Try our beta test site

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

This study has been completed.
Sponsor:
Collaborator:
Essential Pharmaceuticals, LLC
Information provided by (Responsible Party):
Marc Sakwa, MD, William Beaumont Hospitals
ClinicalTrials.gov Identifier:
NCT01681095
First received: August 10, 2012
Last updated: January 10, 2017
Last verified: January 2017
  Purpose
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.

Condition Intervention Phase
Coronary Artery Disease
Myocardial Ischemia
Coronary Disease
Heart Diseases
Valvular Heart Disease
Drug: Custodiol HTK
Drug: Cold Blood Cardioplegia
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Custodiol-HTK Solution as a Cardioplegic Agent- A Prospective Non-Inferiority Randomized Clinical Trial

Resource links provided by NLM:


Further study details as provided by William Beaumont Hospitals:

Primary Outcome Measures:
  • Change in Creatine Phosphokinase-MB Isoenzyme (CK-MB) [ Time Frame: Baseline and 7 hours post surgery ]
    Creatine phosphokinase MB isoenzyme (CK-MB) difference from baseline 7 hours post surgery

  • Change in Troponin I [ Time Frame: Baseline and 7 hours post surgery ]
    Troponin I values, difference from baseline 7 hours post surgery

  • Changes in Left Ventricular (LV) Ejection Fraction (EF) by Transthoracic Echocardiogram (TTE) [ Time Frame: Baseline and 24 hours post surgery ]
    LV ejection fraction by TTE, difference from baseline at 24 hours post surgery


Secondary Outcome Measures:
  • Cardiac Dysrhythmias [ Time Frame: up to 36 hrs post surgery ]
    Number of participants with new or worsening of cardiac dysrhythmias

  • All Cause Mortality [ Time Frame: 30 days post procedure ]
    Number of participants with all-cause mortality AS reported in the Society of Thoracic Surgeons (STS) database after 30 days postoperative

  • Cardiovascular Mortality [ Time Frame: 30 days post procedure ]
    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 Frame: up to 36 hours post procedure ]
    time in hours from intubation to extubation, with intervening transport to the cardiac critical care unit.

  • Duration of Vasopressor / Inotropic Agent [ Time Frame: up to 36 hours post procedure ]
    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 [ Time Frame: during operative procedure ]
    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 [ Time Frame: up to 100 days after admission ]
    Duration of stay in ICU, from ICU admission to ICU discharge

  • Myocardial Infarction [ Time Frame: up to 36 hours post procedure ]
    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) [ Time Frame: pre-operative ]
    CK-MB measured pre-operatively

  • Biochemical Marker - Creatine Kinase MB Isoenzyme (CK-MB) [ Time Frame: 24 hours post procedure ]
    CK-MB measured 24 hours post-operatively

  • Biochemical Marker - Creatine Kinase MB Isoenzyme (CK-MB) [ Time Frame: 48 hours post procedure ]
    CK-MB measured 48 hours post-operatively

  • Cardiac Marker - Troponin-I [ Time Frame: pre-operatively ]
    Troponin-I measured pre-operatively

  • Cardiac Marker - Troponin-I [ Time Frame: 24 hours post procedure ]
    Troponin-I measured 24 hours post-operative

  • Cardiac Marker - Troponin-I [ Time Frame: 48 hours post procedure ]
    Troponin-I measured 48 hours post-operative


Enrollment: 110
Study Start Date: August 2012
Study Completion Date: April 2016
Primary Completion Date: August 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Cardioplegia: Custodiol HTK Solution

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
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.
Other Name: Histidine-tryptophan-ketoglutarate cardioplegia solution
Active Comparator: Cold Blood Cardioplegia

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
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.

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.
  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01681095

Locations
United States, Michigan
William Beaumont Hospital
Royal Oak, Michigan, United States, 48073
Sponsors and Collaborators
Marc Sakwa, MD
Essential Pharmaceuticals, LLC
Investigators
Principal Investigator: Marc Sakwa, M.D. Beaumont Health System
  More Information

Publications:
Athanasuleas C., Buckberg G. Myocardial protection and cardioplegia. Cardiopulmonary Bypass. New York: CambridgeUniversity Press; 2009: p. 82.
Lee D. H., Park N. H., Keum D. Y., Choi S. Y., Lee K. S., Yoo Y. S. Comparison of Myocardial Protective Effect between the Cold Blood Cardioplegia and Histidine-Tryptophan-Ketoglutarate Solution.Korean J Thorac Cardiovasc Surg. 2004;37(9):739-41.
Kim S. , Lee Y. S. , Woo J. S. , Sung S. C. , Choi P. J. , Cho G. J., Bang J. H., Roh M. S. Histidine-tryptophan-ketoglutarate Versus Blood Cardioplegic Solutions: A Prospective, Myocardial Ultrastructural Study.Korean J Thorac Cardiovasc Surg. 2007;40(1):8-16.
Choi Y. S., Bang S. O. , Chang B. C. , Lee S. , Park C. H. , Kwak Y. L. A Comparison of the Effects of Histidine-tryptophan-ketoglutarate Solution versus Cold Blood Cardioplegic Solution on Myocardial Protection in Mitral Valve Surgery.Korean J Thorac Cardiovasc Surg. 2007;40(6):399-406

Responsible Party: Marc Sakwa, MD, Principal Investigator, William Beaumont Hospitals
ClinicalTrials.gov Identifier: NCT01681095     History of Changes
Other Study ID Numbers: 2012-125
Study First Received: August 10, 2012
Results First Received: April 26, 2016
Last Updated: January 10, 2017
Individual Participant Data  
Plan to Share IPD: No

Keywords provided by William Beaumont Hospitals:
Heart Diseases
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

Additional relevant MeSH terms:
Heart Diseases
Coronary Artery Disease
Myocardial Ischemia
Coronary Disease
Ischemia
Heart Valve Diseases
Cardiovascular Diseases
Arteriosclerosis
Arterial Occlusive Diseases
Vascular Diseases
Pathologic Processes
Pharmaceutical Solutions
Mannitol
Procaine
Cardioplegic Solutions
Tryptophan
Diuretics, Osmotic
Diuretics
Natriuretic Agents
Physiological Effects of Drugs
Anesthetics, Local
Anesthetics
Central Nervous System Depressants
Sensory System Agents
Peripheral Nervous System Agents
Antidepressive Agents, Second-Generation
Antidepressive Agents
Psychotropic Drugs

ClinicalTrials.gov processed this record on March 24, 2017