Paediatrics (RCH) - Theses
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ItemThe epidemiology and risk factors of anaphylaxis and food-induced anaphylaxis worldwide( 2019)Anaphylaxis is a severe allergic reaction that is rapid in onset and may cause death. There are increasing reports from individual countries and regions on anaphylaxis prevalence or incidence; however, there has been no systematic summary of the worldwide evidence among the paediatric population. An increasing rate of hospital admissions for food-induced anaphylaxis was observed in Australia from 1993 to 2012, especially among young children. Although rising rates of anaphylaxis have also been reported in other western countries, little is known about the time trends in Asian regions. Time trends of adrenaline auto-injectors (AAI) prescription is a good supplement surrogate for the time trends of anaphylaxis risk in the community. Some studies reported time trends of AAI prescription internationally, such as USA, UK and Canada; however, there is little information on the time trends of AAI prescription or dispensing in Australia in recent years. Previous international studies have reported that ethnicity is associated with the risk of anaphylaxis. Food allergy was found to be more common in children born in Australia with Asian parents than children born in Australia with Caucasian parents. However, it is not known whether ethnicity is also a risk factor for the development of anaphylaxis and food-induced anaphylaxis in Australia. Food allergy is an important cause of anaphylaxis. People with food allergy have a high risk of anaphylaxis, but not all of them will have an anaphylactic reaction. It is hence crucial to know the risk factors of having anaphylactic reactions in the food allergic population. Few studies have examined risk factors for food-induced anaphylaxis in food-allergic children. The characteristics of children with food allergy who are more likely to experience anaphylaxis are unknown. Therefore, this thesis aims to describe the worldwide incidence and prevalence of anaphylaxis and identify risk factors for anaphylaxis and food-induced anaphylaxis in both the general population and the food-allergic population. Firstly, I conducted a systematic review to describe the incidence and prevalence of anaphylaxis in children worldwide. I found a high heterogeneity between studies which limited the interpretation of an overall combined incidence and prevalence. I found increasing time trends of all-cause anaphylaxis and food-induced anaphylaxis in children from included studies and studies in developing areas were underrepresented. By using hospital admission data for anaphylaxis from the Hospital Authority of Hong Kong, I reported increasing time trends of both all-cause anaphylaxis and food-induced anaphylaxis in the paediatric population in Hong Kong between 2001 and 2015. By analysing AAI dispensing data from the Australian Pharmaceutical Benefits Scheme (PBS) database, I found an increasing incidence rate of patients with AAI in Australia from 2005 to 2014. Different trends were reported by sex, age and state. I found a shift towards more AAI prescriptions being provided by general practitioners (GPs) rather than specialists in most regions in Australia. By using the data from the School Entrant Health Questionnaire in Victoria, Australia, I investigated the risk factors of anaphylaxis in the general population. I found an association between Asian ethnicity and anaphylaxis risk in children living in Australia and identified the high-risk group (Australian-born children with Asian-born mothers) for anaphylaxis. Lastly, I used data from the HealthNuts study to explore the frequency and risk factors of anaphylaxis in food allergic children from a community setting. I found a high frequency of experiencing anaphylactic reactions (11.5%) in the preceding 12 months in children with food allergy. In summary, the results presented in this thesis have provided further knowledge on the epidemiology of anaphylaxis and food-induced anaphylaxis in the general population and identified important predictors of anaphylaxis in the general population and the food allergic population. The identification of these essential predictors has important implications for the management of anaphylaxis and will improve our understanding of the development of anaphylaxis.
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ItemPlatelet physiology and function in neonates and children on extracorporeal membrane oxygenation (ECMO)( 2019)Extracorporeal membrane oxygenation (ECMO) is a modified form of heart-lung machine that aims to provide short- to-medium length of support to patients with cardiac and/or respiratory dysfunction. Children represent the majority of the ECMO population. While increasing experience and technical improvements for ECMO over the years have seen some improvement in outcomes, the rates of morbidity and mortality remain high in this population and many complications are related to bleeding and thrombosis. Platelets are a key element of the coagulation system. Platelet dysfunction can cause coagulopathy in adults on ECMO, however, the association between modification of platelet function and coagulopathy remains unknown for children. This study hypothesised that there are platelet-specific differences: I.) for paediatric patients on ECMO according to their age, pathway onto ECMO and duration of ECMO that could be associated with the development of bleeding or thrombosis during ECMO and II.) at different sites in a paediatric ECMO system. This study aimed to characterize the molecular indices of circulating platelets in the paediatric ECMO population using whole blood flow cytometry approach: 1) To examine and compare the effect of a patient’s pathway onto ECMO on platelet phenotype and function and their associations with the development of bleeding or thrombosis during ECMO. 2) To examine and compare the effect of a patient’s age on platelet phenotype and function and their associations with the development of bleeding or thrombosis during ECMO. 3) To examine and compare the effect of a patient’s duration of ECMO on platelet phenotype and function and their associations with the development of bleeding or thrombosis during ECMO. 4) To examine and compare the site-specific differences for platelet phenotype and function in the paediatric ECMO system. A total of 22 paediatric patients [median (interquartile range): 0.34 (0.01 – 3.38) years] were included in this study. Citrated whole blood samples were collected and a whole blood flow cytometry method was developed for the evaluation of platelet phenotype and function in the setting of ECMO. The platelet assays were standardized to ensure minimal pre-analytical activation. By using multiple thrombin receptor activator peptide 6 (a thrombin mimic) concentrations, the platelet panels also showed sensitivity to detect subtle changes in platelet response. The multifaceted flow cytometry panels allowed simultaneous evaluation of platelets for their phenotype, function and interactions with monocytes and neutrophils. Such approach to investigate platelet-specific changes from different aspects suits well for the ECMO population, representing a complex group of patients. These results showed that the whole blood flow cytometry assay is a reliable and useful platelet function test for paediatric ECMO patients. Results from the analysis for platelet-specific markers within the first 24 hours showed no difference in platelet phenotype and function between patients from different pathways onto ECMO and different ages. However, the association of platelet-specific changes and the development of clinical events during ECMO were different according to a patient’s age and pathway onto ECMO. Patients who had cardiopulmonary bypass before coming onto ECMO and had bleeding had increased platelet integrin GPIIb/IIIa receptor expression and reduced circulating neutrophil-platelet aggregates level compared to patients who had no bleeding during ECMO. In contrast, patients who had no cardiopulmonary bypass before coming onto ECMO and developed bleeding had reduced platelet response compared to those who had no bleeding during ECMO. Conversely, increased lysosome release was observed for children with thrombosis and may indicate the presence of a protective mechanism against increased thrombus formation. Duration of ECMO had been recognized as an important factor affecting the outcome of paediatric ECMO patients. The results showed an increased level of von Willebrand factor (VWF) receptor and reduced platelet response for granule exocytosis with increasing number of days on ECMO (Day 2 vs. Day 5). Most importantly, such platelet-specific changes that involved GPIb/IX/V receptor and granule release with increasing duration of ECMO were only observed in patients who had bleeding but not in patients without bleeding after five days on ECMO. In addition, elevated circulating monocyte-platelet aggregates level was only observed in patients who had thrombosis but not for those without thrombosis. Together, these results suggested a link between pathway onto ECMO/age/duration of ECMO, bleeding/thrombosis and platelet dysfunction. Hence, markers relevant to the platelet-specific changes could be used as the indicators for increased bleeding or thrombosis risk for paediatric patients during ECMO. Platelet phenotype and function were also compared at different sites in the ECMO system to identify the site-specific differences of platelet-specific changes that have not previously been investigated in a paediatric ECMO system. In the setting of mechanical circulatory support, shear and oxidative stress are known to modify platelet phenotype via integrin GPIIb/IIIa and GPIb/IX/V receptors and increase platelet response via multiple platelet activation pathways. The results demonstrated that platelet phenotype and function were different at different sites in a paediatric ECMO system. The platelet-specific changes observed included the modification of platelet phenotype via increased VWF and integrin GPIIb/IIIa receptor expression, increased platelet activation through the activation of the integrin GPIIb/IIIa receptor and higher platelet responsiveness at the post-oxygenator site compared to the pre-oxygenator site. However, the exact cause of the site-specific differences of platelet phenotype and function remained to be identified. In summary, this study demonstrated the feasibility of using whole blood flow cytometry method with multifaceted platelet-specific panels as a reliable platelet function test in paediatric patients on ECMO. Platelet-specific changes could be associated with the development of bleeding or thrombosis during ECMO. In addition, platelet phenotype and function were different at different sites in a paediatric ECMO system. Together, this study provides new insights for the circuit-related platelet-specific changes and the understanding of how modifications of platelet phenotype and function that are dependent on patient’s factors may be associated with coagulopathy in children on ECMO.
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ItemEstablishing predictive indicators, or biomarkers, of aminoglycoside nephrotoxicity and the Incidence of ototoxicity in children up to six years with cystic fibrosis (PIANO-CF extension)( 2019)Cystic Fibrosis (CF) is an autosomal recessive condition caused by a mutation in the cystic fibrosis transmembrane regulator (CFTR) gene. It is commonly known as a disease affecting the lungs. Advances in screening, diagnosis and treatment of CF have led to enormous improvements in outcomes and life expectancy. Since pulmonary outcomes are better for patients from centres with aggressive and early use of antibiotic therapies, patients now have an earlier and longer lifetime exposure to antibiotics. People with CF are often treated with prolonged courses of aminoglycosides (AGs), for which known adverse effects include nephro- and ototoxicity. The resulting increase in longevity and ageing of the CF population has led to a paradigm shift from a focus on the lungs to management of a complex multi-system disease. The CFTR gene is abundantly expressed in the kidney, which has been considered ‘spared in CF’. However, renal complications are emerging in childhood with adolescents developing renal impairment and presenting with kidney failure. Correspondingly, renal impairment in CF has been largely attributed to nephrotoxic antibiotic exposure and, in particular, to AGs. Most importantly, it is necessary to recall the time before these complications were observed to understand the risk factors and how the development of renal impairment and kidney failure can be arrested. Acute kidney injury (AKI) is common in people treated with an intravenous AGs yet assessing the prevalence of AKI is difficult and complicated by a multitude of definitions. Serum creatinine is considered the ‘gold standard’ for the detection of AG-induced nephrotoxicity in AKI classification systems, yet it is neither specific nor sensitive and has many limitations, particularly in CF. Predictive indicators and novel renal biomarkers may allow earlier detection of AG-induced nephrotoxicity and provide an opportunity to mitigate risk, the progression AKI and subsequent renal impairment and chronic kidney disease. The primary aim of this study was to investigate predictive indicators and novel renal biomarkers of AG-induced nephrotoxicity in young children with CF in the setting of acute AG exposure. We also sought to uncover whether expression of novel renal biomarkers differed between children with CF and healthy controls—and whether previous AG exposure played a role in this. The secondary aim of this study was to investigate hearing impairment and whether there was a correlation between hearing impairment and cumulative intravenous AG exposure. The predictive indicators that were studied include serum cystatin C, serum magnesium, fractional excretion of magnesium and urinary beta-2-microglobulin. The novel renal biomarkers that were studied include kidney injury molecule-1, neutrophil gelatinase-associated lipocalin, interleukin-18, liver-type fatty acid binding protein and fibroblast growth factor-23. All novel renal biomarkers were measured in urine and for a small cohort, we additionally measured kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin in serum. We also studied hearing at three time points, investigating hearing impairment and ototoxicity in young children with CF in the setting of acute intravenous AG exposure, with longitudinal follow-up up to approximately one year. In children with CF and acute intravenous AG exposure, we observed AKI, no significant change in estimated glomerular filtration rate, hypomagnesaemia with increased fractional excretion of magnesium that resolved, no correlation between serum creatinine and serum cystatin C and significant changes in urinary kidney injury molecule-1 and urinary neutrophil gelatinase-associated lipocalin. A comparison of gentamicin and tobramycin showed significant differences with higher fractional excretion of magnesium, when corrected for difference in dose, and higher levels of kidney injury molecule-1 in children who received gentamicin. Children with CF showed hyperfiltration and increased fractional excretion of magnesium at baseline. There was a large difference in the novel renal biomarkers (urinary kidney injury molecule-1, urinary neutrophil gelatinase-associated lipocalin and urinary fibroblast growth factor-23) between children with CF and healthy controls, irrespective of previous intravenous AG exposure. Hearing impairment was observed on 12% of tests; 7% of which was considered ototoxicity. We did not observe a correlation between hearing impairment and cumulative intravenous AG exposure. This is the first study of predictive indicators, novel renal biomarkers and long-term hearing follow-up in young children with CF. Our findings challenge the traditional view that the kidney is ‘spared’ in CF and suggest that the kidney in CF is different from the normal kidney, which may represent CF-related kidney disease. The results of this study suggest that novel renal biomarkers may be useful for detection of AG-induced nephrotoxicity in CF; however, they must first be understood in this population, as they differ significantly from healthy controls. Additionally, these findings provide insight into the rate of hearing impairment in young children with CF and challenge the traditional view that cumulative intravenous AG exposure increases the rate of hearing impairment. Further considerable work is required to better elucidate the comorbidities of kidney disease and hearing impairment faced by patients with CF. This study has informed on previously under-recognised phenomena and shown that the kidney is involved in CF. Further research in this field should better explicate the role of CFTR in the kidney, the extent of hyperfiltration and the expression of novel renal biomarkers in older children and adults with CF. With regard to hearing outcomes, future studies should consider how to screen for hearing impairment and how to ameliorate auditory ototoxicity using otoprotective agents.
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ItemIntragenic DNA methylation and neurodevelopmental outcomes in children with fragile X-related disorders( 2019)The type and severity of clinical involvement in children with fragile X syndrome (FXS) and disorders related to premutations (PM) of the fragile X mental retardation 1 gene (FMR1), herein collectively denoted as fragile X-related disorders (FXDs), is highly variable. Multiple molecular factors contribute to the heterogeneity of neurodevelopmental outcomes. Increased intragenic DNA methylation (DNAm) in blood of the fragile X-related epigenetic element 2 (FREE2) region, located at the FMR1 exon 1/intron 1 boundary, was associated with lower intellectual functioning in a cohort of female children and adults with FXS and with neuro-cognitive and psychiatric phenotypes in women with PM. Nevertheless, FREE2 DNAm has not yet been investigated in exclusively paediatric male and female FXDs cohorts. The overarching aim of this thesis was to explore FREE2 DNAm and neurodevelopmental outcomes of Australian male and female children with FXDs. Matrix assisted laser desorption/ionization time-of-flight mass spectrometry and methylation specific-quantitative melt analysis were used to analyse FREE2 DNAm in venous blood, buccal epithelial cells (BEC) and retrieved newborn blood spots (NBS). In addition, FMR1 mRNA levels in blood were assessed using real-time polymerase chain reaction (PCR) relative standard curve method. The evaluation of the neurodevelopmental outcomes concentrated on direct clinical assessment of intellectual functioning and autism spectrum disorder (ASD) symptom severity. Intelligence Quotient (IQ) scores were corrected for floor effect using the Whitaker and Gordon (WG) extrapolation method. The findings highlighted the variability of the clinical presentation of children with PM. Results also showed that compared to sex-matched paediatric controls, children with FXS had significantly higher levels of FREE2 DNAm levels in blood and BEC and, within the FXS group, higher FREE2 DNAm levels in blood correlated with lower FMR1 mRNA levels. In children with FXS, the application of the WG method effectively addressed the floor effect inherent in standardised intelligence scales, unmasked inter-individual variability in IQ scores and uncovered significant associations between intragenic DNAm and neurodevelopmental outcomes. Strength and statistical significance of these epigenotype-phenotype relationships varied based on sex, position of the differentially methylated sites, tissue analysed, assay used and neurodevelopmental domain investigated. The most significant finding was in males with FXS, for whom higher levels of BEC FREE2 DNAm were associated with lower WG-corrected Full Scale IQ (cFSIQ) and Performance IQ (cPIQ) scores. Finally, findings showed that the best-performing FREE2 biomarker had sensitivity, specificity, negative and positive predictive values of 100% for detection of full mutation alleles in NBS of males and females with FXS. Additionally, this study revealed that for males with FXS, FREE2 DNAm in NBS was significantly associated with lower cFSIQ and cPIQ scores obtained in childhood and adolescence. This is the first study in any monogenic neurodevelopmental disorder associated with intellectual disability, showing that a perinatal epigenetic biomarker is significantly associated with paediatric neuropsychological outcomes. In conclusion, the results of this thesis contribute to the characterisation of the neurodevelopmental outcomes in children with FXDs, provide evidence that FREE2 DNAm is a sensitive epigenetic biomarker significantly associated with the variability of intellectual functioning in male children with FXS, and may have implications for the development of new methylation specific tests for earlier diagnosis with potential prognostic applications.
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ItemClowns in the midst: understanding clown doctors at The Royal Children's Hospital Melbourne( 2018)Clown doctors are a feature in paediatric hospitals, visiting children and families, providing a welcome escape from the reality of hospitalisation. Though the use of humour to improve health and wellbeing has been widely researched, limited exploration of the clown doctors has occurred. This study aims to elucidate the work of clown doctors within a major paediatric hospital. This was an ethnographic study. Ethnography is an innovative approach to paediatric research, giving an intricate view that is otherwise difficult to attain. Participants for this study included the clown doctors employed at The Royal Children’s Hospital, and every person they had a meaningful encounter with during the course of their work, including patients, families, clinical and non-clinical staff. Data was collected via participant observation, with approximately 1,500 hours of ‘clown ward rounds’ documented over one year. Furthermore, 25 hour-long semi-structured interviews were conducted with a range of key informants. A constructivist framework was used to analyse emergent concepts. Constructivism explores how relationships and interactions create the individual’s understanding of the world. Furthermore, how different understanding, or meaning, can be derived from interactions based on individual context, background, culture and personal history. When asking people about the clown doctors, most ascribed a function, such as: distraction, anxiety reduction and procedural assistance; entertainment and making people laugh; emotional support and providing comfort; and communication, including translating clinical information to families. These functional elements of the clown doctors are the result of a more complex, intimate human connection that develops due to the nature of clown doctors being low-status, open, vulnerable and, in particular, existing as outsiders to the medical establishment. Clown doctors use humour to break down the emotional barriers created by illness, which they achieve through being person-centric and offsetting medically driven interactions the hospital often demands. They empower patients, returning a sense of control that is generally absent for hospitalised children. While almost universally acknowledged as a positive addition to the hospital, most people who encounter the clown doctors have little conception about the scope of their work. Although clown doctors are often described in concrete clinical terms, their real power lies in their ability to connect with people, and the psychosocial advantages that connection provides. The results of this descriptive study deliver valuable insight and a comprehensive understanding of clown doctors and the complexity of human relationships within a major paediatric hospital. Through this research we can identify what the clown doctors bring to the hospital environment, how paediatric staff can employ their unique skills more effectively, and finally give long-overdue credence to the notion that laughter, mirth, creativity and child-like wonder has as much place in a hospital as medicine.
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ItemProximal femoral osteotomy in children and adolescents with cerebral palsy( 2018)Background Cerebral Palsy (CP) is the most common cause of physical disability affecting children in developed countries. Approximately one third of children with CP may develop hip displacement. Non-ambulant children at Gross Motor Function Classification System (GMFCS) levels IV and V are at highest risk. Without early detection through surveillance programs, hip displacement can progress to hip dislocation, which is frequently painful and negatively impacts health-related quality of life (HRQoL). Injections of Botulinum Neurotoxin A (BoNT-A) have no role, and soft tissue surgery has a limited role in preventing hip displacement in non-ambulant children with CP. Bony hip reconstruction surgery such as a proximal femoral osteotomy (PFO) is effective in stabilising the hip and HRQoL. PFOs include Femoral Derotation Osteotomies (FDO) which aim to improve the gait of an ambulant child (GMFCS I-III), and Varus Derotation Osteotomies (VDRO) which aim to contain the hips in non-ambulant children (GMFCS IV-V). However, PFOs can carry high risks, especially in children with medical co-morbidities such as respiratory disease, nutritional deficiencies, hypertonia and osteopenia. Aim This thesis involved a series of three studies, which aimed to expand our knowledge of the trainee learning curve, outcomes and adverse events relating to PFO in children and adolescents with CP. Method and Results A new implant combining locking and cannulated technology (Locking Cannulated Blade Plate, LCBP) was recently developed for use in PFO. A pilot study was performed on the first 25 patients who had surgery with the LCBP, at the Royal Children’s Hospital (RCH), Melbourne. This study established safety for use in children as young as three, with weights as low as eleven kilograms. A further prospective, parallel cohort study of 90 consecutive children with CP was conducted to compare the LCBP against with existing non-cannulated, non-locking implant (Angled Blade Plate, ABP). Technical and radiological outcomes of surgery were similar between implants. However, the surgical technique was reported by trainees to be easier when using the LCBP, with less technical errors. Approximately 60 percent of the children experienced minor adverse events including: constipation, inadequate pain control, and respiratory compromise. However, a CP specific tool was not available to classify the severity of events. Study three was performed to clarify the Modified Clavien-Dindo (MCD) system for lower limb surgery in children with CP and test its’ reliability for classifying adverse events. Very good reliability was demonstrated amongst members within a multidisciplinary team. Conclusion Novel findings from these studies may help improve the safety and efficacy of the management of hip displacement in children with CP. Further research should address the long-term outcomes of PFO in children with CP, evaluate the validity of the MCD for children in CP and determine if the MCD can be embedded in the electronic medical records (EMR) as a routine tool for audit and clinical research.
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ItemImproving oxygen therapy for children and newborns in Nigerian hospitals( 2018)Oxygen is a long-established medical therapy that can be life-saving for severely ill children admitted to hospital. Effective provision of oxygen to patients requires a multifaceted system that involves technical, clinical, supply chain, financing, and other managerial and policy elements. However, this system is currently difficult to achieve in many low-resource settings resulting in poor access to, and use of, oxygen and subsequent excess mortality. Previous work has shown that improved hospital oxygen systems can improve patient access to oxygen therapy and reduce inpatient case fatality rates from childhood pneumonia. However, studies have shown variable impact in different settings due to contextual factors that are not well understood. In addition, the burden of hypoxaemia and impact of oxygen on conditions other than pneumonia is unclear – particularly in the large neonatal population. This study aimed to understand how to improve oxygen systems in particular contexts, and generate evidence to support the scale-up of effective oxygen systems in Nigeria and globally. My realist review of past oxygen projects developed a theoretical framework describing how improved oxygen systems could improve clinical outcomes in particular contexts – highlighting the interaction between efforts to improve oxygen access and the clinical use of oxygen. My oxygen needs assessment in 12 secondary-level Nigerian hospitals provided detailed data on existing oxygen systems – highlighting the impact of poor power supplies, weak maintenance systems, and lack of pulse oximetry. My prospective cohort study provided new data on the epidemiology of hypoxaemia in the Nigerian context. This study showed high prevalence of hypoxaemia among admitted children and neonates with a range of conditions, highlighted the strong association between hypoxaemia and death, and demonstrated poor accuracy of clinical signs to predict hypoxaemia (particularly for children with non-respiratory conditions). My mixed-methods realist evaluation identified how pulse oximetry could be most effectively adopted into routine paediatric and neonatal care – highlighting the role of key influencers to model behaviour, practical training and ongoing encouragement, personal experience of benefit, and the reasons why nurses valued pulse oximetry. My stepped wedge trial evaluated the effect of our intervention (improved oxygen system) on clinical outcomes and care practices. This study demonstrated mortality benefit for children admitted with pneumonia, and suggested that the introduction of pulse oximetry generated most of this benefit by stimulating better use of existing oxygen supplies. We found no mortality benefit for children with other conditions or neonates, and detected an unexpected trend towards higher mortality in the “full oxygen system” period compared to the “pulse oximetry period” for neonates. Post-hoc analysis tested some potential explanatory theories for these findings – highlighting the effects of pre-existing oxygen access and external factors. In conclusion, improving oxygen systems is complex. The studies contained in this thesis have helped fill evidence gaps that are hindering oxygen policy and planning decision-making in Nigeria and globally. They have directly informed national and global policies and program planning.
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ItemHypoplastic left heart syndrome: development of a new animal model for hypothesis testing( 2018)INTRODUCTION: Hypoplastic left heart syndrome (HLHS) is a congenital heart defect that involves severe underdevelopment of the left-sided heart structures. Despite the severity of the cardiac deformity, HLHS is compatible with fetal life. In-utero survival of HLHS is facilitated by compensatory blood flow patterns facilitated by the presence of fetal shunts and the parallel arrangement of the fetal circulation. As the left ventricle (LV) is unable to perfuse the systemic circulation in HLHS, the fetal right ventricle (RV) is able to perfuse territories normally supplied by the LV during development via flow across the ductus arteriosus (DA) and aortic isthmus. However, after birth the DA closes and the RV is no longer able to compensate for the inadequate LV. As a result, newborns with HLHS develop circulatory collapse and die. At present, without intervention HLHS is universally fatal, with palliative surgery being the treatment option of choice offered by most institutions worldwide. Fundamental to the future study of HLHS and progress toward curative therapy is the creation of a clinically relevant mammalian animal model that facilitates hypothesis testing. Thus, the overall aim(s) of this thesis were to utilize an established fetal lamb model of the fetal cardiovascular system to develop a new stable, chronic, and clinically relevant fetal lamb model of congenital aortic stenosis (AoSt) (a condition known to evolve into HLHS in-utero); and quantify the growth-related changes in haemodynamics and cardiac morphology associated with the in-utero progression of the model using serial fetal echocardiography (Study 1). Additional studies using invasive cardiovascular instrumentation aimed to characterise the cardiovascular physiology of the fetal lamb model of congenital AoSt during fetal life (Study 2), the transition from fetus to newborn (Study 3), and closure of the DA (Study 4). METHODOLOGY: Surgery was performed in n=19 anaesthetised time-dated twin-pregnancy ewes (mean 91±3 days; term=147 days), with one fetus undergoing non-constrictive ascending aortic banding, and the second serving as the un-operated control. Serial fetal echocardiography studies were performed under maternal sedation at fortnightly intervals until near-term (140±1 days) in order to measure structural and functional changes in cardiac growth (Study 1). At near-term, sets of twin fetuses (n=12) were anaesthetised and instrumented with aortic (Ao), pulmonary arterial (PA) and left atrial (LA) fluid-filled pressure (P) catheters, and in a subgroup of fetuses (control; n=9, banded; n=4), an LV micromanometer catheter was placed. Haemodynamic and arterial blood gas measurements were made during fetal life (Study 2), as well as during the transition from fetus to newborn (Study 2), and after closure of the DA (Study 4). RESULTS: Echocardiography (Study 1) performed after non-occlusive banding of the ascending aorta of mid-gestation fetal lambs increased the peak ascending aortic (trans-stenosis) pressure gradient from 8±4mmHg at mid-gestation to 26±13 mmHg at near-term (p<0.001). Versus control animals, this pressure gradient was associated with increases in LV posterior wall (15%; p<0.05), and septal (14%; p<0.05), thickness, as well as a reduction in LV chamber short axis dimension during both systole (26%; p<0.001) and diastole (22%; p<0.001). These changes were also coupled with near-term increases in RVO (28%; p<0.005), HR (20%; p<0.001) and CVO (21%; p<0.001) compared to control animals. Invasive instrumentation (Study 2) demonstrated AoP, PAP and HR were similar between control and banded fetuses. However, LAP was paradoxically lower in banded fetuses versus controls (6.2±1.9 vs. 4.3±1.7 mmHg; p<0.05), while LV systolic pressure (56±9 vs. 75±7 mmHg; p<0.05) and LV dP/dtmax (1415±285 vs. 1930±504 mmHg; p<0.05) were higher in banded fetuses. Birth (Study 3) in banded fetuses was related to attenuation of the normal birth-related drop in PAP, as well as absence of the normal birth-related rise in AoP. Higher fetal LV systolic pressures were maintained after birth in banded animals, whereas LV dP/dtmax was reduced (p<0.05). Closure of the DA (Study 4) in banded animals was not associated with the normal rise in AoP seen in control animals. LAP decreased in banded animals after DA closure (32%; p<0.05) but remained unchanged in controls. Further, banded animals sustained hypoxic changes, manifest via reduced arterial blood pO2 (74.1±15.2 vs. 61.7±12.2 mmHg; p<0.05) after DA closure. CONCLUSION: Non-occlusive ascending aortic banding in mid-gestation fetal sheep is associated with a significant chronic rise in LV afterload, as well as substantial changes in LV growth patterns; manifest not only via alterations in LV wall thickness and cavity dimensions, but also in LV chamber geometry. Moreover, these changes are associated with increased right-heart blood flow and CVO, allowing fetuses to remain compatible with life in-utero. In addition, arterial blood pressures were maintained and the blood gas status largely unimpaired in fetal sheep after mid-gestation aortic banding. Although not associated with dramatic changes in haemodynamics and arterial blood gas status during fetal life, birth was associated with findings suggestive of changes in systemic, pulmonary and intra-cardiac blood flow patterns, as well as cardiac function; all of which have potential relevance to the clinical arena and early management of the newborn with HLHS. Finally, closure of the DA was associated with reduced systemic perfusion pressures, and hypoxia, findings akin to those seen in circulatory collapse of infants with HLHS. Therefore, given its favourable characteristics, this model is suitable for future hypothesis testing in the pathogenesis and pathophysiology of AoSt and HLHS.
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ItemFamily adaptation following paediatric acquired brain injury( 2017)Objective: This thesis aims to address the lack of evidence based research in interventions that promote family adaptation following paediatric acquired brain injury (ABI). It reports on the first social work clinical intervention trial designed to measure the effectiveness of a new family intervention titled ‘Family Forward’. This intervention was compared with ‘Usual Care’ social work practice to assess its efficacy in assisting families to make early adaptations during their child’s inpatient rehabilitation phase of care. Method: Participants were parents, caregivers and siblings of 47 children diagnosed with ABI and admitted to an inpatient rehabilitation service. Families were recruited prospectively and sequentially as their child was admitted to an inpatient rehabilitation ward at a statewide tertiary paediatric hospital. The ‘Usual Care’ group (n=22) recruitment, intervention and data collection was completed before the second phase of the intervention, ‘Family Forward’ (n=25) commenced. Patient characteristics were obtained from the child’s medical record. Families provided family demographic and psychosocial risk information using the Psychosocial Assessment Tool (PAT 2.0). Family adaptation outcomes were assessed using family functioning outcomes (Family Assessment Device – General Functioning: FAD-GF) and family management of the injured child’s care at home (Family Management Measure: FAMM). Family members’ appraisal of the child’s injury was also examined in relation to trauma, grief, emotional experience and injury perceptions (Impact of Event Scale – Revised: IES-R; Parent Experience of Childhood Illness: PECI; Brief Illness Perception Questionnaire: Brief-IPQ). Measures were completed at the child’s inpatient rehabilitation admission (pre-intervention), inpatient rehabilitation discharge (post-intervention) and six weeks post inpatient rehabilitation discharge (follow-up). Parents/caregivers and siblings also completed open-ended questions relating to the impact of the child’s injury on family relationships at follow-up. Social workers delivered the ‘Usual Care’ and ‘Family Forward’ interventions and completed the Social Work Activity Form (SWAF) measure at post-intervention and at follow-up. The SWAF measured the social work activity and the level of intensity of the interventions delivered to the families in the two groups. Results: Family adaptation outcomes (FAD-GF and FAMM) were similar for both groups at follow-up. The ‘Family Forward’ group had poorer family functioning pre-intervention (FAD-GF Family Forward mean = 1.626 SD = 0.391; Usual Care mean = 1.491 SD 0.394) and endured longer hospital admissions (Family Forward mean =56.4 days SD 46.1; Usual Care mean = 37.5 days SD 16.4) and inpatient rehabilitation admissions (Family Forward mean = 33.3 SD 29.0; Usual Care mean = 21.4 SD 13.5) than the Usual Care group. There were significant differences in relation to the social work activity and intensity of the interventions delivered to the two groups. The Family Forward group received more services in all areas of service delivery measured by the SWAF and there was an association between poorer family functioning and increased social work activity and level of intensity of the interventions delivered to this group. No significant group differences were found for family appraisal outcomes (IES-R, PECI and Brief IPQ) at any of the three time-points. Both groups reported more adaptive grief responses compared with the PECI normative sample. Trauma responses (IES-R) suggest adaptive family appraisal for both groups. However, the two groups continued to have depleted emotional resources (PECI scale) at follow-up. Parents and siblings also reflected on changes to family relationships at six weeks post discharge. Thematic analysis of free text identified themes common in both groups: ‘negative changes in sibling interactions’ and ‘sibling protectiveness of the injured child’. In addition to these themes, the families in the ‘Family Forward’ group described ‘increased expectation on sibling’; ‘family system challenges’; ‘balancing needs within the sibling subsystem’; and ‘adjustment to parenting’. Conclusions: As this is the first study of its kind, the results can begin to inform social work and rehabilitation clinicians alike about the early family adaptation experience and important foci for psychosocial interventions during a child’s inpatient rehabilitation.
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ItemPopulation-based screening for the prevention of rheumatic heart disease( 2017)Rheumatic heart disease (RHD) is a major cause of global morbidity and mortality, particularly affecting children and young adults in resource-limited settings. Most individuals are diagnosed at an advanced stage of disease, limiting opportunities for prevention. Population-based screening has the potential to detect individuals in an earlier, latent stage of disease, where secondary prevention may be most effective. Several countries, including Fiji, are considering the introduction of screening as part of RHD control. The aim of this thesis was to generate and compile evidence for policy makers in Fiji and other resource-limited settings to consider the viability, appropriateness and effectiveness of population-based screening for RHD. The thesis contains six studies, divided into three Parts, each investigating aspects of the evidence required for RHD screening policy. The first Part describes an evaluation of a screening test that may be viable in resourcelimited settings. Over two thousand school-aged children were screened by brieflytrained nurses, using focused cardiac ultrasound (FoCUS) in a study of diagnostic accuracy. The training curriculum was then adapted into a computer-based training course, and evaluated in another group of non-experts in Uganda. After brief training, non-expert nurses were able to perform FoCUS with high quality, and assess the presence and extent of valvular regurgitation. Screening by the nurses using FoCUS was accurate for the diagnosis of RHD, with a sensitivity of 84% and specificity of 86%. Computerbased training modules were highly effective in increasing the knowledge and confidence of non-expert health workers. The second Part describes an investigation of the natural history and outcomes of young people with screening-detected RHD in Fiji. Repeat echocardiography was performed on young people after screening, evaluating the change in echocardiographic diagnosis and severity after a median of 7.5 years. A cohort study compared the clinical outcomes for young people with screening-detected RHD with matched, screen-negative and clinically-diagnosed groups. The echocardiographic diagnosis remained stable or improved for the majority of young people, however, a proportion progressed to severe disease. In comparison to a matched, screen-negative cohort, young people with screening-detected, definite RHD had worse health outcomes, with 20% developing complications. The third Part describes an assessment of the current management and opportunities to improve secondary prevention in Fiji. The adherence of almost 500 young people was measured over a three-year period, and interviews were conducted with one hundred young people and their families. Adherence to secondary antibiotic prophylaxis after screening was found to be inadequate, with just 6% of individuals receiving sufficient injections to protect against disease progression. A range of factors influencing adherence were found, and strategies to improve secondary prevention were formulated. Despite a potentially viable test strategy, and documentation of worse health for young people with latent disease, the major deficiencies in secondary prevention indicate that screening is not currently effective for disease control in Fiji. Further population-based screening for RHD is therefore not appropriate at this time. RHD control efforts should focus on improvements to secondary prevention. Further research into RHD screening is needed for evidence-based policy, and could occur in parallel. The findings of this thesis have important policy, practice and research implications for the prevention of RHD in Fiji, and globally.