On average, up to 12% of liveborn infants in the developed world are born prior to term. These rates have increased as a consequence of assisted reproductive technology and earlier intervention for either maternal or fetal well-being. The causes of birth prior to term are many ( Table 15.1 ). The care of the premature neonate has improved dramatically over the past 100 years, during which time mortality rate has fallen from 40 deaths for each 1000 live births at the turn of the 20th century, to the current rates of four deaths per 1000 live births in the developed world. These improvements are a direct result of enhanced maternal health and access to quality obstetric and neonatal intensive care. Birth weight remains the major risk factor for neonatal mortality. The past 2 decades have witnessed a number of significant advancements in neonatal care, most notably maternal administration of antenatal steroids, the ability to replace surfactant, use of inhaled nitric oxide (iNO), increased scientific evidence for routine practices, and superior equipment, such as ventilators and incubators. In addition, an increased number of neonatal conditions requiring intensive care are being recognized antenatally, which allows focused resuscitation and timely intervention by specialist teams. This is particularly relevant for neonates with congenitally malformed hearts, particularly premature infants, who represent the most critical and potentially vulnerable patients. Despite regionalized perinatal health care, from 10% to 30% of those born with extremely low weight ( Box 15.1 ) are delivered outside tertiary neonatal centers. Although overall survival for premature infants generally has improved, mortality remains high, particularly at the limits of viability ( Table 15.2 ). The outcome for neonates born outside tertiary centers is less favorable when compared with those patients delivered and resuscitated at perinatal centers specialized in coping with those at high risk. Survival varies by center and country, particularly at the very early gestational ages (<25 weeks), due to highly variable resources, approach to antenatal counseling, and resuscitation practices. The survival for infants less than 23 weeks of gestation remains very poor, with operative delivery and resuscitation not recommended in many centers. Survival with no or minimal disability for infants born at 23 and 24 weeks is 6% to 20%. Death in the first week of life is common, and delivery room mortality remains a concern. Survival at 25 and 26 weeks approaches 60% to 75% and 75% to 85%, respectively. Discharge without major morbidities occurs in approximately 30% of infants born at 25 weeks and 50% at 26 weeks. The contribution of cardiovascular performance and systemic hemodynamics to ongoing neonatal morbidity is poorly understood. Enhanced cardiovascular monitoring and earlier therapeutic intervention may prove to be a necessary step toward improving survival further and minimizing adverse neurodevelopmental sequelae.
| Maternal | Placental | Fetal | Miscellaneous |
|---|---|---|---|
| Preeclampsia Systemic hypertension Renal failure Diabetes mellitus Infection of the urinary tract Chronic disease | Intrauterine infection, or premature rupture of membranes Placental abruption Antepartum hemorrhage Uterine stretch (multiple pregnancies, polyhydramnios, uterine abnormality) | Chromosomal abnormality Fetal distress Hydrops fetalis Congenital infection (e.g., toxoplasmosis, rubella, cytomegalovirus) | Cervical incompetence Idiopathic Familial |
Preterm: A neonate born prior to 37 weeks of completed gestation
Near-term: A neonate between the 34th and 37th weeks of gestation (subpopulation of preterm)
Low birth weight: A neonate born weighing <2500 g
Very low birth weight: A neonate born weighing <1500 g
Extremely low birth weight: A neonate born weighing <1000 g
Perinatal mortality rate: The number of stillbirths and early neonatal deaths, those occurring within 6 days of birth, per 1000 live births and stillbirths
Neonatal mortality rate: The number of neonates dying in the first 4 weeks, specifically within 27 completed days of life, for each 1000 live births
Intrauterine growth retardation: Growth parameters below the third centile for corrected gestational age. Asymmetric retardation is characterized by sparing of the head, the circumference of the head being greater than the third centile.
| Birth Weight (g) | Births (%) | Neonatal Mortality per 1000 Live Births in Each Subgroup |
|---|---|---|
| >2500 | 92.4 | 0.9 |
| <2500 | 7.6 | 48 |
| <1000 | 1.4 | 214 |
Transitioning Circulation
The condition of the infant at birth is dependent, in part, on intrauterine well-being and growth. Intrauterine growth retardation is the failure of the fetus or infant to achieve his or her predetermined genetic potential. Typically, the preterm infant is less than the third centile for weight, length, and head circumference. The consequences to the developing heart include cardiac hypertrophy, abnormal diastolic performance, and impaired vascular relaxation. Doppler interrogation of fetal and neonatal mitral valvar velocities revealed lower E wave amplitude compared with normal mature mitral E peaks. Impaired early left ventricular filling may relate to a diminished ability to relax and higher muscular stiffness. The implications may include impaired myocardial performance, hypertension, and hypotension. Poor glycemic control during pregnancy, particularly in the setting of maternal diabetes, is a known risk factor for structural heart disease and hypertrophic cardiomyopathy. In severe cases, where there is placental malfunction leading to retardation of growth, the same vascular and myocardial dysfunction may occur as described previously.
Physiology of the Postnatal Transition
The preterm infant undergoes dramatic cardiorespiratory changes at birth, which coincide with improved lung compliance and termination of the placental circulation. These critical adaptive changes:
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Include increased pulmonary blood flow, to approximately 20 times fetal levels
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Occur in part due to the exposure of the pulmonary vascular bed to higher alveolar concentrations of oxygen than the relatively hypoxic intrauterine environment. Other metabolically active substances, such as metabolites of prostaglandin, bradykinins, or histamine, may play some role through inducing pulmonary vasodilation.
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Include alteration in flow through fetal channels such as the arterial duct and oval foramen, which may last for many days. The major change in flow through fetal channels is either a direct result of increased flow to the lungs or improved systemic arterial tensions of oxygen. Increased left atrial pressure secondary to improved pulmonary venous return causes displacement of the flap of the oval foramen over the rims of the fossa, thus abolishing any right-to-left atrial flow. The pattern of flow through the arterial duct is significantly altered as lung compliance improves and pulmonary vascular resistance decreases. An increase in systemic vascular resistance also occurs once the compliant placenta is removed from the systemic circuit, and as a result of systemic vasoresponsiveness to increased tensions of oxygen. This will also contribute to increased transductal flow. The architecture of the arterial duct prior to term differs such that ductal tone is less responsive to oxygen, thus delaying closure and potentially contributing to excessive flow to the lungs and compromised systemic flow. The administration of surfactant can alter transductal flow significantly through reduced pulmonary vascular resistance. There is evidence of functional closure by 6 hours in some immature patients, although this is rare. Changes in transductal flow may have a major impact on end-organ perfusion; in particular, the relationship of augmented cardiac output on cerebral reperfusion hemodynamics and intraventricular hemorrhage is subject to recent investigation.
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Include improved left and right ventricular outputs to meet the metabolic needs of immature neonate with insufficient thermoregulatory mechanisms and increased work of breathing. The transition from right to left ventricular dominance occurs over hours and is secondary to increased left atrial preload and left ventricular afterload. In total, there is a threefold increase in left ventricular output, which is necessary to meet the increased demands of the body. The enhanced ability of the left ventricle to increase its output is related, in part, to elimination of constraint by the pressure-loaded right ventricle.
Initial Resuscitation of the Extremely Premature Neonate
Extremely preterm neonates represent a patient population highly vulnerable to morbidity and mortality in the immediate hours after birth. The resuscitation may be challenging, and delivery outside of a center with a specialized neonatal team with tertiary level neonatal intensive care is associated with a threefold greater risk of mortality or major morbidity. Resuscitation should be conducted according to the steps of the Neonatal Resuscitation Program, which is designed to meet the needs of these patients during this critical transitional period.
Temperature Control
Temperature regulation during stabilization is important because preterm neonates may rapidly lose heat via evaporation of amniotic fluid, conductive loss through contact with cold surfaces, and convective loss into the relative cool air of the room. Several interventions have been demonstrated to improve temperature after stabilization including increase in ambient room temperature, occlusive polyethylene wrapping prior to drying, application of a polyethylene or woolen hat, and the use of heated, humidified ventilator gas. Specialized warming mattresses may be used. Close monitoring is important to avoid both hypothermia and iatrogenic hyperthermia.
Placental Transfusion
Delayed cord clamping remains controversial, although it has become standard practice in some units. In lambs, early cord clamping is associated with a rapid decline in right atrial preload unless a ventilation-associated increase in pulmonary blood flow has occurred. Clamping the umbilical cord is associated with significant changes in cerebral blood flow and oxygen extraction that may be mitigated if ventilation is established prior to clamping. Human studies suggest that placental transfusion (delayed cord clamping or umbilical cord milking) is associated with a reduced risk of intraventricular hemorrhage, reduced frequency of blood transfusions, less hypotension, and decreased mortality as compared with immediate cord clamping. In spontaneously breathing preterm infants following an otherwise uncomplicated preterm birth, delayed cord clamping may be beneficial, although concerns have been raised about the impact on cerebral blood flow and requirement for postnatal resuscitation. There remains uncertainty as to the optimal management of nonvigorous preterm infants in whom delay in resuscitation may be detrimental.
Ventilation
Respiratory management in the delivery room focuses on attaining adequate functional residual capacity to promote pulmonary blood flow and oxygenation in the least invasive manner to which the preterm infant will respond. Preterm neonates are at risk of surfactant deficiency and retained fetal lung fluid, which contribute to poor lung compliance. In addition, these patients may have inadequate respiratory muscle strength to compensate. Spontaneously breathing preterm infants should have continuous positive airway pressure applied to help establish and maintain functional residual capacity if they demonstrate respiratory distress or work of breathing. Surfactant replacement is indicated for neonates where adequate recruitment requires high distending pressures or significant oxygen supplementation (typically greater than FiO2 0.3), particularly with classic findings of respiratory distress syndrome on chest radiography. Nonvigorous infants, those with heart rate less than 100 beats/min, and those with irregular breathing or apnea require positive-pressure ventilation and consideration for intubation according to the steps recommended by the Neonatal Resuscitation Program.
Resuscitation Gas
Resuscitation of the term infant should begin in room air because the most likely causes of hypoxemia are related to inadequate recruitment of functional residual capacity and not oxygen delivery. However, there is ongoing debate regarding the most appropriate gas for preterm infants. Studies comparing resuscitation using high oxygen concentration (65% to 100%) as compared with low oxygen concentration (21%) have been done; however, intermediate levels have not been studied. Exposure to high concentrations of oxygen may create undesirable effects such as oxygen free radicals, and initial resuscitation in 100% oxygen has not been shown to be beneficial for survival or the reduction in risk of chronic lung disease, retinopathy of prematurity, or intraventricular hemorrhage. Initial resuscitation using 21% to 30% oxygen is recommended. Once saturation monitoring is established, the use of an oxygen blender to titrate delivery to achieve saturations comparable with a term neonate at a similar age following birth is recommended.
Regulation of Myocardial Performance
Architecture of the Myocyte
Fetal myocardial tissue consists of 70% noncontractile tissue, compared with 40% in the mature adult heart. Histologic studies have shown that the myocytes making up the left ventricular myocardium are aligned circumferentially in the mid wall and longitudinally in the subepicardial and subendocardial layers of the walls. Studies of isolated myocardial tissue in fetal and adult lambs suggest that fetal myocardium is less compliant. Ventricular myocytes change considerably as they transition from fetal to postnatal life. The immature sarcomere and contractile apparatus is relatively disorganized. Myofibrils are irregular and scattered along the interior of the cell. Intrauterine and early postnatal cardiac growth is a combination of both hyperplasia and hypertrophy. Exposure of the developing rodent heart to dexamethasone led to cardiac hypertrophy, characterized by myocytes that were longer and wider, with increased volume. Biventricular hypertrophy is a recognized complication of exposure of the preterm myocardium to prolonged and high doses of steroids. Neonates born to mothers who had received a single antenatal course of steroids had higher systolic blood pressures and increased myocardial thickness, suggesting modified myocardial development. The nature of these changes may relate to earlier transition from a phase of hyperplasia to hypertrophy. The functional consequence of an enlarged hypertrophic myocardium, with a reduced overall number of myocytes, is unknown.
Activation of the Myocyte
In contrast to adults, immature myocytes lack transverse tubules, are smaller in size, and have a greater ratio of surface area to volume. They are more reliant on transsarcolemmal fluxes of calcium for contraction and relaxation. The high ratio of surface area to volume, and the subsarcolemmal location of myofibrils, support direct calcium delivery to and from the contractile proteins. The sodium-calcium exchanger is the major conduit for attachment of calcium to, and release from, the contractile elements.
Control of Myocytic Activation
The control mechanisms governing contraction and relaxation in the immature heart are poorly understood but thought to be substantially different from the fully mature heart. In the mature heart, graded control of release of calcium is related to so-called L-type activity, which triggers release from the sarcoplasmic reticulum. Graded control of release in immature myocytes is thought to be related to factors influencing the activity of the sodium-calcium channel. Recently isoproterenol-induced β-adrenergic stimulation of sodium-calcium exchanger was identified in guinea pig ventricular myocytes. An improved understanding of factors that govern myocardial contractility and relaxation may facilitate more physiologically appropriate choice of therapeutic interventions in premature infants.
Performance and Physiology of the Immature Myocardium
At physiologic heart rates, the immature myocardium shows a positive relationship, albeit that contractility falls with extreme tachycardia. Both the force-rate trajectory and the optimal heart rate reflect myocytic function and global myocardial contractile behavior. Developmentally, the immature myocardium has been shown to exhibit a higher basal contractile state and a greater sensitivity to changes in afterload. The intolerance of the immature myocardium to increased afterload may be attributable to differences in myofibrillar architecture, or immaturity of receptor development or regulation. The Frank-Starling law appears less applicable to the immature myocardium.
Hemodynamic Assessment and Monitoring
The consequences of hemodynamic instability include necrotizing enterocolitis, intraventricular hemorrhage, and periventricular leukomalacia, all of which may lead to mortality or adverse neurodevelopmental outcomes. Intraventricular hemorrhage occurs in up to three-tenths of infants born with very low weight, most commonly in the first 7 hours of life. The origin of the hemorrhage is the germinal matrix, an immature network of capillaries highly susceptible to hypoxemia, hypercapnia, and altered cerebral blood flow. Periventricular leukomalacia is a loss of white matter in the watershed areas around the lateral cerebral ventricles secondary to hypoxic-ischemic injury. The infant born at very low weight is highly susceptible to such morbidities, necessitating focused cardiovascular monitoring and targeted intervention in a timely fashion.
Is Blood Pressure a Reliable Measure of Circulatory Stability?
The determination of hemodynamic stability in premature infants is fraught with uncertainty, myths, and dogma without scientific validity. Suboptimal systemic blood flow is usually suspected on the basis of tachycardia, delayed capillary refill time, hypothermia, oliguria, altered blood pressure, metabolic acidosis, and increased levels of lactate in the plasma. Blood pressure readings are readily available at the bedside as a continuous stream of data from indwelling arterial lines, or periodically using a validated oscillometric cuff method. The approach to monitoring and guiding therapeutic intervention has relied on using mean arterial pressure as a surrogate of the adequacy of tissue perfusion and oxygenation. This reasoning is based on an assumed proportionality between blood pressure and systemic blood flow. In 1992 a report from the former British Paediatric Association stressed the importance of monitoring blood pressure to guide early therapeutic intervention and thus prevent adverse neurologic sequelae. It was suggested that mean arterial pressure equivalent to the gestational age in weeks is adequate as a minimum value. The group also suggested the need to establish accurate normative ranges for systolic and diastolic blood pressure. Unfortunately, achieving a mean blood pressure equal to gestational age has now become dogma and the standard on which therapy is based. Normative centiles for systolic blood pressure that take into account both gestational age at birth and postnatal age have been developed but are rarely used. Monitoring blood pressure in isolation is problematic for a number for reasons. First, blood pressure is but one surrogate of circulatory stability. Second, the concept of numeric hypotension as mean blood pressure less than gestational age in weeks has not been validated against indexes of perfusion of end organs. Third, important changes in either systolic or diastolic blood pressure may be missed. The systolic pressure indicates the pressure generated by the left ventricle and is therefore reflective of cardiac output ( Fig. 15.1A ). Diastolic pressure reflects global vascular resistance and local perfusion of the tissues (see Fig. 15.1B ). In neonates with a hemodynamically significant arterial duct, diastolic pressure is oftentimes compromised in isolation of changes in mean arterial pressure. This may have an unappreciated adverse effect on coronary arterial perfusion and subsequently on myocardial performance. The relationship between mean blood pressure and cardiac output is also weak ( Fig. 15.2 ). The finding of neonates with numeric hypotension but no clinical or biochemical signs of systemic flow, and conversely patients with normal or high blood pressure but signs of circulatory compromise, is not uncommon. It must be recognized that blood pressure is but a surrogate of perfusion and not the end point of interest. Although mean arterial pressure may be a guide to cardiovascular health, clinicians should pay attention to systolic and diastolic pressure when making decisions regarding the most appropriate intervention.
Does Hypotension Lead to Brain Injury?
The rationale for treating hypotension is based on two important considerations. First, the cerebral circulation becomes pressure-passive below a critical level for blood pressure ( Fig. 15.3 ). The autoregulatory mechanism is thought to fail below a mean arterial pressure of 30 mm Hg. There is also evidence suggesting that neonates with hypotension have impaired cerebral oxygenation, as determined by near-infrared spectroscopy, and are at increased risk of intracranial hemorrhage or periventricular leukomalacia. Other investigators have shown no relationship between blood pressure and cerebral blood flow. Second, associations have been shown between adverse neurologic consequences and systemic hypotension. There is a significant body of evidence, nonetheless, which challenges these assumptions. For example, there are data suggesting that the association of hypotension to injury to the white matter and adverse neurodevelopmental outcome is not one of cause and effect, but an epiphenomenon. Studies with superior designs and larger numbers have failed to demonstrate any positive association between blood pressure and adverse neurologic outcomes. When corrected for associated risk factors, such as intrauterine growth retardation, postnatal use of steroids, and chronic lung disease, the association between hypotension and abnormal neurodevelopmental outcomes was lost. The discrepancy between individual studies may reflect the fact that the association is much more complex than any direct effect of blood pressure on cerebral blood flow ( Fig. 15.4 ). There may be concurrent changes in cardiac output and regional differences in flow of blood independent of blood pressure that are influencing cerebral perfusion, but these studies have not been performed.
How Should We Monitor the Preterm Circulation?
Failure of the neonatal transition may lead to myocardial dysfunction, low cardiac output, and hypotension, which may compromise perfusion of the end organs with consequent damage. The vulnerability of the cerebral circulation in the first 72 hours of life increases the likelihood of injury to the brain more than any other organ. It is essential that the systemic flow be monitored adequately at all stages. Tachycardia and capillary refill time are poorly validated and nonspecific measures of systemic flow. In isolation, capillary refill time is inaccurate, highly subjective, and a poor overall predictor of the adequacy of perfusion. The measurement of cardiac output at the bedside is a useful adjunct to the clinical assessment, and there are normative data for both right and left ventricular outputs. The normal range for cardiac output in normal premature infants is between 170 and 320 mL/kg per minute. These measurements should be interpreted in context in the early neonatal period due to the effects of transductal shunting. Left ventricular output reflects flow to the central nervous system because the cerebral circulation is preductal, and its accuracy has been validated using cardiac magnetic resonance imaging. Measurement of superior vena cava flow has been proposed as an alternative method of assessing the adequacy of systemic flow, because it is not confounded by atrial or ductal shunts. Although cardiac magnetic resonance imaging data have raised some questions about measurement accuracy, the relationship between superior vena cava flow and outcomes shows a consistent trend. Reduced flow in the superior caval vein is common in premature infants in the first 24 hours, reaching a nadir between 8 and 12 hours, which coincides with increased systemic vascular resistance. Neonates with the lowest flow are at greatest risk of intraventricular hemorrhage ( Fig. 15.5 ). When 3-year neurodevelopmental assessment was performed, low superior caval venous flow remained significantly associated on multiple logistic regression analysis, when adjusted for gestation and birth weight, with an abnormal developmental quotient and the combined end point of death and abnormal developmental quotient. Both blood pressure and systemic flow are important determinants of the likelihood of altered perfusion, and neither should be monitored nor treated in isolation, without consideration of the influence of the other. Decisions about circulatory adequacy should include a comprehensive assessment of systemic perfusion, and echocardiography assessment of cardiac output may be an invaluable adjunct tool. Other bedside tools such as near-infrared spectroscopy, noninvasive cardiac output monitoring, and heart rate variability have been explored in selected patient populations and may continue to evolve into additional adjunctive monitoring modalities, although further investigation is needed.
Cardiovascular Problems Unique to the Preterm Infant
Hemodynamically Significant Arterial Duct
Patency of the arterial duct is a common problem in preterm babies, especially those born with extremely low weight. Although functionally essential for the normal fetal circulation, persistent ductal patency may have significant effects in preterm infants that include pulmonary overcirculation and systemic hypoperfusion. Persistent patency is found in approximately half of babies born at less than 29 weeks’ gestation and/or weighing less than 800 g.
Biology of Normal Closure
Ductal closure is not immediate, particularly in infants born with extremely low weights, and occurs in two stages. Functional closure, which is a dynamic process that may be reversed if the ambient conditions change to favor patency, depends on the vasoconstricting action of humoral and biochemical factors on the muscular layer of the duct. This constriction results in the development of a zone of profound hypoxia in the media, which is the sentinel stimulus for irreversible closure. Anatomic closure depends on the architectural remodeling of the ductal wall. It consists of extensive neointimal thickening, and loss of smooth muscle cells from the inner media. The remodeling effects start at the pulmonary end, progressing toward the aortic insertion. Both vasodilator prostaglandins, especially PgE 2 and nitric oxide, oppose ductal closure during fetal life. In the second trimester, intimal cushions are formed that closely resemble the pathologic intimal thickening seen in atherosclerotic disease. The media is supplied with oxygen from either the lumen or its mural vessels. The thickness of the avascular zone, adjacent to the lumen, plays a critical role in determining the degree of hypoxia and subsequent remodeling of the ductal wall. Constriction of the circumferential and longitudinal muscle in the ductal wall leads to compaction, increased avascular thickness, and limits luminal supply of oxygen to both the avascular zone and the medial muscle. The resultant hypoxia induces expression of vascular endothelial growth factor or cell death, depending on its severity. The geographic distribution of expression corresponds with the distribution and intensity of mural hypoxia. The biologic consequences of these changes include a decline in tissue distensibility and increased contractile potential. The ductal wall of fetuses during late gestation has a high level of intrinsic tone, which is further increased after delivery by unopposed oxygen-induced contractile forces. After delivery, the increase in arterial content of oxygen, along with the decrease in circulating prostaglandins following placental separation, and reduced intraluminal blood pressure, contribute toward ductal closure. As transductal flow decreases, the wall becomes progressively more ischemic and eventually fibrotic.
Ductal Closure in Infants Born With Extremely Low Weight
The duct remains patent in up to four-fifths of infants born prior to term and weighing less than 1200 g. Such infants have no mural vessels in the medial layer and are nourished entirely via transluminal diffusion or from adventitial vessels. The immature duct, when studied experimentally, has also been shown to have less intrinsic tone and lacks both intimal folds and circumferential medial musculature. It is less responsive to oxygen and more sensitive to prostaglandin E 2 and nitric oxide. It is possible for the immature infant to develop comparable hypoxia in the medial muscle but only if transluminal flow is completely obliterated. Even when the duct constricts, profound hypoxia in the medial wall and anatomic remodeling fails to develop. A progressive increase in levels of nitric oxide synthetase in the ductal mural vessels after the first 15 days of life makes the preterm duct even less sensitive to prostaglandins. Nonsteroidal antiinflammatory agents therefore are less likely to be effective. In baboons, coadministration of an inhibitor of nitric oxide synthase, along with indomethacin, leads to increased contractility and luminal obliteration of the preterm duct. Gestational age may impact on the response to nonsteroidal antiinflammatory agents, although the evidence for this is limited. Gestational age less than 33 weeks at treatment was associated with greater likelihood of response to indomethacin in one small study, although echocardiography was not used universally. Advanced gestational age has also been associated with a reduced likelihood of response to second course indomethacin in those infants who have had a persistent hemodynamically significant ductus arteriosus after one course of nonsteroidal antiinflammatory therapy. However, other studies have identified a greater likelihood of response in infants of older gestational age. It is likely that other ambient conditions have a significant impact on response to indomethacin regardless of gestation. The presence of infection, prenatal exposure to maternal medications such as indomethacin tocolysis or magnesium sulfate for prevention of intraventricular hemorrhage, and platelet count are some factors that have been implicated.
Pathophysiologic Continuum of Ductal Shunt
It is important to emphasize the difference between pulmonary artery pressure and pulmonary artery resistance. When there is an anatomically large communication between the aorta and pulmonary artery, the pressure will be equal in each. However, the net flow through this communication is dependent on the differences between the systemic and pulmonary vascular resistance. Commonly, in clinical vernacular, “pulmonary hypertension” is used synonymously with elevated pulmonary vascular resistance; however, they are not the same. Pulmonary hypertension is defined as elevated pressure in the pulmonary artery: this can be seen when (1) there is an anatomically large ductus or ventricular septal defect, where the systemic pressure is transmitted into the pulmonary vascular bed, and (2) when there is elevated pulmonary vascular resistance, which results in elevated pulmonary artery pressure relatively independent of the amount of flow into the pulmonary vascular bed. It is clinically important to distinguish between the two clinical scenarios.
The presence of a persistent ductus arteriosus may have widely varied clinical implications depending on the circulatory circumstances and the balance of pulmonary and systemic arterial resistance. A patent arterial duct may be pathologic in the setting of a marked difference between the systemic and pulmonary vascular resistance, where the net flow across the ductus is left to right and the volume of shunt is high, leading to the classical symptoms described subsequently. For neonates in whom the pulmonary and systemic resistances are approximately equal, the ductus arteriosus, regardless of its size, may have relatively small volume of shunt and be of minimal clinical significance. In situations where either pulmonary artery resistance is high (e.g., pulmonary hypertension) or systemic delivery of pulmonary venous return is poor (e.g., significant left ventricular dysfunction, or anatomic obstruction to systemic flow, such as in coarctation of the aorta, or hypoplastic left heart syndrome), the presence of an open arterial duct may be beneficial or even lifesaving. Echocardiography assessment of the ductus arteriosus should include both assessment of shunt volume and surveillance for anatomic or physiologic contraindications to ductal treatment before treatment decisions are made.
Pathophysiologic Effects of a Hemodynamically Significant Arterial Duct
Failure of ductal closure, coinciding with the normal postpartum fall in pulmonary vascular resistance, results in a left-to-right transductal shunt. The consequences may include pulmonary overcirculation and/or systemic hypoperfusion, both of which may be associated with significant morbidity ( Fig. 15.6 ). The clinical impact is dependent on the magnitude of the shunt and the ability of the infant to initiate compensatory mechanisms. These infants are less capable of compensating and are prone to developing left ventricular failure, which may lead to alveolar edema and/or low cardiac output syndrome. The increased pulmonary flow and accumulation of interstitial fluid secondary to the large ductal shunt contribute to decreased lung compliance. The cumulative effects of increasing or prolonged ventilator requirements and myocardial dysfunction may increase the risk of chronic lung disease. Systemic flow may also be compromised with left-to-right ductal shunts due to retrograde diastolic flow in the aorta and the arteries supplying organs such as the kidneys and gut; this may be worsened by the effects of supplemental oxygen, hypocarbia, or both (see later). The redistribution of systemic flow is significantly altered even with shunts of small volume. Oftentimes there may be significant hypoperfusion to the kidneys and gastrointestinal tract before a hemodynamically significant duct is clinically suspected. This may lead to significant morbidity, including renal insufficiency, necrotizing enterocolitis, intraventricular hemorrhage, and myocardial ischemia. Early detection and targeted intervention may potentially improve long-term neonatal outcomes.
Diagnosis of a Hemodynamically Significant Arterial Duct
Clinical Presentation.
The classical clinical features include a continuous murmur, hyperactive precordium, bounding pulses, and wide pulse pressure. More commonly, a systolic murmur is audible that radiates widely across the precordium and back. However, in many of those born prior to term, cardiac auscultation is unremarkable. In the first week of life, despite the presence of a large duct, typical clinical signs are often absent. Such a situation is widely recognized as the silent duct, most likely due to continued elevation of pulmonary vascular resistance. Surfactant, by assisting the natural postnatal fall in pulmonary arterial resistance, has been shown to alter the timing of clinical presentation, specifically, by increasing the volume of the systemic-to-pulmonary shunt, which leads to an earlier clinical presentation. The existence of a hemodynamically significant but silent duct has been confirmed by cardiac catheterization and detailed echocardiographic evaluation. Such a situation should be suspected in a setting of delayed hypotension during the second and third days, failure of oxygenation, increasing requirements for ventilator support, or metabolic acidosis. The infant is more likely to present with both systolic and diastolic hypotension due to the inability of the immature myocardium to compensate for shunting at high volume throughout the cardiac cycle.
Ancillary Tests.
Although not very sensitive, chest radiography may show cardiomegaly and/or signs of pulmonary congestion, whereas the electrocardiogram may show signs of left atrial or ventricular enlargement. The latter may be more useful for the identification of subendocardial ischemia secondary to low coronary arterial perfusion pressures in neonates with a large duct, although this association has not been formally evaluated.
Echocardiographic Confirmation of the Hemodynamically Significant Arterial Duct.
Echocardiography is the primary tool for assessment of the ductus arteriosus. Echocardiography confirmation of ductal significance prior to treatment is standard of care in many institutions due to the unreliability of clinical assessment, a desire to avoid the side effects of unnecessary medication, and the potential complications of indomethacin administration to neonates with duct dependent circulation (left-sided congenital heart disease [CHD]). The determination of ductal significance using echocardiography involves assessment of size, patterns of transductal flow, systemic and/or end-organ perfusion, and characterization of the degree of volume loading of the heart.
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The size of the duct is obtained from a suprasternal short-axis view ( Fig. 15.7A ) using two-dimensional or color Doppler. A transductal diameter less than 1.5 mm is associated with retrograde or absent postductal aortic diastolic flow. A diameter of more than 1.5 mm resulted in a positive likelihood ratio of 5.5 and a negative likelihood ratio of 0.22 for prediction of the need for therapeutic intervention. In a prospective study of 116 neonates, transductal diameter was the most accurate echocardiographic marker in predicting clinical and hemodynamic significance. However, reliance on a single measurement may lead to error for several reasons. First, the measurement of internal ductal diameter may be difficult, even with clear two-dimensional images and the measurement using color Doppler may be influenced by gain settings. Second, the transductal diameter is not consistent throughout, often with tapering at the pulmonary end, and shunt volume is determined by the smallest diameter which may not be accurately identified depending on the imaging plane and both patient and operator factors. Third, the studies investigating the predictive value of ductal diameter were limited by small sample sizes. Finally, using an absolute cutoff does not consider the relationship between ductal size and infant size. Some studies have proposed indexing ductal and left pulmonary artery (LPA) diameter, although this approach may also be questionable, particularly in established shunts. A large ductus with high-volume left-to-right shunt may significantly increase flow in the branch pulmonary arteries, and this may result in LPA dilation and reduce the value of indexing.
Fig. 15.7
(A) Two-dimensional echocardiographic representation of a large patent ductus arteriosus from a parasternal short-axis view. (B) Pulsed wave Doppler interrogation at the mid ductal level reveals unrestrictive laminar transductal flow. Ao , Aorta; MPA , main pulmonary artery; PDA , patent ductus arteriosus.
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The pattern of transductal flow , estimated using pulse wave Doppler interrogation from a suprasternal short-axis view, can also be used to characterize ductal significance. High-velocity, continuous left-to-right flow is predictive of imminent functional closure, whereas a low-velocity pulsatile left-to-right flow pattern is likely to be clinically significant (see Fig. 15.7B ).
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Cross-sectional echocardiography has also been used to quantify the degree of volume overload. Specifically, estimates of left atrial or left ventricular size have been used as surrogates of pulmonary overcirculation and/or volume loading. Although the measurement is standardized, it is not very specific and is prone to error dependent on the operator. The presence of a large atrial septal defect permitting left-to-right shunting will lead to further augmentation of pulmonary flow, potentially overestimating the magnitude of the ductal shunt.
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Left ventricular output is significantly higher in preterm infants with a hemodynamically significant ductal shunt. Minimal angle of insonation with the left ventricular outflow tract in the apical five-chamber view is important to ensure accurate measurement.
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Interrogation of descending thoracic aorta diastolic flow at the level of the diaphragm has been investigated using cardiac magnetic resonance imaging. Flow reversal during diastole is highly associated with shunt volume. Evidence of end-organ hypoperfusion may be also inferred from Doppler assessment of the patterns of flow in the mesenteric, cerebral, or renal arteries. Specifically, reversal or absence of diastolic perfusion is pathognomonic of a hemodynamically significant duct.
Management of the Hemodynamically Significant Duct
The aims of treatment are to reduce pulmonary overcirculation and improve systemic blood flow. The decision to treat is based on both clinical and echocardiographic findings, although the optimal time and method of ductal closure remain uncertain. Treatment should be classified as supportive intensive care strategies and therapeutic interventions aimed at closing the duct.
Focused Intensive Care
Ventilation.
Strategies that minimize pulmonary overcirculation in a fashion comparable to that used for congenital cardiac defects should be considered. This can be achieved by accepting P co 2 between 45 and 55 mm Hg, arterial pH of 7.25 to 7.35, and oxygen saturations between 88% and 93%. Improvements in oxygenation and lung compliance may also be achieved by increasing the positive end-expiratory pressure to levels that maintain optimal recruitment, minimize atelectasis-induced lung injury, and lead to improvements in myocardial performance and cardiac output by reducing left ventricular afterload. Reduced hematocrit is associated with both lower pulmonary vascular resistance and decreased oxygen delivery to the tissues which may result in a compensatory increase in cardiac output and peripheral vasodilation. Avoidance of anemia in the presence of a hemodynamically significant ductus arteriosus may be beneficial.
Cardiotropic support.
The optimal treatment for hypotension and/or systemic hypoperfusion is strategies aimed at increasing pulmonary vascular resistance and closure of the duct and, in the absence of left ventricular dysfunction, not cardiotropic support. Excessive α-adrenergic stimulation, by agents such as dopamine or epinephrine, should be avoided because the increased systemic vascular resistance may lead to increased left-to-right shunting or may further compromise an already dysfunctional left ventricle. Dobutamine or newer inodilators currently under investigation, such as milrinone, may be preferred if there is associated left ventricular dysfunction, although medications that reduce systemic vascular resistance (e.g., milrinone) should be avoided in neonates with low diastolic arterial pressure because further reduction may compromise coronary artery perfusion pressure.
Fluid management and diuretic therapy.
Fluid restriction, which has historically been a cornerstone of ductal management, should not be routinely recommended. This strategy may lead to preload-reduced left ventricular stroke volume and cardiac output which may further compromise systemic blood flow without improving ductal shunt. Fluid restriction may be considered in patients who become oliguric and/or volume overloaded during treatment with indomethacin. The evidence for routine diuretic therapy to promote ductal closure is also limited. This may relate to excessive new production of prostaglandin E 2 by the kidneys in babies treated with furosemide. A systematic review of the coadministration of furosemide in indomethacin-treated neonates concluded that evidence was insufficient to support its routine administration. Diuretics should be restricted to the treatment of pulmonary edema or left ventricular failure in neonates awaiting ductal ligation.
Feeding.
Special consideration should be given to feeding, particularly if there is reversal or absence of perfusion in the superior mesenteric artery or there are additional risk factors, such as intrauterine retardation of growth. Specifically, a more cautious feeding regime, lower thresholds for discontinuation of feeds, or consideration to screen for necrotizing enterocolitis should be considered. It may also be advisable to withhold feeds during treatment due to the potential effects of ductal steal and nonsteroidal antiinflammatory agents such as indomethacin on intestinal perfusion.
Specific Treatment.
There are three accepted approaches to ductal treatment, and each have merit and drawbacks. Treatment of the symptomatic ductus, prophylactic therapy, and early targeted therapy prior to the emergence of symptoms have all been adopted. Accepted closure strategies include both medical and surgical options, and catheter-based therapy is gradually gaining wider use (see Chapter 19 ). Therapeutic closure is not recommended in a setting of suprasystemic pulmonary resistance with right-to-left ductal shunting, right heart failure where elevated pulmonary vascular resistance in the presence of an anatomically restrictive ductus results in a pressure-overloaded right ventricle, or left heart failure or anatomic obstruction, where right-to-left ductal flow may support systemic circulation. Treatment with indomethacin fails in up to half the infants born with extremely low weight. This may reflect architectural differences and remodeling in the most immature patients, as described earlier, in addition to the severity of illness. Antenatal administration of indomethacin is also associated with postnatal hyporesponsiveness and increased need for surgical ligation. Architectural remodeling of the ductal wall, secondary to increased expression of vascular endothelial growth factor, and altered regulation of ductal tone by nitric oxide, has been demonstrated in a fetal ovine model.
Nonsteroidal Antiinflammatory Drugs
Because prostaglandins play a major role in preserving ductal patency, inhibitors of cyclooxygenase are conventionally used to assist its closure. Medical treatment should not be attempted, whenever possible, without prior echocardiographic evaluation and exclusion of duct-dependent cardiac lesions. Indomethacin 0.1 mg/kg given for three doses every 12 to 24 hours is currently the treatment of choice for ductal closure in preterm babies, although the ideal dose, duration, and/or time to intervene remain somewhat controversial. Ibuprofen has been suggested as an alternative to indomethacin on the basis of a lower risk of side effects, although whether it has equivalent efficacy to indomethacin remains a question.
Symptomatic Treatment
Early intervention for the symptomatic ductus is preferable to late intervention because the risks of necrotizing enterocolitis, pulmonary morbidity, and need for surgical ligation are significantly reduced. The choice of dose and duration of treatment is controversial. The decision to treat the symptomatic ductus is normally made on the following basis:
- ▪
Echocardiographic confirmation of a patent ductus arteriosus with an internal diameter greater than 1.5 mm and left-to-right ductal shunting with evidence of pulmonary overcirculation (e.g., left heart dilation) and/or systemic underperfusion (e.g., reversed aortic diastolic flow)
- ▪
Clinical signs of pulmonary overcirculation, myocardial dysfunction, or end-organ hypoperfusion.
Prophylactic Treatment
Some centers use a strategy of indomethacin administration to all preterm neonates shortly after birth. This strategy has been associated with reduced frequency of patent ductus arteriosus and reduction in severe intraventricular hemorrhage. However, the merits of this approach may be questionable. Studies have failed to demonstrate an improvement in neonatal outcomes, and many neonates are unnecessarily treated because the duct may have closed spontaneously. Caution is advised in some populations, particularly those with intrauterine growth restriction. In addition, ongoing ductal patency may be of benefit in those preterm neonates where transitional circulation is associated with elevated pulmonary vascular resistance and poor right ventricular function. Severe hypoxemia, responsive to iNO, has been reported in premature infants born prior to 28 weeks following prophylactic exposure to ibuprofen on the first day of life.
Early Targeted Therapy
An alternative approach that centers on early ductal assessment by echocardiography may be preferable in institutions where echocardiography is widely available. This minimizes unnecessary or harmful medication exposure and focuses on treatment of only those patients with ductal characteristics that are likely to become pathologic. This has been associated with reduced risk of pulmonary hemorrhage and lower likelihood of developing a symptomatic ductus.
Complications of Medical Treatment.
The decision to use indomethacin should be carefully balanced against the potential pitfalls of treatment. These include impaired renal function and compromised cerebral and/or mesenteric blood flow. Ibuprofen is a related agent that has been suggested to be associated with a superior safety profile. A lower risk of renal impairment and preserved renal, mesenteric, and cerebral blood flow have been suggested. Comparable efficacy in achieving ductal closure has been shown in some studies, although other authors have suggested indomethacin may be superior. There is also a potential greater risk of kernicterus because ibuprofen interferes with binding of bilirubin to albumin in the serum when given in usual doses.
Acetaminophen/Paracetamol Treatment
Acetaminophen is an inhibitor of the peroxidase component of the prostaglandin-H 2 synthetase enzyme system. It has been investigated as a primary therapy for neonates in whom nonsteroidal antiinflammatory drugs are contraindicated (e.g., necrotizing enterocolitis, renal failure) or as a rescue therapy after failed indomethacin treatment. Preliminary results suggest that acetaminophen has comparable efficacy to ibuprofen and may prevent surgical ligation in almost half of treated infants. The safety profile appears to be similar to ibuprofen, although the number of treated infants thus far is small.
Surgical Intervention
Surgical ligation is normally indicated after failure of medical therapy or where medical therapy is contraindicated. The procedure is most commonly performed via a left lateral thoracotomy, although video-assisted thoracoscopic ligation has been successfully performed. Primary surgical ligation has been suggested as an appropriate alternative to medical therapy, and prophylactic surgical ligation is associated with a reduced risk of necrotizing enterocolitis. Although appealing due to certain success, this approach is not recommended due to a high rate of spontaneous closure, availability of effective medical therapy, and risk of short- and long-term complications. Surgical ligation of the ductus arteriosus has been associated with an increased risk of chronic lung disease, retinopathy of prematurity, scoliosis, injury to the recurrent laryngeal nerve, and neurodevelopmental impairment. However, when postnatal comorbidities occurring prior to ligation are considered, these associations are no longer significant, suggesting that neonates requiring ductal ligation may reflect a sicker population of preterm infants. The most appropriate timing for surgical ligation after failed medical therapy remains unclear. Younger, smaller infants are at greater risk of postligation cardiac syndrome and may have higher likelihood of impaired neurodevelopment, although the latter is likely multifactorial. Earlier ligation after failure of medical therapy may be associated with reduced respiratory and nutritional morbidity as compared with delayed ligation. A selective approach that minimizes exposure to significant shunt and includes a reassessment of ductal significance after medical therapy is recommended.
Postoperative Complications.
Surgical ligation is not a benign procedure and is oftentimes associated with significant early postoperative cardiorespiratory instability resulting from acutely decreased left ventricular preload and increased afterload. Surgical complications may include air-leak syndromes, reexpansion pulmonary edema, and recurrent laryngeal nerve palsy with associated vocal cord paralysis, which occurs in 5% to 50% of patients. Rarely, ligation may be associated with obstruction of the left pulmonary artery or aorta. Sudden cardiovascular changes following removal of ductal shunt may be poorly tolerated. Immediate systolic and diastolic hypertension may contribute to reperfusion intraventricular hemorrhage. Although improvements in lung compliance immediately following ligation have been recorded, the postoperative course is characterized by a postligation cardiac syndrome consisting of failure of oxygenation due to pulmonary edema, systolic hypotension, and the need for cardiotropic support, which typically occur 8 to 12 hours after the procedure ( Fig. 15.8 ). This may relate to altered ventricular loading conditions following ligation. Surgical ligation in preterm baboons is associated with a significant increase in left ventricular afterload within 12 hours of the procedure, coinciding with the development of left ventricular dysfunction and failure.
Postoperative Care.
On the basis of cardiovascular adaptation and other surgical complications, all neonates should be monitored closely in the postoperative period. Specifically, vital signs and urinary output should be carefully monitored, with frequent testing of arterial blood gases and/or lactate. Left ventricular output measured 1 hour after ligation has a high sensitivity for predicting the risk of late cardiorespiratory decompensation. Targeted afterload reduction using milrinone prophylaxis may reduce the requirement for inotropic support and improve oxygenation in the postoperative period. Early commencement of diuretic therapy and increased positive end-expiratory pressure are recommended with failure of oxygenation, and radiologic evidence of pulmonary edema or atelectasis. Inotropic agents with significant vasoconstrictive activity, such as dopamine or epinephrine, which increase systemic vascular resistance through α-adrenergic–mediated mechanisms, should be avoided. Inotropes with afterload-reducing properties, such as dobutamine, may be preferable. Neonates with low cortisol levels are more likely to develop catecholamine-resistant hypotension, and supplementation with hydrocortisone may be of benefit in this situation, although perioperative hydrocortisone is not associated with improved postoperative stability.
Transcatheter Closure
Although catheter-based interventions are common in older patients, there are concerns regarding arterial access and device size that have limited the extrapolation of this technique to preterm patients. Improvements in technology have produced smaller devices making catheter closure possible. Transvenous closure using fluoroscopy and echocardiography to guide device positioning has been published. Side effects may include device migration and occlusion of either the left pulmonary artery or the aorta (see also Chapter 19 ).
Hypotension and Circulatory Collapse
Etiology of Hypotension or Circulatory Collapse
The nature of the disease processes causing cardiovascular instability is variable and should be considered when managing treatment. Myocardial dysfunction related to immaturity or elevated systemic vascular resistance and hypovolemia should be considered as important etiologic factors in the immediate transitional period ( Table 15.3 ). Beyond the first 24 hours of life the hemodynamically significant duct and sepsis are the most common causes. Hypovolemia, adrenal suppression, and the effects of raised intrathoracic pressure may present at any stage and should always be considered. The presence of a duct-dependent obstruction of the systemic outflow tract is just as likely for premature infants and must be considered, particularly for those in refractory shock.
| <24 h | 24–72 h | >72 h |
|---|---|---|
| Myocardial dysfunction, such as increased left ventricular afterload, or sepsis Hypovolemia such as birth-related blood loss, or high insensible losses Hemodynamically significant arterial duct Increased intrathoracic pressure, for example due to pulmonary hyperinflation, or fetal hydrops Duct-dependent systemic disorder of flow | Hemodynamically significant arterial duct Myocardial dysfunction due to, for example, sepsis or asphyxia Hypovolemia, for example due to loss of blood, or insensible losses Duct-dependent systemic disorder of flow Increased intrathoracic pressure, such as pulmonary hyperinflation | Hemodynamically significant arterial duct Myocardial dysfunction due to, for example, necrotizing enterocolitis, or sepsis Relative adrenal insufficiency Postligation cardiac syndrome Increased intrathoracic pressure such as lung hyperinflation, pleural, or pericardial effusion Duct-dependent systemic disorder of flow |
Hypovolemia
All neonates require a normal central venous pressure to optimize pulmonary flow. The lack of a relationship between crystalloid support and blood pressure suggests that hypovolemia is less common than previously considered as a primary etiologic agent. Nevertheless, it should be considered when there is evidence of acute maternal or neonatal blood loss, high insensible losses, or polyuria coinciding with weight loss, where there are major bodily cavity collections of fluid, such as pleural or pericardial effusions or ascites, or where there are excessive gastrointestinal fluid losses due to diseases such as necrotizing enterocolitis or short bowel syndrome.
Myocardial Dysfunction
The maturational differences that make the preterm myocardium susceptible to failure have been described in a previous section. These developmental disadvantages make the neonatal myocardium vulnerable during a hypoxic-ischemic insult or when subjected to preload or afterload compromise. The onset of left ventricular dysfunction within 8 to 12 hours of ductal ligation is one example of the intrinsic vulnerability of the immature myocardium to altered loading conditions. Myocardial dysfunction is also more likely to occur during periods of metabolic acidosis, hypocalcemia, or hypokalemia or as a consequence of release of cytokines in the setting of sepsis or necrotizing enterocolitis.
Vasomotor Regulation
The immediate postnatal period is characterized by increased systemic vascular resistance upon removal of the placenta from the systemic circuit. The placenta is a low resistance organ and a rich source of prostaglandins and other inflammatory mediators with vasodilator properties. Beyond the transitional period, the complex regulation of vascular tone involves balancing of vasoconstrictor and vasodilator modifying factors, including nitric oxide, eicosanoids, and catecholamines. Septic shock is characterized by increased production of nitric oxide due to upregulation of inducible nitric oxide synthase by endotoxins and tumor necrosis factor-α. Stores of vasopressin are also reduced in septic shock. Both of these factors may contribute to excessive systemic vasodilation and low vascular resistance, leading to hypotension. Dysregulation of vasomotor tone should be considered as a possible contributory factor toward circulatory collapse particularly in the presence of isolated low diastolic pressure. The increase in left ventricular–exposed vascular resistance following ductal ligation is temporally associated with impaired myocardial performance and low cardiac output. The nature of the vasomotor imbalance is an essential consideration when choosing between vasopressor and vasodilator agents.
Adrenal Gland Suppression
There is accumulating evidence from animal and human studies that the hypothalamic-pituitary-adrenal axis may be dysfunctional in some premature infants, particularly when subjected to stress. Antenatal administration of multiple courses of steroids may contribute to postnatal impaired adrenal performance. There is evidence that suboptimal adrenal performance is an important contributor to impaired myocardial performance and impaired cardiorespiratory adaptation in the early neonatal period. The association between hypotension and levels of cortisol in the plasma is an important consideration, although assessment of the performance of the adrenal glands in clinical practice is challenging.
Therapeutic Approach to Hypotension and Circulatory Collapse
The traditional approach to cardiovascular care is problematic for a number of reasons. First, it has been predominantly blood pressure based and fails to consider the importance of systemic blood flow. Second, the approach to intervention is based on regimental protocols that recommend administration of volume followed by dopamine, dobutamine, and epinephrine. These protocols do not take into account the nature of the underlying disease or the acute physiologic disturbance, postnatal maturation, or interindividual variation. Hence they lend themselves to incorrect decisions regarding treatment. It is not logical to treat hypotension secondary to sepsis or congenitally malformed hearts in a similar fashion, and therefore an approach based on disease physiology is recommended ( Fig. 15.9 and Tables 15.4 to 15.6 ). It should also be recognized that there is limited clinical evidence to support any current therapeutic agent. In addition, there is limited pharmacologic evidence to support the agents currently used in practice. Nevertheless, it is important to understand the mechanism of action, benefits, and limitations of commonly used agents. It is important to recognize that the goal of treatment is to ensure there is adequate oxygenation to meet the metabolic needs of the cell. Both delivery and consumption of oxygen are important considerations ( Fig. 15.10 ). Delivery is influenced by level of circulatory hemoglobin, saturations, and factors that influence myocardial performance, such as preload, afterload, contractility, and heart rate. Consumption is subject to the influence of work of breathing, agitation, and pain.
| Possible Causes | Therapeutic Approach (Mechanism) |
|---|---|
| PPHN |
|
| Septic (cold) shock |
|
| Cardiogenic shock |
|
| Possible Causes | Therapeutic Approach (Mechanism) |
|---|---|
| Systemic hypovolemia |
|
| Warm shock |
|
| PDA |
|
| Cause | Physiology | Therapeutic Approach (Mechanism) |
|---|---|---|
| PROGRESSION OF SEVERITY AFTER AN INITIAL PERIOD OF LOW SYSTOLIC ATRIAL PRESSURE | ||
| PPHN | LV dysfunction and/or loss of vascular tone |
|
| Cardiogenic shock | Worsening LV function (?impending arrest) | Enhance myocardial systolic performance (e.g., dobutamine, epinephrine) |
| PROGRESSION OF SEVERITY AFTER AN INITIAL PERIOD OF LOW DIASTOLIC ATRIAL PRESSURE | ||
| Hypovolemia or warm shock | Myocardium unable to compensate or progression to cardiac dysfunction |
|
| PDA | Large-volume shunt and myocardium unable to compensate |
|
| BOTH SYSTOLIC AND DIASTOLIC PRESSURE LOW AT PRESENTATION (PROFOUND HYPOTENSION) | ||
| Manage as severe warm shock with LV dysfunction if no echo available (rule out adrenal insufficiency) | As above + early hydrocortisone | |
Volume.
There have been no studies of volume versus no treatment. The systematic review of trials of early expansion found no evidence of benefit, and bench research suggests no benefit to administering volume to hypotensive animals that are not hypovolemic. Trials comparing normal saline with albumin found no advantage of either therapy in reducing mortality or improving cardiovascular outcomes and albumin is associated with a greater risk of impaired gas exchange. Volume should be restricted to treating hypovolemia where there is an identified precipitating factor, such as acute loss of blood.
Vasopressor Agents.
Dopamine is a sympathetic amine and the most commonly used vasoactive agent in the neonatal intensive care unit. It has mixed β-1 and α-adrenergic effects depending on the dose. There is evidence of improved left ventricular performance at levels of less than 2.5 µg/kg per minute in immature neonates. It was previously thought that the vasoconstricting effects occur only at doses greater than 10 µg/kg per minute. There is evidence of significant α-adrenergic effects in some premature infants at doses as low as 6 µg/kg per minute, with marked elevation in systemic vascular resistance leading to decreased cardiac output and decreased flow in the superior mesenteric and middle cerebral arteries. Although dopamine is an effective agent at increasing systemic blood pressure, its effects on systemic flow and end-organ perfusion are concerning. Epinephrine is an endogenous catecholamine produced by the adrenal medulla with similar mixed β 1 -adrenergic, at low doses, and α-adrenergic, at doses greater than 0.375 µg/kg per minute, effects to epinephrine. It is an effective pressor agent in the first 24 hours of life and may augment cerebral flow. Its clinical use is normally reserved as a rescue agent, although it may be a more effective pressor agent than dopamine in septic shock or necrotizing enterocolitis. High doses or prolonged treatment have been associated with ischemia and myocardial dysfunction. These effects may relate to direct β-1 adrenergic receptor mediated damage to the myocardium. Vasopressin is a 9–amino acid peptide synthesized in the posterior pituitary, commonly known as antidiuretic hormone. It displays dichotomous effects through V1 receptors. In the lung, it has pulmonary vasodilator properties via modulation of release of nitric oxide. It acts as a systemic vasoconstrictor, acting through phospholipid complex–mediated calcium release. In adults it is a promising systemic vasopressor in vasodilatory shock and cardiopulmonary resuscitation. Although there are limited neonatal data, vasopressin has been used successfully in extremely low birth weight neonates with catecholamine resistant shock and has demonstrated safety when compared with dopamine as a first-line therapy for early hypotension. Theoretically, it may also be of benefit in restrictive physiologies such as the septal hypertrophy or biventricular hypertrophy that occurs in infants of diabetic mothers and preterm infants with hypotension in the setting of acute pulmonary hypertension.
Inodilator Agents.
Dobutamine is a synthetic analogue of dopamine with a predominantly β-1 adrenergic mode of action and minimal α- and β-2 adrenergic properties. These translate into positive inotropic and afterload reducing effects, which are highly desirable in many neonatal settings (e.g., transitional period, postasphyxial insult, pulmonary hypertension, and following ductal ligation). A systematic review of five randomized controlled trials concluded that dopamine was superior at elevating systemic blood pressure, but there were no differences in survival or neonatal morbidity. Two randomized trials have shown that dobutamine is a more effective agent at improving systemic blood flow. In one study, dopamine was shown to lead to a decrease in left ventricular output. It can be concluded that dobutamine is a more desirable agent for neonates with hypotension and clinical signs of low cardiac output.
Milrinone is an inhibitor of phosphodiesterase type III that acts through increasing the bioavailability of cyclic adenine monophosphate. It is both a systemic and pulmonary vasodilator, with positive inotropic and lusitropic properties. In infants and children undergoing cardiac surgery, it has been shown to decrease the combined end point of death and low cardiac output syndrome. There is also evidence of benefit in neonates with pulmonary hypertension. The pharmacokinetics of milrinone have been characterized in premature infants in the first 24 hours of life. Experimental data suggest that the myocardial effects may be developmentally regulated, with negative inotropy in some species in early gestation. Caution is advised when administering milrinone to neonates with hypotension because the associated reduction in systemic vascular resistance may be associated with severe hypotension, particularly in neonates where metabolism and clearance may be impacted such as those with hepatic or renal impairment.
Steroids.
These are normally considered as rescue therapy after failure of cardiotropic support. A number of clinical trials have demonstrated improved cardiovascular stability facilitating weaning of cardiotropic drugs after commencement of treatment. The mechanism of action is a combination of genomic and nongenomic effects ( Fig. 15.11 ). Their merits must be considered in the context of the potential negative effects on myelination and brain maturation.
In summary, the choice of a cardiovascular treatment should consider the nature of the disease, maturational factors, potential effects on both blood pressure and cardiac output (see Fig. 15.9 ), and pharmacologic properties. The complications of treatment need also be recognized, which may include tachycardia, increased myocardial consumption of oxygen, hypotension produced by vasodilator agents, regional hypoperfusion produced by vasopressors, impaired myocardial compliance, and arrhythmias.
Pulmonary Hypertension and Prematurity
Until recently, the nature and treatment of pulmonary vascular disease in premature infants have received little attention. For the purposes of this section, “pulmonary hypertension” will be used as a surrogate for elevated pulmonary vascular resistance in the absence of anatomic communications between the ventricles and/or great vessels. It is now recognized that premature infants may suffer from acute pulmonary hypertension and that pulmonary vascular disease increases morbidity and mortality associated with chronic lung disease ( Table 15.7 ). It is important to make a distinction between reversible and irreversible causes because the responsiveness to pulmonary vasodilator agents depends on the degree of pulmonary vascular remodeling. Factors contributing to pulmonary remodeling include hypoplasia due to prolonged rupture of membranes or renal agenesis.
| Acute | Chronic, With Variable Reversibility |
|---|---|
| Reversible Respiratory distress syndrome Pneumothorax Sepsis Irreversible Pulmonary hypoplasia Congenital diaphragmatic hernia | Chronic lung disease Chronic patency of arterial duct or other left-to-right shunt lesions Congenitally malformed heart Mild pulmonary hypoplasia |
Acute Pulmonary Hypertension
Persistent pulmonary hypertension of the newborn is defined as the failure of normal postnatal fall in pulmonary vascular resistance to a sufficient degree to facilitate an adequate rise in pulmonary blood flow for oxygenation, regardless of absolute pulmonary artery pressure. The incidence is not clearly described, although a higher frequency than in term neonates has been reported. The regulation of pulmonary vascular resistance represents a balance between vasoconstrictor and vasodilator agents and the biochemical processes integral to transition are developmentally regulated, which may make preterm infants at greater risk. In addition, preterm infants are more frequently affected by lung parenchymal disease, which impacts on the adequacy of recruitment and oxygenation, both of which may modify pulmonary blood flow. The clinical consequences of acute pulmonary hypertension include oxygenation failure and poor systemic blood flow, which may lead to hypotension related to right ventricular failure and/or pulmonary-to-systemic shunting. Early onset acute pulmonary hypertension may be associated with increased risk of chronic lung disease, particularly in those with pulmonary hypoplasia, and the mortality rate for preterm infants with pulmonary hypertension, at 26.2%, is six times higher than matched controls.
Diagnosis of Pulmonary Hypertension in Premature Infants
The diagnosis of pulmonary hypertension in premature infants is challenging, particularly in the presence of lung disease. The signs and symptoms of pulmonary hypertension are nonspecific. A gradient between preductal and postductal oxygen saturation may be helpful, if present; however, it is commonly absent in the presence of a small or absent ductus arteriosus or a bidirectional shunt at the ductal level, and therefore the absence of a gradient does not rule out acute pulmonary hypertension as a diagnosis. The electrocardiogram may reveal features of pulmonary hypertension, such as tall P waves and evidence of right ventricular hypertrophy. Cross-sectional echocardiography is the gold standard because cardiac catheterization is rarely performed and may be poorly tolerated. The estimation of right ventricular systolic pressure from the velocity of the tricuspid regurgitant jet may underestimate the true pulmonary artery pressure in the presence of significant right ventricular dysfunction. Assessment of septal curvature may be used; however, the presence of a patent duct and transductal shunting allows more accurate quantification of pulmonary arterial pressure.
Echocardiography for Identification of Complications of Pulmonary Hypertension
Echocardiographic assessment of ventricular performance may be valuable, particularly on serial examinations, because the right ventricle is uniquely vulnerable to afterload and may tolerate pulmonary hypertension poorly. Similarly, there is evidence in term neonates that pulmonary hypertension is associated with left ventricular dysfunction, which may relate to reduced preload, abnormal conformation, ventricular-ventricular interaction, or impaired coronary oxygen delivery. There are limited, but increasing, reference ranges for measures of myocardial performance in preterm neonates.
Treatment of Acute Pulmonary Hypertension
The management of preterm neonates with acute pulmonary hypertension is based on three principles. First, it is essential that modifiable factors contributing to pulmonary vasoconstriction be corrected. Second, pulmonary vasodilator therapy should be considered. Finally, supportive treatment of cardiovascular complications such as right ventricular dysfunction and poor systemic blood flow should be instituted.
Respiratory Management.
The primary treatment is the administration of oxygen on the basis that hypoxemia leads to worsening of the pulmonary hypertension. Oxygen is a potent pulmonary vasodilator, although animal experimental models demonstrate minimal interval reduction in pulmonary vascular resistance above a partial pressure of oxygen of 50 mm Hg ; this relationship may be blunted in premature infants. Hyperoxia contributes to the development of oxygen free radicals that may be poorly scavenged and are associated with pulmonary vasoconstriction. There remains uncertainty and controversy regarding the most desirable saturation for premature infants. There is some justification for maintaining saturations greater than 93%, and some randomized controlled trials suggest improved mortality at higher oxygen target saturations. The goal of assisted mechanical ventilation is to optimize clearance of carbon dioxide and lung recruitment. Both ventilation less than functional residual capacity and overdistension have been associated with increased pulmonary vascular resistance and impaired pulmonary blood flow. Surfactant therapy is associated with improved compliance and may reduce pulmonary vascular resistance ; however, repeat dosing may impair alveolar oxygenation and should be considered thoughtfully ( Fig. 15.12 ).
