Abstract
Peri/intraventricular hemorrhage (P/IVH), a major complication of prematurity, increases the risk of mortality and is associated with significant short and long-term morbidities. Pathogenesis of P/IVH is complex and multifactorial. Given the immaturity of organ systems, the extremely preterm infant has inherent vulnerabilities, and lifesaving interventions aimed at supporting the developing organs such as mechanical ventilation may have unintended consequences and predispose the immature brain to injury. Among the potential contributors to development of P/IVH, cardiovascular compromise and altered cerebral hemodynamics during the transitional period are considered to play a major role. Recent advances in monitoring technology have enhanced our understanding of the transitional circulation and pathogenesis of P/IVH, and may prove to be useful in the selection of high-risk patients and testing strategies to prevent or decrease the incidence and severity of P/IVH.
Keywords
acidosis, echocardiography, hypercapnia, hypotension, myocardial dysfunction, near-infrared spectroscopy
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A period of systemic and cerebral hypoperfusion in the immediate postnatal period predisposes the extremely preterm infant to peri/intraventricular hemorrhage (P/IVH).
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Cardiovascular immaturity and maladaptation after birth contribute to the postnatal hypoperfusion.
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Ventilatory support, especially inappropriately high mean airway pressure, can accentuate the early postnatal hypoperfusion.
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Following the initial hypoperfusion, a period of improvement in systemic and cerebral perfusion precedes occurrence of P/IVH on the second or third postnatal day. Therefore ischemia-reperfusion is a major hemodynamic contributor to the pathogenesis of P/IVH.
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Hypercapnia especially PaCO 2 above 50 mm Hg may increase the risk of P/IVH by potentiating the reperfusion phase via increasing the cerebral blood flow and attenuating autoregulation.
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Delayed cord clamping and cord milking are associated with improved hemodynamic stability and appear to be beneficial in preventing P/IVH possibly by mitigating the risk of hypoperfusion
Peri/intraventricular hemorrhage (P/IVH) is a devastating complication of prematurity that affects about a third of extremely preterm infants (<28 weeks’ gestation). P/IVH is a major risk factor for poor neurodevelopmental outcome, hydrocephalus, and mortality among these patients. Although the pathogenesis of P/IVH is complex and likely involves multiple different mechanisms, alteration in cerebral hemodynamics is thought to play a major role. Recent advances in noninvasive monitoring have highlighted the hemodynamic antecedents of P/IVH. This chapter reviews the inherent vulnerabilities of preterm infants during the transitional period and how the interaction between transitional hemodynamics and interventions aimed at supporting respiratory and cardiovascular function can increase the risk of P/IVH.
Fetal and Transitional Circulation
As the physiology of fetal circulation is discussed in Chapter 1 in detail, here we only provide a brief review of the main characteristics pertinent to the topic of this chapter. In utero, the most oxygenated blood with oxygen saturation around 75% to 85% flows from the umbilical vein through the ductus venosus to the inferior vena cava (IVC). Due to mixing with venous blood from the portal and hepatic circulations in the liver, and also due to some mixing with the venous blood flowing from the lower body in the IVC, oxygen saturation entering the heart is only about 70%. Of note is that the blood flowing in from the ductus venosus into the IVC is primarily diverted by the Eustachian valve toward the foramen ovale and into the left atrium. The low flow of poorly oxygenated pulmonary venous return to the left atrium admixing with flow via the foramen ovale still ensures supply of relatively well-oxygenated blood to the heart and brain with an oxygen saturation around 60%. On the other hand, blood returning from the superior vena cava (SVC) and the stream in the IVC representing blood returning from the lower part of body are preferentially directed to the right ventricle. As most of right ventricular output (RVO) is diverted through the patent ductus arteriosus (PDA) toward the aorta, both ventricles contribute to the systemic circulation. Given the low blood flow to the lungs due to high pulmonary vascular resistance, left ventricular preload is relatively small. As such, during fetal life, the contribution of the right ventricle to systemic blood flow is greater than that of the left ventricle. In the fetus, the combined cardiac output is about 400 to 450 mL/kg/min with only about 11% to 25% constituting the pulmonary circulation. This is in contrast to the postnatal circulation where the left and right cardiac outputs are equal and average about 200 mL/kg/min. The low resistance placental circulation facilitates the high cardiac output in the fetus by reducing the afterload. At birth, pulmonary vascular resistance drops precipitously as the newborn starts breathing and the lungs become the organ of gas exchange. This increases pulmonary blood flow and changes the ductal flow pattern in a way that progressively directs blood from the right ventricle to the pulmonary circulation. The increased pulmonary blood flow in turn increases left-sided preload and promotes functional closure of the foramen ovale. This, along with the closure of the ductus arteriosus over the following 2 to 3 days, transforms the circulation to the adult-type (postnatal) circulation in which the pulmonary and systemic circuits are not functioning as parallel circulations anymore but as circulations in series. Despite its complexity, this transformation occurs smoothly in the vast majority of term infants. However, in preterm infants, especially those born before 28 weeks’ gestation, this process is hindered by immaturity of the organ systems and is more likely to represent an abnormal cardiorespiratory transition. Accordingly, it is likely to be associated with circulatory compromise, as discussed in detail in this chapter.
Cerebral Blood Flow
Understanding the evolution of cerebral hemodynamics from the fetal circulation through the postnatal transition is critical in understanding the role of abnormal transition in the pathogenesis of P/IVH. However, measurement of cerebral blood flow (CBF) is challenging in neonates, especially in preterm infants and during the immediate postnatal period. CBF has been assessed using radioactive xenon clearance, positron emission tomography, Doppler ultrasonography, magnetic resonance imaging, and near-infrared spectroscopy (NIRS). Each of these methods has its own significant limitations. Due to their noninvasive nature and bedside availability, Doppler and NIRS are the most commonly used methods for the assessment of CBF. With Doppler ultrasonography, various surrogates of CBF, such as SVC blood flow and blood flow velocity in major cerebral arteries have been used to characterize intermittent changes in cerebral hemodynamics. On the other hand, NIRS allows for the continuous assessment of regional tissue oxygen saturation (rSO 2 ) or tissue oxygenation index (TOI). Although NIRS does not measure blood flow directly, by considering cerebral regional oxygen saturation (CrSO 2 ), clinical information, and certain other parameters, changes in CBF can be deduced. Taking into account arterial oxygen saturation (SPO 2 ), the index of cerebral fractional oxygen extraction (CFOE) can be calculated according to the following formula: (SPO 2 – CrSO 2 ) / SPO 2 . CrSO 2 has a direct and CFOE has an inverse relationship with changes in CBF. In other words, a reduction in CrSO 2 or an increase in CFOE indicates a decrease in CBF, provided certain assumptions hold true. These assumptions include no significant changes in SPO 2 (with CrSO 2 ), organ metabolism, hemoglobin and/or the distribution of blood in tissue among arteries, veins, and capillaries.
Normal Changes in Cerebral Blood Flow
During fetal development, brain blood flow increases both as an absolute value and per gram of tissue. Animal and human studies have shown a decrease in CBF at and immediately after birth. The cause of this reduction is unclear, but in part may be related to an increase in tissue oxygenation at birth compared with fetal life. Interestingly, the progressive change of PDA flow pattern from right-to-left to left-to-right during the first few minutes after birth strongly and inversely correlates with middle cerebral artery mean blood flow velocity (MCA-MV), a surrogate of CBF. This suggests a possible role of the PDA immediately after birth in reduction of CBF. Alternatively, the changes in PDA flow pattern and reduction in CBF may be independent, and both reflective of the increasing oxygen tension following delivery. It is clear that more data are needed to elucidate the normal changes in cardiovascular function and cerebral hemodynamics at and immediately after birth, especially in preterm infants.
After the immediate postnatal period, CBF increases rather significantly over the following days and more gradually afterward in both preterm and term infants. Despite the rise in CBF, it remains at only a fraction of the adult value. Moreover, sick preterm infants have even lower CBF. The low CBF in neonates may be explained by lower brain metabolism; however, cardiovascular maladaptation in preterm infants may also contribute to the observed low CBF.
Cerebral Blood Flow and Peri/Intraventricular Hemorrhage
Preterm infants who develop P/IVH have a lower CBF after birth. Studies using NIRS found higher CFOE on the first postnatal day in preterm infants who later develop P/IVH. Serial measurements of SVC flow, a surrogate for CBF, also found that low SVC blood flow in the first few hours after birth is a risk factor for P/IVH. However, caution needs to be exercised when using SVC flow as a surrogate for CBF since, in the preterm neonate, only around 30% of the blood flow in the SVC represents blood returning from the brain (see Chapter 2 ). The last two decades have seen an increased use of ultrasonography by neonatologists to elucidate the cardiovascular adaptation during the transitional period. In addition, advances in monitoring technology have brought NIRS to a more widespread use in research and also have facilitated its introduction into clinical care. The newer NIRS sensors have allowed for more continuous and prolonged monitoring of rSO 2 and for quick application of the sensors in situations when time is of the essence (e.g., in the delivery room). Therefore, despite the limitations mentioned earlier, increased application of the newer NIRS technology and ultrasonography have provided valuable insights into the cerebral hemodynamic changes that precede P/IVH.
A recent nested case-control study compared CrSO 2 and CFOE between preterm infants with and without P/IVH during the first 15 days after birth. Measurements were done daily for 2 hours for 8 days and, then, on day 15. The authors found lower CrSO 2 and higher CFOE in the P/IVH group suggestive of lower CBF throughout the first 8 days. While low CBF in the first postnatal day has consistently been reported, its persistence for a week has not. In contrast, another nested case-control study monitoring cerebral oxygenation during first few postnatal days found higher CrSO 2 and lower CFOE during the 24 hours prior to detection of severe P/IVH. In other words, this study suggests that higher rather than lower CBF precedes brain hemorrhage. This discrepancy may be explained by the differences in the timing and duration of monitoring between the two studies. In a recent study, in addition to performing frequent and regularly timed head ultrasounds and echocardiography, we prospectively and continuously monitored extremely preterm infants (<28 weeks) during the first 3 postnatal days and found a unique pattern with identifiable phases of changes, among others, in the indices of CBF in patients who developed P/IVH ( Fig. 6.1 ). The CrSO 2 and CFOE were indicative of low CBF in the earlier hours of the first postnatal day, followed by a period of an increase in CBF before detection of P/IVH around 48 hours after birth and, thereafter, a subsequent decrease in CBF. These findings suggest that there are two distinct hemodynamic phases in the pathogenesis of P/IVH: an early hypoperfusion and a later reperfusion phase. The prospective, comprehensive, and continuous design of the study allowed for detection of the two phases. Given the dynamic changes in CBF over the first few days, an intermittent or short period of monitoring will miss either the hypoperfusion or reperfusion phase.
In the remainder of this chapter, we will discuss the vulnerabilities of preterm infants during the transitional period that increase the risk of P/IVH and focus on the causes and risk factors that lead to or potentiate the hypoperfusion and/or reperfusion phases.
Vulnerabilities of Preterm Infants During Transition
Inherent Vulnerability of the Immature Brain
The brain of a preterm infant is vulnerable to development of P/IVH due to both structural and functional immaturity. The germinal matrix is the site of active proliferation of future neuronal and glial cells, and as such is a highly vascularized and metabolically active tissue. Its capillary network consisting of thin-walled fragile vessels is susceptible to rupture. The germinal matrix involutes between 28 and 34 weeks. Therefore, until its final involution, the germinal matrix is susceptible to bleeding, especially in preterm infants <28 weeks’ gestation. In addition, the germinal matrix lies within an arterial end zone, which makes it particularly vulnerable to hypoperfusion-reperfusion injury. The immature venous system is prone to congestion, which further increases the risk of hemorrhage in this population.
The ability to maintain CBF relatively constant despite fluctuations in blood pressure (i.e., CBF autoregulation) is an important protective mechanism against ischemia and hyperperfusion (see Chapter 2 ). The correlation between mean blood pressure and TOI or rSO 2 using NIRS allows for continuous assessment of CBF autoregulation by analyzing coherence and transfer function gain. Coherence is a measure of linear correlation between blood pressure and an index of CBF (i.e., cerebral oxygenation), and therefore an arbitrary cutoff, usually 0.5, is used to define the presence or absence of autoregulation. On the other hand, transfer function gain assesses the degree of impairment by measuring the effects of changes in the amplitude of the blood pressure waveform on the amplitude of changes in cerebral tissue oxygenation. Both methods have their strengths and limitations and are not routinely used in clinical settings (see Chapter 2 ).
The brain of preterm infants has immature CBF autoregulation. In addition, the majority of very preterm neonates have mean blood pressures very close to the lower elbow of the blood pressure autoregulatory curve during the first 24 hours after delivery (see Chapter 2 ). Although CBF autoregulation is present even in the most immature preterm infant, the autoregulatory plateau is quite narrow. Moreover, immaturity per se and/or the interventions aiming to support these patients can result in systemic changes that alter CBF autoregulation (see the section on hypotension and permissive hypercapnia in Chapter 2 ). Given the role of CBF autoregulation in ensuring maintenance of adequate CBF and prevention of hyperperfusion, immature and impaired autoregulation has long been considered as a risk factor for P/IVH. Indeed, most but not all studies of CBF autoregulation in preterm infants have shown an association between impaired autoregulation and the occurrence P/IVH.
Another vulnerability of the brain of the very preterm neonate (≤28 weeks’ gestation) is immaturity of the forebrain (including cortex, thalamus, hypothalamus, basal ganglia) vasculature, displaying characteristics of the blood flow regulation of a nonvital organ during the first postnatal days. In other words, the vessels of the forebrain respond with vasoconstriction to decreasing perfusion pressure or hypoxia, rather than with vasodilation, as expected for the vessels of a vital organ (brain, heart, and adrenal gland). Several lines of evidence support this notion. For example, beagle pups exposed to hypoxia exhibit vasodilation of the hindbrain (medulla, pons, cerebellum) but vasoconstriction of the forebrain. In humans, CBF autoregulation appears in the brainstem first and in the forebrain only later in gestation. Therefore vital organ assignment appears to be developmentally regulated, with the forebrain lagging behind the hindbrain in acquiring the properties of a high-priority vascular bed.
Immature Myocardium
The myocardium of a neonate, even at term, is immature and quite different from that of older children and adults. It has more water content and less contractile elements. In addition, the immature sarcoplasmic reticulum makes cytosolic calcium the primary source of second messenger calcium for myocardial function. These differences affect both systolic and diastolic function. Indeed, the neonatal myocardium is more sensitive to afterload, its lower compliance adversely affects ventricular filling, and it is dependent on extracellular calcium for its function. Preterm infants, especially during the transition, exhibit a cardiovascular response to acidosis that is different than that of adults. A recent study in hemodynamically stable very preterm infants during the transitional period showed that while acidic pH was not associated with a decrease in myocardial contractility, cardiac output failed to increase, presumably because the expected, acidosis-associated decrease in systemic vascular resistance did not take place. It has been postulated that immaturity of the myocardium predisposes preterm infants to a low systemic flow state and therefore contributes to the low CBF observed in a subset of very preterm neonates who later develop P/IVH. If we consider SVC flow as a surrogate for systemic flow, the finding of low SVC flow in P/IVH group represents low cardiac output in the immediate postnatal period with the fetal channels open. Indeed, low left ventricular output (LVO) and RVO have been shown to be prevalent in those who later develop P/IVH ( Fig. 6.2 ). However, the underlying causes of this low cardiac output are unclear. Among others, a sudden high afterload following removal of the low resistance placental circulation in the setting of an immature myocardium has been postulated to be one of the underlying causes of this finding. Indeed, there is a difference in the inverse linear relationship of contractility and afterload among preterm infants with normal and low SVC flow, with patients having low SVC flow as a group exhibiting a steeper regression line suggestive of lower contractility in this group. However, this is not a consistent finding, and a recent study found no difference in afterload or load-dependent and load-independent indices of contractility between patients who develop P/IVH and those who don’t. Whether low preload could explain the observed low cardiac output is not known, in part because of the difficulty in assessing preload using noninvasive techniques. However, recent studies of delayed cord clamping and cord milking suggest a possible role for low preload in the observed low cardiac output state (see below). Thus it is likely that the low cardiac output is multifactorial with abnormalities in preload, contractility, and afterload, and other factors such as ductal shunting contributing to a varying degree in different patients. Following the initial low flow state, cardiovascular function improves and cardiac output normalizes. This improvement in systemic flow is also associated with reperfusion of the brain and precedes occurrence of P/IVH (see Fig. 6.2 ).
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