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

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ClinicalTrials.gov Identifier: NCT01681095

Recruitment Status : Completed

First Posted : September 7, 2012

Results First Posted : March 1, 2017

Last Update Posted : March 1, 2017

Sponsor:

Collaborator:

Essential Pharmaceuticals, LLC

Information provided by (Responsible Party):

Marc Sakwa, MD, William Beaumont Hospitals

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.

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

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.

Study Design


Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	110 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	Custodiol-HTK Solution as a Cardioplegic Agent- A Prospective Non-Inferiority Randomized Clinical Trial
Study Start Date :	August 2012
Actual Primary Completion Date :	August 2014
Actual Study Completion Date :	April 2016

Resource links provided by the National Library of Medicine

Drug Information available for: Histidine Tryptophan St. Thomas' Hospital cardioplegic solution Cardioplegic solution

U.S. FDA Resources

Arms and Interventions

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.	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.

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.

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.

Outcome Measures

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

Eligibility Criteria

Information from the National Library of Medicine

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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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): 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:

Braathen B, Jeppsson A, Scherstén H, Hagen OM, Vengen Ø, Rexius H, Lepore V, Tønnessen 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, Téllez S, Sánchez O, Borrayo G, Argüero 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.

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. Review.

Beyersdorf F, Krause E, Sarai K, Sieber B, Deutschländer 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.

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.

Braathen B, Tønnessen 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.

Aarsaether E, Stenberg TA, Jakobsen Ø, 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.

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.

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.

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.

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.

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.


Responsible Party:	Marc Sakwa, MD, Principal Investigator, William Beaumont Hospitals
ClinicalTrials.gov Identifier:	NCT01681095 History of Changes
Other Study ID Numbers:	2012-125
First Posted:	September 7, 2012 Key Record Dates
Results First Posted:	March 1, 2017
Last Update Posted:	March 1, 2017
Last Verified:	January 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	No

Keywords provided by Marc Sakwa, MD, William Beaumont Hospitals:


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

Additional relevant MeSH terms:


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

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