Intermittent antegrade warm blood versus cold blood cardioplegia in children undergoing open heart surgery

Plain English Summary

Background and study aims
Congenital heart disease is a problem in the structure of the heart that is present at birth. It is not uncommon and morbidity (illness) following heart surgery in children remains significant. Surgical repair of congenital heart defects usually requires the heart to be stopped using a cold solution containing potassium (cardioplegia) which protects the heart and keeps it still when operating. Cold cardioplegia solutions may have negative effects on the recovery of the heart after surgery in adults. However, very little is known about the effects of using warm cardioplegia solutions in children. The aim of this study is to compare warm and cold cardioplegia in children undergoing open heart surgery. Temperature monitoring is essential and always measured during the treatment of critically ill children. Rectal temperature monitoring is currently the most commonly used method for estimation of core body temperature in ill children. Multiple studies in adults and children have questioned the accuracy of rectal temperature monitoring when compared to pulmonary artery or urinary catheter monitoring. However, these studies are limited by small numbers. The study therefore also compares measurements of core body temperature obtained using a temperature sensing urinary catheter, a rectal temperature probe, and other temperature measuring devices such as axillary (armpit), oral (mouth), aural (ear) and oesophageal (food pipe) probes.

Who can participate?
Patients undergoing a congenital heart operation requiring cardiopulmonary bypass and cardioplegic arrest

What does the study involve?
Participants are randomly allocated to one of two groups to be treated with either warm or cold cardioplegia solutions to stop and protect the heart. Recovery and complications after surgery are compared between the two groups.

What are the possible benefits and risks of participating?
Participants in the cold cardioplegia group receive the same surgical procedure as patients not participating in the study and receive the same benefits inherent in cardiac surgery. Participants in the warm cardioplegia group receive the same benefits. Recent evidence suggests that warm cardioplegia is safe in children and may improve outcomes.

Where is the study run from?
Bristol Royal Hospital for Children (UK)

When is the study starting and how long is it expected to run for?
December 2017 to September 2021 (updated 30/03/2021, previously: February 2021 (updated 29/06/2020, previously: August 2020))

Who is funding the study?
British Heart Foundation (UK)

Who is the main contact?
Ms Lucy Dabner, thermic3-trial@bristol.ac.uk
(updated 29/06/2020, previously: Miss Rachael Heys, rh13369@bristol.ac.uk)

Study website

Type

Scientific

Contact name

Ms Lucy Dabner

ORCID ID

Contact details

Bristol Trials Centre - Clinical Trials and Evaluation Unit
University of Bristol Medical School
Level 7
Bristol Royal Infirmary
Upper Maudlin Street
Bristol
BS2 8HW
United Kingdom
+44 (0)117 342 2374
thermic3-trial@bristol.ac.uk

EudraCT/CTIS number

IRAS number

211278

ClinicalTrials.gov number

Protocol/serial number

37109, IRAS 211278

Scientific title

Intermittent antegrade warm blood versus cold blood cardioplegia in children undergoing open heart surgery: a randomised controlled trial (THERMIC-3)

Acronym

THERMIC-3

Study hypothesis

Congenital heart disease is not uncommon and morbidity following cardiac surgery in children remains significant. Surgical repair of congenital heart defects usually requires the heart to be stopped using a cold solution containing potassium (cardioplegia) which protects the heart and keeps it still when operating. Cold cardioplegia solutions may have deleterious effects on the recovery of the heart after surgery in adults. However, very little is known about the effects of using warm cardioplegia solutions in children. Therefore, children undergoing open heart surgery will be assigned by chance to one of two groups, using either warm or cold cardioplegia solutions to stop and protect the heart. Clinical and biochemical measures of recovery and complications following surgery will be compared between the two groups.

A sub-study will also look at methods for measuring core body temperature monitoring in children undergoing cardiac surgery with cardiopulmonary bypass. Temperature monitoring is an essential and a universally measured sign in the management of critically ill children. Rectal temperature monitoring is currently the most commonly used method for estimation of the core body temperature in ill children. Multiple studies in adults and children have questioned the accuracy of rectal temperature monitoring when compared to pulmonary artery or urinary catheter monitoring. However, these studies are limited by small numbers. The sub-study is a proof of concept study which will compare measurements of core body temperature obtained using a temperature sensing urinary catheter and a rectal temperature probe and other temperature measuring devices such as axillary, oral, aural and oesophageal probes.

Ethics approval(s)

London Central Research Ethics Committee, 07/03/2018, ref: 18/LO/0205

Study design

Randomised; Interventional; Design type: Process of Care, Surgery

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Study setting(s)

Hospital

Study type

Treatment

Patient information sheet

Not available in web format, please use the contact details to request a patient information sheet

Condition

Congenital malformations of cardiac chambers and connections

Intervention

Eligible patients requiring congenital heart operations who give consent will be randomised to receive either warm blood cardioplegia or cold blood cardioplegia during their cardiac surgery. Clinical and biochemical measures of recovery and complications following surgery will be compared between the two groups.

Sub-study:
The sub-study is a proof of concept study which will compare measurements of core body temperature obtained using a temperature sensing urinary catheter and a rectal temperature probe and investigate the lag in changes in temperature with the two methods during therapeutic or pathological rapid changes in body core temperature. It will also investigate changes in the relationship between urinary bladder and rectal temperature measurements during low urinary output state (defined as urine output of less than 0.5ml/kg/hr) and compare the accuracy of these measurements with other temperature measuring devices such as axillary, oral, aural and oesophageal probes in the same cohort.

Intervention type

Procedure/Surgery

Primary outcome measure

Troponin T (cTnT) levels over the first 48 postoperative hours

Secondary outcome measures

Current secondary outcome measures as of 18/03/2020:
1. Cardiac function, assessed by measuring cardiac output and cardiac index. Central venous saturations (ScvO2), arterial saturations, base deficit & blood lactate will also be recorded as indirect measures of cardiac index. Central venous saturations (ScvO2), arterial saturations, base deficit and blood lactate recorded as indirect measures of cardiac index up to 48 hours postoperatively
2. Routine blood gas and blood sample/test results measured before, during and after surgery (up to 48 hours postoperatively). Results collected will include pH, PO2, PCO2, base excess and lactate from blood gases and serum creatinine and urea nitrogen (measures of renal function), c-reactive protein (CRP), haemoglobin (Hb), haematocrit (Hct), white cell count (WCC) and alanine aminotransferase (ALT) from blood samples.
3. Renal function measured by urinary albumin, urinary creatinine, retinal binding protein (RBP), N- acetyl- β-glucosaminidase (NAG) and neutrophil gelatinase-associated lipocalin (n-GAL) in urine samples, measured before surgery and at 4 hours, 24 hours and 48 hours postoperatively
4. Cardiac and electrical activity on removal off cross clamp and chest closure (arrhythmias including; atrial fibrillation/flutter, ventricular tachycardia, ventricular fibrillation, nodal, junctional ectopic tachycardia (JET) or AV block)
5. Postoperative blood loss in the first 12 hours
6. New onset of arrhythmia post-operatively (either supraventricular tachycardia/atrial fibrillation or ventricular fibrillation/ventricular tachycardia, JET or heart block)
7. Vasoactive-inotrope score (VIS) over the first 48 hours after admission to PICU
8. Intubation time
9. Time from return from theatre until fit for discharge to the ward/high dependency unit (HDU) from the paediatric intensive care unit (PICU). Fit for discharge to the ward/HDU will reflect current HDU/ward admission criteria.
10. Chest and wound infections, recorded post-operatively
11. All-cause mortality to 3 months post-surgery
12. Length of postoperative hospital stay
13. Myocardial injury at the molecular and cellular level (e.g. transciptomics, proteonomics and metabonomics) measured in samples considered clinical waste during surgery
14. Body temperature from rectal, esophageal and urinary bladder and from oral, axillary and aural sites where possible for 8 hours after surgery (sub-study)


Previous secondary outcome measures:
1. Cardiac function, assessed by measuring cardiac output, cardiac index and myocardial contractility using trans-oesophageal echocardiography (TOE) during surgery and transthoracic echocardiography (TTE) pre-operatively and at 24 hours postoperatively. Central venous saturations (ScvO2), arterial saturations, base deficit and blood lactate recorded as indirect measures of cardiac index up to 48 hours postoperatively
2. Routine blood gas and blood sample/test results measured before, during and after surgery (up to 48 hours postoperatively)
3. Cerebral function/injury measured by Glial Fibrillary Acidic Protein (GFAP) before, during surgery and at 2 hours, 6 hours, 24 hours and 48 hours postoperatively
4. Renal function measured by urinary albumin, urinary creatinine, retinal binding protein (RBP), N- acetyl- β-glucosaminidase (NAG) and neutrophil gelatinase-associated lipocalin (n-GAL) in urine samples, measured before surgery and at 4 hours, 24 hours and 48 hours postoperatively
5. Cardiac and electrical activity on removal off cross clamp and chest closure (arrhythmias including; atrial fibrillation/flutter, ventricular tachycardia, ventricular fibrillation, nodal, junctional ectopic tachycardia (JET) or AV block)
6. Postoperative blood loss in the first 12 hours
7. New onset of arrhythmia post-operatively (either supraventricular tachycardia/atrial fibrillation or ventricular fibrillation/ventricular tachycardia, JET or heart block)
8. Vasoactive-inotrope score (VIS) over the first 48 hours after admission to PICU
9. Intubation time
10. Time from return from theatre until fit for discharge to the ward/high dependency unit (HDU) from the paediatric intensive care unit (PICU). Fit for discharge to the ward/HDU will reflect current HDU/ward admission criteria.
11. Chest and wound infections, recorded post-operatively
12. All-cause mortality to 3 months post-surgery
13. Length of postoperative hospital stay
14. Myocardial injury at the molecular and cellular level (e.g. transciptomics, proteonomics and metabonomics) measured in samples considered clinical waste during surgery
15. Body temperature from rectal, esophageal and urinary bladder and from oral, axillary and aural sites where possible for 8 hours after surgery (sub-study)

Overall study start date

01/12/2017

Overall study end date

30/09/2021

Reason abandoned (if study stopped)

Participant inclusion criteria

Patients undergoing a congenital heart operation requiring CPB and cardioplegic arrest at the BRHC

Participant type(s)

Patient

Age group

Child

Sex

Both

Target number of participants

Planned Sample Size: 94; UK Sample Size: 94

Total final enrolment

97

Participant exclusion criteria

1. Patient weighing < 3 kg
2. Patient requires an emergency operation (patient with haemodynamic instability who require immediate surgical intervention defined as operation within 24 hours of admission)
3. Patient requires secundum atrial septal defect repair (ASD) as an isolated procedure
4. Patient judged pre-operatively by surgeon to require deep hypothermic circulatory arrest (e.g. aortic arch repair, repair of total anomalous pulmonary venous drainage (TAPVD), Norwood procedure)
5. Patient judged pre-operatively by the surgeon to require deep hypothermic CPB
6. Patient judged by the surgeon pre-operatively to be too complex. This could be procedure related or patient related (e.g. complex tailor made surgery; necrotising enterocolitis; pre-operative brain haemorrhage; or generalised bleeding state/ongoing major bleeding)
7. Patient of consenting/assenting age lacking capacity to consent/assent
8. Patient under the care of social services and/or parent/guardian unavailable for consent

For the sub-study, the following additional exclusion criteria will apply:
9. Patient aged < 4 months
10. Patient weighing < 6 kg
11. Patient has contraindication for urethral catheterisation due to urethral obstruction or haemorrhage.

Recruitment start date

08/05/2018

Recruitment end date

01/04/2020

Countries of recruitment

England, United Kingdom

Study participating centre

Bristol Royal Hospital for Children
24 Upper Maudlin St
Bristol
BS2 8BJ
United Kingdom

Organisation

University Hospitals Bristol NHS Foundation Trust

Sponsor details

Research and Innovation
Level 3
Education Centre
Upper Maudlin Street
Bristol
BS2 8AE
England
United Kingdom
+44 (0)117 342 0233
abc@email.com

Sponsor type

Hospital/treatment centre

Website

ROR

https://ror.org/04nm1cv11

Funder type

Charity

Funder name

British Heart Foundation (BHF); Grant Codes: CH/1992027/7163 & CH/17/1/32804

Alternative name(s)

the_bhf, The British Heart Foundation, BHF

Funding Body Type

private sector organisation

Funding Body Subtype

Trusts, charities, foundations (both public and private)

Location

United Kingdom

Publication and dissemination plan

The trialists plan to publish a protocol paper in the near future. The findings will be disseminated by the usual academic channels around one year after the overall trial end date, i.e. presentation at international meetings, as well as by peer-reviewed publications and through patient organisations and newsletters to patients, where available.

Intention to publish date

31/03/2022

Individual participant data (IPD) sharing plan

The data sharing plans for the current study are unknown and will be made available at a later date.

IPD sharing plan summary

Data sharing statement to be made available at a later date

Study outputs