Search

Objectives Platform trials were used successfully in adult populations during the COVID-19 pandemic. By testing multiple treatments within a single trial, platform trials can help identify the most effective treatments (and any interactions between treatments) for patients more quickly and with less burden for patients and their families. The aim of this qualitative research was to inform the design of the first adaptive platform trial for paediatric intensive care in the UK with young people, parents/carers and paediatric intensive care unit (PICU) staff.Design Qualitative semistructured focus group study. Data were analysed using reflexive thematic analysis.Participants Young people, parents/carers, and PICU medical, nursing and research staff.Setting The UK.Results A total of 86 participants (18 young people; 15 parents/carers; 53 PICU staff) took part in 1 of 10 focus groups between May and September 2023. Participants viewed the proposed PICU platform trial and use of research without prior consent to be acceptable. Findings provide insight into how the PICU platform trial should be designed and operationalised, including having a broad and inclusive population eligible for inclusion onto the platform trial, with different inclusion and exclusion criteria for each domain; starting the trial with no more than three domains and prioritising the outcomes of Child quality of life and Survival (all participants). Optimal governance structure and suggestions about how any challenges to the success of the full trial can be overcome are also presented.Conclusions Young people, parents/carers and PICU staff viewed the proposed PICU platform trial to be acceptable. These key stakeholders supported us with the design of an adaptive platform trial for PICU that has a rigorous methodology, yet can be operationalised in a family-centred way, to provide high-quality evidence that can support clinical decision-making and guide the treatment of critically ill children. Our findings have informed the PICU platform trial protocol.

Abstract Background Mild hypoxic ischemic encephalopathy is associated with sub optimal cognition and learning difficulties at school age. Although whole-body hypothermia reduces death and disability after moderate or severe encephalopathy in high-income countries, the safety and efficacy of hypothermia in mild encephalopathy is not known. The cooling in mild encephalopathy (COMET) trial will examine if whole-body hypothermia improves cognitive development of neonates with mild encephalopathy. Methods The COMET trial is a phase III multicentre open label two-arm randomised controlled trial with masked outcome assessments. A total of 426 neonates with mild encephalopathy will be recruited from 50 to 60 NHS hospitals over 2 ½ years following parental consent. The neonates will be randomised to 72 h of whole-body hypothermia (33.5 ± 0.5 C) or normothermia (37.0 ± 0.5 C) within six hours or age. Prior to the recruitment front line clinical staff will be trained and certified on expanded modified Sarnat staging for encephalopathy. The neurological assessment of all screened and recruited cases will be video recorded and centrally assessed for quality assurance. If recruitment occurs at a non-cooling centre, neonates in both arms will be transferred to a cooling centre for continued care, after randomisation. All neonates will have continuous amplitude integrated electroencephalography (aEEG) at least for the first 48 h to monitor for seizures. Predefined safety outcomes will be documented, and data collected to assess resource utilization of health care. A central team masked to trial group allocation will assess neurodevelopmental outcomes at 2 years of age. The primary outcome is mean difference in composite cognitive scores on Bayley scales of Infant and Toddler development 4th Edition. Discussion The COMET trial will establish the safety and efficacy of whole-body hypothermia for mild hypoxic ischaemic encephalopathy and inform national and international guidelines in high income countries. It will also provide an economic assessment of whole-body hypothermia therapy for mild encephalopathy in the NHS on cost-effectiveness grounds. Trial registration number NCT05889507 June 5, 2023.

Background Neonates undergoing emergency abdominal surgery frequently require a stoma; closing this stoma with a second operation is an essential part of recovery. Timing of closure varies. Optimal timing is unclear and would be best resolved through a randomised controlled trial; such a trial is likely to be challenging. Aim To determine if it is feasible to conduct a clinical trial comparing ‘early’ versus ‘late’ stoma closure in neonates. Design Mixed methods comprising three parallel workstreams incorporating: a clinician survey, prospective observational cohort study, parent interviews, focus groups, database analyses and consensus meeting. Setting Specialist neonatal surgical centres across the United Kingdom. Participants and data sources Neonatologists, neonatal surgeons, neonatal dietitians and neonatal nurses who care for neonates with stomas. Neonates with recent stoma, their parents and the clinicians looking after them. Three existing, overlapping clinical databases. Results One hundred and sixty-six professionals from all 27 neonatal surgical centres completed the survey: 6 weeks was the most common target time for stoma closure across clinical scenarios, although there was wide variation. Timing of closure was influenced by nutrition, growth and stoma complications. The prospective cohort study enrolled 56 infants from 8 centres. Infants were mostly preterm with necrotising enterocolitis or intestinal perforation. Clinicians identified extreme preterm gestation and clinical conditions as reasons for not randomising babies into a hypothetical trial comparing early and late stoma closure. Parents and healthcare professionals identified that comparator arms needed more clinical flexibility in relation to timing of stoma closure. Analysis of existing databases revealed wide variation in current timing of stoma closure in neonates and identified approximately 300 eligible infants for a trial per annum in the United Kingdom. Conclusions A trial of ‘early’ compared to ‘late’ stoma closure in neonates is feasible and is important to families and health professionals. The population of eligible babies in the United Kingdom is sufficient for such a trial. Challenges centre around lack of equipoise in certain scenarios, specifically: extremely preterm infants; infants waiting too long for stoma closure in the ‘late’ comparator; and logistical issues in closing a stoma at a trial-allocated time. These challenges are addressable by incorporating flexibility based on gestation at birth, communicating that both trial arms are standard practice and valid treatment options, and providing resources, for example, for operating lists. Future work We recommend the following population, intervention, comparator and outcome as a starting point to inform future trial design. Population: neonates with stomas (excluding those with a fixed treatment pathway). Intervention: stoma closure at 6 weeks and after 32 weeks post conceptual age. Comparator: expectant management with stoma closure undertaken when the clinical team determines is best for the infant. Primary outcomes: weight gain/growth or length of hospital stay. Study registration This study is registered as IRAS Project ID 278331, REC Reference 20/LO/1227. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR128617) and is published in full in Health Technology Assessment; Vol. 28, No. 71. See the NIHR Funding and Awards website for further award information. Plain language summary Babies who develop a bowel problem soon after birth may need surgical treatment and a stoma (where the bowel is brought out into a bag on the tummy). Stomas can be life-saving but can also cause problems. They must be ‘closed’ with a second operation once the baby has got better. The timing of this second operation varies between hospitals and we do not know the best time to do it. To find out the best time to close a baby’s stoma, we wanted to conduct a clinical trial. This would mean some babies having their stoma closed ‘early’, and other babies ‘later’ and seeing which group did better. Babies would be put into the ‘early’ or ‘late’ group at random so that we could have a fair comparison. Because doing a trial may be challenging, we first set out to find out if a trial would be feasible in the Timing of Stoma Closure in Neonates study. What we did Found out what currently happens to babies with a stoma through a survey of healthcare staff and looking at data from several national databases. Collected data on 56 babies with stomas in 8 hospitals, including asking their doctors whether they would recruit these babies to a trial and when they would close their stoma. Interviewed parents of children who had had a stoma. Held focus groups with staff at the eight hospitals. Held a meeting for National Health Service staff and parents to discuss the way forwards. What we found Parents and doctors think this question is important and that a clinical trial is a good idea. Deciding on the timing of stoma closure in the trial and what we mean by ‘early’ and ‘late’ is critical to the success of a trial. The timing may need to take into account that some babies born extremely preterm may be difficult to include. A trial that compares how well infants grow and/or length of stay in hospital between babies having early or later stoma closure may well be feasible. What happens next The National Institute for Health and Care Research (research arm of the Department of Health and Social Care) will use this to information to help decide if they would like to fund a trial in the future. Scientific summary Background Neonates undergoing emergency abdominal surgery for problems such as necrotising enterocolitis (NEC), spontaneous intestinal perforation (SIP) or a congenital bowel obstruction frequently require a stoma. While stomas can be life-saving, they pose a number of challenges including fluid and electrolyte imbalance, local wound and skin problems, malnutrition and growth failure. Reversing (closing) these stomas with a second operation is therefore an essential part of an infant’s recovery. The timing of stoma closure is known to vary between hospitals and, indeed, clinicians and the best time remains unclear, with conflicting evidence from published studies of low methodological quality. Rationale Determining the best time to close stomas in neonates is imperative, as it has significant implications for: infant health outcomes (e.g. stoma complications and growth) families (e.g. reduced neonatal unit stay, healthcare burden, time off work) healthcare providers [e.g. neonatal unit bed-days, parenteral nutrition (PN) use, surgery, cost]. In addition, reducing unwarranted variability in surgical care is a key priority for the NHS. The most methodologically robust way to determine optimal timing of stoma closure would be through an adequately powered randomised controlled trial (RCT). A trial of different stoma closure times in neonates is likely to be challenging, due to: the patient group who have heterogenous underlying diseases and comorbidities clinician factors such as willingness to recruit parent factors such as trial acceptability. This study aimed to explore these potential challenges and determine if a trial comparing ‘early’ and ‘late’ stoma closure is feasible. Aims The overarching aim of the Timing of Stoma Closure in Neonates (ToSCiN) study was to answer the question: is it feasible to conduct a RCT comparing ‘early’ versus ‘late’ stoma closure in neonates? Objectives The specific objectives of the ToSCiN study were: to establish current UK practice for stoma closure in neonates to determine whether there is equipoise among clinicians (neonatal surgeons and neonatologists) and allied health professionals (specialist nurses and dietitians) over when it is best to close stomas in neonates to define ‘early’ and ‘late’ stoma closure for a potential trial to define a population of neonates for inclusion in a trial (in whom there is significant uncertainty over timing) and determine how many infants are eligible for inclusion to establish the most appropriate design and outcome measures for a trial to determine the willingness of parents, neonatal surgeons and neonatologists to include neonates in a trial that would randomise to ‘early’ or ‘late’ stoma closure and identify potential barriers to recruitment to assess the suitability of using routinely collected data for gathering clinical information for a trial. Methods The ToSCiN study used a mixed-methods approach (qualitative and quantitative methodology) and comprised three parallel workstreams. Workstream 1: Survey of clinician and allied health professional perspectives on neonatal stoma closure An online survey was sent to clinicians and allied health professionals involved in the care of newborn infants with stomas at neonatal surgical units across the UK. The survey questions and a series of clinical scenarios to explore current practice/preferences, perspectives on ‘early’ versus ‘late’ stoma closure, which groups of infants should be included in a trial comparing these, preferred trial design including outcomes and barriers to achieving the optimal timing of closure. Workstream 2: Parent and clinician perspectives regarding a clinical trial of neonatal stoma closure This workstream took place in eight UK neonatal surgical centres and comprised three elements: (2.1) An observational cohort study of neonates who had a stoma formed Key clinical and demographic information was recorded prospectively. The data set comprised factors that could influence the timing of stoma closure and outcomes which are likely to be important in a future trial. (2.2) Questionnaires for the principal clinicians (surgeon and neonatologist) caring for each infant recruited to the cohort study These were completed at three time points and explored the acceptability of a hypothetical trial to clinicians for each infant. Time points: (1) approximately 1 week after stoma formation to explore randomising the infant to a trial, (2) 6 weeks after stoma formation to explore following an allocation to early closure intervention and (3) 12 weeks after stoma formation to explore following an allocation to late closure comparator. (2.3) A qualitative study incorporating: (1) focus groups with clinicians and (2) interviews with parents of neonates who had a stoma Multidisciplinary healthcare professional focus groups explored equipoise, current practice and views on early versus late closure, willingness to recruit to a trial, acceptability of a trial and prioritised outcome measures. Parents of infants in the cohort study and additional parents recruited via social media were invited for a telephone or video interview. Their views were explored on: having a child with a stoma, acceptability of a trial, timing of recruitment, potential barriers to trial participation, trial participant information materials, approach to consent for a trial and prioritised outcome measures. Workstream 3: Analysis of three existing national databases Analyses were carried out on three existing national data sets [from the National Neonatal Research Database (NNRD), The British Association of Paediatric Surgeons Congenital Anomalies Surveillance System (BAPS-CASS) and Hospital Episode Statistics – Admitted Patient Care (HES-APC)]. The analyses aimed to: (1) establish current UK practice, (2) define a population for trial inclusion and provide the number of eligible infants and (3) establish values for key outcome measures. Consensus meeting This was held using an online video platform at the end of the study period when data collection and preliminary analysis had been completed. Professionals and parents previously involved were invited and further parents were recruited via social media. A summary of results from the three workstreams was presented to attendees. Facilitated small group discussions took place, followed by a summary of small group discussions presented by group facilitators to all attendees, and electronic voting was conducted about trial acceptability and design. Results Workstream 1 Results One hundred and sixty-six professionals completed the survey with at least one respondent from each of the 27 UK centres. Six weeks was the most commonly stated target time for closure across all scenarios, although there was a high degree of variability, with intervals of 12 weeks or more frequently advocated. While 70–76% of respondents preferred closure prior to discharge in preterm infants and a term infant with jejunostomy, only 46% preferred this in term infants with ileostomy. A sizeable proportion (41%) use weight, rather than time, to determine when to close a stoma. Thematic analysis of free text identified nine key themes influencing decision-making, mostly related to nutrition, growth and stoma complications. With regard to potential trial design, 86% of respondents indicated they would include preterm infants with NEC/SIP and 72% term infants with other conditions. Closure at 6 weeks was the most commonly cited timing of early intervention; the preferred later time point was 12 weeks. Growth was most commonly selected as the favoured primary outcome for a trial, followed by time to full feeds, length of stay and duration of PN. Workstream 2 Results Cohort study Fifty-six infants were enrolled from eight UK units. Infants were mostly preterm (44/56), with median birthweight 961 g (range 415–3962 g). The cohort comprised 37 infants with NEC/SIP and 19 with other diagnoses. Most stomas were in the small bowel, formed at a median of 8 days (range 1–80 days). At 1 week following stoma formation, 18/56 infants were mechanically ventilated, 8 were receiving inotropes and 13 had received blood products in the preceding 24 hours. At this point, surgeons stated they would be willing to randomise 31 infants (59%) into a hypothetical trial of 6- versus 12-week closure. The commonest reason for not being willing was the infant being ‘too small or premature’. At 6 weeks post stoma, median weight was 2024 g (range 795–4460 g) and nine remained ventilated. Eighty per cent (42/56) were reported to have gained weight in the past week. Median enteral feed volume was 127 ml/kg/day, stoma output was < 20 ml/kg/day in 86% and stoma-related complications were reported in one-third. Surgeons would be willing to follow theoretical trial allocation for ‘early’ closure in 17/56 (33%). In nine infants, the stoma had already been closed. The main reasons for not being willing to follow trial allocation were current clinical status and size. Among infants whom surgeons said they would not be willing to follow trial allocation, most (16/25) were < 28 weeks’ gestation at birth and were lighter (median weight 1609 vs. 2090 g). Twelve weeks after stoma formation, median weight was 2548 g and 10% (4/52) remained ventilated. Most (23/42; 55%) were still receiving PN (a higher proportion than at 6 weeks) and 12% (5/42) were not receiving any enteral feed. Stoma-related problems were present in one-third and one-quarter had stoma output > 20 ml/kg/day. Surgeons stated they would be unwilling to follow trial allocation of closure at 12 weeks in 24 infants: 12 of these had required earlier stoma closure and 9 (mainly premature infants) were considered unsuitable for stoma closure for a variety of mainly clinical reasons (rather than logistical or family factors). Again, most infants for whom the surgeon was unwilling to follow trial allocation were < 28 weeks' gestation at birth (13/24). Overall stoma closure took place before the end of the data collection period in 82% (46/56 infants, 4 infants died with a stoma in situ and 6 infants still had a stoma). Median time to closure was 9.9 weeks (range 4.4–28.3 weeks), at median 88 days of age and weight of 2631 g. Qualitative study We interviewed 24 parents (17 mothers, 7 fathers) of babies who required a stoma in the last 3 years in the UK (July 2021–February 2022). Fifteen parents were recruited via hospital sites and nine via social media. Thirty-six staff (14 surgeons, 10 consultant neonatologists, 6 neonatal surgical nurses, 2 research nurses, 1 dietitian and 3 ‘other’ roles) from five study sites took part in one of six focus groups (November–December 2021). Most parents and staff considered the proposed ToSCiN trial to be acceptable and wanted the research question to be answered. Staff would be willing to randomise babies, except the most extremely preterm, to the trial and parents would hypothetically consent to their baby taking part if the ‘emotive’ ‘early’ (6 weeks) and ‘late’ (12 weeks) terminology was changed. Some parents and staff, however, had clear trial arm preference and concerns about the alternative trial arm. They felt that decisions about when to close a stoma should be led by the overall health and well-being of the baby. Stoma-related factors, logistical and organisational factors and family factors also influenced views on acceptable timing of stoma closure. These findings highlight potential challenges for recruitment and retention and trial success. Workstream 3 Results While direct comparison was limited by differences in data set populations and coverage, there was a reasonably consistent number of potentially eligible infants with a stoma for NEC/SIP across data sets, with 163 in 1 year in the BAPS-CASS cohort and mean annual volumes of 193 (NNRD) and 192 (HES-APC). HES-APC was used to estimate non-NEC infant numbers, as it had the most comprehensive coverage, with a mean of 118 per year. The total UK population of potentially eligible infants would therefore be approximately 300 per annum. Median stoma durations for babies with NEC/SIP were as follows: BAPS-CASS 63 days; NNRD 60 days and HES-APC 78 days. For infants with stomas for other reasons, closure was usually earlier: NNRD 45 days; HES-APC 74 days; and in the BAPS-CASS meconium ileus cohort, 51 days. HES-APC included babies who were discharged home with a stoma in situ, hence longer median stoma durations. Consensus meeting The consensus meeting was attended by 52 individuals from a range of health professional and non-professional backgrounds, including 7 parents. Voting on key aspects of trial design showed: (1) 83% favoured including all infants with a stoma, (2) 58% favoured comparing closure at 6 weeks after stoma formation with expectant management rather than comparison to a specific late timepoint, and (3) the favoured primary outcomes were weight gain/growth (38%) and length of hospital stay (32%). Conclusions We found that a randomised trial of early compared to late stoma closure in neonates is feasible and is important to families and health professionals. We identified the following components as being critical to a successful future trial: comparison of closure at 6 weeks versus expectant management comparison that accounts for completed gestational age, rather than solely duration of stoma. We identified the potential population and outcomes for such a trial and established that a sufficient population exists in the UK. We also identified that a trial comparing ‘early’ and ‘late’ closure at rigidly defined time points (e.g. closure at 6 compared to 12 weeks) would not be feasible. The principal challenge for trial conduct was found to be the ‘baby-led’ narrative that came through strongly from study participants. Parents and professionals appeared to lack equipoise in certain scenarios. However, this lack of personal equipoise is not exclusive to ToSCiN, and similar themes have been overcome in trials in the past (including complex surgical trials) by optimising communication. Our findings provide valuable insight into how best to do this in a future trial. Other challenges identified include: (1) concerns about inclusion of extremely preterm infants, (2) concerns about infants waiting too long for stoma closure if randomised to the ‘late’ comparator arm and (3) logistical arrangements for closing a stoma at the time dictated by trial allocation. These challenges are eminently addressable, by designing the trial to: (1) incorporate a degree of flexibility (e.g. using ‘expectant management’ as the comparator), (2) make allowances for certain groups (e.g. having a higher corrected gestational age limit for extremely preterm infants) and (3) ensure parents and professionals are aware both trial arms are standard practice and valid treatment options. Key research recommendations We recommend the following population, intervention, comparator and outcome (PICO) as a starting point to inform the design of a future trial: Population: neonates with stomas, excluding those with a stoma as part of a fixed treatment pathway, for example, anorectal malformations and Hirschsprung’s disease. Intervention: stoma closure at 6 weeks post stoma formation and where 32 weeks post-conceptual age has been reached. Comparator: expectant management with stoma closure undertaken when the clinical team determines is best for the infant. Outcomes: weight gain/growth or length of hospital stay should be the primary outcome measure. In order to optimise a trial, we recommend the following practical steps: Involve higher volume neonatal surgical centres for efficient recruitment. Ensure trial staff at each centre are highly trained regarding current standard practice and equipoise. Approach parents 1–2 weeks after stoma formation. Provide resources to centres to permit stoma closure as per the trial protocol, for example, for ring-fenced operating theatre time and possibility of extended hospital stay. Study registration This study is registered as IRAS Project ID 278331, REC Reference 20/LO/1227. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR128617) and is published in full in Health Technology Assessment; Vol. 28, No. 71. See the NIHR Funding and Awards website for further award information.

Objectives As part of the FERN feasibility study, this qualitative research aimed to explore parents’ and clinicians’ views on the acceptability, feasibility and design of a randomised controlled trial (RCT) of active intervention versus expectant management in monochorionic (MC) diamniotic twin pregnancies with early-onset (prior to 24 weeks) selective fetal growth restriction (sFGR). Interventions could include laser treatment or selective termination which could lead to the death or serious disability of one or both twins.Design Qualitative semi-structured interviews with parents and clinicians. Data were analysed using reflexive thematic analysis and considered against the Principles of Biomedical Ethics.Participants and setting We interviewed 19 UK parents experiencing (six mothers, two partners) or had recently experienced (eight mothers, three partners) early-onset sFGR in MC twin pregnancy and 14 specialist clinicians from the UK and Europe.Results Participants viewed the proposed RCT as ‘ethically murky’ because they believed that the management of sFGR in MC twin pregnancy should be individualised according to the type and severity of sFGR. Clinicians prioritised the gestational age, size, decrease in growth velocity, access to the placental vessels and acceptability of intervention for parents. Discussions and decision-making about selective termination appeared to cause long-term harm (maleficence). The most important outcome for parents and clinicians was ‘live birth’. For clinicians, this was the live birth of at least one twin. For parents, this meant the live birth of both twins, even if this meant that their babies had neurodevelopmental impairment or disabilities.Conclusions All three pregnancy management approaches for sFGR in MC twin pregnancy carry risks and benefits, and the ultimate goal for parents is to receive individualised care to achieve the best possible outcome for both twins. An RCT was not acceptable to parents or clinicians or seen as ethically appropriate. Alternative study designs should be considered to answer this important research question.

Introduction Selective fetal growth restriction (sFGR) in monochorionic twin pregnancy, defined as an estimated fetal weight (EFW) of one twin

Abstract Healthcare-associated infections (HCAIs) are a major cause of morbidity and mortality in critically ill children. Data from adult studies suggest Selective Decontamination of the Digestive tract (SDD) may reduce the incidence of HCAIs and improve survival. There are no data from randomised clinical trials in the paediatric setting. An open label, parallel group pilot cRCT and mixed-methods perspectives study was conducted in six paediatric intensive care units (PICUs) in England. Participants were children (> 37 weeks corrected gestational age, up to 16 years) requiring mechanical ventilation expected to last for at least 48 h. Sites undertook standard care for a period of 9 weeks and were randomised into 3 sites which continued standard care and 3 where SDD was incorporated into infection control practice for eligible children. Interviews and focus groups were conducted for parents and staff working in PICU. 434 children fulfilled eligibility criteria, of whom 368 (85%) were enrolled. This included 207 in the baseline phase (Period One) and 161 in the intervention period (Period Two). In sites delivering SDD, the majority (98%) of children received at least one dose of SDD and of these, 68% commenced within the first 6 h. Whilst admission swabs were collected in 91% of enrolled children, consent for the collection of additional swabs was low (44%). Recruited children were representative of the wider PICU population. Overall, 3.6 children/site/week were recruited compared with the potential recruitment rate for a definitive cRCT of 3 children/site/week, based on data from all UK PICUs. Parents (n = 65) and staff (n = 44) were supportive of the aims of the study, suggesting adaptations for a larger definitive trial including formulation and administration of SDD paste, approaches to consent and ecology monitoring. Stakeholders identified preferred clinical outcomes, focusing on complications of critical illness and quality-of-life. A definitive cRCT in SDD to prevent HCAIs in critically ill children is feasible but should include adaptations to ecology monitoring along with the dosing schedule and packaging into a paediatric specific format. A definitive study is supported by the findings with adaptations to ecology monitoring and SDD administration. Trial Registration: ISRCTN40310490 Registered 30/10/2020.

Background Healthcare-associated infections are a major cause of morbidity and mortality in critically ill children. In adults, data suggest the use of selective decontamination of the digestive tract may reduce the incidence of healthcare-associated infections. Selective decontamination of the digestive tract has not been evaluated in the paediatric intensive care unit population. Objectives To determine the feasibility of conducting a multicentre, cluster-randomised controlled trial in critically ill children comparing selective decontamination of the digestive tract with standard infection control. Design Parallel-group pilot cluster-randomised controlled trial with an integrated mixed-methods study. Setting Six paediatric intensive care units in England. Participants Children (> 37 weeks corrected gestational age, up to 16 years) requiring mechanical ventilation expected to last for at least 48 hours were eligible for the PICnIC pilot cluster-randomised controlled trial. During the ecology periods, all children admitted to the paediatric intensive care units were eligible. Parents/legal guardians of recruited patients and healthcare professionals working in paediatric intensive care units were eligible for inclusion in the mixed-methods study. Interventions The interventions in the PICnIC pilot cluster-randomised controlled trial included administration of selective decontamination of the digestive tract as oro-pharyngeal paste and as a suspension given by enteric tube during the period of mechanical ventilation. Main outcome measures The decision as to whether a definitive cluster-randomised controlled trial is feasible is based on multiple outcomes, including (but not limited to): (1) willingness and ability to recruit eligible patients; (2) adherence to the selective decontamination of the digestive tract intervention; (3) acceptability of the definitive cluster-randomised controlled trial; (4) estimation of recruitment rate; and (5) understanding of potential clinical and ecological outcome measures. Results A total of 368 children (85% of all those who were eligible) were enrolled in the PICnIC pilot cluster-randomised controlled trial across six paediatric intensive care units: 207 in the baseline phase (Period One) and 161 in the intervention period (Period Two). In sites delivering selective decontamination of the digestive tract, the majority (98%) of children received at least one dose of selective decontamination of the digestive tract, and of these, 68% commenced within the first 6 hours. Consent for the collection of additional swabs was low (44%), though data completeness for potential outcomes, including microbiology data from routine clinical swab testing, was excellent. Recruited children were representative of the wider paediatric intensive care unit population. Overall, 3.6 children/site/week were recruited compared with the potential recruitment rate for a definitive cluster-randomised controlled trial of 3 children/site/week, based on data from all UK paediatric intensive care units. The proposed trial, including consent and selective decontamination of the digestive tract, was acceptable to parents and staff with adaptations, including training to improve consent and communication, and adaptations to the administration protocol for the paste and ecology monitoring. Clinical outcomes that were considered important included duration of organ failure and hospital stay, healthcare-acquired infections and survival. Limitations The delivery of the pilot cluster-randomised controlled trial was disrupted by the COVID-19 pandemic, which led to slow set-up of sites, and a lack of face-to face training. Conclusions PICnIC’s findings indicate that a definitive cluster-randomised controlled trial in selective decontamination of the digestive tract in paediatric intensive care units is feasible with the inclusion modifications, which would need to be included in a definitive cluster-randomised controlled trial to ensure that the efficiency of trial processes is maximised. Future work A definitive trial that incorporates the protocol adaptations and outcomes arising from this study is feasible and should be conducted. Trial registration This trial is registered as ISRCTN40310490. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 16/152/01) and is published in full in Health Technology Assessment; Vol. 28, No. 8. See the NIHR Funding and Awards website for further award information. Plain language summary Each year, around 20,000 critically ill children are admitted to paediatric intensive care units in the UK. These children are at a higher risk of healthcare-associated infections, one of the main sources of which is the large number of bacteria in the digestive tract. Spread of bacteria from the digestive tract into other organs, such as the lung (causing ventilator-associated pneumonia) or bloodstream (causing sepsis), can be life-threatening. The risk is highest in those children whose illness is so severe that they require prolonged mechanical ventilation. Stopping the growth of bacteria in the digestive tract (called selective decontamination of the digestive tract) has been shown in adults to reduce the number of hospital-acquired infections. However, there have been no trials in children. We wanted to assess how practical and acceptable such a trial would be comparing standard infection control to selective decontamination of the digestive tract-enhanced infection control and monitoring how each intervention affected antimicrobial resistance. We undertook a pilot study to examine whether clinicians could identify eligible children, enrol them in the study and follow study procedures during the course of paediatric intensive care unit admission. Alongside this, we interviewed parents and clinicians to get their views on the proposed trial. Six hospitals recruited 559 patients over a period of roughly 7 months. Hospitals were randomly allocated to continue with the standard infection control procedure or to give selective decontamination of the digestive tract. Overall, recruitment was higher than expected. Alongside this, we examined the views of patients, caregivers and healthcare professionals to assess their views on whether a trial should be carried out to see if selective decontamination of the digestive tract should become part of the infection control regime for children most at risk of hospital-acquired infection in the paediatric intensive care unit. Overall results suggest that a larger PICnIC trial incorporating patient stakeholder and clinical staff feedback on design and outcomes is feasible and that it is appropriate to conduct a trial into the effectiveness of selective decontamination of the digestive tract administration to minimise hospital-acquired infections. Scientific summary Background In critically ill children, healthcare-associated infections (HCAIs) are a major cause of morbidity and mortality, with a reported incidence of 7–14%. In this vulnerable population, contributing factors include the impact of critical illness on innate and adaptive immune responses, as well as the presence of invasive devices such as endotracheal tubes, urinary catheters and vascular lines. Evidence from adult intensive care studies suggests that using selective decontamination of the digestive tract (SDD) alongside standard infection control measures reduces mortality and ventilator-associated pneumonia (VAP). A recent meta-analysis of 32 randomised controlled trials (RCTs) including 24,389 participants suggests that use of SDD compared with standard care or placebo was associated with reduced hospital mortality, VAP and intensive care unit (ICU)-acquired bacteraemia. Selective decontamination of the digestive tract has not been compared directly with modern infection control protocols in the paediatric intensive care unit (PICU) population. Infection Control in Paediatric Intensive Care (PICnIC) was a feasibility study designed to determine whether it is possible to conduct a cluster RCT (cRCT) of SDD in critically ill children expected to require mechanical ventilation for over 48 hours, and to explore and test the acceptability of key components of the study to healthcare professionals and caregivers. The study involved a pilot cRCT with an integrated mixed-methods study. Infection Control in Paediatric Intensive Care pilot cluster-randomised controlled trial Objectives To test the ability to randomise PICUs to either control or intervention. To test the willingness and ability of healthcare professionals to screen and recruit eligible children. To estimate the recruitment rate of eligible children. To test adherence to the SDD protocol. To test the procedures for assessing and collecting selected clinical and ecological outcomes and for adverse event (AE) reporting. To assess the generalisability of the study results to all PICUs using the Paediatric Intensive Care Audit Network (PICANet). To explore parent and healthcare professional views on the acceptability of the proposed trial, including recruitment and consent procedures and patient-centred outcomes. Methods Study design Multicentre pilot cRCT. Sites Six PICUs in the UK. Recruitment A research without prior consent (RWPC) model was used, and retrospective consent sought for additional samples. There were no inclusion/exclusion criteria during ecology weeks. During Periods One and Two, the eligibility criteria were the following: Inclusion criteria > 37 weeks corrected gestational age to 16 years. Receiving mechanical ventilation. Expected to remain on mechanical ventilation for ≥ 48 hours (from time of screening). Exclusion criteria Known allergy, sensitivity or interaction to polymyxin E (colistin), tobramycin or nystatin. Known to be pregnant. Death perceived as imminent. Randomisation Participating PICUs were randomised by the trial statistician using computer-based randomisation to either the control or intervention arm for Period Two of the study. Data collection A secure, dedicated electronic case report form (eCRF) was set up and collection was nested within PICANet. Sample size A sample size of 324 children in 18 weeks was anticipated. A power calculation was deemed not appropriate given the feasibility nature of the study. The sample size was therefore determined on expected eligible caseload based on available data from PICANet. Data analysis The analyses were conducted using Stata/MP™ version 16.1 (StataCorp LP, College Station, TX, USA). Results As planned, six sites participated in the PICnIC pilot cRCT and were randomised in week 6. We confirmed the willingness and ability of healthcare professionals to screen and recruit eligible children. Sites recruited a total of 368 children (85% of all those who were eligible) across six sites: in Period One, 207 children were recruited (93% of those who were eligible), and in Period Two, 161 children were recruited (76% of those who were eligible). All intervention sites delivered SDD during week 12 onwards. We defined the recruitment rate of eligible children. Overall, 3.6 children/site/week were recruited (the recruitment rate for Period One was 4.3 children/site/week; for Period Two, this was 3.0 children/site/week), similar to the average pre-trial estimate of 3 children/site/week. The potential recruitment rate for a future definitive cRCT trial is 2.98 children/site/week, based on a potentially eligible population of 1730 children (national UK PICU data from PICANet) and the overall proportion of eligible children recruited (85%). We confirmed the ability of healthcare professionals to adhere to the SDD protocol. The majority of children eligible for inclusion were recruited in the intervention sites (55/57, 98%) and most (68%) received at least one dose of SDD treatment within the first 6 hours of enrolment. The median number of SDD doses administered per patient was 14 [interquartile range (IQR) 9–32] for the Oral Paste and 14 (IQR 9–32) for Gastric Suspension. The number of missed doses was low: 9.2% for the oral paste and 9.1% for the gastric suspension. Reasons included children being nil by mouth (29.5% and 31.1% for oral paste and gastric suspensions, respectively) and dose missed by clinicians (26.2% and 24.6%). We confirmed that procedures for assessing and collecting selected clinical and ecological outcomes and for AE reporting were adequate. Completeness of the ecology outcome measures was excellent in intervention sites (range between 97.6% and 100%) and very good in the usual care sites (range between 93.1% and 100%). Patient-centred potential outcomes measures had an excellent completion rate and were similar between groups with a range between 96.3% and 100%. Ecological outcomes had high completion rates and were similar between groups. Consent for the collection of additional samples for study-specific ecology monitoring were obtained in 162 patients (44% of those recruited). Over 30% of the recruited patients were deemed unable to approach for consent. We confirmed the generalisability of the study results to all PICUs using the PICANet. Children who were recruited to the PICnIC study were representative of similar potentially eligible patients in the study PICUs and all UK PICUs but were more likely to be male (62% vs. 56%) and with a primary diagnosis of infection (12.8% vs. 7%) when compared with all UK PICUs. Infection Control in Paediatric Intensive Care mixed-methods study Objectives To assess with input from PICU healthcare professionals: the acceptability of implementation of the SDD intervention, recruitment and consent procedures the acceptability of collecting data to assess the selected clinical and ecological data the acceptability of the SDD intervention and confirm interest in participation in a definitive trial in the wider PICU community. To review, explore and test with input from parents/guardians of recruited patients: the acceptability of a definitive trial that includes the SDD intervention the acceptability of the recruitment and consent procedures for the definitive trial, including all proposed information materials the selection of important, relevant, patient-centred primary and secondary outcomes for a definitive trial. Methods Study design This was a mixed-methods study, which employed questionnaires and interviews with parents/legal representatives of children involved in the pilot cRCT and focus groups, as well as an online survey with PICU practitioners (involved in the pilot cRCT and wider UK PICU). Recruitment Parent/legal representatives were recruited via the same process and information materials used in the pilot cRCT. During the recruitment discussion, practitioners invited parents to complete the questionnaire and/or provide contact details if they wished to take part in an interview. Pilot cRCT practitioners were recruited to focus groups via an e-mail invitation, while wider PICU staff were recruited via a Twitter [now X (X Corp., San Francisco, CA, USA); www.twitter.com] advert and presentation (with QR Code link to survey) at the Paediatric Intensive Care Society Study Group biannual meeting. Data collection Informed consent was sought before interviews and focus groups. All methods were online [via Zoom (Zoom Video Communications, San Jose, CA, USA)] or telephone due to the COVID-19 pandemic. Screening and interviews stopped when information power was reached. Parent questionnaires were placed in an envelope and posted to the University of Liverpool team. Sample size It was anticipated that 15–25 parent/legal representatives would be recruited to an interview, that is, until information power and a balance parents of children in each trial arm were reached. Based on previous studies and the pilot cRCT sample size, we aimed to receive approximately 100 parent questionnaires. For practitioners, we aimed to include approximately 8–10 practitioners in each of the focus groups and up to 10 interviews (for those who could not attend a focus group), as well as an online survey using snowball sampling to involve wider PICU staff not involved in the pilot cRCT. Data analysis Qualitative thematic analysis was interpretative and iterative and informed by the constant comparative approach. NVivo 10 software (QSR International, Warrington, UK) was used to assist the coding of data. Survey data were analysed using SPSS version 27 (IBM SPSS Statistics, Armonk, NY, USA) for descriptive statistics. Qualitative and quantitative data were analysed separately and then synthesised through constant comparative analysis. Results A total of 65 parents (44 mothers, 21 fathers) completed the survey across five PICU pilot sites. Of these, 15 (23%) were approached when the child was in the intervention group, 24 (36%) in the control group, and 24 (36%) during ecology week (missing n = 2). Telephone interviews were conducted with 23 parents (7 of which also completed the survey), including 15 mothers (2 ecology week, 7 control and 6 intervention) and 8 fathers (1 ecology week, 4 control and 3 intervention) across five out of the six PICU pilot sites in the UK (3 intervention and 2 control sites). Parents were recruited via sites and 123 parents registered interest. Out of these, 39 were contacted to arrange an interview. Three were no longer interested, six said it was not a good time, and seven did not answer the phone or respond to e-mail. A total of 44 PICU staff completed the survey representing 11 UK PICUs. Of these, 36 (81%) were involved in the PICnIC pilot and were from other PICUs representing six units. Six focus groups with 26 staff were conducted, which was an additional four than originally planned to ensure staff from all PICnIC pilot sites had an opportunity to participate. Overall, the mixed-methods study showed that parents and practitioners found the proposed trial acceptable, but highlighted a number of areas that should be carefully considered when developing the trial protocol and staff site training. Issues with eligible children being missed were due to difficulties in staff knowing whether children would be ventilated for 48 hours, as per the inclusion criteria. Some sites screened more than once up until the 48-hour window, which increased the number of eligible patients identified. Staffing issues due to the pandemic and not remembering to rescreen after the point of admission impacted upon recruitment. Multiple studies recruiting at the same time, as well as difficulties processing samples in overstretched labs, appeared to exacerbate the issues. Staff described how missing data for additional samples was due to concerns about child discomfort, not wishing to broach taking swabs with parents when a child was critically ill, or staff capacity issues. Parents were less concerned about the additional samples, but many stated that consent should be sought prospectively for sample collection. Parents who declined consent for additional samples mentioned their child having gone through a lot and they did not want to add further distress. Having the option to decline certain aspects of trial involvement appeared to make the pilot trial more acceptable for parents. Most parents and staff supported the cRCT design and approach to consent, although any future information materials must make clear that a RWPC approach is being used. Although information leaflets were described as being clear, they were often not read by parents who prioritised discussions with staff. There appeared to be subtle differences in how staff described the nature of the intervention at sites administering SDD, which may have led to parental misconceptions, such as believing that their child would have received the intervention as standard practice outside of the trial. Many parents did not understand that units rather than children had been randomised, as cluster randomisation had not been explained by practitioners. Our findings highlight the need to develop training for recruiters on how to explain the nature of the proposed trial to assist parental understanding, including how whole PICUs are randomised to control or intervention, and the nature of the intervention including information about gut microbiota to address potential parental concerns and to help ensure informed decision-making. Parents’ top prioritised outcomes for the proposed trial were survival and health complications/AEs. Findings suggest that staff were in equipoise and the SDD intervention was acceptable to both parents and staff. Insight from site and wider PICU staff highlights challenges to consider in a definitive proposed trial including delivering the SDD due to the thickness of the paste, sufficient support and engagement of nurse research teams, and sufficient time for trial set-up to help improve trial acceptability and ultimately trial success. Conclusions Insight from parents and PICU staff suggests the proposed trial, SDD intervention and approach to consent was acceptable. Issues such as staff capacity, missed eligible patients and additional sample collection, and parental misunderstandings about the nature of the study were identified. Staff training on recruitment and consent processes is required in any future trial, as well as adaptations on ecology monitoring and dosing regimen of the paste, which should be incorporated into the study design. Patient outcomes for the proposed trial should include complications such as healthcare-acquired infections and antimicrobial use, as well as standard organ failure outcomes such as the need for mechanical ventilation and duration of PICU stay. Recommendations for research A definitive clinical trial for the use of SDD-enhanced infection control using the current PICnIC protocol should not be conducted. A definitive clinical trial for the use of SDD-enhanced infection control using a modified protocol should be conducted. Further work is needed to agree the appropriate measures to monitor ecology in a definitive trial. Trial registration The PICnIC Pilot RCT is registered as Current Controlled Trials ISRCTN40310490. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 16/152/01) and is published in Health Technology Assessment; Vol. 28, No. 8. See the NIHR Funding and Awards website for further award information.

Objective Trial legislation enables research to be conducted without prior consent (RWPC) in emergency situations, yet this approach has rarely been used in time-critical obstetric trials. This study explored views and experiences of antenatal recruitment and consent and RWPC in an emergency intrapartum randomised clinical trial.Design Embedded, mixed-methods study within a trial, involving questionnaires, recorded recruitment discussions, interviews and focus groups in the first 13 months of trial recruitment (December 2020–January 2022).Setting COPE is a double-blind randomised controlled trial, comparing the effectiveness of carboprost or oxytocin as first-line treatment of postpartum haemorrhage.Participants Two hundred and eighty-six people (190 women/96 birth partners), linked to 198/380 (52%) COPE recruits participated in the embedded study. Of these, 272 completed a questionnaire (178 women/94 birth partners), 22 were interviewed (19 women/3 birth partners) and 16 consent discussions with 12 women were recorded. Twenty-seven staff took part in three focus groups and nine staff were interviewed.Results Participants recommended that information about the study should be more accessible antenatally for those who wish to be informed. Most women and staff did not think it would be appropriate to seek consent during pregnancy or early labour as it may cause ‘unnecessary panic’ and lead to research waste, as most women would not become eligible. There was support for the use of RWPC as COPE interventions are used in standard clinical practice and viewed as low risk. Women who were approached about the trial while having a postpartum haemorrhage also supported RWPC as they could not recall research discussions.Conclusions Findings support the use of RWPC for time-critical interventions, and raise questions about the appropriateness of other commonly used consent pathways, including antenatal consent and verbal assent.

Abstract Background Social distancing restrictions to manage the COVID-19 pandemic were put in place from March 2020 in the United Kingdom (UK), with those classed as “highly clinically vulnerable” advised to shield entirely and remain at home. However, personal risk perception has been shown to comprise of various elements beyond those outlined in the national pandemic guidance. It is unclear whether those deemed COVID-19 vulnerable identified as high-risk to COVID-19 and thus complied with the relevant advice. The aim of this research is to explore the perception of risk in catching and spreading COVID-19, amongst individuals from individual households, and vulnerable groups in a region of the UK. Methods Two individual, semi-structured interviews were conducted, four-weeks apart, with adults living in households in the Liverpool City Region. At the follow-up interview, participants were given the option of using photo-elicitation to guide the discussion. Reflexive thematic analysis was employed to conceptualise themes. The qualitative analysis was underpinned with symbolic interactionism. Results Twenty-seven participants (13:14 males:females, and 20 with a vulnerable risk factor to COVID-19) completed a baseline interview, and 15 of these completed a follow-up interview four-weeks later. Following thematic analysis, two overarching themes were conceptualised, with subthemes discussed: theme 1) Confusion and trust in the risk prevention guidance; and theme 2) Navigating risk: compliance and non-compliance with public health guidance. Conclusion Participants developed their own understanding of COVID-19 risk perception through personal experience and comparison with others around them, irrespective of vulnerability status. COVID-19 guidance was not complied with as intended by the government, and at times even rejected due to lack of trust. The format in which future pandemic guidance is conveyed must be carefully considered, and take into account individuals’ experiences that may lead to non-compliance. The findings from our study can inform future public health policy and interventions for COVID-19 and future pandemics.

Abstract Background Informed consent is considered a fundamental requirement for participation in trials, yet obtaining consent is challenging in a number of populations and settings. This may be due to participants having communication or other disabilities, their capacity to consent fluctuates or they lack capacity, or in emergency situations where their medical condition or the urgent nature of the treatment precludes seeking consent from either the participant or a representative. These challenges, and the subsequent complexity of designing and conducting trials where alternative consent pathways are required, contribute to these populations being underserved in research. Recognising and addressing these challenges is essential to support trials involving these populations and ensure that they have an equitable opportunity to participate in, and benefit from, research. Given the complex nature of these challenges, which are encountered by both adults and children, a cross-disciplinary approach is required. Discussion A UK-wide collaboration, a sub-group of the Trial Conduct Working Group in the MRC-NIHR Trial Methodology Research Partnership, was formed to collectively address these challenges. Members are drawn from disciplines including bioethics, qualitative research, trials methodology, healthcare professions, and social sciences. This commentary draws on our collective expertise to identify key populations where particular methodological and ethical challenges around consent are encountered, articulate the specific issues arising in each population, summarise ongoing and completed research, and identify targets for future research. Key populations include people with communication or other disabilities, people whose capacity to consent fluctuates, adults who lack the capacity to consent, and adults and children in emergency and urgent care settings. Work is ongoing by the sub-group to create a database of resources, to update NIHR guidance, and to develop proposals to address identified research gaps. Conclusion Collaboration across disciplines, sectors, organisations, and countries is essential if the ethical and methodological challenges surrounding trials involving complex and alternate consent pathways are to be addressed. Explicating these challenges, sharing resources, and identifying gaps for future research is an essential first step. We hope that doing so will serve as a call to action for others seeking ways to address the current consent-based exclusion of underserved populations from trials.

Introduction Febrile infants 90 days and younger are at risk of invasive bacterial infections (bacteraemia and meningitis) and urinary tract infections. Together this is previously termed serious bacterial infection with an incidence of approximately 10–20%. The National Institute for Health and Care Excellence guidance advocates a cautious approach with most infants requiring septic screening, parenteral broad-spectrum antibiotics and hospital admission. Internationally, variations exist in the approach to febrile infants, with European and North American guidance advocating a tailored approach based on clinical features and biomarker testing. None of the available international clinical decision aids (CDAs) has been validated in the UK and Irish cohorts. The aim of the Febrile Infant Diagnostic Assessment and Outcome (FIDO) Study is to prospectively validate a range of CDAs in a UK and Irish population including CDAs that use procalcitonin testing.Methods and analysis The FIDO Study is a prospective multicentre mixed-methods cohort study conducted in UK and Irish hospitals. All infants aged 90 days and younger presenting with fever or history of fever (≥38°C) are eligible for inclusion. Infants will receive standard emergency clinical care without delay. Clinical data and blood samples will be collected, and consent will be obtained at the earliest appropriate opportunity using research without prior consent methodology. The performance and cost-effectiveness of CDAs will be assessed. An embedded qualitative study will explore clinician and caregiver views on different approaches to care and perceptions of risk.Ethics and dissemination This study was reviewed and approved by the Office for Research Ethics Committees Northern Ireland-Health and Social Care Research Ethics Committee B, Public Benefit and Privacy Panel for Health and Social Care Scotland, and Children’s Health Ireland Research and Ethics Committee Ireland. The results of this study will be presented at academic conferences and in peer-reviewed publications.Trial registration number NCT05259683.

Objectives This mixed-methods feasibility study aimed to explore parents’ and medical practitioners’ views on the acceptability and design of a clinical trial to determine whether routine prophylactic proton pump inhibitors (PPI) reduce the incidence of anastomotic stricture in infants with oesophageal atresia (OA).Design Semi-structured interviews with UK parents of an infant with OA and an online survey, telephone interviews and focus groups with clinicians. Data were analysed using reflexive thematic analysis and descriptive statistics.Participants and setting We interviewed 18 parents of infants with OA. Fifty-one clinicians (49 surgeons, 2 neonatologists) from 20/25 (80%) units involved in OA repair completed an online survey and 10 took part in 1 of 2 focus groups. Interviews were conducted with two clinicians whose survey responses indicated they had concerns about the trial.Outcome Measures Parents and clinicians ranked the same top four outcomes (‘Severity of anastomotic stricture’, ‘Incidence of anastomotic stricture’, ‘Need for treatment of reflux’ and ‘Presence of symptoms of reflux’) as important to measure for the proposed trial.Results All parents and most clinicians found the use, dose and duration of omeprazole as the intervention medication, and the placebo control, as acceptable. Parents stated they would hypothetically consent to their child’s participation in the trial. Concerns of a few parents and clinicians about infants suffering with symptomatic reflux, and the impact of this for study retention, appeared to be alleviated through the symptomatic reflux treatment pathway. Hesitant clinician views appeared to change through discussion of parental support for the study and by highlighting existing research that questions current practice of PPI treatment.Conclusions Our findings indicate that parents and most clinicians view the proposed Treating Oesophageal Atresia with prophylactic proton pump inhibitors to prevent STricture (TOAST) trial to be feasible and acceptable so long as infants can be given PPI if clinicians deem it clinically necessary. This insight into parent and clinician views and concerns will inform pilot phase trial monitoring, staff training and the development of the trial protocol.

Abstract To investigate associations between parent–child relationships, children’s externalizing and internalizing symptoms, and lifestyle responses to the COVID-19 epidemic, we conducted an online survey of a random, representative sample of residents with children aged 3–17 years during mid-March 2020 in Wuhan and Shanghai, China. A total of 1655 parents and children were surveyed with a response rate of 80.1% in the survey. During the epidemic, the frequency of children enquiring about the epidemic (AOR = 1.46, 95% CI: 1.04, 2.06), parents explaining the epidemic to them (AOR = 2.87, 95% CI: 1.80, 4.58), parents expressing negative emotions in front of them (AOR = 2.62; 95% CI = 2.08–3.30), and parents with more irritable attitudes (AOR = 1.93; 95% CI = 1.33–2.81) were significantly associated with children’s externalizing symptoms. For internalizing symptoms, significant associations were found with worse parent–child closeness (AOR = 2.93; 95% CI = 1.80–4.79), the frequency of parents expressing negative emotions in front of them (AOR = 2.64; 95% CI = 1.68, 4.12), and more irritable attitudes (AOR = 2.24; 95% CI = 1.42–3.55). We also found that each indicator of parent–child relationships had the significantly similar associations with children’s lifestyle behaviors. These findings suggest that improving parents’ attitudes towards their children and parent–child closeness during the epidemic, especially among parents with lower educational levels, are important to ensure the wellbeing of children.

Objectives Obtaining informed consent from patients in intensive care units (ICUs) prior to enrolment in a study is practically and ethically complex. Decisions about the participation of critically ill patients in research often involve substitute decision makers (SDMs), such as a patient’s relatives or doctors. We explored the perspectives of different stakeholder groups towards these consent procedures.Design and methods Mixed-methods study comprising surveys completed by ICU patients, their relatives and healthcare practitioners in 14 English ICUs, followed by qualitative interviews with a subset of survey participants. Empirical bioethics informed the analysis and synthesis of the data. Survey data were analysed using descriptive statistics of Likert responses, and analysis of interview data was informed by thematic reflective approaches.Results Analysis included 1409 survey responses (ICU patients n=333, relatives n=488, healthcare practitioners n=588) and 60 interviews (ICU patients n=13, relatives n=30, healthcare practitioners n=17). Most agreed with relatives acting as SDMs based on the perception that relatives often know the patient well enough to reflect their views. While the practice of doctors serving as SDMs was supported by most survey respondents, a quarter (25%) disagreed. Views were more positive at interview and shifted markedly depending on particularities of the study. Participants also wanted reassurance that patient care was prioritised over research recruitment. Findings lend support for adaptations to consent procedures, including collaborative decision-making to correct misunderstandings of the implications of research for that patient. This empirical evidence is used to develop good practice guidance that is to be published separately.Conclusions Participants largely supported existing consent procedures, but their perspectives on these consent procedures depended on their perceptions of what the research involved and the safeguards in place. Findings point to the importance of explaining clearly what safeguards are in place to protect the patient.

Abstract Background Routine measurement of gastric residual volume (GRV) to guide feeding in neonatal and paediatric intensive care is widespread. However, this practice is not evidence based and may cause harm. As part of a feasibility study, we explored parent and practitioner views on the acceptability of a trial comparing GRV measurement or no GRV measurement. Methods A mixed-methods study involving interviews and focus groups with practitioners and interviews with parents with experience of tube feeding in neonatal and/or paediatric intensive care. A voting system recorded closed question responses during practitioner data collection, enabling the collection of quantitative and qualitative data. Data were analysed using thematic analysis and descriptive statistics. Results We interviewed 31 parents and nine practitioners and ran five practitioner focus groups (n=42). Participants described how the research question was logical, and the intervention would not be invasive and potential benefits of not withholding the child’s feeds. However, both groups held concerns about the potential risk of not measuring GRV, including delayed diagnosis of infection and gut problems, increased risk of vomiting into lungs and causing discomfort or pain. Parent’s views on GRV measurement and consent decision making were influenced by their views on the importance of feeding in the ICU, their child’s prognosis and associated comorbidities or complications. Conclusions The majority of parents and practitioners viewed the proposed trial as acceptable. Potential concerns and preferences were identified that will need careful consideration to inform the development of the proposed trial protocol and staff training.

Abstract Background Stillbirth remains a major concern across the globe and in some high-resource countries, such as the UK; efforts to reduce the rate have achieved only modest reductions. One third of stillborn babies are small for gestational age (SGA), and these pregnancies are also at risk of neonatal adverse outcomes and lifelong health problems, especially when delivered preterm. Current UK clinical guidance advocates regular monitoring and early term delivery of the SGA fetus; however, the most appropriate regimen for surveillance of these babies remains unclear and often leads to increased intervention for a large number of these women. This pilot trial will determine the feasibility of a large-scale trial refining the risk of adverse pregnancy outcome in SGA pregnancies using biomarkers of placental function sFlt-1/PlGF, identifying and intervening in only those deemed at highest risk of stillbirth. Methods PLANES is a randomised controlled feasibility study of women with an SGA fetus that will be conducted at two tertiary care hospitals in the UK. Once identified on ultrasound, women will be randomised into two groups in a 3:1 ratio in favour of sFlt-1/PlGF ratio led management vs standard care. Women with an SGA fetus and a normal sFlt-1/PlGF ratio will have a repeat ultrasound and sFlt-1/PlGF ratio every 2 weeks with planned birth delayed until 40 weeks. In those women with an SGA fetus and an abnormal sFlt-1/PlGF ratio, we will offer birth from 37 weeks or sooner if there are other concerning features on ultrasound. Women assigned to standard care will have an sFlt-1/PlGF ratio taken, but the results will be concealed from the clinical team, and the woman’s pregnancy will be managed as per the local NHS hospital policy. This integrated mixed method study will also involve a health economic analysis and a perspective work package exploring trial feasibility through interviews and questionnaires with participants, their partners, and clinicians. Discussion Our aim is to determine feasibility through the assessment of our ability to recruit and retain participants to the study. Results from this pilot study will inform the design of a future large randomised controlled trial that will be adequately powered for adverse pregnancy outcome. Such a study would provide the evidence needed to guide future management of the SGA fetus. Trial registration ISRCTN58254381 . Registered on 4 July 2019

Abstract Background The National Institute for Health and Care Excellence (NICE) have called for research into the role of biomarkers, and specifically procalcitonin (PCT), for the early diagnosis of serious bacterial infections (SBI) in children. The aim of this study was to compare the diagnostic test accuracy of C-reactive protein (CRP) and PCT for the diagnosis of SBI in children. Methods Data was collected prospectively from four UK emergency departments (ED) between November 2017 and June 2019. Consecutive children under 18 years of age with fever and features of possible sepsis and/or meningitis were eligible for inclusion. The index tests were PCT and CRP and the reference standard was the confirmation of SBI. Results 213 children were included in the final analysis. 116 participants (54.5%) were male, and the median age was 2 years, 9 months. Parenteral antibiotics were given to 100 (46.9%), three (1.4%) were admitted to a paediatric intensive care unit and there were no deaths. There were ten (4.7%) confirmed SBI. The area under the curve for PCT and CRP for the detection of SBI was identical at 0.70. Conclusions There was no difference in the performance of PCT and CRP for the recognition of SBI in this cohort. Trial registration Registered at https://www.clinicaltrials.gov (trial registration: NCT03378258 ) on the 19th of December 2017.

Objectives The objective of this study was to develop a core outcome set (COS) for use in future clinical trials in bronchiolitis. We wanted to find out which outcomes are important to healthcare professionals (HCPs) and to parents and which outcomes should be prioritised for use in future clinical trials.Design and setting The study used a systematic review, workshops and interviews, a Delphi survey and a final consensus workshop.Results Thirteen parents and 45 HCPs took part in 5 workshops; 15 other parents were also separately interviewed. Fifty-six items were identified from the systematic review, workshops and interviews. Rounds one and two of the Delphi survey involved 299 and 194 participants, respectively. Sixteen outcomes met the criteria for inclusion within the COS. The consensus meeting was attended by 10 participants, with representation from all three stakeholder groups. Nine outcomes were added, totalling 25 outcomes to be included in the COS.Conclusion We have developed the first parent and HCP consensus on a COS for bronchiolitis in a hospital setting. The use of this COS will ensure outcomes in future bronchiolitis trials are important and relevant, and will enable the trial results to be compared and combined.Trial registration number ISRCTN75766048.

Introduction Healthcare-associated infections (HCAIs) are a major cause of morbidity and mortality in critically ill children. In critically ill adults, there are data that suggest the use of Selective Decontamination of the Digestive tract (SDD), alongside standard infection control measures reduce mortality and the incidence of HCAIs. SDD-enhanced infection control has not been compared directly with standard infection prevention strategies in the Paediatric Intensive Care Unit (PICU) population. The aim of this pilot study is to determine the feasibility of conducting a multicentre cluster randomised controlled trial (cRCT) in critically ill children comparing SDD with standard infection control.Methods and analysis Paediatric Intensive Care and Infection Control is a parallel group pilot cRCT, with integrated mixed-methods study, comparing incorporation of SDD into infection control procedures to standard care. After a 1-week pretrial ecology surveillance period, recruitment to the cRCT will run for a period of 18 weeks, comprising: (1) baseline control period (2) pre, mid and post-trial ecology surveillance periods and (3) intervention period. Six PICUs (in England, UK) will begin with usual care in period 1, then will be randomised 1:1 by the trial statistician using computer-based randomisation, to either continue to deliver usual care or commence delivery of the intervention (SDD) in period 2. Outcomes measures include parent and healthcare professionals’ views on trial feasibility, adherence to the SDD intervention, estimation of recruitment rate and understanding of potential patient-centred primary and secondary outcome measures for the definitive trial. The planned recruitment for the cRCT is 324 participants.Ethics and dissemination The trial received favourable ethical opinion from West Midlands—Black Country Research Ethics Committee (reference: 20/WM/0061) and approval from the Health Research Authority (IRAS number: 239324). Informed consent is not required for SDD intervention or anonymised data collection but is sought for investigations as part of the study, any identifiable data collected and monitoring of medical records. Results will be disseminated via publications in peer-reviewed medical journals.Trial registration number ISRCTN40310490.

Objective Clinical trials and studies in intensive care units (ICUs) have complex consent processes and often encounter problems in recruiting patients. By interviewing research team members about the challenges in critical care research, we aimed to identify strategies to enhance recruitment and consent to ICU studies.Methods Semistructured interviews with UK-based researchers (N=17) and patient–public involvement (PPI) contributors (N=8) with experience of ICU studies. Analysis of transcripts of audio-recorded interviews drew on thematic approaches.Results Seven themes were identified. Participants emphasised the need for substitute decision-making processes in critical care studies, yet some researchers reported that research ethics committees (RECs) were reluctant to approve such processes. Researchers spoke about the potential benefits of research without prior consent (RWPC) for studies with narrow recruitment windows but believed RECs would not approve them. Participants indicated that the activity of PPI contributors was limited in critical care studies, though researchers who had involved PPI contributors more extensively were clear that their input when designing consent processes was important. Researchers and PPI contributors pointed to resource and staffing limitations as barriers to patient recruitment. Researchers varied in whether and how they used professional consultees as substitute decision-makers, in whether they approached families by telephone to discuss research and in whether they disclosed details of research participation to bereaved relatives.Conclusion Critical care research could benefit from RECs having expertise in consent processes that are suited to this setting, better staffing at research sites, more extensive PPI and an evidence base on stakeholder perspectives on critical care research processes. Guidance on professional consultee processes, telephoning relatives to discuss research, RWPC and disclosure of research participation to bereaved relatives could help to harmonise practice in these areas and enhance recruitment and consent to critical care studies.

Abstract Background Fever improves pathogen control at a significant metabolic cost. No randomized clinical trials (RCT) have compared fever treatment thresholds in critically ill children. We performed a pilot RCT to determine whether a definitive trial of a permissive approach to fever in comparison to current restrictive practice is feasible in critically ill children with suspected infection. Methods An open, parallel-group pilot RCT with embedded mixed methods perspectives study in four UK paediatric intensive care units (PICUs) and associated retrieval services. Participants were emergency PICU admissions aged > 28 days to

Abstract Background EcLiPSE (Emergency treatment with Levetiracetam or Phenytoin in Status Epilepticus in children) is a randomised controlled trial (RCT) in the United Kingdom. Challenges to success include the need to immediately administer an intervention without informed consent and changes in staffing during trial conduct, mainly due to physician rotations. Using literature on parents’ perspectives and research without prior consent (RWPC) guidance, we developed an interactive training package (including videos, simulation and question and answer sessions) and evaluated its dissemination and impact upon on practitioners’ confidence in recruitment and consent. Methods Questionnaires were administered before and immediately after training followed by telephone interviews (mean 11 months later), focus groups (mean 14 months later) and an online questionnaire (8 months before trial closure). Results One hundred and twenty-five practitioners from 26/30 (87%) participating hospitals completed a questionnaire before and after training. We conducted 10 interviews and six focus groups (comprising 36 practitioners); 199 practitioners working in all recruiting hospitals completed the online questionnaire. Before training, practitioners were concerned about recruitment and consent. Confidence increased after training for explaining (all scale 0–5, 95% CIs above 0 and p values

Introduction Time-critical neonatal trials in low-and-middle-income countries (LMICs) raise several ethical issues. Using a qualitative-dominant mixed-methods design, we explored informed consent process in Hypothermia for encephalopathy in low and middle-income countries (HELIX) trial conducted in India, Sri Lanka and Bangladesh.Methods Term infants with neonatal encephalopathy, aged less than 6 hours, were randomly allocated to cooling therapy or usual care, following informed parental consent. The consenting process was audio-video (A-V) recorded in all cases. We analysed A-V records of the consent process using a 5-point Likert scale on three parameters—empathy, information and autonomy. In addition, we used exploratory observation method to capture relevant aspects of consent process and discussions between parents and professionals. Finally, we conducted in-depth interviews with a subgroup of 20 parents and 15 healthcare professionals. A thematic analysis was performed on the observations of A-V records and on the interview transcripts.Results A total of 294 A-V records of the HELIX trial were analysed. Median (IQR) score for empathy, information and autonomy was 5 (0), 5 (1) and 5 (1), respectively. However, thematic analysis suggested that the consenting was a ceremonial process; and parental decision to participate was based on unreserved trust in the treating doctors, therapeutic misconception and access to an expensive treatment free of cost. Most parents did not understand the concept of a clinical trial nor the nature of the intervention. Professionals showed a strong bias towards cooling therapy and reported time constraints and explaining to multiple family members as key challenges.Conclusion Despite rigorous research governance and consent process, parental decisions were heavily influenced by situational incapacity and a trust in doctors to make the right decision on their behalf. Further research is required to identify culturally and context-appropriate strategies for informed trial participation.

Background: Convulsive status epilepticus is the most common neurological emergency in children. Its management is important to avoid or minimise neurological morbidity and death. The current first-choice second-line drug is phenytoin (Epanutin, Pfizer Inc., New York, NY, USA), for which there is no robust scientific evidence. Objective: To determine whether phenytoin or levetiracetam (Keppra, UCB Pharma, Brussels, Belgium) is the more clinically effective intravenous second-line treatment of paediatric convulsive status epilepticus and to help better inform its management. Design: A multicentre parallel-group randomised open-label superiority trial with a nested mixed-method study to assess recruitment and research without prior consent. Setting: Participants were recruited from 30 paediatric emergency departments in the UK. Participants: Participants aged 6 months to 17 years 11 months, who were presenting with convulsive status epilepticus and were failing to respond to first-line treatment. Interventions: Intravenous levetiracetam (40 mg/kg) or intravenous phenytoin (20 mg/kg). Main outcome measures: Primary outcome – time from randomisation to cessation of all visible signs of convulsive status epilepticus. Secondary outcomes – further anticonvulsants to manage the convulsive status epilepticus after the initial agent, the need for rapid sequence induction owing to ongoing convulsive status epilepticus, admission to critical care and serious adverse reactions. Results: Between 17 July 2015 and 7 April 2018, 286 participants were randomised, treated and consented. A total of 152 participants were allocated to receive levetiracetam and 134 participants to receive phenytoin. Convulsive status epilepticus was terminated in 106 (70%) participants who were allocated to levetiracetam and 86 (64%) participants who were allocated to phenytoin. Median time from randomisation to convulsive status epilepticus cessation was 35 (interquartile range 20–not assessable) minutes in the levetiracetam group and 45 (interquartile range 24–not assessable) minutes in the phenytoin group (hazard ratio 1.20, 95% confidence interval 0.91 to 1.60; p = 0.2). Results were robust to prespecified sensitivity analyses, including time from treatment commencement to convulsive status epilepticus termination and competing risks. One phenytoin-treated participant experienced serious adverse reactions. Limitations: First, this was an open-label trial. A blinded design was considered too complex, in part because of the markedly different infusion rates of the two drugs. Second, there was subjectivity in the assessment of ‘cessation of all signs of continuous, rhythmic clonic activity’ as the primary outcome, rather than fixed time points to assess convulsive status epilepticus termination. However, site training included simulated demonstration of seizure cessation. Third, the time point of randomisation resulted in convulsive status epilepticus termination prior to administration of trial treatment in some cases. This affected both treatment arms equally and had been prespecified at the design stage. Last, safety measures were a secondary outcome, but the trial was not powered to demonstrate difference in serious adverse reactions between treatment groups. Conclusions: Levetiracetam was not statistically superior to phenytoin in convulsive status epilepticus termination rate, time taken to terminate convulsive status epilepticus or frequency of serious adverse reactions. The results suggest that it may be an alternative to phenytoin in the second-line management of paediatric convulsive status epilepticus. Simple trial design, bespoke site training and effective leadership were found to facilitate practitioner commitment to the trial and its success. We provide a framework to optimise recruitment discussions in paediatric emergency medicine trials. Future work: Future work should include a meta-analysis of published studies and the possible sequential use of levetiracetam and phenytoin or sodium valproate in the second-line treatment of paediatric convulsive status epilepticus. Trial registration: Current Controlled Trials ISRCTN22567894 and European Clinical Trials Database EudraCT number 2014-002188-13. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 58. See the NIHR Journals Library website for further project information.

Objective Despite little evidence, the practice of routine gastric residual volume (GRV) measurement to guide enteral feeding in neonatal units is widespread. Due to increased interest in this practice, and to examine trial feasibility, we aimed to determine enteral feeding and GRV measurement practices in British neonatal units.Design and setting An online survey was distributed via email to all neonatal units and networks in England, Scotland and Wales. A clinical nurse, senior doctor and dietitian were invited to collaboratively complete the survey and submit a copy of relevant guidelines.Results 95/184 (51.6%) approached units completed the survey, 81/95 (85.3%) reported having feeding guidelines and 28 guidelines were submitted for review. The majority of units used intermittent (90/95) gastric feeds as their primary feeding method. 42/95 units reported specific guidance for measuring and interpreting GRV. 20/90 units measured GRV before every feed, 39/90 at regular time intervals (most commonly four to six hourly 35/39) and 26/90 when felt to be clinically indicated. Most units reported uncertainty on the utility of aspirate volume for guiding feeding decisions; 13/90 reported that aspirate volume affected decisions ‘very much’. In contrast, aspirate colour was reported to affect decisions ‘very much’ by 37/90 of responding units. Almost half, 44/90, routinely returned aspirates to the stomach.Conclusions Routine GRV measurement is part of standard practice in British neonatal units, although there was inconsistency in how frequently to measure or how to interpret the aspirate. Volume was considered less important than colour of the aspirate.

Abstract Background and aims Historically, patient and public involvement (PPI) in the design and conduct of surgical trials has been absent or minimal, but it is now routinely recommended and even required by some research funders. We aimed to identify and describe current PPI practice in surgical trials in the United Kingdom, and to explore the views and experiences of surgical trial staff and patient or public contributors in relation to these practices. This was part of a larger study to inform development of a robust PPI intervention aimed at improving recruitment and retention in surgical trials. Methods Our study had two stages: 1) an online survey to identify current PPI practice in active UK-led, adult surgical trials; and 2) focus groups and interviews with key stakeholders (surgical trial investigators, administrators, and patient or public contributors) to explore their views and experiences of PPI. Results Of 129 eligible surgical trial teams identified, 71 (55%) took part in the survey. In addition, 54 stakeholders subsequently took part in focus groups or interviews. Sixty-five (92%) survey respondents reported some kind of PPI, most commonly at the design and dissemination stages and in oversight or advisory roles. The single most common PPI activity was developing participant information sheets (72%). Participants reported mixed practice and views on a variety of issues including the involvement of patients versus lay members of the public, recruitment methods, use of role descriptions and payment for the time of PPI contributors. They suggested some solutions, including the use of written role descriptions and databases of potential PPI contributors to aid recruitment. Conclusions UK surgical trials involve patients and members of the public in a variety of different ways, most commonly at the beginning and end of the trial lifecycle and in oversight or advisory roles. These are not without challenges and there remain uncertainties about who best to involve, why, and how. Future research should aim to address these issues.

Background: The routine measurement of gastric residual volume to guide the initiation and delivery of enteral feeding is widespread in paediatric intensive care and neonatal units, but has little underlying evidence to support it. Objective: To answer the question: is a trial of no gastric residual volume measurement feasible in UK paediatric intensive care units and neonatal units? Design: A mixed-methods study involving five linked work packages in two parallel arms: neonatal units and paediatric intensive care units. Work package 1: a survey of units to establish current UK practice. Work package 2: qualitative interviews with health-care professionals and caregivers of children admitted to either setting. Work package 3: a modified two-round e-Delphi survey to investigate health-care professionals’ opinions on trial design issues and to obtain consensus on outcomes. Work package 4: examination of national databases to determine the potential eligible populations. Work package 5: two consensus meetings of health-care professionals and parents to review the data and agree consensus on outcomes that had not reached consensus in the e-Delphi study. Participants and setting: Parents of children with experience of ventilation and tube feeding in both neonatal units and paediatric intensive care units, and health-care professionals working in neonatal units and paediatric intensive care units. Results: Baseline surveys showed that the practice of gastric residual volume measurement was very common (96% in paediatric intensive care units and 65% in neonatal units). Ninety per cent of parents from both neonatal units and paediatric intensive care units supported a future trial, while highlighting concerns around possible delays in detecting complications. Health-care professionals also indicated that a trial was feasible, with 84% of staff willing to participate in a trial. Concerns expressed by junior nurses about the intervention arm of not measuring gastric residual volumes were addressed by developing a simple flow chart and education package. The trial design survey and e-Delphi study gained consensus on 12 paediatric intensive care unit and nine neonatal unit outcome measures, and identified acceptable inclusion and exclusion criteria. Given the differences in physiology, disease processes, environments, staffing and outcomes of interest, two different trials are required in the two settings. Database analyses subsequently showed that trials were feasible in both settings in terms of patient numbers. Of 16,222 children who met the inclusion criteria in paediatric intensive care units, 12,629 stayed for > 3 days. In neonatal units, 15,375 neonates

Abstract Background Bronchiolitis is an acute lower respiratory infection which predominantly affects young children. Treatment for bronchiolitis is limited to supportive therapy. Nasal oxygen therapy is part of routine care, and delivery now incorporates varying levels of non-invasive continuous positive airway pressure and/or high-flow nasal cannula oxygen therapy. Despite wide clinical use, there remains a lack of evidence on the comparative effectiveness and safety of these interventions. Furthermore, research in this field is hampered by the use of multiple outcome measures in current clinical trials. Methods/design This mixed methods study includes a systematic review of outcome measures, telephone interviews with parents, focus group workshops and a Delphi survey with healthcare professionals and parents. These methods will be used to identify and prioritise outcomes for inclusion in a core outcome set and to explore issues pertinent to the design of a future randomised controlled trial comparing different modes of oxygen therapy for bronchiolitis. UK hospitals will also be contacted and asked to complete a survey to provide an overview of current practice to enable assessment of capability and capacity to run a future clinical trial. Discussion This study will facilitate the design of a future clinical trial of non-invasive ventilation in children with bronchiolitis which is acceptable to important stakeholders. Furthermore, core outcome set development will improve standardisation, measurement and reporting of clinically important outcomes in bronchiolitis. Trial registration ISRCTN Registry, ISRCTN75766048. Registered on 18 December 2017. This study was retrospectively registered in the ISRCTN Registry and on the Core Outcome Measures in Effectiveness Trials (COMET) Initiative database (15 September 2017).

Abstract Background Children commonly present to Emergency Departments (ED) with a non-blanching rash in the context of a feverish illness. While most have a self-limiting viral illness, this combination of features potentially represents invasive serious bacterial infection, including meningococcal septicaemia. A paucity of definitive diagnostic testing creates diagnostic uncertainty for clinicians; a safe approach mandates children without invasive disease are often admitted and treated with broad-spectrum antibiotics. Conversely, a cohort of children still experience significant mortality and morbidity due to late diagnosis. Current management is based on evidence which predates (i) the introduction of meningococcal B and C vaccines and (ii) availability of point of care testing (POCT) for procalcitonin (PCT) and Neisseria meningitidis DNA. Methods This PiC study is a prospective diagnostic accuracy study evaluating (i) rapid POCT for PCT and N. meningitidis DNA and (ii) performance of existing clinical practice guidelines (CPG) for feverish children with non-blanching rash. All children presenting to the ED with a history of fever and non-blanching rash are eligible. Children are managed as normal, with detailed prospective collection of data pertinent to CPGs, and a throat swab and blood used for rapid POCT. The study is running over 2 years and aims to recruit 300 children. Primary objective:Report on the diagnostic accuracy of POCT for (i) N. meningitidis DNA and (ii) PCT in the diagnosis of early MDReport on the diagnostic accuracy of POCT for PCT in the diagnosis of Invasive bacterial infection Secondary objectives:Evaluate the performance accuracy of existing CPGsEvaluate cost-effectiveness of available diagnostic testing strategiesExplore views of (i) families and (ii) clinicians on research without prior consent using qualitative methodologyReport on the aetiology of NBRs in children with a feverish illness Discussion The PiC study will provide important information for policy makers regarding the value of POCT and on the utility and cost of emerging diagnostic strategies. The study will also identify which elements of existing CPGs may merit inclusion in any future study to derive clinical decision rules for this population. Trial registration NCT03378258. Retrospectively registered on December 19, 2017.

Abstract Background Convulsive status epilepticus (CSE) is the most common life-threatening neurological emergency in childhood. These children are also at risk of significant morbidity, with acute and chronic impact on the family and the health and social care systems. The current recommended first-choice, second-line treatment in children aged 6 months and above is intravenous phenytoin (fosphenytoin in the USA), although there is a lack of evidence for its use and it is associated with significant side effects. Emerging evidence suggests that intravenous levetiracetam may be effective as a second-line agent for CSE, and fewer adverse effects have been described. This trial therefore aims to determine whether intravenous phenytoin or levetiracetam is more effective, and safer, in treating childhood CSE. Methods/design This is a phase IV, multi-centre, parallel group, randomised controlled, open-label trial. Following treatment for CSE with first-line treatment, children with ongoing seizures are randomised to receive either phenytoin (20 mg/kg, maximum 2 g) or levetiracetam (40 mg/kg, maximum 2.5 g) intravenously. The primary outcome measure is the cessation of all visible signs of CSE as determined by the treating clinician. Secondary outcome measures include the need for further anti-seizure medications or rapid sequence induction for ongoing CSE, admission to critical care areas, and serious adverse reactions. Patients are recruited without prior consent, with deferred consent sought at an appropriate time for the family. The primary analysis will be by intention-to-treat. The primary outcome is a time to event outcome and a sample size of 140 participants in each group will have 80% power to detect an increase in CSE cessation rates from 60% to 75%. Our total sample size of 308 randomised and treated participants will allow for 10% loss to follow-up. Discussion This clinical trial will determine whether phenytoin or levetiracetam is more effective as an intravenous second-line agent for CSE, and provide evidence for management recommendations. In addition, this trial will also provide data on which of these therapies is safer in this setting. Trial registration ISRCTN identifier, ISRCTN22567894 . Registered on 27 August 2015 EudraCT identifier, 2014-002188-13 . Registered on 21 May 2014 NIHR HTA Grant: 12/127/134

Background Bronchiolitis is a major cause of admission to hospital in children. Non-invasive ventilation (NIV) support with continuous positive airway pressure (CPAP) or high-flow nasal cannula (HFNC) oxygen is routinely used for infants in the UK with bronchiolitis.Objective To establish UK paediatric practice regarding management of bronchiolitis, and to explore issues pertinent to the design of a potential future randomised controlled trial of NIV.Design Screening logs were completed in hospitals in England capturing information on paediatric bronchiolitis admissions. An online national survey of clinical practice was disseminated to healthcare professionals (HCPs) across the UK to ascertain current management strategies.Results Screening logs captured data on 393 infants from 8 hospitals. Reasons for admission were most commonly respiratory distress and/or poor fluid intake. Oxygen was administered for 54% of admissions. Respiratory (CPAP and HFNC) and non-respiratory support administered varied considerably. The national survey was completed by 111 HCPs from 76 hospitals. Data were obtained on criteria used to commence and wean NIV, responsibilities for altering NIV settings, minimum training requirements for staff managing a child on NIV, and numbers of trained staff. Most centres were interested in and capable of running a trial of NIV, even out of normal office hours.Conclusions Respiratory and non-respiratory management of bronchiolitis in UK centres varies widely. A trial of HFNC oxygen therapy in this group of patients is feasible and HCPs would be willing to randomise patients into such a trial. Future work should focus on defining trial eligibility criteria.

Objectives For 300 paediatric trials, we evaluated the reporting of: a data monitoring committee (DMC); interim analyses, stopping rules and early stopping; and adverse events and harm-related endpoints.Methods For this cross-sectional evaluation, we randomly selected 300 paediatric trials published in 2012 from the Cochrane Central Register of Controlled Trials. We collected data on the reporting of a DMC; interim analyses, stopping rules and early stopping; and adverse events and harm-related endpoints. We reported the findings descriptively and stratified by trial characteristics.Results Eighty-five (28%) of the trials investigated drugs, and 18% (n=55/300) reported a DMC. The reporting of a DMC was more common among multicentre than single centre trials (n=41/132, 31% vs n=14/139, 10%, p

Background: Fever accelerates host immune system control of pathogens but at a high metabolic cost. The optimal approach to fever management and the optimal temperature thresholds used for treatment in critically ill children are unknown. Objectives: To determine the feasibility of conducting a definitive randomised controlled trial (RCT) to evaluate the clinical effectiveness and cost-effectiveness of different temperature thresholds for antipyretic management. Design: A mixed-methods feasibility study comprising three linked studies – (1) a qualitative study exploring parent and clinician views, (2) an observational study of the epidemiology of fever in children with infection in paediatric intensive care units (PICUs) and (3) a pilot RCT with an integrated-perspectives study. Setting: Participants were recruited from (1) four hospitals in England via social media (for the FEVER qualitative study), (2) 22 PICUs in the UK (for the FEVER observational study) and (3) four PICUs in England (for the FEVER pilot RCT). Participants: (1) Parents of children with relevant experience were recruited to the FEVER qualitative study, (2) patients who were unplanned admissions to PICUs were recruited to the FEVER observational study and (3) children admitted with infection requiring mechanical ventilation were recruited to the FEVER pilot RCT. Parents of children and clinicians involved in the pilot RCT. Interventions: The FEVER qualitative study and the FEVER observational study had no interventions. In the FEVER pilot RCT, children were randomly allocated (1 : 1) using research without prior consent (RWPC) to permissive (39.5 °C) or restrictive (37.5 °C) temperature thresholds for antipyretics during their PICU stay while mechanically ventilated. Main outcome measures: (1) The acceptability of FEVER, RWPC and potential outcomes (in the FEVER qualitative study), (2) the size of the potentially eligible population and the temperature thresholds used (in the FEVER observational study) and (3) recruitment and retention rates, protocol adherence and separation between groups and distribution of potential outcomes (in the FEVER pilot RCT). Results: In the FEVER qualitative study, 25 parents were interviewed and 56 clinicians took part in focus groups. Both the parents and the clinicians found the study acceptable. Clinicians raised concerns regarding temperature thresholds and not using paracetamol for pain/discomfort. In the FEVER observational study, 1853 children with unplanned admissions and infection were admitted to 22 PICUs between March and August 2017. The recruitment rate was 10.9 per site per month. The majority of critically ill children with a maximum temperature of > 37.5 °C received antipyretics. In the FEVER pilot RCT, 100 eligible patients were randomised between September and December 2017 at a recruitment rate of 11.1 per site per month. Consent was provided for 49 out of 51 participants in the restrictive temperature group, but only for 38 out of 49 participants in the permissive temperature group. A separation of 0.5 °C (95% confidence interval 0.2 °C to 0.8 °C) between groups was achieved. A high completeness of outcome measures was achieved. Sixty parents of 57 children took part in interviews and/or completed questionnaires and 98 clinicians took part in focus groups or completed a survey. Parents and clinicians found the pilot RCT and RWPC acceptable. Concerns about children being in pain/discomfort were cited as reasons for withdrawal and non-consent by parents and non-adherence to the protocol by clinicians. Limitations: Different recruitment periods for observational and pilot studies may not fully reflect the population that is eligible for a definitive RCT. Conclusions: The results identified barriers to delivering the definitive FEVER RCT, including acceptability of the permissive temperature threshold. The findings also provided insight into how these barriers may be overcome, such as by limiting the patient inclusion criteria to invasive ventilation only and by improved site training. A definitive FEVER RCT using a modified protocol should be conducted, but further work is required to agree important outcome measures for clinical trials among critically ill children. Trial registration: The FEVER observational study is registered as NCT03028818 and the FEVER pilot RCT is registered as Current Controlled Trials ISRCTN16022198. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 5. See the NIHR Journals Library website for further project information.

Objectives We evaluated 300 paediatric trials to determine: the consent and recruitment strategies used, who trial information was targeted to, how incentives were used and if they achieved their recruitment targets.Methods For this cross-sectional evaluation, we searched the Cochrane Central Register of Controlled Trials for paediatric trials published in 2012 and randomly selected 300 that reported on outcomes for participants aged ≤21 years. We collected data on consent and recruitment procedures for each trial and undertook descriptive analyses in SPSS statistics V.23.Results All but one trial (99.7%) used a standard recruitment strategy. Most (92%) trials reported that consent was obtained but only 13% reported who obtained consent. Two-thirds (65%) of trials included school-aged participants, and of these 68% reported obtaining assent. Half (50%) of the trials reported who the trial information was targeted to. Most trials (75%) of school-aged participants targeted information towards children or children and their parents. Fourteen per cent of trials reported using incentives, half (50%) of which were in the form of compensation. Only 48% of trials reported sufficient data to determine if their recruitment targets were achieved. Of these, 70% achieved their targets.Conclusions Notable reporting shortcomings included: how families were recruited into the trial, who obtained consent and/or assent and how, who trial information was directed to, whether incentives were used and sufficient data to determine if the recruitment target was achieved. Forthcoming paediatric-specific reporting standards may improve reporting in this priority area. Our data provide a baseline for ongoing monitoring of the state of the research.

Background: There has been no randomised controlled trial (RCT) of fluid bolus therapy in paediatric sepsis in the developed world despite evidence that excess fluid may be associated with harm. Objectives: To determine the feasibility of the Fluids in Shock (FiSh) trial – a RCT comparing restricted fluid bolus (10 ml/kg) with current practice (20 ml/kg) in children with septic shock in the UK. Design: (1) Qualitative feasibility study exploring parents’ views about the pilot RCT. (2) Pilot RCT over a 9-month period, including integrated parental and staff perspectives study. Setting: (1) Recruitment took place across four NHS hospitals in England and on social media. (2) Recruitment took place across 13 NHS hospitals in England. Participants: (1) Parents of children admitted to a UK hospital with presumed septic shock in the previous 3 years. (2) Children presenting to an emergency department with clinical suspicion of infection and shock after 20 ml/kg of fluid. Exclusion criteria were receipt of > 20 ml/kg of fluid, conditions requiring fluid restriction and the patient not for full active treatment (i.e. palliative care plan in place). Site staff and parents of children in the pilot were recruited to the perspectives study. Interventions: (1) None. (2) Children were randomly allocated (1 : 1) to 10- or 20-ml/kg fluid boluses every 15 minutes for 4 hours if in shock. Main outcome measures: (1) Acceptability of FiSh trial, proposed consent model and potential outcome measures. (2) Outcomes were based on progression criteria, including recruitment and retention rates, protocol adherence and separation between the groups, and collection and distribution of potential outcome measures. Results: (1) Twenty-one parents were interviewed. All would have consented for the pilot study. (2) Seventy-five children were randomised, 40 to the 10-ml/kg fluid bolus group and 35 to the 20-ml/kg fluid bolus group. Two children were withdrawn. Although the anticipated recruitment rate was achieved, there was variability across the sites. Fifty-nine per cent of children in the 10-ml/kg fluid bolus group and 74% in the 20-ml/kg fluid bolus group required only a single trial bolus before shock resolved. The volume of fluid (in ml/kg) was 35% lower in the first hour and 44% lower over the 4-hour period in the 10-ml/kg fluid bolus group. Fluid boluses were delivered per protocol (volume and timing) for 79% of participants in the 10-ml/kg fluid bolus group and for 55% in the 20-ml/kg fluid bolus group, mainly as a result of delivery not being completed within 15 minutes. There were no deaths. Length of hospital stay, paediatric intensive care unit (PICU) transfers, and days alive and PICU free did not differ significantly between the groups. Two adverse events were reported in each group. A questionnaire was completed by 45 parents, 20 families and seven staff were interviewed and 20 staff participated in focus groups. Although a minority of site staff lacked equipoise in favour of more restricted boluses, all supported the trial. Conclusions: Even though a successful feasibility and pilot RCT were conducted, participants were not as unwell as expected. A larger trial is not feasible in its current design in the UK. Future work: Further observational work is required to determine the epidemiology of severe childhood infection in the UK in the postvaccine era. Trial registration: Current Controlled Trials ISRCTN15244462. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 51. See the NIHR Journals Library website for further project information.

As genomic research gathers momentum in sub-Saharan Africa, it has become increasingly important to understand the reasons why individuals wish to participate in this kind of medical research. Against the background of communitarianism conceived as typical of African communities, it is often suggested that individuals consent to participate on the grounds of solidarity and to further the common good. In this paper, we seek to explore this contention by presenting data from focus groups with potential research participants about what would influence their decisions to participate in genomic research.These focus groups were conducted as part of a larger qualitative study with a purposively selected group of participants from a community situated in south west Nigeria. We conducted fifteen focus group sessions comprising 50 participants organized by age and sex, namely: 1) adult (>30 years) males, 2) adult females, 3) youth (18-30 years) males, and 4) youth females. A mixed age-group was conducted to probe different views between the age groups. There was discordance and clear division between the adults and youths regarding the decision to participate in genomic research based on commitment to communal values. Adults based their decision to participate on altruism and furthering the common good while youths based their decisions on personal benefits and preferences and also took into account the views and welfare of family members and neighbours.This discordance suggests a 'generational shift' and we advance a model of 'relative solidarity' among the youths, which is different from the communal solidarity model typical of African communitarianism. Our findings suggest the need for a closer look at strategies for implementation of community engagement and informed consent in genomic research in this region, and we recommend further studies to explore this emerging trend.

[This corrects the article DOI: 10.1371/journal.pone.0195171.].

Ensuring parents make an informed decision about their child's participation in a clinical trial is a challenge for practitioners as a parent's comprehension of a trial may differ from that intended by the practitioners responsible for recruitment. We explored what issues parents consider important when making a decision about participation in a paediatric clinical trial and their comprehension of these issues to inform future recruitment practice. This qualitative interview and observational study examined recruitment in four placebo-controlled, double-blind randomised clinical trials of medicines for children. Audio-recorded trial recruitment discussions between practitioners and parents (N = 41) were matched with semi-structured interviews with parents (N = 41). When making a decision about trial entry parents considered clinical benefit, child safety, practicalities of participation, research for the common good, access to medication and randomisation. Within these prioritised issues parents had specific misunderstandings, which had the potential to influence their decisions. While parents had many questions and concerns about trial participation which influenced their decision-making, they rarely voiced these during discussions about the trials with practitioners. Those involved in the recruitment of children to clinical trials need to be aware of parents' priorities and the sorts of misunderstandings that can arise with parents. Providing trial information that is tailored to what parents consider important in making a decision about a clinical trial may improve recruitment practice and ultimately benefit evidence-based paediatric medicine.