On average, up to one-eighth 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 wellbeing. The causes of birth prior to term are many ( Table 11-1 ). 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 4 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 ( Fig. 11-1 ). The past two decades have witnessed a number of significant advancements in neonatal care, most notably maternal administration of antenatal steroids, 1 the ability to replace surfactant, 2 use of inhaled nitric oxide, 3,4 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 recognised 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 regionalised perinatal health care, from one-tenth to one-third of those born with extremely low weight ( Box 11-1 ) are delivered outside tertiary neonatal centers. Although overall survival for premature infants in general has improved, mortality remains high, particularly at the limits of viability ( Table 11-2 ). The outcome for neonates born outside tertiary centres is less favourable when compared to those patients delivered and resuscitated at perinatal centers specialised in coping with those at high risk. 5,6 A large population-based study of mortality and disability, with the acronym EPICURE, was conducted in the United Kingdom of all infants born alive between the gestational ages of 22 and 25 weeks. 7,8 Survival at 30 months reached just over 40% in neonates born at 25 weeks of gestation, falling to 10% for those born at 23 weeks of gestation. Moderate-to-severe disability occurred in almost half of the survivors when compared to school classmates at the age of 6 years. The contribution of cardiovascular performance and systemic haemodynamics to ongoing neonatal morbidity is poorly understood. Enhanced cardiovascular monitoring, and earlier therapeutic intervention, may prove to be a necessary step towards improving survival further, and minimising adverse neurodevelopmental sequels.
| Maternal | Placental | Fetal | Miscellaneous |
|---|---|---|---|
| Pre-eclampsia | Intra-uterine infection, or premature rupture of membranes | Chromosomal abnormality | Cervical incompetence |
| Renal failure | Placental abruption | Hydrops fetalis | Familial |
| Diabetes mellitus | Antepartum haemorrhage | Congenital infection, such as toxoplasmosis, rubella, or cytomegalovirus | |
| Infection of the urinary tract | Uterine stretch
| ||
| Chronic disease | |||
Preterm: A neonate born prior to 37 weeks of completed gestation
Near-term: A neonate between the 34th and 37th weeks of gestation
Low birth weight: A neonate born weighing less than 2500 g
Very low birth weight: A neonate born weighing less than 1500 g
Extremely low birth weight: A neonate born weighing less than 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
Intra-uterine 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 (grams) | Births (%) | Neonatal Mortality per 1000 Live Births in Each Subgroup |
|---|---|---|
| Greater than 2500 | 92.4 | 0.9 |
| Less than 2500 | 7.6 | 48 |
| Less than 1000 | 1.4 | 214 |
THE TRANSITIONING CIRCULATION
The condition of the infant at birth is dependent, in part, on intra-uterine wellbeing and growth. Intra-uterine growth retardation is the failure of the fetus or infant to achieve his or her predetermined genetic potential. Typically, the preterm infant is below 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. 9–11 Doppler interrogation of fetal and neonatal mitral valvar velocities revealed lower E wave amplitude compared with normal mature mitral E peaks. 12,13 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 glycaemic control during pregnancy, particularly in the setting of maternal diabetes, is a known risk factor for structural heart disease and hypertrophic cardiomyopathy. 14–16 In severe cases, where there is placental malfunction leading to retardation of growth, the same vascular and myocardial dysfunction may occur as described above.
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:
- •
Include increased pulmonary blood flow, to about 20 times fetal levels
- •
Occur in part due to the exposure of the pulmonary vascular bed to higher alveolar concentrations of oxygen than the relatively hypoxic intra-uterine environment. Other metabolically active substances, such as metabolites of prostaglandin, bradykinins, or histamine, may play some role through inducing pulmonary vasodilation.
- •
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. 17
- •
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.
REGULATION OF MYOCARDIAL PERFORMANCE
Architecture of the Myocyte
Fetal myocardial tissue consists of 70% noncontractile tissue, compared to 40% in the mature adult heart. Histological 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. 18,19 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 post-natal life. The immature sarcomere and contractile apparatus is relatively disorganised. Myofibrils are irregular and scattered along the interior of the cell. Intra-uterine 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, characterised by myocytes which were longer and wider, with increased volume. 20 Biventricular hypertrophy is a recognised complication of exposure of the preterm myocardium to prolonged and high doses of steroids. 21 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. 22 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. 23 They are more reliant on trans-sarcolemmal fluxes of calcium for contraction and relaxation. 24 The high ratio of surface area to volume, and the subsarcolemmal location of myofibrils, supports 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. 25
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 which 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 physiological 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, reflects myocytic function and global myocardial contractile behaviour. Developmentally, the immature myocardium has been shown to exhibit a higher basal contractile state, and a greater sensitivity to changes in afterload. 26,27 The intolerance of the immature myocardium to increased afterload may be attributable to differences in myofibrillar architecture, or immaturity of receptor development or regulation. 28 The Frank–Starling law appears less applicable to the immature myocardium. 29
HAEMODYNAMIC ASSESSMENT AND MONITORING
The consequences of haemodynamic instability include necrotising enterocolitis, intraventricular haemorrhage, and periventricular leucomalacia, all of which may lead to mortality or adverse neurodevelopmental outcomes. Intraventricular haemorrhage 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 haemorrhage is the germinal matrix, an immature network of capillaries highly susceptible to hypoxaemia, hypercapnaemia, and altered cerebral blood flow. Periventricular leucomalacia is a loss of white matter in the watershed areas around the lateral cerebral ventricles secondary to hypoxic-ischaemic 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 haemodynamic 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. 30 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. 31 In 1992, a report from the former British Paediatric Association stressed the importance of monitoring blood pressure in order to guide early therapeutic intervention, and thus prevent adverse neurological sequelae. 32 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. 33 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 numerical 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, whereas the diastolic pressure reflects local perfusion of the tissues. In neonates with a haemodynamically 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. 11-2 ). The finding of neonates with numerical 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 recognised that blood pressure is but a surrogate of perfusion, and not the end-point of interest.
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. 11-3 ). 34,35 The auto-regulatory mechanism is thought to fail below a mean arterial pressure of 30 mm Hg. 36 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 haemorrhage or periventricular leucomalacia. 37 Other investigators have shown no relationship between blood pressure and cerebral blood flow. 38 Second, associations have been shown between adverse neurological consequences and systemic hypotension. 39–42 There is a significant body of evidence, nonetheless, which challenges these assumptions. For example, there is 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 neurological outcomes. 43–52 When corrected for associated risk factors, such as intra-uterine growth retardation, postnatal use of steroids, and chronic lung disease, the association between hypotension and abnormal neurodevelopmental outcomes was lost. 53 The discrepancy between individual studies may reflect the fact that the association is much more complex than any direct effect of blood pressureon cerebral blood flow ( Fig. 11-4 ). 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 non-specific measures of systemic flow. In isolation, capillary refill time is inaccurate, highly subjective, and a poor overall predictor of the adequacy of perfusion. 54 The measurement of cardiac output at the bedside is a useful adjunct to the clinical assessment and there is normative data for both right and left ventricular outputs. 55,56 The normal range for cardiac output in normal premature infants is between 170 and 320 mL/kg/min. Unfortunately these measurements are potentially inaccurate in the early neonatal period due to the effects of transductal shunting. Recently, measurement of flow in the superior caval vein has been proposed as a novel method of assessing the adequacy of systemic flow, as it is not confounded by atrial or ductal shunts. 57 As four-fifths of flow in the superior caval vein represents venous return from the head and neck, such measurements may provide novel insights into any association between regional cerebral blood flow and cerebral injury. 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 haemorrhage ( Fig. 11-5 ). 58 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 endpoint of death and abnormal developmental quotient. 59 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.
CARDIOVASCULAR PROBLEMS UNIQUE TO THE PRETERM INFANT
The Haemodynamically 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 over-circulation and systemic hypoperfusion. Persistent patency is found in about half of babies born at less than 29 weeks gestation, and/or weighing under 800 g. 60,61
Biology of Normal Closure
Ductal closure is not immediate, particularly in infants born with extremely low weights, and occurs in two stages. Functional closure 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. Anatomical closure depends on the architectural remodeling of the ductal wall. 62 It consists of extensive neointimal thickening, and loss of smooth muscle cells from the inner media. 63 The remodeling effects start at the pulmonary end, progressing toward the aortic insertion. 64 Both vasodilator prostaglandins, especially PgE 2 , and nitric oxide, oppose ductal closure during fetal life. 65,66 In the second trimester, intimal cushions are formed that closely resemble the pathological intimal thickening seen in atherosclerotic disease. 67 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. 63 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. 68 The biologic consequences of these changes include a decline in tissue distensibility and increased contractile potential. 69 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. 68 After delivery, the increase in arterial content of oxygen, along with the decrease in circulating prostaglandins following placental separation, 70 and reduced intraluminal blood pressure, contribute towards ductal closure. 71,72 As transductal flow decreases, the wall becomes progressively more ischaemic, and eventually fibrotic. 73
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 below 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, 68 and lacks both intimal folds and circumferential medial musculature. 74 It is less responsive to oxygen, 68,75 and more sensitive to prostaglandin E 2 and nitric oxide. 66 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 anatomical remodeling fail to develop. 63 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. 73,76 Non-steroidal anti-inflammatory agents, therefore, are less likely to be effective. In baboons, co-administration of an inhibitor of nitric oxide synthase, along with indomethacin, leads to increased contractility and luminal obliteration of the preterm duct. 77 There is data also to suggest that, in more mature preterms, those born prior to 33 weeks gestation, the arterial duct is also less sensitive to non-steroidal anti-inflammatory agents, although the mechanism has not been elucidated. 78
The Pathophysiological Effects of a Haemodynamically 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 over-circulation and/or systemic hypoperfusion , both of which may be associated with significant morbidity ( Fig. 11-6 ). 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 oedema and/or low cardiac output syndrome. 79 The increased pulmonary flow, and accumulation of interstitial fluid secondary to the large ductal shunt, contributes to decreased lung compliance. 80 The cumulative effects of increasing or prolonged ventilator requirements and myocardial dysfunction may increase the risk of chronic lung disease. 81,82 Systemic flow may also be compromised with ductal shunts due to retrograde diastolic flow in the aorta and the arteries supplying organs such as the kidneys and gut. 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 haemodynamically significant duct is clinically suspected. This may lead to significant morbidity, including renal insufficiency, necrotising enterocolitis, intraventricular haemorrhage, and myocardial ischemia. 83,84 Early detection and targeted intervention may potentially improve long-term neonatal outcomes.
Diagnosis of a Haemodynamically Significant Arterial Duct
Clinical Presentation
The classical clinical features include a systodiastolic murmur, hyperactive praecordium, bounding pulses, and wide pulse pressure. More commonly, a systolic murmur is audible that radiates widely across the praecordium and back. In many of those born prior to term, however, cardiac auscultation is unremarkable. 85 In the first week of life, despite the presence of a large duct, typical clinical signs are often absent. Such a situation is widely recognised as the silent duct. Surfactant, by assisting the natural post-natal fall in pulmonary arterial pressure, 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. 86,87 The existence of a haemodynamically significant but silent duct has been confirmed by cardiac catheterisation 88,89 and detailed echocardiographic evaluation. 90 Such a situation should be suspected in a setting of delayed hypotension during the second and third days, failure of oxygenation, increasing requirements for ventilatory 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. 91,92
Ancillary Tests
Although not very sensitive, chest radiography may show cardiomegaly and/or signs of pulmonary congestion, while the electrocardiogram may show signs of left atrial or ventricular enlargement. 93,94 The latter may be more useful for the identification of subendocardial ischaemia secondary to low coronary arterial perfusing pressures in neonates with a large duct, although this association has not been formally evaluated.
Echocardiographic Confirmation of the Haemodynamically Significant Arterial Duct
It is now standard of care, in many centers, to perform routine ductal and functional assessment within the first 72 hours of life due to the unreliability of clinical assessment, the increased likelihood of the ductal sensitivity to closure assisted by indomethacin, and the magnitude of the potential morbidities if left untreated. The determination of ductal significance using echocardiography involves assessment of size, patterns of transductal flow, systemic and/or end-organ perfusion, and characterisation of the degree of volume loading of the heart.
- •
The size of the duct is obtained from a suprasternal short-axis view ( Fig. 11-7A ) although measuring its internal diameter can be difficult, even with clear images. In addition the transductal diameter is not consistent throughout, often becoming tapered at the pulmonary end. A transductal diameter less than 1.5 mm is associated with retrograde or absent postductal aortic diastolic flow. 17 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 haemodynamic significance. 95
Figure 11-7
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.
- •
The pattern of transductal flow , estimated using pulse wave Doppler interrogation from a suprasternal short-axis view, can also be used to characterise 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 ( Fig. 11-7B ). 96
- •
The effects on systemic and/or end-organ perfusion may also be examined. Large ductal shunts are associated with decreased superior caval venous flow. 58,97 This is relevant as low flow, less than 40 mL/kg/min, a surrogate of systemic perfusion, has been shown to correlate with increased risk of late intraventricular haemorrhage. 58 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 haemodynamically significant duct. 98,99
- •
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 over-circulation and/or volume loading. Although the measurement is standardised, it is not very specific, and is prone to error dependent on the operator. 57 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.
Management of the Haemodynamically 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 should be considered in attempts to minimise pulmonary over-circulation in a fashion comparable to other cardiac defects. This can be achieved by accepting Pco 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, minimise atelectasis-induced lung injury, and lead to improvements in myocardial performance and cardiac output by reducing left ventricular afterload. 100,101
Cardiotropic Support.
The optimal treatment for hypotension and/or systemic hypoperfusion is closure of the duct, and not cardiotropic support. Excessive α-adrenergic stimulation, by agents such as dopamine or epinephrine, should be avoided, as 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.
Fluid Management and Diuretic Therapy
A recent meta-analysis suggested that restriction of water to meet the physiologic needs, whilst avoiding dehydration, may prevent the duct from becoming clinically and haemodynamically significant. 102 This strategy should not be routinely recommended, as it may lead to reduced left ventricular stroke volume and cardiac output, further compromising systemic flow. 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. 103,104 This may relate to excessive new production of prostaglandin E 2 by the kidneys in babies treated with furosemide. 105 A systematic review of the co-administration of furosemide in indomethacin-treated neonates concluded that evidence was insufficient to support its routine administration. 106 Diuretics should be restricted to the treatment of pulmonary oedema 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 intra-uterine retardation of growth. Specifically, a more cautious feeding regime, and lower thresholds for discontinuation of feeds, or consideration to screen for necrotising enterocolitis, should be considered. It may also be advisable to withhold feeds during treatment, due to the potential effects of ductal steal and non-steroidal anti-inflammatory agents such as indomethacin on intestinal perfusion. 99
Specific Treatment
Accepted strategies include both medical and surgical options. The decision to treat is normally made on the following basis:
- •
Echocardiographic confirmation of a duct with an internal diameter greater than 1.5 mm and unrestrictive left-to-right ductal shunting.
- •
Clinical signs of pulmonary over-circulation, myocardial dysfunction, or end-organ hypoperfusion.
Therapeutic closure is not recommended in a setting of suprasystemic pulmonary hypertension, or right heart failure where exclusive right-to-left shunting is a means to off-load a stressed right ventricle.
Non-steroidal Anti-inflammatory Drugs
As 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 is currently the treatment of choice for ductal closure in preterm babies, although the ideal dose, duration, and/or time to intervene remains somewhat controversial. Therapeutic options include prophylactic therapy or early targeted intervention.
Prophylactic Treatment
The merits of prophylactic treatment in the first 24 hours of life are highly questionable. Although the numbers of patent ducts are reduced, two-fifths of neonates are unnecessarily treated as the duct may have closed spontaneously. 107 In addition, ongoing ductal patency, in a transitional circulation with elevated pulmonary vascular resistance and poor right ventricular function, may be necessary for augmenting pulmonary perfusion. Severe hypoxaemia, responsive to inhaled nitric oxide, was recently reported in premature infants born prior to 28 weeks following prophylactic exposure to ibuprofen on the first day of life. 108 Prophylactic treatment in the first 24 hours of life, therefore, is not recommended, as the risks substantially outweigh the benefits as outlined previously.
Therapeutic Treatment
Early intervention, on the first to third days, is preferable to late intervention after 1 week, as the risks of necrotising enterocolitis, pulmonary morbidity and need for surgical ligation are significantly reduced. 109 The choice of dose and duration of treatment is controversial. 110 A targeted early approach to intervention appears the most effective and safest option. Treatment with indomethacin fails in up to half the infants born with extremely low weight. 61 This may reflect architectural differences and remodelling in the most immature patients, as described earlier, in addition to the severity of illness. Antenatal administration of indomethacin is also associated with postnatal hypo-responsiveness, and increased need for surgical ligation. 111 Architectural remodelling 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. 69
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 shown to have comparable efficacy in achieving ductal closure. 112–114 A recent meta-analysis confirmed these findings, but also demonstrated an improved safety profile with ibuprofen. 115 Specifically, those treated with ibuprofen had lower levels of creatinine, improved urinary output, and were less likely to have cerebral or mesenteric vasoconstrictive effects. There is, however, a potential greater risk of kernicterus, because ibuprofen interferes with binding of bilirubin to albumin in the serum when given in usual doses. 116
Surgical Intervention
Surgical ligation is normally indicated after failure of medical therapy, or where medical therapy is contraindicated. The procedure is most commonly performed from a lateral subcostal approach, although video-assisted thoracoscopic ligation has been successfully performed. 117–119 Some authors have argued that ligation may be preferable over indomethacin as the initial treatment because it is associated with low morbidity and almost certain success. 120,121 A randomised controlled trial of early surgical ligation demonstrated a lowered incidence of necrotising enterocolitis. 122 An aggressive approach to ductal closure has been proposed as an effective way to reduce the incidence and severity of chronic lung disease. 123 A recent meta-analysis was inconclusive in determining whether medical or surgical intervention was preferable. 124
Post-operative Complications
Ligation is not a benign procedure, and is oftentimes associated with significant post-operative cardiorespiratory instability. The most common complications include air-leak syndromes, pulmonary oedema, 125 hypotension requiring vasopressor support, 126 recurrent laryngeal nerve palsy, 127 and occasionally ligation of the left pulmonary artery, or even the aorta. Ligation is associated with immediate systolic and diastolic hypertension, which may contribute to reperfusion haemorrhage. 128 Although improvements in lung compliance immediately following ligation have been recorded, 80 the post-operative course is characterised by a post-ligation cardiac syndrome consisting of failure of oxygenation due to pulmonary oedema, systolic hypotension, and the need for cardiotropic support, which typically occur 8 to 12 hours after the procedure ( Fig. 11-8 ). 129 This may relate to altered ventricular loading conditions following ligation. 130 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. 131 A number of recent publications highlight an association between ligation and an increased risk of bronchopulmonary dysplasia, severe retinopathy of prematurity, and neurosensory impairment. 132,133 It is impossible to determine whether this relationship reflects causality, or whether the need for ligation is merely a marker of the severity of illness.
Post-operative Care
On the basis of cardiovascular adaptation and other surgical complications, all neonates should be monitored closely in the post-operative period. Specifically, vital signs and urinary output should be carefully monitored, with frequent testing of arterial blood gases and/or lactate. Early commencement of diuretic therapy and increased positive end-expiratory pressure are recommended with failure of oxygenation, and radiologic evidence of pulmonary oedema 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 or milrinone, may be preferable.
Hypotension and Circulatory Collapse
Aetiology 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 hypovolaemia should be considered as important aetiological factors in the immediate transitional period ( Table 11-3 ). Beyond the first 24 hours of life the haemodynamically significant duct and sepsis are the most common causes. Hypovolaemia, 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.
| Less Than 24 Hours | 24 to 72 Hours | Older Than 72 Hours |
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