Review Article - Journal of Pregnancy and Neonatal Medicine (2024) Volume 8, Issue 5

Clinical and Echocardiographic Study of the Ductus Arteriosus in Preterm Infants

Faculty of Medicine, University of Alexandria, Egypt

*Corresponding Author:

Ahmed Said Taha
Faculty of Medicine
University of Alexandria, Egypt
E-mail: drahmedtaha@hotmail.com, drahmedtaha@hotmail.com

Received: 07-Oct-2024, Manuscript No. AAPNM-24-149746; Editor assigned: 08-Oct-2024, PreQC No. AAPNM-24-149746(PQ); Reviewed: 15-Oct-2024, QC No. AAPNM-24-149746; Revised: 21-Oct-2024, Manuscript No. AAPNM-24-149746(R); Published: 28-Oct-2024, DOI: 10.35841/aapnm-8.5.221

Citation: Taha A. S. Clinical and echocardiographic study of the ductus arteriosus in preterm infants. J Preg Neonatal Med. 2024;8(5):221

Introduction

The ductus arteriosus is a wide blood vessel that connects the pulmonary artery to the aorta in the fetus. It has great importance during that stage of life because it is responsible for shunting blood away from the high-resistance pulmonary vascular bed into the systemic circulation [1].

The ductus is derived from the sixth aortic arch. The shape and size of the ductus is related to the haemodynamics in uterus. From the sixth week of fetal life, it carries most of the right ventricular output, which constitutes up to 60% of the total cardiac output. Throughout fetal life, the ductus maintains a short tubular shape, with a caliber that progressively increases with gestation to equal that of the descending aorta (10 mm) at term. At birth, the ductus undergoes rapid changes in size and shape related to the physiological process of closure. The persistent duct may, therefore, vary in morphology, but significant ducts in premature infants usually remain short and tubular. Histologically, the ductal wall is as thick as that of the aorta but has a relatively thick intima. The media contains a thick layer of smooth muscle, which, unlike the aorta, is arranged in a spiral helix that encircles the ductus in both clockwise and anticlockwise directions. This is teleologically suited for postnatal ductal closure [2,3].

Fetal circulation

Highly oxygenated blood from the placenta enters the fetus via the umbilical vein. A proportion of this blood passes into the liver to supply the hepatic sinusoids. The remainder bypasses the liver in the ductus venosus, drains into caudal vena cava and mixes with poorly oxygenated blood returning from the fetal body. The blood in the caudal vena cava, which, although mixed is still well oxygenated, drains into the right atrium of the heart [4].

Most of the blood entering the right atrium from the caudal vena cava is directed through the foramen ovale into the left atrium where it is mixed with a small amount of deoxygenated blood returning from the lungs. The contents of the left atrium enter the left ventricle and are expelled from the heart into the aorta.

The contents of the right atrium (which consist of some well oxygenated blood from the caudal vena cava and poorly oxygenated blood returning from the head and forelimbs via the cranial vena cava) enter the right ventricle and are expelled from the heart via the pulmonary artery. Only approximately 5 -10% of the blood in the pulmonary artery enters the lungs in the fetus due to the high resistance of their non-aerated state. The remainder enters the ductus arteriosus which is a shunt linking the pulmonary artery and the aorta. The convergence of the poorly oxygenated pulmonary blood and the well-oxygenated aortic blood occurs after the main supply to the head and forelimbs have branched off the aortic arch. This ensures that the blood with higher oxygen content reaches the developing brain [5].

Incidence of patent ductus arteriosus

Patent ductus arteriosus (PDA) is now the most frequent form of heart abnormality in the neonatal period, with the increasing incidence primarily resulting from the increased survival of premature infants. Approximately 10 to 70% of premature infants manifest this defect; the majority of these infants require some sort of intervention in order to close the defect [6,7].

PDA remains a common problem for the very preterm infant. Despite being a focus of neonatal research for many years, controversy still surrounds the role of PDA in adverse outcomes and the best method and appropriate timing of treatment [8] (Table 1).

Table 1: Incidence of PDA [9].

Factors maintaining ductal patency in uterus

The original view of the ductus was that it represented a relatively passive structure in uterus that was actively stimulated to contract after delivery [9]. However, recently this theory has been changed. It has become clear that patency of the ductus in uterus is an active state. That is, it has intrinsic tone, or is topically stimulated to contract, and these procontractile mechanisms are topically inhibited by vasodilators. Probably the most important dilator system identified so far is prostaglandin E2 (PGE2), which has a profound inhibitory effect on ductal smooth muscle. However, several accessory dilator systems have also been identified [10].

Prostaglandins

PGE1 and PGE2 have been found, uniformly, to be the most potent mediator, causing ductal relaxation [11].The pharmacological classification of prostanoid (P) receptors has been reviewed . Each receptor is named after the native PG that is its most potent agonist [i.e., EP for PGE1 and PGE2, IP for PGI2, DP for PGD2, FP for PGF2 and TP for thromboxane A2 (TxA2)] [12].There are at least four subtypes of EP receptors encoded by separate genes, and there are variable numbers of isoforms (depending on the species) of EP3 receptors formed by alternative messenger ribonucleic acid (mRNA) splicing from a single gene [13]

The ductus is exposed to both locally released and circulating PGs. The isolated ductus synthesizes a range of PGs. PGI2 was the main product of arachidonic acid (AA) in the ductus, but it also formed small amounts of PGE2, PGF2 , and PGD2 all about 10% the level of PGI2 synthesis , this adds further support for a physiological role for PGI2 in the control of the ductus.

The cellular sources of PGs in the ductus have been partially elucidated. In the ductus from the second trimester human fetus, PGI2 synthase was located (by immunohistochemistry) both in endothelial cells and medial smooth muscle cells, whereas in the fetal aorta, the enzyme was largely confined to the endothelium [14].

The ductus is also exposed to circulating PGE2, and it has been suggested that circulating PGE2 is more important in the control of the vessel patency than locally released PGE2 .Circulating concentrations of PGE2 increased toward term. The placenta is thought to be the major source of circulating PGE2 in the fetus. Because the lungs are the major site of PG catabolism and pulmonary blood flow is only 9% of ventricular output in the fetus, the high circulating concentrations of PGE2 are probably also related to reduced catabolism [15].

Nitric Oxide

Nitric oxide may have a role in maintaining ductal patency, immunohistochemistry studies localized endothelial nitric oxide synthase (eNOS) to the luminal endothelium and the vasa vasorum endothelium. Removing the luminal endothelium of the ductus decreased, but did not abolish, the contractile response to a NOS inhibitor, implying an extraluminal source of NOS. Both sodium nitroprusside (SNP) and glyceryl trinitrate dilate the ductus. These agents are nitric oxide (NO) donors, and they increased the intracellular concentrations of cAMP and cyclic guanosine monophosphate (cGMP) in the ductus. Inhibitors of nitric oxide synthase (NOS) promote duct contraction [16,17].

Carbon Monoxide

The effects of carbon monoxide (CO) on the ductus have been studied for over a decade. It has been found recently that, smooth muscle of the ductus contains an enzyme, heme oxygenase, that can produce CO from heme and that the CO produced may cause vasodilatation through stimulation of cGMP or by effects on potassium channels [18].

Factors mediating contraction at birth

Although the maintenance of ductus arteriosus patency in uterus is an active state and the loss of the dilator effect of PGE2 is central to the control of the ductus in the neonate, the trigger to close the vessel after birth is more than just the withdrawal of dilator influences. The major factor actively stimulating contraction is probably the effect of increasing oxygen tension, although the isolated ductus is sensitive to a wide range of contractile agonists. The multiplicity of these contractile systems seems at odds with the relatively simple physiological role of the ductus. This can be explained by the fact that the two main systems that vary at birth, namely oxygen tension and PGE2, act synergistically to modulate the response of the ductus to vasoconstrictors.

Oxygen-induced contraction

In fetal life, the ductus is exposed to an oxygen tension that has been estimated as between 25 to 40 mmHg. After birth, the ductus is exposed to arterial blood because of the reversal of the direction of flow and arterial oxygen tension rises rapidly after delivery. Rising oxygen tension profoundly contracts the ductus. Even in full-term infants, the DA does not close immediately and, although well constricted, its patency is often apparent on echocardiography for up to, and occasionally beyond 24 hours after birth. The initial phase, or functional closure of the DA, occurs because of muscle constriction. This muscle constriction causes intimal ischemia, which in turn leads to full structural closure. In premature infants, the DA, like every organ system, is immature and not developed for this transition. As a result, the DA is more likely to remain patent and the resulting shunt may have important hemodynamic consequences [19].

Several different mechanisms have been proposed to explain the profound contractile effect of physiological increases in oxygen tension on the ductus.

Elimination of dilator prostaglandins

Loss of the dilator effect of PGE2 is central to the closure of the ductus, and treatment of the neonate with PGE2 is sufficient on its own to prevent postnatal closure. The high fetal circulating concentrations of PGE2 fall dramatically after birth. Loss of the dilator effect of circulating PGE2 has been postulated to be fundamental to the closure of the ductus. The fall in circulating concentrations of PGE2 is because of (a) the increase in lung blood flow that occurs at birth because the lungs are the major site of PG catabolism and (b) the loss of the placenta, the major source of circulating PGE2 in the fetus .

Neural vasoconstriction

The ductus arteriosus is innervated by catecholamine containing nerves. The catecholamine content of the ductus is similar to that of peripheral arteries which are known to be under autonomic neural control [20].

Other Locally Released Vasoconstrictors

The adventitia of the ductus has many mast cells present, which can release other vasoconstrictors such as histamine and 5-hydroxytryptamine both of which contracted the isolated ductus of several species [21].

Myogenic tone

The role of myogenic tone in the physiological control of the ductus is as yet obscures [22].

Circulating Vasoconstrictors

The ductus contracts in response to other circulating vasoactive agents, such as epinephrine through adrenoceptors, and bradykinin.

Ductal remodeling

As the ductus changes from an artery conveying 60% of the combined ventricular output to a permanently closed structure within a matter of hours or days, it is not surprising that the process of closure is associated with morphological changes. After birth, there is extensive remodeling of the vessel's wall, and this renders closure permanent [23].

Closure is associated with the formation of intimal cushions, which are characterized by (a) an area of subendothelial edema, (b) infolding and ingrowth of endothelial cells, and (c) migration into the subendothelial space of undifferentiated medial smooth muscle cells. Postnatal remodeling is also associated with the disassembly of the internal elastic lamina, and loss of elastin may promote smooth muscle cell migration. Some of these changes begin about halfway through gestation in humans but are much more marked after functional closure of the ductus in the neonate. Ductal remodeling may depend on ischemia of the vessel wall , but the loss of medial smooth muscle cells is by apoptosis rather than necrosis [24].

Studies employing Doppler echocardiogram and color flow mapping have indicated that functional closure of the ductus arteriosus in full term infants takes place in practically all newborns at around 72 hours of life. In preterm newborns (PT-NB), the ductus arteriosus closes a little later, taking place in the majority of those with gestational ages of more than 30 weeks by 96 hours of life. In contrast, PT-NB with gestational ages less than 30 weeks and, in particular, those who exhibit hyaline membrane disease have an increased frequency of patent ductus arteriosus (PDA) [25].

Physiologic considerations of a left-to-right shunt

As with all left-to-right shunts, with PDA three major, interrelated factors control the magnitude of shunting: The diameter and length of the ductus arteriosus, which governs the resistance offered to flow; the pressure difference between the aorta and the pulmonary artery; and the systemic and pulmonary vascular resistances.

Normally after birth, systemic vascular resistance (afterload) is high, whereas pulmonary vascular resistance decreases when ventilation begins. As a result, systemic arterial blood pressure becomes higher than that in the pulmonary artery. With a small PDA, a high resistance to flow is offered by the small cross-sectional opening of the ductus arteriosus, so that the left-to-right shunt will be small despite the large pressure difference. However, with a large communication, pressures tend to become equal, and the magnitude of shunting is then determined by the relationship of the systemic and pulmonary vascular resistances. For this reason left-to-right shunting through a PDA has been defined as dependent shunting [26]. Because systemic vascular resistance does not change significantly after birth, changes in pulmonary vascular resistance are the major determinant in regulating the left-to-right shunting through a PDA. This is particularly important in the first 2 months after birth, when pulmonary vascular resistance normally is decreasing.

The physiologic features associated with left-to-right shunting through a PDA depend on the magnitude of the left-to-right shunt and the ability of the infant to handle the extra volume load. Left ventricular output, which normally is high in the immediate newborn period, is increased even further by the volume shunted left to right through the PDA. The resultant increase of pulmonary venous return to the left atrium and left ventricle increases ventricular diastolic volume (preload) and thereby left ventricular stroke volume (Frank Starling's mechanism). Left ventricular dilation will result in an increased left ventricular end-diastolic pressure with secondary increase in left atrial pressure. This may lead to signs of overt left heart failure with left atrial dilation and pulmonary edema. Right ventricular failure may occur if there is a large PDA with pulmonary hypertension or pulmonary edema and an elevated left atrial pressure, in which case pulmonary vascular resistance may be increased. The net result of both these situations is an increased pressure load for the right ventricle. Left-to-right shunting through a stretched, incompetent foramen ovale secondary to left atrial dilation is a fairly common association [27,28].

Several compensatory physiologic mechanisms help to improve myocardial performance and thereby maintain a normal systemic output. In addition to the Frank Starling mechanism, the sympathetic adrenal system is stimulated, as is the development of myocardial hypertrophy. Increased sympathetic stimulation leads to direct stimulation of nerve fibers within the myocardium, with local norepinephrine release as well as an increase in circulating catecholamines released from the adrenal glands. As a result, both the force of contraction and the heart rate are increased. These mechanisms are responsible for the rapid heart rate and the sweating often seen in infants with heart failure. If the increased volume load persists, hypertrophy of the ventricular myocardium will develop.

These compensatory mechanisms are ordinarily well developed in older children or adults; however, they are not as well developed in newborn infants and are even less so in prematurely born infants. It is most important, therefore, to consider the state of maturity (i.e., gestational age at time of birth) of an infant who has a PDA with left-to-right shunting. Many physiologic functions that are present in older children reach full maturation at different rates and periods of gestation. For example, sympathetic nervous innervation of the left ventricular myocardium may be completed only at term, or even after term [29]. So that in an infant born prematurely, sympathetic stimulation of the left ventricular myocardium likely would be incomplete.

The structure of the immature myocardium, too, is quite different from that at term in that there are far fewer contractile elements. Premature infants often have lower than normal serum Ca2+ concentrations, and this too may affect myocardial performance. Probably for one or all of these reasons, premature infants with left-to-right shunts through a PDA develop left ventricular failure earlier than their full-term counterparts and, in addition, with a smaller volume load. The altered myocardial structure also may be partly responsible for the poor response to digitalis of immature infants with left ventricular failure.

Of considerable importance as well is maintenance of myocardial perfusion. Because coronary arterial blood flow to the left ventricle occurs mainly during diastole and depends on the systemic arterial-intramyocardial diastolic pressure differences as well as the duration of diastole, alterations in either can affect coronary blood flow. A reduction in aortic diastolic pressure occurs in a large PDA, and with a significant shunt, left ventricular end-diastolic pressure may be increased and cause an increase in subendocardial intramyocardial pressure. The development of tachycardia will reduce the diastolic period. All three factors that affect adequate myocardial perfusion are therefore jeopardized in the presence of a large PDA [30].

Delivery of oxygen to the myocardium depends on not only the coronary blood flow, but also the oxygen content of arterial blood and the ability of arterial blood to deliver oxygen at the tissue sites. A low hemoglobin concentration caused by physiologic anemia in the newborn period, particularly in premature infants, or by repeated blood sampling as occurs with intensive neonatal care, jeopardizes oxygen delivery to the myocardium as well as to other organs. A further important factor, particularly in premature infants, is the amount of fetal hemoglobin present. Because fetal hemoglobin has a low affinity for the organic phosphates such as 2, 3-diphosphoglycerate, the facilitation of oxygen delivery to peripheral tissues is reduced. This effect is greater with higher amounts of fetal haemoglobin [31].

Diagnosis of PDA

Clinical Picture

The clinical features depend on the magnitude of left-to-right shunt through the PDA and the ability of the infant to initiate compensatory mechanisms to handle the extra volume load. Because many premature infants have respiratory distress syndrome, the stage of development of this disease and the use of surfactant replacement therapy will determine the pulmonary vascular resistance and therefore the shunt. The maturity of the infant and the stage of myocardial development determine the ability to handle the shunt. Three fairly distinct patterns of clinical presentation are recognized in these infants.

Patent Ductus Arteriosus with Little or No Lung Disease

In the first group, there is little or no underlying pulmonary disease (usually infants whose birth weight exceeds 1,500 g). However, smaller infants are encountered, and in many instances their mothers have received steroid or other therapy prior to delivery, or the infants have received surfactant replacement therapy. A systolic murmur is first heard 24 to 72 hours after birth, and as the left-to-right shunt increases, this murmur becomes louder and more prolonged, extending to and often beyond the second heart sound into early diastole. The murmur commonly is heard best at the left sternal border in the second and third intercostal spaces. The classic continuous machinery murmur, described for older children with PDA, is not usual in premature infants, in whom the murmur generally has a high-frequency quality. The pulmonic component of the second sound may become moderately accentuated.

In the most mature infants in this group, a middiastolic flow rumble owing to increased diastolic flow across the normal mitral valve may be heard at the apex. If the shunt becomes large enough, a third heart sound due to rapid ventricular filling during diastole may be heard at the apex. The pericordium becomes increasingly more hyperactive, the pulse pressure widens, and the peripheral pulses become more prominent and bounding as the left-to-right shunt increases. Increased peripheral pulses are best appreciated by the presence of palmar or forearm pulses. If the shunt is allowed to become sufficiently large, clinical evidence of left ventricular failure may appear. This includes tachycardia, tachypnea, and rales on auscultation of the lung fields. Associated with the development of pulmonary edema, there may be a decrease in arterial blood pO2. If left ventricular failure were allowed to progress, a significant number of these infants might develop episodes of apnea, often associated with severe bradycardia. Enlargement of the liver will occur, but usually quite late [32].

Patent Ductus Arteriosus in Infants Recovering from Lung Disease

The second and most common group of infants develops left-to-right shunting while recovering from severe or moderately severe respiratory distress syndrome. These infants usually weigh 1,000 to 1,500 g at birth. The idiopathic respiratory distress syndrome usually is evident within a few hours after birth, and if it follows the usual course, starts to improve after 3 to 4 days. As this improvement continues, early clinical evidence of a left-to-right shunt through a PDA appears. In addition, at about this age, fluid administration generally is increased to deliver adequate calories; this often aggravates the volume-loading effects of the left-to-right shunt on left ventricular function. Probably the ductus arteriosus has been patent since birth and the pulmonary disease with a resultant increase in pulmonary vascular resistance has prevented a detectable left-to-right shunt. As the pulmonary disease improves, oxygenation increases and the ductus arteriosus should constrict. However, most of these infants are quite immature, so a good constrictor response may not occur. Many of these infants are still maintained on mechanical ventilators or continuous positive airway pressure (CPAP), so that careful clinical assessment is required to establish the presence of a shunt through the ductus arteriosus [33].

In many instances the murmurs are not audible until the infant is briefly detached from the ventilator or CPAP system. Because recovery from the respiratory distress syndrome often is not continuously progressive but is interspersed with periods of deteriorating lung function, left-to-right shunting (and therefore the murmur) may be intermittent for several days. The murmur commonly disappears and reappears several times within short periods of time. Initially a systolic murmur alone is heard; however, as the shunt increases, the murmur extends into diastole. The murmur is similar in distribution and quality to that in the first group of premature infants with PDA. Because infants in the second group are usually more immature than those in the first, left ventricular failure may occur in them when clinically there seems to be less left-to-right shunting. A third sound often is heard, but a middiastolic flow rumble is uncommon. The pulmonic component of the second sound ordinarily is already accentuated because of the pulmonary disease but may become louder as the shunt increases. Increasing pericordial activity is a good clinical indication of the magnitude of shunting in these infants, and increased heart rate, pulse pressure, and bounding pulses with a rapid upstroke are often detectable early. Palmar or forearm pulses are often palpable. Because most of these infants have indwelling umbilical arterial catheters, careful monitoring of the umbilical arterial blood pressure often shows a widening pulse pressure and a decrease in diastolic pressure as left-to-right shunting develops [34,35].

Rales are unreliable as an index of pulmonary edema and left ventricular failure because they may be suppressed by positive pressure ventilation used in these infants. However, in those extubated who have recovered sufficiently from their respiratory distress syndrome, rales may be heard. Apneic episodes are also common in this group and may be associated with short periods of bradycardia.

Deterioration in the ventilatory status of an infant recovering from respiratory distress syndrome is often a strong indication of a significant left-to-right shunt through a PDA. However, other causes, such as recurring lung disease and pneumothorax or sepsis, should be actively excluded. Deterioration of the ventilatory status is manifested by the requirement for an increasing concentration of inspired oxygen, alterations in ventilator rate or pressure settings, increased requirements of CPAP, and assisted ventilation and increasing arterial blood pCO2.

Patent Ductus Arteriosus Associated with Lung Disease

The third group consists of infants who have severe respiratory distress syndrome from birth. Because many of these are extremely low birth weight infants (<1,000 g), the likelihood of a PDA being present is very high (>80%). A few show no clinical signs even when carefully evaluated for PDA. Many do show clinical evidence of a left-to-right shunt through the PDA, or fail to show improved respiratory status at an age when they should start to recover from the primary pulmonary disease. They too are extremely sensitive to small increases in Na+ and fluid administration. They require ventilatory assistance by mechanical respirators or CPAP. Deterioration commonly is manifested by the need for increasing ventilator pressure, rate, or oxygen, or CPAP support. Failure to improve is manifested by the inability to wean the infant from ventilatory support. An increase in arterial blood pCO2 is common. Murmurs may be difficult to hear, and in some of these infants the ductus arteriosus may be so widely patent that a murmur is not produced [36].

Changes in the ventilatory status may be due to progression of the primary pulmonary disease, and it is often even more difficult to separate left ventricular failure from increasing pulmonary problems than in the previous group. Increasing pericordial activity, bounding pulses, and a widening arterial pulse pressure suggest the development of left-to-right shunting. When present, the murmur is usually only systolic, the pulmonic component of the second sound is accentuated, and a gallop rhythm is often heard [37].

Premature infants with clinically significant PDA are at increased risk of adverse outcomes. Left to right shunting through a PDA is associated with greater severity of respiratory distress syndrome and requires more ventilatory treatment, which increases the risk of chronic lung disease [38,39]. Pulmonary haemorrhage [40] intraventricular hemorrhage, necrotizing enterocolitis [41] and retinopathy of prematurity [42].

PDA also adversely affects blood pressure, [43] the systemic perfusion patterns to many organ systems, [44] and is associated with an increased risk of intraventricular hemorrhage or ischemic cerebral damage [45,46] and necrotizing enterocolitis. The effects of surfactant replacement on pulmonary vascular resistance lead to the clinical emergence of PDA earlier and more frequently in preterm infants [47].

Investigations

Chest X rays

Chest X rays may reveal cardiomegaly, pulmonary plethora, both left atrial and left ventricular enlargement and perihilar edema. Also an enlarged aortic knob is very specific radiological finding of PDA. However chest radiography plays minimal role in the diagnosis of patent ductus arteriosus in premature infants with hyaline membrane disease. Reported radiographic criteria are difficult to apply in these patients. Cardiac size varies with mechanical ventilation and the degree of hypoxia and acidosis. Hyaline membrane disease and associated lung diseases mask the appearance of pulmonary edema [48].

Echocardiography

Echocardiography is a unique noninvasive method for imaging the living heart. It is based on detection of echoes produced by a beam of ultrasound (very high frequency sound) pulses transmitted into the heart.

Accurate diagnosis of a PDA requires echocardiography. Echocardiography together with Doppler and color Doppler allows assessment of patency, diameter of the DA (using color Doppler), and direction of the shunt (using color and pulsed Doppler). Pulsed Doppler technology allows accurate assessment of the velocity and direction of the shunt through the cardiac cycle. The direction of flow varies from blood shunting predominantly left to right, to bidirectional and predominantly right to left. Pulsed Doppler also allows assessment of disturbances to blood flow on either side of the DA. Specifically, it reveals increased diastolic forward flow in the left pulmonary artery or retrograde diastolic flow in the post ductal descending aorta. Both of these phenomena are useful markers of hemodynamic DA significance [49].

Historically, a variety of indirect echocardiographic measures, such as the left atrial to aortic root ratio, have been used to diagnose and quantify the size of a PDA. With modern ultrasound technology, these markers have become less useful, except where direct imaging is not possible. Direct imaging is now the method of choice both to diagnose patency and determine the significance of the DA.

Clinically significant PDA is difficult to diagnose accurately in early postnatal life [50]. Therefore, echocardiography has become essential in the evaluation of clinically significant ductal shunting [51].

Patency can be confirmed by diastolic turbulence on Doppler in the pulmonary artery. (Figure 1) below contrast the normal Doppler pattern in the pulmonary artery (A) with the turbulent pattern seen with a patent duct (B). This is a highly accurate method for diagnosing ductal patency but tells you little about the haemodynamic significance [52].

Figure 1: Doppler Ultrasound Patterns in the Pulmonary Artery for Assessing Ductal Patency.

Shunt direction is demonstrated with pulsed wave and colour Doppler. There are broadly three direction patterns which are shown below in (Figure 2). Pure left to right (A), bidirectional (B) and right to left (C). Most babies even in the early hours after birth have left to right or bidirectional with a dominant left to right component. Predominantly right to left shunting is unusual.

Figure 2: Shunt Direction Patterns in the Pulmonary Artery Demonstrated by Pulsed Wave and Color Doppler.

Haemodynamic significance is confirmed by diameter (>1.5mm) and absent or retrograde diastolic flow in the postductal aorta. (Figure 3) below contrast two preterm ducts in the first hours after birth. (A) is well constricted at less than 1.0mm diameter, much as you would see in a term baby. Constriction has failed in (B) which is 2.0mm in diameter and a large left to right shunt draining blood from the systemic circulation is already present.

Figure 3: Hemodynamic Significance of Ductal Patency Assessed by Ductal Diameter and Diastolic Flow in the Postductal Aorta.

Echocardiography has shown that four patterns of PDA shunt flow can be identified using pulsed Doppler echocardiography, and the longitudinal observation of the change in Doppler pattern can provide an understanding of the haemodynamics of ductal shunting and is useful for the prediction of risk of clinically significant PDA [53,54].

Pulmonary hypertension pattern

A bi-directional shunt is noted in the profile; a right to left shunt (downward away from the baseline) in early systole was followed by a small left to right shunt (upward away from the baseline) throughout the diastole. This pattern was seen in early postnatal life in the presence of high pulmonary vascular resistance (Figure 4a).

Figure 4a: Characterization of Early Postnatal Bi-Directional Shunt Patterns Due to Elevated Pulmonary Vascular Resistance.

Growing pattern

A bi-directional shunt still could be noted, but the right to left shunt decreased and a growing left to right shunt was seen in the profile. This pattern represents a growing left to right shunt through a large ductus accompanying a fall in pulmonary vascular resistance (Figure 4b).

Figure 4b: Progressive Left-to-Right Shunt Development with Decreasing Pulmonary Vascular Resistance in Neonatal Circulation.

Pulsatile pattern

No right to left shunt was noted in the profile, and a much greater left to right shunt was shown by a pulsatile flow of peak velocity of about 1.5 meters/seconds (Figure 4c).

Figure 4c: Absence of Right-to-Left Shunt and Increased Left-to-Right Shunt with Pulsatile Flow in Neonatal Circulation.

Closing pattern

The prominent difference between this and the pulsatile pattern is that the closing pattern did not show the rhythmically pulsatile change, but rather a continuous left to right shunt with a peak flow velocity of about 2 milliseconds covering the whole cardiac cycle in the profile. According to the Bernoulli equation, this pattern implies that a shunt flows through a constrictive ductus to produce a high flow velocity (Figure 4d).

Figure 4d: Continuous Left-to-Right Shunt through Constrictive Ductus: A Non-Pulsatile High-Velocity Flow Pattern in Neonatal Circulation.

Closed pattern

This pattern had to be sampled in the pulmonary artery, because the Doppler gate was placed in the pulmonary end of the ductus while it was closed, so true ductal sampling would have produced no Doppler signal at all. Thus the closed pattern is similar to the pulmonary artery flow pattern, and was taken to show the contrast with the PDA patterns (Figure 5).

Figure 5: Pulmonary Artery Flow Pattern in Closed Ductus Arteriosus: Doppler Sampling to Differentiate from Patent Ductus Arteriosus (PDA) Profiles.

Plasma b-type natriuretic peptide

Recently measurement of plasma B-type natriuretic peptide (BNP) as early as the third day of life predicts those preterm infants who will have a haemodynamically significant PDA at the end of the first week. This suggests that the test may complement echocardiography as an early indicator of the need to treat the PDA [55].

Treatment of PDA

When to treat a PDA remains controversial. There are 3 broad approaches to the timing of PDA treatment that include the following:

1. Prophylactic treatment.

2. Presymptomatic treatment.

3. Treatment when clinically symptomatic.

None of these approaches has shown clear benefits in short- and long-range outcomes.

Prophylactic treatment

This involves the administration of indomethacin or ibuprofen to all high-risk infants on the first day usually within the first 6 hours. There have been several randomized trials addressing this approach. Indeed, prophylactic administration of indomethacin in preterm infants prior to 28 weeks decreases the incidence of serious pulmonary hypertension, grade III/IV intraventricular hemorrhage, and need for surgical closure, but has not been shown to alter mortality [56,57].

Prophylactic treatment with indomethacin has a number of immediate benefits, in particular a reduction in symptomatic patent ductus arteriosus, the need for duct ligation and severe intraventricular hemorrhage. There is no evidence to suggest either benefit or harm in longer term outcomes including neurodevelopment. Depending on clinical circumstances and personal preferences, there may be a role for prophylactic indomethacin in some infants on some neonatal units [58,59].

Prophylactic ibuprofen also decreases the need for symptomatic treatment but has not yet been shown to alter the incidence of intraventricular haemorrhage [60]. In addition, one trial reported an incidence of significant pulmonary hypertension after prophylactic ibuprofen administration [61].

Pre-symptomatic Treatment

This approach involves using a variety of diagnostic methods, clinical and echocardiographic, to detect ducts in the pre-symptomatic period and then closing at this time. The timing of the interventions in these trials was usually between 24 hours and day 5 of life. There is a significant decrease in the incidence of symptomatic PDA following treatment of an asymptomatic PDA with indomethacin. There is also a small but statistically significant decrease in the duration of requirement for supplemental oxygen. There are no reported long term outcomes in the included trials, and so it is not possible to comment on possible long term effects. Further studies are required to determine the long term benefits or harms of closing a PDA prior to the onset of symptoms [62].

Treating Clinically Apparent Patent Duct

Using this approach, about a third of babies born before 30 weeks will need treatment. Although widely used, there is no evidence that this approach improves outcomes. In all the randomized trials the control groups had backup treatment options which meant in babies randomized to placebo, the ducts were closed only shortly after the treatment groups. The national collaborative trial was the largest of these and this study did show there was no benefit in treating the duct as soon as it becomes clinically apparent as opposed to waiting a day or two [63].

The lines of treatment of PDA include both medical, surgical and non-surgical approach for closure of the PDA [64].

The medical lines involved in closure of the PDA are fluid restriction, the use of diuretics, inotropic agents in case of occurrence of heart failure and the administration of prostaglandins synthase inhibitors (indomethacin, or ibuprofen). Also of vast importance is correction of anemia, general supportive measures to vital systems [65].

The first step to be considered in management of PDA is restricting 10-20% of the total volume administered to the newborn. Where excessive fluid administration has been associated with increase incidence of PDA, also this restriction will act to cause decrease in pulmonary venous pressure, which increase lung compliance and promote weaning from ventilator [66]. Such restriction is monitored through the body weight, serum electrolytes, urine output and specific gravity.

Furosemide, a loop diuretic, is the main diuretic used in cases of PDA. It acts to decrease the volume imposed on the cardiac chambers, given in a dose of 1-2 mg/kg/dose, every 12 hrs, or according to clinical situation. Dehydration state, serum electrolytes should be closely monitored with the use of furosemide. There is not enough evidence to support the administration of furosemide to premature infants treated with indomethacin for symptomatic patent ductus arteriosus. Furosemide appears to be contraindicated in the presence of dehydration in those infants [67].

Digoxin is the main inotropic agent used in case of heart failure caused by haemodynamically significant PDA, it has a mechanical function on cardiac muscle, where it increases the cardiac contractility by increasing interaction between actin and myosin filament in cardiac sarcomere [68]. When using digoxin electrolytes should be monitored closely, in addition observing for the occurrence of digoxin induced arrhythmias.

Indomethacin

Indomethacin is the most widely used prostaglandin synthetase inhibitor for the pharmacological closure of PDA. The response to oral or rectal indomethacin therapy is highly variable, with an overall response rate of about 60 % [69]. Intravenous indomethacin therapy has a higher and more consistent success rate of about 90% (range 75-96%). Absorption of orally administered indomethacin is relatively poor, and the variability in serum levels is greater with oral compared with intravenous therapy. The rate of PDA closure with indomethacin therapy improved following the change to the intravenous route [70]. Treatment failure was confined to therapy after one week of age. It has been shown the poorer response in older infants is the result of pharmacokinetic differences at a greater postnatal age, and a larger dose or an increased number of doses may be required to achieve the same closure rate as in younger infants [71].

Indomethacin traditionally was given at 0.2 mg/kg 12 hourly for 3 doses. Two randomized trials suggested that 0.1 mg/kg daily for 6 days achieved similar closure rates with fewer side effects [72,73]. More recently, some studies showed that 0.2 mg/kg followed by 2 doses of 0.1 mg/kg at 12 hourly intervals was as effective as the 6 daily doses of 0.1 mg/kg, with no difference in side effects [74]. Giving each dose as an infusion over 20 to 60 minutes appears to limit some of the negative effects on organ blood flow [75]. The immediate constrictive effect of indomethacin varies, but there is a measurable and significant response by 2 hours after the first dose [76]. Indomethacin therapy was found to be successful in 90% of infants <1500 g birthweight after the first course with a recurrence rate of 3% [77].

Adverse Effects of Treatment

The renal blood flow velocity decreases for about two hours [78] and dilutional hyponatraemia can result from a transient reduction in glomerular filtration rate and free water clearance [79]. Frusemide given with indomethacin can prevent the reduction in urine output without affecting its therapeutic effectiveness [80], but this is contraindicated in the presence of dehydration [81]. Low-dose dopamine has not been shown to reduce the magnitude of oliguria [82]. Indomethacin is not contraindicated in infants with high serum creatinine and blood urea nitrogen levels, because they are often secondary to poor renal perfusion in infants with PDA and would improve following closure of the PDA with indomethacin therapy. Coagulation defects should be corrected before giving indomethacin, as it impairs synthesis of thromboxane A2, a potent inducer of platelet aggregation, and causes prolongation of the bleeding time.

Indomethacin, though protein bound, does not affect the binding of bilirubin to protein and is safe to use in jaundiced infants [83]. Although one study suggested that indomethacin predisposes the preterm infant to the development of sepsis, this association has not been observed in other studies [84].

Gastrointestinal complications are associated with serious morbidity and mortality. The disturbance in mid-gut perfusion in PDA is known to be exacerbated by indomethacin [85], although this can be minimized with a slow infusion over 30 minutes [86]. A study in infants <1000g birthweight has shown that when indomethacin was given as a slow infusion, the incidence of bowel perforation and NEC in infants treated for a PDA was not significantly different from infants without a PDA and not given indomethacin. NEC following indomethacin therapy is seen only in the early treatment. To avoid NEC with early indomethacin therapy, it has been suggested that the 0.1 mg/kg doses be discontinued as soon as the PDA has closed (mean cumulative dose at ductal closure was 0.35 mg/kg in that study), or that a continuous but slow infusion of indomethacin (0.004 mg/kg/h) be given until ductal closure [87]. Indomethacin increases systemic blood pressure [88] but causes a significant reduction in flow velocity in the anterior cerebral artery [89], which can be minimized with a slow infusion [90,91]. Indomethacin has been shown to improve cerebral auto regulation so that cerebral oxygen metabolism is not compromised even at low cerebral perfusion pressures [92]. A large RCT of early prophylactic indomethacin has reported a reduction in the incidence of PDA and severe periventricular haemorrhage [93]. The latter finding could be explained by the fact that early ductal closure with indomethacin results in improved stability of arterial blood gases and systemic blood pressure, which predispose to periventricular hemorrhage in preterm infants [94].

Ibuprofen

This is a non-steroidal anti-inflammatory agent which has been shown to be effective in closing the PDA but without affecting intestinal haemodynamics [95,96]. It does not have a direct effect on cerebral and renal blood flow velocities, and haemodynamic changes are related to closure of the ductus induced by the drug [97]. Ibuprofen is given intravenously at a dose of 10 mg/kg followed by 5 mg/kg 24 and 48 hours later. A RCT has shown that it is as efficacious as indomethacin and is significantly less likely to induce oliguria [98]. However, this comparison was made with an indomethacin regime of 0.2 mg/kg at 12-hour intervals for three doses, and it is known from another RCT that an indomethacin regime of 0.1 mg/kg at 24-hour intervals for six doses results in a higher ductal closure rate with less renal side effects. Comparison of ibuprofen with this prolonged low-dose indomethacin regime has not been done. Day one prophylactic ibuprofen has been compared in a RCT with later expectant treatment for PDA diagnosed by echocardiography [99]. Unlike when indomethacin was given prophylactically, early ibuprofen did not result in significant adverse effects.

Sulindac

This is a relatively renal-sparing cyclo-oxygenase prostaglandin inhibitor that has comparable anti-inflammatory property and potency to indomethacin. The limited clinical experience with sulindac, given orally at a dose of 3 mg/kg every 12 hours for four doses, suggested that it is as effective as indomethacin in closing PDA but without compromise of the renal function [100]. However, its spectrum of gastrointestinal complications is similar to those described for indomethacin, and one infant was reported to have died from hemorrhagic gastritis following sulindac therapy [101]. Until the question of safety could be adequately addressed, the use of sulindac in the treatment of PDA should remain experimental.

Use of Indomethacin versus Ibuprofen

Both work by a general inhibition of prostaglandin synthesis. Indomethacin has been used for many years and will close the duct in most cases but at the expense of some worrying side effects including reduced cerebral blood flow [102], oliguria, hyponatraemia and gastro-intestinal complications. Infusing the dose over 20 to 30 minutes may reduce but does not eliminate the effect on cerebral blood flow [103]. Two randomized trials have shown that a dose of 0.1mg/kg daily for 6 days is as effective as the traditional 0.2mg/kg 12hrly for three doses but causes less side effects [104]. However, a more recent trial using 0.2mg/kg followed by two lower doses at 0.1mg.kg showed no advantage to a longer course [105]. Because of side effects, Ibuprofen has been suggested as an alternative to indomethacin. Randomized trials have shown it to have similar efficacy in closing the duct with a lower rate of side effects [106,107]. Furthermore, blood flow studies have shown that ibuprofen does not have the negative effects on cerebral blood flow [108]. In Egypt the lack of a commercially available parenteral preparation is one of the major obstacles to its wider use and because of this we continue to use indomethacin. Should a parenteral preparation become available, the recent evidence would support the use of ibuprofen in preference to indomethacin.

Surgical Treatment

The use of surgical ligation as a first line of treatment for PDA is influenced mainly by surgical availability. There is no evidence to support surgery as the preferable treatment approach. A single randomized controlled trial, known as the Collaborative trial, evaluated 405 infants of <1,750 g birth weight. Infants randomized to surgery had higher rates of pneumothorax and retinopathy of prematurity but no difference in other outcomes, including mortality. Cassady et al randomized infants to early prophylactic ligation, and the group with early DA ligation had a lower rate of necrotizing enterocolitis but no differences in other outcomes, including chronic lung disease and mortality [109]. In many neonatal intensive care units (NICUs), surgical ligation is reserved for infants with a symptomatic PDA that has failed to close with medical treatment.

Surgical ligation of PDA is usually seen as the option when medical management has failed or is contra-indicated.. Complications of standard surgical PDA ligation are almost always related to the left lateral thoracotomy. Recanalization of the duct has been reported but rarely following ligation. Inadvertent ligation of the left pulmonary artery and the descending aorta has both been reported, as has the unmasking of a coarctation following ligation of a large PDA. However, complications are rare and any early operative mortality is usually associated with other complications of prematurity [110]. It is important to realize that thoracotomy and lung retraction may have short-term adverse effects upon ventilation. Video-assisted thoracoscopic PDA clipping [111] and catheter PDA occlusion are newer techniques used successfully in older, larger children. Whilst some premature infants have also been treated thoracoscopically, this is not yet widely available or practiced. Catheter PDA ‘coil’ occlusion is usually only practiced upon larger infants, but is an option for those ducts that remain patent throughout infancy but which have not required surgical intervention.

All of these factors lead us to postulate that the presence of PDA may cause echocardiographic alterations that would precede the clinical manifestations. The present study was therefore designed with the objective of analyzing the relationship between the echocardiographic findings in patent ductus arteriosus and the presence of clinical signs in preterm newborns.

Aim of the work

This work had the following objectives

1. To study the correlation between clinical and echocardiographic findings in cases of PDA in preterm newborns.

2. To assess the reliability of clinical examination in detecting significant PDA in preterm newborns.

Patients and methods

The study included 61 preterm newborns admitted to NICU at Alexandria University Children's Hospital.

The babies were divided into three groups according to birth weight

1. Group A: those with birth weight more than 2000 gm.

2. Group B: those with birth weight from 1000 ≤ 2000 gm.

3. Group C: those with birth weight less than 1000 gm.

Newborns with major congenital anomalies, complex congenital heart diseases and those who died before initial or follow up echocardiography were excluded.

Every case in the study was subjected to the following

1. Full history taking including antenatal and perinatal history.

2. Thorough clinical examination stressing on the cardiovascular system, especially presence of

a. Tachycardia (> 170 beats/minute)

b. Visible pericordial activity.

c. Heart murmur.

d. Bounding pulsations (radial, femoral, posterior tibial and dorsalis pedis).

e. Wide pulse pressure (systemic arterial pressure in mmHg, measured with an oscillometric, noninvasive method in the four limbs). Pulse pressure Considered wide if more than 30 mmHg.

The physical examination of the PT-NB was performed by a neonatologist, a member of the nursery's own treatment team, who was unaware of the echocardiogram results.

It was done initially in the first three days of life and repeated daily in the first week.

1. Chest x ray.

2. Monitoring oxygen saturation by pulse oximetry.

3. Echocardiographic evaluation using Sonoace 8000 Ex-prime manufactured by Medison.Probe P3-7AC was the probe used (multiple frequencies 5.5- 7.5 MHz). Echo done on the third day of life (Echo 1) repeated in cases with PDA early on the second week (Echo2) and on the third week (Echo 3).

Such evaluation aimed to detect the following data

a. Patency of the duct.

b. Internal ductal diameter.

c. Maximal shunt velocity.

d. Ratio of the diameter of left atrium to aortic root.

Results

This study included 61 preterm newborns admitted at NICU, Alexandria University Children's Hospital. All had respiratory distress of variable etiology (TTN, RDS and neonatal pneumonia). The characteristics of the newborns evaluated in this study are described in (Table 2). Seventeen NB were more than 2 kg (group A), 26 were 1-2 kg (group B), and 18 were less than 1 kg (group C). The studied groups included 28 males (45.9%) and 33 females (54.1%).The mode of delivery was NVD in 30 cases (49.2%), and C.S in 31 (50.8%). The mean gestational age in group A was 34.94 wks ranged from 34 to 36, that of group B was 32.88 wks ranged from 30 to 36 , and in group C it was 29.2 wks ranged from 27 to 33 wks. (Table 3) & (Figure 6) show the incidence of PDA in Echo 1, Echo 2 and Echo 3. Forty cases had pPDA in Echo 1 (65%), with the highest incidence in group C (77.8%), less in group B (65.4%), and the least incidence in group a (53%). Twelve cases had pPDA in Echo 2 (19.6%) and only 5 cases had pPDA in Echo 3 (8.1%). (Table 4) shows the use of prostaglandin inhibitors in the different groups, 7 cases (all in group C) received prophylactic indomethacin (11.5%). Seventeen cases in all groups received therapeutic indomethacin (27.9%) and 2 cases received therapeutic oral ibuprofen (3.3%).