Pragmatic Randomized Trial of Corticosteroids and Inhaled Epinephrine for Bronchiolitis in Children in Intensive Care.

OBJECTIVE: To determine whether the combination of systemic corticosteroids and nebulized epinephrine, compared with standard care, reduces the duration of positive pressure support in children with bronchiolitis admitted to intensive care. STUDY DESIGN: We performed a pragmatic, multicenter, open-label, randomized trial between July 2013 and November 2019 in children younger than 18 months old with a clinical diagnosis of bronchiolitis. The intervention group received the equivalent of 13 mg/kg prednisolone over 3 days, then 1 mg/kg daily for 3 days, plus 0.05 mL/kg of nebulized 1% epinephrine made up to 6 ml with 0.9% saline via jet nebulizer and mask using oxygen at 12 l/min every 30 minutes for 5 doses, then 1-4 hourly for 3 days, then as required for 3 days. The primary outcome was clinician-managed duration of positive pressure support in intensive care defined as high-flow nasal-prong oxygen, nasopharyngeal continuous positive airway pressure, or mechanical ventilation. RESULTS: In total, 210 children received positive pressure support. In the corticosteroid-epinephrine group, 107 children received positive pressure support for a geometric mean of 26 (95% CI, 22-32) hours compared with 40 (95% CI 34-47) hours in 103 controls, adjusted ratio 0.66 (95% CI 0.51-0.84), P = .001. In the intervention group, 41 (38%) children experienced at least 1 adverse event, compared with 39 (38%) in the control group. CONCLUSIONS: In children with severe bronchiolitis, the duration of clinician-managed pressure support was reduced by regular treatment with systemic corticosteroids and inhaled epinephrine compared with standard care. CLINICAL TRIAL REGISTRATION: Australian Clinical Trials Research Network: ACTRN12613000316707.

Association Between Centralization and Outcome for Children Admitted to Intensive Care in Australia and New Zealand: A Population-Based Cohort Study.

OBJECTIVES: To describe regional differences and change over time in the degree of centralization of pediatric intensive care in Australia and New Zealand (ANZ) and to compare the characteristics and ICU mortality of children admitted to specialist PICUs and general ICUs (GICUs). DESIGN: A retrospective cohort study using registry data for two epochs of ICU admissions, 2003-2005 and 2016-2018. SETTING: Population-based study in ANZ. PATIENTS: A total of 43,256 admissions of children aged younger than 16 years admitted to an ICU in ANZ were included. Infants aged younger than 28 days without cardiac conditions were excluded. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome was risk-adjusted ICU mortality. Logistic regression was used to investigate the association of mortality with the exposure to ICU type, epoch, and their interaction. Compared with children admitted to GICUs, children admitted to PICUs were younger (median 25 vs 47 mo; p < 0.01) and stayed longer in ICU (median 1.6 vs 1.0 d; p < 0.01). For the study overall, 93% of admissions in Australia were to PICUs whereas in New Zealand only 63% of admissions were to PICUs. The adjusted odds of death in epoch 2 relative to epoch 1 decreased (adjusted odds ratio [AOR], 0.50; 95% CI, 0.42-0.59). There was an interaction between unit type and epoch with increased odds of death associated with care in a GICU in epoch 2 (AOR, 1.63; 95% CI, 1.05-2.53 for all admissions; 1.73, CI, 1.002-3.00 for high-risk admissions). CONCLUSIONS: Risk-adjusted mortality of children admitted to specialist PICUs decreased over a study period of 14 years; however, a similar association between time and outcome was not observed in high-risk children admitted to GICUs. The results support the continued use of a centralized model of delivering intensive care for critically ill children.

Characterisation of neurodevelopmental and psychological outcomes in CHD: a research agenda and recommendations from the cardiac neurodevelopmental outcome collaborative.

The Neurodevelopmental and Psychological Outcomes Working Group of the Cardiac Neurodevelopmental Outcome Collaborative was formed in 2018 through support from an R13 grant from the National Heart, Lung, and Blood Institute with the goals of identifying knowledge gaps regarding the neurodevelopmental and psychological outcomes of individuals with CHD and investigations needed to advance science, policy, clinical care, and patient/family outcomes. Accurate characterisation of neurodevelopmental and psychological outcomes in children with CHD will drive improvements in patient and family outcomes through targeted intervention. Decades of research have produced a generalised perspective about neurodevelopmental and psychological outcomes in this heterogeneous population. Future investigations need to shift towards improving methods, measurement, and analyses of outcomes to better inform early identification, prevention, and intervention. Improved definition of underlying developmental, neuropsychological, and social-emotional constructs is needed, with an emphasis on symptom networks and dimensions. Identification of clinically meaningful outcomes that are most important to key stakeholders, including patients, families, schools and providers, is essential, specifically how and which neurodevelopmental differences across the developmental trajectory impact stakeholders. A better understanding of the discontinuity and patterns of neurodevelopment across the lifespan is critical as well, with some areas being more impactful at some ages than others. Finally, the field needs to account for the impact of race/ethnicity, socio-economic status, cultural and linguistic diversity on our measurement, interpretation of data, and approach to intervention and how to improve generalisability to the larger worldwide population of patients and families living with CHD.

Venoarterial Extracorporeal Membrane Oxygenation Versus Conventional Therapy in Severe Pediatric Septic Shock.

OBJECTIVES: The role of venoarterial extracorporeal membrane oxygenation in the treatment of severe pediatric septic shock continues to be intensely debated. Our objective was to determine whether the use of venoarterial extracorporeal membrane oxygenation in severe septic shock was associated with altered patient mortality, morbidity, and/or length of ICU and hospital stay when compared with conventional therapy. DESIGN: International multicenter, retrospective cohort study using prospectively collected data of children admitted to intensive care with a diagnosis of severe septic shock between the years 2006 and 2014. SETTING: Tertiary PICUs in Australia, New Zealand, Netherlands, United Kingdom, and United States. PATIENTS: Children greater than 30 days old and less than 18 years old. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 2,452 children with a diagnosis of sepsis or septic shock, 164 patients met the inclusion criteria for severe septic shock. With conventional therapy (n = 120), survival to hospital discharge was 40%. With venoarterial extracorporeal membrane oxygenation (n = 44), survival was 50% (p = 0.25; CI, -0.3 to 0.1). In children who suffered an in-hospital cardiac arrest, survival to hospital discharge was 18% with conventional therapy and 42% with venoarterial extracorporeal membrane oxygenation (Δ = 24%; p = 0.02; CI, 2.5-42%). Survival was significantly higher in patients who received high extracorporeal membrane oxygenation flows of greater than 150 mL/kg/min compared with children who received standard extracorporeal membrane oxygenation flows or no extracorporeal membrane oxygenation (82%, 43%, and 48%; p = 0.03; CI, 0.1-0.7 and p < 0.01; CI, 0.2-0.7, respectively). Lengths of ICU and hospital stay were significantly longer for children who had venoarterial extracorporeal membrane oxygenation. CONCLUSIONS: The use of venoarterial extracorporeal membrane oxygenation in severe pediatric sepsis is not by itself associated with improved survival. However, venoarterial extracorporeal membrane oxygenation significantly reduces mortality after cardiac arrest due to septic shock. Venoarterial extracorporeal membrane oxygenation flows greater than 150 mL/kg/min are associated with almost twice the survival rate of conventional therapy or standard-flow extracorporeal membrane oxygenation.

Burden of disease and change in practice in critically ill infants with bronchiolitis.

Bronchiolitis represents the most common cause of non-elective admission to paediatric intensive care units (ICUs).We assessed changes in admission rate, respiratory support, and outcomes of infants <24 months with bronchiolitis admitted to ICU between 2002 and 2014 in Australia and New Zealand.During the study period, bronchiolitis was responsible for 9628 (27.6%) of 34 829 non-elective ICU admissions. The estimated population-based ICU admission rate due to bronchiolitis increased by 11.76 per 100 000 each year (95% CI 8.11-15.41). The proportion of bronchiolitis patients requiring intubation decreased from 36.8% in 2002, to 10.8% in 2014 (adjusted OR 0.35, 95% CI 0.27-0.46), whilst a dramatic increase in high-flow nasal cannula therapy use to 72.6% was observed (p<0.001). We observed considerable variability in practice between units, with six-fold differences in risk-adjusted intubation rates that were not explained by ICU type, size, or major patient factors. Annual direct hospitalisation costs due to severe bronchiolitis increased to over USD30 million in 2014.We observed an increasing healthcare burden due to severe bronchiolitis, with a major change in practice in the management from invasive to non-invasive support that suggests thresholds to admittance of bronchiolitis patients to ICU have changed. Future studies should assess strategies for management of bronchiolitis outside ICUs.

Delirium in Critically Ill Children: An International Point Prevalence Study.

OBJECTIVES: To determine prevalence of delirium in critically ill children and explore associated risk factors. DESIGN: Multi-institutional point prevalence study. SETTING: Twenty-five pediatric critical care units in the United States, the Netherlands, New Zealand, Australia, and Saudi Arabia. PATIENTS: All children admitted to the pediatric critical care units on designated study days (n = 994). INTERVENTION: Children were screened for delirium using the Cornell Assessment of Pediatric Delirium by the bedside nurse. Demographic and treatment-related variables were collected. MEASUREMENTS AND MAIN RESULTS: Primary study outcome measure was prevalence of delirium. In 159 children, a final determination of mental status could not be ascertained. Of the 835 remaining subjects, 25% screened positive for delirium, 13% were classified as comatose, and 62% were delirium-free and coma-free. Delirium prevalence rates varied significantly with reason for ICU admission, with highest delirium rates found in children admitted with an infectious or inflammatory disorder. For children who were in the PICU for 6 or more days, delirium prevalence rate was 38%. In a multivariate model, risk factors independently associated with development of delirium included age less than 2 years, mechanical ventilation, benzodiazepines, narcotics, use of physical restraints, and exposure to vasopressors and antiepileptics. CONCLUSIONS: Delirium is a prevalent complication of critical illness in children, with identifiable risk factors. Further multi-institutional, longitudinal studies are required to investigate effect of delirium on long-term outcomes and possible preventive and treatment measures. Universal delirium screening is practical and can be implemented in pediatric critical care units.

Identifying Children at Risk of Malignant Bordetella pertussis Infection.

OBJECTIVE: To identify factors associated with malignant pertussis. DESIGN: A retrospective case notes review from January 2003 to August 2013. Area under the receiver-operator characteristic curve was used to determine how well vital sign and white cell characteristics within 48 hours of hospital presentation identified children with malignant pertussis. SETTING: The national children's hospital in Auckland, New Zealand. PATIENTS: One hundred fifty-two children with pertussis. MEASUREMENTS AND MAIN RESULTS: There were 152 children with confirmed pertussis identified, including 11 children with malignant pertussis. The area under the receiver-operator characteristic curve was 0.88 (95% CI, 0.78-0.97) for maximum heart rate. The optimal cut-point was 180 beats/min, which predicted malignant pertussis with a sensitivity of 73% and a specificity of 91%. The area under the receiver-operator characteristic curve was 0.92 (95% CI, 0.81-1.0) for absolute neutrophil count, 0.85 (95% CI, 0.71-0.99) for total WBC count, 0.80 (95% CI, 0.63-0.96) for neutrophil-to-lymphocyte ratio, and 0.77 (95% CI, 0.58-0.92) for absolute lymphocyte count. All children with malignant pertussis had one or more of heart rate greater than 180 beats/min, total WBC count greater than 25 × 10/L, and neutrophil-to-lymphocyte ratio greater than 1.0 with an area under the receiver-operator characteristic curve of 0.96 (95% CI, 0.91-1.0) for a multivariate model that included these three variables. CONCLUSIONS: Clinical predictors of malignant pertussis are identifiable within 48 hours of hospital presentation. Early recognition of children at risk of malignant pertussis may facilitate early referral to a PICU for advanced life support and selection for trials of investigational therapies.

International Survey of Critically Ill Children With Acute Neurologic Insults: The Prevalence of Acute Critical Neurological Disease in Children: A Global Epidemiological Assessment Study.

OBJECTIVE: The international scope of critical neurologic insults in children is unknown. Our objective was to assess the prevalence and outcomes of children admitted to PICUs with acute neurologic insults. DESIGN: Prospective study. SETTING: Multicenter (n = 107 PICUs) and multinational (23 countries, 79% in North America and Europe). PATIENTS: Children 7 days to 17 years old admitted to the ICU with new traumatic brain injury, stroke, cardiac arrest, CNS infection or inflammation, status epilepticus, spinal cord injury, hydrocephalus, or brain mass. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We evaluated the prevalence and outcomes of children with predetermined acute neurologic insults. Child and center characteristics were recorded. Unfavorable outcome was defined as change in pre-post insult Pediatric Cerebral Performance Category score greater than or equal to 2 or death at hospital discharge or 3 months, whichever came first. Screening data yielded overall prevalence of 16.2%. Of 924 children with acute neurologic insults, cardiac arrest (23%) and traumatic brain injury (19%) were the most common. All-cause mortality at hospital discharge was 12%. Cardiac arrest subjects had highest mortality (24%), and traumatic brain injury subjects had the most unfavorable outcomes (49%). The most common neurologic insult was infection/inflammation in South America, Asia, and the single African site but cardiac arrest in the remaining regions. CONCLUSIONS: Neurologic insults are a significant pediatric international health issue. They are frequent and contribute substantial morbidity and mortality. These data suggest a need for an increased focus on acute critical neurologic diseases in infants and children including additional research, enhanced availability of clinical resources, and the development of new therapies.

Global perspective on training and staffing for paediatric cardiac critical care.

This manuscript provides a global perspective on physician and nursing education and training in paediatric cardiac critical care, including available resources and delivery of care models with representatives from several regions of the world including Africa, Israel, Asia, Australasia, Europe, South America, and the United States of America.

Hypothermia for Traumatic Brain Injury in Children-A Phase II Randomized Controlled Trial.

OBJECTIVES: To perform a pilot study to assess the feasibility of performing a phase III trial of therapeutic hypothermia started early and continued for at least 72 hours in children with severe traumatic brain injury. DESIGN: Multicenter prospective randomized controlled phase II trial. SETTING: All eight of the PICUs in Australia and New Zealand and one in Canada. PATIENTS: Children 1-15 years old with severe traumatic brain injury and who could be randomized within 6 hours of injury. INTERVENTIONS: The control group had strict normothermia to a temperature of 36-37°C for 72 hours. The intervention group had therapeutic hypothermia to a temperature of 32-33°C for 72 hours followed by slow rewarming at a rate compatible with maintaining intracranial pressure and cerebral perfusion pressure. MEASUREMENTS AND MAIN RESULTS: Of 764 children admitted to PICU with traumatic brain injury, 92 (12%) were eligible and 55 (7.2%) were recruited. There were five major protocol violations (9%): three related to recruitment and consent processes and two to incorrect temperature management. Rewarming took a median of 21.5 hours (16-35 hr) and was performed without compromise in the cerebral perfusion pressure. There was no increase in any complications, including infections, bleeding, and arrhythmias. There was no difference in outcomes 12 months after injury; in the therapeutic hypothermia group, four (17%) had a bad outcome (pediatric cerebral performance category, 4-6) and three (13%) died, whereas in the normothermia group, three (12%) had a bad outcome and one (4%) died. CONCLUSIONS: Early therapeutic hypothermia in children with severe traumatic brain injury does not improve outcome and should not be used outside a clinical trial. Recruitment rates were lower and outcomes were better than expected. Conventional randomized controlled trials in children with severe traumatic brain injury are unlikely to be feasible. A large international trials group and alternative approaches to trial design will be required to further inform practice.

New white matter brain injury after infant heart surgery is associated with diagnostic group and the use of circulatory arrest.

BACKGROUND: Abnormalities on magnetic resonance imaging scans are common both before and after surgery for congenital heart disease in early infancy. The aim of this study was to prospectively investigate the nature, timing, and consequences of brain injury on magnetic resonance imaging in a cohort of young infants undergoing surgery for congenital heart disease both with and without cardiopulmonary bypass. METHODS AND RESULTS: A total of 153 infants undergoing surgery for congenital heart disease at <8 weeks of age underwent serial magnetic resonance imaging scans before and after surgery and at 3 months of age, as well as neurodevelopmental assessment at 2 years of age. White matter injury (WMI) was the commonest type of injury both before and after surgery. It occurred in 20% of infants before surgery and was associated with a less mature brain. New WMI after surgery was present in 44% of infants and at similar rates after surgery with or without cardiopulmonary bypass. The most important association was diagnostic group (P<0.001). In infants having arch reconstruction, the use and duration of circulatory arrest were significantly associated with new WMI. New WMI was also associated with the duration of cardiopulmonary bypass, postoperative lactate level, brain maturity, and WMI before surgery. Brain immaturity but not brain injury was associated with impaired neurodevelopment at 2 years of age. CONCLUSIONS: New WMI is common after surgery for congenital heart disease and occurs at the same rate in infants undergoing surgery with and without cardiopulmonary bypass. New WMI is associated with diagnostic group and, in infants undergoing arch surgery, the use of circulatory arrest.

Cortical folding is altered before surgery in infants with congenital heart disease.

Infants with congenital heart disease have altered brain development. We characterized cortical folding, a critical part of brain development, in congenital heart disease infants and demonstrated an overall decrease in cortical surface area and cortical folding with regional alterations in the right lateral sulcus and left orbitofrontal region, cingulate region, and central sulcus. These abnormalities were present prior to surgery.

Emergency arterial switch: Rescue therapy for life-threatening hypoxemia in infants with transposition of great arteries with intact intraventricular septum.

OBJECTIVE: A small percentage of infants with d-loop transposition of the great arteries with intact intraventricular septum have life-threatening refractory hypoxemia often due to coexistent persistent pulmonary hypertension of the newborn. In this case series we describe the outcomes of a "rescue" emergency arterial switch operation (ASO). METHODS: We undertook a retrospective medical record analysis of infants with d-loop transposition of the great arteries with intact intraventricular septum who underwent an ASO in New Zealand from January 1, 1996, to April 30, 2017. Data were compared for those who received an emergency ASO and those with a nonemergency ASO for descriptive purposes. An emergency ASO was defined as one that was undertaken for life-threatening refractory hypoxemia when the only alternative stabilization strategy was preoperative extracorporeal life support. Primary outcome measures were 30-day postoperative mortality and abnormal neurodevelopmental outcome in the survivors. Secondary outcomes were low cardiac output, arrhythmia, renal dysfunction, postoperative seizures, and length of stay. Other known risk factors for morbidity and mortality were also assessed. RESULTS: Two hundred seventy-two infants underwent an ASO with 25 (9%) who received an emergency ASO. No infants received preoperative extracorporeal life support. The emergency group had greater 30-day postoperative mortality (8.0% vs 0.4%; P = .01) with no difference in abnormal neurodevelopmental outcome among the survivors (17.4% vs 13.8%; P = .35). The emergency group had more therapies for low cardiac output syndrome, more postoperative seizures, and a longer length of stay. CONCLUSIONS: An emergency ASO is a definitive rescue therapy that can be undertaken with acceptable mortality and neurodevelopmental outcome with consideration of the preoperative clinical state.

Longitudinal cohort study investigating neurodevelopmental and socioemotional outcomes in school-entry aged children after open heart surgery in Australia and New Zealand: the NITRIC follow-up study protocol.

INTRODUCTION: Despite growing awareness of neurodevelopmental impairments in children with congenital heart disease (CHD), there is a lack of large, longitudinal, population-based cohorts. Little is known about the contemporary neurodevelopmental profile and the emergence of specific impairments in children with CHD entering school. The performance of standardised screening tools to predict neurodevelopmental outcomes at school age in this high-risk population remains poorly understood. The NITric oxide during cardiopulmonary bypass to improve Recovery in Infants with Congenital heart defects (NITRIC) trial randomised 1371 children <2 years of age, investigating the effect of gaseous nitric oxide applied into the cardiopulmonary bypass oxygenator during heart surgery. The NITRIC follow-up study will follow this cohort annually until 5 years of age to assess outcomes related to cognition and socioemotional behaviour at school entry, identify risk factors for adverse outcomes and evaluate the performance of screening tools. METHODS AND ANALYSIS: Approximately 1150 children from the NITRIC trial across five sites in Australia and New Zealand will be eligible. Follow-up assessments will occur in two stages: (1) annual online screening of global neurodevelopment, socioemotional and executive functioning, health-related quality of life and parenting stress at ages 2-5 years; and (2) face-to-face assessment at age 5 years assessing intellectual ability, attention, memory and processing speed; fine motor skills; language and communication; and socioemotional outcomes. Cognitive and socioemotional outcomes and trajectories of neurodevelopment will be described and demographic, clinical, genetic and environmental predictors of these outcomes will be explored. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the Children's Health Queensland (HREC/20/QCHQ/70626) and New Zealand Health and Disability (21/NTA/83) Research Ethics Committees. The findings will inform the development of clinical decision tools and improve preventative and intervention strategies in children with CHD. Dissemination of the outcomes of the study is expected via publications in peer-reviewed journals, presentation at conferences, via social media, podcast presentations and medical education resources, and through CHD family partners. TRIAL REGISTRATION NUMBER: The trial was prospectively registered with the Australian New Zealand Clinical Trials Registry as 'Gene Expression to Predict Long-Term Neurodevelopmental Outcome in Infants from the NITric oxide during cardiopulmonary bypass to improve Recovery in Infants with Congenital heart defects (NITRIC) Study - A Multicentre Prospective Trial'. TRIAL REGISTRATION: ACTRN12621000904875.

Congenital heart disease affects cerebral size but not brain growth.

Infants with congenital heart disease (CHD) have delayed brain maturation and alterations in brain volume. Brain metrics is a simple measurement technique that can be used to evaluate brain growth. This study used brain metrics to test the hypothesis that alterations in brain size persist at 3 months of age and that infants with CHD have slower rates of brain growth than control infants. Fifty-seven infants with CHD underwent serial brain magnetic resonance imaging (MRI). To evaluate brain growth across the first 3 months of life, brain metrics were undertaken using 19 tissue and fluid spaces shown on MRIs performed before surgery and again at 3 months of age. Before surgery, infants with CHD have smaller frontal, parietal, cerebellar, and brain stem measures (p < 0.001). At 3 months of age, alterations persisted in all measures except the cerebellum. There was no difference between control and CHD infants in brain growth. However, the cerebellum trended toward greater growth in infants with CHD. Somatic growth was the primary factor that related to brain growth. Presence of focal white matter lesions before and after surgery did not relate to alterations in brain size or growth. Although infants with CHD have persistent alterations in brain size at 3 months of age, rates of brain growth are similar to that of healthy term infants. Somatic growth was the primary predictor of brain growth, emphasizing the importance of optimal weight gain in this population.

Comparison of Intracranial Pressure Measurements Before and After Hypertonic Saline or Mannitol Treatment in Children With Severe Traumatic Brain Injury.

Importance: Hyperosmolar agents are cornerstone therapies for pediatric severe traumatic brain injury. Guideline recommendations for 3% hypertonic saline (HTS) are based on limited numbers of patients, and no study to date has supported a recommendation for mannitol. Objectives: To characterize current use of hyperosmolar agents in pediatric severe traumatic brain injury and assess whether HTS or mannitol is associated with greater decreases in intracranial pressure (ICP) and/or increases in cerebral perfusion pressure (CPP). Design, Setting, and Participants: In this comparative effectiveness research study, 1018 children were screened and 18 were excluded; 787 children received some form of hyperosmolar therapy during the ICP-directed phase of care, with 521 receiving a bolus. Three of these children were excluded because they had received only bolus administration of both HTS and mannitol in the same hour, leaving 518 children (at 44 clinical sites in 8 countries) for analysis. The study was conducted from February 1, 2014, to September 31, 2017, with follow-up for 1 week after injury. Final analysis was performed July 20, 2021. Interventions: Boluses of HTS and mannitol were administered. Main Outcomes and Measures: Data on ICP and CPP were collected before and after medication administration. Statistical methods included linear mixed models and corrections for potential confounding variables to compare the 2 treatments. Results: A total of 518 children (mean [SD] age, 7.6 [5.4] years; 336 [64.9%] male; 274 [52.9%] White) were included. Participants' mean (SD) Glasgow Coma Scale score was 5.2 (1.8). Bolus HTS was observed to decrease ICP and increase CPP (mean [SD] ICP, 1.03 [6.77] mm Hg; P < .001; mean [SD] CPP, 1.25 [12.47] mm Hg; P < .001), whereas mannitol was observed to increase CPP (mean [SD] CPP, 1.20 [11.43] mm Hg; P = .009). In the primary outcome, HTS was associated with a greater reduction in ICP compared with mannitol (unadjusted ß, -0.85; 95% CI, -1.53 to -0.19), but no association was seen after adjustments (adjusted ß, -0.53; 95% CI, -1.32 to 0.25; P = .18). No differences in CPP were observed. When ICP was greater than 20 mm Hg, greater than 25 mm Hg, or greater than 30 mm Hg, HTS outperformed mannitol for each threshold in observed ICP reduction (>20 mm Hg: unadjusted ß, -2.51; 95% CI, -3.86 to -1.15, P < .001; >25 mm Hg: unadjusted ß, -3.88; 95% CI, -5.69 to -2.06, P < .001; >30 mm Hg: unadjusted ß, -4.07; 95% CI, -6.35 to -1.79, P < .001), with results remaining significant for ICP greater than 25 mm Hg in adjusted analysis. Conclusions and Relevance: In this comparative effectiveness research study, bolus HTS was associated with lower ICP and higher CPP, whereas mannitol was associated only with higher CPP. After adjustment for confounders, both therapies showed no association with ICP and CPP. During ICP crises, HTS was associated with better performance than mannitol.

Serum biomarkers in severe paediatric traumatic brain injury-a narrative review.

Severe traumatic brain injury continues to present complex management and prediction challenges for the clinician. While there is some evidence that better systems of care can improve outcome, multiple multi-centre randomised controlled trials of specific therapies have consistently failed to show benefit. In addition, clinicians are challenged in attempting to accurately predict which children will recover well and which children will have severe and persisting neurocognitive deficits. Traumatic brain injury is vastly heterogeneous and so it is not surprising that one therapy or approach, when applied to a mixed cohort of children in a clinical trial setting, has yielded disappointing results. Children with severe traumatic brain injury have vastly different brain injury pathologies of widely varying severity, in any number of anatomical locations at what may be disparate stages of brain development. This heterogeneity may also explain why clinicians are unable to accurately predict outcome. Biomarkers are objective molecular signatures of injury that are released following traumatic brain injury and may represent a way of unifying the heterogeneity of traumatic brain injury into a single biosignature. Biomarkers hold promise to diagnose brain injury severity, guide intervention selection for clinical trials, or provide vital prognostic information so that early intervention and rehabilitation can be planned much earlier in the course of a child's recovery. Serum S100B and serum NSE levels show promise as a diagnostic tool with biomarker levels significantly higher in children with severe TBI including children with inflicted and non-inflicted head injury. Serum S100B and serum NSE also show promise as a predictor of neurodevelopmental outcome. The role of biomarkers in traumatic brain injury is an evolving field with the potential for clinical application within the next few years.

Statistical analysis plan for the NITric oxide during cardiopulmonary bypass to improve Recovery in Infants with Congenital heart defects (NITRIC) trial.

Background: The NITric oxide during cardiopulmonary bypass (CPB) to improve Recovery in Infants with Congenital heart defects (NITRIC) trial, a 1320-patient, multicentre, randomised controlled trial, is aiming to improve survival free of ventilation after CPB by using nitric oxide delivered into the oxygenator of the CPB. Objective: To provide a statistical analysis plan before completion of patient recruitment and data monitoring. Final analyses for this study will adhere to this statistical analysis plan, which details all key pre-planned analyses. Stata scripts for analyses have been prepared alongside this statistical analysis plan. Methods: The statistical analysis plan was designed collaboratively by the chief investigators and trial statistician and builds on the previously published study protocol. All authors remain blinded to treatment allocation. Detail is provided on statistical analyses including cohort description, analysis of primary and secondary outcomes and adverse events. Statistical methods to compare outcomes are planned in detail to ensure methods are verifiable and reproducible. Results: The statistical analysis plan developed provides the trial outline, list of mock tables, and analysis scripts. The plan describes statistical analyses on cohort and baseline description, primary and secondary outcome analyses, process of care measures, physiological descriptors, and safety and adverse event reporting. We define the pre-specified subgroup analyses and the respective statistical tests used to compare subgroups. Conclusion: The statistical analysis plan for the NITRIC trial establishes detailed pre-planned analyses alongside Stata scripts to analyse the largest trial in the field of neonatal and paediatric heart surgery. The plan ensures standards for trial analysis validity aiming to minimise bias of analyses. Trial registration: ACTRN12617000821392.

The Bayley-III scale may underestimate neurodevelopmental disability after cardiac surgery in infants.

OBJECTIVES: Neurodevelopmental disability is the most common complication among congenital heart surgery survivors. The Bayley scales are standardized instruments to assess neurodevelopment. The most recent edition (Bayley Scales of Infant and Toddler Development 3rd Edition, Bayley-III) yields better-than-expected scores in typically developing and high-risk infants than the second edition (Bayley Scales of Infant Development 2nd Edition, BSID-II). We compared BSID-II and Bayley-III scores in infants undergoing cardiac surgery. METHODS: We evaluated 2198 infants who underwent operations with cardiopulmonary bypass between 1996 and 2009 at 26 institutions. We used propensity score matching to limit confounding by indication in a subset of patients (n = 705). RESULTS: Overall, unadjusted Bayley-III motor scores were higher than BSID-II Psychomotor Development Index scores (90.7 ± 17.2 vs 77.6 ± 18.8, P < 0.001), and unadjusted Bayley-III composite cognitive and language scores were higher than BSID-II Mental Development Index scores (92.0 ± 15.4 vs 88.2 ± 16.7, P < 0.001). In the propensity-matched analysis, Bayley-III motor scores were higher than BSID-II Psychomotor Development Index scores [absolute difference 14.1, 95% confidence interval (CI) 11.7-17.6; P < 0.001] and the Bayley-III classified fewer children as having severe [odds ratio (OR) 0.24; 95% CI 0.14-0.42] or mild-to-moderate impairment (OR 0.21; 95% CI 0.14-0.32). The composite of Bayley-III cognitive and language scores was higher than BSID-II Mental Development Index scores (absolute difference 4.0, 95% CI 1.4-6.7; P = 0.003), but there was no difference between Bayley editions in the proportion of children classified as having severe cognitive and language impairment. CONCLUSIONS: The Bayley-III yielded higher scores than the BSID-II and classified fewer children as severely impaired. The systematic bias towards higher scores with the Bayley-III precludes valid comparisons between early and contemporary cardiac surgery cohorts.

Extracorporeal Membrane Oxygenation for 2009 Influenza A(H1N1) Acute Respiratory Distress Syndrome.

CONTEXT: The novel influenza A(H1N1) pandemic affected Australia and New Zealand during the 2009 southern hemisphere winter. It caused an epidemic of critical illness and some patients developed severe acute respiratory distress syndrome (ARDS) and were treated with extracorporeal membrane oxygenation (ECMO). OBJECTIVES: To describe the characteristics of all patients with 2009 influenza A(H1N1)-associated ARDS treated with ECMO and to report incidence, resource utilization, and patient outcomes. DESIGN, SETTING, AND PATIENTS: An observational study of all patients (n = 68) with 2009 influenza A(H1N1)-associated ARDS treated with ECMO in 15 intensive care units (ICUs) in Australia and New Zealand between June 1 and August 31, 2009. MAIN OUTCOME MEASURES: Incidence, clinical features, degree of pulmonary dysfunction, technical characteristics, duration of ECMO, complications, and survival. RESULTS: Sixty-eight patients with severe influenza-associated ARDS were treated with ECMO, of whom 61 had either confirmed 2009 influenza A(H1N1) (n = 53) or influenza A not subtyped (n = 8), representing an incidence rate of 2.6 ECMO cases per million population. An additional 133 patients with influenza A received mechanical ventilation but no ECMO in the same ICUs. The 68 patients who received ECMO had a median (interquartile range [IQR]) age of 34.4 (26.6-43.1) years and 34 patients (50%) were men. Before ECMO, patients had severe respiratory failure despite advanced mechanical ventilatory support with a median (IQR) Pao(2)/fraction of inspired oxygen (Fio(2)) ratio of 56 (48-63), positive end-expiratory pressure of 18 (15-20) cm H(2)O, and an acute lung injury score of 3.8 (3.5-4.0). The median (IQR) duration of ECMO support was 10 (7-15) days. At the time of reporting, 48 of the 68 patients (71%; 95% confidence interval [CI], 60%-82%) had survived to ICU discharge, of whom 32 had survived to hospital discharge and 16 remained as hospital inpatients. Fourteen patients (21%; 95% CI, 11%-30%) had died and 6 remained in the ICU, 2 of whom were still receiving ECMO. CONCLUSIONS: During June to August 2009 in Australia and New Zealand, the ICUs at regional referral centers provided mechanical ventilation for many patients with 2009 influenza A(H1N1)-associated respiratory failure, one-third of whom received ECMO. These ECMO-treated patients were often young adults with severe hypoxemia and had a 21% mortality rate at the end of the study period.