Race-Conscious Research Using Extracorporeal Life Support Organization Registry Data: A Narrative Review.

Race-conscious research identifies health disparities with 1) rigorous and responsible data collection, 2) intentionality and considered analyses, and 3) interpretation of results that advance health equity. Individual registries must overcome specific challenges to promote race-conscious research, and this paper describes ways to achieve this with a focus on the international Extracorporeal Life Support Organization (ELSO) registry. This article reviews ELSO registry publications that studied race with outcomes to consider whether research outputs align with race-conscious concepts and describe the direction of associations reported. Studies were identified via secondary analysis of a comprehensive scoping review on ECMO disparities. Of 32 multicenter publications, two (6%) studied race as the primary objective. Statistical analyses, confounder adjustment, and inclusive, antibiased language were inconsistently used. Only two (6%) papers explicitly discussed mechanistic drivers of inequity such as structural racism, and five (16%) discussed race variable limitations or acknowledged unmeasured confounders. Extracorporeal Life Support Organization registry publications demonstrated more adverse ECMO outcomes for underrepresented/minoritized populations than non-ELSO studies. With the objective to promote race-conscious ELSO registry research outputs, we provide a comprehensive understanding of race variable limitations, suggest reasoned retrospective analytic approaches, offer ways to interpret results that advance health equity, and recommend practice modifications for data collection.

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.

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.

COVID-19 related ICU admissions in paediatric and young adult patients in Australia: a national case series 2020-2022.

Background: COVID-19 pandemic research efforts have focused on disease phenotypes in adults. A distinct spectrum of illness has been documented in paediatric populations. We aimed to review paediatric intensive care unit (ICU) admissions in Australia, across differing variant predominant phases of the pandemic. Methods: Data reported to the Short PeRiod IncideNce sTudy of Severe Acute Respiratory Infection (SPRINT-SARI) Australia, across 49 ICUs from February 2020 to June 2022 were extracted. We defined 'child' as patients aged <12 years, 'adolescent' as patients aged 12-17 years, and 'young adult' as patients aged 18-25 years. Findings: We identified 226 paediatric ICU admissions with COVID-19, representing 3.9% of ICU admissions across the study period. Comorbidity was present in 34.6% of children, 51.4% of adolescents, and 48.7% of young adults. The need for respiratory support was highest in young adults. While 28.3% of patients <18 years required invasive ventilation, in-hospital mortality in paediatric patients was 3.6%. During the Omicron period, there was an increase in the annualised incidence of age-specific COVID-19 ICU admissions per 100,000 population, albeit a decrease in the incidence per 1000 SARS-CoV-2 notifications. Interpretation: This study demonstrated an appreciable burden of COVID-19 in paediatric patients. Adolescent patients presented phenotypically similar to young adults, however, illness severity was lower in younger cohorts. The Omicron phase of the pandemic demonstrated an increased age-specific population incidence of COVID-19 ICU admissions, albeit a reduced incidence when based on SARS-CoV-2 notifications. Funding: SPRINT-SARI Australia is supported by the Department of Health, Commonwealth of Australia [Standing Deed SON60002733].

Quality care close to home: Objectives and early outcomes of a second paediatric heart transplant service in Australia.

AIM: We describe the experience of a new paediatric heart transplant (HT) centre in Australia. New South Wales offers quaternary paediatric cardiac services including comprehensive care pre- and post-HT; however, perioperative HT care has previously occurred at the national paediatric centre or in adult centres. Internationally, perioperative HT care is highly protocol-driven and a majority of HT occurs in low volume centres. Establishing a low volume paediatric HT centre in New South Wales offers potential for quality HT care close to home. METHODS: Retrospective review of programme data for the first 12 months was undertaken. Patient selection was audited against the programme's intended initiation criteria. Longitudinal patient data on outcomes and complications were obtained from patient medical records. RESULTS: The programme's initial phase offered HT to children with non-congenital heart disease and no requirement for durable mechanical circulatory support. Eight patients met criteria for HT referral. Three underwent interstate transfer to the national paediatric centre. Five children (13-15 years, weight 36-85 kg) underwent HT in the new programme. Individual predicted 90-day mortality was 1.3-11.6%, with increased risk for recipients transplanted from veno-arterial extracorporeal membrane oxygenation (VA-ECMO) and with restrictive/hypertrophic cardiomyopathies. Survival at 90 days and for duration of follow-up is 100%. Observed programme benefits include mitigation of family dislocation and improved continuity of care within a family-centred programme. CONCLUSION: Audit of the first 12 months' activity of a second paediatric HT centre in Australia demonstrates adherence to proposed patient selection criteria and excellent 90-day patient outcomes. The programme demonstrates feasibility of care close to home, providing continuity for all patients including those requiring increased rehabilitation and psychosocial support post-transplantation.

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.

Severe Influenza-Associated Neurological Disease in Australian Children: Seasonal Population-Based Surveillance 2008-2018.

BACKGROUND: Influenza-associated neurological disease (IAND) is uncommon but can result in death or neurological morbidity in children. We aimed to describe the incidence, risk factors, and outcome of children with IAND from seasonal influenza in Australia. METHODS: We analyzed national, population-based, surveillance data for children aged ≤ 14 years with severe influenza and neurological involvement, over 11 Australian influenza seasons, 2008-2018, by the Australian Paediatric Surveillance Unit. RESULTS: There were 633 laboratory-confirmed cases of severe influenza reported. Of these, 165 (26%) had IAND. The average annual incidence for IAND was 3.39 per million children aged ≤ 14 years. Compared to cases without neurological complications, those with IAND were more likely to have a pre-existing neurological disease (odds ratio [OR] 3.03, P < .001), but most children with IAND did not (n = 135, 82%). Children with IAND were more likely to receive antivirals (OR 1.80, P = .002), require intensive care (OR 1.79, P = .001), require ventilation (OR 1.99; P = .001), and die (OR 2.83, P = .004). CONCLUSIONS: IAND is a preventable cause of mortality, predominantly in otherwise well children. Incidence estimates validate previous sentinel site estimates from Australia. IAND accounted for a quarter of all severe influenza, is associated with intensive care unit admission, and accounted for half of all influenza deaths.

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.

Computerized Clinical Decision Support Systems for the Early Detection of Sepsis Among Pediatric, Neonatal, and Maternal Inpatients: Scoping Review.

BACKGROUND: Sepsis is a severe condition associated with extensive morbidity and mortality worldwide. Pediatric, neonatal, and maternal patients represent a considerable proportion of the sepsis burden. Identifying sepsis cases as early as possible is a key pillar of sepsis management and has prompted the development of sepsis identification rules and algorithms that are embedded in computerized clinical decision support (CCDS) systems. OBJECTIVE: This scoping review aimed to systematically describe studies reporting on the use and evaluation of CCDS systems for the early detection of pediatric, neonatal, and maternal inpatients at risk of sepsis. METHODS: MEDLINE, Embase, CINAHL, Cochrane, Latin American and Caribbean Health Sciences Literature (LILACS), Scopus, Web of Science, OpenGrey, ClinicalTrials.gov, and ProQuest Dissertations and Theses Global (PQDT) were searched by using a search strategy that incorporated terms for sepsis, clinical decision support, and early detection. Title, abstract, and full-text screening was performed by 2 independent reviewers, who consulted a third reviewer as needed. One reviewer performed data charting with a sample of data. This was checked by a second reviewer and via discussions with the review team, as necessary. RESULTS: A total of 33 studies were included in this review-13 (39%) pediatric studies, 18 (55%) neonatal studies, and 2 (6%) maternal studies. All studies were published after 2011, and 27 (82%) were published from 2017 onward. The most common outcome investigated in pediatric studies was the accuracy of sepsis identification (9/13, 69%). Pediatric CCDS systems used different combinations of 18 diverse clinical criteria to detect sepsis across the 13 identified studies. In neonatal studies, 78% (14/18) of the studies investigated the Kaiser Permanente early-onset sepsis risk calculator. All studies investigated sepsis treatment and management outcomes, with 83% (15/18) reporting on antibiotics-related outcomes. Usability and cost-related outcomes were each reported in only 2 (6%) of the 31 pediatric or neonatal studies. Both studies on maternal populations were short abstracts. CONCLUSIONS: This review found limited research investigating CCDS systems to support the early detection of sepsis among pediatric, neonatal, and maternal patients, despite the high burden of sepsis in these vulnerable populations. We have highlighted the need for a consensus definition for pediatric and neonatal sepsis and the study of usability and cost-related outcomes as critical areas for future research. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/24899.

Factors associated with admission of children to an intensive care unit and readmission to hospital within 28 days of discharge: A population-based study.

AIM: Hospital readmissions within 28 days are an important performance measurement of quality and safety of health care. The aims of this study were to examine the rates, trends and characteristics of paediatric intensive care unit admissions, and factors associated with readmissions to hospital within 28 days of discharge. METHODS: This retrospective, population-based record linkage study included all children ≥28 days and <16 years old admitted to an intensive care unit (ICU) in a New South Wales (NSW) public hospital from 2004 to 2013. Data were sourced from the NSW Admitted Patients Data Collection and the NSW Registry of Births, Deaths and Marriages, Death Registration. RESULTS: We identified 21 200 ICU admissions involving 17 130 children. Admissions increased by 24% over the study period with the greatest increase attributed to respiratory and musculoskeletal conditions. A higher proportion of children were <5 years, male, lived in major cities, were publicly insured and had chronic conditions. The median length of ICU stay was 42 h and overall hospital stay was 7 days. There were 905 deaths, two-thirds during the index admission with the leading causes being injuries, cancer and infections. Twenty-three per cent of ICU admissions were readmitted to hospital within 28 days of discharge. Associated independent factors were younger age, longer index hospital stay and emergency index admission. Children with chronic conditions of cancer and genitourinary disorders were more likely to be readmitted. CONCLUSIONS: Identification of complex chronic conditions, consideration of long-term health planning and interventions intended to reduce readmission is warranted in order to reduce the burden to families and the health-care system.

Retrieval of neonatal and paediatric patients on extracorporeal membrane oxygenation support in New South Wales, Australia.

New South Wales has recently added the capability of extracorporeal membrane oxygenation to the neonatal and paediatric retrieval process and this paper describes the early experiences and protocol development for the first eight cases transported.

Resuscitation in Paediatric Sepsis Using Metabolic Resuscitation-A Randomized Controlled Pilot Study in the Paediatric Intensive Care Unit (RESPOND PICU): Study Protocol and Analysis Plan.

Introduction: Septic shock remains amongst the leading causes of childhood mortality. Therapeutic options to support children with septic shock refractory to initial resuscitation with fluids and inotropes are limited. Recently, the combination of intravenous hydrocortisone with high dose ascorbic acid and thiamine (HAT therapy), postulated to reduce sepsis-related organ dysfunction, has been proposed as a safe approach with potential for mortality benefit, but randomized trials in paediatric patients are lacking. We hypothesize that protocolised early use of HAT therapy ("metabolic resuscitation") in children with septic shock is feasible and will lead to earlier resolution of organ dysfunction. Here, we describe the protocol of the Resuscitation in Paediatric Sepsis Using Metabolic Resuscitation-A Randomized Controlled Pilot Study in the Paediatric Intensive Care Unit (RESPOND PICU). Methods and Analysis: The RESPOND PICU study is an open label randomized-controlled, two-sided multicentre pilot study conducted in paediatric intensive care units (PICUs) in Australia and New Zealand. Sixty children aged between 28 days and 18 years treated with inotropes for presumed septic shock will be randomized in a 1:1 ratio to either metabolic resuscitation (1 mg/kg hydrocortisone q6h, 30 mg/kg ascorbic acid q6h, 4 mg/kg thiamine q12h) or standard septic shock management. Main outcomes include feasibility of the study protocol and survival free of organ dysfunction censored at 28 days. The study cohort will be followed up at 28-days and 6-months post enrolment to assess neurodevelopment, quality of life and functional status. Biobanking will allow ancillary studies on sepsis biomarkers. Ethics and Dissemination: The study received ethical clearance from Children's Health Queensland Human Research Ethics Committee (HREC/18/QCHQ/49168) and commenced enrolment on June 12th, 2019. The primary study findings will be submitted for publication in a peer-reviewed journal. Trial Registration: Australian and New Zealand Clinical Trials Registry (ACTRN12619000829112). Protocol Version: V1.8 22/7/20.

Priorities for paediatric critical care research: a modified Delphi study by the Australian and New Zealand Intensive Care Society Paediatric Study Group.

Objective: Most interventions in paediatric critical care lack high grade evidence. We aimed to identify the key research priorities and key clinical outcome measures pertinent to research in paediatric intensive care patients. Design: Modified three-stage Delphi study combining staged online surveys, followed by a face-to-face discussion and final voting. Setting: Paediatric intensive care units in Australia and New Zealand. Participants: Medical and nursing staff working in intensive care. Main outcome measurements: Self-reported priorities for research. Results: 193 respondents provided a total of 267 research questions and 234 outcomes. In Stage 3, the top 56 research questions and 50 outcomes were discussed face to face, which allowed the identification of the top 20 research questions with the Hanlon prioritisation score and the top 20 outcomes. Topics centred on the use of intravenous fluids (restrictive v liberal fluids, use of fluid resuscitation bolus, early inotrope use, type of intravenous fluid, and assessment of fluid responsiveness), and patient- and family-centred outcomes (health-related quality of life, liberation) emerged as priorities. While mortality, length of stay, and organ support/organ dysfunction were considered important and the most feasible outcomes, long term quality of life and neurodevelopmental measures were rated highly in terms of their importance. Conclusions: Using a modified Delphi method, this study provides guidance towards prioritisation of research topics in paediatric critical care in Australia and New Zealand, and identifies study outcomes of key relevance to clinicians and experts in the field.

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.

Ten Years of National Seasonal Surveillance for Severe Complications of Influenza in Australian Children.

BACKGROUND: Severe complications of influenza in children are uncommon but may result in admission to hospital or an intensive care unit (ICU) and death. METHODS: Active prospective surveillance using the Australian Paediatric Surveillance Unit with monthly reporting by pediatricians of national demographic and clinical data on children with <15 years of age hospitalized with severe complications of laboratory-confirmed influenza during ten influenza seasons 2008-2017. RESULTS: Of 722 children notified, 613 had laboratory-confirmed influenza and at least one severe complication. Most (60%) were <5 years of age; 10% were <6 months, hence ineligible for vaccination. Almost half of all cases were admitted to ICU and 30 died. Most children were previously healthy: 40.3% had at least one underlying medical condition. Sixty-five different severe complications were reported; pneumonia was the most common, occurring in over half of all cases. Influenza A accounted for 68.6% hospitalizations; however, influenza B was more often associated with acute renal failure (P = 0.014), rhabdomyolysis (P = 0.019), myocarditis (P = 0.015), pericarditis (P = 0.013), and cardiomyopathy (P = 0.035). Children who died were more likely to be older (5-14 years), have underlying medical conditions, be admitted to ICU, and have encephalitis, acute renal failure, or myocarditis. Only 36.1% of all children reported received antiviral medications, and 8.5% were known to be vaccinated for seasonal influenza. CONCLUSIONS: Severe influenza complications cause morbidity and mortality in children, which may increase if coinfection with COVID-19 occurs in the 2020 season and beyond. Increased vaccination rates, even in healthy children, early diagnosis and timely antiviral treatment are needed to reduce severe complications and death.

Dexmedetomidine Sedation in Mechanically Ventilated Critically Ill Children: A Pilot Randomized Controlled Trial.

OBJECTIVES: To assess the feasibility, safety, and efficacy of a sedation protocol using dexmedetomidine as the primary sedative in mechanically ventilated critically ill children. DESIGN: Open-label, pilot, prospective, multicenter, randomized, controlled trial. The primary outcome was the proportion of sedation scores in the target sedation range in the first 48 hours. Safety outcomes included device removal, adverse events, and vasopressor use. Feasibility outcomes included time to randomization and protocol fidelity. SETTING: Six tertiary PICUs in Australia and New Zealand. PATIENTS: Critically ill children, younger than 16 years old, requiring intubation and mechanical ventilation and expected to be mechanically ventilated for at least 24 hours. INTERVENTIONS: Children randomized to dexmedetomidine received a dexmedetomidine-based algorithm targeted to light sedation (State Behavioral Scale -1 to +1). Children randomized to usual care received sedation as determined by the treating clinician (but not dexmedetomidine), also targeted to light sedation. MEASUREMENTS AND MAIN RESULTS: Sedation with dexmedetomidine as the primary sedative resulted in a greater proportion of sedation measurements in the light sedation range (State Behavioral Scale -1 to +1) over the first 48 hours (229/325 [71%] vs 181/331 [58%]; p = 0.04) and the first 24 hours (66/103 [64%] vs 48/116 [41%]; p < 0.001) compared with usual care. Cumulative midazolam dosage was significantly reduced in the dexmedetomidine arm compared with usual care (p = 0.002).There were more episodes of hypotension and bradycardia with dexmedetomidine (including one serious adverse event) but no difference in vasopressor requirements. Median time to randomization after intubation was 6.0 hours (interquartile range, 2.0-9.0 hr) in the dexmedetomidine arm compared with 3.0 hours (interquartile range, 1.0-7.0 hr) in the usual care arm (p = 0.24). CONCLUSIONS: A sedation protocol using dexmedetomidine as the primary sedative was feasible, appeared safe, achieved early, light sedation, and reduced midazolam requirements. The findings of this pilot study justify further studies of sedative agents in critically ill children.

Gestational Age and Risk of Mortality in Term-Born Critically Ill Neonates Admitted to PICUs in Australia and New Zealand.

OBJECTIVES: Gestational age at birth is declining, probably because more deliveries are being induced. Gestational age is an important modifiable risk factor for neonatal mortality and morbidity. We aimed to investigate the association between gestational age and mortality in hospital for term-born neonates (≥ 37 wk') admitted to PICUs in Australia and New Zealand. DESIGN: Observational multicenter cohort study. SETTING: PICUs in Australia and New Zealand. PATIENTS: Term-born neonates (≥ 37 wk) admitted to PICUs. INTERVENTIONS: None MEASUREMENTS AND MAIN RESULTS:: We studied 5,073 infants born with a gestational age greater than or equal to 37 weeks and were less than 28 days old when admitted to a PICU in Australia or New Zealand between 2007 and 2016. The association between gestational age and mortality was estimated using a multivariable logistic regression model, adjusting for age, sex, indigenous status, Pediatric Index of Mortality version 2, and site. The median gestational age was 39.1 weeks (interquartile range, 38.2-40 wk) and mortality in hospital was 6.6%. Risk of mortality declined log-linearly with gestational age. The adjusted analysis showed a 20% (95% CI, 11-28%) relative reduction in mortality for each extra week of gestation beyond 37 weeks. The effect of gestation was stronger among those who received extracorporeal life support: each extra week of gestation was associated with a 44% (95% CI, 25-57%) relative reduction in mortality. Longer gestation was also associated with reduced length of stay in hospital: each week increase in gestation, the average length of stay decreased by 4% (95% CI, 2-6%). CONCLUSIONS: Among neonates born at "term" who are admitted to a PICU, increasing gestational age at birth is associated with a substantial reduction in the risk of dying in hospital. The maturational influence on outcome was more strongly noted in the sickest neonates, such as those requiring extracorporeal life support. This information is important in view of the increasing proportion of planned births in both high- and low-/middle-income countries.

Study protocol: NITric oxide during cardiopulmonary bypass to improve Recovery in Infants with Congenital heart defects (NITRIC trial): a randomised controlled trial.

INTRODUCTION: Congenital heart disease (CHD) is a major cause of infant mortality. Many infants with CHD require corrective surgery with most operations requiring cardiopulmonary bypass (CPB). CPB triggers a systemic inflammatory response which is associated with low cardiac output syndrome (LCOS), postoperative morbidity and mortality. Delivery of nitric oxide (NO) into CPB circuits can provide myocardial protection and reduce bypass-induced inflammation, leading to less LCOS and improved recovery. We hypothesised that using NO during CPB increases ventilator-free days (VFD) (the number of days patients spend alive and free from invasive mechanical ventilation up until day 28) compared with standard care. Here, we describe the NITRIC trial protocol. METHODS AND ANALYSIS: The NITRIC trial is a randomised, double-blind, controlled, parallel-group, two-sided superiority trial to be conducted in six paediatric cardiac surgical centres. One thousand three-hundred and twenty infants <2 years of age undergoing cardiac surgery with CPB will be randomly assigned to NO at 20 ppm administered into the CPB oxygenator for the duration of CPB or standard care (no NO) in a 1:1 ratio with stratification by age (<6 and ≥6 weeks), single ventricle physiology (Y/N) and study centre. The primary outcome will be VFD to day 28. Secondary outcomes include a composite of LCOS, need for extracorporeal membrane oxygenation or death within 28 days of surgery; length of stay in intensive care and in hospital; and, healthcare costs. Analyses will be conducted on an intention-to-treat basis. Preplanned secondary analyses will investigate the impact of NO on host inflammatory profiles postsurgery. ETHICS AND DISSEMINATION: The study has ethical approval (HREC/17/QRCH/43, dated 26 April 2017), is registered in the Australian New Zealand Clinical Trials Registry (ACTRN12617000821392) and commenced recruitment in July 2017. The primary manuscript will be submitted for publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: ACTRN12617000821392.