Effect of the Addition of Adenosine on Myocardial Protection During Cardiopulmonary Bypass

Official title

Effect of the Addition of Adenosine on Myocardial Protection During Cardiopulmonary Bypass: A Double-Blind Randomized Clinical Trial

Overview

The goal of this clinical trial is to evaluate whether the addition of adenosine to standard cardioplegia improves myocardial protection in adult patients undergoing on-pump cardiac surgery. The study population includes adult patients of both sexes undergoing elective cardiac procedures requiring cardiopulmonary bypass and cardioplegic arrest. The main questions this trial aims to answer are: Does the addition of adenosine to cardioplegia affect myocardial protection as assessed by transesophageal echocardiography (TEE)? What is the effect of adenosine on biochemical markers of myocardial injury, such as postoperative high-sensitivity troponin levels? What is the effect of adenosine on perioperative hemodynamic support requirements, as quantified by the Vasoactive-Inotropic Score (VIS)? Researchers will compare patients receiving adenosine-supplemented cardioplegia with those receiving standard cardioplegia (placebo) to assess differences in echocardiographic indicators of myocardial protection, biomarker release, and need for vasoactive/inotropic support. Participants will: Receive either adenosine-supplemented cardioplegia (adenosine 1.2 mmol/L; 24 mg) or placebo according to randomization. Undergo standard perioperative monitoring during cardiac surgery. Undergo intraoperative transesophageal echocardiography (TEE) to evaluate myocardial protection by comparing pre- and post-cardiopulmonary bypass (CPB) measurements. Have postoperative laboratory testing for high-sensitivity troponin at baseline, 2h, 12h, and 24h after clamp release. Have hemodynamic support requirements recorded and VIS calculated at the end of surgery and at 12h and 24h postoperatively. Be followed for perioperative clinical outcomes including arrhythmias, need for cardioversion or mechanical circulatory support, ICU/hospital length of stay, myocardial infarction, and mortality.

Detailed description

Myocardial ischemia-reperfusion injury remains a key contributor to postoperative myocardial dysfunction and adverse outcomes in patients undergoing cardiac surgery with cardiopulmonary bypass (CPB). Despite refinements in cardioplegic solutions and perfusion strategies, biochemical evidence of myocardial injury and transient or persistent ventricular dysfunction remain common, particularly among older patients and those with preexisting ventricular impairment. These observations underscore the ongoing need for adjunctive strategies that enhance myocardial protection during both the ischemic arrest and early reperfusion phases.

Adenosine is an endogenous purine nucleoside with pleiotropic cardioprotective properties, including negative chronotropic and dromotropic effects, coronary vasodilation, attenuation of calcium influx, and modulation of inflammatory and endothelial pathways. Experimental data and small clinical studies suggest that adenosine administration at the onset of ischemia or during early reperfusion may reduce ischemia-reperfusion injury by facilitating rapid electrical arrest, limiting intracellular calcium overload, improving microvascular perfusion, and attenuating inflammatory activation. However, the optimal timing, dosing strategy, and clinical relevance of adenosine administration as an adjunct to modern cardioplegia in routine adult cardiac surgery remain incompletely defined.

This prospective, randomized, double-blind, placebo-controlled, parallel-group trial is designed to evaluate whether a single bolus of adenosine administered immediately after aortic cross-clamping and immediately before infusion of standard del Nido cardioplegia improves myocardial protection in adult patients undergoing elective coronary artery bypass grafting and/or valve surgery with CPB. Following cross-clamp application, patients allocated to the intervention group will receive adenosine at a concentration of 1.2 mmol/L (total dose 24 mg) delivered into the aortic root, while control patients will receive an equivalent volume of sterile water. Thereafter, cardioplegia delivery and all subsequent intraoperative management will proceed according to institutional standards, ensuring that the only protocolized difference between groups is the administration of adenosine or placebo.

Randomization will be performed using permuted blocks to ensure balanced group allocation. Blinding will be maintained for patients, surgeons, anesthesiologists, perfusionists, investigators, outcome assessors, and data analysts throughout the study period. Anesthesia management, CPB strategy, myocardial protection techniques, and postoperative care will follow standardized institutional protocols to minimize confounding.

The extent of myocardial injury will be assessed primarily through serial measurements of high-sensitivity cardiac troponin T obtained preoperatively and at predefined intervals following aortic cross-clamp removal. Hemodynamic support requirements will be quantified using the vasoactive-inotropic score (VIS), providing an integrated assessment of postoperative circulatory support needs. In addition to biochemical and hemodynamic endpoints, myocardial protection will be directly evaluated using transesophageal echocardiography (TEE). Comprehensive TEE examinations will be performed immediately before initiation of CPB and again after successful weaning from CPB, allowing for paired assessment of global and regional ventricular function, wall motion abnormalities, and overall myocardial performance in the immediate reperfusion period.

Secondary clinical observations will include intraoperative rhythm disturbances, need for electrical cardioversion or defibrillation, postoperative ventricular function, requirements for mechanical circulatory support, incidence of postoperative atrial fibrillation, length of intensive care unit and hospital stay, perioperative myocardial infarction, and mortality.

Safety monitoring will be conducted throughout the trial. Given the ultra-short half-life of adenosine and its extensive use in clinical cardiology, adverse effects are expected to be transient and self-limited, most commonly brief atrioventricular conduction disturbances or asystole occurring immediately after administration. These effects are anticipated to resolve spontaneously within seconds in the controlled operative setting. All adverse events will be recorded and reviewed according to predefined safety protocols.

By integrating biochemical markers, echocardiographic assessment, and clinical outcomes, this trial aims to provide a comprehensive evaluation of adenosine as an adjunct to conventional cardioplegia. The findings may help clarify its role in mitigating ischemia-reperfusion injury and inform future myocardial protection strategies in adult cardiac surgery.

Interventions

• Drug Adenoseine
  Participants randomized to the adenosine group will receive a single bolus of adenosine 1.2 mmol/L (24 mg) administered directly into the aortic root immediately after aortic cross-clamping and immediately before infusion of standard del Nido cardioplegia. The solution will be prepared by the perfusionist under sterile conditions.
• Drug Placebo (sterile distilled water)
  Participants randomized to the placebo group will receive a single bolus of sterile distilled water, matched in volume and appearance to the adenosine solution, administered into the aortic root immediately after aortic cross-clamping and immediately prior to infusion of standard del Nido cardioplegia. The solution will be prepared by the perfusionist under sterile conditions to ensure identical volume and appearance to the placebo solution. Perioperative and postoperative management will be ide

Primary outcome measures

• High-sensitivity troponin [Time frame: baseline (upon entry to the operating room) and at 2, 12, and 24 hours after aortic cross-clamp release]
• Vasoactive-Inotropic Score (VIS) [Time frame: Immediately after completion of surgery and at 12 and 24 hours after aortic cross-clamp release]
• TEE assessment of myocardial protection [Time frame: The first measurement will be done at the day of the surgery in the operating room befere skin incision and the second one will be done whitin 1 hour after separation from cardiopulmonary bypass]

Secondary outcome measures (12)

• Arrhythmias requiring cardioversion or defibrillation [Time frame: Perioperative]
• Need for temporary pacing [Time frame: Periprocedural]
• New-onset atrial fibrillation [Time frame: Day 1]
• Use of mechanical circulatory support [Time frame: Perioperative period (during hospitalization after surgery)]
• Mortality [Time frame: Perioperative period (during hospitalization after surgery)]
• New ischemic stroke [Time frame: Perioperative period (during hospitalization after surgery)]
• Acute myocardial infarction [Time frame: Perioperative period (during hospitalization after surgery)]
• Arterial blood gas parameters [Time frame: On the day of surgery and at 12 and 24 hours after aortic cross-clamp release]
• Complete blood count [Time frame: On the day of surgery and at 12 and 24 hours after aortic cross-clamp release]
• Serum lactate level [Time frame: On the day of surgery and at 12 and 24 hours after aortic cross-clamp release]
• C-reactive protein [Time frame: On the day of surgery and at 12 and 24 hours after aortic cross-clamp release]
• Blood glucose [Time frame: On the day of surgery and at 12 and 24 hours after aortic cross-clamp release]

Eligibility criteria

Inclusion criteria

• All patients aged 18 years or older undergoing elective isolated valve replacement or coronary artery bypass grafting with cardiopulmonary bypass at Hospital Nossa Senhora da Conceição, Porto Alegre

Exclusion criteria

• Previous cardiac surgery;
• Chronic kidney disease (serum creatinine greater than 2.0 mg/dL);
• Severe psychiatric illness;
• Urgent or emergency surgery;
• Multiple cardiac procedures.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

Brazil · 1 center

• Hospital Nossa Senhora da Conceição — Porto Alegre

Publications

• Allen BS. Myocardial protection: a forgotten modality. Eur J Cardiothorac Surg. 2020 Feb 1;57(2):263-270. doi: 10.1093/ejcts/ezz215. PMID 31364690
• Singh A, Huang X, Dai L, Wyler D, Alfirevic A, Blackstone EH, Pettersson GB, Duncan AE. Right ventricular function is reduced during cardiac surgery independent of procedural characteristics, reoperative status, or pericardiotomy. J Thorac Cardiovasc Surg. 2020 Apr;159(4):1430-1438.e4. doi: 10.1016/j.jtcvs.2019.04.035. Epub 2019 Apr 26. PMID 31133354
• Lira KB, Delvaux RS, Spadini FA, Hauschild LH, Ceron RO, Anschau F, Kopittke L, Rode J, Rey RAW, Wittke EI, Rombaldi AR, Cambruzzi E, Lopes ERC, Almeida AS. Myocardial protection: comparing histological effects of single-dose cardioplegic solutions-study protocol for a secondary analysis of the CARDIOPLEGIA trial. J Thorac Dis. 2024 Feb 29;16(2):1480-1487. doi: 10.21037/jtd-23-1442. Epub 2024 Feb PMID 38505015
• Almeida AS, Ceron RO, Anschau F, Kopittke L, Lira KB, Delvaux RS, Rode J, Rey RAW, Wittke EI, Rombaldi AR. Comparison between Custodiol, del Nido and modified del Nido in the myocardial protection - Cardioplegia Trial: a study protocol for a randomised, double-blind clinical trial. BMJ Open. 2021 Sep 6;11(9):e047942. doi: 10.1136/bmjopen-2020-047942. PMID 34489276
• Ammar A, Mahmoud K, Elkersh A, Kasemy Z. A Randomized Controlled Trial of Intra-Aortic Adenosine Infusion Before Release of the Aortic Cross-Clamp During Coronary Artery Bypass Surgery. J Cardiothorac Vasc Anesth. 2018 Dec;32(6):2520-2527. doi: 10.1053/j.jvca.2017.10.041. Epub 2017 Dec 8. PMID 29225152
• Abdelwahab AA, Sabry M, Elshora HA, Arafat AA. Effect of Fast Cardioplegic Arrest Induced by Adenosine on Cardiac Troponin Levels After Heart Valve Surgery. Heart Lung Circ. 2019 Nov;28(11):1714-1719. doi: 10.1016/j.hlc.2018.08.017. Epub 2018 Sep 12. PMID 30253969
• Jakobsen O, Naesheim T, Aas KN, Sorlie D, Steensrud T. Adenosine instead of supranormal potassium in cardioplegia: it is safe, efficient, and reduces the incidence of postoperative atrial fibrillation. A randomized clinical trial. J Thorac Cardiovasc Surg. 2013 Mar;145(3):812-8. doi: 10.1016/j.jtcvs.2012.07.058. Epub 2012 Sep 7. PMID 22964356
• Mentzer RM Jr, Birjiniuk V, Khuri S, Lowe JE, Rahko PS, Weisel RD, Wellons HA, Barker ML, Lasley RD. Adenosine myocardial protection: preliminary results of a phase II clinical trial. Ann Surg. 1999 May;229(5):643-9; discussion 649-50. doi: 10.1097/00000658-199905000-00006. PMID 10235522

Identifiers

NCT: NCT07426237 · 7.975.821

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗