Diagnosis and management of selective fetal growth restriction in monochorionic twin pregnancies: A cross-sectional international survey.

OBJECTIVE: To identify current practices in the management of selective fetal growth restriction (sFGR) in monochorionic diamniotic (MCDA) twin pregnancies. DESIGN: Cross-sectional survey. SETTING: International. POPULATION: Clinicians involved in the management of MCDA twin pregnancies with sFGR. METHODS: A structured, self-administered survey. MAIN OUTCOME MEASURES: Clinical practices and attitudes to diagnostic criteria and management strategies. RESULTS: Overall, 62.8% (113/180) of clinicians completed the survey; of which, 66.4% (75/113) of the respondents reported that they would use an estimated fetal weight (EFW) of <10th centile for the smaller twin and an inter-twin EFW discordance of >25% for the diagnosis of sFGR. For early-onset type I sFGR, 79.8% (75/94) of respondents expressed that expectant management would be their routine practice. On the other hand, for early-onset type II and type III sFGR, 19.3% (17/88) and 35.7% (30/84) of respondents would manage these pregnancies expectantly, whereas 71.6% (63/88) and 57.1% (48/84) would refer these pregnancies to a fetal intervention centre or would offer fetal intervention for type II and type III cases, respectively. Moreover, 39.0% (16/41) of the respondents would consider fetoscopic laser surgery (FLS) for early-onset type I sFGR, whereas 41.5% (17/41) would offer either FLS or selective feticide, and 12.2% (5/41) would exclusively offer selective feticide. For early-onset type II and type III sFGR cases, 25.9% (21/81) and 31.4% (22/70) would exclusively offer FLS, respectively, whereas 33.3% (27/81) and 32.9% (23/70) would exclusively offer selective feticide. CONCLUSIONS: There is significant variation in clinician practices and attitudes towards the management of early-onset sFGR in MCDA twin pregnancies, especially for type II and type III cases, highlighting the need for high-level evidence to guide management.

Whole-body hypothermia in mild neonatal encephalopathy: protocol for a multicentre phase III randomised controlled trial.

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.

The perception of risk in contracting and spreading COVID-19 amongst individuals, households and vulnerable groups in England: a longitudinal qualitative study.

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.

Community engagement in genomic research: Proposing a strategic model for effective participation of indigenous communities.

Community engagement (CE) contributes to successful research. There is, however, a lack of literature on the effectiveness of different models of CE and, specifically, on CE strategies for the conduct of genomic research in sub-Saharan Africa. There is also a need for models of CE that transcend the recruitment stage of engaging prospective individuals and communities and embed CE throughout the research process and after the research has concluded. The qualitative study reported here was designed to address these knowledge gaps and comprised of 36 key informant semi-structured interviews and fifteen focus groups with 50 participants. We interviewed selected stakeholders in genomic research in Nigeria: biomedical researchers, community rulers, opinion leaders, community health workers, and prospective research participants. We explored these stakeholders' views on their understanding of community engagement, their expectations, experiences, and their opinions on acceptable processes of community consultation in genomic research. The methodological design, adapted from grounded theory, used the constant comparative method of data analysis; while normative conclusions were made using the symbiotic empirical ethics approach. Data analysis revealed five main themes important for successfully engaging communities in genomic research: effective communication, diversity of community gatekeeping, trust, cultural integration of research, and conservation of the research setting. From these themes, we have developed a four-stage model of community engagement that covers all stages of the research process; namely, the Community Approach, Intermediate phase, Collaboration and Post-research Cordiality model (CICP). This model could be used to improve the integration of CE in genomic research among local communities.

Seven-step framework to enhance practitioner explanations and parental understandings of research without prior consent in paediatric emergency and critical care trials.

BACKGROUND: Alternatives to prospective informed consent enable the conduct of paediatric emergency and critical care trials. Research without prior consent (RWPC) involves practitioners approaching parents after an intervention has been given and seeking consent for their child to continue in the trial. As part of an embedded study in the 'Emergency treatment with Levetiracetam or Phenytoin in Status Epilepticus in children' (EcLiPSE) trial, we explored how practitioners described the trial and RWPC during recruitment discussions, and how well this information was understood by parents. We aimed to develop a framework to assist trial conversations in future paediatric emergency and critical care trials using RWPC. METHODS: Qualitative methods embedded within the EcLiPSE trial processes, including audiorecorded practitioner-parent trial discussions and telephone interviews with parents. We analysed data using thematic analysis, drawing on the Realpe et al (2016) model for recruitment to trials. RESULTS: We analysed 76 recorded trial discussions and conducted 30 parent telephone interviews. For 19 parents, we had recorded trial discussion and interview data, which were matched for analysis. Parental understanding of the EcLiPSE trial was enhanced when practitioners: provided a comprehensive description of trial aims; explained the reasons for RWPC; discussed uncertainty about which intervention was best; provided a balanced description of trial intervention; provided a clear explanation about randomisation and provided an opportunity for questions. We present a seven-step framework to assist recruitment practice in trials involving RWPC. CONCLUSION: This study provides a framework to enhance recruitment practice and parental understanding in paediatric emergency and critical care trials involving RWPC. Further testing of this framework is required.

Planning for success: overcoming challenges to recruitment and conduct of an open-label emergency department-led paediatric trial.

BACKGROUND: Key challenges to the successful conduct of The Emergency treatment with Levetiracetam or Phenytoin in Status Epilepticus in children (EcLiPSE) trial were identified at the pre-trial stage. These included practitioner anxieties about conducting research without prior consent (RWPC), inexperience in conducting an ED-led trial and use of a medication that was not usual ED practice. As part of an embedded study, we explored parent and practitioner experiences of recruitment, RWPC and conduct of the trial to inform the design and conduct of future ED-led trials. METHODS: A mixed-methods study within a trial involving (1) questionnaires and interviews with parents of randomised children, (2) interviews and focus groups with EcLiPSE practitioners and (3) audio-recorded trial discussions. We analysed data using thematic analysis and descriptive statistics as appropriate. RESULTS: A total of 143 parents (93 mothers, 39 fathers, 11 missing information) of randomised children completed a questionnaire and 30 (25 mothers, 5 fathers) were interviewed. We analysed 76 recorded trial recruitment discussions. Ten practitioners (4 medical, 6 nursing) were interviewed, 36 (16 medical, 20 nursing) participated in one of six focus groups. Challenges to the success of the trial were addressed by having a clinically relevant research question, pragmatic trial design, parent and practitioner support for EcLiPSE recruitment and research without prior consent processes, and practitioner motivation and strong leadership. Lack of leadership negatively affected practitioner engagement and recruitment. EcLiPSE completed on time, achieving its required sample size target. CONCLUSIONS: Successful trial recruitment and conduct in a challenging ED-led trial was driven by trial design, recruitment experience, teamwork and leadership. Our study provides valuable insight from parents and practitioners to inform the design and conduct of future trials in this setting.

Levetiracetam versus phenytoin for second-line treatment of paediatric convulsive status epilepticus (EcLiPSE): a multicentre, open-label, randomised trial.

BACKGROUND: Phenytoin is the recommended second-line intravenous anticonvulsant for treatment of paediatric convulsive status epilepticus in the UK; however, some evidence suggests that levetiracetam could be an effective and safer alternative. This trial compared the efficacy and safety of phenytoin and levetiracetam for second-line management of paediatric convulsive status epilepticus. METHODS: This open-label, randomised clinical trial was undertaken at 30 UK emergency departments at secondary and tertiary care centres. Participants aged 6 months to under 18 years, with convulsive status epilepticus requiring second-line treatment, were randomly assigned (1:1) using a computer-generated randomisation schedule to receive levetiracetam (40 mg/kg over 5 min) or phenytoin (20 mg/kg over at least 20 min), stratified by centre. The primary outcome was time from randomisation to cessation of convulsive status epilepticus, analysed in the modified intention-to-treat population (excluding those who did not require second-line treatment after randomisation and those who did not provide consent). This trial is registered with ISRCTN, number ISRCTN22567894. FINDINGS: Between July 17, 2015, and April 7, 2018, 1432 patients were assessed for eligibility. After exclusion of ineligible patients, 404 patients were randomly assigned. After exclusion of those who did not require second-line treatment and those who did not consent, 286 randomised participants were treated and had available data: 152 allocated to levetiracetam, and 134 to phenytoin. Convulsive status epilepticus was terminated in 106 (70%) children in the levetiracetam group and in 86 (64%) in the phenytoin group. Median time from randomisation to cessation of convulsive status epilepticus was 35 min (IQR 20 to not assessable) in the levetiracetam group and 45 min (24 to not assessable) in the phenytoin group (hazard ratio 1·20, 95% CI 0·91-1·60; p=0·20). One participant who received levetiracetam followed by phenytoin died as a result of catastrophic cerebral oedema unrelated to either treatment. One participant who received phenytoin had serious adverse reactions related to study treatment (hypotension considered to be immediately life-threatening [a serious adverse reaction] and increased focal seizures and decreased consciousness considered to be medically significant [a suspected unexpected serious adverse reaction]). INTERPRETATION: Although levetiracetam was not significantly superior to phenytoin, the results, together with previously reported safety profiles and comparative ease of administration of levetiracetam, suggest it could be an appropriate alternative to phenytoin as the first-choice, second-line anticonvulsant in the treatment of paediatric convulsive status epilepticus. FUNDING: National Institute for Health Research Health Technology Assessment programme.

Diagnostic test accuracy of point-of-care procalcitonin to diagnose serious bacterial infections in children.

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.

Permissive versus restrictive temperature thresholds in critically ill children with fever and infection: a multicentre randomized clinical pilot trial.

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 < 16 years receiving respiratory support and supplemental oxygen. Subjects were randomly assigned to permissive (antipyretic interventions only at ≥ 39.5 °C) or restrictive groups (antipyretic interventions at ≥ 37.5 °C) whilst on respiratory support. Parents were invited to complete a questionnaire or take part in an interview. Focus groups were conducted with staff at each unit. Outcomes were measures of feasibility: recruitment rate, protocol adherence and acceptability, between group separation of temperature and safety. RESULTS: One hundred thirty-eight children met eligibility criteria of whom 100 (72%) were randomized (11.1 patients per month per site) without prior consent (RWPC). Consent to continue in the trial was obtained in 87 cases (87%). The mean maximum temperature (95% confidence interval) over the first 48 h was 38.4 °C (38.2-38.6) in the restrictive group and 38.8 °C (38.6-39.1) in the permissive group, a mean difference of 0.5 °C (0.2-0.8). Protocol deviations were observed in 6.8% (99/1438) of 6-h time periods and largely related to patient comfort in the recovery phase. Length of stay, duration of organ support and mortality were similar between groups. No pre-specified serious adverse events occurred. Staff (n = 48) and parents (n = 60) were supportive of the trial, including RWPC. Suggestions were made to only include invasively ventilated children for the duration of intubation. CONCLUSION: Uncertainty around the optimal fever threshold for antipyretic intervention is relevant to many emergency PICU admissions. A more permissive approach was associated with a modest increase in mean maximum temperature. A definitive trial should focus on the most seriously ill cases in whom antipyretics are rarely used for their analgesic effects alone. TRIAL REGISTRATION: ISRCTN16022198 . Registered on 14 August 2017.

Gastric Residual Volume Measurement in U.K. PICUs: A Survey of Practice.

OBJECTIVES: Despite little evidence, the practice of routine measurement of gastric residual volume to guide both the initiation and delivery of enteral feeding in PICUs is widespread internationally. In light of increased scrutiny of the evidence surrounding this practice, and as part of a trial feasibility study, we aimed to determine enteral feeding and gastric residual volume measurement practices in U.K. PICUs. DESIGN: An online survey to 27 U.K. PICUs. SETTING: U.K. PICUs. SUBJECTS: A clinical nurse, senior doctor, and dietician were invited to collaboratively complete one survey per PICU and send a copy of their unit guidelines on enteral feeding and gastric residual volume. INTERVENTIONS: None. MEASUREMENT AND MAIN RESULTS: Twenty-four of 27 units (89%) approached completed the survey. Twenty-three units (95.8%; 23/24) had written feeding guidelines, and 19 units (19/23; 83%) sent their guidelines for review. More units fed continuously (15/24; 62%) than intermittently (9/24; 37%) via the gastric route as their primary feeding method. All but one PICU routinely measured gastric residual volume, regardless of the method of feeding. Eighteen units had an agreed definition of feed tolerance, and all these included gastric residual volume. Gastric residual volume thresholds for feed tolerance were either volume based (mL/kg body weight) (11/21; 52%) or a percentage of the volume of feed administered (6/21; 29%). Yet only a third of units provided guidance about the technique of gastric residual volume measurement. CONCLUSIONS: Routine gastric residual volume measurement is part of standard practice in U.K. PICUs, with little guidance provided about the technique which may impact the accuracy of gastric residual volume. All PICUs that defined feed tolerance included gastric residual volume in the definition. This is important to know when proposing a standard practice arm of any future trial of no-routine gastric residual volume measurement in critically ill children.

The "Petechiae in children" (PiC) study: evaluating potential clinical decision rules for the management of feverish children with non-blanching rashes, including the role of point of care testing for Procalcitonin & Neisseria meningitidis DNA - a study protocol.

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 MD Report on the diagnostic accuracy of POCT for PCT in the diagnosis of Invasive bacterial infection Secondary objectives: Evaluate the performance accuracy of existing CPGs Evaluate cost-effectiveness of available diagnostic testing strategies Explore views of (i) families and (ii) clinicians on research without prior consent using qualitative methodology Report 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.

Priorities for methodological research on patient and public involvement in clinical trials: A modified Delphi process.

BACKGROUND: Despite increasing international interest, there is a lack of evidence about the most efficient, effective and acceptable ways to implement patient and public involvement (PPI) in clinical trials. OBJECTIVE: To identify the priorities of UK PPI stakeholders for methodological research to help resolve uncertainties about PPI in clinical trials. DESIGN: A modified Delphi process including a two round online survey and a stakeholder consensus meeting. PARTICIPANTS: In total, 237 people registered of whom 219 (92%) completed the first round. One hundred and eighty-seven of 219 (85%) completed the second; 25 stakeholders attended the consensus meeting. RESULTS: Round 1 of the survey comprised 36 topics; 42 topics were considered in round 2 and at the consensus meeting. Approximately 96% of meeting participants rated the top three topics as equally important. These were as follows: developing strong and productive working relationships between researchers and PPI contributors; exploring PPI practices in selecting trial outcomes of importance to patients; and a systematic review of PPI activity to improve the accessibility and usefulness of trial information (eg participant information sheets) for participants. CONCLUSIONS: The prioritized methodological research topics indicate important areas of uncertainty about PPI in trials. Addressing these uncertainties will be critical to enhancing PPI. Our findings should be used in the planning and funding of PPI in clinical trials to help focus research efforts and minimize waste.

Stakeholders' perspectives on clinical trial acceptability and approach to consent within a limited timeframe: a mixed methods study.

OBJECTIVES: The Bronchiolitis Endotracheal Surfactant Study (BESS) is a randomised controlled trial to determine the efficacy of endo-tracheal surfactant therapy for critically ill infants with bronchiolitis. To explore acceptability of BESS, including approach to consent within a limited time frame, we explored parent and staff experiences of trial involvement in the first two bronchiolitis seasons to inform subsequent trial conduct. DESIGN: A mixed-method embedded study involving a site staff survey, questionnaires and interviews with parents approached about BESS. SETTING: Fourteen UK paediatric intensive care units. PARTICIPANTS: Of the 179 parents of children approached to take part in BESS, 75 parents (of 69 children) took part in the embedded study. Of these, 55/69 (78%) completed a questionnaire, and 15/69 (21%) were interviewed. Thirty-eight staff completed a questionnaire. RESULTS: Parents and staff found the trial acceptable. All constructs of the Adapted Theoretical Framework of Acceptability were met. Parents viewed surfactant as being low risk and hoped their child's participation would help others in the future. Although parents supported research without prior consent in studies of time critical interventions, they believed there was sufficient time to consider this trial. Parents recommended that prospective informed consent should continue to be sought for BESS. Many felt that the time between the consent process and intervention being administered took too long and should be 'streamlined' to avoid delays in administration of trial interventions. Staff described how the training and trial processes worked well, yet patients were missed due to lack of staff to deliver the intervention, particularly at weekends. CONCLUSION: Parents and staff supported BESS trial and highlighted aspects of the protocol, which should be refined, including a streamlined informed consent process. Findings will be useful to inform proportionate approaches to consent in future paediatric trials where there is a short timeframe for consent discussions. TRIAL REGISTRATION NUMBER: ISRCTN11746266.

Exploring communication preferences and risk thresholds of clinicians and parents of febrile infants under 90 days presenting to the emergency department: a qualitative study.

BACKGROUND: Febrile infants under 3 months of age are at higher risk of invasive bacterial illness (IBI) when compared with older children. Increasingly sequential assessment based on age, clinical appearance and biomarkers is used to determine the risk of IBI, and appropriateness of invasive procedures such as lumbar puncture. The purpose of this qualitative study is to report parents and clinicians' opinions on communication of risks and benefits of sequential assessment and tailored treatment. METHODS: 18 parents enrolled in the Febrile Infant Diagnostic Assessment and Outcomes study and seven clinicians from England, Wales and Northern Ireland were purposively selected to participate in virtual qualitative interviews. Data were analysed thematically. RESULTS: Tailored treatment plans were widely supported. Confidence in the clinician was central to parents' attitude towards management recommendations. Parents' decision-making preferences change throughout their child's clinical journey, with an initial preference for clinician-led decisions evolving towards collaborative decision-making as their stress and anxiety reduce. There were widespread differences in preferences for how risk was discussed. Parents self-reported poor retention of information and felt communication adjuncts helped their understanding. Clinicians were generally positive about the use of clinical decision aids as a communication tool, rather than relying on them for decision-making. DISCUSSION: Parents want to feel informed, but their desire to be involved in shared decision-making evolves over time.Clinicians appear to use their clinical judgement to provide individualised information, evolving their communication in response to perceived parental needs.Poor information retention highlights the need for repetition of information and use of communication adjuncts. TRIAL REGISTRATION NUMBER: NCT05259683.

Questioning approaches to consent in time critical obstetric trials: findings from a mixed-methods study.

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.

Developments in the Design, Conduct, and Reporting of Child Health Trials.

To identify priority areas to improve the design, conduct, and reporting of pediatric clinical trials, the international expert network, Standards for Research (StaR) in Child Health, was assembled and published the first 6 Standards in Pediatrics in 2012. After a recent review summarizing the 247 publications by StaR Child Health authors that highlight research practices that add value and reduce research "waste," the current review assesses the progress in key child health trial methods areas: consent and recruitment, containing risk of bias, roles of data monitoring committees, appropriate sample size calculations, outcome selection and measurement, and age groups for pediatric trials. Although meaningful change has occurred within the child health research ecosystem, measurable progress is still disappointingly slow. In this context, we identify and review emerging trends that will advance the agenda of increased clinical usefulness of pediatric trials, including patient and public engagement, Bayesian statistical approaches, adaptive designs, and platform trials. We explore how implementation science approaches could be applied to effect measurable improvements in the design, conducted, and reporting of child health research.

Use of selective gut decontamination in critically ill children: PICnIC a pilot RCT and mixed-methods study.

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.

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.

How experience makes a difference: practitioners' views on the use of deferred consent in paediatric and neonatal emergency care trials.

BACKGROUND: In 2008 UK legislation was amended to enable the use of deferred consent for paediatric emergency care (EC) trials in recognition of the practical and ethical difficulties of obtaining prospective consent in an emergency situation. However, ambiguity about how to make deferred consent acceptable to parents, children and practitioners remains. In particular, little is known about practitioners' views and experiences of seeking deferred consent in this setting. METHODS: As part of a wider study investigating consent methods in paediatric emergency care trials (called CONNECT), a 20 item online questionnaire was sent by email inviting practitioners (doctors and nurses) who were involved in talking with families about children's and young people's (aged 0-16 years) participation in UK EC trials. To ensure those with and without experience of deferred consent were included, practitioners were sampled using a combination of purposive and snowball sampling methods. Simple descriptive statistics were used to analyse the quantitative data, whilst the constant comparative method was used to analyse qualitative data. Elements of a symbiotic empirical ethics approach was used to integrate empirical evidence and bioethical literature to explore the data and draw practice orientated conclusions. RESULTS: Views on deferred consent differed depending upon whether or not practitioners were experienced in this consent method. Practitioners who had no experience of deferred consent reported negative perceptions of this consent method; these practitioners were concerned about the impact that deferred consent would have upon the parent-practitioner relationship. In contrast, practitioners experienced in deferred consent described how families had been receptive to the consent method, if conducted sensitively and in a time appropriate manner. Experienced practitioners also described how deferred consent had improved recruitment, parental decision-making capacity and parent-practitioner relationships in the emergency care setting. CONCLUSIONS: The views of practitioners with first-hand experience of deferred consent should be considered in the design and ethical review of future paediatric EC trials; the design and ethical review of such trials should not solely be informed by the beliefs of those without experience of using deferred consent. Further research involving parents and children is required to inform practitioner training and normative guidance on the use and appropriateness of deferred consent in emergency settings.

Applying clinical decision aids for the assessment and management of febrile infants presenting to emergency care in the UK and Ireland: Febrile Infant Diagnostic Assessment and Outcome (FIDO) Study protocol.

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.