Study on Optimal Temperature During Cardiopulmonary Bypass (THERMIC-4) (THERMIC-4)

Normothermic Versus Hypothermic Cardiopulmonary Bypass in Adult Cardiac Surgery: a Multicentre Feasibility Randomised Controlled Trial

In order to perform heart surgery, a machine called cardiopulmonary bypass (CPB), or more commonly known as a heart-lung machine, is used to maintain the circulation of oxygenated blood needed by the rest of the body and its organs.

Historically, when a patient is connected to CPB, their body is cooled below the normal body temperature. This is known as hypothermia. This is because scientific studies have previously shown that reduced body temperature lowers metabolism and therefore offers more protection to the brain and other organs due to the reduced oxygen requirement. The evidence supporting this practice, however, has been challenged throughout the history of cardiac surgery, with studies supporting that normothermia, or normal body temperature, is a safe alternative. Despite this, the practice of hypothermia has persisted. Published data from a survey of 139 cardiac surgeons in the United Kingdom showed that 84% still routinely employ hypothermic CPB during surgery.

To assess whether normothermic or hypothermic CPB is safer, a clinical trial requiring a large sample size and high recruitment rates will be required. Therefore, the investigators aim to assess firstly the feasibility of trial recruitment and allocation adherence in this study. 100 adults across 10 different cardiac surgery centres in the United Kingdom will be recruited to a multicentre feasibility randomised controlled trial comparing normothermia (active comparator) against hypothermia (control comparator) during cardiopulmonary bypass in cardiac surgery. This study will also test the ability of the Cardiothoracic Interdisciplinary Research Network (CIRN), a trainee-led research collaborative, to collect pilot data on Major Adverse Cardiac and Cerebrovascular Events (MACCE) using a regulation-approved electronic application HealthBitⓇ. Participants will also be asked to complete quality of life surveys. The results of this study will subsequently inform a large, adequately powered randomised controlled trial for optimal temperature management during CPB.

Study Overview

• Status: Not yet recruiting
• Conditions: Cardiovascular Diseases; Ischemic Heart Disease; Valvular Heart Disease; Surgery-Complications
• Intervention / Treatment: Procedure: Hypothermic Cardiopulmonary Bypass; Procedure: Normothermic Cardiopulmonary Bypass

Detailed Description

Primary Objective

To assess the feasibility of trial recruitment and delivery to target in the United Kingdom of a multicentre randomised controlled trial on normothermia versus hypothermia during cardiopulmonary bypass in adult cardiac surgery.

Secondary Objective

To assess the feasibility of conducting a multicentre randomized controlled trial (RCT) using a novel Good Clinical Practice (GCP) approved remote data capture as the primary trial database alongside analysis of routinely collected healthcare data.

To obtain pilot data, undertaken by the Cardiothoracic Interdisciplinary Research Network (CIRN), to inform a subsequent large, adequately powered RCT for optimal temperature management during CPB.

• Study Type: Interventional
• Enrollment (Estimated): 100
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Gavin J Murphy, FRCS, MD, MBChB, BSc; Phone Number: 0116 258 3054; Email: gjm19@le.ac.uk
• Study Contact Backup: Name: Ann Cheng, MBChB, MSc; Email: ann.cheng1@nhs.net

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

INCLUSION CRITERIA

Participants may enter the trial if all of the following apply

1. Adult patients (≥ 18 years) scheduled for coronary artery bypass surgery and/or valve replacement/ repair, either in the elective or urgent setting.
2. European System for Cardiac Operative Risk Evaluation (EuroSCORE) II of 2 or higher.
3. Able to understand and communicate to provide informed consent.
4. Able to read and understand the English language.

EXCLUSION CRITERIA

Participants may not enter the trial if any of the following apply:

1. Patients undergoing coronary artery bypass surgery in combination with other procedures including cardiac or vascular procedures that require deep hypothermic arrest.
2. Patients undergoing emergency or salvage surgery.
3. Patients undergoing off-pump cardiac surgery.
4. Patients who are participating in another interventional trial.
5. Unable to provide informed consent.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Hypothermic Cardiopulmonary Bypass; Patients allocated to this arm will undergo standard care for coronary artery bypass grafting and/or valve surgery with mild hypothermia during CPB.	Procedure: Hypothermic Cardiopulmonary Bypass; Mild hypothermia (between 32 - 35 °C) during cardiopulmonary bypass
Active Comparator: Normothermic Cardiopulmonary Bypass; Patients allocated to this arm will undergo intervention care for coronary artery bypass grafting and/or valve surgery with normothermia hypothermia during CPB.	Procedure: Normothermic Cardiopulmonary Bypass; Normothermia (active maintenance of temperature between 36.5 °C to 37.5°C; no active cooling below 36.5 °C) during cardiopulmonary bypass

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total number of participants recruited over a 6 month period	The target recruitment rate is 1 participant per week per centre. The feasibility trial will be considered positive if 80% of target met, together with outcome 2.	6 months
Adherence rate to allocation	The feasibility trial will be considered positive if 74%* of target adherence to trial allocation is met, together with outcome 1. *74% is derived from 80% of target adherence of 92% as per Warm Heart Study	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of 6-week composite endpoint of Major Adverse Cardiac and Cerebrovascular Events (MACCE)	MACCE is defined as any post-operative death, stroke, new intra-aortic balloon pump insertion, new renal replacement therapy, re-operation and major bleeding in this feasibility trial.	6 weeks
Incidence of deep sternal wound infection, with or without treatment	Deep sternal wound infection is defined with at least one of the following criteria: (I) an organism is isolated from culture of mediastinal tissue or fluid (II) evidence of mediastinitis seen intraoperatively (III) presence of chest pain, sternal instability, or fever (> 38 °C), and purulent drainage from the mediastinum or isolation of organism present in a blood culture or from the mediastinal area.	6 weeks
Incidence of all adverse events	Composite of all reported adverse events. Examples of adverse events include: low cardiac output, suspected myocardial infarction, arrhythmias, infections, haemorrhage, and pulmonary embolus.	6 weeks
Critical care length of stay	Number of days a participant is admitted in cardiac critical care unit	6 weeks
Post-operative length of stay	Number of days a participant is an in-patient after index operation	6 weeks
Frequency of post-discharge healthcare resource utilisation	Number of visits to general practitioner (GP) and/or hospital, either district general hospital or tertiary hospital, will be recorded via HealthBitⓇ.	6 weeks
Quality of life post-operation: Medical Outcomes Study Short-Form 36 (SF-36)	Quality of life questionnaire (SF-36) will administered before surgery and at 6-week follow up	6 weeks
Quality of life post-operation: European Quality of Life-5 Dimensions (EQ-5D)	Quality of life questionnaire (EQ-5D) will administered before surgery and at 6-week follow up	6 weeks
Quality of life post-operation: World Health Organisation Disability Assessment Schedule (WHODAS)	Quality of life questionnaire (WHODAS) will administered before surgery and at 6-week follow up	6 weeks
Clinical Frailty Scale (CFS) post-operation	Clinical Frailty Scale will be recorded before surgery and at 6-week follow up	6 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Data completeness	Data recorded on HealthBitⓇ will be assessed for percentage of completion	6 months
Attrition rate	For ascertainment of the primary outcome and for planning of future large-scale study	6 months
User satisfaction of ResearchApp	Participants will be invited to complete optional survey on user satisfaction of ResearchApp	6 months

Collaborators and Investigators

• Sponsor: University of Leicester
• Collaborators: Guy's and St Thomas' NHS Foundation Trust; Sheffield Teaching Hospitals NHS Foundation Trust; University Hospitals, Leicester; University Hospitals Bristol and Weston NHS Foundation Trust; Hull University Teaching Hospitals NHS Trust; Oxford University Hospitals NHS Trust; NHS National Waiting Times Centre Board; Blackpool Teaching Hospitals NHS Foundation Trust

Study record dates

Study Major Dates

• Study Start (Estimated): January 1, 2024
• Primary Completion (Estimated): July 1, 2024
• Study Completion (Estimated): August 1, 2024

Study Registration Dates

• First Submitted: July 2, 2023
• First Submitted That Met QC Criteria: August 10, 2023
• First Posted (Actual): August 16, 2023

Study Record Updates

• Last Update Posted (Actual): November 29, 2023
• Last Update Submitted That Met QC Criteria: November 28, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: cardiopulmonary bypass; hypothermia; myocardial protection; neurologic protection
• Additional Relevant MeSH Terms: Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Coronary Disease; Heart Diseases; Coronary Artery Disease; Myocardial Ischemia; Cardiovascular Diseases; Heart Valve Diseases
• Other Study ID Numbers: 0910; IRAS (Other Identifier: 332422)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Fully anonymised individual participant data can be made available on request for future studies with ethics approval.
• IPD Sharing Time Frame: The investigators will retain the fully anonymised dataset indefinitely. The duration for which this will be shared will be determined on a case-by-case basis and defined in a Data Sharing Agreement.
• IPD Sharing Access Criteria: Requests must be from studies with appropriate ethics approval in place.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; CSR

Drug and device information, study documents

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