Congenital heart disease : the timing of brain injury
Mebius, Mirthe Johanna
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Publication date: 2018
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Mebius, M. J. (2018). Congenital heart disease : the timing of brain injury. [S.n.].
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General introduction and
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General introduction
The heart (noun): A hollow muscle with a pump function, the ‘engine’ of our body, the central
part of a place or region, love and affection, and some even believe that the heart contains our feelings and our soul.
Development of the heart
The cardiovascular system is one of the first systems to develop in the embryo. The heart begins to develop by the third week of intrauterine life, it begins to beat at the 22nd or
23rd day, and blood flow begins by the fourth week.1 The origin of the heart lies within the
mesoderm, one of the three germ layers. Initially, the heart is a simple endothelial tube surrounded by cardiac jelly and primitive myocardium. The tube receives venous drainage at its caudal pole and starts to pump blood into the aorta at its cranial pole. Furthermore, several dilatations and constrictions of the tube develop, such as the truncus arteriosus, bulbus cordis, ventricle, atrium, and sinus venosus.1-4 The second stage in the development
of the heart is the formation of the cardiac loop. Normally, the straight tube folds to the right during the fourth week and is completed at the 28th day of intrauterine life.1-4 After cardiac
looping is complete, partitioning of the heart begins. During this stage the atria, chambers and major blood vessels of the heart are formed by three septa. One septum separates the right and left atrium, another septum separates the right and left ventricle and the third septum divides the truncus arteriosus into the pulmonary artery and aortic artery.1-4 The last
step in cardiogenesis is development of the four valves and after approximately 50 days of intrauterine life, all cardiac structures are developed (Figure 1).1-4
Figure 1 Development of the human heart
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Brain injury and neurodevelopmental impairments
Due to its complexity, cardiogenesis is a process susceptible to mistakes. Congenital heart disease (CHD) is the most common human birth defect and occurs in five to twelve per 1,000 live births.5,6 Advances in surgical techniques, cardiopulmonary bypass, postoperative
intensive care and medical therapies have led to a significant decline in mortality in infants
with CHD.6,7 Many of the surviving infants, however, have neurodevelopmental impairments
later in life. The prevalence and severity of neurodevelopmental impairments depend on the complexity of the CHD. In infants with severe CHD, a prevalence of up to 50% has been reported.7,8 Brain injury, responsible for neurodevelopmental impairments, could develop at
several periods in life in these infants. It might occur prenatally, but it might also occur after birth prior to surgery, or during or after surgical procedures.7 To allow for new preventative
therapeutic strategies for brain injury, it is essential to gain more insight into the timing of brain injury in infants with severe CHD. There are several (non-invasive) clinical tools that might aid in detecting brain injury.
Prenatal measurements
Doppler sonography is commonly used to assess fetal hemodynamic condition. On (pulsed wave) Doppler ultrasound traces of fetal and placental blood vessels, maximum blood flow velocities and pulsatility indices (an index of downstream resistance to flow) can be calculated. The technique has been used since the 1980s and abnormal fetal Doppler flow patterns have been associated with adverse neonatal outcome in various study populations.9-11
Postnatal measurements
Postnatally, there are several bedside clinical tools to monitor hemodynamic characteristics regarding cerebral circulation or brain function. Near-infrared spectroscopy (NIRS) is a reliable technique to assess multisite tissue oxygen saturation. Since its first use in preterm neonates
in 1985,12 NIRS has further developed and improved tremendously to become an essential
part of routine clinical care in many neonatal intensive care units all over the world. It is based on two principles, that is the relative translucency of young biological tissue for near-infrared light and the ability to differentiate oxygenated hemoglobin from deoxygenated hemoglobin. The ratio between oxygenated and total hemoglobin represents the tissue
oxygen saturation.13-14 Near-infrared spectroscopy can be applied to monitor oxygenation
of vital organs such as the brain and kidneys. Both low and high cerebral oxygen saturation
values have been associated with poorer neurodevelopmental outcome.15
Amplitude-integrated electroencephalography (aEEG) is used since the 1980s to assess electro-cortical activity in neonates.13 Two biparietal electrodes are placed on the neonatal
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General introduction
signal is then filtered, compressed, enhanced and displayed on a semi-logarithmic scale. Interpretation of aEEG is based on pattern recognition of background activity (continuous normal voltage, discontinuous normal voltage, continuous low voltage, burst suppression, and flat trace). Furthermore, the presence of epileptic activity and sleep-wake-cycling can
be assessed.16 Amplitude-integrated EEG is known to be an early predictor of brain injury
and neurodevelopmental impairments in several different populations.17-20
Neurological outcome
The study of general movements (GMs) according to Prechtl’s method is a validated diagnostic tool to assess the integrity of the young nervous system. General movements are part of the spontaneous movement repertoire from early fetal life to approximately five months of age. They are gross movements involving the whole body and are characterized by the complex and variable sequence of arm, neck and trunk movements and their elegant and fluent character. The characteristics of GMs change with increasing age and three different stages can be distinguished: preterm GMs, writhing GMs and fidgety movements (Table 1).21,22 The quality of GMs changes when the nervous system is impaired. The quality
of fidgety movements is a particularly accurate marker for neurological outcome.21,23 Fidgety
movements are continuous small movements of moderate speed in all directions that are present from nine to 20 weeks post-term, with the most distinct fidgety movements at approximately twelve weeks post term. Furthermore, more detailed aspects of the motor repertoire, reflected in a motor optimality score, are also predictive for motor outcome and minor neurological dysfunction at school age.23-26
Table 1 Age-specific characteristics of normal general movements
GM type Description
Preterm GMs Extremely variable movements, large amplitudes, many pelvic and trunk movements
Writhing GMs Forceful movements, slower movements, smaller amplitude and less pelvic and trunk movements than preterm GMs
Fidgety movements Continuous flow of small and elegant movements of the whole body GMs, general movements.
Aim of the thesis
The aim of this thesis was to gain more insight into the timing of brain injury in infants with prenatally diagnosed severe congenital heart disease. This thesis focuses on several non-invasive clinical tools to monitor hemodynamic characteristics regarding cerebral circulation or brain function from prenatal diagnosis to the postoperative period. Furthermore, the
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thesis focuses on the association between these non-invasive clinical tools and short-term neurological outcome in infants with severe congenital heart disease.
Outline of the thesis
This thesis consists of three parts.
Part I Literature overview
In this part, we systematically reviewed all available literature on the association between prenatal and postnatal preoperative abnormal cerebral findings and neurodevelopmental outcome in infants with severe CHD (Chapter 2).
Part II Prenatal and postnatal cerebral findings
This part focuses on abnormal hemodynamic characteristics regarding cerebral circulation and brain function during the prenatal period and postnatal life in infants with severe CHD. In Chapter 3, the association between prenatal Doppler flow patterns and fetal biometry was assessed. In Chapter 4, cerebral oxygen saturation during the first three days after birth in neonates with prenatally diagnosed duct-dependent CHD was assessed. In Chapter 5, we assessed whether the direction of blood flow in the ascending and descending aorta was associated with cerebral and renal oxygen saturation in infants with left-sided obstructive lesions. Chapter 6 is a prospective observational cohort study that assessed whether prenatal Doppler flow patterns were associated with postnatal cerebral oxygen saturation in infants with prenatally diagnosed severe CHD. Furthermore, we assessed whether prenatal Doppler flow patterns were associated with postnatal aEEG (Chapter 7). Part II ends with an example from clinical practice in which near-infrared spectroscopy was helpful in predicting clinical deterioration in two infants with duct-dependent CHD (Chapter 8).
Part III Neurodevelopmental outcome
This part consists of the first prospective study that longitudinally assessed the association between hemodynamic characteristics regarding cerebral circulation and short-term neurodevelopmental outcome in infants with severe CHD. In Chapter 9, we studied prenatal Doppler flow patterns and postnatal preoperative, intraoperative and postoperative near-infrared spectroscopy in relation to short-term neurological outcome in infants with prenatally diagnosed severe CHD.
We conclude with a general discussion on the findings presented in this thesis and future perspectives regarding the timing of brain injury in infants with severe CHD (Chapter 10). In
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General introduction
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