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.

Agreement Between Measured Weight and Fluid Balance in Mechanically Ventilated Children in Intensive Care.

OBJECTIVES: To investigate the agreement between change in body weight (BW) and fluid balance (FB), and the precision and safety of BW measurement in mechanically ventilated infants in intensive care. DESIGN: Prospective observational study. SETTING: Tertiary PICU. PATIENTS: Infants following cardiac surgery, at baseline, 24 hours, and 48 hours. INTERVENTIONS: BW and FB measurement at three time points. MEASUREMENTS AND MAIN RESULTS: Between May 2021 and September 2022, we studied 61 children. The median age was 8 days (interquartile range [IQR], 1.0-14.0 d). The median BW at baseline was 3,518 g (IQR, 3,134-3,928 g). Change in BW was -36 g (IQR, -145 to 105 g) and -97 g (IQR, -240 to -28 g) between baseline and 24 hours, and between 24 and 48 hours, respectively. Change in FB was -82 mL (IQR, -173 to 12 mL) and -107 mL (IQR, -226 to 103) between baseline and 24 hours, and between 24 and 48 hours, respectively. In Bland-Altman analyses, the mean bias between BW and FB at 24 and 48 hours was 54 g (95% CI, 12-97) and -43 g (95% CI, -108 to 23), respectively. This exceeded 1% of the median BW, and limits of agreement ranged from 7.6% to 15% of baseline BW. The precision of paired weight measurements, performed sequentially at each time interval, was high (median difference of ≤1% of BW at each time point). The median weight of connected devices ranged from 2.7% to 3% of BW. There were no episodes of tube or device dislodgments and no change in vasoactive therapies during weight measurements. CONCLUSIONS: There is moderate agreement between the changes in FB and BW, albeit greater than 1% of baseline BW, and the limits of this agreement are wide. Weighing mechanically ventilated infants in intensive care is a relatively safe and precise method for estimating change in fluid status. Device weight represents a relatively large proportion of BW.

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.

Characteristics and Physiologic Changes After 4% Albumin Fluid Boluses in a PICU.

OBJECTIVES: To describe the characteristics, hemodynamic, and physiologic changes after 4% albumin fluid boluses in critically ill children. DESIGN: Retrospective observational study. SETTING: Single-center PICU. PATIENTS: Children in a cardiac and general PICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Between January 2017 and May 2019, there were 1,003 fluid boluses of 4% albumin during 420 of 5,731 admissions (7.8%), most commonly in children with congenital/acquired heart disease (71.2%) and sepsis (7.9%). The median fluid bolus dose was 10 mL/kg (interquartile range, 5.8-14.6 mL/kg), and its duration 30 minutes (interquartile range, 14.0-40.0 min; n = 223). After the fluid bolus, a significant change in mean arterial pressure (2.3 mm Hg [5.1%], 2.7 mm Hg [5.8%], 2.9 mm Hg [6.1%], and 3.8 mm Hg [8.0%] at 1, 2, 3, and 4 hr, respectively [p ≤ 0.001]) only occurred in children less than or equal to 12 months old. A mean arterial pressure response, defined by an increase greater than or equal to 10% from baseline, occurred in 290 of 887 patients (33%) with maximal response at 1 hour. Hypotension at baseline predicted the magnitude of mean arterial pressure increase at 60 (coefficient 24.3 [95% CI, 0.79-7.87]; p = 0.04) and 120 minutes (coefficient 26.1 [95% CI, 2.75-48.2]; p = 0.02). There were no biochemical or hematocrit changes within 4 hours of the fluid bolus. Urine output for the entire cohort was 2 mL/kg/hr at baseline and did not change with the fluid bolus. CONCLUSIONS: Fluid boluses of 4% albumin were common and predominantly in children with cardiac disease and sepsis with a median dose of 10 mL/kg given over half an hour. Such treatment was associated with significant hemodynamic changes only in children less than 12 months old, and we failed to identify an association with urine output.

Fluid Accumulation in Mechanically Ventilated, Critically Ill Children: Retrospective Cohort Study of Prevalence and Outcome.

OBJECTIVES: To describe the prevalence, patterns, explanatory variables, and outcomes associated with fluid accumulation (FA) in mechanically ventilated children. DESIGN: Retrospective cohort study. SETTING: Tertiary PICU. PATIENTS: Children mechanically ventilated for greater than or equal to 24 hours. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Between July 2016 and July 2021, 1,636 children met eligibility criteria. Median age was 5.5 months (interquartile range [IQR], 0.7-46.5 mo), and congenital heart disease was the most common diagnosis. Overall, by day 7 of admission, the median maximum cumulative FA, as a percentage of estimated admission weight, was 7.5% (IQR, 3.3-15.1) occurring at a median of 4 days after admission. Overall, higher FA was associated with greater duration of mechanical ventilation (MV) (mean difference, 1.17 [95% CI, 1.13-1.22]; p < 0.001]), longer intensive care length of stay (LOS) (mean difference, 1.16 [95% CI, 1.12-1.21]; p < 0.001]), longer hospital LOS (mean difference, 1.19 [95% CI, 1.13-1.26]; p < 0.001]), and increased mortality (odds ratio, 1.31 [95% CI, 1.08-1.59]; p = 0.005). However, these associations depended on the effects of children with extreme values, and there was no increase in risk up to 20% FA, overall, in children following cardiopulmonary bypass and in children in the general ICU. When excluding children with maximum FA of >10%, there was no association with duration of MV (mean difference, 0.99 [95% CI, 0.94-1.04]; p = 0.64) and intensive care or hospital LOS (mean difference, 1.01 [95% CI, 0.96-1.06]; p = 0.70 and 1.01 [95% CI, 0.95-1.08]; 0.79, respectively) but an association with reduced mortality 0.71 (95% CI, 0.53-0.97; p = 0.03). CONCLUSIONS: In mechanically ventilated critically ill children, greater maximum FA was associated with longer duration of MV, intensive care LOS, hospital LOS, and mortality. However, these findings were driven by extreme values of FA of greater than 20%, and up to 10%, there was reduced mortality and no signal of harm.

Characteristics, management and changing incidence of children with empyema in a paediatric intensive care unit.

AIM: Paediatric intensive care unit (PICU) admissions for empyema increased following the 13-valent pneumococcal conjugate vaccine (PCV13). We describe the clinical characteristics, management and outcomes for children with empyema and compare incidence before and after PCV13. METHODS: Retrospective study of patients <18 years admitted to The Royal Children's Hospital Melbourne PICU with empyema between January 2016 and July 2019. We investigated the incidence of empyema during two time periods: 2007-2010 (pre-PCV13) and 2016-2019 (post-PCV13). RESULTS: Seventy-one children (1.9% of all PICU admissions) were admitted to PICU with empyema between 2016 and 2019. Sixty-one (86%) had unilateral disease, 11 (16%) presented with shock and 44 (62%) were ventilated. Streptococcus pneumoniae and group A Streptococcus were the most commonly identified pathogens. Forty-five (63%) were managed with video-assisted thoracoscopic surgery (VATS). There was a 31% reduction in empyema hospitalisations as a proportion of all hospitalisations (IRR 0.69, 95% CI 0.59-0.8), but a 2.8-fold increase in empyema PICU admissions as a proportion of all PICU admissions (95% CI 2.2-3.5, P < 0.001). For the PICU cohort, this was accompanied by reduction in PIM2 probability of death (median 1% vs. 1.9%, P = 0.02) and duration of intubation (median 69 h vs. 126.5 h, P = 0.045). CONCLUSIONS: In children with empyema in PICU 62% required ventilation, 16% had features of shock and 63% received VATS. Empyema admissions, as a proportion of all PICU admissions, increased in the era post-PCV13 compared to pre-PCV13 despite no increase in illness severity at admission.

Carboxyhemoglobin levels in children during extracorporeal membrane oxygenation support: a retrospective study.

INTRODUCTION: Hemolysis is a common complication of extracorporeal membrane oxygenation (ECMO). There are few data on whether carboxyhemoglobin (COHb), a potential marker of hemolysis, are elevated during ECMO support. METHODS: We conducted a single-center, retrospective study comparing peak COHb levels of children pre-, during, and post-ECMO from January 2017 to August 2020. RESULTS: There were 154 ECMO runs in 147 children (154 PICU admissions) included in the study. The median age was 3.5 (IQR 0.2, 39.2) months. Veno-arterial ECMO was the predominant mode: 146/154 (94.8%). Eighty-seven children (56.5%) underwent cardiac surgery. Peak COHb levels during ECMO were statistically significantly higher compared to pre ECMO (COHb 1.8% (IQR 1.4, 2.6) vs COHb 1.2% (IQR 0.7, 1.7), p < 0.001) and post ECMO (COHb 1.6% (IQR 1.3, 2.2), p = 0.009). Children with COHb ⩾2% were younger and had longer duration of ECMO support. Plasma hemoglobin weakly correlated with COHb level (r = 0.14; p = 0.04). CONCLUSIONS: Carboxyhemoglobin levels increased during ECMO support compared to the pre and post ECMO period. Younger age and longer ECMO duration were associated with COHb levels ⩾2%. Plasma hemoglobin weakly correlated with COHb level.

Hemodynamic Response to Fluid Boluses for Hypotension in Children in a Cardiac ICU.

OBJECTIVES: To describe the hemodynamic response to fluid boluses for hypotension in children in a cardiac ICU. DESIGN: A prospective, observational study. SETTING: Single-centered cardiac ICU. PATIENTS: Children in a cardiac ICU with hypotension. INTERVENTIONS: Clinician prescribed fluid bolus. MEASUREMENTS AND MAIN RESULTS: Sixty-four fluid boluses were administered to 52 children. Fluid composition was 4% albumin in 36/64 (56%), 0.9% saline in 18/64 (28%), and cardiopulmonary bypass pump blood in 10/64 (16%). The median volume and duration were 5.0 mL/kg (interquartile range, 4.8-5.4) and 8 minutes (interquartile range, 4-19), respectively. Hypovolemia/low filling pressures was the most common additional indication (25/102 [25%]). Mean arterial pressure response, defined as a 10% increase from baseline, occurred in 42/64 (66%) of all fluid boluses at a median time of 6 minutes (interquartile range, 4-11). Mean arterial pressure responders had a median peak increase in the mean arterial pressure of 15 mm Hg (43 mm Hg [interquartile range, 29-50 mm Hg] to 58 mm Hg [interquartile range, 49-65 mm Hg]) at 17 minutes (interquartile range, 14-24 min) compared with 4 mm Hg (48 mm Hg [interquartile range, 40-51 mm Hg] to 52 mm Hg [interquartile range, 45-56 mm Hg]) at 10 minutes (interquartile range, 3-18 min) in nonresponders. Dissipation of mean arterial pressure response, when defined as a subsequent decrement in mean arterial pressure below 10%, 5%, and 2% increases from baseline, occurred in 28/42 (67%), 18/42 (43%), and 13/42 (31%) of mean arterial pressure responders, respectively. Cardiopulmonary bypass pump blood was strongly associated with peak change in mean arterial pressure from baseline (coefficient 11.0 [95% CI, 4.3-17.7]; p = 0.02). Fifty out of 64 (78%) were receiving a vasoactive agent. However, change in vasoactive inotrope score was not associated with change in mean arterial pressure (coefficient 2.3 [95% CI, -2.5 to -7.2]; p = 0.35). Timing from admission, nor fluid bolus duration, influenced mean arterial pressure response. CONCLUSIONS: In children with hypotension in a cardiac ICU, the median dose and duration of fluid boluses were 5 mL/kg and 8 minutes. Peak response occurred shortly following administration and commonly returned to baseline.

Development of a multinational registry of pediatric deceased organ donation activity.

BACKGROUND: There are no currently agreed upon international standards for reporting of pediatric deceased organ donation activity. This leads to difficulty in comparisons between jurisdictions for both researchers and policy stakeholders. The goal of this project was to develop and test a standardized registry for pediatric deceased donation activity. METHODS: Four countries (Canada, Spain, USA, and the UK) with geographical and practice diversity were approached to participate. Iterative exchanges were used to create data fields and definitions that were acceptable to all participants. Data from 2011 to 2015 (inclusive) were requested from national health databases and analyzed on a secure, web-based survey platform. RESULTS: Data were obtained from three of the four countries (Canada unable to provide). Total pediatric donation rates were stable over the 5-year period, but with variation between countries. pDCD rates were the most variable, representing 32.2% of total pediatric donation in the UK, 14.4% in the United States, and 2.6% in Spain during the studied period. Most organs from pediatric donors were allocated to adult recipients, though the rates of allocation of pediatric kidneys to pediatric recipients ranged from 7% in the United States to 40% in Spain. DISCUSSION: In this limited cohort of three countries, we demonstrated substantial variation in pediatric donation rates and practice. These data highlight opportunities for practice improvement such as the development of rigorous clinical practice guidelines. Future development of this registry will seek to engage more countries, and address barriers that prevented full participation of approached jurisdictions.

Rhabdomyolysis in a Tertiary PICU: A 10-Year Study.

OBJECTIVES: Rhabdomyolysis is a disorder of muscle breakdown. The aim of this study was to describe the epidemiology of rhabdomyolysis in children admitted to a PICU and to assess the relationship between peak creatinine kinase and mortality. DESIGN: Retrospective cohort study in children admitted to the PICU with rhabdomyolysis between January 1, 2005, and December 31, 2014. Demographic, clinical, and outcome data were recorded. Outcomes were analyzed by level of peak creatinine kinase value (0-10,000, 10,001-50,000, > 50,000IU/L). Long-term renal outcomes were reported for PICU survivors. SETTING: A single-centre academic tertiary PICU. PATIENTS: Children admitted to the PICU with serum creatinine kinase level greater than 1,000 IU/L. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: There were 182 children with rhabdomyolysis. The median peak creatinine kinase value was 3,583 IU/L (1,554-9,608). The primary diagnostic categories included sepsis, trauma, and cardiac arrest. Mortality for peak creatinine kinase values 0-10,000, 10,001-50,000, and > 50,000 IU/L were 24/138 (17%), 6/28 (21%), and 3/16 (19%), respectively (p = 0.87). Children with a peak creatinine kinase greater than 10,000 IU/L had a longer duration of mechanical ventilation and ICU length of stay than children with peak creatinine kinase less than 10,000. Renal replacement therapy was administered in 29/182 (16%). There was longer duration of mechanical ventilation (273 [141-548] vs. 73 [17-206] hr [p < 0.001]) and ICU length of stay (334 [147-618] vs. 100 [37-232] hr (p < 0.001)] in children receiving renal replacement therapy. Continuous veno-venous hemofiltration was the most common modality 23/29 (79%). Only one child required renal replacement therapy postintensive care stay, and adverse long-term renal outcomes were uncommon. CONCLUSIONS: In children with rhabdomyolysis requiring intensive care, peak creatinine kinase was not associated with mortality but is associated with greater use of intensive care resources. Chronic kidney disease is an uncommon sequelae of rhabdomyolysis in children requiring intensive care.

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.

Challenges of paediatric organ donation.

Paediatric organ donation represents a small fraction of overall organ donation in Australia and New Zealand and indeed world-wide. Many factors contribute to low donation rates including low paediatric intensive care mortality, consent rates and medical suitability relating to disease, age and size. In the past decade, the re-emergence of donation after circulatory death has changed the landscape for the paediatric population. This article reviews the current status and challenges of organ donation for the paediatric population.

Fluid Bolus Therapy-Based Resuscitation for Severe Sepsis in Hospitalized Children: A Systematic Review.

OBJECTIVES: To review systematically data from randomized and nonrandomized studies of fluid bolus therapy in hospitalized children with septic shock. DATA SOURCES: Medline, EMBASE, and Cochrane Central Register of Controlled Trials. STUDY SELECTION: We searched for randomized controlled studies of fluid bolus therapy in children with severe sepsis. We identified retrospective, prospective, and observational studies. We excluded studies of severe sepsis/septic shock due to a specific microbiological etiology, neonatal studies, and studies where advanced supportive therapies were unavailable. DATA EXTRACTION: Two authors screened articles for inclusion. DATA SYNTHESIS: We identified and analyzed three randomized controlled trials and eight nonrandomized studies. Heterogeneity precluded meta-analysis. Two single-center Indian studies and one Brazilian study assessed three different fluid bolus therapy regimens in small cohorts with different populations, physiological triggers, and physiological and clinical outcomes. No randomized controlled trials compared fluid bolus therapy with alternative interventions, such as vasopressors. The nonrandomized studies were heterogeneous in populations, methodology, and outcome measures. No observed physiological differences were identified based on volume of fluid bolus therapy. CONCLUSIONS: There are only limited data to support the use of fluid bolus therapy in hospitalized children. Prospective observational data and randomized controlled trials are urgently needed to evaluate this therapy in resource rich settings.

Time to Continuous Renal Replacement Therapy Initiation and 90-Day Major Adverse Kidney Events in Children and Young Adults.

Importance: In clinical trials, the early or accelerated continuous renal replacement therapy (CRRT) initiation strategy among adults with acute kidney injury or volume overload has not demonstrated a survival benefit. Whether the timing of initiation of CRRT is associated with outcomes among children and young adults is unknown. Objective: To determine whether timing of CRRT initiation, with and without consideration of volume overload (VO; <10% vs ≥10%), is associated with major adverse kidney events at 90 days (MAKE-90). Design, Setting, and Participants: This multinational retrospective cohort study was conducted using data from the Worldwide Exploration of Renal Replacement Outcome Collaborative in Kidney Disease (WE-ROCK) registry from 2015 to 2021. Participants included children and young adults (birth to 25 years) receiving CRRT for acute kidney injury or VO at 32 centers across 7 countries. Statistical analysis was performed from February to July 2023. Exposure: The primary exposure was time to CRRT initiation from intensive care unit admission. Main Outcomes and measures: The primary outcome was MAKE-90 (death, dialysis dependence, or persistent kidney dysfunction [>25% decline in estimated glomerular filtration rate from baseline]). Results: Data from 996 patients were entered into the registry. After exclusions (n = 27), 969 patients (440 [45.4%] female; 16 (1.9%) American Indian or Alaska Native, 40 (4.7%) Asian or Pacific Islander, 127 (14.9%) Black, 652 (76.4%) White, 18 (2.1%) more than 1 race; median [IQR] patient age, 8.8 [1.7-15.0] years) with data for the primary outcome (MAKE-90) were included. Median (IQR) time to CRRT initiation was 2 (1-6) days. MAKE-90 occurred in 630 patients (65.0%), of which 368 (58.4%) died. Among the 601 patients who survived, 262 (43.6%) had persistent kidney dysfunction. Of patients with persistent dysfunction, 91 (34.7%) were dependent on dialysis. Time to CRRT initiation was approximately 1 day longer among those with MAKE-90 (median [IQR], 3 [1-8] days vs 2 [1-4] days; P = .002). In the generalized propensity score-weighted regression, there were approximately 3% higher odds of MAKE-90 for each 1-day delay in CRRT initiation (odds ratio, 1.03 [95% CI, 1.02-1.04]). Conclusions and Relevance: In this cohort study of children and young adults receiving CRRT, longer time to CRRT initiation was associated with greater risk of MAKE-90 outcomes, in particular, mortality. These findings suggest that prospective multicenter studies are needed to further delineate the appropriate time to initiate CRRT and the interaction between CRRT initiation timing and VO to continue to improve survival and reduce morbidity in this population.

Sepsis epidemiology in Australian and New Zealand children (SENTINEL): protocol for a multicountry prospective observational study.

INTRODUCTION: Sepsis affects 25.2 million children per year globally and causes 3.4 million deaths, with an annual cost of hospitalisation in the USA of US$7.3 billion. Despite being common, severe and expensive, therapies and outcomes from sepsis have not substantially changed in decades. Variable case definitions, lack of a reference standard for diagnosis and broad spectrum of disease hamper efforts to evaluate therapies that may improve sepsis outcomes. This landscape analysis of community-acquired childhood sepsis in Australia and New Zealand will characterise the burden of disease, including incidence, severity, outcomes and cost. Sepsis diagnostic criteria and risk stratification tools will be prospectively evaluated. Sepsis therapies, quality of care, parental awareness and understanding of sepsis and parent-reported outcome measures will be described. Understanding these aspects of sepsis care is fundamental for the design and conduct of interventional trials to improve childhood sepsis outcomes. METHODS AND ANALYSIS: This prospective observational study will include children up to 18 years of age presenting to 12 emergency departments with suspected sepsis within the Paediatric Research in Emergency Departments International Collaborative network in Australia and New Zealand. Presenting characteristics, management and outcomes will be collected. These will include vital signs, serum biomarkers, clinician assessment of severity of disease, intravenous fluid administration for the first 24 hours of hospitalisation, organ support therapies delivered, antimicrobial use, microbiological diagnoses, hospital and intensive care unit length-of-stay, mortality censored at hospital discharge or 30 days from enrolment (whichever comes first) and parent-reported outcomes 90 days from enrolment. We will use these data to determine sepsis epidemiology based on existing and novel diagnostic criteria. We will also validate existing and novel sepsis risk stratification criteria, characterise antimicrobial stewardship, guideline adherence, cost and report parental awareness and understanding of sepsis and parent-reported outcome measures. ETHICS AND DISSEMINATION: Ethics approval was received from the Royal Children's Hospital of Melbourne, Australia Human Research Ethics Committee (HREC/69948/RCHM-2021). This included incorporated informed consent for follow-up. The findings will be disseminated in a peer-reviewed journal and at academic conferences. TRIAL REGISTRATION NUMBER: ACTRN12621000920897; Pre-results.