Adverse Events Sustained by Children in The Intensive Care Unit: Guiding local quality improvement

Objective: To determine the frequency, nature and consequence of adverse events sustained by children admitted to a combined general and cardiac paediatric intensive care unit (PICU). Design: Retrospective analysis of data collected between January 1st 2008 and December 31st 2017 from PICU. Setting: The Royal Children’s Hospital, a paediatric tertiary referral centre in Melbourne, Victoria, Australia. The PICU has thirty beds. Results: During the study period, PICU received 15208 admissions, of which 73% sustained at least one adverse event with a frequency of 67 adverse events per 100 PICU-days and 3 per admission. One adverse event was sustained for every 35 hours of care. The risk of an adverse event was highest in children less than a month of age, or if mechanically ventilated, a high Pediatric Index of Mortality (PIM2) score, longer PICU length of stay, had a pre-existing disability or a high risk adjustment for congenital heart surgery (RACHS) score. Those patients who sustained an adverse event, as compared to those who did not, were mechanically ventilated for longer (80 hrs Vs. 7 hrs, p=<0.001), had a longer PICU length of stay (131 hrs Vs. 35 hrs, p=<0.001), had a longer hospital length of stay (484 hrs Vs. 206 hrs, p=<0.001) and had a higher mortality rate (3% vs. 0.1%, p=<0.001). Conclusion: Whilst admission to PICU is an essential aspect of care for many patients, the risk of adverse events is high and is associated with significant clinical consequences. Monitoring of adverse events as part of quality improvement enables targeted intervention to improve patient safety

Interleukin-8 predicts fatigue at 12 months post-injury in children with traumatic brain injury

Despite many children experiencing fatigue after childhood brain injury, little is known about the predictors of this complaint. To date, traditional indices of traumatic brain injury (TBI) severity have not reliably predicted persisting fatigue (up to 3 years post‐injury). This study aimed to establish if persisting fatigue is predicted by serum biomarker concentrations in child TBI. We examined if acute serum biomarker expression would improve prediction models of 12‐month fatigue based on injury severity. Blood samples were collected from 87 children (1 – 17 years at injury) sustaining mild to severe TBI (GCS range 3‐15; mean 12.43; classified as mild TBI (n=50, 57%) vs moderate/severe TBI n=37, 43%), and presenting to the Emergency Departments (ED) and Pediatric Intensive Care Units (PICU) at one of three tertiary pediatric hospitals (Royal Children’s Hospital (RCH); Hospital for Sick Children (HSC), Toronto St Justine Children’s Hospital (SJH), Montreal). Six serum biomarker concentrations were measured within 24 hours of injury [interleukin‐6 (IL‐6), interleukin‐8 (IL‐8), soluble vascular cell adhesion molecule (SVCAM), S100 calcium binding protein B (S100B), neuron specific enolase (NSE), and soluble neural cell adhesion molecule (sNCAM)]. Fatigue at 12 months post‐injury was measured using the Pediatric Quality of Life Inventory Multidimensional Fatigue Scale (parent report), classified as present/absent using previously derived cut‐points. At 12 months post‐injury, 22% of participants experienced fatigue. A model including interleukin‐8 (IL‐8) was the best serum biomarker for estimating the probability of children experiencing fatigue at 12 months post‐injury. IL‐8 also significantly improved predictive models of fatigue based on severity

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.</p

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

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.administered via an online REDCap database,11 and consent was obtained at the start of the survey. The study was approved by the Human Research and Ethics Committee (Children’s Health Queensland LNR/19/QCHQ/54762).</p

sj-docx-1-ctj-10.1177_17407745231222019 – Supplemental material for Assessing the impact of risk-based data monitoring on outcomes for a paediatric multicentre randomised controlled trial

Supplemental material, sj-docx-1-ctj-10.1177_17407745231222019 for Assessing the impact of risk-based data monitoring on outcomes for a paediatric multicentre randomised controlled trial by Renate Le Marsney, Kerry Johnson, Jenipher Chumbes Flores, Shelley Coetzer, Jennifer Darvas, Carmel Delzoppo, Arielle Jolly, Kate Masterson, Claire Sherring, Hannah Thomson, Endrias Ergetu, Patricia Gilholm and Kristen S Gibbons in Clinical Trials</p

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: ACTRN1261700082139

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