Back to resultsCustodiol-HTK (Histidine-tryptophan-ketoglutarate) Solution as a Cardioplegic Agent
Primary Purpose
Coronary Artery Disease, Myocardial Ischemia, Coronary Disease
Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Custodiol HTK
Cold Blood Cardioplegia
Sponsored by
About this trial
This is an interventional treatment trial for Coronary Artery Disease focused on measuring 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
Eligibility Criteria
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.
Sites / Locations
- William Beaumont Hospital
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Active Comparator
Arm Label
Cardioplegia: Custodiol HTK Solution
Cold Blood Cardioplegia
Arm Description
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.
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.
Outcomes
Primary Outcome Measures
Change in Creatine Phosphokinase-MB Isoenzyme (CK-MB)
Creatine phosphokinase MB isoenzyme (CK-MB) difference from baseline 7 hours post surgery
Change in Troponin I
Troponin I values, difference from baseline 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
Secondary Outcome Measures
Cardiac Dysrhythmias
Number of participants with new or worsening of cardiac dysrhythmias
All Cause Mortality
Number of participants with all-cause mortality AS reported in the Society of Thoracic Surgeons (STS) database after 30 days postoperative
Cardiovascular Mortality
Number of participants with cardiovascular-related mortality AS reported in the Society of Thoracic Surgeons (STS) database after 30 days postoperative
Time on Mechanically Assisted Ventilation
time in hours from intubation to extubation, with intervening transport to the cardiac critical care unit.
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
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.
Intensive Care Unit (ICU) Length of Stay
Duration of stay in ICU, from ICU admission to ICU discharge
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.
Biochemical Marker - Creatine Kinase MB Isoenzyme (CK-MB)
CK-MB measured pre-operatively
Biochemical Marker - Creatine Kinase MB Isoenzyme (CK-MB)
CK-MB measured 24 hours post-operatively
Biochemical Marker - Creatine Kinase MB Isoenzyme (CK-MB)
CK-MB measured 48 hours post-operatively
Cardiac Marker - Troponin-I
Troponin-I measured pre-operatively
Cardiac Marker - Troponin-I
Troponin-I measured 24 hours post-operative
Cardiac Marker - Troponin-I
Troponin-I measured 48 hours post-operative
Full Information
NCT ID
NCT01681095
First Posted
August 10, 2012
Last Updated
July 23, 2019
Sponsor
Marc Sakwa, MD
Collaborators
Essential Pharmaceuticals, LLC
1. Study Identification
Unique Protocol Identification Number
NCT01681095
Brief Title
Custodiol-HTK (Histidine-tryptophan-ketoglutarate) Solution as a Cardioplegic Agent
Official Title
Custodiol-HTK Solution as a Cardioplegic Agent- A Prospective Non-Inferiority Randomized Clinical Trial
Study Type
Interventional
2. Study Status
Record Verification Date
January 2017
Overall Recruitment Status
Completed
Study Start Date
August 2012 (undefined)
Primary Completion Date
August 2014 (Actual)
Study Completion Date
April 2016 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Marc Sakwa, MD
Collaborators
Essential Pharmaceuticals, LLC
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
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
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Coronary Artery Disease, Myocardial Ischemia, Coronary Disease, Heart Diseases, Valvular Heart Disease
Keywords
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
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
110 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Cardioplegia: Custodiol HTK Solution
Arm Type
Experimental
Arm Description
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.
Arm Title
Cold Blood Cardioplegia
Arm Type
Active Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Custodiol HTK
Other Intervention Name(s)
Histidine-tryptophan-ketoglutarate cardioplegia solution
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Cold Blood Cardioplegia
Intervention Description
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.
Primary Outcome Measure Information:
Title
Change in Creatine Phosphokinase-MB Isoenzyme (CK-MB)
Description
Creatine phosphokinase MB isoenzyme (CK-MB) difference from baseline 7 hours post surgery
Time Frame
Baseline and 7 hours post surgery
Title
Change in Troponin I
Description
Troponin I values, difference from baseline 7 hours post surgery
Time Frame
Baseline and 7 hours post surgery
Title
Changes in Left Ventricular (LV) Ejection Fraction (EF) by Transthoracic Echocardiogram (TTE)
Description
LV ejection fraction by TTE, difference from baseline at 24 hours post surgery
Time Frame
Baseline and 24 hours post surgery
Secondary Outcome Measure Information:
Title
Cardiac Dysrhythmias
Description
Number of participants with new or worsening of cardiac dysrhythmias
Time Frame
up to 36 hrs post surgery
Title
All Cause Mortality
Description
Number of participants with all-cause mortality AS reported in the Society of Thoracic Surgeons (STS) database after 30 days postoperative
Time Frame
30 days post procedure
Title
Cardiovascular Mortality
Description
Number of participants with cardiovascular-related mortality AS reported in the Society of Thoracic Surgeons (STS) database after 30 days postoperative
Time Frame
30 days post procedure
Title
Time on Mechanically Assisted Ventilation
Description
time in hours from intubation to extubation, with intervening transport to the cardiac critical care unit.
Time Frame
up to 36 hours post procedure
Title
Duration of Vasopressor / Inotropic Agent
Description
Total time in minutes on any vasopressor or inotropic agent, including norepinephrine, epinephrine, vasopressin, milrinone, dobutamine, dopamine and/or neo-synephrine
Time Frame
up to 36 hours post procedure
Title
Postoperative Inotropic Infusion >20 Minutes
Description
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.
Time Frame
during operative procedure
Title
Intensive Care Unit (ICU) Length of Stay
Description
Duration of stay in ICU, from ICU admission to ICU discharge
Time Frame
up to 100 days after admission
Title
Myocardial Infarction
Description
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.
Time Frame
up to 36 hours post procedure
Title
Biochemical Marker - Creatine Kinase MB Isoenzyme (CK-MB)
Description
CK-MB measured pre-operatively
Time Frame
pre-operative
Title
Biochemical Marker - Creatine Kinase MB Isoenzyme (CK-MB)
Description
CK-MB measured 24 hours post-operatively
Time Frame
24 hours post procedure
Title
Biochemical Marker - Creatine Kinase MB Isoenzyme (CK-MB)
Description
CK-MB measured 48 hours post-operatively
Time Frame
48 hours post procedure
Title
Cardiac Marker - Troponin-I
Description
Troponin-I measured pre-operatively
Time Frame
pre-operatively
Title
Cardiac Marker - Troponin-I
Description
Troponin-I measured 24 hours post-operative
Time Frame
24 hours post procedure
Title
Cardiac Marker - Troponin-I
Description
Troponin-I measured 48 hours post-operative
Time Frame
48 hours post procedure
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Marc Sakwa, M.D.
Organizational Affiliation
Beaumont Health System
Official's Role
Principal Investigator
Facility Information:
Facility Name
William Beaumont Hospital
City
Royal Oak
State/Province
Michigan
ZIP/Postal Code
48073
Country
United States
12. IPD Sharing Statement
Plan to Share IPD
No
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Custodiol-HTK (Histidine-tryptophan-ketoglutarate) Solution as a Cardioplegic Agent
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