European Journal of Heart Failure Supplements (2017) 19 (Suppl.

2) 124–127
doi:10.1002/ejhf.857

Extra corporeal membrane oxygenation in the

therapy of cardiogenic shock (ECMO-CS):
rationale and design of the multicenter
randomized trial
Petr Ostadal1, Richard Rokyta2, Andreas Kruger1, Dagmar Vondrakova1, Marek
Janotka1, Ondrej Smíd3, Jana Smalcova3, Milan Hromadka2, Ales Linhart3, and
Jan Bělohlávek3*
1 Department of Cardiology, Na Homolce Hospital, Prague, Czech Republic; 2 Department of Cardiology, University Hospital and Faculty of Medicine Pilsen, Charles University,
Czech Republic; and 3 2nd Department of Medicine - Department of Cardiovascular Medicine, First Faculty of Medicine, Charles University and General University Hospital,
Prague, Czech Republic

Aims Extracorporeal membrane oxygenation (ECMO) in veno-arterial configuration represents an increasingly used
method for circulatory support. ECMO in cardiogenic shock offers rapid improvement of circulatory status and
significant increase in tissue perfusion. Current evidence on the use of ECMO in cardiogenic shock remains
insufficient. The aim of the ECMO-CS trial is to compare two recognized therapeutic approaches in the management
of severe cardiogenic shock: early conservative therapy and early implantation of veno-arterial ECMO on the
background of standard care.
.....................................................................................................................................................................
Methods Eligible patients have either rapidly deteriorating or severe cardiogenic shock, defined using echocardiography,
hemodynamic and metabolic criteria. Patients are randomized to the one of two arms: immediate veno-arterial
ECMO therapy or early conservative therapy. All other diagnostic and therapeutic procedures are performed as per
current standard of care, including other cardiovascular interventions (i.e. percutaneous coronary intervention or
cardiac surgery). Follow-up includes visits at 30 days, 6 months and 12 months. Primary endpoint is a composite of
death from any cause, resuscitated circulatory arrest, and implantation of another mechanical circulatory support
device at 30 days. The sample size of 120 individuals (60 in each arm) provides 80% power to detect 50% reduction
of primary endpoint, at alpha = 0.05. Patient recruitment started in October 2014.
.....................................................................................................................................................................
Conclusion The results of the ECMO-CS trial may significantly influence current practice in the management of patients with
severe and rapidly deteriorating cardiogenic shock. ECMO-CS trial registration number is NCT02301819.
..........................................................................................................
Keywords cardiogenic shock • extracorporeal membrane oxygenation • extracorporeal life support •
clinical trial

Introduction 5 L/min and veno-arterial ECMO can, therefore, either sup-

.............

port or fully substitute the cardiac pump and pulmonary gas

Extracorporeal membrane oxygenation (ECMO) in veno-arterial exchange.1 ECMO has been used for many years in neonates
configuration represents an increasingly used method for cir- and infants with pulmonary hypertension and severe respiratory
culatory support. Extracorporeal blood flow may exceed failure.2 – 5 During the past two decades increasing number of

*Corresponding author: Jan Bělohlávek, MD, PhD., 2nd Department of Medicine - Department of Cardiovascular Medicine, First Faculty of Medicine, Charles University and General
University Hospital, Prague, Czech Republic, Tel.: + 420 724 371 594, Email: Jan.Belohlavek@vfn.cz

© 2017 The Authors

European Journal of Heart Failure © 2017 European Society of Cardiology, 19 (Suppl. 2), 124–127
 18790844, 2017, S2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ejhf.857 by CAPES, Wiley Online Library on [27/08/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Extra Corporeal Membrane Oxygenation in the therapy of Cardiogenic Shock (ECMO-CS) 125

reports has been published showing successful application of

........................................................................................................................................................................
Table 1 Inclusion criteria of the ECMO-CS trial.
veno-arterial ECMO also in adult patients with rapidly progress-
ing severe cardiogenic shock6 – 11 or with refractory cardiac
Patients must fulfil criteria for rapidly
arrest.9,11 – 20
deteriorating (A) or severe (B) cardiogenic shock:
Current clinical Guidelines of the European Society of Car-
diology recommend consideration of ECMO use in patients A. Rapidly deteriorating cardiogenic shock is defined as
with cardiogenic shock, remaining unstable despite administra- a progressive hemodynamic instability necessitating repeated
bolus administration of vasopressors to maintain mean arterial
tion of inotropes, vasopressors, ventilatory support, reperfusion
pressure > 50 mmHg + impaired left ventricle systolic function
and revascularization21 or as a “bridge to decision” to stabi-
(left ventricle ejection fraction (LVEF) < 35% or LVEF 35-55%
lize hemodynamics.22 However, this recommendation is based on
in case of severe mitral regurgitation or aortic stenosis)
expert consensus. Currently, there are no prospective randomized B. Severe cardiogenic shock is defined by all following criteria:
trials available, focusing on the use of ECMO in patients with severe
cardiogenic shock.9 – 11 1. Hemodynamic:
Therapy with veno-arterial ECMO in cardiogenic shock offers Cardiac Index (CI) < 2.2 L/min/m2 + norepinephrine
rapid improvement of circulatory status and significant increase in dose > 0.1 μg/kg/min + dobutamine dose > 5 μg/kg/min
tissue perfusion. On the other hand, ECMO is an invasive method, or Systolic blood pressure < 100 mmHg + norepinephrine
requiring anticoagulation, and the use of ECMO is, therefore, asso- dose > 0.2 μg/kg/min + dobutamin dose > 5 μg/kg/min +
ciated with possible complications, i.e. bleeding or leg ischemia.23 (LVEF < 35% or LVEF 35-55% + severe mitral regurgitation or
Veno-arterial ECMO may also negatively influence the left ventric- aortic stenosis)
ular functions.24 Furthermore, implantation of ECMO represents 2. Metabolic:
also considerable financial costs and mortality remains high despite
Lactate – two consecutive values ≥ 3 mmol/L (with at least
the improvement of circulatory status.25,26 30 min interval between samples), with non-decreasing trend on
The aim of the ExtraCorporeal Membrane Oxygenation in the steady doses of inotropes and/or vasopressors
therapy of Cardiogenic Shock (ECMO-CS) trial is to compare two or SvO2 – two consecutive values < 50% (with at least 30 min
recognized therapeutic approaches in the management of severe interval between samples), with non-increasing trend on steady
cardiogenic shock: early conservative therapy and early implanta- doses of inotropes and/or vasopressors
tion of veno-arterial ECMO on the background of standard care.
3. Hypovolemia must be excluded:
Central venous pressure > 7 mmHg or pulmonary capillary
Study design wedge pressure > 12 mmHg

Overview
The ECMO-CS is a multi-center randomized prospective trial All patients should provide written informed consent with the
focused on the efficacy of ECMO in the therapy of advanced participation in the study. If patient status does not allow to
cardiogenic shock. The trial was approved by Ethics Committees of give informed consent, it will be provided retrospectively after
all participating centers and is registered at ClinicalTrials.gov with improvement of clinical conditions. If a patient deceases, remains
No. NCT02301819. First subject was randomized in 2014 and the unconscious or with significant brain dysfunction, written informed
last patient-last visit is projected to 2019. consent will be obtained from a patient’s next of kin. If informed
Eligible patients for ECMO-CS trial have rapidly deteriorating or consent is not obtained, all acquired data will be removed from the
severe cardiogenic shock defined in inclusion criteria (Table 1) and database and will not be used in the analysis.
do not meet exclusion criteria (Table 2). Subjects are randomized
using web-based randomization system in 1:1 ratio to the one of
two arms: immediate ECMO therapy or early conservative therapy.
In the invasive group, veno-arterial ECMO is inserted according
Endpoints
to the local practice with flow settings to ensure sufficient tissue Primary endpoint is defined as a composite of death from any
perfusion. All other diagnostic and therapeutic procedures includ- cause, resuscitated circulatory arrest, and implantation of another
ing other cardiovascular interventions (i.e. percutaneous coronary mechanical circulatory support device at 30 days. Secondary end-
intervention or cardiac surgery) are performed according to the points include all-cause mortality at 30 days, at 6 months and at
current standard of care at the tertiary cardiovascular center. 1 year, neurological outcome (according to Cerebral Performance
Acute implantation of other mechanical support devices (including Category scale) at 30 days, intensive care unit stay duration, hos-
ECMO in the conservative group) is allowed in the case of shock pital stay duration, need for intubation, renal replacement therapy
progression, ie. rapid deterioration of hemodynamic or metabolic and duration of mechanical ventilation.
status (defined as a need for increasing doses of vasopressors or a Sample size was determined to detect clearly clinically signif-
rise of serum lactate by 3 mmol/L within a minimum of 30 minutes icant 50% reduction of primary endpoint with 80% power at
after randomization). Follow-up includes visits at 30 days, 6 months alpha = 0.05. The calculation indicates enrollment of 120 subjects
and 12 months. (60 individuals in each arm).

© 2017 The Authors

European Journal of Heart Failure © 2017 European Society of Cardiology, 19 (Suppl. 2), 124–127
 18790844, 2017, S2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ejhf.857 by CAPES, Wiley Online Library on [27/08/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
126 P. Ostadal et al.

2. Bartlett RH, Gazzaniga AB, Jefferies MR, Huxtable RF, Haiduc NJ, Fong SW.

........................................................................................................................................................................
Table 2 Exclusion criteria of the ECMO-CS trial. Extracorporeal membrane oxygenation (ECMO) cardiopulmonary support in
infancy. Trans Am Soc Artif Intern Organs. 1976;22:80–93. PubMed PMID:
951895.
1 Age < 18 years 3. Bartlett RH, Roloff DW, Cornell RG, Andrews AF, Dillon PW, Zwis-
chenberger JB. Extracorporeal circulation in neonatal respiratory failure:
2. Life expectancy lower than 1 year a prospective randomized study. Pediatrics. 1985 Oct;76(4):479–87. PubMed
PMID: 3900904.
3. High suspicion of pulmonary embolism or cardiac tampon- 4. Shanley CJ, Hirschl RB, Schumacher RE, Overbeck MC, Delosh TN, Chapman
ade as a cause of shock RA, et al. Extracorporeal life support for neonatal respiratory failure. A 20-year
experience. Ann Surg. 1994 Sep;220(3):269–80; discussion 81–2. PubMed PMID:
4. Significant bradycardia or tachycardia which might be 8092896. Pubmed Central PMCID: 1234378.
responsible for hemodynamic instability and not treated by 5. MacLaren G, Dodge-Khatami A, Dalton HJ, Writing C, MacLaren G,
Dodge-Khatami A, et al. Joint statement on mechanical circulatory sup-
pacing or cardioversion
port in children: a consensus review from the Pediatric Cardiac Intensive Care
5. Cardiac arrest survivors remaining comatose Society and Extracorporeal Life Support Organization. Pediatr Crit Care Med.
2013 Jun;14(5 Suppl 1):S1-2. PubMed PMID: 23735979.
6. Hyperthrophic obstructive cardiomyopathy 6. Pranikoff T, Hirschl RB, Steimle CN, Anderson HL, 3rd, Bartlett RH. Efficacy of
extracorporeal life support in the setting of adult cardiorespiratory failure. ASAIO
7. Peripheral artery disease disabling insertion of outflow J. 1994 Jul-Sep;40(3):M339-43. PubMed PMID: 8555536.
7. Combes A, Leprince P, Luyt CE, Bonnet N, Trouillet JL, Leger P, et al. Out-
cannula to femoral artery
comes and long-term quality-of-life of patients supported by extracorporeal
8. Moderate to severe aortic regurgitation membrane oxygenation for refractory cardiogenic shock. Crit Care Med. 2008
May;36(5):1404–11. PubMed PMID: 18434909.
9. Aortic dissection 8. Beurtheret S, Mordant P, Paoletti X, Marijon E, Celermajer DS, Leger P, et al.
Emergency circulatory support in refractory cardiogenic shock patients in remote
10. Uncontrolled bleeding or TIMI major bleeding within last 6 institutions: a pilot study (the cardiac-RESCUE program). Eur Heart J. 2013
Jan;34(2):112–20. PubMed PMID: 22513777.
months
9. Abrams D, Combes A, Brodie D. Extracorporeal membrane oxygenation in
cardiopulmonary disease in adults. Journal of the American College of Cardiology.
11. Known cognitive dysfunction with CPC ≥ 3
2014 Jul 1;63(25 Pt A):2769–78. PubMed PMID: 24814488.
10. Werdan K, Gielen S, Ebelt H, Hochman JS. Mechanical circulatory support in
cardiogenic shock. Eur Heart J. 2014 Jan;35(3):156–67. PubMed PMID: 24014384.
11. Napp LC, Kuhn C, Bauersachs J. ECMO in cardiac arrest and cardiogenic
shock. Herz. 2017 Feb;42(1):27–44. PubMed PMID: 28127638. Pubmed Central
Participating Centers PMCID: 5306351. ECMO bei Herz-Kreislauf-Stillstand und kardiogenem Schock.
All participating sites are tertiary cardiovascular centers experi- 12. Younger JG, Schreiner RJ, Swaniker F, Hirschl RB, Chapman RA, Bartlett
RH. Extracorporeal resuscitation of cardiac arrest. Acad Emerg Med. 1999
enced in the management of severely compromised patients with Jul;6(7):700–7. PubMed PMID: 10433529.
cardiogenic shock and in the therapy with veno-arterial ECMO. 13. Chen YS, Chao A, Yu HY, Ko WJ, Wu IH, Chen RJ, et al. Analysis and results
All sites are fully equipped for the management of these patients of prolonged resuscitation in cardiac arrest patients rescued by extracorporeal
membrane oxygenation. Journal of the American College of Cardiology. 2003 Jan
according to the current standards of care and recommendations 15;41(2):197–203. PubMed PMID: 12535808.
of the European Society of Cardiology. All sites offer 24/7 cathlab 14. Megarbane B, Leprince P, Deye N, Resiere D, Guerrier G, Rettab S, et al.
service for acute and emergency cases. Emergency feasibility in medical intensive care unit of extracorporeal life support
for refractory cardiac arrest. Intensive care medicine. 2007 May;33(5):758–64.
PubMed PMID: 17342517.
15. Le Guen M, Nicolas-Robin A, Carreira S, Raux M, Leprince P, Riou B, et al.
Conclusion Extracorporeal life support following out-of-hospital refractory cardiac arrest.
Critical care. 2011;15(1):R29. PubMed PMID: 21244674. Pubmed Central PMCID:
Despite the fact, that veno-arterial ECMO is increasingly used in 3222065.
16. Haneya A, Philipp A, Diez C, Schopka S, Bein T, Zimmermann M, et al. A
the therapy of severe or rapidly progressing cardiogenic shock, 5-year experience with cardiopulmonary resuscitation using extracorporeal life
current evidence for this strategy is clearly insufficient and data support in non-postcardiotomy patients with cardiac arrest. Resuscitation. 2012
from a prospective randomized trial are lacking. The results of the Nov;83(11):1331–7. PubMed PMID: 22819880.
17. Fagnoul D, Combes A, De Backer D. Extracorporeal cardiopulmonary
ECMO-CS trial may significantly influence current practice in the resuscitation. Curr Opin Crit Care. 2014 Jun;20(3):259–65. PubMed PMID:
management of patients with severe and deteriorating cardiogenic 24785674.
shock. 18. Lin JW, Wang MJ, Yu HY, Wang CH, Chang WT, Jerng JS, et al. Comparing the
survival between extracorporeal rescue and conventional resuscitation in adult
in-hospital cardiac arrests: propensity analysis of three-year data. Resuscitation.
2010 Jul;81(7):796–803. PubMed PMID: 20413202.
Funding 19. Wang CH, Chen YS, Ma MH. Extracorporeal life support. Curr Opin Crit Care.
2013 Jun;19(3):202–7. PubMed PMID: 23587757.
The ECMO-CS trial is supported by the grant from the Agency for 20. Belohlavek J, Kucera K, Jarkovsky J, Franek O, Pokorna M, Danda J, et al.
Hyperinvasive approach to out-of hospital cardiac arrest using mechanical chest
the Czech Republic health research No. 15-27994A. compression device, prehospital intraarrest cooling, extracorporeal life sup-
Conflict of Interest: Authors report no conflicts of interest. port and early invasive assessment compared to standard of care. A ran-
domized parallel groups comparative study proposal. “Prague OHCA study”. J
Transl Med. 2012;10:163. PubMed PMID: 22883307. Pubmed Central PMCID:
3492121.
References 21. Task Force on Myocardial Revascularization of the European Society of C,
1. ECMO: Extracorporeal Cardiopulmonary Support in Critical Care. 4 ed: Extra- the European Association for Cardio-Thoracic S, European Association for
corporeal Life Support Organization; 2012. Percutaneous Cardiovascular I, Wijns W, Kolh P, Danchin N, et al. Guidelines

© 2017 The Authors

European Journal of Heart Failure © 2017 European Society of Cardiology, 19 (Suppl. 2), 124–127

Extra Corporeal Membrane Oxygenation in the therapy of Cardiogenic Shock (ECMO-CS)
on myocardial revascularization. Eur Heart J. 2010 Oct;31(20):2501–55. PubMed
..........................
PMID: 20802248.
22. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, et al. 2016
ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure:
The Task Force for the diagnosis and treatment of acute and chronic heart
failure of the European Society of Cardiology (ESC)Developed with the special
contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2016
Jul 14;37(27):2129–200. PubMed PMID: 27206819.
23. Muller G, Flecher E, Lebreton G, Luyt CE, Trouillet JL, Brechot N, et al. The
ENCOURAGE mortality risk score and analysis of long-term outcomes after
VA-ECMO for acute myocardial infarction with cardiogenic shock. Intensive care
medicine. 2016 Mar;42(3):370–8. PubMed PMID: 26825953.
© 2017 The Authors
European Journal of Heart Failure © 2017 European Society of Cardiology, 19 (Suppl. 2), 124–127
18790844, 2017, S2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ejhf.857 by CAPES, Wiley Online Library on [27/08/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
127
24. Ostadal P, Mlcek M, Kruger A, Hala P, Lacko S, Mates M, et al. Increasing
venoarterial extracorporeal membrane oxygenation flow negatively affects left
ventricular performance in a porcine model of cardiogenic shock. J Transl Med.
2015;13:266. PubMed PMID: 26275717. Pubmed Central PMCID: 4537539. Epub
2015/08/16. eng.
25. Chiu R, Pillado E, Sareh S, De La Cruz K, Shemin RJ, Benharash P. Financial
and clinical outcomes of extracorporeal mechanical support. J Card Surg. 2017
Mar;32(3):215–21. PubMed PMID: 28176385.
26. Aso S, Matsui H, Fushimi K, Yasunaga H. In-hospital mortality and successful
weaning from venoarterial extracorporeal membrane oxygenation: analysis of
5,263 patients using a national inpatient database in Japan. Critical care. 2016 Apr
05;20:80. PubMed PMID: 27044572. Pubmed Central PMCID: 4820970.