Paediatrics (RCH) - Theses
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ItemUrinary tract infection in children – changing the management paradigm so more children can be treated at home( 2023-07)Urinary tract infections (UTI) are a common reason for paediatric emergency department (ED) presentations. Although most children are successfully treated with oral antibiotics, approximately one-third receive intravenous (IV) antibiotics and hospital admission. However, there is limited evidence supporting these decisions, and consequently an opportunity to approach antibiotic use differently to potentially treat more children out of hospital. Guidelines recommend most patients can be treated with oral antibiotics, but the studies used to support these guidelines excluded several cohorts. The aims of this thesis were to investigate current UTI management, particularly use of antibiotics and Hospital-in-the-Home (HITH), to define which children actually need IV antibiotics, and to explore the feasibility of using shorter IV antibiotic durations. The initial study focused on use of HITH for IV antibiotics for UTI. The study found that 90% of patients successfully completed treatment without readmission to hospital, and none became severely unwell at home. However, HITH was underused, with only 8% of patients on IV antibiotics using this model. The study supports home IV antibiotics for selected UTI management. The next study used a wider lens, examining all current UTI management in ED and found little variation in antibiotic route, choice, and duration for lower UTIs and uncomplicated upper UTIs. However, complicated upper UTIs, where there is less evidence, showed more variation. No single feature reliably predicted use of IV antibiotics, but multiple complicating factors were associated with their initiation, suggesting they represent ‘red flags’ for clinicians. In the following study, clinicians were asked why they used IV antibiotics for UTI and admitted children to hospital. Although they had defined reasons for using IV, objective clinical evidence did not always support their reasons. The study hypothesised that multiple features lead to the decision to prescribe IV antibiotics and that these features may group together. Given the finding that multiple but not always the same features led to IV antibiotic initiation, the next study aimed to develop a clinical score to determine which children need IV antibiotics. The Melbourne RUPERT score was successfully developed and tested on patients with confirmed and probable UTI. Using six clinical features, the score is straightforward, easily attainable, reproducible and aids consistent stratification of patients to determine route of initial antibiotic treatment. Finally, using outcomes and learnings from the preceding studies, a randomised control trial protocol was developed. This trial aims to investigate whether an ultra-short IV duration (1 day) is non-inferior to the standard duration for children requiring IV antibiotics. If a single daily dose of IV antibiotics followed by oral antibiotics proves sufficient, patients could be discharged home from the ED on oral antibiotics, eliminating the need for hospital admission. In questioning whether more children with UTI could be treated out of hospital, this thesis found that indeed they can, through delivering IV antibiotics at home, treating more children with oral antibiotics, and investigating an identified practice of earlier switch from IV to oral. This has the potential for major impacts on patient care and hospital sustainability.
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ItemNovel technology for the measurement of newborn and infant heart rate( 2017)Background: Monitoring heart rate in newborns and infants is crucially important in guiding resuscitation and medical care. Established methods for heart rate assessment of these children have inherent drawbacks. In recent years, novel methods for assessing neonatal and infant heart rate have been developed, with varying levels of evaluation conducted. Digital stethoscopes may provide a better means of heart rate assessment for newborns and infants. Aim: The aim of this thesis was to comprehensively review existing established and novel technologies used to monitor newborn and infant heart rate, and compare new digital stethoscope technology with the gold standard, electrocardiogram (ECG). Methods: This thesis (a) outlines the definition and importance of heart rate in medicine, presented in the context of a review of cardiac anatomy and physiology relevant to understanding this vital sign and aspects of its measurement in neonates and infants; (b) presents a narrative review of established methods for monitoring heart rate; (c) expands the scope of this review from established to emerging methods for monitoring heart rate with a systematic literature review of novel methods for newborn and infant heart rate assessment; (d) describes original research using a prototype digital stethoscope attached to a smart device containing software for detecting and displaying heart rate in real-time that was conducted on infants in the neonatal intensive and special care setting, as well in the delivery room setting using an improved version of the device and software. Results: A review of the literature analysing methods of assessing neonatal and infant heart rate found strengths as well as significant weaknesses in the various methods in clinical use or in development. In the neonatal unit, a prototype digital stethoscope and smartphone device for assessing heart rate had a mean difference (±2 standard deviations) of 7.4 (48.5) beats per minute (bpm) when compared to the gold standard of electrocardiography. The mean (interquartile range) time to first digital stethoscope heart rate display was 4.8 (1 to 7) seconds, and the device failed in 12.3% of use attempts. Repeating the comparison in the delivery room setting using an updated algorithm and new hardware, Bland-Altman analysis revealed a smaller mean difference (±2 standard deviations) between the digital stethoscope and electrocardiography of 0.2 (-18 to +18) bpm including crying periods (Figure 23), and 1.0 (-11 to +12) bpm excluding crying periods. The improved digital stethoscope took a median (interquartile range) of 7 (5 to 11.5) seconds after application to display a heart rate. It failed to detect heart rate in 37% of cases, all of which were in crying infants. Conclusion: A digital stethoscope and smart device with software can rapidly detect neonatal and infant heart rate. In the delivery room, device failure primarily occurred during infant crying, with improved accuracy during non-crying periods.
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ItemThe epidemiology and aetiologies of the severe epilepsies of infancy( 2016)The severe epilepsies of infancy (SEI) are a group of infantile-onset seizure disorders characterised by frequent seizures, abnormal EEG and pharmacoresistance to anti-epileptic therapy. SEI include well-described epilepsy syndromes such as early infantile epileptic encephalopathy (EIEE), epilepsy of infancy with migrating focal seizures (EIMFS) and West syndrome. Cognitive outcome is often poor, due to effects of seizures, the underlying aetiology, and antiepileptic drugs (AEDs) on the developing brain. There is an urgent need for novel treatments. Where effective therapies are available, such as epilepsy surgery for brain malformations, treatment can be life-changing. Given that developmental outcomes may be significantly improved in the context of optimal seizure control at an early age, determining the underlying cause of SEI early in life is paramount. The aetiologies of SEI are heterogeneous; a large number of acquired and genetic brain disorders are reported. In many infants, the cause remains unknown despite investigation, and is presumed to be genetic. With the emergence of next generation sequencing (NGS) techniques such as whole exome sequencing (WES), a rapidly growing number of genetic causes of SEI is now recognised and gene discovery is ongoing. The genetic epidemiology of SEI has not been studied and the relative importance of each genetic cause is not known. Brain malformations, chromosomal abnormalities, inborn errors of metabolism and some genetic disorders can be diagnosed with technologies currently available in clinical practice. Studies of WES and other NGS techniques in epilepsy populations have shown that these techniques identify the aetiology in 10-50% of undiagnosed patients. No study has specifically looked at the yield in SEI, and no population-based studies have been reported. The yield and cost-effectiveness of NGS for SEI at a population level remains unknown, and access to genetic testing is currently poor in most regions of the world. This population-based study of SEI in Victoria, Australia aimed to study the incidence and determine the aetiologies, electroclinical phenotypes and other phenotypic characteristics of SEI. As part of a particular focus on genetic aetiologies, the study aimed to identify genetic causes in infants with SEI of unknown aetiology using WES, and determine the yield and cost of early genetic testing relative to current standard diagnostic pathways for investigation of SEI aetiology. Infants with SEI born in Victoria during 2011-2013 were identified by a comprehensive state-wide search of multiple sources. Infants with potential SEI were identified by review of all electroencephalogram (EEG) reports on children under two years old during 2011-2015 (n=4505), and search of neonatal intensive care unit (NICU) databases for neonates with seizures born 2011-2013 (n=379). Hospital records of infants with potential SEI from the three main paediatric hospitals in Victoria, The Royal Children’s Hospital (RCH), Monash Health (MMC) and The Austin Hospital, and the two NICUs not co-located with a paediatric hospital, The Royal Women’s Hospital (RWH) and The Mercy Hospital for Women (MHW), were reviewed to confirm clinical and demographic inclusion criteria were met. SEI was defined as epilepsy onset before age 18 months, frequent seizures (> daily for a week or > weekly for a month), epileptiform EEG and pharmacoresistance (failed 2 appropriate anti-epileptic therapies); infantile spasms were automatically included. In infants with confirmed SEI, medical records, EEG recordings and brain magnetic resonance imaging (MRI) were reviewed to determine each infant’s epileptic syndrome, outcome at two year old, and aetiology. Clinical assessment and WES were performed if aetiology or electroclinical phenotype was unknown. 114 infants with SEI were ascertained. The incidence of SEI in Victoria is 51/100,000 live births/year. West syndrome/infantile spasms was the most common epileptic syndrome, with an incidence of 33/100,000 live births/year. EIMFS and EIEE had incidences of 4.5 and 3.6/100,000 live births/year respectively. At two years old, 18 (16%) infants were deceased. 86/98 (90%) survivors had delayed development, and 46/98 (47%) ongoing seizures. All infants whose presenting epileptic syndrome was EIEE, early myoclonic encephalopathy (EME) or EIMFS at epilepsy onset were deceased or had severe developmental impairment. Normal development was seen in 9/64 (14%) infants who presented with West syndromes/infantile spasms or a unifocal epilepsy, and only two were deceased. The aetiology was identified in 76 (67%) and unknown in 38 (33%). Fourteen (12%) infants had an acquired brain insult such as hypoxic-ischaemic encephalopathy or perinatal stroke. The remaining infants had genetic or presumed genetic aetiologies. Brain malformations were identified in 31 (27%), including focal cortical dysplasia (FCD) in 14 (12%). Six (5%) infants had metabolic disorders and nine (8%) had chromosomal abnormalities. Sixteen (14%) had single gene disorders, including 11 (10%) with disorders of ion channel function (channelopathies). Aetiology was known from clinical testing in 61 (54%). Research MRI review identified the cause in a further 4 (4%) and research genetic testing in 11 (10%). Among 86 (75%) infants with no aetiological diagnosis prior to epilepsy onset, the highest yield investigations were MRI and genetic testing, which identified the cause in 25/85 (29%) and 16/50 (32%) respectively. 13/50 (26%) infants had a genetic variant of unknown significance (VOUS) identified on WES; these are being further investigated. Modelling of diagnostic pathways showed that performing WES early in the diagnostic pathway and reducing the amount of metabolic testing increases diagnostic yield for less cost compared with the current standard diagnostic pathway. Approximately 1:2000 infants have SEI, equating to over 150 new cases of SEI in Australia per year. Outcomes for seizure control, development and survival are poor. Brain malformations were the most common cause, were under-recognised, and should be considered in those with unknown aetiology, especially in those with West syndrome or unifocal epilepsy. Channelopathies were the most common group of single gene disorders. Next-generation genetic testing and high quality brain imaging improved diagnostic yield, with implications for treatment and reproductive counselling, and should be implemented early in the diagnostic pathway in clinical practice. Future work will focus on identifying the aetiology in the remaining infants, determining the genetic basis of brain malformations causing SEI, and studying the yield of other NGS and brain imaging techniques to improve the rate of early diagnosis. This work will inform research into development of novel and targeted treatments for these devastating disorders.
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ItemNeonatal mortality and morbidity in Da Nang, Viet Nam( 2013)Neonatal morbidity and mortality are major global public health challenges. There are surprisingly few data on neonatal morbidity and mortality from the Southeast Asia region. The aim of this study is to evaluate the burden and pattern of neonatal morbidity and mortality in the neonatal unit in Da Nang Hospital in central Viet Nam. A one-year prospective cross sectional study of all neonatal admissions was conducted from November 2010 to October 2011. During this time, there were 2555 neonatal admissions to the unit and the overall mortality rate was 8.6%. The case fatality rate was inversely associated with birth weight, the highest rate of 96% being among those with a birth weight of <1000 grams, 59% among neonates with a birth weight of <1500 grams and the lowest rate of 4% in neonates with birth weight ≥2500 grams. There were 220 deaths in the study, 21% occurred within the first 24 hours of life and 57% occurred within the first 7 days of life. Causes of deaths were often multifactorial. However, the leading primary causes of deaths were infections (32%), prematurity and its complications (25%), birth defects (24%) and birth asphyxia (6%). Risk factors associated with death were being outborn, gestational age of <34 weeks, small for gestational age, birth defects and confirmed sepsis. Risk factors associated with preterm births included the mother having a history of previous preterm births or having medical problems during pregnancy. Early-onset sepsis was associated with maternal infections while late-onset sepsis was correlated with low gestational age and the use of invasive procedures such as central catheters. Birth asphyxia was more common in infants born in other hospitals and transferred after birth. Birth defects were associated with congenital rubella. Hypothermia was common on admission among preterm infants or infants with respiratory distress. Low usage of antenatal corticosteroids was noted. Practices noted to be suboptimal included nutritional support for preterm infants, the practice of breastfeeding, and respiratory support for neonates with respiratory distress. The high mortality and suboptimal practices found in this study suggest that better outcomes could be achieved by a co-ordinated approach that emphasises improving neonatal care practices. Current infection control practices and antibiotic guidelines and practices need to be immediately reviewed and improved. The study has identified an urgent need to prevent hypothermia and to improve nutrition for preterm neonates. Practices such as Kangaroo Mother Care and encouraging breast feeding have huge potential to improve outcomes and should be implemented. Preconception and antenatal care needs to be improved including antenatal corticosteroid for women delivering at <34 weeks. Rubella immunisation for women among child-bearing age should also be prioritised. This prospective study provides comprehensive background data on the leading causes of neonatal mortality and morbidity in the resource-limited setting of Viet Nam. These data can be used to identify and prioritise interventions, especially low-cost interventions, that could improve neonatal care and outcomes in this population, and to evaluate the benefits of these interventions.
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ItemThe incidence and timing of brain injury and its influence on neurodevelopmental outcome in infants undergoing surgery for congenital heart disease( 2010)INTRODUCTION: Brain injury is the most common complication amongst infants with congenital heart disease (CHD) who require surgery during the newborn period. Up to one half of children demonstrate impairment in neurodevelopment following cardiac surgery early in life. The developing brain of the newborn infant may be vulnerable to injury and impairment of normal development, due to abnormalities in cerebral blood flow related to the underlying cardiac abnormality in utero and following birth. Numerous peri-operative factors may also influence the risk of brain injury and development including interventions and management including surgical and perfusion techniques and intensive care factors, in addition to individual patient factors. Links between early detection of brain anomalies and later neurodevelopment in children following cardiac surgery have not previously been described. AIMS: The aim of this study was to determine the incidence and timing of brain injury and impaired brain development in young infants undergoing surgery for CHD, and to ascertain the impact of risk factors, associated with cardiac surgery and peri-operative intensive care during early infancy, on neurodevelopmental outcome at two years of age. METHODS: Seventy-five full-term infants undergoing surgery for CHD prior to two months of age were enrolled in a prospective study at the Royal Children’s Hospital, Melbourne. Infants were excluded if they were born prior to 36 weeks’ gestation, if they had a known genetic abnormality independently associated with impaired neurodevelopment, if they were considered too clinically unstable to be able to undergo a pre-operative magnetic resonance imaging (MRI) scan and if they were unlikely to be able to undergo a late MRI scan for geographic reasons. Study participants underwent a series of neurological investigations in the peri-operative period: 1) serial MRI scans before, at one week following surgery and at 2-3 months of age, and 2) amplitude-integrated electroencephalography (aEEG) before, during and for 72 hours following surgery. Surviving children were then assessed at two years of age using the Bayley Scales of Infant and Toddler Development, 3rd Edition (BSID-III) and a neurological evaluation. RESULTS: The enrolled cohort of 75 infants had a mean birth weight of 3.3 ± 0.5kg, head circumference 34.4 ± 2.2cm and gestational age at birth of 39.0 ± 1.4 weeks. They had a median age at surgery of seven days (IQR 3-14) and the surgical categories of participants were as follows: closed biventricular repair (6); open biventricular repair (26); open biventricular repair with arch repair (4); single ventricle palliation (25); isolated Blalock-Taussig shunt (14). Cardiopulmonary bypass (CPB) was utilised during surgery in 84% and antegrade cerebral perfusion (ACP) in 39% of infants. Recovery of a continuous background pattern on aEEG occurred at a median of 13 (IQR 3-25) post-operative hours and sleep-wake-cycling (SWC) returned at 27 (IQR 17-49) post-operative hours. A longer recovery time to a continuous background pattern following surgery increased the risk of neurological and motor impairment, and a longer recovery time to SWC increased the risk of cognitive and language impairment. Electrical seizures were identified in 29% of infants during the peri-operative period for a median cumulative time of six minutes. Intra-operative seizures occurred in 19% of infants during CPB, predominantly occurred during the institution of ACP and moderate hypothermia, and were strongly related to mortality (p<0.0001). Post-operative seizures also occurred in 19% of infants, predominantly during support with extra-corporeal membrane oxygenation, but were not related to subsequent outcome. Delay in brain maturation on MRI was common, with almost half the infants demonstrating up to four weeks delay in cortical folding pattern on their pre-operative scans. However, myelination impairment was most strongly related to subsequent impairment of neurodevelopment at two years. Punctate deep white matter and periventricular signal abnormalities occurred frequently, especially during the post-operative period, but tended to resolve spontaneously and did not relate to neurodevelopmental outcome. Stroke occurred rarely during peri-operative period and was unrelated to the performance of a balloon atrial septostomy. A complete neurodevelopmental evaluation was undertaken at 23.8 ± 1.6 months of age in 65 children. Two year mortality was 12%. The mean cognitive, language and motor composite scores were 90.2 ± 14.0, 91.1 ± 16.5 and 93.5 ± 13.5. Neurological deficits were identified in 26% of children at two years, most commonly hypotonia and eye abnormalities. The risk of cognitive function developing more than two standard deviations below the expected mean was three times that anticipated by test norms, whilst language function had an almost five-fold risk of significant delay compared with test norms. Peri-operative risk factors identified for mortality before two years of age were a higher serum lactate at six post-operative hours and the presence of white matter injury on the late MRI scan (p<0.0001). Patient-related risk factors for impairment in neurodevelopment at two years were a lower gestational age at birth, male gender and impaired myelination in the posterior limb of the internal capsule on pre-operative MRI. Peri-operative risk factors for impaired neurodevelopment were the absence of pre-operative vasoactive infusions, a higher serum lactate at the conclusion of surgery, a longer hospital length of stay and delayed recovery of the aEEG following surgery. The type of surgery undertaken and a variety of intra-operative surgical and perfusion techniques appeared to have little impact on subsequent outcome in survivors. CONCLUSIONS: Neurodevelopmental delay and neurological impairment is common in two-year-olds following cardiac surgery during early infancy. A relationship was found between early markers of brain maturation and subsequent neurodevelopment in this group of full-term infants. However, a clear-cut link between early injury, as evidenced by abnormalities on imaging or aEEG, and subsequent performance could not be demonstrated.
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ItemRespiratory function tracking in survivors of prematurity and low birth weight( 2009)INTRODUCTION: To investigate longitudinal ‘tracking’ in lung growth, decline or stability of adult preterm/very low birth weight survivors over the study period. To investigate whether those who have clinically abnormal lung function fall further behind their contemporaries or demonstrate evidence of ‘catch-up’ growth. METHODS: 210 babies born ≤34 weeks’ gestation and with birth weights ≤ 1500g in 1977-1982 were followed up at 8, 11, 14, 18 and 25 years of age. Respiratory outcome was evaluated using Spirometry. Spirometry was performed at each of the follow-up periods. Mixed model regression was used to assess longitudinal lung function trajectories and the influence of Bronchopulmonary dysplasia, being small for gestational age and abnormal lung function. Restricted maximum likelihood modelling was used for longitudinal FEV1 z-score as it allows for analysis of data from different time points that are not necessarily evenly spaced, without being affected by missing data. RESULTS: 137 VLBW children completed lung function testing at 8 years of age. Twenty VLBW children (14.6%) had abnormal FEV1 z-scores and 26 (21.0%) [Defined as >2 standard deviation’s below the mean]. VLBW survivors showed minimal ‘catch-up’ in FEV1 z-score over the 13 years of the study; those without BPD (Bronchopulmonary dysplasia) FEV1 improved 0.034 (p=0.014) z-scores, those with BPD FEV1 improved 0.033 (p=0.039) z-scores. VLBW with BPD survivors did not return to within normal limits; those with abnormal FEF25-75 z-scores did not show significant ‘catch-up’ growth (p=0.41) and remained abnormal. CONCLUSIONS: Mixed models do not reveal any significant effects from being born with VLBW and its interaction with age; it does lead to a reduction in FEV1/FVC mean z-score. Although those VLBW individuals who were small for gestational age had significantly reduced FEV1, FVC and FEV1/FVC mean z-scores and these small for gestational age individuals show evidence of ‘catch-up’ growth in terms of lung function, with the exception of FEV1/FVC z-score which falls further from their contemporaries. This effect on FEV1 and FVC z-scores may suggest some protective element or compensatory mechanism of being born small for gestational age. Reassuringly, Bronchopulmonary dysplasia as a neonate did not significantly affect lung function variables as these individuals as they age. Those with clinically abnormal lung function show a progressive failure to achieve optimal lung function whether or not they had Bronchopulmonary dysplasia.