Custodiol-HTK (Histidine-tryptophan-ketoglutarate) Solution as a Cardioplegic Agent

Study Overview
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Brief Summary
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The purpose of the study is to demonstrate that Custodiol-HTK is not inferior to cold cardioplegic solution in patients undergoing cardiovascular surgery requiring cardioplegic arrest.

Detailed Description
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The objective of this study is to demonstrate that Custodiol is not inferior to cold cardioplegic solution for myocardial protection by comparing standard cold blood cardioplegia to Custodiol solution with respect to myocardial injury as measured by Creatine phosphokinase MB isoenzyme (CK-MB),troponin-I at 7 hours post surgery and changes in ejection fraction by trans-thoracic echocardiogram (TTE)or trans-esophageal echocardiogram (TEE) at 24 hours post surgery.

Official Title
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Custodiol-HTK Solution as a Cardioplegic Agent- A Prospective Non-Inferiority Randomized Clinical Trial

Conditions
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Coronary Artery Disease, Myocardial Ischemia, Coronary Disease, Heart Diseases, Valvular Heart Disease

Intervention / Treatment
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* Drug: Custodiol HTK
* Drug: Cold Blood Cardioplegia


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients undergoing scheduled cardiac surgery requiring cardioplegic arrest with expected cross clamp time>45 minutes Patients age 18 and older Exclusion Criteria: Pregnant women* Urgent or emergent cases Repeat cardiovascular surgical procedures Patients on dialysis Any known allergies to components of either cardioplegia solution *All women of child bearing potential must have a negative serum or urine pregnancy test.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cardioplegia: Custodiol HTK Solution<br>Custodiol HTK (histidine-tryptophan-ketoglutarate) cardioplegia: One liter of HTK solution (Custodiol; Koehler Chemi, Alsbach-Haenlien, Germany) contains the following components: 15 mmol/L sodium chloride, 9 mmol/L potassium chloride, 4 mmol/L magnesium chloride, 18 mmol/L histidine hydrochloride, 180 mmol/L histidine, 2 mmol/L tryptophan, 30 mmol/L mannitol, 0.015 mmol/L calcium chloride, 1 mmol/L potassium hydrogen 2-ketoglutarate, osmolarity 310 mOsm/kg, pH 7.02-7.20. Custodiol-HTK was delivered to establish and maintain cardiac arrest. After cross-clamping of the aorta approximately 1-2 L of Custodiol-HTK was infused into the ascending aorta over 6-8 minutes. Additional doses of 100-200 ml were administered as needed. Custodiol-HTK was delivered at a temperature of 4°C - 10°C. | Drug: Custodiol HTK<br>* After cross-clamping of the aorta approximately 1-2 L of Custodiol-HTK was infused into the ascending aorta over 6-8 minutes. Additional doses of 100-200 ml were administered as needed. The cardioplegic solution was delivered at a temperature of 4°C - 10°C.<br>* Other names: Histidine-tryptophan-ketoglutarate cardioplegia solution;|
| Active Comparator: Cold Blood Cardioplegia<br>Cold Blood Cardioplegia: One liter of cold blood cardioplegic solution, mixed at a ratio of 4:1 per Beaumont standard of care (blood /cardioplegic solution), contains the following in a 500 cc bag of D5W (dextrose 5% in water): 50meq/L potassium chloride, 37.5 meq/L sodium bicarbonate and 7.5 meq/L magnesium sulfate. After cross-clamping the aorta, at least 1000 mL of a 4:1 mixture of cold blood: cold crystalloid was administered at a pressure of 300 mmHg or less via a twin roller pump. Every 20 minutes an additional > 200 mL was administered as needed. The cardioplegic solution was delivered at a temperature of 4°C - 8°C. | Drug: Cold Blood Cardioplegia<br>* After cross-clamping the aorta, at least 1000 mL of a 4:1 mixture of cold blood: cold crystalloid was administered at a pressure of 300 mmHg or less via a twin roller pump. Every 20 minutes an additional > 200 mL was administered in an antegrade/retrograde fashion throughout the remainder of the case. The cardioplegic solution was delivered at a temperature of 4°C - 8°C.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Creatine Phosphokinase-MB Isoenzyme (CK-MB) | Creatine phosphokinase MB isoenzyme (CK-MB) difference from baseline 7 hours post surgery | Baseline and 7 hours post surgery | 
| Change in Troponin I | Troponin I values, difference from baseline 7 hours post surgery | Baseline and 7 hours post surgery | 
| Changes in Left Ventricular (LV) Ejection Fraction (EF) by Transthoracic Echocardiogram (TTE) | LV ejection fraction by TTE, difference from baseline at 24 hours post surgery | Baseline and 24 hours post surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cardiac Dysrhythmias | Number of participants with new or worsening of cardiac dysrhythmias | up to 36 hrs post surgery | 
| All Cause Mortality | Number of participants with all-cause mortality AS reported in the Society of Thoracic Surgeons (STS) database after 30 days postoperative | 30 days post procedure | 
| Cardiovascular Mortality | Number of participants with cardiovascular-related mortality AS reported in the Society of Thoracic Surgeons (STS) database after 30 days postoperative | 30 days post procedure | 
| Time on Mechanically Assisted Ventilation | time in hours from intubation to extubation, with intervening transport to the cardiac critical care unit. | up to 36 hours post procedure | 
| Duration of Vasopressor / Inotropic Agent | Total time in minutes on any vasopressor or inotropic agent, including norepinephrine, epinephrine, vasopressin, milrinone, dobutamine, dopamine and/or neo-synephrine | up to 36 hours post procedure | 
| Postoperative Inotropic Infusion >20 Minutes | Number of patients receiving vasopressor or inotropic infusion for greater than 20 minutes in the operating room, including norepinephrine, epinephrine, vasopressin, milrinone, dobutamine, dopamine and/or neo-synephrine. | during operative procedure | 
| Intensive Care Unit (ICU) Length of Stay | Duration of stay in ICU, from ICU admission to ICU discharge | up to 100 days after admission | 
| Myocardial Infarction | Number or participants fulfilling at least two of the following 3 criteria: (1) CK-MB of 100 ug/L or more and/or troponin-I of 3.0 ug/L or more, (2) appearance of new postoperative Q waves on the EKG of more than 0.03 seconds, and (3) a new hypokinetic or akinetic area in the left or right ventricle by echocardiography. | up to 36 hours post procedure | 
| Biochemical Marker - Creatine Kinase MB Isoenzyme (CK-MB) | CK-MB measured pre-operatively | pre-operative | 
| Biochemical Marker - Creatine Kinase MB Isoenzyme (CK-MB) | CK-MB measured 24 hours post-operatively | 24 hours post procedure | 
| Biochemical Marker - Creatine Kinase MB Isoenzyme (CK-MB) | CK-MB measured 48 hours post-operatively | 48 hours post procedure | 
| Cardiac Marker - Troponin-I | Troponin-I measured pre-operatively | pre-operatively | 
| Cardiac Marker - Troponin-I | Troponin-I measured 24 hours post-operative | 24 hours post procedure | 
| Cardiac Marker - Troponin-I | Troponin-I measured 48 hours post-operative | 48 hours post procedure | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Physiological Effects of Drugs, Cardiovascular Agents, Therapeutic Uses, Pharmacologic Actions, Mannitol, Cardiac Surgery, Cardioplegic Solutions, HTK solution, Myocardial protection, Coronary Artery Disease, Myocardial Ischemia, Coronary Disease, Heart Diseases