Cardiovascular Compromise in the Newborn Infant

Principles of Oxygen Delivery

Oxygen is essential for mitochondrial respiration but is not stored in the body. Thus, interruption of oxygen supply to cells can result in irreversible damage (sometimes within minutes), particularly in vital organs such as the brain and myocardium.

The primary function of the cardiorespiratory system is to provide adequate oxygen delivery to tissues. Accordingly, shock is defined as inadequate systemic tissue oxygen delivery (see earlier). Oxygen delivery can be expressed as

where

and

Stroke volume is the result of a complex interplay among preload, afterload, and contractility ( Fig. 46.2 ), all three of which are, at present, impossible to monitor reliably and continuously at the bedside. Although these parameters are more fully described below, in brief preload is the end-diastolic volume of the ventricle (a three-dimensional reflection of pre-contractile myocardial cell fiber length), and, up to a point, the greater the preload, the larger the stroke volume (the Frank-Starling relationship). Afterload is the force the ventricle must generate against the systemic or pulmonary vascular resistance. As long as appropriate perfusion pressure is ensured, the lower the afterload, the higher the cardiac output. Contractility (the intrinsic ability to generate force per unit time) may be assessed noninvasively but not continuously by echocardiogram. Since at present most of the measures of cardiac contractility are both preload and afterload dependent, contractility is not truly an independent variable. In addition, cardiac output in neonates is considered more dependent on heart rate than contractility because the ability of neonates to augment their stroke volume is limited when compared to children or adults.

From this simple model, it is easily appreciated that if there is an acute decline in CaO ₂ , by a decrease in either the hemoglobin concentration or SaO ₂ or both, the cardiac output will increase in response to maintain DO ₂ . On the other hand, because neither hemoglobin concentration nor SaO ₂ can be physiologically increased rapidly, other than increasing tissue oxygen extraction and selective blood flow distribution, there is no acute compensation for a low cardiac output due to decreases in myocardial contractility and/or preload.

The purpose of oxygen delivery is to provide for oxygen consumption (VO ₂ ), which can be expressed as

where CvO ₂ is the mixed venous oxygen content.

This relationship is based on the Fick principle, from which, knowing the flow rate and arterial-venous content difference of a trace element (in this case, oxygen), one can calculate the uptake or removal rate of the tracer.

Normally DO ₂ and VO ₂ are well matched, with O ₂ extraction being approximately 25%. Accordingly, if the SaO ₂ is 100%, SvO ₂ would be expected to be 75%. If cardiac output falls, VO ₂ may be maintained constant by capillary bed vasodilation and recruitment and/or by increased O ₂ extraction by the tissues. Increased O ₂ extraction is manifested as a lower CvO ₂ and therefore greater CaO ₂ − CvO ₂ difference. The relationship between DO ₂ and VO ₂ may be graphically displayed as in Fig. 46.3 . Once oxygen extraction is maximal, at the critical DO ₂ threshold, anaerobic metabolism ensues, resulting in lactic acidosis. If not reversed, the oxygen debt accumulates, and organ failure and death will ensue. In general, during aerobic metabolism 38 mol adenosine triphosphate (ATP) is produced per 1 mol glucose, whereas during anaerobic metabolic conditions, 2 mol ATP and 2 mol lactate are produced per 1 mol glucose.

Before reaching the stage of delivery-dependent VO ₂ , the SvO ₂ can be used as a proxy for DO ₂ . Assuming VO ₂ , hemoglobin concentration, and SaO ₂ are constant over a short period of time, a decline in SvO ₂ represents a decrease in cardiac output. This relationship is clinically important, as SvO ₂ can be measured intermittently via a venous catheter, ideally placed in the pulmonary artery in a patient without intracardiac shunts in order to obtain a true mixed venous sample. Central venous oxygen saturation (ScvO ₂ ) may also be used as a proxy for DO ₂ , measured via a venous catheter with its tip at the superior vena cava—right atrial junction. It is of note that the location of the catheter tip is critical; if the tip is located lower in the right atrium, it will sample more desaturated blood streaming from the coronary sinus and/or hepatic veins. However, for several reasons, measurement of ScvO ₂ is not done routinely in neonates in neonatal intensive care units except for some neonates with congenital heart disease in the postoperative period following surgical correction of the underlying cardiac condition.

In general, these principles are valuable guides to understanding and managing global DO ₂ and VO ₂ , but they do not readily assist with the assessment of individual organ DO ₂ . Furthermore, the limitations of measuring VO ₂ , DO ₂ , and even just ScvO ₂ are often daunting. However, advances in noninvasive regional tissue oxygen saturation (rSO ₂ ) monitoring via NIRS have increasingly allowed for such assessments in different tissues including the brain, kidneys, intestine, and muscle (see later discussion).

Finally, there is a class of neonates where calculations using the Fick principle can be critical in directing therapy. Newborns with congenital heart disease and intracardiac shunts may have perturbations in the usual pulmonary to systemic blood flow ratio (Qp:Qs). Normally, of course, in patients with the two circulations in series and no shunts, Qp:Qs = 1. By comparing the oxygen utilized by the body with the oxygen taken up by the lung, Qp:Qs can be estimated.

and

where pv and pa represent pulmonary vein and pulmonary artery, respectively.

After substituting and eliminating common terms

This formula requires two assumptions unless saturation values are determined directly, as done in the cardiac catheterization laboratory: first, SpvO ₂ is 95% to 100%, and second, SvO ₂ measured through a central venous line reflects a mixed venous sample. A Qp:Qs ratio of < 1 would suggest the presence of a right-to-left shunt and, typically, decreased pulmonary circulation, both of which result in less oxygenated blood entering the systemic circulation with resultant cyanosis. A Qp:Qs ratio of>1, in turn, would suggest left-to-right shunting with resultant pulmonary overcirculation. Of note is that changes in Qp:Qs ratio in either direction will affect oxygen content and/or oxygen delivery to the organs.

The value of this calculation can be illustrated with the following example. A newborn infant with hypoplastic left heart syndrome (HLHS) is found to have an SaO ₂ of 95% and an SvO ₂ of 80%. Using the formula just given, assuming a SpvO ₂ of 100% and recognizing that SaO ₂ and SpaO ₂ are the same in this patient, we arrive at a Qp:Qs ratio of 3:1. If systemic blood flow is to be preserved, the single right ventricle will need to sustain a fourfold increase in cardiac output while the significant pulmonary overcirculation will lead to the development of congestive heart failure. The inability of the right ventricle to sustain such an increase in cardiac output will then lead to inadequate systemic blood flow, resulting in shock. Importantly, both conditions can be present at the same time. However, by maintaining an SaO ₂ within the target range of 75% to 85% in these patients, the Qp:Qs ratio will shift closer to 1:1, providing a simplistic rationale for using such an SaO ₂ target range. However, in patients with HLHS, the effects of shunting on blood oxygen content and/or delivery are far more complex as systemic oxygen availability is determined, along with other factors, by the relationship among SpvO ₂ , SaO ₂ , SvO _2, and cardiac output. Accordingly, in addition to a targeted SaO ₂ range, management of these patients must be guided by the difference in systemic arterial and venous oxygen saturations and other indicators of tissue perfusion (see also Chapter 50 ).

Developmental Regulation of Cardiac Output and Its Determinants

Cardiac output is the product of stroke volume and heart rate and is determined by the amount of blood returning to the heart (preload), the strength of myocardial contractility, and the load against which the heart must pump (afterload). Unlike preload, afterload is in general more difficult to conceptualize and therefore often used interchangeably with the simpler but less accurate term, vascular resistance. However, although afterload is altered by changes in vascular resistance, other factors also determine its magnitude. Afterload is the load or force the heart faces during contraction and is affected by the impedance of the central vasculature, the resistance of the peripheral vascular beds, the ventricular mass, blood pressure, and the inertia of the blood. In addition, it is affected by myocardial contractility and preload as well. If the myocardial function is intact, cardiac output depends solely on preload and afterload according to the relationships described by the Starling curve.

Therefore, low cardiac output and thus low systemic blood flow can result from various combinations of abnormalities of the three determinants of cardiac output: low cardiac preload, poor myocardial contractility, or high cardiac afterload. In addition, extremes of these variables in the opposite direction (i.e., high cardiac preload, increased myocardial contractility, or low cardiac afterload) can contribute to cardiovascular insufficiency, albeit not as commonly. This is due to the fact that these three variables as well as heart rate affect one another. For example, in an infant of a diabetic mother with hypertrophied cardiomyopathy, increased contractility and low afterload can further compromise systemic flow by reducing preload and worsening left ventricular outflow tract obstruction.

Changes in Preload, Contractility, and Afterload During Transition

With delivery and the separation of the placenta, the fetal circulation begins its transition to the mature (adult-type) circulation in which the systemic and pulmonary circuits are in series and, with the closure of the fetal shunts between the two circulations, the right and left cardiac outputs are equal. However, some component of the normal transition (e.g., removal of placental circulation) is rather abrupt while others (cessation of flow through the ductus arteriosus and foramen ovale) are more gradual. With the initiation of breathing resulting in lung expansion and the separation of the placenta, the pulmonary vascular resistance drops precipitously and systemic vascular resistance increases, respectively. The resultant increase in the left ventricular (LV) afterload could lead to a decrease in myocardial contractility, which in selected populations of vulnerable preterm infants may result in decreased cardiac output. In addition, the above-mentioned changes in the pulmonary and systemic vascular resistance lead to an evolution in ductal flow pattern from a purely right-to-left to bidirectional and, eventually, purely left-to-right ductal flow. In healthy term infants, LV stroke volume and output increase in the first few minutes after birth. This change coincides with increasing net left-to-right ductal shunting. The increase in LV preload from ductal shunting likely explains the increase in LV output, and the increase in LV output may offset the potential impact of the left-to-right ductal shunt on the systemic circulation. Therefore, there is usually no evidence of circulatory compromise in the healthy neonate. Subsequently, the ductus arteriosus constricts and then closes in the vast majority of term neonates within 24-to-48 hours. Therefore, in the healthy term neonate, the rapidly constricting ductus arteriosus prevents the development of hemodynamically significant left-to-right shunting across the ductus. However, the transition to adult-type circulation is prolonged in preterm, especially in extremely preterm infants and can result in circulatory compromise. Indeed, by 2 months of age, less than 50% of preterm infants born at <26 weeks’ gestation close their ductus arteriosus spontaneously and, as the right-sided pressures fall, blood will shunt left-to-right from the systemic circulation back into the pulmonary circulation. In most VLBW neonates, pulmonary vascular resistance (PVR) initially decreases relatively rapidly for physiologic and non-physiologic reasons. Physiologic mechanisms most important in the postnatal decrease of PVR include the mechanical effects of initiation of breathing on PVR and the increased postnatal oxygenation-associated direct, paracrine, and endocrine vasodilation. Iatrogenic causes include surfactant administration or the inappropriate targeting of higher arterial oxygen saturations. With the left-to-right ductal shunting, pulmonary overcirculation develops and left ventricular output, the gold standard of bedside assessment of systemic perfusion, cannot be used as a measure of systemic perfusion ( Fig. 46.4 ). Indeed, under these circumstances, left ventricular output measures systemic perfusion and ductal blood flow. In earlier studies investigating the post-transitional changes in systemic perfusion and/or the effects of vasoactive agents on cardiovascular function, this fact has often not been acknowledged. Therefore, the conclusions drawn from some of these studies need to be reevaluated. More recent studies have acknowledged this hemodynamic paradigm and used right ventricular output to assess systemic perfusion in the VLBW neonate during the transitional period. However, right ventricular output only represents systemic perfusion as long as left-to-right shunting across the foramen ovale does not become significant. In many preterm neonates, however, as left-to-right shunting across a nonconstricting patent ductus arteriosus (PDA) increases during the first 12 to 36 hours, left atrial volume and pressure increase, often leading to the development of a significant left-to-right shunt across the foramen ovale. The left-to-right shunt through the patent foramen ovale (PFO) will then render the use of right ventricular output as a measure of systemic blood flow inaccurate because right ventricular output now represents systemic inflow and PFO flow. This hemodynamic scenario results in the lack of an acceptable conventional measure of systemic blood flow in these neonates. To circumvent this problem, superior vena cava (SVC) flow has been used as a measure of upper body blood flow in preterm neonates with the fetal channels open. The use of SVC flow has provided novel insights into the mechanisms of transitional hemodynamics, such as the observation that intraventricular hemorrhage (IVH) develops in many VLBW neonates as systemic blood flow improves, resulting in reperfusion of the brain (see discussion below). However, the vulnerability of SVC flow measurements to error and the technical difficulties associated with its use as a surrogate measure of systemic blood flow have forced these measurements to remain primarily a research rather than a clinical tool.

Developmental Regulation of Systemic Blood Pressure

Systemic blood pressure is the product of systemic blood flow and systemic vascular resistance. There is an association between low blood pressure and central nervous system injury in the preterm neonate. Yet, blood pressure correlates only weakly with blood flow in this patient population during the period of immediate postnatal adaptation when the fetal channels are open. Thus, in preterm infants during the first postnatal day, blood pressure may be low because resistance (vasomotor tone) is low even in the presence of normal or high blood flow ( Fig. 46.5 ). Alternatively, blood pressure may be normal or high because resistance is high in the presence of normal or low blood flow. The lack of clarity surrounding the nature of the relationship between blood pressure and systemic blood flow during the transitional period results, at least in part, from our inability to appropriately define the normal blood pressure range and systemic blood flow (see earlier), and to characterize the developmental regulation of organ blood flow and vital organ assignment (see later discussion) in the preterm neonate. Indeed, the recent findings of a higher rate of survival without severe morbidity and a lower rate of severe IVH and cerebral injury among preterm infants with isolated (asymptomatic) hypotension who were treated compared to those who were not treated highlights the complexity of the blood pressure and blood flow interaction during the postnatal transitional period. These findings also challenge the “permissive hypotension” strategy stemming from the uncertainty surrounding the nature of the relationship between blood pressure and systemic blood flow during the transitional period as well as from the potential side effects of vasopressor-inotropes, especially when not appropriately titrated.

Developmental Regulation of Organ Blood Flow and Its Autoregulation and Vital Organ Assignment

Phases of Shock

From a pathophysiologic standpoint, three phases of shock depicting advancing severity have been identified.

In the “compensated phase,” complex neuroendocrine and autonomic compensatory mechanisms maintain perfusion and oxygen delivery in the normal range to the vital organs (brain, heart, and adrenal glands) at the expense of decreased perfusion to the remaining organs (nonvital organs). This is achieved by vasodilation and vasoconstriction of the vessels to vital and nonvital organs, respectively, in response to a fall in perfusion pressure and/or oxygen delivery. Blood pressure is maintained within the normal range, and heart rate increases. As perfusion of nonvital organs is decreased because of the compensatory vasoconstriction of their vascular beds, there often are clinical signs of compromised nonvital organ function such as decreased urine output. In addition, signs of poor peripheral perfusion can often be detected, such as cold extremities and prolonged capillary refill time.

If adequate treatment is not commenced, compensatory neuroendocrine and autonomic mechanisms begin to be exhausted and hypotension develops as the shock enters its “uncompensated phase.” Systemic perfusion (cardiac output) will decrease, perfusion of all organs including the vital organs becomes compromised, and lactic acidosis develops.

If treatment is ineffective in the uncompensated phase of shock, multiorgan failure develops and shock may enter its “irreversible phase,” where permanent damage to the various organ systems occurs and further interventions will be ineffective in reversing the patient’s condition.

Pathogenesis of Neonatal Shock

Etiologic Factors

The etiologic factors leading to the development of neonatal shock include hypovolemia, myocardial dysfunction, abnormal peripheral vasoregulation, or a combination of two or all three of these factors.

Hypovolemia

Hypovolemia may be absolute (loss of intravascular volume), relative (increased venous capacitance), or combined, such as is often seen in septic shock ( Fig. 46.6 ). Hypovolemia results in cardiovascular compromise primarily by the decrease in cardiac output (systemic blood flow) caused by the decrease in preload. In addition, if blood loss is the primary cause of hypovolemia, the associated decrease in oxygen carrying capacity contributes to the development of the circulatory compromise. Because of the weak relationship between blood pressure and blood volume in hypotensive preterm neonates, hypovolemia was traditionally thought to be a relatively uncommon primary cause of circulatory compromise, especially during the first postnatal day. However, given the difficulty in assessing intravascular volume, especially during the transition, hypovolemia can be difficult to detect clinically. Therefore, the true contribution of hypovolemia to circulatory failure is uncertain. Interestingly, recent studies comparing the effects of delayed umbilical cord clamping or cord milking with immediate cord clamping found increased blood pressure and decreased use of vasopressor-inotropes suggestive of improved hemodynamic status in the delayed cord clamping and cord milking groups. In addition, patients with delayed cord clamping have higher blood volume and fewer receive transfusions. These findings imply that hypovolemia might be a more common presentation in preterm neonates who receive standard care with immediate cord clamping than previously thought.

Absolute hypovolemia in the newborn can be due to several conditions. Intrapartum fetal blood loss is usually caused by open bleeding from the fetal side of the placenta, and therefore it is likely to be detected. More difficult to diagnose is the closed bleeding of an acute fetomaternal hemorrhage or an acute fetoplacental hemorrhage. The latter can occur during delivery when the umbilical cord comes under some pressure (breech presentation or nuchal cord). Because the umbilical vein is more compressible, it is occluded before the artery and blood continues to be pumped into the placenta. If the cord is clamped early, the excess blood remains trapped in the placenta. This probably happens to some degree in all babies with tight nuchal cords who, as a group, have lower hemoglobin levels. However, in some neonates, a tight nuchal cord may also cause severe circulatory compromise. Postnatally, acute blood loss may occur from any site and is frequently associated with perinatal infections or severe asphyxia-induced endothelial damage and the ensuing disseminated intravascular coagulation. Finally, acute abdominal surgical problems and conditions associated with the nonspecific inflammatory response syndrome and subsequent increased capillary leak with loss of fluid into the interstitium can lead to significant decreases in the circulating blood volume. Iatrogenic causes of absolute hypovolemia include inadequate fluid replacement in conditions of increased insensible losses in the very preterm neonate and gastroschisis before closure of the defect, or the inappropriate use of diuretics.

Relative hypovolemia, that is, a decrease in the effective circulating blood volume, may occur in pathologic conditions leading to vasodilation, such as those associated with the nonspecific inflammatory response syndrome (sepsis, necrotizing enterocolitis [NEC], asphyxia, major surgical procedures, use of extracorporeal membrane oxygenation [ECMO]). In addition, the use of afterload-reducing agents (e.g., milrinone, PGE ₂ ) may cause significant vasodilation (especially venodilation), thereby decreasing the effective circulating blood volume.

Finally, absolute and relative hypovolemia most frequently occurs in conditions associated with the nonspecific inflammatory response syndrome such as sepsis, asphyxia, and major surgical procedures.

Myocardial Dysfunction

Both systolic and diastolic cardiac dysfunction can cause circulatory failure. As echocardiographic assessment of diastolic function is complex and not well established, except in extreme cases, diastolic dysfunction often goes undetected. Nevertheless, diastolic dysfunction is recognized to be the primary cause of circulatory failure associated with hypertrophic cardiomyopathy in infants of diabetic mothers. In addition, extrinsic factors such as pericardial effusion evolving to tamponade and tension pneumothorax can lead to diastolic dysfunction. Systolic dysfunction, on the other hand, is easier to diagnose using echocardiography.

Acquired heart disease presenting as circulatory compromise includes cardiomyopathies, postasphyxial myocardial dysfunction due to hypoxic-ischemic injury, viral myocarditis, and myocardial dysfunction in the late stages of septic shock. For more detail on structural heart disease and cardiomyopathies, see Chapter 50 .

Among the different types of congenital heart disease, structural heart defects that produce a ductus arteriosus–dependent systemic circulation such as the hypoplastic left heart syndrome, critical coarctation, and critical aortic stenosis, if not diagnosed prenatally or immediately after delivery, classically present as acute circulatory compromise with pallor, tachypnea, impalpable pulses, and hepatomegaly as the ductus starts closing. The presentation may be initially misdiagnosed as sepsis.

Abnormal Peripheral Vasoregulation

Peripheral vasodilation causes circulatory compromise by resultant decreases in perfusion pressure. However, patients with intact myocardial function usually present with normal or high cardiac output as they attempt to compensate for the decrease in organ blood flow. Pathologic peripheral vasodilation in neonates occurs primarily in conditions associated with the nonspecific inflammatory response syndrome such as sepsis, NEC, severe asphyxia, major surgical procedures, use of ECMO, or respiratory distress syndrome of prematurity. It is of clinical importance that preterm neonates born to mothers with chorioamnionitis, especially if they have evidence of funisitis (fetal vessel inflammation), frequently present with hypotension and hyperdynamic, vasodilatory cardiovascular compromise at birth or shortly afterward.

Transitional Circulatory Compromise of the Very Preterm Neonate

The transitional circulatory changes at birth and in the first 12 to 24 hours after birth denote a period of unique circulatory vulnerability, especially for the extremely preterm infant. As mentioned earlier, the timing of umbilical cord clamping has a significant effect on volume status and systemic hemodynamics. During normal postnatal adaptation, pulmonary vascular resistance falls, systemic vascular resistance rises with removal of the placenta from the circulation, the ductus arteriosus closes, and the foramen ovale is closed by the reversal of the atrial pressure gradient. During this time frame, the left ventricle must double its output. Given that the very preterm infant’s cardiovascular system is adapted to the low-resistance intrauterine environment and its myocardium is immature, it is not surprising that these patients have difficulties during this critical period. In addition, as discussed earlier, developmentally regulated factors such as the state of vital organ assignment of the forebrain and cerebral oxygen demand-flow coupling make cardiovascular adaptation of the very preterm neonate an even more complex process. It is important to note that there is much more to understand about the complex interactions between immediate postnatal cardiovascular adaptation and immaturity, organ development, myocardial and vasoregulatory function, and vital organ assignment.