Paediatrics (RCH) - Research Publications

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    A child presents with acute kidney injury, alkalosis and hypercalcaemia-a new-age cause for a historical syndrome: Answers
    Kermond, R ; Carter, S ; Quinlan, C (Springer, 2022-08)
    On further history, it was discovered that the family had been using alkaline water as an alternate source of oral fluids given its reported health benefits. Alkaline water is advertised as negatively charged water with a pH of 8–10. These properties are marketed to provide significant health benefits including increased energy levels, reduced effects of ageing and stress and reduced incidence of illness and disease. Alkaline water contains calcium and magnesium carbonate, both exogenous sources of absorbable alkaline. The consumption of alkaline water in this case resulted in a milk-alkali syndrome with hypercalcaemia, metabolic alkalosis and an acute on chronic kidney injury. It was not detected for several months, and as a result, had a significant negative impact on this patient and his family. He required frequent venepuncture, increased clinical reviews (further complicated by the current COVID-19 pandemic) and regular titration of medications. Fortunately, on cessation of the alkaline water, his creatinine returned to baseline and calcium and acid–base normalised.
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    Interhospital transport of children with bronchiolitis by a statewide emergency transport service
    Fahey, KP ; Gelbart, B ; Oberender, F ; Thompson, J ; Rozen, T ; James, C ; McLaren, C ; Sniderman, J ; Uahwatanasakul, W (AUSTRALASIAN MED PUBL CO LTD, 2021-09)
    Objective: To investigate the rate of interhospital emergency transport for bronchiolitis and intensive care admission following the introduction of high flow nasal cannula and standardised paediatric observation and response charts. Design: Retrospective cohort study. Setting: A statewide paediatric intensive care transport service and its two referral paediatric intensive care units (PICUs) in Victoria, Australia. Participants: Children less than 2 years old emergently transported with bronchiolitis during two time periods: 2008-2012 and 2015-2019. Main outcome measures: Incidence rates of bronchiolitis transport episodes, PICU admissions and respiratory support. Results: 802 children with bronchiolitis were transported during the study period, 233 in the first period (2008-2012) and 569 in the second period (2015-2019). The rate of interhospital transport for bronchiolitis increased from 32.9 to 71.8 per 100 000 children aged 0-2 years. The population-adjusted rate of PICU admission increased from 16.2 to 36.6 per 100 000 children aged 0-2 years. Metropolitan hospitals were the predominant referral source and this increased from 60.1% of transports to 78.6% (P < 0.001). In children admitted to a PICU, the administration of high flow nasal cannula during transport increased significantly from 1.7% to 75.9% (P < 0.001) and a concomitant reduction in continuous positive airway pressure and mechanical ventilation occurred (40-12.4% and 27-6.9% respectively; P < 0.001). The proportion of mechanical ventilation as well as PICU and hospital length of stay decreased over time. Conclusions: The population-adjusted rate of interhospital transport and admission to the PICU for bronchiolitis increased over time. This occurred despite a lower rate of non-invasive and invasive mechanical ventilation during transport and in the PICU.
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    Characteristics and outcomes of children receiving intensive care therapy within 12 hours following a medical emergency team event
    Gelbart, B ; Vidmar, S ; Stephens, D ; Cheng, D ; Thompson, J ; Segal, A ; Gadish, T ; Carlin, J (AUSTRALASIAN MED PUBL CO LTD, 2021-09)
    Objectives: To describe characteristics and outcomes of children requiring intensive care therapy (ICT) within 12 hours following a medical emergency team (MET) event. Design: Retrospective cohort study. Setting: Quaternary paediatric hospital. Patients: Children experiencing a MET event. Measurements and main results: Between July 2017 and March 2019, 890 MET events occurred in 566 patients over 631 admissions. Admission to intensive care followed 183/890 (21%) MET events. 76/183 (42%) patients required ICT, defined as positive pressure ventilation or vasoactive support in intensive care, within 12 hours. Older children had a lower risk of requiring ICT than infants aged < 1 year (age 1-5 years [risk difference, -6.4%; 95% CI, -11% to -1.6%; P = 0.01] v age > 5 years [risk difference, -8.0%; 95% CI, -12% to -3.8%; P < 0.001]), while experiencing a critical event increased this risk (risk difference, 16%; 95% CI, 3.3-29%; P = 0.01). The duration of respiratory support and intensive care length of stay was approximately double in patients requiring ICT (ratio of geometric means, 2.0 [95% CI, 1.4-3.0] v 2.1 [95% CI, 1.5-2.8]; P < 0.001) and the intensive care mortality increased (risk difference, 9.6%; 95% CI, 2.4-17%; P = 0.01). Heart rate, oxygen saturation and respiratory rate were the most commonly measured vital signs in the 6 hours before the MET event. Conclusions: Approximately one-fifth of MET events resulted in intensive care admission and nearly half of these required ICT within 12 hours. This group had greater duration of respiratory support, intensive care and hospital length of stay, and higher mortality. Age < 1 year and a critical event increased the risk of ICT.
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    Statistical analysis plan for the NITric oxide during cardiopulmonary bypass to improve Recovery in Infants with Congenital heart defects (NITRIC) trial
    Gibbons, KS ; Schlapbach, LJ ; Horton, SB ; Long, DA ; Beca, J ; Erickson, S ; Festa, M ; d'Udekem, Y ; Alphonso, N ; Winlaw, D ; Johnson, K ; Delzoppo, C ; van Loon, K ; Gannon, B ; Fooken, J ; Blumenthal, A ; Young, PJ ; Butt, W ; Schibler, A (ELSEVIER, 2021-03)
    Background: The NITric oxide during cardiopulmonary bypass (CPB) to improve Recovery in Infants with Congenital heart defects (NITRIC) trial, a 1320-patient, multicentre, randomised controlled trial, is aiming to improve survival free of ventilation after CPB by using nitric oxide delivered into the oxygenator of the CPB. Objective: To provide a statistical analysis plan before completion of patient recruitment and data monitoring. Final analyses for this study will adhere to this statistical analysis plan, which details all key pre-planned analyses. Stata scripts for analyses have been prepared alongside this statistical analysis plan. Methods: The statistical analysis plan was designed collaboratively by the chief investigators and trial statistician and builds on the previously published study protocol. All authors remain blinded to treatment allocation. Detail is provided on statistical analyses including cohort description, analysis of primary and secondary outcomes and adverse events. Statistical methods to compare outcomes are planned in detail to ensure methods are verifiable and reproducible. Results: The statistical analysis plan developed provides the trial outline, list of mock tables, and analysis scripts. The plan describes statistical analyses on cohort and baseline description, primary and secondary outcome analyses, process of care measures, physiological descriptors, and safety and adverse event reporting. We define the pre-specified subgroup analyses and the respective statistical tests used to compare subgroups. Conclusion: The statistical analysis plan for the NITRIC trial establishes detailed pre-planned analyses alongside Stata scripts to analyse the largest trial in the field of neonatal and paediatric heart surgery. The plan ensures standards for trial analysis validity aiming to minimise bias of analyses.
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    The parenting skill development and education service: Telehealth support for families at risk of child maltreatment during the COVID-19 pandemic
    Fogarty, A ; Jones, A ; Seymour, M ; Savopoulos, P ; Evans, K ; O'Brien, J ; O'Dea, L ; Clout, P ; Auletta, S ; Giallo, R (WILEY, 2022-08)
    Children are at heightened risk of maltreatment during community wide crises. The Parenting Skill Development and Education (PSDE) Service is a 6‐week telehealth intervention designed and implemented during the COVID‐19 pandemic to support families with young children in Australia at risk of child maltreatment. This study aimed to conduct a formative review of the PSDE service to (a) describe families accessing the PSDE during the pandemic, (b) determine parent and referrers' satisfaction of the service and (c) explore clinicians' experiences of service delivery. A mixed‐method study design incorporating the analysis of routinely collected data, and qualitative interviews with clinicians was conducted. Participants were 11 families displaying child maltreatment risk and 11 clinicians. Parents accessing the service were experiencing considerable risk factors for child maltreatment. The service was deemed acceptable by parents and referrers; however, several challenges in telehealth delivery were documented including parent engagement, technology difficulties and assessing child safety. Our findings highlighted the importance of ensuring adequate support and monitoring of families where there is child maltreatment risk during the COVID‐19 pandemic. In addition, these findings highlight the acceptability of telehealth services to support families at risk of child maltreatment for families, clinicians, and referrers.
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    Structural lung disease following allergic bronchopulmonary aspergillosis complicating pediatric cystic fibrosis
    McCashney, A ; Robinson, P (WILEY, 2021-12)
    BACKGROUND: Allergic bronchopulmonary aspergillosis (ABPA) complicating cystic fibrosis (CF) is frequently associated with significant structural lung damage as assessed by computed tomography (CT) scanning. METHODS: Using a validated CF scoring system (structural lung disease [SLD] score) we examined the degree of structural lung disease in a group of 25 children with CF who had received steroid therapy for ABPA (CF-ABPA) and compared our findings to a matched group of CF patients without ABPA (CF-CON) using both cross-section and longitudinal analysis. Further, we examined the structure-function correlation between CT findings and lung function. RESULTS: Mean SLD score (expressed as a percentage of maximal score) was significantly higher (worse) in the CF-ABPA group than the CF-CON group (29.3% CF-ABPA vs. 18.7% CF-CON p < .05). CF-ABPA patients showed significantly greater rate of development of structural lung disease over time than CF-CON patients (6.8% per year vs 1.4% p < .01). We found no correlation between lung function and the degree of structural lung disease. CONCLUSIONS: ABPA in children with CF is associated with significantly more structural lung disease than that found in children with CF without ABPA. Despite interventive steroid therapy lung disease progresses more rapidly in those patients with ABPA and CF than control patients with CF.
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    Clinical overlap of PHACE and LUMBAR syndromes
    Davenport, R ; Su, JC ; Nathalie, J ; Richmond, CM ; Tan, TY ; Robertson, SJ (WILEY, 2022-09)
    Segmental infantile hemangiomas affecting the upper body are associated with PHACE(S) (Posterior fossa anomalies, Hemangioma, Arterial anomalies, Cardiac anomalies, Eye anomalies, and Sternal defects) syndrome, whereas segmental infantile hemangiomas affecting the lower body are the cutaneous hallmark of LUMBAR (Lower body hemangioma and other skin defects, Urogenital anomalies and Ulceration, Myelopathy, Bony deformities, Anorectal malformations and Arterial anomalies, and Renal anomalies) syndrome. We present two individuals with concurrent features of both PHACE and LUMBAR syndromes demonstrating an overlap phenotype. The overlapping features seen in our patients suggest that these syndromes occur on the same phenotypic spectrum and derive from a common embryonic pathophysiology.
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    Immuno-epigenomic analysis identifies attenuated interferon responses in naive CD4 T cells of adolescents with peanut and multifood allergy
    Imran, S ; Neeland, MR ; Peng, S ; Vlahos, A ; Martino, D ; Dharmage, SC ; Tang, MLK ; Sawyer, S ; Dang, TD ; McWilliam, V ; Peters, RL ; Koplin, JJ ; Perrett, KP ; Novakovic, B ; Saffery, R (WILEY, 2022-11)
    BACKGROUND: IgE-mediated food allergies have been linked to suboptimal naïve CD4 T (nCD4T) cell activation in infancy, underlined by epigenetic and transcriptomic variation. Similar attenuated nCD4T cell activation in adolescents with food allergy have also been reported, but these are yet to be linked to specific epigenetic or transcriptional changes. METHODS: We generated genome-wide DNA methylation data in purified nCD4 T cells at quiescence and following activation in a cohort of adolescents (aged 10-15 years old) with peanut allergy (peanut only or peanut + ≥1 additional food allergy) (FA, n = 29), and age-matched non-food allergic controls (NA, n = 18). Additionally, we assessed transcriptome-wide gene expression and cytokine production in these cells following activation. RESULTS: We found widespread changes in DNA methylation in both NA and FA nCD4T cells in response to activation, associated with the T cell receptor signaling pathway. Adolescents with FA exhibit unique DNA methylation signatures at quiescence and post-activation at key genes involved in Th1/Th2 differentiation (RUNX3, RXRA, NFKB1A, IL4R), including a differentially methylated region (DMR) at the TNFRSF6B promoter, linked to Th1 proliferation. Combined analysis of DNA methylation, transcriptomic data and cytokine output in the same samples identified an attenuated interferon response in nCD4T cells from FA individuals following activation, with decreased expression of several interferon genes, including IFN-γ and a DMR at a key downstream gene, BST2. CONCLUSION: We find that attenuated nCD4T cell responses from adolescents with food allergy are associated with specific epigenetic variation, including disruption of interferon responses, indicating dysregulation of key immune pathways that may contribute to a persistent FA phenotype. However, we recognize the small sample size, and the consequent restraint on reporting adjusted p-value statistics as limitations of the study. Further study is required to validate these findings.
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    Grass pollen exposure is associated with higher readmission rates for pediatric asthma
    Batra, M ; Dharmage, SC ; Newbigin, E ; Tang, M ; Abramson, MJ ; Erbas, B ; Vicendese, D (WILEY, 2022-11)
    BACKGROUND: Pediatric asthma hospital readmission is a burden on the individual and costly for Australian hospitals. Grass pollen's role, a known trigger for asthma admissions, is unexamined in readmissions. We examined the association between grass pollen and pediatric asthma readmission. METHODS: The Victorian Admitted Episodes Dataset was used to identify all primary admissions with a principal diagnosis of asthma in children aged 2-18 years between 1997 and 2009. Readmissions were defined as subsequent admissions within 28 days of index admission discharge. Generalized additive models were used to assess associations between readmission, grass pollen season, and daily grass pollen counts, lagged and cumulative. Models were further stratified by sex and age group. RESULTS: Mean daily readmission was higher during grass pollen season than other times of the year, incidence rate ratio (IRR) 1.44 (95% CI, 1.03, 2.02) and for children aged 2-5 years, IRR 1.99 (1.26, 3.14). Same day grass pollen was nonlinearly associated with daily readmission for the 13-18 age group between 110 and 256 grains/m3 , p < .01. Lag 2 grass pollen was nonlinearly associated with daily readmissions overall (p = .03), boys (p = .01), and younger age groups 2-5 (p = .02) and 6-12 (p < .001). CONCLUSIONS: Grass pollen exposure was associated with higher readmission rates for pediatric asthma. Treatment plans prior to discharge could be implemented to reduce the likelihood of readmission by younger children during the pollen season.
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    Levobupivacaine plasma concentrations following repeat caudal anesthetics
    Frawley, G ; Ignacio Cortinez, L ; Anderson, BJ ; Bjorksten, A ; King, S (WILEY, 2022-12)
    AIM: A single caudal anesthetic at the start of lower abdominal surgery is unlikely to provide prolonged analgesia. A second caudal at the end of the procedure extends the analgesia duration but total plasma concentrations may be associated with toxicity. Our aim was to measure total plasma levobupivacaine concentrations after repeat caudal anesthesia in infants and to generate a pharmacokinetic model for prediction of plasma concentrations after repeat caudal anesthesia in neonates, infants and children. METHODS: Infants undergoing definitive repair of anorectal malformations or Hirschsprung's disease received a second caudal anesthesia at the end of the procedure. Total levobupivacaine concentrations were assayed 3-4 times in the first 6 h after the initial caudal. These data were pooled with data from four studies describing plasma concentrations after levobupivacaine caudal or spinal anesthesia. Population pharmacokinetic parameters were estimated using nonlinear mixed-effects models. Covariates included postmenstrual age and body weight. Parameter estimates were used to simulate concentrations after a repeat levobupivacaine 2.5 mg kg-1 caudal at 3 or 4 h following an initial levobupivacaine 2.5 mg kg-1 caudal. RESULTS: Twenty-one infants (postnatal age 11-32 weeks, gestation 37-39 weeks, weight 5.2-8.6 kg) were included. The measured peak plasma concentration after repeat caudal levobupivacaine 2.5 mg kg-1 4 h after initial caudal was 1.38 mg L-1 (95% prediction interval 0.60-2.6 mg L-1 ) and 3 h after initial caudal was 1.46 mg L-1 (0.60-2.80) mg L-1 . Simulation of total plasma concentrations in neonates (7 kg, 57 weeks postmenstrual age) given caudal levobupivacaine 4 h after the initial caudal were 1.76 mg L-1 (0.68-3.50) mg L-1 if 2.5 mg kg-1 levobupivacaine was used and 0.88 mg L-1 (0.34-1.73) mg L-1 if 1.25 mg kg-1 of 0.125% levobupivacaine was used. In simulated older children (20 kg, 6 years), the mean maximum concentration was 1.43 mg L-1 (0.60-2.70) mg L-1 if 2.5 mg kg-1 levobupivacaine was repeated at 3 h. CONCLUSION: Repeat caudal levobupivacaine 2.5 mg kg-1 at 3 h after an initial 2.5 mg kg-1 dose does not exceed the concentration associated with systemic local anesthetic toxicity. In 2.5% of simulated neonates (weight 3.8 kg, PMA 40 weeks), repeat caudal anesthesia demonstrates broaching of the lower concentration limit associated with toxicity at both 3 and 4 h after initial caudal.