Custodiol-HTK Solution as a Cardioplegic Agent - Full Text View

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 Endpoint Classification: Safety/Efficacy Study Intervention Model: Single Group 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:

MedlinePlus related topics: Coronary Artery Disease Heart Diseases

Drug Information available for: Plegisol Cardioplegic solution

U.S. FDA Resources

Further study details as provided by William Beaumont Hospitals:

Primary Outcome Measures:

Creatine phosphokinase MB isoenzyme (CK-MB)and troponin-I [ Time Frame: 7 hours post surgery ] [ Designated as safety issue: Yes ]
To demonstrate that Custodiol-HTK 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:

o Creatine phosphokinase MB isoenzyme (CK-MB)and troponin-I at 7 hours post surgery
Changes in ejection fraction by TTE [ Time Frame: at 24 hours post surgery ] [ Designated as safety issue: Yes ]
To demonstrate that Custodiol-HTK is not inferior to cold cardioplegic solution for myocardial protection by comparing standard cold blood cardioplegia to Custodiol solution with respect tomyocardial injury as measured by:

o Changes in ejection fraction by TTE at 24 hours post surgery

Secondary Outcome Measures:

Cardiac dysrhythmias [ Time Frame: up to 36 hrs post surgery ] [ Designated as safety issue: Yes ]
The frequency of new or worsening of cardiac dysrhythmias will be compared between the two randomization arms.
All cause mortality [ Time Frame: 30 days post procedure ] [ Designated as safety issue: No ]
All cause mortality and cardiovascular related mortality will be recorded. A Society of Thoracic Surgeons (STS) database review will be conducted post-op after 30 days to assess for cause mortality
Time on Mechanically Assisted Ventilation [ Time Frame: up to 36 hours post procedure ] [ Designated as safety issue: No ]
time of intubation, time of arrival in the cardiac critical care unit and time of extubation.
Biochemical Markers - Creatine phosphokinase MB isoenzyme (CK-MB)and troponin [ Time Frame: 24 and 48 hours ] [ Designated as safety issue: Yes ]
Biochemical Markers - Creatine phosphokinase MB isoenzyme(CK-MB)and troponin-I cardiac markers will be measured preoperatively, at 24 and 48 hours postoperatively1
Duration of Vasopressor / Inotropic Agent [ Time Frame: up to 36 hours post procedure ] [ Designated as safety issue: Yes ]
Postoperative inotropic support greater than 20 minutes will be recorded.
ICU Length of Stay [ Time Frame: ICU length of stay in total hours of an expected average of 3 days ] [ Designated as safety issue: No ]
Participants will be followed for the duration of their hospital stay an expected average of 5 days. The ICU length of stay is expected to average 3 days.
Arterial Blood Gases [ Time Frame: up to 36 hours post procedure ] [ Designated as safety issue: Yes ]
recorded in surgery after anesthesia induction, upon arrival to ICU, after accelerated vent wean and after spontaneous breathing trial.
Creatinine Levels [ Time Frame: 24 and 48 hours post procedure ] [ Designated as safety issue: Yes ]
Myocardial Infarction [ Time Frame: up to 36 hours post procedure ] [ Designated as safety issue: Yes ]
Two of the following 3 criteria will need to be fulfilled to diagnose a myocardial infarction: (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.

Other Outcome Measures:

Q waves on EKG of more than 0.03 seconds [ Time Frame: 24 and 48 hours post procedure ] [ Designated as safety issue: Yes ]
A 12-lead EKG will be recorded daily, upon arrival to the ICU, at 24 and 48 hours post-op. These will be compared with a pre-operative EKG for changes relating to Q waves or dysrhythmias.


Enrollment:	110
Study Start Date:	August 2012
Study Completion Date:	May 2014
Primary Completion Date:	May 2014 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Cardioplegia: Custodiol HTK Solution 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-HTKcardioplegia will be delivered to establish and maintain cardiac arrest. After cross-clamping of the aorta approximately 1-2L of Custodiol-HTK will be infused into the ascending aorta over 6-8 minutes. Additional doses of 100-200 ml may be administered as needed. The cardioplegic solution will be delivered at a temperature of 4°C - 10°C	Drug: Custodiol HTK After cross-clamping of the aorta approximately 1-2L of Custodiol-HTK will be infused into the ascending aorta over 6-8 minutes. Additional doses of 100-200 ml may be administered as needed. The cardioplegic solution will be delivered at a temperature of 4°C - 10°C.
Active Comparator: Cold Blood Cardioplegia Blood Cardioplegic Solution: One liter of cold blood cardioplegic solution, mixed at a ratio of 4:1 per Beaumont standard of care (blood /cardioplegic solution)22, contains the following components in a 500cc bag of D5W: 50meq/L potassium chloride, 37.5 meq/L sodium bicarbonate and 7.5 meq/L magnesium sulfate. Cold blood cardioplegia will be administered after cross-clamping the aorta, at least 1000mL of a 4:1 mixture of cold blood: cold crystalloid will be administered at a pressure of 300mmHg or less via a twin roller pump. Every 20 minutes an additional > 200mL will be administered in an antegrade/retrograde fashion throughout the remainder of the case. The cardioplegic solution will be delivered at a temperature of 4°C - 8°C.	Drug: Cold Blood Cardioplegia After cross-clamping the aorta, at least 1000mL of a 4:1 mixture of cold blood: cold crystalloid will be administered at a pressure of 300mmHg or less via a twin roller pump. Every 20 minutes an additional > 200mL will be administered in an antegrade/retrograde fashion throughout the remainder of the case. The cardioplegic solution will be delivered at a temperature of 4°C - 8°C.

Arms

Assigned Interventions

Experimental: Cardioplegia: Custodiol HTK Solution

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-HTKcardioplegia will be delivered to establish and maintain cardiac arrest. After cross-clamping of the aorta approximately 1-2L of Custodiol-HTK will be infused into the ascending aorta over 6-8 minutes. Additional doses of 100-200 ml may be administered as needed. The cardioplegic solution will be delivered at a temperature of 4°C - 10°C

Drug: Custodiol HTK

After cross-clamping of the aorta approximately 1-2L of Custodiol-HTK will be infused into the ascending aorta over 6-8 minutes. Additional doses of 100-200 ml may be administered as needed. The cardioplegic solution will be delivered at a temperature of 4°C - 10°C.

Active Comparator: Cold Blood Cardioplegia

Blood Cardioplegic Solution: One liter of cold blood cardioplegic solution, mixed at a ratio of 4:1 per Beaumont standard of care (blood /cardioplegic solution)22, contains the following components in a 500cc bag of D5W: 50meq/L potassium chloride, 37.5 meq/L sodium bicarbonate and 7.5 meq/L magnesium sulfate.

Cold blood cardioplegia will be administered after cross-clamping the aorta, at least 1000mL of a 4:1 mixture of cold blood: cold crystalloid will be administered at a pressure of 300mmHg or less via a twin roller pump. Every 20 minutes an additional > 200mL will be administered in an antegrade/retrograde fashion throughout the remainder of the case. The cardioplegic solution will be delivered at a temperature of 4°C - 8°C.

Drug: Cold Blood Cardioplegia

After cross-clamping the aorta, at least 1000mL of a 4:1 mixture of cold blood: cold crystalloid will be administered at a pressure of 300mmHg or less via a twin roller pump. Every 20 minutes an additional > 200mL will be administered in an antegrade/retrograde fashion throughout the remainder of the case. The cardioplegic solution will be 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
Genders Eligible for Study:	Both
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:

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.

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.

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:	HIC# 2012-125
Study First Received:	August 10, 2012
Last Updated:	June 24, 2014
Health Authority:	United States: Institutional Review Board United States: Food and Drug Administration

Keywords provided by William Beaumont Hospitals:


Physiological Effects of Drugs Cardiovascular Agents Therapeutic Uses Pharmacologic Actions Mannitol Cardiac Surgery Cardiovascular agents	Cardioplegic Solutions HTK solution Myocardial protection Coronary Artery Disease Myocardial Ischemia Coronary Disease Heart Diseases

Additional relevant MeSH terms:


Coronary Artery Disease Coronary Disease Heart Diseases Heart Valve Diseases Myocardial Ischemia Arterial Occlusive Diseases Arteriosclerosis	Cardiovascular Diseases Vascular Diseases Cardioplegic Solutions Cardiovascular Agents Pharmaceutical Solutions Pharmacologic Actions Therapeutic Uses

ClinicalTrials.gov processed this record on March 03, 2015