Diagnosis, evaluation, and monitoring of patent ductus arteriosus in the very preterm infant

Introduction

The diagnosis and management of a patent ductus arteriosus (PDA) with cardiorespiratory, and thus clinical, relevance in preterm neonates poses a major challenge in neonatal medicine. It is the most common cardiovascular abnormality in premature infants. Most (∼70%) infants born at a gestational age (GA) of less than 29 weeks will have a persistent PDA by the end of the first postnatal week. PDA is associated with several morbidities and mortality; however, a cause-and-effect relationship between the presence of a PDA and important short- and long-term clinical outcomes has not been definitively established. In addition, there are limitations due to study design of randomized control trials and the retrospective nature of cohort studies reporting clinical outcomes and the impact of various approaches to treatment (conservative, medical, device and surgical). More than 50% have a high rate of open-label treatment in the control arm and high treatment failure rate in the intervention arm. There is considerable heterogeneity in infants included in PDA trials due to lack of a standardized definition of hemodynamic significance, resulting in inclusion of patients who may not benefit from PDA treatment. As a result, the impact of PDA treatment on outcomes and treatment strategies (particularly modality and timing) varies between centers. Finally, there continues to be a lack of physician equipoise such that the most vulnerable infants, potentially at greatest risk of PDA-attributable morbidity, are not always enrolled in clinical trials.

Developmental role of the ductus arteriosus

The ductus arteriosus (DA) connects the main pulmonary artery to the descending aorta and is necessary for fetal survival. In the fetus the left ventricle (LV) receives oxygenated blood, returning from the placenta via the inferior vena cava and through the foramen ovale, and delivers it mainly to the upper part of the body. The right ventricle (RV) receives most blood draining from the superior vena cava (SVC) and a proportionately lower amount of oxygenated blood from the umbilical venous system. Due to high pulmonary vascular resistance (PVR), most (80% to 90% depending on the gestational age of the fetus) of right ventricular output flows from the pulmonary artery to the descending aorta across the DA; hence the DA modulates flow to the lower part of the body. Similarly, the patent foramen ovale (PFO) is the route that modulates the delivery of oxygenated blood to the head and neck. After birth, LV afterload rises suddenly due to loss of the low resistance placental circulation. This is accompanied by lung aeration, which promotes a fall in PVR and an increase in pulmonary blood flow. This results in a change in the organ of gas exchange from the placenta to the lungs. The DA eventually closes (first functionally and then anatomically) over the subsequent days in term infants. However, in preterm infants the DA can remain patent for a prolonged period of time for a variety of reasons.

Regulation of ductal tone and constriction

In term infants closure of the PDA occurs within the first 48 hours after birth. Closure of the DA occurs in two phases. The first phase (within the first hours after birth), termed “functional closure,” involves narrowing of the lumen by smooth muscle constriction. The second phase , termed “anatomic remodeling”, consists of occlusion of the residual lumen by extensive neointimal thickening and loss of muscle media smooth muscle over the next few days.

The rate and degree of initial “functional” closure are determined by the balance between factors (mediators, second messengers and channels, among others) that favor constriction (oxygen, endothelin, calcium channels, catecholamines, and Rho kinase) and those that oppose it (intraluminal pressure, prostaglandins [PGs], nitric oxide [NO], carbon monoxide, potassium channels, cyclic adenosine monophosphate [AMP], and cyclic guanosine monophosphate). PGs play a key role in the regulation of ductal tone, especially during the first few postnatal weeks. Of these, PGE ₂ is the most important factor in the regulation of DA tone during fetal development and acts on G protein–coupled E-prostanoid receptors to maintain ductal patency. It is generated from arachidonic acid by cyclooxygenase-1 (COX-1) and COX-2, the COX component of PG-H ₂ synthase, followed by peroxidation by the same enzyme complex and, finally, by the action of PGE synthase (see Chapter 5 ). COX-2 plays a major role in maintaining ductal patency during fetal life. The current approach to medical therapy exploits this mechanism by the use of nonselective COX inhibitors (such as indomethacin and ibuprofen) and also by the use of acetaminophen, a peroxidase inhibitor, to close the DA postnatally.

Low oxygen tension in the fetus is another important factor for maintaining ductal patency. Following birth, the rise in oxygen tension promotes an oxygen-mediated constriction that is facilitated by the inhibition of the potassium voltage channels (K _V channels) present on the ductal smooth muscle cells and function to keep the cells in a hyperpolarized state. The presence of oxygen leads to depolarization, which in turn activates L-type calcium channels, allowing an influx of calcium into the smooth muscle cells causing constriction. A counter-mechanism via the mitochondrial electron transport chain serves as the intrinsic oxygen-sensing mechanism that regulates this constrictive effect via formation of reactive oxygen radicals, which inhibit K _V channels. Interestingly, in vitro studies using rings of human DA tissue incubated in relatively low oxygen tension conditions (to mimic conditions of prematurity) for several days selectively fail to constrict in response to oxygen. This may explain, at least in part, failure of the DA to close in preterm infants.

The fall in PG levels following birth (due to the loss of placental PG production and increase in its removal by the lungs), accompanied by the rise in oxygen tension, promotes functional closure of the DA over the first 24–48 postnatal hours. After functional DA closure is achieved, the smooth muscle cells migrate from the media to the subendothelial layer, leading to neointimal formation. Expansion of the neointima forms protrusions, or mounds, that permanently occlude the already constricted lumen. ^, This process results in an interruption of the blood supply to the innermost cellular layer, resulting in hypoxia and cell death. The presence of intramural vasa vasorum is essential to ensure adequate provision of oxygen and nutrition to the thicker wall of the DA at term. During postnatal constriction, the intramural tissue pressure obliterates vasa vasorum flow in the muscle media. The ensuing ischemic and hypoxic insult inhibits local PGE ₂ and NO production, induces local production of hypoxia-inducible factors (HIF) like HIF-1α and vascular endothelial growth factor (VEGF), and produces smooth muscle apoptosis in the muscle media. In addition, monocytes/macrophages adhere to the ductus wall and appear to be necessary for ductus remodeling.

Myocardial adaptation in preterm infants to patent ductus arteriosus

Cardiac output is the result of the interactions between preload, afterload, intrinsic myocardial contractility, and heart rate. Under normal conditions, and in the absence of a PDA, LV output (LVO) in a neonate is in the range of 150–300 mL/min/kg. The presence of a PDA results in increased pulmonary blood flow and both left atrial (LA) and LV volume loading. In a prospective observational study, using two-dimensional speckle tracking echocardiography, most infants with a PDA displayed signs of LA dysfunction due to increased volume load. PDA diameter was found to be an independent contributor to poor LA contraction. Studies have consistently shown a higher LV end-diastolic volume (preload) when the DA is open with a predominantly left-to-right shunting pattern. According to the Starling curve, the increase in myocardial muscle fiber stretch from higher preload augments stroke volume. Indeed, most studies have demonstrated increased LVO in the presence of a PDA with a predominant left-to-right shunt. In the presence of a PDA the low-resistance pulmonary vascular bed is in parallel with the systemic vascular bed. This results in a reduction of LV afterload, which, in combination with the increased preload, enhances the myocardium’s ability to increase its stroke volume. Traditionally, the presence of a PFO was thought to alter the effects of a PDA on LV stroke volume by exclusively decompressing the left atrium. Interestingly, a recent study has shown that larger atrial communication in the first week of life may be a surrogate marker of hemodynamically significant PDA rather than shunt volume modulator. The presence of a large atrial communication may in fact increase the risk of ventilator requirement and composite outcome of death or CLD.

There are important differences in both the structure and function of the myocardium between preterm and term neonates, and older children and adults. These differences place the immature myocardium at a disadvantage as far as contractility is concerned. Furthermore, because coronary blood flow takes place primarily during diastole, myocardial performance might be adversely affected if diastolic blood pressure is low in the presence of a high-volume PDA shunt. Previous studies have suggested that myocardial ischemia may occur in the presence of a hemodynamically significant PDA (hsPDA). More recently, studies have demonstrated compromised coronary artery perfusion and the presence of high cardiac-specific troponin levels (indicative of myocardial damage) in the presence of a PDA, suggesting a detrimental effect on myocardial perfusion and potential ischemia. ^, As premature infants have a less compliant myocardium than term infants, ventricular filling becomes dependent on the late diastolic phase of atrial contraction. In the setting of higher LV preload impaired diastolic function can lead to an increase in LA pressure and secondary pulmonary venous hypertension, potentially creating the biologic milieu that increases the risk of hemorrhagic pulmonary edema.

Some authors have suggested that because higher preload is associated with a greater stretch of myocardial fibers ; therefore myocardial contractility should increase in the presence of a PDA concurrent with the increased LVO. On the contrary, the lack of change in myocardial contractility, in the presence of a PDA, could also suggest a relative deterioration of myocardial function based on increased demands. However, using a relatively load-independent measure of myocardial contractility, Barlow et al. showed that hsPDA had no effect on contractility. More recent studies, using more advanced functional parameters such as strain analyses, have also failed to demonstrate worsening function in the presence of the PDA. Preservation of LV function occurs despite major changes in LV morphology over the first 4 postnatal weeks. This includes an increase in LA volume, LV end-diastolic volume, sphericity index (indicating a more globular heart), and filling pressure.

The potential impact of a PDA on RV function remains poorly understood. Changes seen in the LV are typically a consequence of pulmonary overcirculation, as described previously. Conversely, systemic hypoperfusion may result in a reduction in RV preload even in the presence of a left-to-right PFO shunt. In addition, prolonged exposure to increased pulmonary blood flow may promote an increase in PVR and a resultant increase in RV afterload. Recent studies have demonstrated reduced RV function as early as day 7 in infants with a large PDA. The clinical relevance of these changes to heart function and morphology and their potential impact on the evolution of PDA-associated morbidities is currently unknown.

Effects of patent ductus arteriosus on blood pressure

Blood pressure (BP) is the product of the interaction between cardiac output and peripheral vascular resistance (see Chapter 3 ). In general, systolic BP is primarily affected by changes in stroke volume, whereas diastolic BP is mainly reflective of changes in peripheral vascular resistance. Traditionally, low diastolic BP has been considered the hallmark of an hsPDA, and many studies have supported this notion. ^, Studies that specifically looked at the relationship between BP and PDA have shown similar decreases in both systolic and diastolic BP (and therefore no change in the pulse pressure), at least during the first postnatal week. ^, However, differences in BP and pulse pressure may be influenced by the location of BP measurements, pre- vs post-ductal. Typically, BP is measured from the umbilical arterial catheter (thus post-ductal) in the first postnatal week. Pre-ductal systolic BP is likely to be reflective of the increase in LV preload and higher than post-ductal values in patients with high-volume run-off through the PDA. This may generate discordance in systolic BP measurements, although this physiological hypothesis has yet to be confirmed in clinical trials. Older infants born at weights between 1000 and 1500 g with a PDA have slight, but clinically nonsignificant, decreases in systolic, diastolic, and mean BP. In contrast, infants born at less than 1000 g and with a PDA have both clinically and statistically lower systolic, diastolic, and mean BP but no change in pulse pressure. Because stroke volume increases and vascular resistance decreases in the presence of a PDA, one might expect that systolic BP would be maintained despite the decrease in diastolic pressure. As mentioned previously, the recorded systolic BP in most studies to date is post-ductal, which is not likely to reflect shunt-driven increases in LVO. In addition, cardiac output, ductal shunt volume, and peripheral resistance were not measured in any of these studies, making it difficult to accurately characterize the pulse pressure changes in the pre- vs post-ductal circulation. Therefore the lack of a discordance in pulse pressure from BP measured through an umbilical arterial line (post-ductal) could be used to exclude the presence of a high-volume PDA shunt. In immature animals a decrease in the diastolic and mean BP occurs even when the shunt is small, whereas a significant decrease in systolic BP occurs only when the PDA shunt is moderate or large. In a more recent cohort of 141 preterm infants, born less than 29 weeks’ gestation, systolic BP in infants with a PDA by the first postnatal week was only slightly lower than those without a PDA. It is not clear, however, if the location of BP measurement (pre- vs post-ductal) was consistent. On the contrary, diastolic and mean blood pressure was lower by the end of the first postnatal week, which translates into a higher pulse pressure ( Figure 16.1 ). In this group LVO was higher and diastolic flow in systemic vessels was lower, possibly explaining those findings ( Figure 16.2 ). PDA may also contribute to the development of hypotension, even during the transitional period, in patients with rapid drop in pulmonary vascular resistance. A study found evidence for a possible role of a moderate-large PDA in vasopressor-dependent hypotension. Similarly, PDA is reported to be an independent risk factor for refractory hypotension.