Two-dimensional Doppler echocardiographic assessment of closure of the ductus arteriosus in normal newborn infants

To elucidate the mechanism involved in closure of the ductus arteriosus (DA), 50 normal full-term infants were examined with two-dimensional and pulsed Doppler echocardiography. The examinations were performed initially within 1 hour after delivery and serially for 3 days. The two-dimensionally derived long-axis plane of the DA disclosed a characteristic localized protrusion into its lumen in 30% of the subjects within 1 hour, in 80% by 4 hours, in 96% by 8 hours, and in all by 24 hours after birth. In 10 infants in whom the intraluminal protrusion did not appear within 4 hours after birth, none had any recognizable changes in the inner diameter or length of the DA during this initial period. The development of the intraluminal protrusion resulted in localized narrowing of the ductal lumen. Doppler echocardiography revealed a high-velocity jet within and downstream from the narrowed portion of the DA. Thereafter, ductal narrowing progressed along the entire length. The intraluminal protrusion may be early evidence of ductal changes leading to eventual functional and anatomic closure.     

Gastric thumbprinting: diffuse gastric wall mucosal and submucosal thickening in infants with ductal-dependent cyanotic congenital heart disease maintained on long-term prostaglandin therapy

Seven infants with ductal dependent cyanotic congenital heart disease are reported. All were on prostaglandin E1 therapy to maintain ductus patency. All showed chest radiographic evidence of multiple masses indenting the stomach lumen (gastric thumbprinting). Other than feeding intolerance in two patients, the findings were incidental and disappeared with cessation of PGE1 therapy. "Gastric thumbprinting" appears to be a more common consequence of PGE1 therapy than actual obstructing antral masses (antral foveolar hyperplasia).     

Cross sectional echocardiography in determining persistent patency of the ductus arteriosus in preterm infants.

Thirty preterm infants (gestational age 26 to 30 weeks) were investigated by cross sectional echocardiography using a 5 or 7.5 MHz transducer positioned in the suprasternal notch or the left subclavicular position to enable visualisation of the aortic arch, main pulmonary artery, left pulmonary artery, and ductus arteriosus. Each infant was investigated on at least one occasion during both the first and second weeks of life and when possible between the ages of 26 and 31 days. There was prolonged patency of the ductus arteriosus during the first two weeks of life in all infants, and complete closure of the ductus arteriosus occurred only in four patients, all of whom had reached a postconceptional age of 32 to 34 weeks. Eighteen infants received intravenous indomethacin between the age of 5 and 10 days. In these patients ductal narrowing did not occur until a maximum postconceptional age of 29 weeks.     

Changes in left ventricular volume and systolic function before and after the closure of ductus arteriosus in full-term infants

Using echocardiographic techniques, the change in left ventricular (LV) volume and its effect on systolic function were studied before and after the closure of ductus arteriosus in 18 full-term infants. Examinations were performed twice in each infant, within 6 h after birth and on day 5, and the patency of the ductus with left-to-right shunt was confirmed at the first examination by Doppler echocardiography. A biplane Simpson's rule method was used for volume measurements. The LV end-diastolic volume, stroke volume, and cardiac output were more than 1.3-fold before the ductal closure, and the ejection fraction showed the similar change. However, the mean normalized systolic ejection rate, an index of contractility, and heart rate showed no significant difference. The Frank-Starling curve was obtained from the relationship between the LV end-diastolic and stroke volumes, and the LV performance was operated at a higher level on that curve when the ductus was open. Our data indicated that LV cardiac output was significantly higher during the patency of the ductus arteriosus and that this high cardiac performance might depend more on the Frank-Starling response to the volume load through the ductus arteriosus than on the increase of LV contractility and heart rate.     

Bidirectional flow through the ductus arteriosus in normal newborns: Evaluation by Doppler color flow imaging

Summary To determine the duration of bidirectional flow through the ductus arteriosus and to confirm the time of functional closure of the ductus arteriosus, 25 normal full-term newborns were studied serially using Doppler color flow imaging beginning at 2–7 h after birth and continuing until no ductal flow was detected (defined as functional closure). At the first examination, blood flow was bidirectional in 19 of 25 infants and continuously left-to-right in the remaining six. Subsequent studies revealed that bidirectional ductal flow changed to continuous left-to-right flow in 17 of 19 infants, whereas two of 19 abolished the flow completely at the second examination. Three of the 19 infants still had bidirectional flow through the ductus arteriosus at 12, 18.5, and 24 h after birth. The percentage of newborns who had bidirectional flow through the ductus arteriosus decreased roughly as a negative exponential function of age. The earliest functional closure of the ductus arteriosus was at 8 h after birth: by 24 hours 44% and by 48 h, 88% were functionally closed. By 72 h of age, the ductus arteriosus was functionally closed in all 25 infants. This study shows that bidirectional flow through the ductus arteriosus changes to continuous left-to-right flow before the functional closure, but can persist up to 24 h after birth.     

Patent ductus arteriosus: lack of evidence for common treatments

Patent ductus arteriosus (PDA) is a common diagnosis among extremely premature infants, especially in those with lung disease. Treatments are often used to close the PDA. Despite nearly three decades of research, the question of whether the benefits of treatments to prevent ductal patency or promote closure outweigh the risks of these treatments remains unanswered. The authors rarely use treatments designed to close the PDA. This article reviews three considerations in support of this restrained approach: rates of spontaneous closure of the ductus arteriosus; adverse effect of persistent ductal patency; and benefits and risks of treatments for closure.     

Ductal Left-to-Right Flow and Pulmonary Circulation in Normal Neonates: Pulsed Doppler Echocardiographic Evaluation

To determine whether ductal left-to-right flow affects pulmonary circulation in the neonatal period, ductal patency and flow patterns of the right ventricular outflow tract were studied using Doppler echocardiography in 40 normal neonates. The ductus arteriosus was defined as being patent when diastolic or continuous flow could be detected at the pulmonary end of the ductus. Evaluation of pulmonary circulation was carried out by examining the flow velocity pattern of the right ventricular outflow tract; pulmonary hypertension was considered to be present when the Doppler echocardiogram pattern was triangular with peak velocity in early systole. Neonates were initially examined within nine hours (mean 5.3 hrs) after birth, and two to three times daily thereafter, until no ductal flow could be detected. In all the neonates, the ductus arteriosus was patent at the initial examination. The predicted time of closure of the ductus arteriosus was within seven hours after birth in 5% of the neonates, within 21 hours in 50%, and within 65 hours in 95%. The flow velocity pattern of the right ventricular outflow tract changed from a triangular shape with peak velocity in early systole soon after birth to a domelike contour with peak velocity in mid-systole: thus the mean ratio of acceleration time to right ventricular ejection time increased with age. In neonates with patent ductus arteriosus at age 13.6–20.7 hours, the mean ratio of acceleration time to right ventricular ejection time was less than in age-matched neonates with closed ductus arteriosus. These results indicate that the ductal left-to-right flow affects the pulmonary circulation.     

Side-effects of long-term prostaglandin E1 treatment in neonates

BACKGROUND: In some neonates suffering from ductus arteriosus dependent congenital heart defect, a Prostaglandin E(1) (PGE1) therapy longer than 2 weeks may be needed. However, PGE1 analogue compounds may produce several adverse effects. METHODS: The authors retrospectively analyzed the data of nine patients who underwent a PGE1 treatment lasting longer than 14 days. RESULTS: The leukocyte count of the patients remained high throughout the treatment period, and the proportion of neutrophils was over 50%. Transient feeding difficulty and abdominal distension, and possible signs of gastric-outlet obstruction, were observed in two cases. In the case of three patients, cortical hyperostosis developed after different cumulative doses (1584, 3384 and 4320 microg). Significant correlations were found between the doses of PGE1 and serum K(+) levels (r=-0.770, P < 0.05) and between the blood standard bicarbonate levels and PGE1 doses (r= 0.889, P < 0.01). Bartter syndrome-like condition developed in those three patients who received the largest cumulative doses. CONCLUSIONS: Fluid-electrolyte parameters must be controlled frequently in the case of each patient treated with PGE1 for longer than 2 weeks. Although the dose, the length of the therapy and individual susceptibility may be equally important, fluid-electrolyte disturbances and the development of pseudo-Bartter syndrome seem to be more dose-dependent than cortical hyperostosis.     

Gene transfer of prostaglandin synthase maintains patency of the newborn lamb arterial duct

In congenital heart disease with left- or right-sided obstruction, prostaglandin E (PGE)1 or PGE2 is infused to maintain ductus arteriosus (DA) patency. We hypothesized that transfection of the DA with PGE synthase would lead to a greater production of PGE2 in situ and, hence, patency of the DA. The cDNA for human prostaglandin synthase was sequenced and ligated into a eukaryotic expression vector. The negative control was created by ligating the cDNA encoding the bacterial protein chloramphenicol acetyltransferase into the same plasmid. Transfection (600 microg DNA) was achieved in lambs within the first 24 h of life using the hemagglutinating virus of Japan (HVJ)-liposome transfection method with a custom-made, basket-weave-perforated catheter. Echocardiography was performed to assess DA patency until the time of sacrifice. To confirm expression of the transgene, PGE2 concentration was measured in organ culture of the DA by immunoassay and by Western immunoblotting of homogenized DA tissue. Patency of the DA was demonstrated by color Doppler in all the lambs (7/7) in which the PGE synthase was delivered, whereas functional closure was seen in the control group (6/6). The PGE2 concentration in the culture medium of the explanted DA in the treatment group was 3-fold higher than that of the control groups. Western immunoblotting confirmed the presence of PGE synthase in the treatment group. Gene transfer of PGE synthase to the DA is feasible and will maintain patency for at least 1 wk.     

Patent ductus arteriosus: to treat or not to treat?

Persistent patency of the ductus arteriosus in the preterm infant is associated with numerous morbidities, including higher rates of bronchopulmonary dysplasia and increased mortality. These strong associations have led to widespread use of cyclooxygenase inhibitors and surgical ligation to achieve ductal closure in the expectation that closing the ductus will reduce these complications. Each of these interventions has its own associated adverse effects. Neither individual randomised controlled trials nor meta-analyses of those trials have been able to demonstrate long-term benefits of these treatments despite their efficacy in inducing ductal closure and reducing the need for ductal ligation. Despite the potential shortcomings of those trials, they provide substantial cumulative evidence that early, routine treatment to close a persistently patent ductus arteriosus in preterm infants does not improve outcomes and should therefore be abandoned. Future trials of these interventions for patent ductus management should address different questions. Persistence of ductal patency should be considered a sign of rather than a direct cause of the several morbidities with which it is clearly associated. Practitioners should tolerate ductal patency and learn to manage its causes and consequences rather than focusing on achievement of ductal closure.     

Duration of ductal shunting in healthy preterm infants: an echocardiographic color flow Doppler study

The purpose of this investigation was to assess the duration of ductal shunting after birth in healthy preterm infants (30 to 37 weeks gestational age) without evidence of respiratory distress. Thirty-six infants were evaluated in the first 12 hours of life by means of two-dimensional echocardiography and color flow Doppler techniques, and then once daily until no ductal flow was detected (defined as functional closure). Preterm infants were subdivided into two groups by gestational age: group 1 = 30 to 33 weeks (n = 12); group 2 = 34 to 37 weeks (n = 24). Sixteen full-term infants (38 to 41 weeks) were similarly evaluated as control subjects (Group 3). One infant from each group had a closed ductus at the time of the first study (performed at a mean of 7.7 +/- 3.2 hours). Subsequent studies for the entire group were performed at a mean of 31.3 +/- 5.4 hours (day 2), 55.0 +/- 4.5 hours (day 3), and 80.3 +/- 6.1 hours (day 4). For the three groups, the rates of ductal closure ranged from 50.0% to 58.3% on day 2 and 81.3% to 87.5% on day 3. For the entire group, all but one infant had demonstrated closure of the ductus arteriosus by day 4. Within the range of gestational ages studied, we conclude that prematurity, in the absence of respiratory distress syndrome, does not prolong the initial duration of physiologic ductal shunting.     

Pulsed Doppler measurement of left ventricular output as early predictor of symptomatic patent ductus arteriosus in very preterm infants

High left ventricular output (LVO) values are associated with symptomatic left-to-right ductal shunting in preterm infants. However, LVO data prior to the occurrence of symptomatic patent ductus arteriosus (SPDA) are lacking. To determine whether serial measurements could predict a SPDA, we measured LVO from day 1 until day 10 with pulsed Doppler echocardiography in 25 preterm infants with birth weights of less than 1,250 g and hematocrits of more than 0.40. Eleven infants never developed patent ductus arteriosus symptoms and had LVO values within the normal range (190-310 ml/min/kg) with only minimal daily variations. The remaining 14 infants developed SPDA which required treatment with indomethacin, ductal ligation, or fluid restriction on days 2-5. From day 1 until day 5 their mean LVO values were significantly higher compared to the group without left-to-right ductal shunt and this increase was secondary to higher stroke volume values. An increase in LVO of more than 60 ml/min/kg consistently preceded SPDA by at least 24 h. Serial measurements of LVO using a single-pulsed Doppler approach can be used for early prediction of SPDA.     

Recovery of prostaglandin production associated with reopening of the ductus arteriosus after indomethacin treatment in preterm infants with respiratory distress syndrome

Increased PGE production has been demonstrated in 9 of 17 preterm infants with patent ductus arteriosus (PDA) associated with respiratory distress syndrome (RDS). Inhibition of PGE production in eight preterm infants with PDA and RDS was associated with marked improvement in the respiratory and circulatory function of all of them. However, in six of them this effect was only transient. In the posttreatment period of five and a half days reopening of the ductus arteriosus was frequently associated with increased PGE production and a drop of indomethacin serum levels. Three of these six infants were transferred for surgical ligation whereas the other three were successfully treated with a second course of indomethacin. However, the margin between closure of the ductus arteriosus and the deterioration of kidney function in preterm infants treated with a presently recommended indomethacin dosage was narrow. In conclusion, until an acceptable therapeutic serum level of indomethacin for ductal closure in preterm infants has been established and the duration of effective prostaglandin synthesis inhibition is known, it is too early for a general recommendation of a dosage regime of indomethacin for the pharmacological closure of PDA in infants with RDS.     

Variations in local PGE levels: A potential factor in therapeutic responsiveness?

Summary It was hypothesized that it is the concentration of PGE in the plasma which actually reaches the ductus arteriosus which determines ductal response to PGE administration. Therefore, site specific PGE levels were studied in two infants with ductus dependent congenital heart lesions who were receiving PGE₁ infusions. PGE levels were found to vary in a fashion related to the infusion site and the specific cardiac anatomy and hemodynamics of each patient. One of our patients, for instance, had a double outlet right ventricle with high pulmonary vascular resistance and right to left ductal shunting. This infant was given an intraarterial infusion of PGE. The plasma concentrations of PGE in the ductal blood of the infant were negligible. Assuming that ductal site specific PGE levels are critical in mediating the therapeutic response, hemodynamics and infusion site are factors that should be considered when initiating a PGE infusion, or in evaluating a therapeutic failure of PGE.     

Determination of the time of closure of the ductus arteriosus in severely ill premature infants

In order to investigate the time of ductal closure in the premature infant, we performed multiple echocardiographic examination in each of 42 premature infants. Twenty eight of these infants had spontaneous closure of the ductus arteriosus (median date of closure--3 days). Twelve required medical or surgical closure of the ductus arteriosus and two died of severe lung disease. There was a significant relationship of decreasing birth weight to prolonged patency of the ductus arteriosus.     

The pharmacologic closure of the patent ductus arteriosus

The ductus arteriosus is a fetal vessel that allows most of the blood leaving the right ventricle of the heart to bypass the lungs. Fetal patency of the ductus, and its spontaneous closure after birth, is the result of a balanced interaction of locally produced and circulating mediators (of which prostaglandins seem to be the most important), and the unique structure of the vessel wall. Persistent patency of the ductus occurs in almost 60% of very low birthweight infants. A significant left-to-right shunt through the ductus increases morbidity and mortality in premature infants. As prostaglandins play a major role in patency of the ductus, cyclooxygenase inhibitors are conventionally used to induce its closure. This chapter focuses on some of the basic mechanisms underlying ductal patency and the clinical attempts to diminish side effects associated with indomethacin, including the alternative use of ibuprofen.     

Prostaglandin E1 -Associated Pathology of Pulmonary Microvasculature in Newborn Pups: Similarity to Findings in Prostaglandin E1 -Treated Human Newborns

Prostaglandin El (PGE1) administration is a useful therapeutic measure for short-term maintenance of ductal patency in patients with obstructions to pulmonary or systemic blood flow. Such treatment is not without complications, however, and a report of three infants from our institution with abnormalities of the pulmonary microvasculature after varying periods of PGE1 therapy was recently published (Heffelfinger et al, Pediatr Pathol 1987; 7: 165-73). The vascular abnormalities appeared to be temporally related to the PGE1 administration, lb test this hypothesis, we investigated the effects of PGE1 in newborn beagles by infusing PGE1 for periods of up to 21 days in four experimental pups. Two control pups were infused with saline for the same period of time. Five of the animals developed respiratory infection during the course of the infusions. One PGE1-treated pup was not infected. Both the PGE1- and saline-treated pups had bronchopneumonias of similar severity; however, pulmonary arteritis occurred only in the PGE1-treated pups. The severity of the arteritis varied with the amount of pulmonary parenchymal inflammation and not with the duration of PGE1 administration. Inflammatory and vascular lesions were found in organs other than the lung only in two pups receiving longer courses of PGE1 treatment. We conclude that systemic PGE1 infusion at therapeutic levels plays a role in the development of arterial lesions in small muscular arteries and that this is potentiated by the presence of infection.     

Role of microsomal prostaglandin E synthase-1 (mPGES1)-derived PGE2 in patency of the ductus arteriosus in the mouse

Prostaglandin E2 (PGE2) plays a key role in the ductus arteriosus, prenatally by maintaining patency and postnatally by promoting tissue remodeling for closure. Here, by using near-term mouse fetuses with (wild-type, WT) and without microsomal PGE synthase-1 (mPGES1-/-), we have examined the importance of this enzyme for PGE2 formation and function. mPGES1-/- ductus, unlike WT ductus, contracted little, or not all, to indomethacin in vitro. Coincidentally, as evident from responses to NG-nitro-L-arginine methyl ester and zinc photoporphyrin, the mutant showed no significant enhancement of nitric oxide (NO)- and carbon monoxide (CO)-based relaxation. mPGES1 suppression differs, therefore, from cyclooxygenase (COX) suppression, whether genetically or pharmacologically induced, where NO is markedly up-regulated. In vivo, the ductus was patent, albeit occasionally with a narrowed lumen, in all mPGES1-/- fetuses. Conversely, postnatal closure progressed regularly in mPGES1-/- animals thanks to residual PGE2 originating via mPGES2. We conclude that mPGES1 is critical for PGE2 formation in the ductus but its loss does not entail compensatory up-regulation of other relaxing mechanisms. Accordingly, an mPGES1 inhibitor stands out as a prospective better tool, compared with the currently used COX inhibitors, for the management of premature infants with persistent ductus.     

Postnatal Changes in Left Ventricular Volume and Contractility in Healthy Term Infants

To evaluate how the size of the ductus arteriosus affects neonatal left ventricular (LV) volume and contractility, we serially obtained two-dimensional and Doppler echocardiograms at 2, 12, 24, and 120 hours after birth in 20 healthy infants. LV volume was calculated by the biplanar Simpson's rule, and ductus arteriosus size with left-to-right shunting was measured by two-dimensional and Doppler echocardiography. At 2 hours, the ductus arteriosus was at its maximal size, and the LV end-diastolic volume was 1.2-fold higher than at the subsequent hours after birth. Additionally, there was a significant linear correlation between the end-diastolic volume and the ductal diameter. In contrast, the peripheral vascular resistance, derived from blood pressure measurements and Doppler echocardiography, was lowest at 2 hours of age. The mean normalized systolic ejection rate, an index of contractility, remained constant throughout the study period. These results suggest that alterations in the LV end-diastolic volume soon after birth depend on changes in ductal flow, which in turn is affected by ductal diameter, and that the neonatal left ventricle operates at its maximal performance with limited contractility during ductal patency.     

Cerebral and Abdominal Arterial Hemodynamics in Preterm Infants with Patent Ductus Arteriosus

Using Doppler echocardiography we evaluated the effect of ductal shunt flow on the cerebral and abdominal arterial blood flow in 25 preterm infants. Eligible for inclusion in this study were healthy preterm newborn infants. They were divided into two groups based on their gestational age: group A, 33-36 weeks (15 infants) and group B, 28–32 weeks (10 infants). Two-dimensional Doppler echocardiograms were obtained in each infant during the first 8 hours of life and repeated every 6–12 hours until no ductal shunt flow could be detected. Flow in the ductus arteriosus, the basilar artery and the coeliac artery were examined. Closure of the ductus arteriosus occurred significantly later(p< 0.05) in group B than in group A. Pulsatility indices of flow in the basilar and coeliac arteries were high when the ductus was patent, decreasing to a fixed level with closure. This study suggests that a shunt of the patent ductus arteriosus (PDA) adversely influences the cerebral and abdominal blood flow in preterm infants.