A Study on the Effects of Left Ventricular Unloading in the Setting of VA ECMO Support

ExtraCorporeal Membrane Oxygenation (ECMO) is increasingly used but remains associated with high weaning failure- and mortality- rates. This seems in part attributable to a knowledge gap on how to properly manage ECMO and its related therapies as current knowledge and treatment protocols are based on observational studies and expert opinions. The "Randomized Embedded Multifactorial Adaptive Platform in ECMO" (REMAP ECMO) study was developed to study, in an efficient and randomized way, different ECMO related patient management issues and will consist of two parts:

1. A patient registry that will serve for quality monitoring and observational studies of ECMO patients being treated in participating centers.
2. Embedded within the registry, multiple response adaptive randomized clinical trials (trial domains) which aim to evaluate the effectiveness of a range of therapeutic interventions on ECMO weaning success. These interventions all have in common that they are all already used in ECMO care but their use depends on center and/or doctors preferences as no high quality (randomized) evidence guiding their indication, timing and management exists.

* LV unloading trial A first trial domain to be initiated within the REMAP ECMO platform will address the effects of left ventricular (LV) unloading, through application of an intra-aortic balloon pump (IABP), on weaning success in the setting of venoarterial (VA) ECMO. The rationale of this trial domain is based on the increase in LV loading conditions, as induced by VA ECMO, which could lead to pulmonary edema, intracardiac thrombosis and even death. These serious sequelae could possibly be prevented by adding IABP as adjunct to VA ECMO therapy.
* Physiological substudy on IABP as adjunct to V-A ECMO

A nested physiological observational substudy within the ongoing REMAP ECMO RCT, using the trial arms where patients are randomized between receiving V-A ECMO with or without IABP in the Erasmus Medical Center Rotterdam. The substudy aims to evaluate the physiological effects of IABP in conjunction with V-A ECMO on respiratory and hemodynamic parameters. The substudy consists of two parts:

1. Microcirculation and Macrocirculation: This part investigates the impact of IABP on both microcirculation and macrocirculation in the setting of V-A ECMO.
2. PEEP as an Unloading Modality: This part examines the effect of Positive End-Expiratory Pressure (PEEP) as an unloading modality during a decremental PEEP trial in patients receiving V-A ECMO, either with or without IABP.

Endpoints in both substudies that can be assessed blindly will be evaluated by an assessor who is blinded to the assigned treatment arm and the objectives of the substudy

• Intra-aortic balloon pump (Device), also known as IABP: An IABP is placed percutaneously into the thoracic aorta and supports the heart through synchronized inflation and deflation of a balloon.

Primary outcomes

• ECMO weaning success [30 days]: Proportion of patients successfully weaned from VA ECMO at 30 days being defined by; a) being alive, b) without ECMO, IABP or Impella support, and c) not having received a heart transplantation or left ventricular assist device (LVAD).
• Physiological substudy: End diastolic volume [within 24 hours after ECMO initiation]: End diastolic volume as assessed by echocardiography

Secondary outcomes

• Treatment failure [During ECMO support]: The proportion of patients in whom LV unloading therapy was escalated. Escalation is defined by the insertion of an IABP (only in the VA ECMO alone arm), or Impella or left vent (IABP unloading arm or VA ECMO alone arm).
• 30 day, 90 day and 1 year mortality [30 days, 90 days and 1 year after ECMO initiation]: Mortality rate at 30 days, 90 days and 1 year after ECMO initiation
• ECMO support duration [Until 30 days after ECMO initiation]: The duration of ECMO support in days
• Major bleeding events [Until 30 days after ECMO initiation]: The occurrence of major bleeding events (fatal, in a critical area (intracranial, intraspinal, or intraocular), requiring intervention (coiling or surgery) and/or transfusion of ≥3 packed cells) until 30 days after VA ECMO initiation.
• Unplanned surgical or catheter based intervention of the leg(s) [Until 30 days after ECMO initiation]: Unplanned surgical or catheter based intervention of the leg(s) in which ECMO and/or IABP or Impella was inserted until 30 days after ECMO initiation.
• Time to lactate normalization [Until 30 days after ECMO initiation]: Time to lactate normalization (<2 mmol/L).
• Time to first negative net fluid balance [Until 30 days after ECMO initiation]: Time to first negative net fluid balance (calculated per 24 hours).
• The occurrence of continuous venovenous hemofiltration initiation during ECMO support [Until 30 days after ECMO initiation]: The occurrence of continuous venovenous hemofiltration (dialysis) (CVVH(D)) initiation during ECMO support.
• Course in PF ratio [Until 30 days after ECMO initiation.]: Course in PaO2/FiO2 (PF) ratio (PaO2 divided by FiO2 provided)
• Duration of mechanical ventilation. [Until 30 days after ECMO initiation.]: Duration of mechanical ventilation. Patients on mechanical ventilation via tracheostomy need to be 24 hours free of mechanical ventilation.
• Left ventricular ejection fraction 30 days after ECMO initiation. [At 30 days after ECMO initiation.]: Left ventricular ejection fraction 30 days after ECMO initiation.
• Time course in vasoactive inotropic score (VIS) during ECMO support [Until 30 days after ECMO initiation.]: Time course in vasoactive inotropic score (VIS) during ECMO support
• Time course in NT-pro BNP during ECMO support. [Until 30 days after ECMO initiation.]: Time course in NT-pro BNP during ECMO support.
• Quality of life at 1 year [1 year after ECMO initiation]: Quality of life on basis of EQ5D questionnaires
• Total health care costs [6 and 12 months after ECMO initiation]: Total healthcare costs in euros are determined by using the International Medical Consumption Questionnaire (iMCQ) and the calculated costs after 6 and 12 months of follow up
• Hospital readmission rate [1 year]: The number of hospital readmissions based on the information provided in the international Medical Consumption Questionnaire (iMCQ)
• Physiological substudy: Heart rate [24 and 48 hours after ECMO initiation]: The average heart rate measured during 5 minutes
• Physiological substudy: pulmonary artery catheter parameters [24 and 48 hours after ECMO initiation]: pulmonary artery catheter parameters: pulmonary capillary wedge pressure, cardiac output, central venous pressure
• Physiological substudy: Echocardiography [24 and 48 hours after ECMO initiation]: Echocardiography: LV ejection fraction, TAPSE, VTI LVOT
• Physiological substudy: microcirculation measurements [24 and 48 hours after ECMO initiation]: Microcirculation measurements: Perfused vessel density (PVD \[mm/mm2\], Total vessel density (TVD \[mm/mm2\]
• Physiological substudy: respiratory parameters [24 and 48 hours after ECMO initiation]: Respiratory: FiO2, PEEP, Respiratory System Compliance (CRS) as the ratio between Vt/Dp.
• Physiological substudy: delta NT-pro BNP [24 and 48 hours after ECMO initiation]: delta NT-pro BNP

Sex: All, ages: 18 Years to any

Inclusion criteria for the registry backbone:

* Having received ECMO support for severe circulatory and/or respiratory insufficiency

Inclusion Criteria for the LV unloading trial domain (VA ECMO + IABP vs VA ECMO alone):

* Cardiogenic shock
* Having received VA ECMO support for severe circulatory (and respiratory insufficiency).
* Age ≥ 18 years
* Initiation of LV unloading (IABP or Impella) possible ≤ 8 hours after ECMO initiation

Exclusion criteria for the registry backbone

* Objection to participation in the registry by the patient and/or proxy
* VA ECMO usage confined to the period during surgery or another intervention (the VA ECMO was removed at the end of the intervention in the operation room).

Exclusion criteria for the LV unloading trial domain (VA ECMO + IABP vs VA ECMO alone)

* No (deferred) informed consent provided by the patient and/or proxy.
* Pregnancy
* ECMO usage confined to the period during surgery or another intervention (the ECMO was removed at the end of the intervention).
* Isolated right ventricular failure (e.g. due to pulmonary embolism).
* Left ventricular assist device (LVAD), Impella or IABP in situ.
* Ventricular septal defect or papillary muscle rupture as the cause of shock.
* Thoracic or abdominal aortic dissection.
* Moderate or severe aortic regurgitation
* Mechanical prosthesis in mitral valve position

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• Christiaan Meuwese, Principal investigator, Erasmus Medical Center