Abstract Introduction Myocardial protection against ischaemia–reperfusion injury is a key determinant of heart function and outcome following cardiac surgery in children. However, myocardial injury still occurs routinely following aortic cross-clamping, as demonstrated by the ubiquitous rise in circulating troponin. del Nido cardioplegia was designed to protect the immature myocardium and is widely used in the USA but has not previously been available in the UK, where St. Thomas’ blood cardioplegia is most common. The del Nido versus St. Thomas’ blood cardioplegia in the young (DESTINY) trial will evaluate whether one solution is better than the other at improving myocardial protection by reducing myocardial injury, shortening ischaemic time and improving clinical outcomes. Methods and analysis The DESTINY trial is a multicentre, patient-blinded and assessor-blinded, parallel-group, individually randomised controlled trial recruiting up to 220 children undergoing surgery for congenital heart disease. Participants will be randomised in a 1:1 ratio to either del Nido cardioplegia or St. Thomas’ blood cardioplegia, with follow-up until 30 days following surgery. The primary outcome is area under the time–concentration curve for plasma high-sensitivity troponin I in the first 24 hours after aortic cross-clamp release. Secondary outcome measures include the incidence of low cardiac output syndrome and Vasoactive-Inotropic Score in the first 48 hours, total aortic cross-clamp time, duration of mechanical ventilation and lengths of stay in the paediatric intensive care unit and the hospital. Ethics and dissemination The trial was approved by the West Midlands—Coventry and Warwickshire National Health Service Research Ethics Committee (21/WM/0149) on 30 June 2021. Findings will be disseminated to the academic community through peer-reviewed publications and presentation at national and international meetings. Parents will be informed of the results through a newsletter in conjunction with a national charity. Trial registration number ISRCTN13638147; Pre-results. Keywords: Paediatric cardiac surgery, Clinical Trial, Congenital heart disease __________________________________________________________________ STRENGTHS AND LIMITATIONS OF THIS STUDY. * This multicentre randomised controlled trial will compare two types of cardioplegia in children, recruiting across several paediatric cardiac surgical centres in the UK. * The broad inclusion criteria, limited exclusions and pragmatic nature of the protocol will support the real-world nature of the trial and ensure the generalisability of its findings. * Through the trial, we will make del Nido cardioplegia available in the UK for the first time, with an extended 12-month refrigerated shelf-life, thereby evaluating a product that is viable for ongoing use in the National Health Service. * A potential limitation is the need for the operating surgeon, perfusionist, anaesthetist and theatre team to be unblinded to the allocation to protect patient safety, as cardioplegia delivery and dosing intervals necessarily differ between treatment groups, although patients and outcome assessors will be blinded. * The effect of the intervention may be concealed if incision or resection of ventricular myocardium is performed, which may significantly increase troponin release above that associated with ischaemia–reperfusion. Introduction Myocardial protection with cardioplegia During most surgery for congenital heart disease, it is necessary to stop the heart, allowing access to a still and bloodless field to enable repair of intracardiac defects. Cardioplegia has been fundamental to arresting the heart and protecting against ischaemia–reperfusion injury during surgery for over 40 years, with approximately 3200 cardiac surgical operations with cardioplegic arrest performed in children in the UK and Ireland each year.[54]^1 While on cardiopulmonary bypass (CPB), a cross-clamp is placed across the proximal aorta and cardioplegia infused into the coronary arteries via the aortic root, leading to electromechanical arrest. This reduces myocardial oxygen uptake by 90%, and progressive hypothermia leads to a further stepwise reduction.[55]^2 However, myocardial injury still occurs routinely following aortic cross-clamping in children, as demonstrated by the ubiquitous release of troponin after surgery.[56]^3 4 Myocardial protection, therefore, is a key determinant of heart function and outcome following cardiac surgery, and improving organ protection during surgery was recently identified as the top national priority for research in children with congenital heart disease.[57]^5 Current paediatric cardioplegia techniques are primarily derived from adult practice or laboratory models; however, the immature myocardium has significant structural, physiological and metabolic differences from the adult heart, including sarcoplasmic reticulum development, mitochondrial density, substrate utilisation, calcium handling and antioxidant defences.[58]^3 It is less tolerant of ischaemia and more sensitive to calcium overload-mediated injury during reperfusion, particularly with hypoxaemia.[59]^6 7 Myocardial protection that is effective in adults therefore may not be optimal for young children,[60]^8 9 especially neonates and those with preoperative cyanosis.[61]^10 However, there are no late phase clinical trials of cardioplegia in children; most published trials are small, low quality, single-centre studies, with inconsistent endpoints and at risk of systematic bias.[62]^11 Of concern, these trials have recruited very few neonates, a high-risk group in whom the effects of cardioplegia are less well understood.[63]^3 Identifying the best cardioplegia for specific patient groups will enable the care of the child undergoing surgery to be individualised, potentially improve outcomes by reducing myocardial injury, morbidity and costs and may improve long-term cardiac function.[64]^12 Many types of cardioplegia solution are available, and there is wide variation in their use worldwide.[65]^13 In North America, del Nido cardioplegia is the most commonly used solution in children, with a recent survey finding its use by 78% of respondents from the Congenital Heart Surgeons’ Society.[66]^14 On the other hand, St. Thomas’ blood cardioplegia is used by most paediatric cardiac surgeons in most centres in the UK,[67]^15 where del Nido solution is not currently commercially available. There are significant theoretical and practical differences between these two autologous blood cardioplegia solutions; the usual interval between doses of del Nido is much longer (60–90 min)[68]^16 than for St. Thomas’ (20–30 min),[69]^15 such that in most cases, only a single dose is required. Eliminating or reducing the need to interrupt surgical flow to re-dose with cardioplegia improves the efficiency of the operation[70]^17 and may shorten the overall burden of ischaemia (cross-clamp time).[71]^18 Duration of aortic cross-clamp is an independent predictor of outcome after surgery,[72]^19 and therefore purely by reducing the duration of ischaemia, del Nido cardioplegia might be expected to reduce myocardial injury and potentially improve outcomes. Assessment of myocardial protection Low cardiac output syndrome (LCOS) in the early postoperative period reflects the degree of myocardial injury and the need for inotropic support to maintain adequate systemic oxygen delivery. The presence of LCOS is a major determinant of outcome after heart surgery in children, and most deaths in the early postoperative period are attributed to a low cardiac output.[73]^20 21 However, there are no widely accepted methods for directly measuring cardiac output in young children, and therefore the identification of low cardiac output is dependent on the use of surrogate clinical signs such as need for inotropic support, arterial lactate concentration or omega. Postoperative elevation of plasma troponin is a marker of myocardial injury and has been shown to strongly correlate with clinical outcomes including inotropic support requirements, duration of ventilation, ventricular dysfunction and early death[74]^4 22; consequently, it is the most common primary outcome measure in clinical trials of myocardial protection in children.[75]^11 While the rise in troponin is strongly correlated with the duration of ischaemia,[76]^23 it may be further elevated by surgical interventions, such as ventricular incision or resection.[77]^24 Rationale In this multicentre, phase II/III trial, we will test whether del Nido cardioplegia improves myocardial protection in children undergoing surgery for congenital heart disease compared with St. Thomas’ blood cardioplegia. In a recent UK and Ireland survey, we found that 29 (91%) respondent surgeons would be willing to use del Nido in a clinical trial, with the combination of del Nido and St. Thomas’ blood having the greatest acceptability.[78]^15 The trial was developed with advice from Professor Pedro del Nido and colleagues at Boston Children’s Hospital, who designed the eponymous solution and have the largest experience with its use in children in the world.[79]^16 Its pragmatic design was also informed by the survey findings, taking account of current UK practice on composition, temperature, dose and dosing interval, and noting concerns over the use of del Nido with an expected short cross-clamp time, thereby maximising its acceptability to the surgical community.[80]^15 del Nido cardioplegia will be made available for the first time in the UK through this trial, providing a unique and timely opportunity to address this important question. Once completed, it will be the largest clinical trial in paediatric cardiac surgery in the UK[81]^25 and the only multicentre trial of cardioplegia in children,[82]^11 with the potential to change routine clinical practice. Methods and analysis Design The del Nido versus St. Thomas’ blood cardioplegia in the young (DESTINY) trial is a multicentre, patient-blinded and assessor-blinded, parallel-group, individually randomised controlled trial to compare the effects of two cardioplegia solutions on myocardial protection in children undergoing surgery for congenital heart disease at level 1 paediatric cardiac surgical centres in the UK (see Acknowledgements).