Neurodevelopmental outcome and quality of life in children admitted to the paediatric intensive care unit: A single-centre Australian cohort study.

BACKGROUND: The development of new morbidities has become increasingly identified in paediatric critical care medicine. To date, there has been limited research of long-term outcomes following paediatric critical illness in Australia. OBJECTIVES: The objective of this study was to quantify neurodevelopmental impairments in children following paediatric intensive care unit (PICU) discharge and their association with health-related quality of life (HRQoL). METHODS: A single-centre ambidirectional cohort study at an Australian hospital. Parents of children admitted to the PICU between 2015 and 2017 were invited to participate. Neurodevelopmental outcome and HRQoL was prospectively evaluated, using the Ages and Stages Questionnaire (<5 years), Strengths and Difficulties Questionnaire (≥5 years), and Pediatric Quality of Life Inventory™, respectively. RESULTS: A total of 230 parents of critically ill children participated. Children were 1.9 years old (median, interquartile range [IQR]: 0.2, 7.5), male (59.6%), and ventilated (49.1%) at PICU admission. The median time to follow-up was 24.4 months (IQR: 16.3, 36.7). Parent respondents were more likely to be female (85.5%), White (88.3%), and partnered (81.1%). The incidence of overall neurodevelopmental impairment was 30% (33% in children aged <5 years; 24% in children aged ≥5 years). The incidence of poor HRQoL was 37.9%. History of developmental delay was independently associated with overall neurodevelopmental impairment (adjusted odds ratio [aOR]: 4.21, 95% confidence interval: 2.05, 8.63) and poor HRQoL (aOR: 7.29, 95% confidence interval: 3.26, 16.27). Two or more PICU admissions (aOR: 4.10, IQR: 1.82, 9.26) was also associated with poor HRQoL. CONCLUSIONS: This is the first contemporary view of PICU long-term outcomes conducted in Australia and significantly informs ongoing research in this area. Approximately one-third of PICU survivors demonstrate neurodevelopmental impairment and reduced quality of life. Multiple domains of post-intensive care syndrome-paediatrics must be considered to have a comprehensive understanding of child outcomes. Assessment of baseline/premorbid functioning is also essential in order to understand the true impact of illness and PICU admission.

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.

Assessing the impact of risk-based data monitoring on outcomes for a paediatric multicentre randomised controlled trial.

BACKGROUND/AIMS: Regulatory guidelines recommend that sponsors develop a risk-based approach to monitoring clinical trials. However, there is a lack of evidence to guide the effective implementation of monitoring activities encompassed in this approach. The aim of this study was to assess the efficiency and impact of the risk-based monitoring approach used for a multicentre randomised controlled trial comparing treatments in paediatric patients undergoing cardiac bypass surgery. METHODS: This is a secondary analysis of data from a randomised controlled trial that implemented targeted source data verification as part of the risk-based monitoring approach. Monitoring duration and source to database error rates were calculated across the monitored trial dataset. The monitored and unmonitored trial dataset, and simulated trial datasets with differing degrees of source data verification and cohort sizes were compared for their effect on trial outcomes. RESULTS: In total, 106,749 critical data points across 1,282 participants were verified from source data either remotely or on-site during the trial. The total time spent monitoring was 365 hours, with a median (interquartile range) of 10 (7, 16) minutes per participant. An overall source to database error rate of 3.1% was found, and this did not differ between treatment groups. A low rate of error was found for all outcomes undergoing 100% source data verification, with the exception of two secondary outcomes with error rates >10%. Minimal variation in trial outcomes were found between the unmonitored and monitored datasets. Reduced degrees of source data verification and reduced cohort sizes assessed using simulated trial datasets had minimal impact on trial outcomes. CONCLUSIONS: Targeted source data verification of data critical to trial outcomes, which carried with it a substantial time investment, did not have an impact on study outcomes in this trial. This evaluation of the cost-effectiveness of targeted source data verification contributes to the evidence-base regarding the context where reduced emphasis should be placed on source data verification as the foremost monitoring activity.

Perioperative dexmedetomidine compared to midazolam in children undergoing open-heart surgery: A pilot randomised controlled trial.

Objective: There is a need for evidence on the best sedative agents in children undergoing open heart surgery for congenital heart disease. This study aimed to evaluate the feasibility and safety of dexmedetomidine in this group compared with midazolam. Design: Double blinded, pilot randomized controlled trial. Setting: Cardiac operating theatre and paediatric intensive care unit in Brisbane, Australia. Participants: Infants (≤12 months of age) undergoing their first surgical repair of a congenital heart defect. Interventions: Dexmedetomidine (up to 1.0mcg/kg/hr) versus midazolam (up to 80mcg/kg/hr), commenced in the cardiac operating theatre prior to surgery. Main outcome measures: The primary outcome was the time spent in light sedation (Sedation Behavior Scale [SBS] -1 to +1); Co-primary feasibility outcome was recruitment, retention and protocol adherence. Secondary outcomes were use of supplemental sedatives, ventilator free days, delirium, vasoactive drug support, and adverse events. Neurodevelopment and health-related quality of life (HRQoL) were assessed at 12 months post-surgery. Results: Sixty-six participants were recruited. The number of SBS scores in the light sedation range were greater in the dexmedetomidine group at 24 hours, 48 hours, and overall study duration (0-14 days) versus the midazolam group (24hr: 76/170 [45%] vs 60/178 [34%], aOR 4.14 [95% CI 0.48, 35.92]; 48hr: 154/298 [52%] vs 122/314 [39%], aOR 6.95 [95% CI 0.77, 63.13]; 0-14 days: 597/831 [72%] vs 527/939 [56%], aOR 3.93 [95% CI 0.62, 25.03]). Feasibility was established with no withdrawals or loss to follow-up at 14 days and minimal protocol deviations. There were no differences between the groups relating to clinical, safety, neurodevelopment or HRQoL outcomes. Conclusions: The use of dexmedetomidine was associated with more time spent in light sedation when compared with midazolam. The feasibility of conducting a blinded RCT of midazolam and dexmedetomidine in children undergoing open heart surgery was also established. The findings justify further investigation in a larger trial. Clinical trial registration: ACTRN12615001304527.

Transnasal Humidified Rapid Insufflation Ventilatory Exchange in children requiring emergent intubation (Kids THRIVE): a statistical analysis plan for a randomised controlled trial.

The placement of an endotracheal tube for children with acute or critical illness is a low-frequency and high-risk procedure, associated with high rates of first-attempt failure and adverse events, including hypoxaemia. To reduce the frequency of these adverse events, the provision of oxygen to the patient during the apnoeic phase of intubation has been proposed as a method to prolong the time available for the operator to insert the endotracheal tube, prior to the onset of hypoxaemia. However, there are limited data from randomised controlled trials to validate the efficacy of this technique in children. The technique known as transnasal humidified rapid insufflation ventilatory exchange (THRIVE) uses high oxygen flow rates (approximately 2 L/kg/min) delivered through nasal cannulae during apnoea. It has been shown to at least double the amount of time available for safe intubation in healthy children undergoing elective surgery. The technique and its application in real time have not previously been studied in acutely ill or injured children presenting to the emergency department or admitted to an intensive care unit. The Kids THRIVE trial is a multicentre, international, randomised controlled trial (RCT) in children less than 16 years old undergoing emergent intubation in either the intensive care unit or emergency department of participating hospitals. Participants will be randomised to receive either the THRIVE intervention or standard care (no apnoeic oxygenation) during their intubation. The primary objective of the trial is to determine if the use of THRIVE reduces the frequency of oxygen desaturation and increases the frequency of first-attempt success without hypoxaemia in emergent intubation of children compared with standard practice. The secondary objectives of the study are to assess the impact of the use of THRIVE on the rate of adverse events, length of mechanical ventilation and length of stay in intensive care. In this paper, we describe the detailed statistical analysis plan as an update of the previously published protocol.

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.

Research monitoring practices in critical care research: a survey of current state and attitudes.

BACKGROUND/AIMS: In 2016, international standards governing clinical research recommended that the approach to monitoring a research project should be undertaken based on risk, however it is unknown whether this approach has been adopted in Australia and New Zealand (ANZ) throughout critical care research. The aims of the project were to: 1) Gain an understanding of current research monitoring practices in academic-led clinical trials in the field of critical care research, 2) Describe the perceived barriers and enablers to undertaking research monitoring. METHODS: Electronic survey distributed to investigators, research co-ordinators and other research staff currently undertaking and supporting academic-led clinical trials in the field of critical care in ANZ. RESULTS: Of the 118 respondents, 70 were involved in the co-ordination of academic trials; the remaining results pertain to this sub-sample. Fifty-eight (83%) were working in research units associated with hospitals, 29 (41%) were experienced Research Coordinators and 19 (27%) Principal Investigators; 31 (44%) were primarily associated with paediatric research. Fifty-six (80%) develop monitoring plans with 33 (59%) of these undertaking a risk assessment; the most common barrier reported was lack of expertise. Nineteen (27%) indicated that centralised monitoring was used, noting that technology to support centralised monitoring (45/51; 88%) along with support from data managers and statisticians (45/52; 87%) were key enablers. Coronavirus disease-19 (COVID-19) impacted monitoring for 82% (45/55) by increasing remote (25/45; 56%) and reducing onsite (29/45; 64%) monitoring. CONCLUSIONS: Contrary to Good Clinical Practice guidance, risk assessments to inform monitoring plans are not being consistently performed due to lack of experience and guidance. There is an urgent need to enhance risk assessment methodologies and develop technological solutions for centralised statistical monitoring.

Prediction of Acute Kidney Injury on Admission to Pediatric Intensive Care.

OBJECTIVES: Up to 37% of children admitted to the PICU develop acute kidney injury as defined by Kidney Disease: Improving Global Outcomes criteria. We describe the prevalence of acute kidney injury in a mixed pediatric intensive care cohort using this criteria. As tools to stratify patients at risk of acute kidney injury on PICU admission are lacking, we explored the variables at admission and day 1 that might predict the development of acute kidney injury. DESIGN: Single-center retrospective observational study. SETTING: Thirty-six-bed surgical/medical tertiary PICU. PATIENTS: Children from birth to less than or equal to 16 years old admitted between 2015 and 2018. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Clinical data were extracted from the PICU clinical information system. Patients with baseline creatinine at admission greater than 20 micromol/L above the calculated normal creatinine level were classified as "high risk of acute kidney injury." Models were created to predict acute kidney injury at admission and on day 1. Out of the 7,505 children admitted during the study period, 738 patients (9.8%) were classified as high risk of acute kidney injury at admission and 690 (9.2%) developed acute kidney injury during PICU admission. Compared to Kidney Disease: Improving Global Outcomes criteria as the reference standard, high risk of acute kidney injury had a lower sensitivity and higher specificity compared with renal angina index greater than or equal to 8 on day 1. For the admission model, the adjusted odds ratio of developing acute kidney injury for high risk of acute kidney injury was 4.2 (95% CI, 3.3-5.2). The adjusted odds ratio in the noncardiac cohort for high risk of acute kidney injury was 7.3 (95% CI, 5.5-9.7). For the day 1 model, odds ratios for high risk of acute kidney injury and renal angina index greater than or equal to 8 were 3.3 (95% CI, 2.6-4.2) and 3.1 (95% CI, 2.4-3.8), respectively. CONCLUSIONS: The relationship between high risk of acute kidney injury and acute kidney injury needs further evaluation. High risk of acute kidney injury performed better in the noncardiac cohort.

Incident cancers and late mortality in Australian children treated by allogeneic stem cell transplantation for non-malignant diseases.

BACKGROUND: Hematopoietic stem cell transplantation (HSCT) is a life-saving procedure for children with a variety of non-malignant conditions. However, these children face an increased risk of late death and incident cancers after HSCT, which may occur many years after their initial HSCT. PROCEDURE: We examined cancer occurrence and late mortality in a population-based cohort of 318 Australian children who underwent allogeneic HSCT for non-malignant disease. Standardized incident ratios (SIRs) and standardized mortality ratios (SMRs) were calculated and compared with population controls. RESULTS: We identified six (1.9%) cancers at a median 9.2 years post-HSCT. Cancer occurred 15 times more frequently than in the general population (SIR 15.4, 95% CI = 6.9-34.2). Of the 198 patients who survived for at least 2 years post-HSCT, 11 (5.6%) died at a median 7.5 years post-HSCT. The mortality rate was 17 times higher than in the general population (SMR 17.5, 95% CI = 9.7-31.2). DISCUSSION: Children transplanted for non-malignant conditions require evidence-based survivorship programs to reduce excess morbidity and mortality.

Second Cancer Risk and Late Mortality in Adult Australians Receiving Allogeneic Hematopoietic Stem Cell Transplantation: A Population-Based Cohort Study.

We quantified the risk of second cancer and late mortality in a population-based Australian cohort of 3273 adult (≥15 years) allogeneic hematopoietic stem cell transplant recipients (1992 to 2007). Most recipients received nonradiation-based conditioning and a peripheral blood graft from a matched related donor. Using record linkage with death and cancer registries, 79 second cancers were identified a median of 3.5 years after transplantation. The competing-risk adjusted cumulative incidence of second cancers was 3.35% (95% CI, 2.59 to 4.24) at 10 years, and the cancer risk relative to the matched general population was 2.10 (95% CI, 1.65 to 2.56). We observed an excess risk of melanoma and lip, tongue, esophagus, and soft tissue cancers. Cancer risk relative to the general population was elevated for those transplanted for lymphoma, some leukemia subtypes, and severe aplastic anemia, recipients who developed chronic graft-versus-host disease (cGVHD) and irrespective of radiation-based conditioning or stem cell source. In those alive 2 years after transplantation (n = 1463), the cumulative incidence of late mortality was 22.2% (95% CI, 19.7 to 24.9) at 10 years, and the risk of death relative to the matched general population was 13.8 (95% CI, 12.2 to 15.6). In multivariable modeling, risk of late death was reduced for females compared with males and those transplanted for chronic myeloid leukemia compared with acute myeloid leukemia; risk was increased for recipients with discordant sex donors, cGVHD, those undergoing second transplants, and disease relapse. Adults undergoing allogeneic transplantation have unique cancer and mortality risk profiles that continue to warrant prevention and surveillance activities targeted at high-risk subgroups.

A population-based cohort study of late mortality in adult autologous hematopoietic stem cell transplant recipients in Australia.

We assessed overall and cause-specific mortality and risk factors for late mortality in a nation-wide population-based cohort of 4547 adult cancer patients who survived 2 or more years after receiving an autologous hematopoietic stem cell transplantation (HSCT) in Australia between 1992 and 2005. Deaths after HSCT were identified from the Australasian Bone Marrow Transplant Recipient Registry and through data linkage with the National Death Index. Overall, the survival probability was 56% at 10 years from HSCT, ranging from 34% for patients with multiple myeloma to 90% for patients with testicular cancer. Mortality rates moved closer to rates observed in the age- and sex-matched Australian general population over time but remained significantly increased 11 or more years from HSCT (standardized mortality ratio, 5.9). Although the proportion of deaths from nonrelapse causes increased over time, relapse remained the most frequent cause of death for all diagnoses, 10 or more years after autologous HSCT. Our findings show that prevention of disease recurrence remains 1 of the greatest challenges for autologous HSCT recipients, while the increasing rates of nonrelapse deaths due to the emergence of second cancers, circulatory diseases, and respiratory diseases highlight the long-term health issues faced by adult survivors of autologous HSCT.