPSII);[1]
Sepsis-related Organ Failure Assessment (SOFA) score [2]; mobile extracorporeal membrane
oxygenation (ECMO)-team patient retrieval; pre-venoarterial (VA)-ECMO cardiac arrest;
pre-ECMO EKG; pre-ECMO thrombolysis for acute myocardial infarction (AMI); AMI
location; ICU admission- and percutaneous coronary intervention (PCI)-to-ECMO–
implantation times; ECMO initiation under cardiopulmonary resuscitation (CPR); use of
intra-aortic balloon pump (IABP); pre-ECMO mechanical ventilation (MV); PCI attempts
and successes, numbers of coronary vessels dilated and stents implanted; Glasgow Coma
Score (GCS), the last value recorded when the patient was assessable (before intubation or
when the patient was still awake); hemodynamic variables pre- and post-ECMO initiation;
blood-gas analyses; serum lactate, hemoglobin, bicarbonate, creatininemia and troponin Ic
levels; platelet and leukocyte counts; and prothrombin activity.
ECMO implantation and management
The detailed surgical procedure for femorofemoral VA-ECMO placement was described
previously [3-6]. Briefly, all procedures were performed by trained cardiovascular surgeons
at the bedside because of patients’ hemodynamic instability. Femoral vessels were cannulated
after limited cut-down using the Seldinger technique and an additional 7–10 Fr catheter was
systematically inserted distally into the femoral artery to prevent severe leg ischemia. For
highly unstable patients diagnosed with refractory cardiogenic shock at other hospitals, our
institution’s Mobile Circulatory Assistance Unit traveled rapidly to primary-care hospitals
with a portable ECMO system, installed the device before refractory multiorgan failure or
cardiac arrest took hold and then transported the patient to our tertiary-care ICUs [7]. The
detailed management of VA-ECMO–treated patients was described previously [3-5]. Briefly,
pump speed was adjusted to obtain a blood flow of 3.5–5 L/min. Intravenous unfractionated
heparin was given to maintain the activated partial thromboplastin time at 1.5–2-times
normal. ECMO-associated complications were carefully monitored: cannulation-related
injuries, like leg ischemia, femoral hemorrhage due to arterial laceration, cannula insertion-
site infection, hemolysis or other technical problems. Patients classified as developing
pulmonary edema under ECMO were those with overt pulmonary edema, defined as marked
progression of alveolar consolidation on chest X-ray after ECMO initiation or expelling
abundant pink frothy sputum through the intubation tube. When a pulsatile arterial waveform
was maintained for at least 24 hours, an ECMO-weaning trial was undertaken, as previously
described [3].
Health-related quality of life (HRQOL) and psychological assessment
During a telephone interview, in September 2013, after the purpose and objectives of the
study were explained, survivors self-assessed their HRQOL psychological status by
completing the French version of the Medical Outcome Study Short-Form 36 (SF-36)
questionnaire [8-10]. This standardized, widely used questionnaire has been validated for the
French population [8]. Its 36 items combined evaluate eight domains (physical functioning,
role-physical, bodily pain, general health, vitality, social functioning, role-emotional and
mental health). The aggregate physical and mental component scores were then computed as
recommended [8]. Our patients’ mean SF-36 levels were compared with those obtained for
French age- and sex-matched controls with no adverse health conditions (or minor, non-acute
conditions) [8], 424 AMI survivors evaluated 4 years post-event [11], 1-year survivors after
non-ST–segment elevation acute coronary syndromes included in the early interventional
strategy of the Randomized Intervention Trial of unstable Angina-3 (RITA-3) [12],
venovenous (VV)-ECMO–treated severe acute respiratory distress (ARDS) survivors [10]
and ECMO-rescued severe myocarditis patients [5].
Anxiety and depression symptoms were also analyzed, using the Hospital Anxiety and
Depression (HAD) Scale [13], which contains 14 questions: seven to assess anxiety and
seven for depression (respectively, HAD-A/-D), using a four-point Likert scale (range, 0–3)
giving a possible score of 0 (none) to 21 (severe) for each subscale. Subscale scores ≥8/21
indicated clinically significant anxiety or depression symptoms, whereas subscale scores of
≥11/21 suggested severe psychological distress [13]. Our patients’ scores were compared to
those of VV-ECMO–treated severe ARDS survivors [10], VA-ECMO–rescued severe
myocarditis patients[5] and 335 post-AMI patients [14]. Finally, post-traumatic stress
disorder (PTSD)-related symptoms were assessed with the Impact of Event Scale (IES) [15],
consisting of 15 questions divided into two subscales: intrusion (seven items) and avoidance
(eight items). The total score ranges from 0 (no symptoms) to 75 (severe symptoms). In
agreement with previous reports, patients with a total IES score ≥30/75 points were
considered at high risk for PTSD [5]. Our patients’ IES scores were compared with those of
VV-ECMO–treated severe ARDS survivors [10], VA-ECMO–rescued severe myocarditis
patients [5], 268 car-accident survivors[16] and survivors of acute coronary syndromes [17].
Ethics
In accordance with the ethical standards of our hospitals’ institutional review boards
(Committees for the Protection of Human Subjects), informed consent for demographic,
physiological and hospital-outcome data analyses was not obtained because this observational
study did not modify existing diagnostic or therapeutic strategies. Survivors gave oral consent
to participate in the telephone interview, conducted by the same investigator, who asked the
questionnaire questions in the same order. The protocol for long-term evaluation with
quality-of-life questionnaires was submitted to CPP Ile de France II under the title
“Evaluation à long terme des séquelles fonctionnelles des survivants après un séjour en
réanimation”.
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Table S1. Patients’ characteristics at ECMO initiation according to ICU-survival status
Characteristic All patients
(n = 138)
Survivors
(n = 65)
Non-survivors
(n = 73)
P-
value
Height, cm 175 (167–180) 175 (169–180) 173 (165–178) 0.27
Weight, kg 80 (70–89) 80 (70–84) 80 (70–90) 0.57
Body mass index, kg/m2 26 (24–29) 25 (24–28) 26 (24–30) 0.06
Co-morbidity
Diabetes 23 (17) 10 (15) 13 (18) 0.68
Active smoking 59 (43) 33 (51) 26 (36) 0.08
Dyslipidemia 38 (28) 17 (26) 21 (29) 0.70
Hypertension 38 (28) 19 (29) 19 (26) 0.71
Ischemic cardiomyopathy 17 (12) 8 (12) 9 (12) 0.99
Peripheral arterial disease 10 (7) 4 (6) 6 (8) 0.61
SOFA score 11 (8–15) 10 (7–12) 13 (9–16) 0.001
Respiratory SOFA 2 (1–3) 2 (1–3) 3 (1–3) 0.54
Liver SOFA 0 (0–1) 0 (0–1) 0 (0–1) 0.69
Platelet SOFA 1 (0–2) 1 (0–1) 1 (0–2) 0.90
Glasgow SOFA 3 (1–4) 2 (1–4) 4 (1–4) 0.003
Renal SOFA 2 (0–4) 1 (0–3) 2 (1–4) <0.001
Pre-ECMO EKG
STEMI 123 (89) 60 (92) 63 (86)
Non-STEMI 10 (7) 4 (6) 5 (7)
LBBB 5 (4) 1 (2) 4 (5)
Pre-ECMO LVEF 20 (15–25) 20 (15–25) 20 (15–25) 0.99
Door-to-balloon time, min 200 (120–360) 180 (120–293) 240 (130–360) 0.17
Patients with attempted PCI 112 (81) 54 (83) 58 (80) 0.59
Pre-PCI TIMI 0 (0–0) 0 (0–0) 0 (0–1) 0.92
Patients with successful PTCA 99 (72) 48 (74) 51 (70) 0.60
Number of vessels dilated 1 (1–2) 1 (1–1) 1 (1–2) 0.53
Number of stents implanted 1 (0–2) 1 (1–2) 1 (0–2) 0.97
Post-PCI TIMI 3 (1–3) 3 (1–3) 3 (2–3) 0.94
ECMO pre-PCI 14 (10) 8 (12) 6 (8) 0.46
ECMO to PCI, hours 2 (1–6) 1 (1–5) 4 (1–24) 0.99
ECMO post-PCI 124 (90) 57 (88) 67 (92) 0.66
PCI to ECMO, hours 12 (4–24) 11 (3–24) 12 (5–24) 0.88
IABP associated with ECMO 96 (70) 46 (71) 50 (69) 0.77
Pre-ECMO IABP 76 (55) 37 (57) 39 (53) 0.91
Antegrade limb perfusion 132 (96) 64 (98) 68 (93) 0.92
Pre-ECMO hemodynamic parametersa
SAP, mmHg 84 (70–100) 88 (69–100) 83 (74–100) 0.70
DAP, mmHg 54 (40–60) 60 (44–65) 50 (40–60) 0.45
MAP, mmHg 64 (53–73) 67 (54–75) 63 (51–75) 0.72
Pulse pressure, mmHg 32 (20–40) 31 (20–40) 32 (20–45) 0.32
Heart rate, /min 100 (80–120) 103 (87–120) 100 (67–120) 0.30
Post-ECMO hemodynamic parameters
SAP, mmHg 110 (91–128) 112 (95–128) 109 (90–129) 0.53
DAP, mmHg 67 (55–82) 66 (55–81) 67 (56–82) 0.86
MAP, mmHg 83 (71–96) 81 (74–101) 85 (67–94) 0.66
Pulse pressure, mmHg 38 (24–57) 41 (26–57) 35 (23–55) 0.27
Heart rate, /min 94 (79–109) 89 (79–105) 96 (80–112) 0.30
Respiratory rate, /min 16 (14–21) 16 (14–22) 17 (13–20) 0.83
Inotropic scoreb 52 (26–145) 34 (14–65) 78 (33–200) 0.001
Biological parameters
pH 7.32 (7.22–7.45) 7.39 (7.29–7.47) 7.27 (7.15–7. 42) <0.001
HCO3–, mmol/L 18 (13–23) 21 (16–24) 16 (11–21) <0.001
Arterial lactate, mmol/L 4.1 (2.1–8.2) 2.8 (1.7–6.1) 6.0 (3.0–11.0) <0.001
Bilirubin, mmol/L 14 (9–25) 15 (9–22) 14 (8–25) 0.69
Prothrombin activity, % 57 (40–69) 61 (50–79) 48 (32–64) <0.001
Creatininemia, µmol/L 148 (100–237) 118 (87–199) 165 (126–248) 0.002
Hemoglobin, g/dL 10.2 (8.7–12.2) 10.2 (9.0–12.2) 10.2 (8.6–12.2) 0.72
Hematocrit, % 0.31 (0.28–0.39) 0.31 (0.28–0.38) 0.32 (0.28–0.40) 0.78
Platelet, G/L 166 (103–244) 159 (112–245) 170 (101–242) 0.54
Troponin Ic, µg/L 45 (10–188) 31 (4–104) 67 (19–294) 0.02
Values are expressed as medians (25th to 75th percentile). STEMI, ST-elevation myocardial
infarction; non-STEMI, non-ST-elevation myocardial infarction; LBBB, left bundle-branch
block; LVEF, left ventricle ejection fraction; TIMI, thrombolysis in myocardial infarction;
PTCA, percutaneous transluminal coronary angioplasty; SAP, DAP and MAP, systolic,
diastolic and mean arterial blood pressure, respectively.
aValues were obtained for 76/138 patients (33 survivors and 43 non-survivors).
bInotropic score, expressed in µg/kg/min, was calculated as follows: 100 epinephrine + 100
norepinephrine + dobutamine.
Table S2. ENCOURAGE (PrEdictioN of Cardiogenic shock OUtcome foR AMI patients
salvaGed by VA-ECMO) mortality-risk score generation: transformation of continuous
variables into categorical variables
Variable Quartile
(25th, 50th, 75th percentiles) 1 2 3 4
Age (46, 55, 63) 56 50 50 32
Body mass index (24, 26, 29) 60 50 38 38
SAPSII (48, 66, 82) 72 39 54 28
Glasgow Coma Score (3, 6, 14) 36 45 64 49
Creatininemia (100, 148, 237) 74 43 32 40
Lactate (2.1, 4.1, 8.2) 77 51 45 21
Prothrombin activity (40, 57, 69) 26 41 52 71
Troponin Ic (10, 45, 188) 56 54 48 36
Inotropic score (25, 50, 145) 36 50 66 73
Door to balloon time (120, 200, 360) 45 51 66 61
Median values were chosen for body mass index, SAPSII, Glasgow Coma Score, troponin Ic
and creatininemia. Because mortality for age was similar for quartiles 2 and 3 but much
higher for quartile 4, we reanalyzed quartile-3 mortality and determined that the breakpoint
was 60. Similarly, the breakpoint was 50 for prothrombin activity. Lactate was
trichotomized because mortality was comparable for quartiles 2 and 3 but markedly different
for quartiles 1 and 4. For practical purposes, values were rounded to the nearest integer.
Table S3. Univariable and multivariable analyses of factors associated with in-ICU death
Factor Univariable analysis Multivariable analysis
OR (95% CI) P-value OR (95% CI) P-value
Age >60 years 1.86 (0.903.84) 0.093 2.63 (1.016.85) 0.048
Female 1.80 (0.764.25) 0.179 4.35 (1.2914.72) 0.018
Body mass index >25 kg/m² 2.24 (1.124.48) 0.020 3.10 (1.217.92) 0.018
Active smoker 0.54 (0.271.08) 0.082
SAPSII >65 1.75 (0.893.44) 0.106
Glasgow Coma Score <6 1.97 (1.003.91) 0.054 3.09 (1.198.05) 0.021
Creatininemia >150 mol/L 2.45 (1.234.87) 0.011 2.60 (1.056.49) 0.040
Serum lactate
<2 mmol/L 1 1
2–8 mmol/L 6.80 (2.1321.65) 0.001 4.71 (1.3117.01) 0.020
>8 mmol/L 22.18 (5.7685.44) <0.001 8.71 (1.7643.10) 0.004
Inotropic score >50 3.85 (1.82–8.16) 0.001Door to balloon time >200 min 2.27 (0.95–5.42) 0.065Prothrombin activity <50% 3.85 (1.82–8.16) 0.001 2.80 (1.017.77) 0.049Troponin Ic >45 µg/L 2.93 (1.004.07) 0.047
OR, odds ratio.
The SOFA score was not included in the model. Only renal (creatininemia) and neurological
(Glasgow Coma Score) SOFA subscores were included.
Mobile ECMO retrieval, Pre-ECMO cardiac arrest, ECMO under CPR, AMI location, IABP
associated with ECMO and Post-PCI TIMI were forced into the final multivariable model
although not P values for the difference between survivors and non-survivors was >0.20.
None of these factors were retained in the final multivariable model. Arterial HCO3– and pH
were not included since they were collinear to arterial lactate.
Table S4. Spearman rank correlation matrix for the prediction scoring systems
ENCOURAGE SAVE SAPSII SOFA CHENG SLEEPER GRACE
ENCOURAGE 1.000
SAVE [18] -0.660 1.000
SAPSII [1] 0.495 -0.520 1.000
SOFA [2] 0.413 -0.573 0.660 1.000
CHENG [19] 0.648 -0.524 0.263 0.173 1.000
SLEEPER [20] 0.575 -0.636 0.631 0.695 0.365 1.000
GRACE [21] 0.331 -0.535 0.246 0.199 0.361 0.319 1.000
Table S5. Long-term outcome variables and comparisons of scores according to the median
duration of follow-up
Outcome variable All followed Follow-up duration P- value
patients
(n = 41)
<945 days
(n = 21)
≥945 days
(n = 20)
SF-36 domains
Physical Functioning 75 (54–90) 65 (45–81) 80 (68–95) 0.03
Role-Physical 75 (25–100) 75 (25–100) 100 (63–100) 0.03
Bodily Pain 100 (67–100) 100 (67–100) 100 (64–100) 0.84
General Health 58 (46–75) 58 (38–75) 56 (50–73) 0.68
Vitality 50 (44–76) 50 (40–71) 65 (55–80) 0.10
Social Functioning 88 (50–100) 63 (34–100) 100 (75–100) 0.01
Role-Emotional 100 (33–100) 100 (25–100) 100 (50–100) 0.27
Mental Health 76 (59–80) 72 (44–82) 76 (64–78) 0.66
SF-36 Physical Component Score 50 (42–53) 44 (40–52) 50 (46–54) 0.16
SF-36 Mental Component Score 50 (39–56) 47 (34–55) 53 (49–56) 0.16
HAD Scale 9 (7–14) 10 (6–17) 9 (8–12) 0.54
HAD-A Subscale 5 (4–9) 5 (3–10) 6 (4–9) 0.81
HAD-A ≥8 14 (34) 7 (33) 7 (35) 0.99
HAD-D Subscale 3 (3–7) 5 (3–10) 3 (2–4) 0.21
HAD-D ≥8 8 (20) 7 (33) 1 (5) 0.04
IES 5 (0–16) 7 (2–21) 3 (0–13) 0.11
IES ≥30 2 (5) 2 (10) 0 0.16
NYHA class 2 (1–2) 2 (1–3) 1 (1–2) 0.07
Values are medians (25th to 75th percentile) or n (%). SF-36, Short-Form 36 questionnaire; HAD-A/-D, Hospital Anxiety and Depression Scale-Anxiety/-Depression; IES, Impact of Event Scale; NYHA, New York Heart Association.
Table S6. Comparison of ENCOURAGE and IABP-SHOCK[22] populations
Characteristic ENCOURAGE
(n = 138)
IABP-SHOCK
(n = 600)
Age, years 55 70
Men 110 (80) 413 (69)
SAPSII 66 52
Arterial lactate, mmol/L 4.1 4.1
LVEF, % 20 35
Pre-ECMO cardiac arrest 79 (57) 270 (45)
Catecholamines used 138 (100) 538 (90)
On mechanical ventilation 134 (97) 492 (82)
Renal replacement therapy 63 (46) 109 (18)
Post-PCI hemodynamics
SAP, mmHg 84 102
DAP, mmHg 54 57
MAP, mmHg 64 73
Heart rate, /min 100 90
Values are medians or n (%).
SAPS, Simplified Acute Physiology Score; LVEF, left ventricle ejection fraction; PCI,
percutaneous coronary intervention; SAP, DAP, MAP, systolic, diastolic and mean arterial
blood pressure, respectively.
Figure Legends
Figure S1. Study flow chart for survivors. LVAD, left ventricular assist device; BiVAD, bi-
ventricular assist device; MOF, multiorgan failure.
Figure S2. Study flow chart for non-survivors. LVAD, left ventricular assist device;
BiVAD, bi-ventricular assist device; MOF, multiorgan failure. Of the 67 patients who died
while still on mechanical assistance, 61 had refractory multiple organ failure. Early death
related to initial refractory shock (within the first 7 days of ECMO) occurred in 38 patients.
Eleven and twelve patients died after 8-14 and 15-28 days of ECMO support, respectively.
Causes of multiple organ failure in these patients were 5 septic shock due to nosocomial
pneumonia, 5 post-operative shock, 2 hemorrhagic shock and 11 non-specific shock.
Figure S3. KaplanMeier estimates of cumulative probabilities of 180-day survival for
patients with the indicated pre-ECMO ENCOURAGE-score classes.
Figure S4. Comparison of median SF-36 scores of 41 of our ECMO-treated AMI survivors
after median follow-up of 32 months post-ECMO initiation and their 41 age- and sex-
matched controls [8], 424 AMI survivors evaluated 4 years post-event [11], 1-year survivors
after non-ST–segment elevation acute coronary syndromes included in the early
interventional strategy of the Randomized Intervention Trial of unstable Angina-3 (RITA-3)
[12], venovenous-ECMO–treated severe ARDS survivors [10] or ECMO-rescued severe
myocarditis patients [5]. PF, physical functioning; RP, role-physical; BP, body pain; GH,
general health; VT, vitality; SF, social functioning; RE, role-emotional; MH, mental health.
Figure S5. A, Mean percentages of our ECMO-treated ARDS survivors (evaluated after
median follow-up of 17 months post-ICU discharge) with clinically significant anxiety and/or
depression (Hospital Anxiety and Depression [HAD-A/D] subscale scores ≥8/21) compared
to those of VV-ECMO–treated severe ARDS survivors,[10] VA-ECMO–rescued severe
myocarditis patients [5] and 335 AMI patients [14]. B, Mean percentages of our ECMO-
treated ARDS survivors at risk of developing PTSD compared to those of VV-ECMO–treated
severe ARDS survivors [10], VA-ECMO–rescued severe myocarditis patients [5], 268 car-
accident survivors [16] and survivors of acute coronary syndromes (ACS) [17].
Figure S1.
Figure S2
Figure S3
0.0
0.2
0.4
0.6
0.8
1.0
0
Cum
ulati
ve P
roba
bilit
yof
Sur
viva
l
0.0
0 20 40 60 80 100 120 140 160 180Days after ECMO Initiation
P<0.001, log-rank test
ENCOURAGE 0–12
ENCOURAGE 13–18
ENCOURAGE ≥28
ENCOURAGE 19–22
ENCOURAGE 23–27
Number at risk
26 24 23 23 22 22
27 18 17 17 17 17
26 14 12 11 9 8
29 8 7 5 5 3
30 8 7 5 5 3
Figure S4
0
20
40
60
80
100
PF
RP
BP
GH
VT
SF
RE
MH
Controls, (20)
VA-ECMO ENCOURAGE
ECMO PRESERVE ARDS, (22)
Myocarditis & ECMO, (5)
Myocardial Infarction, (33)
NonSTEMI RITA-3, (34)
Figure S5
AMI survivors (14)ECMO PRESERVE ARDS (10)
Myocarditis & ECMO (5)
VA-ECMO ENCOURAGE
10
20
30
40
50
HAD-A HAD-D
Scor
e ≥8 (
%)
A
B
ACS survivors (17)ECMO PRESERVE ARDS (10)
Myocarditis & ECMO (5)
Car-accident survivors (16)
10
20
30
40
Impact of Event Scale
Scor
e ≥30
(%)
VA-ECMO ENCOURAGE