Pros and cons of patent ductus arteriosus ligation: hemodynamic changes and other morbidities after patent ductus arteriosus ligation

Although surgical ligation of a persistent patent ductus arteriosus resolves the adverse hemodynamic consequences of the systemic-to-pulmonary shunt and may confer some long-term benefits, it is also associated with both immediate and long-term negative effects. The population that benefits from or is harmed by the procedure is not clearly defined. Although indiscriminate ligation of the patent ductus arteriosus in all patients is not supported by the available information, the recent suggestion declaring the ductus harmless is not supported either. As we await the results of appropriately designed randomized control studies to define the indications for ligation, we must use clinical and echocardiographic indicators of a hemodynamically significant ductus arteriosus and thoughtful assessment of each individual patient to help guide us in addressing this complex problem.     

The patent ductus arteriosus in term infants, children, and adults

During fetal life, the ductus arteriosus is a normal and essential structure that connects the pulmonary artery to the distal aortic arch, permitting right ventricular ejection into the aorta. After birth, with commencement of pulmonary blood flow and a 2-ventricle circulation, a variety of physiological and biochemical signals normally result in complete closure of the ductus. Persistent patency of the ductus arteriosus may impair systemic cardiac output and result in deleterious effects on the cardiovascular system and lungs. Although surgery is still the treatment of choice for most premature infants with patent ductus arteriosus (PDA), transcatheter techniques have largely supplanted surgery for closure of PDA in children and adults. This article is a review of the PDA in term infants, children, and adults, with focus on the clinical manifestations and management.     

Genetics of patent ductus arteriosus susceptibility and treatment

The ductus arteriosus is a vital fetal structure designed to close shortly after birth. Although many physiologic and pharmacologic investigations have characterized the closure of this structure, genetic studies of persistent patency of the ductus arteriosus (patent ductus arteriosus, PDA) are relatively recent. Progress in the identification of specific genes associated with PDA is well behind that of many adult-onset diseases because of several reasons ranging from the lack of large biorepositories for this unique population to the belief that any genetic contribution to PDA is minimal. Viewing the PDA as a complex, developmentally influenced disease with both genetic and environmental risk factors has resulted in initial successes in some genetic studies. We will introduce several genetic approaches, which have been or are currently being applied to the study of PDA, that have been successful in identifying polymorphisms associated with adult diseases. Genetic investigations of PDA will be discussed with respect to heritability, in general, and to specific risk genes. Several animal models that have been used to study PDA-related genes will also be presented. Further advances in discovering genetic variation causing PDA will drive the more rational use of current therapies, and may help identify currently unknown targets for future therapeutic manipulation.     

Mesenteric oxyhemoglobin desaturation improves with patent ductus arteriosus ligation.

Near-infrared spectroscopy was used to monitor cerebral and mesenteric regional oximetry in a preterm neonate undergoing surgical ligation of a patent ductus arteriosus. This patient initially demonstrated severe mesenteric oxyhemoglobin desaturation, which improved immediately following ductal ligation.     

Diagnosis of patent ductus arteriosus by a neonatologist with a compact, portable ultrasound machine.

OBJECTIVES: To conduct a pilot study assessing a neonatologist's accuracy in diagnosing patent ductus arteriosus (PDA) using compact, portable ultrasound after limited training. STUDY DESIGN: Prospective study of premature infants scheduled for echocardiography for suspected PDA. A neonatologist with limited training performed study exams before scheduled exams. Sensitivity and specificity were calculated, compared to the scheduled echocardiogram interpreted by a cardiologist. RESULTS: There were 24 exams. Compared to the scheduled exam, the neonatologist's exam had sensitivity 69% (95% confidence interval (CI), 41 to 89%) and specificity 88% (95% CI, 47 to 99%). When a cardiologist interpreted the study exams, the sensitivity was 87% (95% CI, 60 to 98%) and specificity 71% (95% CI, 29 to 96%). CONCLUSION: A neonatologist with limited training was able to detect PDA with moderate success. A more rigorous training process or real-time transmission with cardiologist interpretation may substantially improve accuracy. Institutions with experienced technicians and on-site pediatric cardiologists may not gain from intensive training of neonatologists, but hospitals where diagnosis and treatment of PDA would be delayed may benefit from such processes.     

Acquired aortic regurgitation after coil occlusion of patent ductus arteriosus.

Some patients with patent ductus arteriosus (PDA) may develop new aortic regurgitation (AR) after coil occlusion. This study evaluated the risk factors for the development of AR after coil occlusion of PDA. A total of 23 patients with PDA were managed with coil embolization over a three-and-a-half-year period. Three patients with pre-embolization AR were excluded. A post-occlusion transthoracic echocardiogram was performed within 24 hours after the procedure. Ten patients developed AR and 10 did not. Gender, age, weight, body surface area (BSA), pulmonary artery pressure, and pulmonary vascular resistance did not differ significantly between the 2 groups. Both larger PDA size (either corrected for weight or BSA, p = 0.008 and 0.002, respectively) and a higher ratio of pulmonary to systemic flow (Qp/Qs) [p = 0.013] were significant risk factors for the development of AR after coil occlusion. Re-evaluation of the patients at 3 and 6 months after the procedure revealed 7 patients still had a regurgitant jet. The results of this study suggest that the larger the PDA and larger the shunt, the greater the likelihood of developing AR after coil occlusion.     

Reexpansion pulmonary edema following patent ductus arteriosus ligation in a preterm infant

Reexpansion pulmonary edema (RPE) is rare and usually follows rapid reexpansion of a collapsed lung. We report on a preterm infant who developed pulmonary edema within an hour of surgical ligation of patent ductus arteriosus (PDA). There were no other cardiac anomalies, fluid overload or airway obstruction to explain the change in clinical status. With supportive treatment the patient's condition became stable and was extubated within 48 hours. Lung retraction for better field exposure is often needed when performing PDA ligation in preterm infants. Reinflation of a retracted lung is thought to be the cause of our patient's pulmonary edema. We conclude that RPE, although uncommon, may occur following surgical ductal ligation and that clinicians should be aware of such a possible complication.     

Hemodynamic changes in a term newborn piglet model of patent ductus arteriosus

Patent ductus arteriosus (PDA) is a common form of congenital heart disease in full-term infants. To investigate the morbidities associated with a left to right PDA shunt, we produced a PDA in six full-term newborn piglets (less than 36 hours old) by bathing the ductus arteriosus with prostaglandin E (PGE) and infiltrating it with formalin. In five age-matched piglets, the ductus arteriosus was ligated to serve as controls. Microsphere determinations of left ventricular output (LVO) and regional blood flow (Q) were made on three consecutive days. We produced left to right shunts of 36 to 47% (mean) in the experimental piglets. The experimental piglets had a 22 to 36% increase in LVO with a one- to twofold reduction in percentage of LVO to the kidneys and carcass (p less than 0.05). Although percentage of LVO to the gastrointestinal tract was reduced (p less than 0.05), no reduction of absolute Q to the gastrointestinal tract was observed. Brain and heart Q were similar in both groups. We conclude that significant hemodynamic changes result from left to right shunting in the full-term newborn piglet with PDA. These hemodynamic changes, such as reduction in renal blood flow, are relevant information that will help explain the morbidities observed in infants with a hemodynamically significant PDA with a left to right shunt.     

Treatment strategies to prevent or close a patent ductus arteriosus in preterm infants and outcomes.

OBJECTIVE: To describe the current use of treatments to prevent or treat patent ductus arteriosus (PDA) in preterm infants, examine the association between different treatment strategies and neonatal outcomes and review the variation in these practices between centers. STUDY DESIGN: Cohort study of infants born between 23 and 30 weeks gestation managed by the Pediatrix Medical Group from 1997 to 2004. We collected data on demographics, indomethacin and ligation, and outcomes of the following five groups: prophylactic indomethacin treatment: infants treated with indomethacin on day of life (DOL) 0 or 1; indicated indomethacin treatment: infants treated with indomethacin after DOL 1; PDA without treatment: infants with a PDA without report of treatment; ligation only: infants with a PDA ligation without use of indomethacin and no PDA: infants without a PDA and without treatment. RESULTS: There were 6189 (18%) patients who received prophylactic indomethacin, 5690 (16%) patients received indicated treatment, 3886 (11%) patients had a PDA without treatment, 702 (2%) patients received ligation only and 18 136 (52%) patients had no PDA. In multivariate analysis, mortality among survivors to 2 days of age was lower (odds ratio (OR) 0.6, 95% confidence interval (CI) 0.5 to 0.7, P<0.01) and chronic lung disease, isolated intestinal perforation and severe retinopathy of prematurity (stages 3 and 4) were higher (OR 1.5, 95% CI 1.3 to 1.6, P<0.01; OR 1.5, 95% CI 1.1 to 2.0, P<0.01 and 1.4, 95% CI 1.2 to 1.6, P<0.01, respectively) in the indicated treatment group compared with the PDA without treatment group. The proportion of infants receiving prophylactic indomethacin among all infants and infants receiving indicated treatment among neonates with a report of a PDA varied by site from 0 to 59% (median 9.5%) and 0 to 100% (median 62%), respectively. CONCLUSIONS: Indomethacin use for intraventricular hemorrhage prevention and/or treatment of a PDA is common, but the selection of infants for treatment, and the decision of when and how to treat vary widely between centers. Our findings suggest the need for randomized, placebo-controlled trials of the effect of treatment of the PDA in preterm infants.     

Supernumerary nostrils together with oesophageal atresia and patent ductus arteriosus

Supernumerary nostril is an extremely rare congenital anomaly. It can be unilateral or bilateral and it sometimes occurs in association with other congenital abnormalities. We describe a newborn infant with bilateral supernumerary nostrils together with oesophageal atresia and patent ductus arteriosus, an association that has not been reported previously in the literature.     

Perinatal risk assessment for patent ductus arteriosus in premature infants

Data from 2107 inborn premature infants monitored for hemodynamically significant patent ductus arteriosus were used to develop means for clinically assessing at birth the risk of developing patent ductus arteriosus during the first 30 days of life. The overall 30-day incidence rates in birth weight categories 500 to 999, 1000 to 1499 g, and 1500 to 1750 g were 41, 17, and 7%, respectively. At-birth risk estimates obtainable from the derived multivariate functions ranged from 0 to 78% for the 500 to 999 and 1000- to 1499-g categories, and from 0 to 20% for the 1500- to 1750-g category. The derived risk functions provide for enhanced selectivity in the application of measures for the prevention of patent ductus arteriosus.     

Milrinone use for hemodynamic instability in patent ductus arteriosus ligation

Objective: Determine if prophylactic milrinone improves cardiovascular or long-term clinical outcomes in preterm neonates who receive surgical patent ductus arteriosus (PDA) ligation.

Study design: Retrospective review of 45 infants over a 4-year period that received a PDA ligation at one institution. Data were collected on morbidity and mortality outcomes for all infants as well as milrinone therapy perioperatively.

Results: Of the 45 infants that were studied 15 received milrinone in the perioperative period of PDA ligation and the remaining 30 infants did not receive milrinone. The use of milrinone showed no statistically significant improvement in acute markers of hemodynamic stability. There was also no statistically significant difference in morbidity and mortality outcomes in milrinone group compared to the non-milrinone group.

Conclusion: Prophylactic milrinone use for premature infants following PDA ligation does not show a significant cardiovascular or long-term clinical benefit.     

Morbidities associated with patent ductus arteriosus in preterm infants. Nationwide cohort study

Purpose: To evaluate the predictive factors for the development of haemodynamically significant patent ductus arteriosus (PDA) in preterm infants and to study the morbidities associated with the treatment of PDA during the first hospitalization.

Materials and methods: Data were collected from the Finnish national register of preterm infants (<32 gestational weeks) born in 2005–2013. In total, 3668 infants were included. Morbidities during the first hospitalization were analysed and compared between infants who received treatments for the closure of PDA (n?=?1132) and infants who received no treatment for PDA (n?=?2536). The results were adjusted for the duration of pregnancy, intrauterine growth pattern, antenatal steroids, delivery hospital and respiratory distress syndrome (RDS).

Results: RDS and mechanical ventilation were independently associated with an increased risk of PDA requiring treatment. Medical and surgical treatments were associated with the risk of severe bronchopulmonary dysplasia (BPD). Primary surgical ligation was associated with an increased risk of severe intraventricular haemorrhage (IVH) and necrotizing enterocolitis (NEC). Medical treatment itself and also followed by surgical ligation was associated with lower mortality.

Conclusion: The severity of lung disease rather than prematurity per se was associated with the development of PDA requiring therapy. Both medical and surgical therapies for PDA were associated with severe BPD, and primary surgical ligation was associated with NEC and severe IVH.     

Char syndrome (unusual mouth, patent ductus arteriosus, phalangeal anomalies).

A mother and son are described with unusual facies, patent ductus arteriosus, fusion of distal interphalangeal joints and mild learning difficulties. The facial features include hypertelorism, strabismus, flat nasal bridge, short philtrum and a triangular mouth. This autosomal dominant syndrome has been reported in one other family by F. Char (1978).     

Catheter-based closure of the patent ductus arteriosus in lower weight infants

Risks associated with drug therapy and surgical ligation have led health care providers to consider alternative strategies for patent ductus arteriosus (PDA) closure. Catheter-based PDA closure is the procedure of choice for ductal closure in adults, children, and infants ≥6 kg. Given evidence among older counterparts, interest in catheter-based closure of the PDA in lower weight (<6 kg) infants is growing. Among these smaller infants, the goals of this review are to: (1) provide an overview of the procedure; (2) review the types of PDA closure devices; (3) review the technical success (feasibility); (4) review the risks (safety profile); (5) discuss the quality of evidence on procedural efficacy; (6) consider areas for future research. The review provided herein suggests that catheter-based PDA closure is technically feasible, but the lack of comparative trials precludes determination of the optimal strategy for ductal closure in this subgroup of infants.