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PubMed2002

Factors associated with permanent closure of the ductus arteriosus: a role for prolonged indomethacin therapy.

BACKGROUND: The most important factor determining anatomic remodeling and permanent closure of the ductus arteriosus is the degree of ductus constriction after indomethacin treatment. Muscular constriction produces a region of ischemic hypoxia in the middle of the ductus muscle media that initiates the process of permanent closure. Previous studies have shown that infants delivered before 28 weeks' gestation, who still have evidence of ductus flow on Doppler examination (performed after the standard 3-dose course of indomethacin), have a high likelihood (>85% chance) of reopening their ductus in the future. In contrast, if there is no evidence of luminal patency on the posttreatment Doppler examination, the incidence of ductus reopening is <20%. In the following study, we examined infants who still had a patent ductus on Doppler examination after a 3-dose course of indomethacin, to identify which factors might be associated with permanent ductus closure. We hypothesized that infants who received additional doses of indomethacin after the standard 3-dose course might develop an even tighter degree of ductus constriction and increase their chance of developing permanent closure. METHODS: We performed a retrospective cohort study of preterm infants (< or =26; weeks' gestation) who were treated with indomethacin. Between 12 and 24 hours after the third dose of indomethacin, infants were examined for the presence or absence of ductus-related signs, and an echocardiogram was performed. Infants responded to the initial 3 doses of indomethacin in 1 of 3 ways: 1) the ductus was closed clinically (absent clinical signs) with no evidence of luminal flow on Doppler examination ("clinically closed"; n = 214); 2) the ductus was closed clinically, but a small amount of left-to-right luminal flow was evident on Doppler examination ("partially closed"; n = 69); 3) or the ductus was open clinically and echocardiographically ("nonresponder"; n = 30). Nonresponders underwent surgical ligation (n = 30). Infants with a partially closed ductus formed our study population. We used a hierarchical regression model to identify which, if any, of the following factors might be associated with permanent anatomic closure in the 69 infants with a partially closed ductus: 1) gestational age, 2) exposure to antenatal steroids, 3) birth weight, 4) sex, 5) presence and severity of respiratory distress, 6) fluid administration during the first 96 hours after birth, 7) indomethacin treatment approach (prophylactic vs symptomatic), 8) year of birth, 9) use of surfactant, 10) preeclampsia, 11) chorioamnionitis, 12) bacterial septicemia, 13) necrotizing enterocolitis, or 14) duration of indomethacin treatment (standard 3-dose course vs prolonged 6-dose course). Infants who received the standard 3-dose course of indomethacin treatment were given 0.2, 0.1, and 0.1 mg/kg indomethacin during a 48-hour period. Infants who received the prolonged 6-dose course of indomethacin treatment were given a fourth, fifth, and sixth dose of 0.1 mg/kg at 24 hour-intervals, starting 24 hours after the third dose. RESULTS: Sixty-eight of the 69 infants survived long enough to complete all of the study evaluations. Seventy-five percent (51/68) reopened their ductus and became symptomatic; 71% (48/68) were eventually ligated. Only gestational age and duration of indomethacin treatment were significantly and independently associated with permanent closure. A prolonged 6-dose course of indomethacin was more likely than the standard 3-dose course to be associated with an increased incidence of echocardiographic closure, a decreased incidence of symptomatic reopening (odds ratio: 0.19; 95% confidence interval: 0.04-0.96), and a decreased incidence of ductus ligation (odds ratio: 0.14; 95% confidence interval: 0.03-0.68). DISCUSSION: Several older studies have suggested that a longer initial course of indomethacin therapy may be more effective in producing permanent ductus closure than the standard 3-dose course. In contrast, more recent studies have found that a longer course of indomethacin is no more effective than the standard 3-dose course in producing permanent closure. We hypothesize that the different outcomes among these studies may be attributable to differences in the degree of ductus constriction during the standard 3-dose course of indomethacin. Both the increased use of antenatal steroids and the earlier use of indomethacin has increased the effectiveness of the standard 3-dose course of indomethacin in recent years. We hypothesize that, in contrast with earlier studies, a significant proportion of the infants in the recent studies may have developed complete Doppler closure with just 3 doses of indomethacin (as occurred in 214 of the 313 infants treated with the standard 3-dose course in our study). Because the degree of ductus constriction seems to determine the rate of anatomic remodeling and permanent closure, daily echocardiographic evaluations of ductal patency may be the best way to decide when indomethacin therapy is no longer needed. Our study suggests that infants who still have evidence of luminal patency, after a standard 3-dose course of indomethacin, may be likely to benefit from a longer course of indomethacin. Future randomized trials that examine the benefits of different lengths of indomethacin treatment may wish to take this into consideration. CONCLUSIONS: Despite the increased effectiveness of a prolonged course of indomethacin, the rates of ductus reopening and surgical ligation were still very high in infants with a partially closed ductus. Other therapeutic approaches will need to be developed before permanent closure is likely to occur in this group of immature infants.

Cardiovascular Agents↗
PubMed1994

[Aneurysm of the diverticulum of the ductus arteriosus].

Aneurysm of the diverticulum of the ductus arteriosus in adult is rare, with only 37 cases reported so far in the literatures. A 18-year-old male was admitted for abnormal tumor shadow in the scout chest X-ray film. Ductal aneurysm was preoperatively diagnosed by chest CT scan, MRI, UCG, and angiography, and was confirmed by the intraoperative findings. In this patient, narrow isthmus and ductus diverticulum were supposed to be contributing factors for aneurysm formation. The aneurysm was approached through a posterolateral thoracotomy and aneurysmal orifice was closed with a trimmed dacron graft under partial femoro-femoral cardiopulmonary bypass. Postoperative course was uneventful.

Adolescent↗
PubMed1989

Betamethasone and the human fetal ductus arteriosus.

We used a sensitive Doppler echocardiographic technique to evaluate in utero the effects of betamethasone on the human ductus arteriosus. Transient, mild constriction of the ductus arteriosus 4-5 hours after the first injection of betamethasone occurred in two of 11 trials. The relatively mild and brief effects on the human ductus of betamethasone in usual doses are probably not clinically significant in most instances. Hence, they do not appear to contraindicate the use of glucocorticoids to promote fetal lung maturation.

Betamethasone↗
PubMedDate not supplied

[Patent ductus arteriosus in premature newborns. Treatment with indomethacin (author's transl)].

The pharmacokinetic and pharmacodynamic effects of indomethacin were studied in 18 prematures with patent ductus arteriosus, treated either enterally (group I, n = 7), or intravenously (group II, n = 11). A definitive closure assessed by echocardiography was observed in 13 cases (72%), and it was only transient in 4 cases (21%). Assisted ventilation was discontinued between 1 and 6 days following therapy in 14 cases. In most cases, indomethacin induced a significant reduction of diuresis but the plasma creatinine level increased above 15 mg/l in 3 cases only. The elimination half life of indomethacin (t 1/2 beta), of 40.3 +/- 12.2 hours in group I and 33.9 +/- 11.7 hours in group II, is increased as compared with adults. The difference of the surface under the curve (AUC O leads to 24 h, ng.ml-1.h-1) between the infants who presented complete or transient closure, suggests a relationship between the biodisponibility of the drug and the effect on patent ductus arteriosus. Treatment with indomethacin is an interesting alternative to surgical ligation in prematures with patent ductus arteriosus. Because of its side effects, especially on the kidneys, it is recommended to use this treatment only in intensive care units. The intravenous route seems to be better than the enteral route.

Administration, Oral↗
PubMed1989

Aneurysm of the ductus arteriosus.

Two neonates with aneurysms of the ductus arteriosus were seen. One suffered a fatal spontaneous rupture of the aneurysm, and the second (in which it was an incidental finding) the aneurysm was monitored by echocardiography, and seemed to resolve spontaneously.

Aneurysm↗
PubMed1981

Case report. Aneurysm of the ductus arteriosus in an adult.

Aneurysm of the ductus arteriosus is unusual in the adult. Computed tomography (CT) may be critical in making a preoperative diagnosis. The value of CT in the diagnosis of this entity, as well as its likely pathogenesis, is discussed.

Aged↗
PubMed1987

Valve-incompetent foramen ovale in premature infants with ductus arteriosus: a Doppler echocardiographic study.

In a 1 year period, 56 neonates with a clinical diagnosis of ductus arteriosus had Doppler echocardiographic confirmation of the ductus; 33 (59%) had additional, turbulent left to right flow at the atrial level through a valve-incompetent foramen ovale. Normalized left atrial dimensions in the group with the atrial shunt were significantly larger than when there was a competent foramen ovale; when the ductus closed and left atrial enlargement receded, the atrial shunt disappeared. However, several infants with large left chambers had no interatrial shunting. When the atrial shunt was present, there were up to three flow pulses, corresponding to atrial systole, ventricular systole and ventricular diastole, but these were frequently fused into two pulses or even one pulse per cycle. The atrial septal morphology provided supporting clues: general bowing of the septum or a localized bulge in the region of the foramen ovale indicated relatively high left atrial pressure, and frequently a slitlike dropout could be seen at the superior edge of the foramen. During the study, three additional neonates with a ductus arteriosus were found to have a secundum atrial septal defect with a typical echographic image, "matchhead" appearance of the septal rim of the defect, but the Doppler flow patterns were indistinguishable from those of a valve-incompetent foramen ovale. The hemodynamic effects of the interatrial shunt, from either cause, seemed slight during the hospital course, but the presence of a valve-incompetent foramen ovale indicated a relatively large ductal shunt. Quantification of the ductal shunt, however, continues to rely primarily on measurement of the left atrial and ventricular size.

Ductus Arteriosus, Patent↗
PubMed1996

Percutaneous catheter closure of the persistently patent ductus arteriosus in the adult.

The USCI patent ductus occluder has been shown to be an effective nonsurgical technique for closure of the persistently patent ductus in a primarily pediatric population. Its clinical impact in the adult has been reported only within small subgroups of larger pediatric studies or for a small population. This study was conducted to determine the feasibility, success rate, and complications of device closure for the persistently patent ductus arteriosus (PDA) in the adult. The population consisted of 55 patients (4 men and 51 women; mean age 38.8 +/- 15.0 years) with follow-up of 2.2 +/- 2.1 years. All patients underwent echocardiography obtained as part of their follow-up assessment. The device was successfully placed in 54 patients, with 75% clinical and echocardiographic closure at the first follow-up assessment 2.4 +/- 2.6 months). One patient with initial clinical and echocardiographic evidence of closure was subsequently found to have an open ductus. Spontaneous closure (2 patients) or second implant (6 patients) resulted in 86% closure at the most recent assessment. Thus, the percutaneous PDA double-umbrella occluder device is a feasible and effective technique for closing persistent PDA in the adult and will result in occlusion of the shunt in most patients without the need for thoracotomy.

Adolescent↗
PubMed2000

Prophylactic indomethacin: factors determining permanent ductus arteriosus closure.

BACKGROUND: Permanent closure of the ductus arteriosus (DA) requires both effective muscular constriction to block luminal blood flow and anatomic remodeling to prevent later reopening. OBJECTIVE: We examined the role of prophylactic indomethacin in producing permanent DA closure and the mechanism by which this occurs. METHODS: We studied 2 separate approaches to managing a patent DA in 257 preterm infants (gestation 24 to 27 weeks): (1) prophylactic indomethacin (all infants treated during the first 15 hours after birth) or (2) symptomatic treatment (infants in this group received indomethacin only if clinical symptoms appeared; infants whose ductus closed spontaneously and never received indomethacin were included in this group). Echocardiography was performed 24 to 36 hours after the last dose of indomethacin was administered or by age 5 days if spontaneous closure occurred. Infants were monitored for the development of ductus reopening. RESULTS: The prophylactic treatment group had a greater degree of initial ductus constriction, a higher rate of permanent anatomic closure, and a decreased need for surgical ligation than did the symptomatic treatment group. The degree of initial ductus constriction was the most important factor determining the rate of ductus reopening. Post-treatment echocardiography proved to be the best test for predicting eventual reopening. CONCLUSION: Prophylactic indomethacin improved the rate of permanent ductus closure by increasing the degree of initial constriction. Prophylactic indomethacin did not affect the remodeling process, nor did it alter the inverse relationship between infant maturity and subsequent reopening. Even when managed with prophylactic indomethacin, the rate of ductus reopening remained unacceptably high in the most immature infants.

Cardiovascular Agents↗
PubMed1977

Synthesis of prostaglandins by the ductus arteriosus of the bovine fetus.

Previous studies demonstrated that prostaglandins are local or tissue hormones which can be released from blood vessel walls. In the present study, we investigated the capacity of bovine ductus arteriosus to synthetize prostaglandins in vitro. After incubation of slices of ductus arteriosus in Krebs' solution with (1-14C) arachidonic acid for 3 hours, more than 40% of the radiolabeled material recovered from the incubating medium were metabolites of arachidonic acid. The major product was indistinguishable from 6 keto-PGF1alpha as determined by its chromatographic motility and resistance to alkaline conversion to PGB. The PGI2 synthetic capacity of the ductus arteriosus, as revealed by the predominance of its major metabolite 6 keto-PGF1alpha, suggests that this metabolic pathway of arachidonic acid may contribute to the hemodynamic changes occurring during fetal life and at birth.

Animals↗
PubMed1979

Constriction of the fetal ductus arteriosus after administration of indomethacin to the pregnant ewe.

The prostaglandin synthetase inhibitor indomethacin was given orally or intravenously to pregnant ewes. This resulted in the fetal pulmonary to systemic arterial mean blood pressure difference across the ductus arteriosus rising significantly, presumably secondary to constriction of the ductus arteriosus. The pressure difference was due to pulmonary arterial hypertension, and not due to a fall in systemic arterial mean blood pressure. Fetal arterial blood gas tensions and pH values were normal throughout. In five experiments the pressure difference could be promptly but temporarily reversed by the administration of PGE1 into the fetal inferior vena cava. Indomethacin was present in fetal blood, and maternal plasma prostaglandin levels were suppressed. Indomethacin administration during pregnancy causes constriction of the fetal ductus arteriosus and fetal pulmonary arterial hypertension which, if severe, may cause rapid fetal death. It is possible that this mechanism may be one cause of persistent pulmonary hypertension or tricuspid insufficiency or both in the newborn infant.

Animals↗
PubMed1993

[Long-term results of surgical treatment of patent ductus arteriosus in adults].

284 patients with patent ductus arteriosus were operated. Among them, 81 aged from 20-41. Special managements were made because of their serious pathologic changes. There was no operative mortality. 72 patients (88.9%) were followed up for 1-17 years. The results of follow-up indicated that the postoperative cardiopulmonary function improved greatly. 63 patients returned normal work. The long-term results were satisfactory.

Adult↗
PubMed1996

Early ibuprofen administration to prevent patent ductus arteriosus in premature newborn infants.

OBJECTIVE: To test whether early postnatal (0 to 3 hours) intravenous administration of ibuprofen will prevent patent ductus arteriosus (PDA) in preterm neonates. DESIGN: Prospective sequential controlled trial with three treatment arms. SETTING: Level 3 perinatal-neonatal intensive care nursery. PATIENTS: Thirty-four premature newborn infants born from February to August 1993 with a mean birth weight of 913 g (range, 565 to 1460 g) and gestational age of 26.9 weeks (range, 22.4 to 31.0). INTERVENTION: Infants were consecutively assigned within 3 hours of age to treatment with either one dose of ibuprofen lysine (10 mg/kg intravenously) followed by 5 mg/kg per dose intravenously at 24 and 48 hours of age (n = 12), one dose of ibuprofen lysine (10 mg/kg intravenously; n = 11), or saline (n = 11). OUTCOME VARIABLES: Primary outcome variable was the presence of ductus arteriosus by echocardiography and clinical assessments at 3, 7, and 21 days of life. Secondary outcome variables included presence of intraventricular hemorrhage, renal function, ventilatory and oxygen needs, hematologic changes, gastrointestinal function, time to full enteral feeding, duration of hospitalization, and age at discharge. RESULTS: The three groups of patients were comparable in birth weight, gestational age, antenatal administration of betamethasone, and other perinatal characteristics. Ibuprofen treatment significantly reduced plasma levels of prostaglandins, and the levels remained low for 72 hours in newborns who received three doses of the drug. The incidence of PDA and other variables did not differ between patients who received a single dose of ibuprofen and those given saline. However, compared with the saline-treated newborns, babies who received three doses of ibuprofen had no PDA (0/12 vs 7/11 for saline; P < .02), had lower daily mean airway pressures (mean +/- SD, 5.2 +/- 1.1 cm H2O vs 8.3 +/- 2.8 cm H2O for saline; P < .02) and better oxygenation index (2.6 +/- 0.6 vs 4.7 +/- 1.8 for saline; P < .02) at the end of the first week of life, and required fewer days of ventilation (25 +/- 14 days vs 44 +/- 26 days for saline; P < .03). Babies given three doses of ibuprofen tended to tolerate full oral feedings earlier (35 +/- 19 days vs 56 +/- 34 days for saline; P = .09), had shorter duration of hospitalization (71.2 +/- 22.6 days vs 127.3 +/- 74.7 days for saline; P < .05), and were discharged to home at an earlier postconceptional age (37.8 +/- 2.0 weeks vs 44.8 +/- 9.8 weeks for saline; P < .05). ibuprofen treatment in this phase I trial was not associated with any apparent early neurological, intestinal, renal, hepatic, or hematologic complications. CONCLUSIONS: Administration of three doses of ibuprofen within 3 hours after birth in preterm neonates reduced the incidence of PDA without causing notable early adverse drug reactions in this phase I trial. Early closure of the ductus arteriosus was also associated with better respiratory outcome and earlier discharge from the hospital.

Analysis of Variance↗
PubMed1989

Does the respiratory distress syndrome in twins and singletons run different risks of persistent ductus arteriosus?

The incidence and evolution of patent ductus arteriosus (PDA) was evaluated in twins and preterm singletons with birth weight less than or equal to 1750 g admitted to our Department in 1987 for respiratory distress syndrome (RDS). Screening by echocardiography and Doppler-flow studies (AT MK 600) was performed on the third day of life. Out of 91 neonates who needed intubation and ventilation during this 12-month period (23.8% of admissions), 40 weighed less than 1750 g and of these 40, 14 were twins (35%). Hemodynamically significant PDA was documented in 13 patients; of these, only 5 were preterm singletons and 8 were twins. Two twins weighing less than 1000 g received no therapy for ductus closure; one ductus closed spontaneously, the other had an early demise. Three twins and 2 preterm singletons received indomethacin; one of the twins needed a second cycle for definitive ductus closure. Three twins and three preterm singletons underwent surgery, while one twin died on the 10th postoperative day. Screening and early therapy of PDA during RDS could be of great clinical importance. Twinning seems to play a role in the incidence and evolution of PDA and this needs to be evaluated in further studies.

Diseases in Twins↗
PubMed1995

Familial occurrence of patent ductus arteriosus.

We describe 7 relatives with patent ductus arteriosus (PDA) and a slightly unusual facial appearance with prominent midface with nose elongation and flattening of the nasal bridge, wide-set eyes, downturned palpebral fissures, mild ptosis, thickened lips, and apparently slightly low-set ears. Autosomal dominant inheritance is suggested in this family. Other families where affected members have PDA and a similar facial appearance and autosomal dominant inheritance were described previously by Char [1978: BD:OAS XIV (6B):303-305] and Temple [1992: Clin Dysmorphol 1:17-21].

Child↗