Clinical trial NCT06522594: REMAP ECMO - Beta Receptor Modulation Trial
Official title: Randomized Embedded Multifactorial Adaptive Platform in ExtraCorporeal Membrane Oxygenation - Beta Receptor Modulation Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Heart Failure
Cardiogenic Shock
Keywords: Veno-Arterial ExtraCorporeal Membrane Oxygenation
Betablocker
Esmolol
Cardiogenic shock
Lead sponsor: Erasmus Medical Center
Sponsor class: OTHER
First posted: 2024-07-26
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: In this phase 2, single center, randomized clinical pilot trial, investigators will study the effect of a strategy involving a reduction of beta receptor (BR) stimulation (by decreasing dobutamine dosages) and subsequent BR inhibition (through ultra-short acting betablockers), versus a (routine) strategy with continued BR stimulation through dobutamine infusion, on heart rate in patients with cardiogenic shock due to left- or bi-ventricular failure being supported by V-A ECMO.

Detailed description: Despite the great benefits of Venoarterial ExtraCorporeal Membrane Oxygenation (V-A ECMO) and its rapidly increasing usage, even today, 30 till 70 percent of patients cannot be weaned from ECMO support and up to 50 percent of patients will eventually die in the first year. These high incidences of mortality and failure to wean from V-A ECMO support seem largely attributable to failure of the heart to recover in the context of inotropic drug administration and high sympathetic drive due to severe illness (further stressing an already failing heart). As V-A ECMO support creates a "safety window" where organ perfusion no longer relies on native cardiac output, therapeutic focus could be shifted to cardioprotective treatments. Cardioprotective treatments typically include beta blockers (BB) which have unequivocally shown benefits on mortality and morbidity in other patient categories with heart failure with reduced ejection fraction (HFrEF).

The investigators hypothesize that, in selected patients with cardiogenic shock undergoing V-A ECMO support, application of BBs is feasible and safe, and can effectively reduce heart rate.

Eligibility criteria: Inclusion Criteria:

* Age ≥ 18 years,
* Having received V-A ECMO support for severe circulatory insufficiency due to left- or bi-ventricular failure.
* ≤ 16 hours after initiation of V-A ECMO support
* Receiving ≥ 2 mcg/kg/min of dobutamine.
* Norepinephrine infusion ≤ 0.4 mcg/kg/min
* Heart rate ≥ 80 bpm (being sinus rhythm, atrial fibrillation or atrial flutter) after V-A ECMO initiation

Exclusion Criteria:

* Objection during the deferred consent procedure
* V-A ECMO usage confined to the period during surgery or another intervention (the ECMO was removed at the end of the intervention).
* Concomitant durable Left Ventricular Assist Device (LVAD)
* Polymorphic ventricular tachycardia necessitating BB therapy
* Isolated right ventricular failure (e.g. due to pulmonary embolism)
* Need of high dose dobutamine \> 6.0 mcg/kg/min
* Epinephrine infusion
* Signs of insufficient trans cardiac flow:

  * Absence of aortic valve opening
  * Pulse pressure \<10 mmHg (with intra-aortic balloon pump (IABP) standby)
  * Spontaneous contrast in the heart at echocardiography
* Contraindications for-, intolerance to- or allergy to esmolol
* Second- or third- degree AV block
* Pregnancy
* Life expectancy of less than 24 hours
* Participation in another randomized clinical trial (e.g. On Scene trial or Left Ventricular unloading trial)
* Inability to start study treatment within 4 hours after randomization
* Post heart transplantation patients

Primary outcomes:
measure: Change (delta) in heart rate 24 hours after randomization.
timeFrame: 24 hours after randomization
Secondary outcomes:
measure: Percentage of patients having received esmolol
timeFrame: after 48 hours
measure: Vasopressor score
timeFrame: at baseline, 24 and 48 hours
measure: Occurrence of new onset ventricular and/or atrial arrhythmias after randomization
timeFrame: during the first 48 hours
measure: Left ventricular outflow tract velocity time integral (LVOT VTI)
timeFrame: at baseline, 24 and 48 hours
measure: Cardiac output
timeFrame: at baseline, 24 and 48 hours
measure: Stroke volume index
timeFrame: at baseline, 24 and 48 hours
measure: Pulmonary capillary wedge pressure
timeFrame: at baseline, 24 and 48 hours
measure: Central venous pressure
timeFrame: at baseline, 24 and 48 hours
measure: Mixed venous oxygen saturation (SvO2)
timeFrame: at baseline, 24 and 48 hours
measure: Lactate level
timeFrame: at baseline, 24 and 48 hours
measure: Troponin
timeFrame: At 24 and 48 hours after randomization
measure: Myocardial oxygen consumption
timeFrame: At 24 and 48 hours after randomization
measure: Plasma NT-proBNP levels
timeFrame: At baseline and 48 hours after randomization
measure: Plasma Creatine Kinase MB levels
timeFrame: At baseline and 48 hours after randomization
measure: FiO2 suppletion
timeFrame: At 24 and 48 hours after randomization
measure: Plasma metanephrine levels
timeFrame: At baseline and 24 after randomization
measure: Plasma normetanephrines levels
timeFrame: At baseline and 24 after randomization
measure: Maximum median dosages of esmolol
timeFrame: after 48 hours
measure: Ejection fraction (EF)
timeFrame: at baseline, 24 and 48 hours
measure: Tricuspid annular plane systolic excursion (TAPSE).
timeFrame: at baseline, 24 and 48 hours
measure: Positive End Expiratory Pressure (PEEP) level
timeFrame: At 24 and 48 hours after randomization
Other outcomes:
Locations:
city: Rotterdam
country: Netherlands
facility: Erasmus Medical Center
state: Zuid Holland
Study officials:
affiliation: Erasmus Medical Center
name: Christiaan L. Meuwese
role: PRINCIPAL_INVESTIGATOR
References:
citation: Meuwese CL, Hermens JA, de Haan M, Braithwaite SA, Ramjankhan F, Buijsrogge MP, de Jonge N, Kirkels JH, de Jong M, Pasma W, Vromen-Wijsman JLP, Kraaijeveld AO, de Waal EE, Torn E, Platenkamp M, van der Heijden JJ, Cremer OL, van Dijk D, Donker DW. Twelve years of circulatory extracorporeal life support at the University Medical Centre Utrecht. Neth Heart J. 2021 Jul;29(7-8):394-401. doi: 10.1007/s12471-021-01552-z. Epub 2021 Mar 6.
citation: McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Bohm M, Burri H, Butler J, Celutkiene J, Chioncel O, Cleland JGF, Coats AJS, Crespo-Leiro MG, Farmakis D, Gilard M, Heymans S, Hoes AW, Jaarsma T, Jankowska EA, Lainscak M, Lam CSP, Lyon AR, McMurray JJV, Mebazaa A, Mindham R, Muneretto C, Francesco Piepoli M, Price S, Rosano GMC, Ruschitzka F, Kathrine Skibelund A; ESC Scientific Document Group. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2021 Sep 21;42(36):3599-3726. doi: 10.1093/eurheartj/ehab368. No abstract available.
citation: Flather MD, Gollop ND. Understanding Mechanisms of Action of Beta-Blockers in Heart Failure With Reduced and Preserved Ejection Fraction. JACC Heart Fail. 2016 Feb;4(2):150-151. doi: 10.1016/j.jchf.2015.12.009. No abstract available.
citation: Rahhal A, Omar AS, Aljundi A, Kasem M, Mahfouz A, Alyafei S. Successful Use of Intravenous B-blocker Therapy in Cardiogenic Shock Supported With Venoarterial Extracorporeal Membrane Oxygenation: A Case Series. Curr Probl Cardiol. 2022 Nov;47(11):101071. doi: 10.1016/j.cpcardiol.2021.101071. Epub 2021 Nov 26.
citation: Brugts JJ, Manintveld O, Constantinescu A, Donker DW, van Thiel RJ, Nieman K, Jewbali LS, Zijlstra F, Caliskan K. Preventing LVAD implantation by early short-term mechanical support and prolonged inodilator therapy : A case series with acute refractory cardiogenic shock treated with veno-arterial extracorporeal membrane oxygenation and optimised medical strategy. Neth Heart J. 2014 Apr;22(4):176-81. doi: 10.1007/s12471-013-0509-5.