Paediatrics (RCH) - Theses
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ItemNon-invasive arterial wave analysis in congenital heart disease( 2018)Elevated large arterial stiffness is an independent risk factor for adult cardiovascular and cerebrovascular disease. Arterial dysfunction may already be evident in childhood, and children born preterm, or with a history of congenital cardiac surgery, particularly coarctation of the aorta, have a high burden of adult cardiovascular disease and hypertension. Novel arterial wave analyses such as Wave Intensity (WI) and Wave Power (WP) assess the interaction between the heart and great vessels, providing insights into mechanisms of hypertension. Non-invasive WI/WP analyses rely on accurate acquisition of velocity (U), and diameter (D) with ultrasound. Although ultrasound methods are well suited to measuring peak U, WI/WP rely on mean U, which is difficult to obtain routinely. Local pulse-wave speed (c), a measure of arterial stiffness, can also be determined by constructing PU or ln(D)U loops, which also rely on mean U. Errors in c with PU and ln(D)U loop methods due to inaccurate U were determined using MRI-based verification and simulated virtual cohort. A novel method for acquiring local c, which accounts for errors in U and those related to proximal wave reflections, was developed. This technique allowed for scaling factors to be derived to convert peak U into mean U, enabling WI/WP analysis using widely available clinical equipment. In an animal model, invasive and non-invasive WI/WP analyses were compared. The correlations for WI and WP indices were good, but agreement was poor- with a majority of the bias accounted for by either inaccurate invasive U or non-invasive flow estimation, and to non-invasive underestimation of peak P rates of change. Agreement and correlation for wave-related pressure changes were acceptable, and non-invasive WI analysis detected similar relative changes in wave indices during haemodynamic perturbations. Ex-preterm adolescents born at <28 weeks gestation and largely at appropriate weight for gestational age were found to have elevated systolic blood pressure, with no difference in conventional vascular indices. They had a smaller ascending aorta and greater wave reflection on non-invasive WI assessed in the aorta, which was associated with systolic blood pressure on multivariable analysis. Non-invasive WI/WP was also applied in a study of young adults after coarctation repair. They had higher aortic stiffness, but despite higher carotid IMT, there was no increased carotid stiffness. They had higher aortic WI indices, but not WP. In contrast, in the carotid artery both WI and WP indices were greater. Aortic stiffness was related to forward carotid WP in the coarctation group, but not controls. These findings demonstrate that greater stiffness of the aorta leads to increased transmission of wave energy towards the brain. Non-invasive WI/WP analyses have the potential to be more widely deployed using the methods developed in this thesis, and may yield novel insights into the circulatory phenomena that are encountered in children and young people with congenital cardiac and vascular disease.
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ItemMinimising complications after surgical repair of coarctation of the aorta( 2018)Coarctation of the aorta is one of the most common congenital heart defects, often requiring surgery soon after birth. In Australia alone, approximately 150 babies are born with coarctation each year with an estimated 3,000 people living with a coarctation repair. Coarctation can no longer be considered a benign condition cured by surgery. There has been renewed interest into the late outcomes after coarctation repair as rates of late aortic arch reobstruction and late hypertension have recently been demonstrated to be much higher than initially expected. Alarmingly, studies have demonstrated that this late hypertension is directly linked to mortality at a young age. Unfortunately, late hypertension is often resistant to conventional antihypertensive medication and its exact mechanism is unknown. This thesis aimed to (i) determine the long-term outcomes after surgical repair of coarctation with a particular focus on determining the mechanisms leading to the development of late hypertension, (ii) examine the impact of an associated bicuspid aortic valve on patients with previous coarctation repair, and (iii) examine the complication of vocal cord paresis after aortic arch repair via sternotomy approach. A broad range of potential mechanisms for late hypertension including mechanical, arterial wall, neural, and genetic factors were all explored. In this thesis, I present our current understanding of the population, their outcomes and risk factors for early and late complications, and, finally, present initial data serving as a foundation for a prospective aortic arch anomaly biobank and hypothesis-generated research. Through a collaboration with the Royal Brompton Hospital, London, UK, this thesis has also resulted in the largest and longest cohort study in the world comprising 834 coarctation patients spanning seven decades of follow-up. Through this thesis, I have demonstrated that: (i) there is likely a high prevalence of late hypertension after coarctation repair, (ii) there is significant device-dependence of 24-hour blood pressure monitoring devices, making the identification of the hypertensive patient challenging, (iii) the risk of late mortality is three times higher than a healthy matched population, with the majority of deaths attributable to complications related to hypertension, (iv) there is four times increased risk of aortic valve and ascending aortic interventions in those with an associated bicuspid aortic valve, (v) the use of extensive aortic arch repair techniques may reduce long-term complications, and (vi) there is a high incidence of left vocal cord paresis after aortic arch repair via sternotomy approach. This journey began when I was an undergraduate medical student investigating the outcomes of patients with coarctation repaired at The Royal Children’s Hospital. This thesis has refined our understanding and management of complications after coarctation repair and will ultimately improve the long-term outcomes of many patients with coarctation of the aorta.
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ItemComputer modelling and wave intensity analysis of perinatal cardiovascular function and dysfunction( 2011)Recent experimental work has highlighted a number of complex issues relating to blood flow dynamics in the normal fetus, where the structure and function of the cardiovascular system differs substantially from the normal adult or neonate. Neonates with congenital heart disease may also display quite complex haemodynamics due to a persistence of some features of the fetal circulation after birth, along with heart and vascular abnormalities that disturb normal blood flow patterns. For example, in pulmonary atresia with intact ventricular septum (PAIVS), the right ventricular outflow path fails to develop, while the combination of an underdeveloped right ventricle and profound coronary abnormalities may give rise to quite unusual coronary arterial flow patterns. This thesis employs two research tools that are ideal for clarifying the processes that govern haemodynamics in these contexts. The first is computer modelling, in which cardiac and vascular variables and configuration can be directly manipulated in a simulated physiological system without ethical concern. The second is wave intensity analysis, which is a powerful technique for discerning the origin of pressure/flow waves, as well as wave interactions, that occur at or between different vascular measurement sites. To enable investigation of a wide range of circulatory interactions in the perinatal period, this thesis describes computer models of the entire circulation for the normal fetus and neonate, these being derived from a model of the adult circulation that also provides an essential haemodynamic reference point. The normal fetal and neonatal models are adapted to form a model of PAIVS, which includes commonly occurring coronary abnormalities such as a fistula connecting to the right ventricular cavity and an interruption of the normal aorto-coronary pathway. These `comprehensive' models contain all of the major functional and anatomical segments of the circulation, including one-dimensional (1D) representations of the arterial and venous networks, and lumped parameter (0D) representations of the heart, valves and microvascular beds. In combination with wave intensity analysis and available experimental data, the normal fetal model is used to further investigate the determinants of the distinctive pressure/flow waveforms and wave intensity patterns in the pulmonary trunk, proximal branch pulmonary arteries and ductus arteriosus that have been observed in recent experimental studies in fetal lambs. Additionally, the fetal model is harnessed to investigate factors that contribute to a so-called fetal right-ventricular dominance, and to delineate the likely physical basis of mean aorto-pulmonary pressure differences and a functional separation of the upper body and lower body circulations in the fetus. The model of neonatal PAIVS is then used to elucidate the determinants of coronary arterial blood flow patterns and regional myocardial perfusion in the presence or absence of coronary abnormalities, both before and after surgical opening of the right-ventricular outflow path. The potential for coronary collateral connections to provide protection against myocardial ischemia is also explored. The findings of this thesis underscore the potential for both computer modelling and wave intensity analysis to provide insights into complex haemodynamic interactions that may occur normally or abnormally in the perinatal period.
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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.