Title: NEUROlogical Prognosis After Cardiac arrest in Kids: Derivation, validation and impact assessment of a clinical prediction model. 'The NEURO-PACK study'
Funder: Department of Health and Social Care

Abstract: Background: Children resuscitated after either out-of-hospital or in-hospital cardiac arrest (CA) remains at risk of dying or surviving with severe brain injury. After resuscitation, owing to a lack of data, uncertainty exists amongst clinicians to accurately prognosticate these outcomes (16-18). Clinicians can be pessimistic, optimistic or un-necessarily ambiguous in their predictions affecting the clarity of communication with families and on-going treatment plans (19). Improved prognostication is therefore a high research priority amongst parents of children who have suffered a CA. In addition, early stratification of patients who may benefit from critical care interventions would also be a significant advancement (20, 21) and has been lacking in major studies to date (6).Development of a clinical prediction tool requires three key steps; derivation, validation and impact assessment (22). The challenges are to ensure the neurodevelopmental outcome assessment reflects clinical concerns, the tool design is fit for purpose by clinicians and families, the clinical prediction model and tool remains accurate in an external validation cohort (23), and when the tool is used, it improves clinically important outcomes (24). We hypothesise that a clinical prediction tool will improve clinician-parent communication, by improving early prognostication after paediatric CA.Successful evaluation of clinical interventions in the field of paediatric critical care, and in-particular cardiac arrest, will require international multicentre trials (25-28). This fellowship aims to train Dr Scholefield with exemplary leadership and management skills as a prognostic modeller and international, multi-centre, trialist.Aims: Derive a clinical prediction model for predicting good neurodevelopmental outcome at six months in children admitted to PICUs after CA. Convert the model to a bed-side clinical prediction tool that is useful and usable by clinicians and acceptable to parents. Assess the feasibility of research tools to quantify clinician-parent communication quality and clinician's certainty in prognostication. Externally validate the clinical prediction model and tool Assess the feasibility of performing a cluster, stepped-wedge randomised controlled trial (RCT) comparing post paediatric cardiac arrest clinical prediction tool use with no tool on clinically important outcomes including clinician-parent communication and clinician's prognostic certainty. Plan of investigation & Research questions: Work package one: Prospective observational study. What combination of (early) factors in a clinical prediction model best predict good neurodevelopmental outcome at six months in children admitted to UK and Republic of Ireland PICUs after CA? Work package two: Qualitative and mixed methods study of clinicians and parents in PICU. How should the clinical prediction model be converted into a clinical prediction tool? Are the validated assessment tools of clinician-parent communication and clinician certainty suitable in the post cardiac arrest setting? Work package three: External validation study. Do the clinical prediction model and prediction tool (if simpler than the original model) perform well in an external population? Work package four: Feasibility study. Is it feasible to recruit patients into a RCT, use the clinical prediction tool and complete follow up? Potential benefits to patients and the NHS: This programme will reduce uncertainty and distress in parents of children after CA by improved knowledge and accurate communication of prognosis using a validated clinical prediction tool. Early stratification of CA patients using the tool will enable individualised patient selection for appropriate neuro-protective treatment. The tool will also allow more efficient assessment of interventions in future trials to reduce neurological injury after CA. The creation of a UK CA data-set with important neurodevelopmental outcomes will benefit collaborative research into paediatric resuscitation(29) informing UK and international guidelines. Translation of improved understanding of how uncertainty impacts prognosis and decision making will benefit other areas of medicine (eg cancer, head injury).

Lay abstract: Background Up to 2000 children a year suffer a cardiac arrest in the UK. Unfortunately, over half will not be successfully resuscitated and die. Even if the heart is restarted they may be left with a significant level of damage to their brain which affects their and their family's subsequent quality of life. Those resuscitated will be admitted to a paediatric intensive care unit (PICU). When children first come to PICU it is difficult for doctors to predict how much damage there may be to the brain which makes it difficult to assess if the child will survive with permanent injury. Individual doctors might draw on different sources of information to decide how severe the injury may be, which means predictions about the future of these children can be inconsistent and in some cases less than accurate. This may add to the distress felt by parents and differences in the treatment given to children by different teams in different places. Aims This programme aims to: Collect information about children admitted to PICU after a cardiac arrest To use computer modelling to understand how the information will best help doctors to predict a child's outcome. Then to use information from another source to prove the accuracy of the model created. To use this model to create a useful tool that will support doctors and parents to make treatment decisions after cardiac arrest. To determine if we can perform a large trial to test whether using the tool allows better communication with families helping to minimise distress and help doctors decide the best treatment. Design and methods: There are four work stages: Over 18 months we will observe children in the UK and Republic of Ireland admitted to PICU after a cardiac arrest collecting relevant information. This information will be combined mathematically in a clinical prediction model that will help predict the extent of any damage to the nervous system of a child six month later. We will talk to consultants working in PICU, and parents whose children have been admitted to PICU about the design the appearance of the final tool to ensure it is acceptable for doctors and parents at the bedside. We will also explore if the questionnaires we wish to use with parents and doctors in the main trial cover areas that are important to families. We will explore whether the tool is useful and accurate in countries beyond the UK by looking at information collected in a similar group of children in the USA. We will test whether we are able to design a trial to compare the clinical impact on patients and communication between parents and doctors in a group of doctors using the tool with a group of doctors not using the tool. This will allow us to ask for further funding to conduct a larger trial in a number of countries to test if it improves clinical care. Because the numbers of children are small it will not be possible to do this study in the UK alone. Patient and public involvement: Parents of children who have either had a cardiac arrest, experienced uncertainty about the long term outcomes for their child in PICU, or childhood bereavement have kindly helped prepare this grant. All agree that the aims and research questions are important. They will continue to input their experiences and views in each stage ensuring sensitive parent issues are correctly handled during a distressing time. They will also help decide which clinical outcomes are important to demonstrate that the tool is of value to patients and families in the NHS. Two members will oversee the full fellowship programme to maintain a patient and family centered focus. The Young Person's Advisory Group have also shared valuable views on the design of the programme and recommended sharing information with surviving children where possible. Their advice on age appropriate language and picture use in patient facing research material in this programme will be a useful contribution. Dissemination: Doctors, nurses and researches caring for children after cardiac arrest will be informed of all the findings via presentations, articles in the medical journals, and inclusion in the influential international resuscitation guidelines and web-site produced by the International Liaison Committee on Resuscitation (ILCOR). Finally, parents and children involved in the programme will input when reviewing the study findings, writing the publications, and how to disseminate the key research messages to the wider public.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL