Adenosine as an Adjunct to Blood Cardioplegia

The Effect of Adenosine on Myocardial Protection in Intermittent Warm Blood Cardioplegia: A Randomized Placebo-controlled Trial

Myocardial protection is a major issue in cardiac surgery, since inadequate protection increases the risk of postoperative cardiac dysfunction. The main principle of myocardial protection in cardiac surgery is to preserve myocardial function by preventing ischemia with blood cardioplegia . Previous studies have shown that adenosine as an adjunct to blood cardioplegia can be safely used in cardiac surgery. In the Amphia Hospital, adenosine is already used as standard care as an initial cardioplegic bolus in minimally invasive port access operations. Whether, adenosine as an adjunct to intermittent warm blood cardioplegia, has an added value remains unclear. Therefore the investigators would like to investigate the effect of the addition of adenosine to standard intermittent warm blood cardioplegia in patients scheduled for minimally invasive, port access operations (mitral valve surgery).

Half of the participants will receive standard intermittent warm blood cardioplegia, while the other half will receive intermittent warm blood cardioplegia enriched with adenosine.

Study Overview

• Status: Unknown
• Conditions: Cardiomyopathies; Pathological Processes
• Intervention / Treatment: Drug: Adenosine

Detailed Description

Myocardial protection is a major issue in cardiac surgery, since inadequate protection increases the risk of postoperative cardiac dysfunction. The main principle of myocardial protection in cardiac surgery is to preserve myocardial function by preventing ischemia with blood cardioplegia . Previous studies have shown that adenosine as an adjunct to blood cardioplegia can be safely used in cardiac surgery. In the Amphia Hospital, adenosine is already used as standard care as an initial cardioplegic bolus in minimally invasive port access operations. Whether, adenosine as an adjunct to intermittent warm blood cardioplegia, has an added value remains unclear. Therefore the investigators would like to investigate whether the addition of adenosine to standard intermittent warm blood cardioplegia reduces the 6-hours post-operative cardiac troponin T (cTnT) in patients scheduled for minimally invasive, port access operations (mitral valve surgery).

• Study Type: Interventional
• Enrollment (Anticipated): 100
• Phase: Phase 2

Contacts and Locations

Study Locations

• Netherlands
  • Noord-Brabant
    • Breda, Noord-Brabant, Netherlands, 4818CK
      • Recruiting
      • Amphia Hospital
      • Contact: Jeffrey Engelhart, PharmD; Phone Number: 0031765954391; Email: jengelhart@amphia.nl
      • Contact: Thierry Scohy, MD; Phone Number: 0031765955570; Email: tscohy@amphia.nl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Elective cardiac surgical patients

  • minimally invasive, port access surgery (mitral valve surgery)

Exclusion Criteria:

• All non-minimally invasive, port access surgery
• Theophylline or dipyridamole use up to 24 hours prior to surgery
• Products that contain caffeine of theobromine up to 12 hours prior to surgery (coffee, chocolate, energizing drinks (e.g. Red Bull), tea, soda (coke), etc)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: standard cardioplegia; Delivery of cardioplegic solutions will be according to the standard protocol (Amphia hospital, Breda, the Netherlands). Oxygenated blood and cardioplegic maintenance solution is delivered in a 20:1 ratio. Cardioplegic solutions will be administered at 20-minutes intervals. The flow of the cardioplegia must be at 300 ml/min, the duration is approximately 1 minute. The cardioplegic maintenance solution consists of a 500 ml normal saline (0.9% NaCl) infusion bag. Potassiumchloride (20 mmol) and magnesiumsulphate (1000 mg) is added according to standard protocol. This arms receives standard intermittent 20:1 diluted warm blood cardioplegic solution. Intervention: n/a
Experimental: adenosine enriched cardioplegia; Delivery of cardioplegic solutions will be according to the standard protocol (Amphia hospital, Breda, the Netherlands). Oxygenated blood and cardioplegic maintenance solution is delivered in a 20:1 ratio. Cardioplegic solutions will be administered at 20-minutes intervals. The flow of the cardioplegia must be at 300 ml/min, the duration is approximately 1 minute. The cardioplegic maintenance solution consists of a 1000 mg = 500 ml adenosine infusion bag (2 mg/ml). Potassiumchloride (20 mmol) and magnesiumsulphate (1000 mg) is added according to standard protocol. This arms receives adenosine enriched, intermittent 20:1 diluted warm blood cardioplegic solution. Intervention: Drug: Adenosine	Drug: Adenosine; This group receives intermittent warm blood cardioplegia enriched with adenosine; Other Names: Adenocor

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
6-hour cardiac Troponin T (cTnT) release	The primary end point is 6-hour cTnT release	6 hours post-operative

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
18-hour cardiac Troponin T (cTnT) area under the curve (AUC) release	18-hour postoperative AUC release of cardiac troponin T Routine blood samples pre-operatively from peripheral blood (T0); post-operatively, from peripheral blood, at arrival at ICU (T1) and 6 hours after arrival at ICU (T2), and 18 hours after arrival at ICU (T3).	cardiac Troponin T (cTnT) AUC will be assessed at different time points, the latest up to 18 hours after ICU arrival
Incidence of myocardial injury on 12-lead ECG	Incidence of myocardial injury on 12-lead ECG; New-onset Left bundle branch block (LBBB); New-onset Q wave	participants will be followed for the duration of ICU stay, an expected average of 2 days
Vasoactive-inotropic score	The hourly doses of the following inotropic and vasoactive medications are recorded for the first 18 h after post-operative admission to the ICU: dopamine, dobutamine, epinephrine, norepinephrine, milrinone and vasopressin.	participants will be followed for the duration of ICU stay, an expected average of 2 days
Vasoconstrictor usage	Vasoconstrictor usage yes/no	participants will be followed for the duration of ICU stay, an expected average of 2 days
Incidence of new onset Atrial fibrillation (AF)	Incidence of new onset AF	participants will be followed for the duration of ICU stay, an expected average of 2 days
Routine blood samples	The amount of creatine kinase MB (CK-MB) and Creatinine at different time intervals. preoperatively from peripheral blood (T0); post-operatively, from peripheral blood, at arrival at ICU (T1) and 6 hours after arrival at ICU (T2)	Routine blood samples will be assessed at different time points, the latest up to 6 hours after ICU arrival
Mean arterial pressure (MAP)	Haemodynamic monitoring	participants will be followed for the duration of ICU stay, an expected average of 2 days
postoperative left ventricular ejection fraction (LVEF)	3-D transesophageal echocardiography (TEE) postoperative left ventricular ejection fraction (LVEF) after skin closure	postoperative after skin closure, an expected average of 3 hours after starting surgery
Wall Motion Score Index (WMSI)	3-D transesophageal echocardiography (TEE) Wall Motion Score Index (WMSI) after skin closure	postoperative after skin closure, an expected average of 3 hours after starting surgery
Heart rate (HR)	Haemodynamic monitoring. Heart rate will be measured in beats per minute (bpm).	participants will be followed for the duration of ICU stay, an expected average of 2 days
Cardiac index (CI)	Cardiac index (CI) is a haemodynamic parameter that relates the cardiac output (CO) from left ventricle in one minute to body surface area (BSA)	participants will be followed for the duration of ICU stay, an expected average of 2 days
Systemic vascular resistance index (SVRI)	SVRI = 80 x (MAP - RAP)/CI MAP = Mean Arterial Pressure (mmHg) RAP = Right Arterial Pressure (mmHg) CI = Cardiac Index (L/min/m2)	participants will be followed for the duration of ICU stay, an expected average of 2 days

Collaborators and Investigators

• Sponsor: Amphia Hospital
• Investigators: Principal Investigator: Jeffrey Engelhart, PharmD, Amphia Hospital

Publications and helpful links

General Publications

• Onorati F, Santini F, Dandale R, Ucci G, Pechlivanidis K, Menon T, Chiominto B, Mazzucco A, Faggian G. "Polarizing" microplegia improves cardiac cycle efficiency after CABG for unstable angina. Int J Cardiol. 2013 Sep 10;167(6):2739-46. doi: 10.1016/j.ijcard.2012.06.099. Epub 2012 Jul 12.
• Ahlsson A, Sobrosa C, Kaijser L, Jansson E, Bomfim V. Adenosine in cold blood cardioplegia--a placebo-controlled study. Interact Cardiovasc Thorac Surg. 2012 Jan;14(1):48-55. doi: 10.1093/icvts/ivr027. Epub 2011 Nov 15.
• Cohen G, Feder-Elituv R, Iazetta J, Bunting P, Mallidi H, Bozinovski J, Deemar C, Christakis GT, Cohen EA, Wong BI, McLean RD, Myers M, Morgan CD, Mazer CD, Smith TS, Goldman BS, Naylor CD, Fremes SE. Phase 2 studies of adenosine cardioplegia. Circulation. 1998 Nov 10;98(19 Suppl):II225-33.
• Cohen G, Borger MA, Weisel RD, Rao V. Intraoperative myocardial protection: current trends and future perspectives. Ann Thorac Surg. 1999 Nov;68(5):1995-2001. doi: 10.1016/s0003-4975(99)01026-7.
• Chauhan S, Wasir HS, Bhan A, Rao BH, Saxena N, Venugopal P. Adenosine for cardioplegic induction: a comparison with St Thomas solution. J Cardiothorac Vasc Anesth. 2000 Feb;14(1):21-4. doi: 10.1016/s1053-0770(00)90050-8.
• 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.
• 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.
• Liu R, Xing J, Miao N, Li W, Liu W, Lai YQ, Luo Y, Ji B. The myocardial protective effect of adenosine as an adjunct to intermittent blood cardioplegia during open heart surgery. Eur J Cardiothorac Surg. 2009 Dec;36(6):1018-23. doi: 10.1016/j.ejcts.2009.06.033. Epub 2009 Aug 15.

Study record dates

Study Major Dates

• Study Start: February 1, 2016
• Primary Completion (Anticipated): July 1, 2018
• Study Completion (Anticipated): December 1, 2018

Study Registration Dates

• First Submitted: February 3, 2016
• First Submitted That Met QC Criteria: February 10, 2016
• First Posted (Estimate): February 15, 2016

Study Record Updates

• Last Update Posted (Actual): April 20, 2017
• Last Update Submitted That Met QC Criteria: April 19, 2017
• Last Verified: April 1, 2017

More Information

Terms related to this study

• Keywords: Adenosine; Cardiac Surgery; Therapeutic Uses; Cardioplegia; Minimally Invasive Surgery; Intermittent warm blood cardioplegia; minimally invasive mitral valve plasty (mini-MPL); minimally invasive mitral valve replacement (mini-MVR)
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Cardiomyopathies; Pathologic Processes; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Vasodilator Agents; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Purinergic Agents; Purinergic P1 Receptor Agonists; Purinergic Agonists; Adenosine
• Other Study ID Numbers: 1437; 2015-001923-22 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No