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

NCT ID: NCT01681095

Last Updated: 2019-08-06

Study Results

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE2

Total Enrollment

110 participants

Study Classification

INTERVENTIONAL

Study Start Date

2012-08-31

Study Completion Date

2016-04-30

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.

Conditions

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

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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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.

Group Type EXPERIMENTAL

Custodiol HTK

Intervention Type DRUG

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.

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.

Group Type ACTIVE_COMPARATOR

Cold Blood Cardioplegia

Intervention Type DRUG

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.

Interventions

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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.

Intervention Type 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.

Intervention Type DRUG

Other Intervention Names

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Histidine-tryptophan-ketoglutarate cardioplegia solution

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.
Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Essential Pharmaceuticals, LLC

OTHER

Sponsor Role collaborator

Marc Sakwa, MD

OTHER

Sponsor Role lead

Responsible Party

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Marc Sakwa, MD

Principal Investigator

Responsibility Role SPONSOR_INVESTIGATOR

Principal Investigators

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Marc Sakwa, M.D.

Role: PRINCIPAL_INVESTIGATOR

Beaumont Health

Locations

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William Beaumont Hospital

Royal Oak, Michigan, United States

Site Status

Countries

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United States

References

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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.

Reference Type BACKGROUND
PMID: 20800244 (View on PubMed)

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.

Reference Type BACKGROUND
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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.

Reference Type BACKGROUND
PMID: 8698763 (View on PubMed)

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.

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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.

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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.

Reference Type BACKGROUND
PMID: 15769709 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 19660338 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 10469959 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 19628529 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 3145585 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 16213352 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 19324152 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 3088335 (View on PubMed)

Athanasuleas C., Buckberg G. Myocardial protection and cardioplegia. Cardiopulmonary Bypass. New York: CambridgeUniversity Press; 2009: p. 82.

Reference Type BACKGROUND

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.

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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.

Reference Type BACKGROUND
PMID: 7776676 (View on PubMed)

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.

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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.

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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.

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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

Reference Type BACKGROUND

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.

Reference Type BACKGROUND
PMID: 10024809 (View on PubMed)

Other Identifiers

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2012-125

Identifier Type: -

Identifier Source: org_study_id

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