Recommendations for the College of Intensive Care Medicine (CICM) trainee research project: A modified Delphi study.

Objective: To determine the perceived barriers and enablers to efficient completion of the College of Intensive Care Medicine (CICM) of Australia and New Zealand Formal Project - a trainee research project mandated for award of CICM Fellowship - and to develop consensus-based recommendations to support Intensive Care trainees and supervisors. Design: A two-stage modified Delphi study was conducted. In stage one, an anonymous electronic survey was distributed with three targeted open-ended questions relating to perceived key steps, barriers to, and improvements for efficient completion of the Formal Project. A thematic analysis used the survey results to generate a list of close-ended questions.In stage two, a consensus panel comprising of 30 panellists including CICM trainees, Formal Project supervisors and assessors, and critical care researchers, underwent a Delphi process with two rounds of voting and discussion to generate consensus-based recommendations. Setting: Surveys were distributed to Intensive Care Units across Australia and New Zealand. The consensus panel convened at the Queensland Critical Care Research Network Annual Scientific Meeting in Redcliffe, Queensland, Australia, on 9 June 2023. Participants: CICM trainees, Formal Project supervisors and assessors, and critical care researchers in Australia and New Zealand. Main outcome measures: Consensus-based recommendations for the CICM Formal Project. Results: We received 88 responses from the stage one survey. Stage two finalised 22 consensus-based recommendations, centring on key steps of the research process, resources for trainees, and support and training for supervisors. Conclusions: Twenty-two recommendations were developed aiming to make the process of completing the mandatory CICM research project more efficient, and to improve the quality of research produced from these projects.

An ovine septic shock model of live bacterial infusion.

BACKGROUND: Escherichia coli is the most common cause of human bloodstream infections and bacterial sepsis/septic shock. However, translation of preclinical septic shock resuscitative therapies remains limited mainly due to low-fidelity of available models in mimicking clinical illness. To overcome the translational barrier, we sought to replicate sepsis complexity by creating an acutely critically-ill preclinical bacterial septic shock model undergoing active 48-h intensive care management. AIM: To develop a clinically relevant large-animal (ovine) live-bacterial infusion model for septic shock. METHODS: Septic shock was induced by intravenous infusion of the live antibiotic resistant extra-intestinal pathogenic E. coli sequence type 131 strain EC958 in eight anesthetised and mechanically ventilated sheep. A bacterial dose range of 2 × 105-2 × 109 cfu/mL was used for the dose optimisation phase (n = 4) and upon dose confirmation the model was developed (n = 5). Post-shock the animals underwent an early-vasopressor and volume-restriction resuscitation strategy with active haemodynamic management and monitoring over 48 h. Serial blood samples were collected for testing of pro-inflammatory (IL-6, IL-8, VEGFA) and anti-inflammatory (IL-10) cytokines and hyaluronan assay to assess endothelial integrity. Tissue samples were collected for histopathology and transmission electron microscopy. RESULTS: The 2 × 107 cfu/mL bacterial dose led to a reproducible distributive shock within a pre-determined 12-h period. Five sheep were used to demonstrate consistency of the model. Bacterial infusion led to development of septic shock in all animals. The baseline mean arterial blood pressure reduced from a median of 91 mmHg (71, 102) to 50 mmHg (48, 57) (p = 0.004) and lactate levels increased from a median of 0.5 mM (0.3, 0.8) to 2.1 mM (2.0, 2.3) (p = 0.02) post-shock. The baseline median hyaluronan levels increased significantly from 25 ng/mL (18, 86) to 168 ng/mL (86, 569), p = 0.05 but not the median vasopressor dependency index which increased within 1 h of resuscitation from zero to 0.39 mmHg-1 (0.06, 5.13), p = 0.065, and. Over the 48 h, there was a significant decrease in the systemic vascular resistance index (F = 7.46, p = 0.01) and increase in the pro-inflammatory cytokines [IL-6 (F = 8.90, p = 0.02), IL-8 (F = 5.28, p = 0.03), and VEGFA (F = 6.47, p = 0.02)]. CONCLUSIONS: This critically ill large-animal model was consistent in reproducing septic shock and will be applied in investigating advanced resuscitation and therapeutic interventions.

Achievement of therapeutic antibiotic exposures using Bayesian dosing software in critically unwell children and adults with sepsis.

PURPOSE: Early recognition and effective treatment of sepsis improves outcomes in critically ill patients. However, antibiotic exposures are frequently suboptimal in the intensive care unit (ICU) setting. We describe the feasibility of the Bayesian dosing software Individually Designed Optimum Dosing Strategies (ID-ODS™), to reduce time to effective antibiotic exposure in children and adults with sepsis in ICU. METHODS: A multi-centre prospective, non-randomised interventional trial in three adult ICUs and one paediatric ICU. In a pre-intervention Phase 1, we measured the time to target antibiotic exposure in participants. In Phase 2, antibiotic dosing recommendations were made using ID-ODS™, and time to target antibiotic concentrations were compared to patients in Phase 1 (a pre-post-design). RESULTS: 175 antibiotic courses (Phase 1 = 123, Phase 2 = 52) were analysed from 156 participants. Across all patients, there was no difference in the time to achieve target exposures (8.7 h vs 14.3 h in Phase 1 and Phase 2, respectively, p = 0.45). Sixty-one courses in 54 participants failed to achieve target exposures within 24 h of antibiotic commencement (n = 36 in Phase 1, n = 18 in Phase 2). In these participants, ID-ODS™ was associated with a reduction in time to target antibiotic exposure (96 vs 36.4 h in Phase 1 and Phase 2, respectively, p < 0.01). These patients were less likely to exhibit subtherapeutic antibiotic exposures at 96 h (hazard ratio (HR) 0.02, 95% confidence interval (CI) 0.01-0.05, p < 0.01). There was no difference observed in in-hospital mortality. CONCLUSIONS: Dosing software may reduce the time to achieve target antibiotic exposures. It should be evaluated further in trials to establish its impact on clinical outcomes.

Host gene expression signatures to identify infection type and organ dysfunction in children evaluated for sepsis: a multicentre cohort study.

BACKGROUND: Sepsis is defined as dysregulated host response to infection that leads to life-threatening organ dysfunction. Biomarkers characterising the dysregulated host response in sepsis are lacking. We aimed to develop host gene expression signatures to predict organ dysfunction in children with bacterial or viral infection. METHODS: This cohort study was done in emergency departments and intensive care units of four hospitals in Queensland, Australia, and recruited children aged 1 month to 17 years who, upon admission, underwent a diagnostic test, including blood cultures, for suspected sepsis. Whole-blood RNA sequencing of blood was performed with Illumina NovaSeq (San Diego, CA, USA). Samples with completed phenotyping, monitoring, and RNA extraction by March 31, 2020, were included in the discovery cohort; samples collected or completed thereafter and by Oct 27, 2021, constituted the Rapid Paediatric Infection Diagnosis in Sepsis (RAPIDS) internal validation cohort. An external validation cohort was assembled from RNA sequencing gene expression count data from the observational European Childhood Life-threatening Infectious Disease Study (EUCLIDS), which recruited children with severe infection in nine European countries between 2012 and 2016. Feature selection approaches were applied to derive novel gene signatures for disease class (bacterial vs viral infection) and disease severity (presence vs absence of organ dysfunction 24 h post-sampling). The primary endpoint was the presence of organ dysfunction 24 h after blood sampling in the presence of confirmed bacterial versus viral infection. Gene signature performance is reported as area under the receiver operating characteristic curves (AUCs) and 95% CI. FINDINGS: Between Sept 25, 2017, and Oct 27, 2021, 907 patients were enrolled. Blood samples from 595 patients were included in the discovery cohort, and samples from 312 children were included in the RAPIDS validation cohort. We derived a ten-gene disease class signature that achieved an AUC of 94·1% (95% CI 90·6-97·7) in distinguishing bacterial from viral infections in the RAPIDS validation cohort. A ten-gene disease severity signature achieved an AUC of 82·2% (95% CI 76·3-88·1) in predicting organ dysfunction within 24 h of sampling in the RAPIDS validation cohort. Used in tandem, the disease class and disease severity signatures predicted organ dysfunction within 24 h of sampling with an AUC of 90·5% (95% CI 83·3-97·6) for patients with predicted bacterial infection and 94·7% (87·8-100·0) for patients with predicted viral infection. In the external EUCLIDS validation dataset (n=362), the disease class and disease severity predicted organ dysfunction at time of sampling with an AUC of 70·1% (95% CI 44·1-96·2) for patients with predicted bacterial infection and 69·6% (53·1-86·0) for patients with predicted viral infection. INTERPRETATION: In children evaluated for sepsis, novel host transcriptomic signatures specific for bacterial and viral infection can identify dysregulated host response leading to organ dysfunction. FUNDING: Australian Government Medical Research Future Fund Genomic Health Futures Mission, Children's Hospital Foundation Queensland, Brisbane Diamantina Health Partners, Emergency Medicine Foundation, Gold Coast Hospital Foundation, Far North Queensland Foundation, Townsville Hospital and Health Services SERTA Grant, and Australian Infectious Diseases Research Centre.

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.

Rapid nanopore sequencing and predictive susceptibility testing of positive blood cultures from intensive care patients with sepsis.

We aimed to evaluate the performance of Oxford Nanopore Technologies (ONT) sequencing from positive blood culture (BC) broths for bacterial identification and antimicrobial susceptibility prediction. Patients with suspected sepsis in four intensive care units were prospectively enrolled. Human-depleted DNA was extracted from positive BC broths and sequenced using ONT (MinION). Species abundance was estimated using Kraken2, and a cloud-based system (AREScloud) provided in silico predictive antimicrobial susceptibility testing (AST) from assembled contigs. Results were compared to conventional identification and phenotypic AST. Species-level agreement between conventional methods and AST predicted from sequencing was 94.2% (49/52), increasing to 100% in monomicrobial infections. In 262 high-quality AREScloud AST predictions across 24 samples, categorical agreement (CA) was 89.3%, with major error (ME) and very major error (VME) rates of 10.5% and 12.1%, respectively. Over 90% CA was achieved for some taxa (e.g., Staphylococcus aureus) but was suboptimal for Pseudomonas aeruginosa. In 470 AST predictions across 42 samples, with both high quality and exploratory-only predictions, overall CA, ME, and VME rates were 87.7%, 8.3%, and 28.4%. VME rates were inflated by false susceptibility calls in a small number of species/antibiotic combinations with few representative resistant isolates. Time to reporting from sequencing could be achieved within 8-16 h from BC positivity. Direct sequencing from positive BC broths is feasible and can provide accurate predictive AST for some species. ONT-based approaches may be faster but significant improvements in accuracy are required before it can be considered for clinical use.IMPORTANCESepsis and bloodstream infections carry a high risk of morbidity and mortality. Rapid identification and susceptibility prediction of causative pathogens, using Nanopore sequencing direct from blood cultures, may offer clinical benefit. We assessed this approach in comparison to conventional phenotypic methods and determined the accuracy of species identification and susceptibility prediction from genomic data. While this workflow holds promise, and performed well for some common bacterial species, improvements in sequencing accuracy and more robust predictive algorithms across a diverse range of organisms are required before this can be considered for clinical use. However, results could be achieved in timeframes that are faster than conventional phenotypic methods.

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.

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.

Implementing paediatric appropriate use criteria for endotracheal suction to reduce complications in mechanically ventilated children with respiratory infections.

BACKGROUND: Endotracheal suction is used to maintain endotracheal tube patency. There is limited guidance to inform clinical practice for children with respiratory infections. OBJECTIVE: The objective of this study was to determine whether implementation of a paediatric endotracheal suction appropriate use guideline Paediatric AirWay Suction (PAWS) is associated with an increased use of appropriate and decreased use of inappropriate suction interventions. METHODS: A mixed-method, pre-implementation-post-implementation study was conducted between September 2021 and April 2022. Suction episodes in mechanically ventilated children with a respiratory infection were eligible. Using a structured approach, we implemented the PAWS guideline in a single paediatric intensive care unit. Evaluation included clinical (e.g., suction intervention appropriateness), implementation (e.g., acceptability), and cost outcomes (implementation costs). Associations between implementation of the PAWS guideline and appropriateness of endotracheal suction intervention use were investigated using generalised linear models. RESULTS: Data from 439 eligible suctions were included in the analysis. Following PAWS implementation, inappropriate endotracheal tube intervention use reduced from 99% to 58%, an absolute reduction (AR) of 41% (95% confidence interval [CI]: 25%, 56%). Reductions were most notable for open suction systems (AR: 48%; 95% CI: 30%, 65%), 0.9% sodium chloride use (AR: 23%; 95% CI: 8%, 38%) and presuction and postsuction manual bagging (38%; 95% CI: 16%, 60%, and 86%; 95% CI: 73%, 99%), respectively. Clinicians perceived PAWS as acceptable and suitable for use. CONCLUSIONS: Implementation of endotracheal tube suction appropriate use guidelines in a mixed paediatric intensive care unit was associated with a large reduction in inappropriate suction intervention use in paediatric patients with respiratory infections.

REstrictive versus StandarD FlUid Management in Mechanically Ventilated ChildrEn Admitted to PICU: study protocol for a pilot randomised controlled trial (REDUCE-1).

INTRODUCTION: Intravenous fluid therapy is the most common intervention in critically ill children. There is an increasing body of evidence questioning the safety of high-volume intravenous fluid administration in these patients. To date, the optimal fluid management strategy remains unclear. We aimed to test the feasibility of a pragmatic randomised controlled trial comparing a restrictive with a standard (liberal) fluid management strategy in critically ill children. METHODS AND ANALYSIS: Multicentre, binational pilot, randomised, controlled, open-label, pragmatic trial. Patients <18 years admitted to paediatric intensive care unit and mechanically ventilated at the time of screening are eligible. Patients with tumour lysis syndrome, diabetic ketoacidosis or postorgan transplant are excluded. INTERVENTIONS: 1:1 random assignment of 154 individual patients into two groups-restrictive versus standard, liberal, fluid strategy-stratified by primary diagnosis (cardiac/non-cardiac). The intervention consists of a restrictive fluid bundle, including lower maintenance fluid allowance, limiting fluid boluses, reducing volumes of drug delivery and initiating diuretics or peritoneal dialysis earlier. The intervention is applied for 48 hours postrandomisation or until discharge (whichever is earlier). ENDPOINTS: The number of patients recruited per month and proportion of recruited to eligible patients are feasibility endpoints. New-onset acute kidney injury and the incidence of clinically relevant central venous thrombosis are safety endpoints. Fluid balance at 48 hours after randomisation is the efficacy endpoint. Survival free of paediatric intensive care censored at 28 days is the clinical endpoint. ETHICS AND DISSEMINATION: Ethics approval was gained from the Children's Health Queensland Human Research Ethics Committee (HREC/21/QCHQ/77514, date: 1 September 2021), and University of Zurich (2021-02447, date: 17 March 2023). The trial is registered with the Australia New Zealand Clinical Trials Registry (ACTRN12621001311842). Open-access publication in high impact peer-reviewed journals will be sought. Modern information dissemination strategies will also be used including social media to disseminate the outcomes of the study. TRIAL REGISTRATION NUMBER: ACTRN12621001311842. PROTOCOL VERSION/DATE: V5/23 May 2023.

Resuscitation-associated endotheliopathy (RAsE): a conceptual framework based on a systematic review and meta-analysis.

INTRODUCTION: Shock-induced endotheliopathy (SHINE), defined as a profound sympathoadrenal hyperactivation in shock states leading to endothelial activation, glycocalyx damage, and eventual compromise of end-organ perfusion, was first described in 2017. The aggressive resuscitation therapies utilised in treating shock states could potentially lead to further worsening endothelial activation and end-organ dysfunction. OBJECTIVE: This study aimed to systematically review the literature on resuscitation-associated and resuscitation-induced endotheliopathy. METHODS: A predetermined structured search of literature published over an 11-year and 6-month period (1 January 2011 to 31 July 2023) was performed in two indexed databases (PubMed/MEDLINE and Embase) per PRISMA guidelines. Inclusion was restricted to original studies published in English (or with English translation) reporting on endothelial dysfunction in critically ill human subjects undergoing resuscitation interventions. Reviews or studies conducted in animals were excluded. Qualitative synthesis of studies meeting the inclusion criteria was performed. Studies reporting comparable biomarkers of endothelial dysfunction post-resuscitation were included in the quantitative meta-analysis. RESULTS: Thirty-two studies met the inclusion criteria and were included in the final qualitative synthesis. Most of these studies (47%) reported on a combination of mediators released from endothelial cells and biomarkers of glycocalyx breakdown, while only 22% reported on microvascular flow changes. Only ten individual studies were included in the quantitative meta-analysis based on the comparability of the parameters assessed. Eight studies measured syndecan-1, with a heterogeneity index, I2 = 75.85% (pooled effect size, mean = 0.27; 95% CI - 0.07 to 0.60; p = 0.12). Thrombomodulin was measured in four comparable studies (I2 = 78.93%; mean = 0.41; 95% CI - 0.10 to 0.92; p = 0.12). Three studies measured E-selectin (I2 = 50.29%; mean = - 0.15; 95% CI - 0.64 to 0.33; p = 0.53), and only two were comparable for the microvascular flow index, MFI (I2 = 0%; mean = - 0.80; 95% CI - 1.35 to - 0.26; p < 0.01). CONCLUSION: Resuscitation-associated endotheliopathy (RAsE) refers to worsening endothelial dysfunction resulting from acute resuscitative therapies administered in shock states. In the included studies, syndecan-1 had the highest frequency of assessment in the post-resuscitation period, and changes in concentrations showed a statistically significant effect of the resuscitation. There are inadequate data available in this area, and further research and standardisation of the ideal assessment and panel of biomarkers are urgently needed.

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.

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.

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

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

Effect of Saline vs Gluconate/Acetate-Buffered Solution vs Lactate-Buffered Solution on Serum Chloride Among Children in the Pediatric Intensive Care Unit: The SPLYT-P Randomized Clinical Trial.

Importance: Most children admitted to pediatric intensive care units (PICUs) receive intravenous fluids. A recent systematic review suggested mortality benefit in critically ill adults treated with balanced solutions compared with sodium chloride, 0.9% (saline). There is a lack of clinically directive data on optimal fluid choice in critically ill children. Objective: To determine if balanced solutions decrease the rise of plasma chloride compared with saline, 0.9%, in critically ill children. Design, Setting, and Participants: This single-center, 3-arm, open-label randomized clinical trial took place in a 36-bed PICU. Children younger than 16 years admitted to the PICU and considered to require intravenous fluid therapy by the treating clinician were eligible. Children were screened from November 2019 to April 2021. Interventions: Enrolled children were 1:1:1 allocated to gluconate/acetate-buffered solution, lactate-buffered solution, or saline as intravenous fluids. Main Outcomes and Measures: The primary outcome was an increase in serum chloride of 5 mEq/L or more within 48 hours from randomization. New-onset acute kidney injury, length of hospital and intensive care stay, and intensive care-free survival were secondary outcomes. Results: A total of 516 patients with a median (IQR) age of 3.8 (1.0-10.4) years were randomized with 178, 171, and 167 allocated to gluconate/acetate-buffered solution, lactate-buffered solution, and saline, respectively. The serum chloride level increased 5 mEq/L or more in 37 patients (25.2%), 34 patients (23.9%), and 58 patients (40.0%) in the gluconate/acetate-buffered solution, lactate-buffered solution, and saline groups. The odds of a rise in plasma chloride 5 mEq/L or more was halved with the use of gluconate/acetate-buffered solution compared with saline (odds ratio, 0.50 [95% CI, 0.31-0.83]; P = .007) and with the use of lactate-buffered solution compared with saline (odds ratio, 0.47 [95% CI, 0.28-0.79]; P = .004). New-onset acute kidney injury was observed in 10 patients (6.1%), 6 patients (3.7%), and 5 patients (3.2%) in the gluconate/acetate-buffered solution, lactate-buffered solution, and saline groups, respectively. Conclusions and Relevance: Balanced solutions (gluconate/acetate-buffered solution and lactate-buffered solution) administered as intravenous fluid therapy reduced the incidence of rise in plasma chloride compared with saline in children in PICU. Trial Registration: anzctr.org.au Identifier: ACTRN12619001244190.

Combined effects of sepsis and extracorporeal membrane oxygenation on left ventricular performance in a murine model.

Extracorporeal membrane oxygenation (ECMO) may be a viable salvage therapy in selected patients with septic shock. As ECMO use increases, we studied left ventricular (LV) performance during sepsis with and without ECMO using a pressure-volume (PV) loop in a murine model and aimed to understand LV hemodynamics in septic shock with ECMO. The rats were divided into Group 1 (ECMO applied to healthy rats), Group 2 (ECMO for septic rats), Group 3 (Controls, n = 20) and Group 4 (Sepsis induction only, n = 20). The cardiac parameters include end-diastolic volume (EDV), end-systolic volume (ESV), end-diastolic pressure (EDP), and end-systolic pressure (ESP), ejection fraction (EF), end-systolic elastance (Ees), diastolic time constant (Tau) index, arterial elastance (Ea), pressure-volume area (PVA), stroke work (SW), and potential energy (PE). We compared the changes of parameters in all groups. A total of 74 rats were included in the analyses. After 2 h on ECMO, Group 2 was associated with significant increases in ESP, EDV, ESV, PVA, PE, and SW. The difference ratio of PE and PVA was significantly higher in Group 2 compared to Group 1 (P < 0.01). In conclusion, myocardial oxygen consumption was higher in septic shock with ECMO than in controls.

Patient and economic impact of implementing a paediatric sepsis pathway in emergency departments in Queensland, Australia.

We examined systems-level costs before and after the implementation of an emergency department paediatric sepsis screening, recognition and treatment pathway. Aggregated hospital admissions for all children aged < 18y with a diagnosis code of sepsis upon admission in Queensland, Australia were compared for 16 participating and 32 non-participating hospitals before and after pathway implementation. Monte Carlo simulation was used to generate uncertainty intervals. Policy impacts were estimated using difference-in-difference analysis comparing observed and expected results. We compared 1055 patient episodes before (77.6% in-pathway) and 1504 after (80.5% in-pathway) implementation. Reductions were likely for non-intensive length of stay (- 20.8 h [- 36.1, - 8.0]) but not intensive care (-9.4 h [- 24.4, 5.0]). Non-pathway utilisation was likely unchanged for interhospital transfers (+ 3.2% [- 5.0%, 11.4%]), non-intensive (- 4.5 h [- 19.0, 9.8]) and intensive (+ 7.7 h, [- 20.9, 37.7]) care length of stay. After difference-in-difference adjustment, estimated savings were 596 [277, 942] non-intensive and 172 [148, 222] intensive care days. The program was cost-saving in 63.4% of simulations, with a mean value of $97,019 [- $857,273, $1,654,925] over 24 months. A paediatric sepsis pathway in Queensland emergency departments was associated with potential reductions in hospital utilisation and costs.