Detection of coagulopathy in paediatric heart surgery

Sponsor: University Hospitals Bristol 

Approximately 3000 children undergo major cardiac surgery each year in the UK and around 40% of these experience serious bleeding.  This is usually caused by abnormalities in the blood clotting system which can develop quickly and change rapidly. 

The Decision study is currently recruiting 200 children undergoing major cardiac surgery at the Bristol Royal Hospital for Children.  We are collecting blood samples from these children and using these to identify the most important clotting abnormalities.   We are also investigating whether a rapid blood test called the rotational thromboelastometry test (ROTEM) can detect these clotting abnormalities and whether it is reliable enough to allow doctors to select appropriate blood components for transfusion and minimise exposure to unnecessary or incorrect blood components.

If successful, we will use these results to create guidelines that will help doctors in the future to select individualised treatments using ROTEM test results for all children after cardiac surgery.

Contact Information

Chief Investigator: Dr Andrew Mumford

Study coordinator: Wendy Underwood


Treatment of Barth Syndrome by CARDIOlipin MANipulation (CARDIOMAN): A randomised placebo controlled pilot trial conducted by the nationally commissioned Barth Syndrome Service

Sponsor: University Hospitals Bristol NHS Foundation Trust

Status: Analysis

Funding: National Institute for Health Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme and the Barth Syndrome Foundation USA.

Barth syndrome is a rare, life threatening, genetic disease which affects young males. It is caused by abnormal fats (lipids) in the powerhouses of cells (mitochondria) and those who suffer with it often develop heart failure, heart rhythm abnormalities, bacterial infections, poor growth or feeding, weak muscles, developmental delay, severe exercise intolerance, lethargy and fatigue; all of which affect their daily life. Low white blood cell counts occur frequently due to intermittent or persistent reduction in numbers of the neutrophils that are responsible for fighting bacterial infections. This requires expensive and distressing injections to stimulate the bone marrow to produce more neutrophils. In addition, approximately one third of all males living with this disease in the UK have required heart transplantation.

Scientific research has shown that several treatments can improve the fat abnormalities in cells affected by Barth syndrome from either mice or humans; one of which is a drug called bezafibrate. Bezafibrate is particularly attractive as it has been safely administered for over 20 years in the UK to both adults and children for the treatment of high blood fats. The purpose of this study is to see if bezafibrate can be given safely and effectively to boys and men with Barth syndrome in a blinded randomised trial.

Bezafibrate or an inactive (placebo) treatment will be given to patients for 4 months, followed by a one month break, and then followed by 4 months of the alternate treatment (e.g. if bezafibrate is given for the first 4 months, a placebo will be given for the second 4 months) . Half of the participants will take bezafibrate first, the other half will take placebo first. Participants and research staff will not know which order the treatments are given in (double-blind trial).

Tests will be performed when patients enrol onto the study and at the end of each 4 month treatment period. The tests will investigate the effects bezafibrate on blood cells, exercise capacity, heart function and quality of life. The laboratory work performed at Bristol University and Great Ormond St Hospital will test the effect of bezafibrate on participant’s cells and mitochondria (which have been shown to be abnormal in Barth syndrome). This is to see whether we can predict any improvement in symptoms in order to tell us which patients would benefit from this treatment in future. Laboratory work will also be carried out on participant’s cells using another drug called resveratrol, which has also shown promise in laboratory tests, to see if this could provide an alternative treatment.

We wish to study up to 18 boys and young men with Barth syndrome in the UK, aged 6 years or over. In order to minimise travel to Bristol for participants, we will use local GPs and hospitals to perform monthly blood tests. Safety will be monitored by an independent Data Monitoring and Safety Committee.

Results from this study will be shared with our American and European colleagues so that this work will have worldwide benefit.


Contact information

Chief Investigator: Professor Colin Steward

Study Coordinator: Lucy Dabner




The INCIDENCE/IMPACT study is an NIHR-funded study of morbidity occurring following cardiac surgery in 5 UK paediatric cardiac surgical centres: Great Ormond Street Hospital, Evelina Children’s Hospital, Bristol Royal Hospital for Children, Birmingham Children’s Hospital, and The Royal Hospital for Sick Children, Glasgow.

Unit Role: Recruiting Centre 


Over 5000 paediatric cardiac surgery procedures are performed in the UK each year. Peri-operative mortality rates have steadily improved, with the efforts of clinical teams supported by world-leading collection and sharing of data on mortality. There is growing attention within the literature on the burden of surgical morbidity (complications) in this population but little account has been taken of patient and family perspectives. No systematic measurement of the incidence and impact of surgical morbidity on children, carers and health services is available and no routine monitoring is in place.

Aims and Objectives

We aim to identify the surgical morbidities that present the greatest burden on patients and health services and to develop and pilot routine monitoring and feedback of these key morbidities. Our objectives are to: identify key measures of surgical morbidity that can be used to capture the clinical and economic burden; measure the incidence of the selected morbidities; evaluate the clinical burden of these morbidities and their impact on quality of life and financial costs to the NHS and families; develop and pilot sustainable methods for collection and feedback of surgical morbidity data for use in quality assurance and continuous improvement.

Study Details

We will collect basic data on every patient under 16 years of age undergoing cardiac surgery (INCIDENCE) and follow them through their journey to see what morbidities, if any, they develop.  If a child has a morbidity from the list we are looking at, we will approach them to take part in the IMPACT part of the study where we will follow them up for 6 months to see what consequences the morbidity has on the patient and their family. 

 The study started on October 1st 2015, with recruitment lasting for 18 months with a further 6 month follow up.

Contact Information 

Research Nurse: Karen Sheehan


The effectiveness on post-operative recovery of using ‘off pump’ self-expanding tissue valves (IPVR) versus ‘on pump’ conventional tissue valves (PVR) for pulmonary valve replacement: an early phase randomised controlled trial (RCT)

In(jectable) V(alve) I(mplantation) T(rial) (InVITe)

Funder: NIHR and British Heart Foundation 

Sponsor: University Hospitals Bristol 

REC Number: 15/SW/0179

Status: Recruiting 

Many patients who are born with problems with their heart valves require repeated operations throughout their life to replace the affected valves. The standard operation for valve replacement involves opening the chest, extensive exposure by the surgeon and the use of the heart-lung bypass machine to take over the function of the heart and lungs (pumping blood and oxygen through the body) during the operation. The heart-lung bypass machine is an extremely useful tool, however, using it is not without risk and it often takes patients many weeks to recover after an open heart operation.

Recent advances in technology have introduced new replacement valves which can be ‘injected’ into position with the heart still beating (avoiding the need to use the heart-lung bypass machine) and without a need for the surgeon to expose all the heart. However, the new valve has not been extensively studied and has been used in around 300 patients so far. Surgeons have reported their experiences but only for small numbers of patients and without comparing their experiences directly with the conventional replacement valves.

InVITe will investigate the effectiveness of injectable pulmonary valve replacement compared to standard pulmonary valve replacement. Patients will be allocated at random (by chance) to receive either the “injectable” valve or standard valve. We will follow patients to determine whether the use of injectable valves results in quicker recovery and shorter stay in hospital and is cost saving for the NHS. We will also determine whether these valves function as well as the conventional ones.


Contact Information

Chief InvestigatorMr Andrew Parry, Consultant Paediatric Cardiac Surgeon, Bristol Royal Hospital for Children 

Study coordinator: Rachael Heys



A randomised controlled trial to compare normoxic versus standard cardiopulmonary bypass in cyanotic children undergoing cardiac surgery

Sponsor: University Hospitals Bristol 

REC Number: 01/H0106/172

Children with congenital heart disease often have lower than normal levels of oxygen in the blood (cyanosis) and need heart surgery to increase oxygen levels to normal.  Cyanotic children who undergo this type of surgery are put on a heart-lung bypass machine, which pumps blood around the body while the heart is being operated on and allows surgical staff to decide how much oxygen the child gets during surgery. 

Currently, cyanotic children are given 100% oxygen throughout their surgery, but there is evidence that this practice may damage the heart and other organs.  This may be caused by introducing 100% oxygen at the beginning of surgery when the child’s body is not used to it. 

The Oxic2 study aims to find out whether it is better to give lower levels of oxygen at the start of the operation.  Children who participate in the study are allocated by chance to receive either the higher level of oxygen (100%) or lower levels of oxygen at the start of the operation (similar to what a child is used to), which is slowly increased until it reaches a level we would expect to see by the end of the operation. 

We will compare how fast children recover in each group and determine whether the way their oxygen was managed during the operation has any effect on their development in the long term.

Contact Information

Chief Investigator: Prof Massimo Caputo

Study coordinator: Lucy Dabner


Hypothalamic-pituitary-adrenal (HPA) axis: function and control mechanisms in children undergoing cardiac surgery

Funder: British Heart Foundation 

Sponsor: University Hospitals Bristol 

Status: set up 

We aim to study the stress response to cardiac surgery and cardiac catheterisation in children and babies. Cardiac surgery triggers a major inflammatory response. The ‘inflammatory response’ is a set of reactions which when localised (such as a twisted ankle) can promote rapid healing of the injured part. When the injury is larger however (such as major surgery, burns or infection), this set of reactions can affect all tissues of the body leading to generalised inflammation that can result in the body’s organs failing and in some cases death. One of the hormones that can protect against an uncontrolled inflammatory response is the steroid hormone ‘cortisol’. Some hospitals give synthetic steroid type drugs to all children having cardiac surgery in an attempt to reduce this inflammatory response. However, it is currently unclear if this is needed or not. While too little cortisol leads to a large inflammatory response, too much cortisol leads to poor wound healing, high blood sugars and changes in the body’s metabolism. Humans produce their own cortisol in a diurnal rhythm (it is high when you first wake in the morning and lowest in the late evening). If you measure it frequently enough however, you can show that this rhythm actually consists of much more frequent pulses of cortisol (an ultradian rhythm). No-one has ever investigated the changes in the ultradian rhythm of cortisol around the time of cardiac surgery in neonates, infants and children. There is good reason to believe that both the size and frequency of these pulses is important for the best function of cortisol.  It has been shown by our group that these pulses change dramatically after adult heart surgery. The current study is designed to see what happens to these pulses when children and babies undergo cardiac surgery. We will compare this ‘surgical’ cohort with a group of children undergoing non-surgical cardiac investigations.  Once we know what is ‘normal’ we will then be in a position to make better decisions about when and if extra steroid therapy is needed in paediatric cardiac surgery.


Contact Information

Chief Investigator: Professor Gianni Angelini

Study coordinator: Jon Evans 


Unit Role: Recruiting Centre


It is estimated that about one percent of all live-born babies are affected by cardiac congenital malformations. Intra-cardiac surgical repair in these patients is associated with a low mortality in infants and children (< 5 %). More importantly, a growing number of patients survive into adulthood with an hypertensive right ventricle (RV). Heart failure due to RV dysfunction is a major cause of morbidity in this population and a significant proportion of them will die as a result.


The purpose of this proposal is to investigate the cellular signalling changes associated with RV hypertension in the setting of congenital heart disease. This will lead to a better understanding of the determinants of RV function in patients with hypertrophy associated with different congenital cardiac malformations. The hypotheses we will test are: 

  1. Changes in key myocardial cellular signalling pathways triggered by hypertension-induced RV dysfunction in high-risk congenital cardiac disorders depend on the type of malformation and oxygen saturation. These would include the Wnt pathway and the effect on cadherins.
  2. The pathology-induced cellular and molecular changes will result in differences in short term outcome within the hospital stay.
  3. Identifying differences in the cellular signalling pathways in three major types of malformation will enable us to tailor therapies for each pathology to improve outcome

Inclusion Criteria

  • All patients will have RV hypertension (RV systolic pressure > ½ systemic systolic)
  • Downs syndrome allowed
  • Age 0-16 years

Exclusion Criteria

  • Sick children (on ventilatory support)
  • Children who have had cardiac intervention in previous month
  • Other syndromes apart from Downs

Plan of Investigation

We will compare three groups of patients with RV hypertension: Group 1 - pulmonary hypertension, Group 2 - obstructed RV (as in Tetralogy of Fallot), and Group 3 - RV as the systemic ventricle.

We aim to recruit 100 patients across the 3 groups.  Tissue samples are taken from RA, RV & PA where appropriate. Echocardiographic assessment to document cardiac function.

Clinical outcome parameters: Recorded within the hospital stay, reviewing the need to standard cardiac support, such as oxygen, pulmonary vasodilators, chest drains and length of stay to discharge.

Contact Information

Research Nurse: Karen Sheehan 


Unit Role: Recruiting Centre


Congenital heart defects (CHD) affect approximately 1% of live births. Many complicated CHD require surgical correction to establish anatomic continuity and physiological restoration of flow. Although primary repair of the defect is sometimes possible, implementation of prosthetic replacement grafts in the form of new valves, conduits and patches, has allowed for establishment of anatomic continuity and physiological restoration in more complicated cases. 

Overall the use of prosthetic material is very common in congenital cardiac surgery, and even though these grafts may be lifesaving, they have limited durability and are prone to infection, immunological reactivity, and thrombosis, which often require repeat operations in the future.

A very promising approach to solve the above problem may be the use of tissue engineering, in which cells are seeded in three-dimensional matrices to form living tissue products having structure and function properties that can be used to restore, maintain or improve tissue function. Induction of autologous stem cells provides a powerful source for all types of cell regeneration and would be of great advantage in cardiovascular tissue engineering. These cells are easy to obtain and can be manipulated for multiple passages. The repopulation of homograft with patient’s stem cells before surgery can potentially create a vital homograft with a physiological high replacement of all components and subsequent long-term preservation of mechanical and biological properties.

Hypothesis and aims of the project

Tissue-engineered cardiovascular structures, including valves, conduits and vascular patches would consist of viable and autologous tissue which could theoretically function like a native biological structure with the potential to grow, to repair, and to model, and thus providing a longer lasting therapeutic effect than acellular allografts and significantly improve the quality of lives in children with congenital heart disease.

The aim of this project is to upgrade the valved-conduits and patches commonly used in reconstructive CHD surgery, by creating biomaterials/medical devices endowed with potential to grow, remodel and regenerate the failing right ventricle in vivo. We will test different cell products, including autologous stem cells from neonatal heart and bone marrow and blood, and cardiovascular cells derived from autologous induced pluripotent cells, to verify the optimal regenerative component within the medical device. We shall then use an in vivo CHD piglet model to test the new devices for proof of concept of feasibility and efficacy. If feasibility and efficacy is demonstrated we will perform a first-in-human clinical trial, comparing bio-engineered and conventional scaffolds for reconstruction of the right ventricular outflow tract and pulmonary arteries which will be the subject of future applications for regulatory approval.


The research participants (parents) will be asked permission to use the small left over surgical specimens that are normally discarded during the operation for isolating and growing stem cells and populate the biomaterials for our tissue engineering experiments.  Furthemore we will collect small samples of bone marrow removed from the sternum after the median sternotomy that is necessary to access the heart. We will also collect samples from the thymus, which is routinely removed during congenital heart surgery to gain access to the heart structures.   A small amount of blood (2 mls) will be withdrawn from the venous neck line that is routinely used in cardiac surgery without any need for invasive procedure.  The sample will be completely anonymized.

Inclusion Criteria

All participants will have congenital heart disease and be children (0-16 yrs old). All must be undergoing cardiopulmonary bypass operations.

Exclusion criteria

  • Sick children who need emergency operations
  • Children who are not within the above diagnostic groups above
  • Syndromes or genetic conditions other than Downs syndrome
  • Children who have had recent cardiac intervention within the previous month.

Contact Information

Research Nurse: Karen Sheehan


A Randomised Controlled Trial to Compare Normothermic Versus Hypothermic Cardiopulmonary Bypass in Children Undergoing Open Heart Surgery

Funder: NIHR - Bristol Cardiovascular Biomedical Research Unit 

Sponsor: University Hospitals Bristol 

REC Number: 11/SW/0122

Status: analysis 

When we operate on the heart we stop the heart and use a heart-lung bypass machine to pump the blood around the body. At the moment it is normal for the blood to be cooled down during the operation (‘hypothermic perfusion’). It is then warmed to a normal temperature again at the end of surgery.

This technique (sometimes called “whole body cooling”) is standard practice at the Bristol Children’s Hospital. We now think that it could be better to keep the blood at normal body temperature during the operation (‘normothermic perfusion’) instead of cooling it. Research on adults who need heart surgery has shown that it might be even better to leave blood at its normal temperature and not cool it down. The effects of the two techniques on younger people have not yet been directly compared so we do not know which is best.

The reason for this study is to compare the two temperatures used (hypothermic and normothermic) and look at their effects on the heart and other organs in detail. We will also look at whether the blood temperature used during the operation has an effect on memory and language skills and physical and social development at 3 months and 1 year post-operation.

Thermic-2 is a single-centre, randomised controlled trial. A total of 141 patients have been successfully randomised over 2 years and 10 months and followed-up for 1 year. A protocol paper was published in May 2015 in JMIR Research Protocols. The trial is currently in analysis phase and results are expected to be published in summer 2017.

The Thermic-2 study is funded by the National Institute for Health Research (NIHR) Bristol Cardiovascular Biomedical Research Unit. The views and opinions expressed herein are those of the authors and do not necessarily reflect those of the NIHR, NHS or the Department of Health. This study is sponsored by the University Hospitals Bristol NHS Foundation Trust. All surgery has been performed at the Bristol Royal Hospital for Children

Contact Information

Chief Investigator: Mr Massimo Caputo



Intermittent Antegrade Warm Blood versus Cold Blood Cardioplegia in Children Undergoing Open Heart Surgery: A Prospective, Multicentre, Randomised Controlled Trial (THERMIC-3)

Funder: British Heart Foundation 

Sponsor: University Hospitals Bristol 

Status: set up

During heart surgery, we stop the heart and use a heart-lung bypass machine to pump blood around the body. To keep the heart still during surgery we use a solution called ‘cardioplegia’ that also contains substances to protect the heart. At the moment it is normal for a cold cardioplegia solution to be used ‘cold blood cardioplegia’. However, we now think that it could be better to use a warm cardioplegia solution ‘warm blood cardioplegia’ instead.

Research suggests that using a warm solution in heart surgery on adults is less harmful than using a cold one. However, little is known about the effects of using warm cardioplegia solutions in children. Therefore, the study will compare the two cardioplegia temperatures used (‘cold’ or ‘warm’ blood cardioplegia) and look at their effects on the heart and recovery after heart surgery for paediatric patients.


Contact Information

Chief Investigator: Professor Massimo Caputo

Study coordinator: Rachael Heys