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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Ischemic Heart Disease, Valvular Heart Disease, Cardiovascular Diseases, Surgery-Complications

Intervention / Treatment
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* Procedure: Hypothermic Cardiopulmonary Bypass
* Procedure: Normothermic Cardiopulmonary Bypass


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA Participants may enter the trial if all of the following apply Adult patients (≥ 18 years) scheduled for coronary artery bypass surgery and/or valve replacement/ repair, either in the elective or urgent setting. European System for Cardiac Operative Risk Evaluation (EuroSCORE) II of 2 or higher. Able to understand and communicate to provide informed consent. Able to read and understand the English language. EXCLUSION CRITERIA Participants may not enter the trial if any of the following apply: Patients undergoing coronary artery bypass surgery in combination with other procedures including cardiac or vascular procedures that require deep hypothermic arrest. Patients undergoing emergency or salvage surgery. Patients undergoing off-pump cardiac surgery. Patients who are participating in another interventional trial. Unable to provide informed consent.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Parallel group, open label, statistician blinded, multicentre, randomised controlled feasibility trial.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Hypothermic Cardiopulmonary Bypass<br>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<br>* Mild hypothermia (between 32 - 35 °C) during cardiopulmonary bypass<br>|
| Active Comparator: Normothermic Cardiopulmonary Bypass<br>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<br>* Normothermia (active maintenance of temperature between 36.5 °C to 37.5°C; no active cooling below 36.5 °C) during cardiopulmonary bypass<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cardiopulmonary bypass, hypothermia, myocardial protection, neurologic protection