Outcomes of interventions in neonatal sepsis: A systematic review of qualitative research.

BACKGROUND: While a systematic review exists detailing neonatal sepsis outcomes from clinical trials, there remains an absence of a qualitative systematic review capturing the perspectives of key stakeholders. OBJECTIVES: Our aim is to identify outcomes from qualitative research on any intervention to prevent or improve the outcomes of neonatal sepsis that are important to parents, other family members, healthcare providers, policymakers, and researchers as a part of the development of a core outcome set (COS) for neonatal sepsis. SEARCH STRATEGY: A literature search was carried out using MEDLINE, EMBASE, CINAHL, and PsycInfo databases. SELECTION CRITERIA: Publications describing qualitative data relating to neonatal sepsis outcomes were included. DATA COLLECTION AND ANALYSIS: Drawing on the concepts of thematic synthesis, texts related to outcomes were coded and grouped. These outcomes were then mapped to the domain headings of an existing model. MAIN RESULTS: Out of 6777 records screened, six studies were included. Overall, 19 outcomes were extracted from the included studies. The most frequently reported outcomes were those in the domains related to parents, healthcare workers and individual organ systemas such as gastrointestinal system. The remaining outcomes were classified under the headings of general outcomes, miscellaneous outcomes, survival, and infection. CONCLUSIONS: The outcomes identified in this review are different from those reported in neonatal sepsis clinical trials, thus highlighting the importance of incorporating qualitative studies into COS development to encapsulate all relevant stakeholders' perspectives.

Consensus definition and diagnostic criteria for neonatal encephalopathy-study protocol for a real-time modified delphi study.

BACKGROUND: 'Neonatal encephalopathy' (NE) describes a group of conditions in term infants presenting in the earliest days after birth with disturbed neurological function of cerebral origin. NE is aetiologically heterogenous; one cause is peripartum hypoxic ischaemia. Lack of uniformity in the terminology used to describe NE and its diagnostic criteria creates difficulty in the design and interpretation of research and complicates communication with families. The DEFINE study aims to use a modified Delphi approach to form a consensus definition for NE, and diagnostic criteria. METHODS: Directed by an international steering group, we will conduct a systematic review of the literature to assess the terminology used in trials of NE, and with their guidance perform an online Real-time Delphi survey to develop a consensus diagnosis and criteria for NE. A consensus meeting will be held to agree on the final terminology and criteria, and the outcome disseminated widely. DISCUSSION: A clear and consistent consensus-based definition of NE and criteria for its diagnosis, achieved by use of a modified Delphi technique, will enable more comparability of research results and improved communication among professionals and with families. IMPACT: The terms Neonatal Encephalopathy and Hypoxic Ischaemic Encephalopathy tend to be used interchangeably in the literature to describe a term newborn with signs of encephalopathy at birth. This creates difficulty in communication with families and carers, and between medical professionals and researchers, as well as creating difficulty with performance of research. The DEFINE project will use a Real-time Delphi approach to create a consensus definition for the term 'Neonatal Encephalopathy'. A definition formed by this consensus approach will be accepted and utilised by the neonatal community to improve research, outcomes, and parental experience.

Using behavioral science to increase core outcome set use in trials.

OBJECTIVES: Core outcome sets (COS) are agreed sets of outcomes for use in clinical trials, which can increase standardization and reduce heterogeneity of outcomes in research. Using a COS, or not, is a behavior that can potentially be increased using behavioral strategies. The aim of this study was to identify behavioral intervention components to potentially increase use of COS in trials. METHODS: This project was informed by the Behavior Change Wheel framework. Two reviewers extracted barriers and facilitators to COS use from four recently published studies examining COS use in trials. Barriers and facilitators were coded to the Capability, Opportunity, Motivation-Behavior (COM-B) model, which forms part of the Behavior Change Wheel. COM-B findings were mapped to intervention functions by two reviewers, and then mapped to behavior change techniques (BCTs). Full-team Affordability, Practicability, Effectiveness/Cost-effectiveness, Acceptability, Side effects/Safety, Equity ratings were used to reach consensus on intervention functions and BCTs. BCTs were operationalized using examples of tangible potential applications and were categorized based on similarity. RESULTS: Barriers and facilitators were identified for all capability, opportunity and motivation aspects of the COM-B model. Five intervention functions (education, training, enablement, persuasion, and modeling) and 15 BCTs were identified. Thirty-six BCT examples were developed, including providing information on benefits of COS for health research, and information choosing COS. BCT examples are categorized by approaches related to "workshops," "guidance," "audio/visual resources," and "other resources." CONCLUSION: Study findings represent diverse ways to potentially increase COS use in trials. Future work is needed to examine effects of these behavioral intervention components on COS use. If effective, increased use of COS can improve outcome reporting and minimize outcome heterogeneity and research waste.

COHESION: a core outcome set for the treatment of neonatal encephalopathy.

BACKGROUND: Heterogeneity in outcomes reported in trials of interventions for the treatment of neonatal encephalopathy (NE) makes evaluating the effectiveness of treatments difficult. Developing a core outcome set for NE treatment would enable researchers to measure and report the same outcomes in future trials. This would minimise waste, ensure relevant outcomes are measured and enable evidence synthesis. Therefore, we aimed to develop a core outcome set for treating NE. METHODS: Outcomes identified from a systematic review of the literature and interviews with parents were prioritised by stakeholders (n = 99 parents/caregivers, n = 101 healthcare providers, and n = 22 researchers/ academics) in online Delphi surveys. Agreement on the outcomes was achieved at online consensus meetings attended by n = 10 parents, n = 18 healthcare providers, and n = 13 researchers/ academics. RESULTS: Seven outcomes were included in the final core outcome set: survival; brain injury on imaging; neurological status at discharge; cerebral palsy; general cognitive ability; quality of life of the child, and adverse events related to treatment. CONCLUSION: We developed a core outcome set for the treatment of NE. This will allow future trials to measure and report the same outcomes and ensure results can be compared. Future work should identify how best to measure the COS. IMPACT: We have identified seven outcomes that should be measured and reported in all studies for the treatment of neonatal encephalopathy. Previously, a core outcome set for neonatal encephalopathy treatments did not exist. This will help to reduce heterogeneity in outcomes reported in clinical trials and other studies, and help researchers identify the best treatments for neonatal encephalopathy.

Protocol for the development of a core outcome set for neonatal sepsis (NESCOS).

Neonatal sepsis is a serious public health problem; however, there is substantial heterogeneity in the outcomes measured and reported in research evaluating the effectiveness of the treatments. Therefore, we aim to develop a Core Outcome Set (COS) for studies evaluating the effectiveness of treatments for neonatal sepsis. Since a systematic review of key outcomes from randomised trials of therapeutic interventions in neonatal sepsis was published recently, we will complement this with a qualitative systematic review of the key outcomes of neonatal sepsis identified by parents, other family members, parent representatives, healthcare providers, policymakers, and researchers. We will interpret the outcomes of both studies using a previously established framework. Stakeholders across three different groups i.e., (1) researchers, (2) healthcare providers, and (3) patients' parents/family members and parent representatives will rate the importance of the outcomes in an online Real-Time Delphi Survey. Afterwards, consensus meetings will be held to agree on the final COS through online discussions with key stakeholders. This COS is expected to minimize outcome heterogeneity in measurements and publications, improve comparability and synthesis, and decrease research waste.

Multi-Round versus Real-Time Delphi survey approach for achieving consensus in the COHESION core outcome set: a randomised trial.

BACKGROUND: Delphi surveys are commonly used to prioritise critical outcomes in core outcome set (COS) development. This trial aims to compare a three-round (Multi-Round) Delphi (MRD) with a Real-Time Delphi (RTD) in the prioritisation of outcomes for inclusion in a COS for neonatal encephalopathy treatments and explore whether 'feedback', 'iteration', and 'initial condition' effects may occur in the two survey methods. METHODS: We recruited 269 participants (parents/caregivers, healthcare providers and researchers/academics) of which 222 were randomised to either the MRD or the RTD. We investigated the outcomes prioritised in each survey and the 'feedback', 'iteration', and 'initial condition' effects to identify differences between the two survey methods. RESULTS: In the RTD, n = 92 participants (83%) fully completed the survey. In the MRD, n = 60 participants (54%) completed all three rounds. Of the 92 outcomes presented, 26 (28%) were prioritised differently between the RTD and MRD. Significantly fewer participants amended their scores when shown stakeholder responses in the RTD compared to the MRD ('feedback effect'). The 'iteration effect' analysis found most experts appeared satisfied with their initial ratings in the RTD and did not amend their scores following stakeholder response feedback. Where they did amend their scores, ratings were amended substantially, suggesting greater convergence. Variance in scores reduced with subsequent rounds of the MRD ('iteration effect'). Whilst most participants did not change their initial scores in the RTD, of those that did, later recruits tended to align their final score more closely to the group mean final score than earlier recruits (an 'initial condition' effect). CONCLUSION: The feedback effect differed between the two Delphi methods but the magnitude of this difference was small and likely due to the large number of observations rather than because of a meaningfully large difference. It did not appear to be advantageous to require participants to engage in three rounds of a survey due to the low change in scores. Larger drop-out through successive rounds in the MRD, together with a lesser convergence of scores and longer time to completion, indicate considerable benefits of the RTD approach. TRIAL REGISTRATION: NCT04471103. Registered on 14 July 2020.

Core outcomes in neonatal encephalopathy: a qualitative study with parents.

OBJECTIVE: To identify the outcomes considered important to parents or caregivers of infants diagnosed with neonatal encephalopathy, hypoxic ischaemic encephalopathy or birth asphyxia in high-income and low- to middle-income countries (LMiCs), as part of the outcome-identification process in developing a core outcome set (COS) for the treatment of neonatal encephalopathy. DESIGN: A qualitative study involving 25 semistructured interviews with parents or other family members (caregivers) of infants who were diagnosed with, and treated for, neonatal encephalopathy, hypoxic ischaemic encephalopathy or birth asphyxia. SETTING: Interviews were conducted in high-income countries (HiCs) (n=11) by Zoom video conferencing software and in LMiCs (n=14) by phone or face to face. FINDINGS: Parents identified 54 outcomes overall, which mapped to 16 outcome domains. The domains identified were neurological outcomes, respiratory outcomes, gastrointestinal outcomes, cardiovascular outcomes, motor development, cognitive development, development (psychosocial), development (special senses), cognitive development, development (speech and social), other organ outcomes, survival/living outcomes, long-term disability, hospitalisation, parent-reported outcomes and adverse events. CONCLUSIONS: This study provides insight into the outcomes that parents of infants diagnosed with neonatal encephalopathy have identified as the most important, to be considered in the process of developing a COS for the treatment of neonatal encephalopathy. We also provide description of the processes employed to ensure the inclusion of participants from LMiCs as well as HiCs.

Using behavioural science to enhance use of core outcome sets in trials: protocol.

Background: Core outcome sets (COS) represent agreed-upon sets of outcomes, which are the minimum that should be measured and reported in all trials in specific health areas. Use of COS can reduce outcome heterogeneity, selective outcome reporting, and research waste, and can facilitate evidence syntheses. Despite benefits of using COS, current use of COS in trials is low. COS use can be understood as a behaviour, in that it is something trialists do, or not do, adequately. The aim of this study is to identify strategies, informed by behaviour change theory, to increase COS use in trials. Methods: The project will be conducted in two stages, informed by the behaviour change wheel (BCW). The BCW is a theoretically based framework that can be used to classify, identify, and develop behaviour change strategies. In Stage 1, barriers and enablers to COS use will be extracted from published studies that examined trialist's use of COS. Barriers and facilitators will be mapped to the components of COM-B model (capability, opportunity, and motivation), which forms part of the BCW framework. Stage 2 will build on Stage 1 findings to identify and select intervention functions and behaviour change techniques to enhance COS use in trials. Discussion: The findings of this study will provide an understanding of the behavioural factors that influence COS use in trials and what strategies might be used to target these factors to increase COS use in trials.

Use of core outcome sets was low in clinical trials published in major medical journals.

OBJECTIVES: To examine current practices in late-phase trials published in major medical journals and examine trialists' views about core outcome set (COS) use. STUDY DESIGN AND SETTING: A sequential multi-methods study was conducted. We examined late-phase trials published between October 2019 and March 2020 in JAMA, NEJM, The Lancet, BMJ, and Annals of Internal Medicine. The COMET database was searched for COS potentially relevant to trials not reporting using a COS; overlap of trial and COS outcomes was examined. An online survey examined awareness of, and decisions to search for and use a COS. RESULTS: Ninety-five trials were examined; 93 (98%) did not report using a COS. Relevant COS were identified for 31 trials (33%). Core outcomes were measured in 9 (23%) studies; all trials measured at least one core outcome. Thirty-one trialists (33%) completed our survey. The most common barrier to COS use was trialist's own outcome preferences and choice (68%). The most common perceived facilitator was awareness and knowledge about COS (90%). CONCLUSION: COS use in this cohort of trials was low, even when relevant COS were available. Increased use of COS in clinical trials can improve evaluation of intervention effects and evidence synthesis and reduce research waste.

COHESION: core outcomes in neonatal encephalopathy (protocol).

BACKGROUND: Neonatal encephalopathy is a complex syndrome in infants that predominantly affects the brain and other organs. The leading cause is a lack of oxygen in the blood reaching the brain. Neonatal encephalopathy can result in mortality or complications later in life, including seizures, movement disorders and cerebral palsy. Treatment options for neonatal encephalopathy are limited mainly to therapeutic hypothermia, although other potential treatments are emerging. However, evaluations of the effectiveness of treatments are challenging because of heterogeneity and inconsistency in outcomes measured and reported between trials. In this paper, we detail how we will develop a core outcome set to standardise outcomes measured and reported upon for interventions for the treatment of neonatal encephalopathy. METHODS: We will systematically review the literature to identify outcomes reported previously in randomised trials and systematic reviews of randomised trials. We will identify outcomes important to parents or caregivers of infants diagnosed with and who have received treatment for neonatal encephalopathy. We will do this by conducting in person or by video teleconferencing interviews with parents or caregivers in high-income and low- to middle-income countries. Stakeholders with expertise in neonatal encephalopathy (parents/caregivers, healthcare providers and researchers) will rate the importance of identified outcomes in an online Delphi survey using either a three-round Delphi survey or a "Real-Time" Delphi survey to which stakeholders will be allocated at random. Consensus meetings will take place by video conference to allow for an international group of stakeholder representatives to discuss and vote on the outcomes to include in the final core outcome set (COS). DISCUSSION: More research is needed on treatments for neonatal encephalopathy. Standardising outcomes measured and reported in evaluations of the effectiveness of interventions for the treatment of neonatal encephalopathy will improve evidence synthesis and improve results reported in systematic reviews and meta-analysis in this area. Overall, this COS will allow for improved treatments to be identified, heterogeneity in research to be reduced, and overall patient care to be enhanced. TRIAL REGISTRATION: This study is registered in the Core Outcome Measures for Effectiveness (COMET) database http://www.comet-initiative.org/Studies/Details/1270 .

Multi-Round compared to Real-Time Delphi for consensus in core outcome set (COS) development: a randomised trial.

BACKGROUND: The Delphi method is used in a wide variety of settings as a method of building consensus on important issues. Traditionally, the Delphi method uses multiple rounds of a survey to allow for feedback of other participants' survey responses in between rounds. By informing participants about how others answer a question or prioritise specific topics, it allows for diverse opinions to inform the consensus process. For this reason, the Delphi method is popular as a consensus building approach in developing core outcome sets (COS), i.e. the minimum agreed set of standardised outcomes that should be measured and reported in studies on a specific health condition. In a COS setting, participants prioritise the importance of outcomes for inclusion in a COS. This usually involves participating in multiple rounds of a survey that can span several weeks or months. Challenges with participant retention have been highlighted in previous COS. We will compare a three-round with a Real-Time Delphi approach on prioritised outcomes. This trial is embedded within the COHESION study which is developing a COS for interventions treating neonatal encephalopathy. METHODS: One hundred and eighty stakeholders (parents/caregivers of infants diagnosed and treated with neonatal encephalopathy, healthcare providers and researchers) will be randomised using stratified randomisation to take part in either the Multi-Round or Real-Time Delphi. Stakeholders will rate the importance of the same set of outcomes in both arms. We will compare the prioritised outcomes at the end of both surveys as well as other parameters such as feedback, initial condition and iteration effects. DISCUSSION: This trial will provide evidence to inform decisions on the use of Multi-Round compared to Real-Time Delphi survey methods. TRIAL REGISTRATION: NCT04471103 . Registered on 14 July 2020.