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.

Serum Levels of Vitamin C and Thiamin in Children With Suspected Sepsis: A Prospective Observational Cohort Study.

OBJECTIVES: Vitamin C and thiamin have been trialed as adjunctive therapies in adults with septic shock but their role in critically ill children is unclear. We assessed serum levels of vitamin C and thiamin in children evaluated for sepsis. DESIGN: Single-center prospective observational study. Serum levels of vitamin C and thiamin were measured on admission and association with multiple organ dysfunction syndrome (MODS) was explored using logistic regression. SETTING: Emergency department and PICU in a tertiary children's hospital, Queensland, Australia. PATIENTS: Children greater than 1 month and less than 17 years evaluated for sepsis. INTERVENTIONS: Not applicable. MEASUREMENTS AND MAIN RESULTS: Vitamin levels were determined in 221 children with a median age of 3.5 (interquartile range [IQR] 1.6, 8.3) years. Vitamin C levels were inversely correlated with severity as measured by pediatric Sequential Organ Failure Assessment (Spearman's rho = -0.16, p = 0.018). Median (IQR) vitamin C levels on admission were 35.7 (17.9, 54.1) µmol/L, 36.1 (21.4, 53.7) µmol/L, and 17.9 (6.6, 43.0) µmol/L in children without organ dysfunction, single organ dysfunction, and MODS, respectively (p = 0.017). In multivariable analyses, low levels of vitamin C at the time of sampling were associated with greater odds of MODS (adjusted odds ratio [aOR] 3.04; 95% CI, 1.51-6.12), and vitamin C deficiency was associated with greater odds of MODS at 24 hours after sampling (aOR 3.38; 95% CI, 1.53-7.47). Median (IQR) thiamin levels were 162 (138, 192) nmol/L, 185 (143, 200) nmol/L, and 136 (110, 179) nmol/L in children without organ dysfunction, single organ dysfunction, and MODS, respectively (p = 0.061). We failed to identify an association between thiamin deficiency and either MODS at sampling (OR 2.52; 95% CI, 0.15-40.86) or MODS at 24 hours (OR 2.96; 95% CI, 0.18-48.18). CONCLUSIONS: Critically ill children evaluated for sepsis frequently manifest decreased levels of vitamin C, with lower levels associated with higher severity.

Resuscitation With Early Adrenaline Infusion for Children With Septic Shock: A Randomized Pilot Trial.

OBJECTIVES: In children with septic shock, guidelines recommend resuscitation with 40-60 mL/kg of fluid boluses, yet there is a lack of evidence to support this practice. We aimed to determine the feasibility of a randomized trial comparing early adrenaline infusion with standard fluid resuscitation in children with septic shock. DESIGN: Open-label parallel randomized controlled, multicenter pilot study. The primary end point was feasibility; the exploratory clinical endpoint was survival free of organ dysfunction by 28 days. SETTING: Four pediatric Emergency Departments in Queensland, Australia. PATIENTS: Children between 28 days and 18 years old with septic shock. INTERVENTIONS: Patients were assigned 1:1 to receive a continuous adrenaline infusion after 20 mL/kg fluid bolus resuscitation (n = 17), or standard care fluid resuscitation defined as delivery of 40 to 60 mL/kg fluid bolus resuscitation prior to inotrope commencement (n = 23). MEASUREMENTS AND MAIN RESULTS: Forty of 58 eligible patients (69%) were consented with a median age of 3.7 years (interquartile range [IQR], 0.9-12.1 yr). The median time from randomization to inotropes was 16 minutes (IQR, 12-26 min) in the intervention group, and 49 minutes (IQR, 29-63 min) in the standard care group. The median amount of fluid delivered during the first 24 hours was 0 mL/kg (IQR, 0-10.0 mL/kg) in the intervention group, and 20.0 mL/kg (14.6-28.6 mL/kg) in the standard group (difference, -20.0; 95% CI, -28.0 to -12.0). The number of days alive and free of organ dysfunction did not differ between the intervention and standard care groups, with a median of 27 days (IQR, 26-27 d) versus 26 days (IQR, 25-27 d). There were no adverse events reported associated with the intervention. CONCLUSIONS: In children with septic shock, a protocol comparing early administration of adrenaline versus standard care achieved separation between the study arms in relation to inotrope and fluid bolus use.

Resuscitation With Vitamin C, Hydrocortisone, and Thiamin in Children With Septic Shock: A Multicenter Randomized Pilot Study.

OBJECTIVES: Adjunctive therapy with vitamin C, hydrocortisone, and thiamin has been evaluated in adults, but randomized controlled trial (RCT) data in children are lacking. We aimed to test the feasibility of vitamin C, hydrocortisone, and thiamin in PICU patients with septic shock; and to explore whether the intervention is associated with increased survival free of organ dysfunction. DESIGN: Open-label parallel, pilot RCT multicenter study. The primary endpoint was feasibility. Clinical endpoints included survival free of organ dysfunction censored at 28 days and nine secondary outcomes, shock reversal, and two proxy measures of intervention efficacy. SETTING: Six PICUs in Australia and New Zealand. PATIENTS: Children of age between 28 days and 18 years requiring vasoactive drugs for septic shock between August 2019 and March 2021. INTERVENTIONS: Patients were assigned 1:1 to receive 1 mg/kg hydrocortisone every 6 hours (q6h), 30 mg/kg ascorbic acid q6h, and 4 mg/kg thiamin every 12 hours (n = 27), or standard septic shock management (n = 33). MEASUREMENTS AND MAIN RESULTS: Sixty of 77 (78%) eligible patients consented with 91% of approached parents providing consent. The median time from randomization to intervention was 44 (interquartile range [IQR] 29-120) min. Seventy of seventy-seven (28%) patients had received IV steroids before randomization. Median survival alive and free of organ dysfunction was 20.0 (0.0-26.0) days in the intervention and 21.0 (0.0-25.0) days in the standard care group. Median PICU length of stay was 5.3 (2.5-11.3) days in the intervention group versus 6.9 (3.0-11.5) days in the control group. Shock reversal occurred at a median of 35.2 (14.6-101.2) hours in the intervention group versus 47.3 (22.4-106.8) hours in the standard care group (median difference -12 hr; 95% CI, -56.8 to 32.7 hr). CONCLUSIONS: In children requiring vasopressors for septic shock, a protocol comparing adjunctive treatment with high-dose vitamin C, hydrocortisone, and thiamin versus standard care was feasible. These findings assist in making modifications to the trial protocol to enable a better-designed larger RCT.

Long-term outcomes after paediatric sepsis (LOTUS)-A protocol for an Australian cohort study.

BACKGROUND: Globally, sepsis has been identified as one of the leading causes of preventable childhood mortality and morbidity. Previous studies on intensive care patients estimated that approximately 30% of children with sepsis experience some form of disability at discharge. Development of care has seen growing numbers of children treated for sepsis not requiring a PICU admission; however, outcomes in this population are yet to be understood. Further focus is required to understand sepsis survivorship across the wider population to address knowledge gaps and morbidity burden in the broader surviving population. AIMS: To assess the cognitive, physical, emotional and social health of children surviving sepsis 2 years after hospital discharge. STUDY DESIGN: A prospective, observational cohort study. RESULTS: Two hundred and thirty-two children will be screened, 2 years after their hospital admission, and approached for participation in this study. Children who are <18 years of age at follow-up, treated for sepsis-related organ dysfunction or septic shock in Queensland between October 2018 and December 2019, will be included. Children who are deceased at follow-up, under care of the state, or require English interpreters will be excluded from participation. Data will be collected through an online follow-up survey comprising validated caregiver-reported questionnaires covering the four Post Intensive Care Syndrome-paediatrics (PICS-p) domains (cognitive, physical, emotional and social health; Manning et al. Pediatr Crit Care Med, 2018, 19, 298-300). The primary outcome is an adaptive behaviour of the participants assessed using the Vinelands-3 tool. Secondary outcomes will include neurodevelopment, quality of life, child distress, overall function, executive function, caregiver's distress and caregiver's stress. Analysis of variance (ANOVA), Kruskal-Wallis and Fisher's exact test/chi-squared tests will be used for statistical analyses. No adjustments will be made for multiple comparisons but it is acknowledged that comparisons made in this study are exploratory. RELEVANCE TO CLINICAL PRACTICE: With more children surviving sepsis, there is a need for a more comprehensive assessment of patient and family outcomes to allow support structures for families leaving the hospital after sepsis. This study is expected to inform clinicians and stakeholders of patient and family well-being after sepsis survivorship.

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.

Neurodevelopmental outcome and quality of life in children admitted to the paediatric intensive care unit: A single-centre Australian cohort study.

BACKGROUND: The development of new morbidities has become increasingly identified in paediatric critical care medicine. To date, there has been limited research of long-term outcomes following paediatric critical illness in Australia. OBJECTIVES: The objective of this study was to quantify neurodevelopmental impairments in children following paediatric intensive care unit (PICU) discharge and their association with health-related quality of life (HRQoL). METHODS: A single-centre ambidirectional cohort study at an Australian hospital. Parents of children admitted to the PICU between 2015 and 2017 were invited to participate. Neurodevelopmental outcome and HRQoL was prospectively evaluated, using the Ages and Stages Questionnaire (<5 years), Strengths and Difficulties Questionnaire (≥5 years), and Pediatric Quality of Life Inventory™, respectively. RESULTS: A total of 230 parents of critically ill children participated. Children were 1.9 years old (median, interquartile range [IQR]: 0.2, 7.5), male (59.6%), and ventilated (49.1%) at PICU admission. The median time to follow-up was 24.4 months (IQR: 16.3, 36.7). Parent respondents were more likely to be female (85.5%), White (88.3%), and partnered (81.1%). The incidence of overall neurodevelopmental impairment was 30% (33% in children aged <5 years; 24% in children aged ≥5 years). The incidence of poor HRQoL was 37.9%. History of developmental delay was independently associated with overall neurodevelopmental impairment (adjusted odds ratio [aOR]: 4.21, 95% confidence interval: 2.05, 8.63) and poor HRQoL (aOR: 7.29, 95% confidence interval: 3.26, 16.27). Two or more PICU admissions (aOR: 4.10, IQR: 1.82, 9.26) was also associated with poor HRQoL. CONCLUSIONS: This is the first contemporary view of PICU long-term outcomes conducted in Australia and significantly informs ongoing research in this area. Approximately one-third of PICU survivors demonstrate neurodevelopmental impairment and reduced quality of life. Multiple domains of post-intensive care syndrome-paediatrics must be considered to have a comprehensive understanding of child outcomes. Assessment of baseline/premorbid functioning is also essential in order to understand the true impact of illness and PICU admission.

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.

Effect of Early High-Flow Nasal Oxygen vs Standard Oxygen Therapy on Length of Hospital Stay in Hospitalized Children With Acute Hypoxemic Respiratory Failure: The PARIS-2 Randomized Clinical Trial.

Importance: Nasal high-flow oxygen therapy in infants with bronchiolitis and hypoxia has been shown to reduce the requirement to escalate care. The efficacy of high-flow oxygen therapy in children aged 1 to 4 years with acute hypoxemic respiratory failure without bronchiolitis is unknown. Objective: To determine the effect of early high-flow oxygen therapy vs standard oxygen therapy in children with acute hypoxemic respiratory failure. Design, Setting, and Participants: A multicenter, randomized clinical trial was conducted at 14 metropolitan and tertiary hospitals in Australia and New Zealand, including 1567 children aged 1 to 4 years (randomized between December 18, 2017, and March 18, 2020) requiring hospital admission for acute hypoxemic respiratory failure. The last participant follow-up was completed on March 22, 2020. Interventions: Enrolled children were randomly allocated 1:1 to high-flow oxygen therapy (n = 753) or standard oxygen therapy (n = 764). The type of oxygen therapy could not be masked, but the investigators remained blinded until the outcome data were locked. Main Outcomes and Measures: The primary outcome was length of hospital stay with the hypothesis that high-flow oxygen therapy reduces length of stay. There were 9 secondary outcomes, including length of oxygen therapy and admission to the intensive care unit. Children were analyzed according to their randomization group. Results: Of the 1567 children who were randomized, 1517 (97%) were included in the primary analysis (median age, 1.9 years [IQR, 1.4-3.0 years]; 732 [46.7%] were female) and all children completed the trial. The length of hospital stay was significantly longer in the high-flow oxygen group with a median of 1.77 days (IQR, 1.03-2.80 days) vs 1.50 days (IQR, 0.85-2.44 days) in the standard oxygen group (adjusted hazard ratio, 0.83 [95% CI, 0.75-0.92]; P < .001). Of the 9 prespecified secondary outcomes, 4 showed no significant difference. The median length of oxygen therapy was 1.07 days (IQR, 0.50-2.06 days) in the high-flow oxygen group vs 0.75 days (IQR, 0.35-1.61 days) in the standard oxygen therapy group (adjusted hazard ratio, 0.78 [95% CI, 0.70-0.86]). In the high-flow oxygen group, there were 94 admissions (12.5%) to the intensive care unit compared with 53 admissions (6.9%) in the standard oxygen group (adjusted odds ratio, 1.93 [95% CI, 1.35-2.75]). There was only 1 death and it occurred in the high-flow oxygen group. Conclusions and Relevance: Nasal high-flow oxygen used as the initial primary therapy in children aged 1 to 4 years with acute hypoxemic respiratory failure did not significantly reduce the length of hospital stay compared with standard oxygen therapy. Trial Registration: anzctr.org.au Identifier: ACTRN12618000210279.

Research monitoring practices in critical care research: a survey of current state and attitudes.

BACKGROUND/AIMS: In 2016, international standards governing clinical research recommended that the approach to monitoring a research project should be undertaken based on risk, however it is unknown whether this approach has been adopted in Australia and New Zealand (ANZ) throughout critical care research. The aims of the project were to: 1) Gain an understanding of current research monitoring practices in academic-led clinical trials in the field of critical care research, 2) Describe the perceived barriers and enablers to undertaking research monitoring. METHODS: Electronic survey distributed to investigators, research co-ordinators and other research staff currently undertaking and supporting academic-led clinical trials in the field of critical care in ANZ. RESULTS: Of the 118 respondents, 70 were involved in the co-ordination of academic trials; the remaining results pertain to this sub-sample. Fifty-eight (83%) were working in research units associated with hospitals, 29 (41%) were experienced Research Coordinators and 19 (27%) Principal Investigators; 31 (44%) were primarily associated with paediatric research. Fifty-six (80%) develop monitoring plans with 33 (59%) of these undertaking a risk assessment; the most common barrier reported was lack of expertise. Nineteen (27%) indicated that centralised monitoring was used, noting that technology to support centralised monitoring (45/51; 88%) along with support from data managers and statisticians (45/52; 87%) were key enablers. Coronavirus disease-19 (COVID-19) impacted monitoring for 82% (45/55) by increasing remote (25/45; 56%) and reducing onsite (29/45; 64%) monitoring. CONCLUSIONS: Contrary to Good Clinical Practice guidance, risk assessments to inform monitoring plans are not being consistently performed due to lack of experience and guidance. There is an urgent need to enhance risk assessment methodologies and develop technological solutions for centralised statistical monitoring.

Early short course of neuromuscular blocking agents in patients with COVID-19 ARDS: a propensity score analysis.

BACKGROUND: The role of neuromuscular blocking agents (NMBAs) in coronavirus disease 2019 (COVID-19) acute respiratory distress syndrome (ARDS) is not fully elucidated. Therefore, we aimed to investigate in COVID-19 patients with moderate-to-severe ARDS the impact of early use of NMBAs on 90-day mortality, through propensity score (PS) matching analysis. METHODS: We analyzed a convenience sample of patients with COVID-19 and moderate-to-severe ARDS, admitted to 244 intensive care units within the COVID-19 Critical Care Consortium, from February 1, 2020, through October 31, 2021. Patients undergoing at least 2 days and up to 3 consecutive days of NMBAs (NMBA treatment), within 48 h from commencement of IMV were compared with subjects who did not receive NMBAs or only upon commencement of IMV (control). The primary objective in the PS-matched cohort was comparison between groups in 90-day in-hospital mortality, assessed through Cox proportional hazard modeling. Secondary objectives were comparisons in the numbers of ventilator-free days (VFD) between day 1 and day 28 and between day 1 and 90 through competing risk regression. RESULTS: Data from 1953 patients were included. After propensity score matching, 210 cases from each group were well matched. In the PS-matched cohort, mean (± SD) age was 60.3 ± 13.2 years and 296 (70.5%) were male and the most common comorbidities were hypertension (56.9%), obesity (41.1%), and diabetes (30.0%). The unadjusted hazard ratio (HR) for death at 90 days in the NMBA treatment vs control group was 1.12 (95% CI 0.79, 1.59, p = 0.534). After adjustment for smoking habit and critical therapeutic covariates, the HR was 1.07 (95% CI 0.72, 1.61, p = 0.729). At 28 days, VFD were 16 (IQR 0-25) and 25 (IQR 7-26) in the NMBA treatment and control groups, respectively (sub-hazard ratio 0.82, 95% CI 0.67, 1.00, p = 0.055). At 90 days, VFD were 77 (IQR 0-87) and 87 (IQR 0-88) (sub-hazard ratio 0.86 (95% CI 0.69, 1.07; p = 0.177). CONCLUSIONS: In patients with COVID-19 and moderate-to-severe ARDS, short course of NMBA treatment, applied early, did not significantly improve 90-day mortality and VFD. In the absence of definitive data from clinical trials, NMBAs should be indicated cautiously in this setting.

Comparison of two measures of behavior change in children after day surgery.

BACKGROUND: A contemporary, well-validated instrument for the measurement of behavior change in children after general anesthesia is lacking. The Post Hospitalization Behavior Questionnaire for Ambulatory Surgery (PHBQ-AS) has been developed as an updated version of the original Post Hospitalization Behavior Questionnaire (PHBQ) to better reflect the current patient population and modern anesthetic practices. AIMS: To assess the reliability of the PHBQ-AS and determine concurrent validity with another measure of child behavior, the Strength and Difficulties Questionnaire (SDQ). METHODS: We compared the PHBQ-AS with the SDQ in 248 children presenting for day-case surgery. A baseline SDQ measurement was taken prior to surgery, and then, both scales were administered on days 3, 14, and 28 postsurgery. RESULTS: The PHBQ-AS demonstrated good reliability in terms of internal consistency with a Cronbach's alpha of 0.79 and split-half correlation with Spearman Brown adjustment of 0.85. There was weak correlation with the SDQ on day 3 postoperatively (Pearson's r = 0.201), moderate correlation on day 14 (Pearson's r = 0.421), and weak-to-moderate correlation on day 28 (Pearson's r = 0.340). A cut-off score of 3.2 on the PHBQ-AS for the diagnosis of negative behavior demonstrated equivalence with the SDQ results; however, the SDQ results remained relatively constant throughout the study period and reflected the expected rate of increased risk of problem behavior in children. CONCLUSIONS: The PHBQ-AS showed good reliability but only had weak-to-moderate correlation with another measure of child behavior, the SDQ. Further validation is required before the PHBQ-AS is used for the routine measurement of behavior change in children after anesthesia, or alternatively, a new instrument needs to be developed in order for research to advance in this area.

Effect of Nitric Oxide via Cardiopulmonary Bypass on Ventilator-Free Days in Young Children Undergoing Congenital Heart Disease Surgery: The NITRIC Randomized Clinical Trial.

Importance: In children undergoing heart surgery, nitric oxide administered into the gas flow of the cardiopulmonary bypass oxygenator may reduce postoperative low cardiac output syndrome, leading to improved recovery and shorter duration of respiratory support. It remains uncertain whether nitric oxide administered into the cardiopulmonary bypass oxygenator improves ventilator-free days (days alive and free from mechanical ventilation). Objective: To determine the effect of nitric oxide applied into the cardiopulmonary bypass oxygenator vs standard care on ventilator-free days in children undergoing surgery for congenital heart disease. Design, Setting, and Participants: Double-blind, multicenter, randomized clinical trial in 6 pediatric cardiac surgical centers in Australia, New Zealand, and the Netherlands. A total of 1371 children younger than 2 years undergoing congenital heart surgery were randomized between July 2017 and April 2021, with 28-day follow-up of the last participant completed on May 24, 2021. Interventions: Patients were assigned to receive nitric oxide at 20 ppm delivered into the cardiopulmonary bypass oxygenator (n = 679) or standard care cardiopulmonary bypass without nitric oxide (n = 685). Main Outcomes and Measures: The primary end point was the number of ventilator-free days from commencement of bypass until day 28. There were 4 secondary end points including a composite of low cardiac output syndrome, extracorporeal life support, or death; length of stay in the intensive care unit; length of stay in the hospital; and postoperative troponin levels. Results: Among 1371 patients who were randomized (mean [SD] age, 21.2 [23.5] weeks; 587 girls [42.8%]), 1364 (99.5%) completed the trial. The number of ventilator-free days did not differ significantly between the nitric oxide and standard care groups, with a median of 26.6 days (IQR, 24.4 to 27.4) vs 26.4 days (IQR, 24.0 to 27.2), respectively, for an absolute difference of -0.01 days (95% CI, -0.25 to 0.22; P = .92). A total of 22.5% of the nitric oxide group and 20.9% of the standard care group developed low cardiac output syndrome within 48 hours, needed extracorporeal support within 48 hours, or died by day 28, for an adjusted odds ratio of 1.12 (95% CI, 0.85 to 1.47). Other secondary outcomes were not significantly different between the groups. Conclusions and Relevance: In children younger than 2 years undergoing cardiopulmonary bypass surgery for congenital heart disease, the use of nitric oxide via cardiopulmonary bypass did not significantly affect the number of ventilator-free days. These findings do not support the use of nitric oxide delivered into the cardiopulmonary bypass oxygenator during heart surgery. Trial Registration: anzctr.org.au Identifier: ACTRN12617000821392.

Outcomes After Stage I Norwood Palliation in a Recently Established Program Can Achieve Results Similar to Longer Established Services.

BACKGROUND: Infants with hypoplastic left heart syndrome (HLHS) or similar single ventricle cardiac lesions require a three-stage surgical approach, the first step being the Stage I Norwood procedure. The Queensland Children's Hospital (QCH) in Australia is a tertiary hospital providing the only cardiac surgical service to children in Queensland and northern New South Wales. OBJECTIVE: To review the centre's outcomes of Norwood procedures performed in the last 6 years. MATERIALS AND METHODS: We retrospectively evaluated all infants undergoing the stage I Norwood procedure between January 2015 and August 2021. Mortality, intensive care length of stay, events of cardiac arrest following surgery and duration of mechanical ventilation were calculated and analysed for subgroups depending on type of pulmonary shunt type (right-ventricle-to-pulmonary-artery shunt [RVPAS] vs the modified Blalock-Taussig shunt [MBTS]). RESULTS: Forty-nine (49) patients were included. Overall survival to stage two operation (Glenn) was 90%. Both shunts were used evenly with the RVPA conduit preferred for HLHS and the MBTS largely chosen for hypoplastic left heart variants. In univariable analysis there was no difference in cardiac arrest or mortality rate for the patient with a RVPAS compared to the patient with a MBTS. CONCLUSION: We show that a recently established Norwood program can achieve results that are comparable to those reported by longer established centres, and the international literature.

Midazolam exposure in the paediatric intensive care unit predicts acute post-traumatic stress symptoms in children.

BACKGROUND: Clinically significant post-traumatic stress symptoms (PTSS) have been reported in up to a quarter of paediatric intensive care unit (PICU) survivors. Ongoing PTSS negatively impacts children's psychological development and physical recovery. However, few data regarding associations between potentially modifiable PICU treatment factors, such as analgosedatives and invasive procedures, and children's PTSS have been reported. OBJECTIVES: We sought to investigate the medical treatment factors associated with children's PTSS after PICU discharge. METHODS: A prospective longitudinal cohort study was conducted in two Australian tertiary referral PICUs. Children aged 2-16 y admitted to the PICU between June 2008 and January 2011 for >8 h and <28 d were eligible for participation. Biometric and clinical data were obtained from medical records. Parents reported their child's PTSS using the Trauma Symptom Checklist for Young Children at 1, 3, 6, and 12 months after discharge. Logistic regression was used to assess potential associations between medical treatment and PTSS. RESULTS: A total of 265 children and their parents participated in the study. In the 12-month period following PICU discharge, 24% of children exhibited clinically elevated PTSS. Median risk of death (Paediatric Index of Mortality 2 [PIM2]) score was significantly higher in the PTSS group (0.31 [IQR 0.14-1.09] v 0.67 [IQR 0.20-1.18]; p = 0.014). Intubation and PICU and hospital length of stay were also significantly associated with PTSS at 1 month, as were midazolam, propofol, and morphine. After controlling for gender, reason for admission, and PIM2 score, only midazolam was significantly and independently associated with PTSS and only at 1 month (adjusted odds ration (aOR) 3.63, 95% CI 1.18, 11.12, p = 0.024). No significant relationship was observed between the use of medications and PTSS after 1 month. CONCLUSIONS: Elevated PTSS were evident in one quarter (24%) of children during the 12 months after PICU discharge. One month after discharge, elevated PTSS were most likely to occur in children who had received midazolam therapy.

Do variations in insulin sensitivity and insulin secretion in pregnancy predict differences in obstetric and neonatal outcomes?

AIMS/HYPOTHESIS: Gestational diabetes mellitus (GDM) is generally defined based on glycaemia during an OGTT, but aetiologically includes women with defects in insulin secretion, insulin sensitivity or a combination of both. In this observational study, we aimed to determine if underlying pathophysiological defects evaluated as continuous variables predict the risk of important obstetric and neonatal outcomes better than the previously used dichotomised or categorical approaches. METHODS: Using data from blinded OGTTs at mean gestational week 28 from five Hyperglycemia and Adverse Pregnancy Outcome study centres, we estimated insulin secretion (Stumvoll first phase) and sensitivity (Matsuda index) and their product (oral disposition index [DI]) in 6337 untreated women (1090 [17.2%] with GDM as defined by the International Association of Diabetes and Pregnancy Study Groups). Rather than dichotomising these variables (i.e. GDM yes/no) or subtyping by insulin impairment, we related insulin secretion and sensitivity as continuous variables, along with other maternal characteristics, to obstetric and neonatal outcomes using multiple regression and receiver operating characteristic curve analysis. RESULTS: Stratifying by GDM subtype offered superior prediction to GDM yes/no only for neonatal hyperinsulinaemia and pregnancy-related hypertension. Including the DI and the Matsuda score significantly increased the area under the receiver operating characteristic curve (AUROC) and improved prediction for multiple outcomes (large for gestational age [AUROC 0.632], neonatal adiposity [AUROC 0.630], pregnancy-related hypertension [AUROC 0.669] and neonatal hyperinsulinaemia [AUROC 0.688]). Neonatal hypoglycaemia was poorly predicted by all models. Combining the DI and the Matsuda score with maternal characteristics substantially improved the predictive power of the model for large for gestational age, neonatal adiposity and pregnancy-related hypertension. CONCLUSION/INTERPRETATION: Continuous measurement of insulin secretion and insulin sensitivity combined with basic clinical variables appeared to be superior to GDM (yes/no) or subtyping by insulin secretion and/or sensitivity impairment in predicting obstetric and neonatal outcomes in a multi-ethnic cohort. Graphical abstract.

High flow in children with respiratory failure: A randomised controlled pilot trial - A paediatric acute respiratory intervention study.

AIMS: High-flow is increasingly used in children with acute hypoxaemic respiratory failure (AHRF), despite limited evidence. The primary feasibility endpoint for this pilot-study was the proportion of treatment failure, secondary outcomes being intensive care unit (ICU) admissions and proportion of patients requiring escalation of care. We measured duration of hospital stay, duration of oxygen therapy and rates of ICU admission. METHODS: An open-labelled randomised controlled trial feasibility design was used in two tertiary children's hospitals in the emergency department and general wards. Children aged 0-16 years with AHRF were randomised (1:1) to either high-flow or standard-oxygen. Children on standard-oxygen received rescue high-flow in general wards if failure criteria were met. RESULTS: Of 563 randomised, 283 received high-flow and 280 standard-oxygen with no adverse events. The proportion of children who failed treatment and receiving escalation of care was 11.7% (32/283 children) on high-flow and 18.1% (50/280 infants) on standard-oxygen (odds ratio 0.68, 95% confidence interval 0.38-1.00). In children with obstructive airway disease, 9.7% on high-flow and 17.4% on standard-oxygen required escalation (risk-difference -7.7% percentage points; 95% confidence interval -14.3, -1.1); in children with non-obstructive disease no difference was observed. Neither difference in ICU admissions nor any difference in length of hospital stay was observed. Sixty percent of children who failed standard-oxygen responded to rescue high-flow. CONCLUSION: High-flow outside ICU appears to be feasible in children with AHRF and the required proportion of escalation was lower compared to standard-oxygen. The trial design can be applied in a future large randomised controlled trial.

Prediction of Acute Kidney Injury on Admission to Pediatric Intensive Care.

OBJECTIVES: Up to 37% of children admitted to the PICU develop acute kidney injury as defined by Kidney Disease: Improving Global Outcomes criteria. We describe the prevalence of acute kidney injury in a mixed pediatric intensive care cohort using this criteria. As tools to stratify patients at risk of acute kidney injury on PICU admission are lacking, we explored the variables at admission and day 1 that might predict the development of acute kidney injury. DESIGN: Single-center retrospective observational study. SETTING: Thirty-six-bed surgical/medical tertiary PICU. PATIENTS: Children from birth to less than or equal to 16 years old admitted between 2015 and 2018. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Clinical data were extracted from the PICU clinical information system. Patients with baseline creatinine at admission greater than 20 micromol/L above the calculated normal creatinine level were classified as "high risk of acute kidney injury." Models were created to predict acute kidney injury at admission and on day 1. Out of the 7,505 children admitted during the study period, 738 patients (9.8%) were classified as high risk of acute kidney injury at admission and 690 (9.2%) developed acute kidney injury during PICU admission. Compared to Kidney Disease: Improving Global Outcomes criteria as the reference standard, high risk of acute kidney injury had a lower sensitivity and higher specificity compared with renal angina index greater than or equal to 8 on day 1. For the admission model, the adjusted odds ratio of developing acute kidney injury for high risk of acute kidney injury was 4.2 (95% CI, 3.3-5.2). The adjusted odds ratio in the noncardiac cohort for high risk of acute kidney injury was 7.3 (95% CI, 5.5-9.7). For the day 1 model, odds ratios for high risk of acute kidney injury and renal angina index greater than or equal to 8 were 3.3 (95% CI, 2.6-4.2) and 3.1 (95% CI, 2.4-3.8), respectively. CONCLUSIONS: The relationship between high risk of acute kidney injury and acute kidney injury needs further evaluation. High risk of acute kidney injury performed better in the noncardiac cohort.

Antithrombin Dosing Guidelines in Children Underestimate Dose Needed for Plasma Level Increase.

OBJECTIVES: Antithrombin is a cofactor in the coagulation cascade with mild anticoagulant activity and facilitates the action of heparin as an anticoagulant. Antithrombin concentrate dosing guidelines vary but most commonly suggest that each unit of antithrombin concentrate per body weight increases the plasma antithrombin level by 1.5% to 2.2% (depending on manufacturer). We aimed to establish a dosing recommendation dependent on age and disease state. DESIGN: A retrospective analysis of all antithrombin concentrate doses over a period of 5 years. We calculated the increase any respective antithrombin concentrate dose achieved, indexed by body weight, and performed a multivariable analysis to establish independent factors associated with the effectiveness of antithrombin concentrate. SETTING: A PICU at a university-affiliated children's hospital. PATIENTS: One hundred fifty-five patients treated in a PICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The effect of 562 doses of antithrombin concentrate on plasma antithrombin levels administered to 155 patients, of which 414 (73.7%) antithrombin concentrate doses administered during extracorporeal life support treatment, were analyzed. For all patients, each unit of antithrombin concentrate/kg increased plasma antithrombin level by 0.86% (SD 0.47%). Plasma antithrombin level increase was influenced by body weight (increase of 0.76% [interquartile range, 0.6-0.92%] for patients < 5 kg; 1.38% [interquartile range, 1.11-2.10%] for > 20 kg), disease state (liver failure having the poorest antithrombin increase) and whether patients were treated with extracorporeal circulatory support (less antithrombin increase on extracorporeal life support). Heparin dose at the time of administration did not influence with amount of change in antithrombin level. CONCLUSIONS: Current antithrombin concentrate dosing guidelines overestimate the effect on plasma antithrombin level in critically ill children. Current recommendations result in under-dosing of antithrombin concentrate administration. Age, disease state, and extracorporeal life support should be taken into consideration when administering antithrombin concentrate.

Testing for Common Respiratory Viruses in Children Admitted to Pediatric Intensive Care: Epidemiology and Outcomes.

OBJECTIVES: Viral infections are common in children, but there is a lack of data on severe viral infections in critically ill children. We investigated testing for viral infections in children requiring PICU admission and describe the epidemiology and outcomes. DESIGN: Multicenter retrospective study. Results of viral testing for nine respiratory viruses using polymerase chain reaction were collected. PARTICIPANTS: Children less than 16 years old nonelectively admitted to PICU over a 6-year period. SETTING: Two tertiary PICUs in Queensland, Australia. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Primary outcome was PICU length of stay. Secondary outcomes included need for and duration of intubation and mortality in PICU. Univariate and multivariate regression analyses were performed, adjusting for age, indigenous status, comorbidities, and severity of illness. RESULTS: Of 6,426 nonelective admissions, 2,956 (46%) were polymerase chain reaction tested for a virus of which 1,353 (46%) were virus positive. Respiratory syncytial virus was the most common pathogen identified (n = 518, 33%), followed by rhinovirus/enterovirus and adenovirus. Across all patients who underwent polymerase chain reaction testing, identification of a respiratory virus was not significantly associated with longer overall length of stay (multivariate odds ratio, 1.08; 95% CI, 0.99-1.17; p = 0.068) or longer intubation (p = 0.181), whereas the adjusted odds for intubation and mortality were significantly lower (p < 0.01). Subgroup analyses restricted to patients with acute respiratory infections (n = 1,241), bronchiolitis (n = 761), pneumonia (n = 311), confirmed bacterial infection (n = 345), and malignancy (n = 95) showed that patients positive for a virus on testing had significantly longer PICU length of stay (multivariate p < 0.05). In children with pneumonia, identification of a respiratory virus was associated with significantly increased duration of ventilation (p = 0.003). No association between positive test results for multiple viruses and outcomes was observed. CONCLUSION: Viral infections are common in critically ill children. Viral infections were associated with lower intubation and mortality rates compared with all children testing negative for viral infections. In several subgroups studied, identification of viral pathogens was associated with longer PICU length of stay while mortality was comparable. Prospective studies are required to determine the benefit of routine testing for respiratory viruses at the time of PICU admission.