- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01681095
Custodiol-HTK (Histidine-tryptophan-ketoglutarate) Solution as a Cardioplegic Agent
Custodiol-HTK Solution as a Cardioplegic Agent- A Prospective Non-Inferiority Randomized Clinical Trial
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
Study Type
Enrollment (Actual)
Phase
- Phase 2
Contacts and Locations
Study Locations
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-
Michigan
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Royal Oak, Michigan, United States, 48073
- William Beaumont Hospital
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-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
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. |
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 Names:
|
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. |
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.
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
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
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Baseline and 7 hours post surgery
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Change in Troponin I
Time Frame: Baseline and 7 hours post surgery
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Troponin I values, difference from baseline 7 hours post surgery
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Baseline and 7 hours post surgery
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Changes in Left Ventricular (LV) Ejection Fraction (EF) by Transthoracic Echocardiogram (TTE)
Time Frame: Baseline and 24 hours post surgery
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LV ejection fraction by TTE, difference from baseline at 24 hours post surgery
|
Baseline and 24 hours post surgery
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Cardiac Dysrhythmias
Time Frame: up to 36 hrs post surgery
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Number of participants with new or worsening of cardiac dysrhythmias
|
up to 36 hrs post surgery
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All Cause Mortality
Time Frame: 30 days post procedure
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Number of participants with all-cause mortality AS reported in the Society of Thoracic Surgeons (STS) database after 30 days postoperative
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30 days post procedure
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Cardiovascular Mortality
Time Frame: 30 days post procedure
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Number of participants with cardiovascular-related mortality AS reported in the Society of Thoracic Surgeons (STS) database after 30 days postoperative
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30 days post procedure
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Time on Mechanically Assisted Ventilation
Time Frame: up to 36 hours post procedure
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time in hours from intubation to extubation, with intervening transport to the cardiac critical care unit.
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up to 36 hours post procedure
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Duration of Vasopressor / Inotropic Agent
Time Frame: up to 36 hours post procedure
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Total time in minutes on any vasopressor or inotropic agent, including norepinephrine, epinephrine, vasopressin, milrinone, dobutamine, dopamine and/or neo-synephrine
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up to 36 hours post procedure
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Postoperative Inotropic Infusion >20 Minutes
Time Frame: during operative procedure
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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.
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during operative procedure
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Intensive Care Unit (ICU) Length of Stay
Time Frame: up to 100 days after admission
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Duration of stay in ICU, from ICU admission to ICU discharge
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up to 100 days after admission
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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.
|
up to 36 hours post procedure
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Biochemical Marker - Creatine Kinase MB Isoenzyme (CK-MB)
Time Frame: pre-operative
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CK-MB measured pre-operatively
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pre-operative
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Biochemical Marker - Creatine Kinase MB Isoenzyme (CK-MB)
Time Frame: 24 hours post procedure
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CK-MB measured 24 hours post-operatively
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24 hours post procedure
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Biochemical Marker - Creatine Kinase MB Isoenzyme (CK-MB)
Time Frame: 48 hours post procedure
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CK-MB measured 48 hours post-operatively
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48 hours post procedure
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Cardiac Marker - Troponin-I
Time Frame: pre-operatively
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Troponin-I measured pre-operatively
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pre-operatively
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Cardiac Marker - Troponin-I
Time Frame: 24 hours post procedure
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Troponin-I measured 24 hours post-operative
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24 hours post procedure
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Cardiac Marker - Troponin-I
Time Frame: 48 hours post procedure
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Troponin-I measured 48 hours post-operative
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48 hours post procedure
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Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Principal Investigator: Marc Sakwa, M.D., Beaumont Health System
Publications and helpful links
General Publications
- Allen BS, Winkelmann JW, Hanafy H, Hartz RS, Bolling KS, Ham J, Feinstein S. Retrograde cardioplegia does not adequately perfuse the right ventricle. J Thorac Cardiovasc Surg. 1995 Jun;109(6):1116-24; discussion 1124-6. doi: 10.1016/S0022-5223(95)70195-8.
- Braathen B, Jeppsson A, Schersten H, Hagen OM, Vengen O, Rexius H, Lepore V, Tonnessen T. One single dose of histidine-tryptophan-ketoglutarate solution gives equally good myocardial protection in elective mitral valve surgery as repetitive cold blood cardioplegia: a prospective randomized study. J Thorac Cardiovasc Surg. 2011 Apr;141(4):995-1001. doi: 10.1016/j.jtcvs.2010.07.011. Epub 2010 Aug 30.
- Careaga G, Salazar D, Tellez S, Sanchez O, Borrayo G, Arguero R. Clinical impact of histidine-ketoglutarate-tryptophan (HTK) cardioplegic solution on the perioperative period in open heart surgery patients. Arch Med Res. 2001 Jul-Aug;32(4):296-9. doi: 10.1016/s0188-4409(01)00296-x.
- Hachida M, Ookado A, Nonoyama M, Koyanagi H. Effect of HTK solution for myocardial preservation. J Cardiovasc Surg (Torino). 1996 Jun;37(3):269-74.
- Yang Q, He GW. Effect of cardioplegic and organ preservation solutions and their components on coronary endothelium-derived relaxing factors. Ann Thorac Surg. 2005 Aug;80(2):757-67. doi: 10.1016/j.athoracsur.2004.10.003.
- Beyersdorf F, Krause E, Sarai K, Sieber B, Deutschlander N, Zimmer G, Mainka L, Probst S, Zegelman M, Schneider W, et al. Clinical evaluation of hypothermic ventricular fibrillation, multi-dose blood cardioplegia, and single-dose Bretschneider cardioplegia in coronary surgery. Thorac Cardiovasc Surg. 1990 Feb;38(1):20-9. doi: 10.1055/s-2007-1013985.
- Savini C, Camurri N, Castelli A, Dell'Amore A, Pacini D, Suarez SM, Grillone G, Di Bartolomeo R. Myocardial protection using HTK solution in minimally invasive mitral valve surgery. Heart Surg Forum. 2005;8(1):E25-7. doi: 10.1532/HSF98.20041145.
- Braathen B, Tonnessen T. Cold blood cardioplegia reduces the increase in cardiac enzyme levels compared with cold crystalloid cardioplegia in patients undergoing aortic valve replacement for isolated aortic stenosis. J Thorac Cardiovasc Surg. 2010 Apr;139(4):874-80. doi: 10.1016/j.jtcvs.2009.05.036. Epub 2009 Jul 26.
- Hendrikx M, Jiang H, Gutermann H, Toelsie J, Renard D, Briers A, Pauwels JL, Mees U. Release of cardiac troponin I in antegrade crystalloid versus cold blood cardioplegia. J Thorac Cardiovasc Surg. 1999 Sep;118(3):452-9. doi: 10.1016/s0022-5223(99)70182-0.
- Aarsaether E, Stenberg TA, Jakobsen O, Busund R. Mechanoenergetic function and troponin T release following cardioplegic arrest induced by St Thomas' and histidine-tryptophan-ketoglutarate cardioplegia--an experimental comparative study in pigs. Interact Cardiovasc Thorac Surg. 2009 Oct;9(4):635-9. doi: 10.1510/icvts.2009.208231. Epub 2009 Jul 23.
- Gallandat Huet RC, Karliczek GF, van der Heide JN, Brenken U, Mooi B, van der Broeke JJ, Jenkins I, de Geus AF. Clinical effect of Bretschneider-HTK and St. Thomas cardioplegia on hemodynamic performance after bypass measured using an automatic datalogging database system. Thorac Cardiovasc Surg. 1988 Jun;36(3):151-6. doi: 10.1055/s-2007-1020064.
- Arslan A, Sezgin A, Gultekin B, Ozkan S, Akay T, Uguz E, Tasdelen A, Aslamaci S. Low-dose histidine-tryptophan-ketoglutarate solution for myocardial protection. Transplant Proc. 2005 Sep;37(7):3219-22. doi: 10.1016/j.transproceed.2005.08.020.
- Fannelop T, Dahle GO, Salminen PR, Moen CA, Matre K, Mongstad A, Eliassen F, Segadal L, Grong K. Multidose cold oxygenated blood is superior to a single dose of Bretschneider HTK-cardioplegia in the pig. Ann Thorac Surg. 2009 Apr;87(4):1205-13. doi: 10.1016/j.athoracsur.2009.01.041.
- Schaper J, Scheld HH, Schmidt U, Hehrlein F. Ultrastructural study comparing the efficacy of five different methods of intraoperative myocardial protection in the human heart. J Thorac Cardiovasc Surg. 1986 Jul;92(1):47-55.
- Athanasuleas C., Buckberg G. Myocardial protection and cardioplegia. Cardiopulmonary Bypass. New York: CambridgeUniversity Press; 2009: p. 82.
- Bical OM, Fromes Y, Paumier D, Gaillard D, Foiret JC, Trivin F. Does warm antegrade intermittent blood cardioplegia really protect the heart during coronary surgery? Cardiovasc Surg. 2001 Apr;9(2):188-93. doi: 10.1016/s0967-2109(00)00087-9.
- Sakata J, Morishita K, Ito T, Koshino T, Kazui T, Abe T. Comparison of clinical outcome between histidine-triptophan-ketoglutalate solution and cold blood cardioplegic solution in mitral valve replacement. J Card Surg. 1998 Jan;13(1):43-7. doi: 10.1111/j.1540-8191.1998.tb01053.x.
- 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
- Asano H, Kyo S, Ogiwara M, Tsunemoto M, Yokote Y, Omoto R, Koike K, Kobayashi T, Kobayashi J, Taketazu M. [Single-dose and high-volume Bretschneider cardioplegic solution for congenital heart surgery]. Kyobu Geka. 1999 Jan;52(1):82-6. Japanese.
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Pathologic Processes
- Cardiovascular Diseases
- Vascular Diseases
- Arteriosclerosis
- Arterial Occlusive Diseases
- Heart Diseases
- Coronary Artery Disease
- Myocardial Ischemia
- Coronary Disease
- Ischemia
- Heart Valve Diseases
- Psychotropic Drugs
- Antidepressive Agents
- Antidepressive Agents, Second-Generation
- Tryptophan
Other Study ID Numbers
- 2012-125
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
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