Immune and metabolic markers for identifying and investigating severe Coronavirus disease and Sepsis in children and young people (pSeP/COVID ChYP study): protocol for a prospective cohort study.

INTRODUCTION: Early recognition and appropriate management of paediatric sepsis are known to improve outcomes. A previous system's biology investigation of the systemic immune response in neonates to sepsis identified immune and metabolic markers that showed high accuracy for detecting bacterial infection. Further gene expression markers have also been reported previously in the paediatric age group for discriminating sepsis from control cases. More recently, specific gene signatures were identified to discriminate between COVID-19 and its associated inflammatory sequelae. Through the current prospective cohort study, we aim to evaluate immune and metabolic blood markers which discriminate between sepses (including COVID-19) from other acute illnesses in critically unwell children and young persons, up to 18 years of age. METHODS AND ANALYSIS: We describe a prospective cohort study for comparing the immune and metabolic whole-blood markers in patients with sepsis, COVID-19 and other illnesses. Clinical phenotyping and blood culture test results will provide a reference standard to evaluate the performance of blood markers from the research sample analysis. Serial sampling of whole blood (50 µL each) will be collected from children admitted to intensive care and with an acute illness to follow time dependent changes in biomarkers. An integrated lipidomics and RNASeq transcriptomics analyses will be conducted to evaluate immune-metabolic networks that discriminate sepsis and COVID-19 from other acute illnesses. This study received approval for deferred consent. ETHICS AND DISSEMINATION: The study has received research ethics committee approval from the Yorkshire and Humber Leeds West Research Ethics Committee 2 (reference 20/YH/0214; IRAS reference 250612). Submission of study results for publication will involve making available all anonymised primary and processed data on public repository sites. TRIAL REGISTRATION NUMBER: NCT04904523.

Development, implementation and evaluation of an evidence-based paediatric early warning system improvement programme: the PUMA mixed methods study.

BACKGROUND: Paediatric mortality rates in the United Kingdom are amongst the highest in Europe. Clinically missed deterioration is a contributory factor. Evidence to support any single intervention to address this problem is limited, but a cumulative body of research highlights the need for a systems approach. METHODS: An evidence-based, theoretically informed, paediatric early warning system improvement programme (PUMA Programme) was developed and implemented in two general hospitals (no onsite Paediatric Intensive Care Unit) and two tertiary hospitals (with onsite Paediatric Intensive Care Unit) in the United Kingdom. Designed to harness local expertise to implement contextually appropriate improvement initiatives, the PUMA Programme includes a propositional model of a paediatric early warning system, system assessment tools, guidance to support improvement initiatives and structured facilitation and support. Each hospital was evaluated using interrupted time series and qualitative case studies. The primary quantitative outcome was a composite metric (adverse events), representing the number of children monthly that experienced one of the following: mortality, cardiac arrest, respiratory arrest, unplanned admission to Paediatric Intensive Care Unit, or unplanned admission to Higher Dependency Unit. System changes were assessed qualitatively through observations of clinical practice and interviews with staff and parents. A qualitative evaluation of implementation processes was undertaken. RESULTS: All sites assessed their paediatric early warning systems and identified areas for improvement. All made contextually appropriate system changes, despite implementation challenges. There was a decline in the adverse event rate trend in three sites; in one site where system wide changes were organisationally supported, the decline was significant (ß = -0.09 (95% CI: - 0.15, - 0.05); p = < 0.001). Changes in trends coincided with implementation of site-specific changes. CONCLUSIONS: System level change to improve paediatric early warning systems can bring about positive impacts on clinical outcomes, but in paediatric practice, where the patient population is smaller and clinical outcomes event rates are low, alternative outcome measures are required to support research and quality improvement beyond large specialist centres, and methodological work on rare events is indicated. With investment in the development of alternative outcome measures and methodologies, programmes like PUMA could improve mortality and morbidity in paediatrics and other patient populations.

Validity and effectiveness of paediatric early warning systems and track and trigger tools for identifying and reducing clinical deterioration in hospitalised children: a systematic review.

OBJECTIVE: To assess (1) how well validated existing paediatric track and trigger tools (PTTT) are for predicting adverse outcomes in hospitalised children, and (2) how effective broader paediatric early warning systems are at reducing adverse outcomes in hospitalised children. DESIGN: Systematic review. DATA SOURCES: British Nursing Index, Cumulative Index of Nursing and Allied Health Literature, Cochrane Central Register of Controlled Trials, Database of Abstracts of Reviews of Effectiveness, EMBASE, Health Management Information Centre, Medline, Medline in Process, Scopus and Web of Knowledge searched through May 2018. ELIGIBILITY CRITERIA: We included (1) papers reporting on the development or validation of a PTTT or (2) the implementation of a broader early warning system in paediatric units (age 0-18 years), where adverse outcome metrics were reported. Several study designs were considered. DATA EXTRACTION AND SYNTHESIS: Data extraction was conducted by two independent reviewers using template forms. Studies were quality assessed using a modified Downs and Black rating scale. RESULTS: 36 validation studies and 30 effectiveness studies were included, with 27 unique PTTT identified. Validation studies were largely retrospective case-control studies or chart reviews, while effectiveness studies were predominantly uncontrolled before-after studies. Metrics of adverse outcomes varied considerably. Some PTTT demonstrated good diagnostic accuracy in retrospective case-control studies (primarily for predicting paediatric intensive care unit transfers), but positive predictive value was consistently low, suggesting potential for alarm fatigue. A small number of effectiveness studies reported significant decreases in mortality, arrests or code calls, but were limited by methodological concerns. Overall, there was limited evidence of paediatric early warning system interventions leading to reductions in deterioration. CONCLUSION: There are several fundamental methodological limitations in the PTTT literature, and the predominance of single-site studies carried out in specialist centres greatly limits generalisability. With limited evidence of effectiveness, calls to make PTTT mandatory across all paediatric units are not supported by the evidence base. PROSPERO REGISTRATION NUMBER: CRD42015015326.

A prospective, mixed-methods, before and after study to identify the evidence base for the core components of an effective Paediatric Early Warning System and the development of an implementation package containing those core recommendations for use in the UK: Paediatric early warning system - utilisation and mortality avoidance- the PUMA study protocol.

BACKGROUND: In hospital, staff need to routinely monitor patients to identify those who are seriously ill, so that they receive timely treatment to improve their condition. A Paediatric Early Warning System is a multi-faceted socio-technical system to detect deterioration in children, which may or may not include a track and trigger tool. It functions to monitor, detect and prompt an urgent response to signs of deterioration, with the aim of preventing morbidity and mortality. The purpose of this study is to develop an evidence-based improvement programme to optimise the effectiveness of Paediatric Early Warning Systems in different inpatient contexts, and to evaluate the feasibility and potential effectiveness of the programme in predicting deterioration and triggering timely interventions. METHODS: This study will be conducted in two district and two specialist children's hospitals. It deploys an Interrupted Time Series (ITS) design in conjunction with ethnographic cases studies with embedded process evaluation. Informed by Translational Mobilisation Theory and Normalisation Process Theory, the study is underpinned by a functions based approach to improvement. Workstream (1) will develop an evidence-based improvement programme to optimise Paediatric Early Warning System based on systematic reviews. Workstream (2) consists of observation and recording outcomes in current practice in the four sites, implementation of the improvement programme and concurrent process evaluation, and evaluation of the impact of the programme. Outcomes will be mortality and critical events, unplanned admission to Paediatric Intensive Care (PICU) or Paediatric High Dependency Unit (PHDU), cardiac arrest, respiratory arrest, medical emergencies requiring immediate assistance, reviews by PICU staff, and critical deterioration, with qualitative evidence of the impact of the intervention on Paediatric Early Warning System and learning from the implementation process. DISCUSSION: This paper presents the background, rationale and design for this mixed methods study. This will be the most comprehensive study of Paediatric Early Warning Systems and the first to deploy a functions-based approach to improvement in the UK with the aim to improve paediatric patient safety and reduce mortality. Our findings will inform recommendations about the safety processes for every hospital treating paediatric in-patients across the NHS. TRIAL REGISTRATION: Sponsor: Cardiff University, 30-36 Newport Road, Cardiff, CF24 0DE Sponsor ref.: SPON1362-14. Funder: National Institute for Health Research, Health Services & Delivery Research Programme (NIHR HS&DR) Funder reference: 12/178/17. Research Ethics Committee reference: 15/SW/0084 [13/04/2015]. PROSPERO reference: CRD42015015326 [23/01/2015]. ISRCTN: 94228292 https://doi.org/10.1186/ISRCTN94228292 [date of application 13/05/2015; date of registration: 18/08/2015]. Prospective registration prior to data collection and participant consent commencing in September 2014.

Evolution, safety and efficacy of targeted temperature management after pediatric cardiac arrest.

BACKGROUND: It is unknown whether targeted temperature management (TTM) improves survival after pediatric out-of-hospital cardiac arrest (OHCA). The aim of this study was to assess the evolution, safety and efficacy of TTM (32-34 °C) compared to standard temperature management (STM) (<38 °C). METHODS: Retrospective, single center cohort study. Patients aged >one day up to 16 years, admitted to a UK Paediatric Intensive Care Unit (PICU) after OHCA (January 2004-December 2010). Primary outcome was survival to hospital discharge; efficacy and safety outcomes included: application of TTM, physiological, hematological and biochemical side effects. RESULTS: Seventy-three patients were included. Thirty-eight patients (52%) received TTM (32-34 °C). Prior to ILCOR guidance adoption in January 2007, TTM was used infrequently (4/25; 16%). Following adoption, TTM (32-34 °C) use increased significantly (34/48; 71% Chi(2); p < 0.0001). TTM (32-34 °C) and STM (<38 °C) groups were similar at baseline. TTM (32-34 °C) was associated with bradycardia and hypotension compared to STM (<38 °C). TTM (32-34 °C) reduced episodes of hyperthermia (>38 °C) in the 1st 24h; however, excessive hypothermia (<32 °C) and hyperthermia (>38 °C) occurred in both groups up to 72 h, and all patients (n = 11) experiencing temperature <32 °C died. The study was underpowered to determine a difference in hospital survival (34% (TTM (32-34 °C)) versus 23% (STM (<38 °C)); p = 0.284). However, the TTM (32-34 °C) group had a significantly longer PICU length of stay. CONCLUSIONS: TTM (32-34 °C) was feasible but associated with bradycardia, hypotension, and increased length of stay in PICU. Temperature <32 °C had a universally grave prognosis. Larger studies are required to assess effect on survival.