Paediatrics (RCH) - Theses
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ItemThe cognitive effect of exercise in children and adolescents: when is return to play safe( 2015)Introduction: Traumatic brain injuries (TBI), including concussion, are among the most common injuries in children and can lead to lifelong disabilities and impairments. While the poor rate of recovery following severe TBI is well established for child and adolescent populations compared with adults, it is also important that we understand the post-concussion trajectory period in these populations. Furthermore, the effect of physical exertion on cognitive functioning of normal and injured children has yet to be identified. It is crucial to understand how the post-concussive course is affected by exercise in order to i) provide guidance regarding return to sports and ii) prevent further injury during the recovery of TBI. A thorough understanding of this will provide a basis for the development of appropriate return-to-play guidelines for the children and adolescent populations. Rationale and Study Aims: This project aimed to examine the effect of exercise on the cognitive symptoms of concussion in children and adolescents over time following a concussive injury. More specifically, this study focused on changes in the information processing speed and attention in children and adolescents following an exercise routine during the post-concussive phase. The following four hypotheses were proposed: (1) participants with concussion will report increased physical symptoms and higher levels of cognitive impairment after exercise, (2) cognitive impairment and physical symptoms post-exercise will reduce from Day 2 (post symptom resolution) to Day 10, (3) at Day 10, physical and cognitive symptoms in the concussed group will be comparable to that of the non-concussed controls, both pre- and post-exercise, and (4) at Day 10, quality of life (QOL) will be predicted by post-concussive symptoms (PCS), as well as age, gender, and history of previous concussion. Method: Thirty patients aged 10 to less than 18 years who presented to the emergency department of The Royal Children’s Hospital, Melbourne, with a concussion were recruited. A further 30 healthy controls were also recruited from the general public. Once concussed participants reported that they were asymptomatic at rest, they were invited to attend the clinic (Day 2) and complete their first set of assessments. Subjective symptom report and cognitive function (using CogSport) were assessed, followed by an exercise routine, and then a repeat of the initial assessments. Quality of life (QOL) was also assessed at Day 10. This protocol was then repeated eight days later (Day 10) in order to better understand the effects of exercise and the pattern of recovery over time post-symptoms. Results and Discussion: Results support the expected recovery pattern for PCS, regardless of exercise. Analysis of neurocognition found that recovery was dependent on the degree of cognitive demand, with an unexpected reduction from Day 2 to Day 10. Surprisingly, when compared to healthy controls, concussed individuals showed a reduction in PCS as well as faster reaction times on cognitive tasks. This study supports the current return-to-play guidelines for children and adolescents, and suggests that the use of moderate exercise may be beneficial in the management of concussion post-symptom resolution.
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ItemRapid diagnosis of childhood stroke: time is brain( 2015)An estimated two million neurones die every minute in an average-sized adult stroke. Thrombolysis within 4½ hours, and endovascular intervention within about 6 hours – to salvage viable brain at risk of infarction – are established as effective treatments to improve long-term outcomes of stroke in adults. Restoring blood flow is a race against the clock, because every minute saved from symptom onset to commencement of treatment means a gain of almost two additional days of healthy life. As a consequence there is now a major focus on reducing delays to stroke diagnosis, through educational interventions targeting the community and emergency health professionals, and the development of coordinated systems of care. Stroke is among the top ten causes of death in children, and more than half of survivors have long-term neurological impairments, yet children are not receiving the benefits of hyperacute stroke interventions because of inordinate delays to diagnosis, extending beyond 24 hours. There is currently a poor understanding of the reasons for these delays. Emergency protocols for clinical identification, investigation and acute management of childhood stroke are lacking. This thesis, which has three related areas of focus, aims to improve understanding of barriers and enablers to accessing hyperacute treatments in childhood arterial ischaemic stroke (AIS), along the time continuum from symptom onset in the pre-hospital setting, to clinical diagnosis in the emergency department. In the first component of the thesis, a conceptual model is developed to map the current process of paediatric stroke care from symptom onset through to radiological confirmation of stroke diagnosis. Value-focused event-driven process modelling is used to identify key barriers and potential intervention targets, in order to achieve the fundamental objectives of improving timeliness and accuracy of stroke diagnosis. This modelling uses an iterative approach of interviewing key stakeholders in pre-hospital and emergency department settings to inform design, development and demonstration of the model. The most important barriers to rapid and accurate diagnosis of AIS identified include (i) exclusion of children from paramedic clinical practice guidelines, (ii) failure to allocate a high triage category on arrival at hospital, (iii) absence of emergency practice guidelines for the assessment of children with focal neurological deficits, and (iv) selection of computed tomography as the first imaging investigation. The second component of the thesis involves the use of a structured interview, informed by the conceptual model, to describe parental knowledge, care-seeking behaviour, pathway to hospital and pre-hospital timelines of care in children with arterial ischaemic stroke. The key findings are that most parents thought symptoms were serious and that immediate action was required, but only half considered the possibility of stroke or called an ambulance. Sudden symptom onset, stroke severity and recognition of the seriousness of symptoms influence care-seeking behaviours. Parental knowledge of stroke symptoms was variable, and care-seeking behaviour was suboptimal. The third component of the thesis describes the prevalence and scope of conditions causing stroke-like (“brain attack”) symptoms, and the different presenting features of stroke and its mimics in children presenting to the emergency department. The key findings are that (i) stroke is a far less common cause of brain attack symptoms in children than in adults, (ii) mimic aetiologies differ from adults, with migraine being the most common diagnosis, (iii) the clinical features that discriminate childhood stroke from its mimics also differ from adults, and (iv) adult bedside stroke recognition tools perform poorly in children. Factors influencing timelines of care and emergency physician practice were also explored. To conclude, in this thesis, the key barriers and intervention targets along the continuum of acute paediatric stroke care have been identified. Future research should focus on three areas. Firstly, strategies are required to link parental knowledge to appropriate action, particularly for children at high risk of stroke. Secondly, paediatric stroke clinical recognition tools, which take into account differences between children and adults, are required to improve stroke recognition among health professionals in the pre-hospital and emergency department settings. Thirdly, characterising the ischaemic penumbra in children using advanced imaging techniques is important, because it cannot be assumed that the time course of infarction is the same as adults.
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ItemUsing massively parallel sequencing to understand the genetic basis of mitochondrial disorders: a population-based approach( 2015)Inherited defects in mitochondrial oxidative phosphorylation (OXPHOS) are the most common inborn error of metabolism, affecting at least 1 in 5000 live births (Skladal, Halliday et al. 2003), and predominantly affect organs with high-energy consumption such as the brain, skeletal muscle, cardiac muscle and liver. Mitochondrial diseases are notoriously difficult to diagnose, as they show extreme clinical heterogeneity, presenting at any age and with any level of severity, and typically impact on multiple organ systems (Munnich and Rustin 2001). They are also genetically heterogeneous with over 200 mitochondrial DNA and nuclear DNA encoding genes associated with OXPHOS disease. Despite the large number of disease genes being identified, many patients with OXPHOS disease remain without a molecular diagnosis. We developed a targeted DNA capture and massively parallel sequencing method to detect variants within 1,034 genes encoding proteins known or implicated as having a mitochondrial function, known as the MitoExome. My PhD studies have focused on the characterisation of two novel genes identified by MitoExome sequencing; UQCC2 and UQCR10. Both UQCC2 and UQCR10 are components of mitochondrial complex III. By using a panel of patients with causative mutations in a range of different complex III subunits and assembly factors, we have further characterised the assembly pathway of complex III. Of the 45 patients who underwent MitoExome sequencing, a third remain without a molecular cause identified. To address this, I utilised several alternative analysis strategies to pursue molecular diagnoses in patients where a causative mutation had not been easily identified. Reanalysis of the MitoExome data using two different analysis pipelines (Cpipe and xBrowse) identified an additional patient diagnosis in RMND1. Comparison between the two pipelines highlighted some key differences between analyses for research compared to a clinical setting. The Birth Prevalence cohort is a 12 year follow up study to revisit the original cohort reported by Skladal and colleagues in 2003 (Skladal, Halliday et al. 2003). This study identified 86 patients with a confirmed diagnosis of mitochondrial disease who were born in South Eastern Australia between 1987 and 1996. This cohort was used to calculate the birth prevalence of mitochondrial disorders as 1 in 5000 live births. At the time of publication 23% (n=20/86) of patients had a molecular diagnosis identified. The 2015 review of this cohort found an additional 19 patients who fit the inclusion criteria, bringing the total number of patients to 105. Currently, 70% (n=73/105) of Birth Prevalence cohort patients have a molecular cause identified. This PhD describes some preliminary molecular investigation of 19 patients, who are as yet without a molecular diagnosis.
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ItemAppearance-altering facial surgery on children: An empirically informed ethical analysis( 2015)Using empirically informed ethical analysis, this thesis investigates the ethics of appearance-altering facial surgeries performed on children. These surgeries have attracted controversy in the media and ethics literature and are the subject of legislation and professional guidelines, which leave much to individual practitioners’ discretion. Despite their contentious nature, very little is known about surgeons’ practices and decision-making processes regarding these surgeries. This thesis is ‘empirically informed’ in two different ways: (1) by existing empirical data on psychosocial outcomes of children with facial differences and children who have undergone appearance-altering facial surgeries and (2) by new interview data from 22 surgeons who encounter requests for these surgeries. Using reflective equilibrium as my method of ethical analysis, these two kinds of empirical data are combined with established paediatric bioethical principles and concepts, including the zone of parental discretion and children’s assent and dissent, to arrive at a comprehensive position on the ethics of performing these surgeries. Using reflective equilibrium, I found some aspects of surgeons’ decision-making processes and practices diverged from existing ethical understandings about the relative roles of children and parents in medical decisions. One such area related to the ethical weight surgeons attach to children’s refusals. While most ethicists in the literature advocate including children in decisions, they do not necessarily recommend giving them decision-making authority. In contrast, most surgeons tended to give children a larger role in decisions about appearance-altering facial surgeries, viewing them as ultimate decision makers. In this thesis, I make normative claims about the relative levels of ethical weight surgeons should place on children’s and parents’ wishes when making decisions about these surgeries. Using the established ethical framework of the zone of parental discretion and related ethical concepts of harm and benefit, I claim that several morally relevant differences exist between these surgeries and other medical procedures requested for children. These include their uncertain risk-benefit ratio, their elective nature, uncertainty as to how the child will later perceive their facial difference and the acceptability of surgery, and the existence of alternative, less risky and invasive psychosocial interventions for alleviating appearance-related psychosocial harm. I argue these differences warrant placing greater (even absolute) ethical weight on children’s wishes, especially when children refuse these surgeries, and comparably less ethical weight on parents’ wishes, when making these decisions. Although my ethical position is similar to most of the surgeons’ judgments, I argue it would be worthwhile for surgeons to know about and use ethical principles and concepts more explicitly when making decisions and communicating with children and/or their parents. I also claim that surgeons ought to make more of a considered effort to ascertain children’s actual wishes and inform parents and/or children about non-surgical options for alleviating appearance-related psychosocial distress, and be taught strategies for saying no and how to articulate their ethical reasoning. These findings have significant implications for clinical practice, raise questions for further ethical analysis and contribute to refinement of existing understandings of children’s assent and dissent and parents’ role as proxy decision makers for their children.
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ItemCardiovascular associations of HIV infection in children( 2015)Vertically-acquired HIV infection is a devastating disease in childhood that may affect any organ, including the cardiovascular system. With increased survival of HIV infected children due to antiretroviral (ART) treatment availability, chronic cardiovascular problems become a confronting challenge, not only because HIV infection may cause cardiac problems readily manifesting in childhood but also because it potentially increases future cardiovascular disease risk in adulthood. This thesis explores various possible cardiovascular effects of HIV infection in children, particularly the differential effects of ART-naïve compared to ART-exposed HIV infection on left ventricular (LV) remodelling, pulmonary hypertension, and arterial elasticity. We conducted a cross-sectional study enrolling 56 ART-naïve, 59 ART-exposed HIV infected, and 51 healthy children in Jakarta, Indonesia and performed cardiac/vascular ultrasound, and blood tests for biomarkers. There were marked differences in the cardiovascular parameters between the two groups. We found that ART-naïve HIV infection was associated with LV dilation while the ART-exposed seemed to cause concentric hypertrophic remodelling. ART-exposed HIV infected children who showed evidence of higher pulmonary artery pressure than healthy children, whereas the ART-naïve children had reduced right ventricular function. For arterial elasticity, the ART-naïve had higher strain and lower elastic modulus, but thicker intima-media thickness, whereas the ART-exposed had similar vascular properties as healthy children. In conclusion, HIV infection in children have significant impacts on childhood cardiovascular system with particular differential effects between ART-naïve and ART exposed HIV infection. Routine cardiovascular surveillance is needed for children with HIV infection.
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ItemTherapeutic potential of cord blood for congenital cardiac disease( 2015)Umbilical cord blood, rich in hematopoietic stem cells, is a recognised valuable alternative source to bone marrow for treating disorders such as leukaemia. Many progenitor cell types have been derived from cord blood, including mesenchymal stem cells. Such cells from the bone marrow have been studied for their potential therapeutic use for cardiac diseases. This thesis examines the potential of cord blood cells to adopt cardiac fate in vitro, the presence of cardiac progenitor cells within the cord blood and therapeutic delivery of cord blood cells during congenital heart disease surgery in neonates.
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ItemAnosmia in paediatric traumatic brain injury( 2015)Objective: Paediatric traumatic brain injury (TBI) is a leading cause of childhood disability, and is associated with significant physical, sensory, psychosocial and neuropsychological sequelae. While our knowledge of outcomes after paediatric TBI has expanded over the past 20-30 years little is known about olfactory function outcomes. This is despite the fact that olfactory dysfunction (OD) is known to be common after adult TBI, has poor prognosis for recovery and is associated with significant functional implications in health, safety, and activities of daily living. In adults with TBI, OD has been linked to injury variables including severity, site of impact, neuropathology and skull fracture and to deficits in executive function (EF), with OD suggested as a potential marker of EF deficits following TBI, though little is known about these relationships in paediatric TBI. The overall aim of this thesis was to address the dearth of research in paediatric OD. The study investigated the frequency with which OD occurs following paediatric TBI, and the relationship between OD and injury variables such as severity, fracture, and injury impact. The relationship between olfactory function and EF was examined and recovery of OD documented up to 18 months post injury. Overall, it was hypothesised that children with moderate/severe TBI would demonstrate poorer olfactory function than those with mild TBI and that children with TBI and OD would perform more poorly on measures of EF than those without OD. Method: Thirty-seven children aged 8-16 years with TBI were recruited to our prospective longitudinal study. Olfactory assessment using the University of Pennsylvania Smell Identification Test was conducted at 0-3 months (T1), 8 months (T2) and 18 months (T3) post injury. Children completed EF tests at T2 and parents completed ratings of behavioural EF at T2 and T3. Results: At T1 19% of participants demonstrated impaired olfaction, with 5% classified as anosmic. OD was significantly related to injury severity at T1, with those with moderate/severe TBI showing poorer olfactory function than those with mild TBI. Longitudinal follow-up indicated evidence of recovery in olfactory function at T2, however, only 16% of those with the most severe OD showed recovery to normal olfactory function, with the remainder demonstrating ongoing OD at T3. Occipital site of impact was a significant predictor of olfactory performance at T3. Children with OD showed significantly poorer performance on a single EF measure of fluency at T2 compared to those with normal olfaction. Acute olfactory function did not significantly predict EF outcomes at either 8 or 18 months post injury. Conclusions: OD appears to be relatively common after paediatric TBI, with limited prospects for recovery, consistent with previous adult research. Acute OD was significantly related to injury severity, though those children at greatest risk of poor later olfactory function were those with an occipital site of impact. Evidence for a link between OD and EF was limited and in particular, acute olfactory function did not appear to be an accurate predictor of later EF deficits. Our findings indicate the need for a focus on OD in clinical practice with routine screening and implementation of education and management strategies recommended. There is a need for further longitudinal research in larger cohorts to elucidate further the links between OD and injury variables, identify clinical predictors of OD, and investigate the functional implications for children and adolescents with TBI.
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ItemIsotonic intravenous fluid for maintenance hydration in hospitalised children( 2015)Introduction This thesis comprises a systematic review, a laboratory based study, and a randomised controlled trial comparing isotonic with hypotonic intravenous fluid for maintenance hydration in children: the Paediatric Intravenous Maintenance Solution (PIMS) study. Objectives The general objective of this research was to study the use of isotonic intravenous fluid for maintenance hydration in children. Specific objectives were: • To establish the current evidence for the use of isotonic fluid, compared with hypotonic fluid (Chapter 2) by comparing the incidence of hyponatraemia and hypernatraemia, the effect on mean serum sodium concentration, and the incidence of attributable adverse effects. • To design a randomised controlled trial in a broad paediatric population comparing isotonic fluid with hypotonic fluid (Chapter 3). • To describe the effect of progressive dilution of blood samples with 0.45% sodium chloride with 5% glucose on measured concentrations of sodium and glucose, and to use these results to inform the PIMS study by identifying samples that were potentially contaminated with study fluid (Chapter 4). • To assess the risk of hyponatraemia when an isotonic fluid is compared with a hypotonic fluid for maintenance intravenous hydration in a broad paediatric population (Chapter 5); secondarily to compare the risk of hypernatraemia and other attributable adverse effects and outcomes. Methods Children aged between 3 months and 18 years requiring intravenous fluid to maintain hydration were the population of interest for this research. • A systematic review was conducted including randomised controlled trials which compared isotonic with hypotonic intravenous fluids for maintenance hydration in children. • A laboratory study sampled blood from three healthy adult volunteers. The blood was contaminated by 0.45% sodium chloride with 5% glucose using six different contamination ratios. The impact on measured concentrations of sodium and glucose was described. • A blinded, randomised controlled trial (the PIMS study) was designed and conducted, enrolling children who needed intravenous maintenance hydration for six hours or longer. With an online randomisation system that used unequal block sizes, patients were randomly assigned to receive either isotonic intravenous fluid containing 140mmol/L of sodium (Plasma-Lyte 148 with 5% glucose) or hypotonic fluid containing 77mmol/L of sodium (0.45% sodium chloride with 5% glucose) for 72 hours, or until their intravenous fluid requirement decreased to below 50% of standard maintenance rate. Assignment was stratified by baseline serum sodium level. Study investigators, treating clinicians, nurses, and patients were masked to treatment assignment. The primary outcome was the occurrence of hyponatraemia (serum sodium <135mmol/L with a decrease of at least 3mmol/L from baseline) during the treatment period, analysed by intention to treat. Results • The systematic review revealed a lack of evidence for the use of isotonic intravenous fluid for maintenance hydration outside of surgical or intensive care populations. In addition, there was limited evidence beyond the first 24 hours of therapy. • The laboratory study showed that a glucose level above 16.1mmol/L indicated that a decrease in measured sodium by at least 3mmol/L was a possible consequence of contamination of a blood sample with intravenous fluid. This was used as the basis of a sensitivity analysis within the PIMS study. • Over a three year period, 690 children were randomly assigned to receive either isotonic or hypotonic fluid. Of these patients, primary outcome data were available for 319 who received isotonic fluid and 322 who received hypotonic fluid. The PIMS study found that fewer patients given an isotonic fluid than those given a hypotonic fluid developed hyponatraemia (12 patients [4%] vs 35 [11%]; odds ratio [OR] 0.31, 95% CI 0.16 to 0.61; p=0.001) without evidence of an increase in adverse events. Conclusions • There was a lack of prior evidence in a broad paediatric population for the use of isotonic fluid over hypotonic fluid. • The use of isotonic intravenous fluid with a sodium concentration of 140mmol/L had a lower risk of hyponatraemia without an increase in adverse effects when compared with a fluid containing 77mmol/L of sodium. An isotonic fluid should be used as intravenous fluid for maintenance hydration in children.
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ItemAn investigation of multiple imputation for missing data in a longitudinal study of mental health and behaviour in young people( 2015)Longitudinal studies involve the repeated follow-up of individuals over a period of time. In epidemiological research, longitudinal studies are used to observe changes in health and behaviour, and to investigate associations between risk factors and outcomes measured at a later time point. The current study uses data from the Victorian Adolescent Health Cohort Study (VAHCS), a longitudinal study of young people recruited in adolescence and followed into adulthood. During the adolescent phase, the VAHCS collected data on participants’ mental health and behavioural problems, including substance use and antisocial behaviour. During the young adult phase, data were also collected on key social-role transitions, including the completion of education, leaving the family home, becoming financially independent, forming a committed relationship, and having children. The epidemiological research presented in this thesis focused on the transition from school into the workforce, and examined the extent to which adolescent mental health and behavioural problems were associated with being not in employment, education, or training (NEET) in young adulthood. When analysing data from longitudinal studies, it is common to face the problem of missing data. To handle the missing data in the VAHCS, I used the method of multiple imputation. Multiple imputation is a powerful tool for the analysis of incomplete data, but it requires a range of decisions on issues that arise when building the imputation model. One such decision concerns how to impute different variable types. When outlining the proposed imputation model for the epidemiological analysis, I was unsure about which methods would be most appropriate for the imputation of two types of variable. The first type was a limited-range variable, which had a restriction to both ends of its range. The second type of variable was a semi-continuous variable that was to be categorised for analysis. Semi-continuous variables have a large proportion of zeros and a continuous range of values otherwise. An example of a semi-continuous variable is weekly units of alcohol consumed. In the methodological research component of this thesis, simulation experiments were used to compare available methods for imputing missing values in these variables, with the goal to identify the most appropriate method. A key finding from both simulation studies was that methods that required values to be rounded after imputation (either to the limits of the range or to discrete categories) performed poorly, producing estimates with the greatest bias. The results from the epidemiological analysis, with multiple imputation used to handle the missing data in the VAHCS, identified that around 8 per cent of males were NEET at the age of 21 years, decreasing to around 6 per cent at 24 years. The percentage of females who were NEET actually increased slightly from just below 9 per cent at the age of 21 years to 10 per cent at 24 years of age. The risk of being NEET in young adulthood was higher for participants who reported repeated antisocial behaviours and frequent cannabis use, and who had a longer duration of mental health disorder in adolescence.
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ItemNovel microRNA regulation in cardiopulmonary development and preterm birth complications( 2015)Spatial and temporal miRNA expression profiles regulate numerous cellular processes, including early organogenesis and development. Cardiopulmonary miRNAs in late gestation and the perinatal period, including those underlying abnormal gestation and preterm birth complications are unknown. Using an ovine experimental model, I have investigated whether differences in miRNA expression exist: a) in discrete regions of the fetal cardiopulmonary and placental systems b) during late gestation; c) in response to maternal stress; d) in preterm birth; e) in steroid-dependent maturation.