Assessing the impact of risk-based data monitoring on outcomes for a paediatric multicentre randomised controlled trial.

BACKGROUND/AIMS: Regulatory guidelines recommend that sponsors develop a risk-based approach to monitoring clinical trials. However, there is a lack of evidence to guide the effective implementation of monitoring activities encompassed in this approach. The aim of this study was to assess the efficiency and impact of the risk-based monitoring approach used for a multicentre randomised controlled trial comparing treatments in paediatric patients undergoing cardiac bypass surgery. METHODS: This is a secondary analysis of data from a randomised controlled trial that implemented targeted source data verification as part of the risk-based monitoring approach. Monitoring duration and source to database error rates were calculated across the monitored trial dataset. The monitored and unmonitored trial dataset, and simulated trial datasets with differing degrees of source data verification and cohort sizes were compared for their effect on trial outcomes. RESULTS: In total, 106,749 critical data points across 1,282 participants were verified from source data either remotely or on-site during the trial. The total time spent monitoring was 365 hours, with a median (interquartile range) of 10 (7, 16) minutes per participant. An overall source to database error rate of 3.1% was found, and this did not differ between treatment groups. A low rate of error was found for all outcomes undergoing 100% source data verification, with the exception of two secondary outcomes with error rates >10%. Minimal variation in trial outcomes were found between the unmonitored and monitored datasets. Reduced degrees of source data verification and reduced cohort sizes assessed using simulated trial datasets had minimal impact on trial outcomes. CONCLUSIONS: Targeted source data verification of data critical to trial outcomes, which carried with it a substantial time investment, did not have an impact on study outcomes in this trial. This evaluation of the cost-effectiveness of targeted source data verification contributes to the evidence-base regarding the context where reduced emphasis should be placed on source data verification as the foremost monitoring activity.

Post-traumatic stress and health-related quality of life after admission to paediatric intensive care: Longitudinal associations in mother-child dyads.

OBJECTIVE: Elevated post-traumatic stress symptoms (PTSS) and reduced health-related quality of life (HRQoL) are commonly experienced in both children and their parent's following admission to the paediatric intensive care unit (PICU). Previous research has demonstrated a conflict in the directionality between PTSS and HRQoL in children and their parents. Our study sought to explore the interconnection and transmission between PTSS and HRQoL in children and their mothers following an admission to the PICU. DESIGN: Prospective longitudinal design. SETTING: Two tertiary care PICUs in Brisbane, Australia. PATIENTS: Two hundred eighty-two mother-child dyads of children aged 2-16 years admitted to the PICU for >8 h. INTERVENTIONS: None. MEASUREMENT AND MAIN RESULTS: Four waves of dyadic data (n = 282 mother-child dyads) over a 12-month period from the PICU post-traumatic stress study were used. Cross-lagged panel modelling was used to examine the link between maternal-rated PTSS and HRQoL across children and their mothers. Actor-partner interdependence modelling was then used to examine the interconnections between mothers and children over time. In the dyadic model, partner effects were only present from mother to their child (i.e., higher maternal PTSS was predictive of higher child PTSS at subsequent time points). Higher maternal PTSS predicted lower maternal mental HRQoL but not lower child psychosocial HRQoL. Actor effects were also present with lower child psychosocial HRQoL, predicting higher child PTSS at subsequent time points. Findings indicated that a unidirectional transmission process from mother to child may be present after a child's life-threatening illness. CONCLUSIONS: This study provides evidence for a long-term negative influence of maternal PTSS on child PTSS in families who have experienced a paediatric critical illness or injury. This highlights the important role of maternal wellbeing in children's mental health outcomes following PICU admission. Further research needs to explore the temporal and dyadic relationships of PTSS and HRQoL.

Adaptive Clinical Trials in Pediatric Critical Care: A Systematic Review.

OBJECTIVES: This systematic review investigates the use of adaptive designs in randomized controlled trials (RCTs) in pediatric critical care. DATA SOURCES: PICU RCTs, published between 1986 and 2020, stored in the www.PICUtrials.net database and MEDLINE, EMBASE, CENTRAL, and LILACS databases were searched (March 9, 2022) to identify RCTs published in 2021. PICU RCTs using adaptive designs were identified through an automated full-text screening algorithm. STUDY SELECTION: All RCTs involving children (< 18 yr old) cared for in a PICU were included. There were no restrictions to disease cohort, intervention, or outcome. Interim monitoring by a Data and Safety Monitoring Board that was not prespecified to change the trial design or implementation of the study was not considered adaptive. DATA EXTRACTION: We extracted the type of adaptive design, the justification for the design, and the stopping rule used. Characteristics of the trial were also extracted, and the results summarized through narrative synthesis. Risk of bias was assessed using the Cochrane Risk of Bias Tool 2. DATA SYNTHESIS: Sixteen of 528 PICU RCTs (3%) used adaptive designs with two types of adaptations used; group sequential design and sample size reestimation. Of the 11 trials that used a group sequential adaptive design, seven stopped early due to futility and one stopped early due to efficacy. Of the seven trials that performed a sample size reestimation, the estimated sample size decreased in three trials and increased in one trial. CONCLUSIONS: Little evidence of the use of adaptive designs was found, with only 3% of PICU RCTs incorporating an adaptive design and only two types of adaptations used. Identifying the barriers to adoption of more complex adaptive trial designs is needed.

Knowledge translation following the implementation of a state-wide Paediatric Sepsis Pathway in the emergency department- a multi-centre survey study.

BACKGROUND: Several health care systems internationally have implemented protocolised sepsis recognition and treatment bundles for children to improve outcomes, as recommended by the Surviving Sepsis Campaign. Successful implementation of clinical pathways is challenging and dependent on nurse engagement. There is limited data on knowledge translation during implementation of sepsis quality improvement programs. METHODS: This cross-sectional, multicentre observational survey study evaluated knowledge and perceptions of Emergency Department nurses in relation to the recognition, escalation and management of paediatric sepsis following implementation of a sepsis pathway. The study was conducted between September 2019 and March 2020 across 14 Emergency Departments in Queensland, Australia. The primary outcome was a sepsis knowledge score. An exploratory factor analysis was conducted to identify factors impacting nurses' perceptions of recognition, escalation and management of paediatric sepsis and their association with knowledge. Using a logistic mixed effects model we explored associations between knowledge, identified factors and other clinical, demographic and hospital site variables. RESULTS: In total, 676 nurses responded to the survey and 534 were included in the analysis. The median knowledge score was 57.1% (IQR = 46.7-66.7), with considerable variation observed between sites. The exploratory factor analysis identified five factors contributing to paediatric sepsis recognition, escalation and management, categorised as 1) knowledge and beliefs, 2) social influences, 3) beliefs about capability and skills delivering treatment, 4) beliefs about capability and behaviour and 5) environmental context. Nurses reported strong agreement with statements measuring four of the five factors, responding lowest to the factor pertaining to capability and skills delivering treatment for paediatric sepsis. The factors knowledge and beliefs, capability and skills, and environmental context were positively associated with a higher knowledge score. Years of paediatric experience and dedicated nurse funding for the sepsis quality improvement initiative were also associated with a higher knowledge score. CONCLUSION: Translation of evidence to practice such as successful implementation of a sepsis care bundle, relies on effective education of staff and sustained uptake of protocols in daily practice. Our survey findings identify key elements associated with enhanced knowledge including dedicated funding for hospitals to target paediatric sepsis quality improvement projects.

Is Inspiring Group Members an Effective Predictor of Social Dominance in Early Adolescence? Direct and Moderated Effects of Behavioral Strategies, Social Skills, and Gender on Resource Control and Popularity.

Dominance in the peer group is important for adolescents. Resource Control Theory posits that both coercive and prosocial (positively assertive) strategies are associated with dominance. Combining Resource Control Theory with Socioanalytic Theory on personality, we hypothesized that inspiring group members would be an additional effective strategy. This study examined whether the three behavioral strategies and two types of social skills (social competence and manipulation) predicted dominance (resource control and popularity). Participants were 619 Dutch adolescents (Mage = 13.1; 47% female) in the first grade of secondary school. They completed peer reports (behavioral strategies and dominance) and self-reports (social skills). Only inspirational and coercive strategies substantially predicted dominance. Main effects of social skills emerged. Moderation between strategies and social skills was only observed for girls (e.g., coercive strategy use was associated with more popularity for girls with higher levels of social manipulation skills). This study furthered our understanding of the predictors of dominance in adolescence by including inspirational behavior and examining prosocial and antisocial skills.

Validation of a paediatric sepsis screening tool to identify children with sepsis in the emergency department: a statewide prospective cohort study in Queensland, Australia.

OBJECTIVE: The Surviving Sepsis Campaign guidelines recommend the implementation of systematic screening for sepsis. We aimed to validate a paediatric sepsis screening tool and derive a simplified screening tool. DESIGN: Prospective multicentre study conducted between August 2018 and December 2019. We assessed the performance of the paediatric sepsis screening tool using stepwise multiple logistic regression analyses with 10-fold cross-validation and evaluated the final model at defined risk thresholds. SETTING: Twelve emergency departments (EDs) in Queensland, Australia. PARTICIPANTS: 3473 children screened for sepsis, of which 523 (15.1%) were diagnosed with sepsis. INTERVENTIONS: A 32-item paediatric sepsis screening tool including rapidly available information from triage, risk factors and targeted physical examination. PRIMARY OUTCOME MEASURE: Senior medical officer-diagnosed sepsis combined with the administration of intravenous antibiotics in the ED. RESULTS: The 32-item paediatric sepsis screening tool had good predictive performance (area under the receiver operating characteristic curve (AUC) 0.80, 95% CI 0.78 to 0.82). A simplified tool containing 16 of 32 criteria had comparable performance and retained an AUC of 0.80 (95% CI 0.78 to 0.82). To reach a sensitivity of 90% (95% CI 87% to 92%), the final model achieved a specificity of 51% (95% CI 49% to 53%). Sensitivity analyses using the outcomes of sepsis-associated organ dysfunction (AUC 0.84, 95% CI 0.81 to 0.87) and septic shock (AUC 0.84, 95% CI 0.81 to 0.88) confirmed the main results. CONCLUSIONS: A simplified paediatric sepsis screening tool performed well to identify children with sepsis in the ED. Implementation of sepsis screening tools may improve the timely recognition and treatment of sepsis.

Impact of parental and healthcare professional concern on the diagnosis of pediatric sepsis: a diagnostic accuracy study.

Objective: The Surviving Sepsis Campaign recommends systematic screening for sepsis. Although many sepsis screening tools include parent or healthcare professional concern, there remains a lack of evidence to support this practice. We aimed to test the diagnostic accuracy of parent and healthcare professional concern in relation to illness severity, to diagnose sepsis in children. Design: This prospective multicenter study measured the level of concern for illness severity as perceived by the parent, treating nurse and doctor using a cross-sectional survey. The primary outcome was sepsis, defined as a pSOFA score >0. The unadjusted area under receiver-operating characteristic curves (AUC) and adjusted Odds Ratios (aOR) were calculated. Setting: Two specialised pediatric Emergency Departments in Queensland. Patients: Children aged 30 days to 18 years old that were evaluated for sepsis. Intervention: None. Main Results: 492 children were included in the study, of which 118 (23.9%) had sepsis. Parent concern was not associated with sepsis (AUC 0.53, 95% CI: 0.46-0.61, aOR: 1.18; 0.89-1.58) but was for PICU admission (OR: 1.88, 95% CI: 1.17-3.19) and bacterial infection (aOR: 1.47, 95% CI: 1.14-1.92). Healthcare professional concern was associated with sepsis in both unadjusted and adjusted models (nurses: AUC 0.57, 95% CI-0.50, 0.63, aOR: 1.29, 95% CI: 1.02-1.63; doctors: AUC 0.63, 95% CI: 0.55, 0.70, aOR: 1.61, 95% CI: 1.14-2.19). Conclusions: While our study does not support the broad use of parent or healthcare professional concern in isolation as a pediatric sepsis screening tool, measures of concern may be valuable as an adjunct in combination with other clinical data to support sepsis recognition. Clinical Trial Registration: ACTRN12620001340921.

Machine learning to predict poor school performance in paediatric survivors of intensive care: a population-based cohort study.

PURPOSE: Whilst survival in paediatric critical care has improved, clinicians lack tools capable of predicting long-term outcomes. We developed a machine learning model to predict poor school outcomes in children surviving intensive care unit (ICU). METHODS: Population-based study of children < 16 years requiring ICU admission in Queensland, Australia, between 1997 and 2019. Failure to meet the National Minimum Standard (NMS) in the National Assessment Program-Literacy and Numeracy (NAPLAN) assessment during primary and secondary school was the primary outcome. Routine ICU information was used to train machine learning classifiers. Models were trained, validated and tested using stratified nested cross-validation. RESULTS: 13,957 childhood ICU survivors with 37,200 corresponding NAPLAN tests after a median follow-up duration of 6 years were included. 14.7%, 17%, 15.6% and 16.6% failed to meet NMS in school grades 3, 5, 7 and 9. The model demonstrated an Area Under the Receiver Operating Characteristic curve (AUROC) of 0.8 (standard deviation SD, 0.01), with 51% specificity to reach 85% sensitivity [relative Area Under the Precision Recall Curve (rel-AUPRC) 3.42, SD 0.06]. Socio-economic status, illness severity, and neurological, congenital, and genetic disorders contributed most to the predictions. In children with no comorbidities admitted between 2009 and 2019, the model achieved a AUROC of 0.77 (SD 0.03) and a rel-AUPRC of 3.31 (SD 0.42). CONCLUSIONS: A machine learning model using data available at time of ICU discharge predicted failure to meet minimum educational requirements at school age. Implementation of this prediction tool could assist in prioritizing patients for follow-up and targeting of rehabilitative measures.

The Current and Future State of Pediatric Sepsis Definitions: An International Survey.

BACKGROUND AND OBJECTIVES: Definitions for pediatric sepsis were established in 2005 without data-driven criteria. It is unknown whether the more recent adult Sepsis-3 definitions meet the needs of providers caring for children. We aimed to explore the use and applicability of criteria to diagnose sepsis and septic shock in children across the world. METHODS: This is an international electronic survey of clinicians distributed across international and national societies representing pediatric intensive care, emergency medicine, pediatrics, and pediatric infectious diseases. Respondents stated their preferences on a 5-point Likert scale. RESULTS: There were 2835 survey responses analyzed, of which 48% originated from upper-middle income countries, followed by high income countries (38%) and low or lower-middle income countries (14%). Abnormal vital signs, laboratory evidence of inflammation, and microbiologic diagnoses were the criteria most used for the diagnosis of "sepsis." The 2005 consensus definitions were perceived to be the most useful for sepsis recognition, while Sepsis-3 definitions were stated as more useful for benchmarking, disease classification, enrollment into trials, and prognostication. The World Health Organization definitions were perceived as least useful across all domains. Seventy one percent of respondents agreed that the term sepsis should be restricted to children with infection-associated organ dysfunction. CONCLUSIONS: Clinicians around the world apply a myriad of signs, symptoms, laboratory studies, and treatment factors when diagnosing sepsis. The concept of sepsis as infection with associated organ dysfunction is broadly supported. Currently available sepsis definitions fall short of the perceived needs. Future diagnostic algorithms should be pragmatic and sensitive to the clinical settings.

Bayesian Hierarchical Multidimensional Item Response Modeling of Small Sample, Sparse Data for Personalized Developmental Surveillance.

Developmental surveillance tools are used to closely monitor the early development of infants and young children. This study provides a novel implementation of a multidimensional item response model, using Bayesian hierarchical priors, to construct developmental profiles for a small sample of children (N = 115) with sparse data collected through an online developmental surveillance tool. The surveillance tool records 348 developmental milestones measured from birth to three years of age, within six functional domains: auditory, hands, movement, speech, tactile, and vision. The profiles were constructed in three steps: (1) the multidimensional item response model, embedded in the Bayesian hierarchical framework, was implemented in order to measure both the latent abilities of the children and attributes of the milestones, while retaining the correlation structure among the latent developmental domains; (2) subsequent hierarchical clustering of the multidimensional ability estimates enabled identification of subgroups of children; and (3) information from the posterior distributions of the item response model parameters and the results of the clustering were used to construct a personalized profile of development for each child. These individual profiles support early identification of, and personalized early interventions for, children with developmental delay.

Queensland Pediatric Sepsis Breakthrough Collaborative: Multicenter Observational Study to Evaluate the Implementation of a Pediatric Sepsis Pathway Within the Emergency Department.

OBJECTIVES: To evaluate the implementation of a pediatric sepsis pathway in the emergency department as part of a statewide quality improvement initiative in Queensland, Australia. DESIGN: Multicenter observational prospective cohort study. SETTING: Twelve emergency departments in Queensland, Australia. PATIENTS: Children less than 18 years evaluated for sepsis in the emergency department. Patients with signs of shock, nonshocked patients with signs of organ dysfunction, and patients without organ dysfunction were assessed. INTERVENTIONS: Introduction of a pediatric sepsis pathway. MEASUREMENTS AND MAIN RESULTS: Process measures included compliance with and timeliness of the sepsis bundle, and bundle components. Process and outcome measures of children admitted to the ICU with sepsis were compared with a baseline cohort. Five-hundred twenty-three children were treated for sepsis including 291 with suspected sepsis without organ dysfunction, 86 with sepsis-associated organ dysfunction, and 146 with septic shock. Twenty-four (5%) were admitted to ICU, and three (1%) died. The median time from sepsis recognition to bundle commencement for children with septic shock was 56 minutes (interquartile range, 36-99 min) and 47 minutes (interquartile range, 34-76 min) for children with sepsis-associated organ dysfunction without shock; 30% (n = 44) and 40% (n = 34), respectively, received the bundle within the target timeframe. In comparison with the baseline ICU cohort, bundle compliance improved from 27% (n = 45) to 58% (n = 14) within 60 minutes of recognition and from 47% (n = 78/167) to 75% (n = 18) within 180 minutes of recognition (p < 0.05). CONCLUSIONS: Our findings on the introduction of protocolized care in a large and diverse state demonstrate ongoing variability in sepsis bundle compliance. Although bundle compliance improved compared with a baseline cohort, continued efforts are required to ensure guideline targets and sustainability are achieved.

Identifying latent subgroups of children with developmental delay using Bayesian sequential updating and Dirichlet process mixture modelling.

Identifying children who are at-risk for developmental delay, so that these children can have access to interventions as early as possible, is an important and challenging problem in developmental research. This research aimed to identify latent subgroups of children with developmental delay, by modelling and clustering developmental milestones. The main objectives were to (a) create a developmental profile for each child by modelling milestone achievements, from birth to three years of age, across multiple domains of development, and (b) cluster the profiles to identify groups of children who show similar deviations from typical development. The ensemble methodology used in this research consisted of three components: (1) Bayesian sequential updating was used to model the achievement of milestones, which allows for updated predictions of development to be made in real time; (2) a measure was created that indicated how far away each child deviated from typical development for each functional domain, by calculating the area between each child's obtained sequence of posterior means and a sequence of posterior means representing typical development; and (3) Dirichlet process mixture modelling was used to cluster the obtained areas. The data used were 348 binary developmental milestone measurements, collected from birth to three years of age, from a small community sample of young children (N = 79). The model identified nine latent groups of children with similar features, ranging from no delays in all functional domains, to large delays in all domains. The performance of the Dirichlet process mixture model was validated with two simulation studies.