Histidine-Tryptophan-Ketoglutarate Solution Versus Blood Cardioplegia in CABG

Efficacy of Histidine-Tryptophan-Ketoglutarate Solution Versus Blood Cardioplegia in Coronary Artery Bypass Graft Surgery: A Randomized Double Blinded Study

Background: In cardiac surgery, myocardial protection is mandatory during cross clamp time followed by reperfusion. Use of cardioplegic solutions preserves myocardial energy stores, hindering electrolyte disturbances and acidosis during periods of myocardial ischemia. This study was designed to compare the efficacy and safety of Histidine-tryptophan-ketoglutarate (HTK) solution versus blood cardioplegia in coronary artery bypass graft surgery.

Methods: Three hundred and twenty patients were randomized into Histidine-tryptophan-ketoglutarate (HTK) group and blood cardioplegia group. Ventilation time, total bypass time, cross clamp time, length of ICU or hospital stay and the early postoperative outcomes were analysed.

Study Overview

• Status: Completed
• Conditions: Cardioplegia Solution Adverse Reaction
• Intervention / Treatment: Drug: HTK cardioplegic solution; Drug: blood cardioplegia

Detailed Description

The Ethics Committee of Ain Shams university approved this randomized prospective double-blinded controlled parallel group study to be held in Cardiothoracic Academy for three months from December 2019 to April 2020. The study was conducted on three hundred and twenty older patients aged from 60-80 years old posted for elective coronary artery bypass grafting (CABG). Written informed consents were signed by all patients. Exclusion criteria included (1) patients with Unstable angina (class III or IV); (2) Poor left ventricular function (LVEF <40%) ;(3) Patient with acute myocardial infarction; (4) Previous CABG; (5) Previous renal failure; (6) Preoperative Aortic valve or Mitral valve disease requiring replacement ;(7) Urgent CABG operation.

A detailed medical history, including medications used, symptoms and risk factors for ischemic heart disease (smoking, DM, hypertension), NYHA classification and full investigations were assessed on the night of the surgical procedure. Anesthesia management was standardized for all patients. Premedication with midazolam was limited to a maximum of 0.05 mg/kg. Anesthesia was done with 12 μg/kg fentanyl, 5-7 mg/kg thiopental sodium, and 0.15 mg/kg pancuronium and was maintained with 1-2.0% isoflurane. Heart rate and blood pressure were maintained within 20% of the baseline values. Anticoagulation was achieved with heparin 300 U/kg administered into the right atrium to maintain an activated clotting time above 480 s. Cardiopulmonary bypass (CPB) was established by non-occlusive roller pumps, membrane oxygenators and arterial line filtration. The CPB circuit was primed with 1.8 l lactated Ringer's solution and 50 ml of 20% mannitol. Management of CPB included systemic hypothermia during aortic cross-clamping, targeted mean perfusion pressure between 60 and 80 mmHg, and pump flow rates of 2.2 l/min/m2.Intraoperatively the patients were monitored using ECG, pulse oximetry, Invasive blood pressure monitoring, arterial blood gases, central venous line catheter and temperature probe. Surgical approach was performed by median sternotomy.

Patients were randomly allocated into 2 groups either HTK group and blood cardioplegia group according to a computer-generated randomization code, with allocation ratio 1:1. Opaque sealed envelopes were prepared according to the randomization schedule, and were opened by a clinician not involved in any part of the study.

In the HTK group, patients received 30 ml/kg of HTK cardioplegic solution at 4°C through an antegrade fashion at an initial perfusion pressure of 80-100 mmHg. In blood cardioplegia group, patients received one liter of blood cardioplegia was given with the antegrade route at 30°C, or lower. Blood maintenance cardioplegia was repeated every 30-45mins. The study medications were calculated and prepared by ICU residents who were not a part of the research team. To ensure blinding of study drug administration, the medication vials were kept in opaque bags. Trial bags were blinded and marked with a unique number. The allocation of trial drugs was determined by the web-based randomization system by the allocation of the bag number. The end-point assessor of the outcomes was blinded to the study drugs.

Before separation from CPB, patients were rewarmed to 36-37°C. After separation from CPB, heparin was neutralized with protamine sulfate 1 mg/100 U heparin to reach an activated clotting time within 10% of baseline. All patients were then transferred to the ICU after surgery.

The primary end-point of the study included early postoperative outcomes including cardiac enzymes preoperatively, 8 & 24 hour post-operatively, 30-day mortality, wall motion abnormalities and pericardial effusion. The secondary end-points included ventilation time, cross clamp and total bypass time, length of ICU stay, length of hospital stay, need for inotropic support, 30-day readmission, the incidence of late postoperative complications as renal dysfunction.

• Study Type: Interventional
• Enrollment (Actual): 320
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• Egypt
  • Cairo, Egypt
    • Ain shams university
  • Cairo, Egypt, 11566
    • Ain shams university

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 56 years to 76 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• age from 60-80 years old
• elective CABG
• no comorbidities

Exclusion Criteria:

• patients with Unstable angina
• Poor left ventricular function
• Patient with acute myocardial infarction
• previous renal failure
• Preoperative Aortic valve or Mitral valve disease requiring replacement

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Sham Comparator: HTK group; Patients received 30 ml/kg of HTK cardioplegic solution at 4°C through an antegrade fashion at an initial perfusion pressure of 80-100 mmHg	Drug: HTK cardioplegic solution; 30 ml/kg of HTK cardioplegic solution at 4°C through an antegrade fashion at an initial perfusion pressure of 80-100 mmHg; Other Names: Histidine-tryptophan-ketoglutarate solution
Active Comparator: blood cardioplegia group; patients received one liter of blood cardioplegia was given with the antegrade route at 30°C, or lower. Blood maintenance cardioplegia was repeated every 30-45mins	Drug: blood cardioplegia; one liter of blood cardioplegia was given with the antegrade route at 30°C, or lower. Blood maintenance cardioplegia was repeated every 30-45mins

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
mortality rate	mortality rate	up to 30 days postoperative

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Troponin I level	level of troponin in the blood	Up to 24 hours postoperative
length of ICU stay	ICU stay duration	up to 3 days postoperative
length of hospital stay	hospital stay duration	up to 7 days postoperative

Collaborators and Investigators

• Sponsor: Ain Shams University
• Investigators: Study Chair: Ayman shoeb, Ain shams university

Study record dates

Study Major Dates

• Study Start (Actual): December 25, 2019
• Primary Completion (Actual): March 31, 2020
• Study Completion (Actual): April 25, 2020

Study Registration Dates

• First Submitted: December 16, 2019
• First Submitted That Met QC Criteria: December 17, 2019
• First Posted (Actual): December 18, 2019

Study Record Updates

• Last Update Posted (Actual): May 7, 2020
• Last Update Submitted That Met QC Criteria: May 5, 2020
• Last Verified: May 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Psychotropic Drugs; Antidepressive Agents; Antidepressive Agents, Second-Generation; Pharmaceutical Solutions; Tryptophan; Cardioplegic Solutions
• Other Study ID Numbers: FMASU R 61/ 2019

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: study protocol
• IPD Sharing Time Frame: 4 months
• IPD Sharing Access Criteria: Data were analyzed using SPSS Statistics version 23 (IBM© Corp., Armonk, NY, USA). Normally distributed numerical data were presented as mean and SD, and skewed data were presented as median and interquartile range. Qualitative data were presented as number and percentage or ratio. Normally distributed numerical data were compared using the unpaired t-test. Skewed numerical data were compared using the Mann-Whitney test and categorical data were compared using Fisher's exact test. P-value < 0.05 were considered statistically significant.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No