New aspects on the pathogenesis of patent ductus arteriosus in premature infants

It is generally accepted that vasodilator prostaglandins are involved in the pathogenesis of persistent ductus arteriosus (PDA) in preterm infants suffering from respiratory distress syndrome (RDS). When studying the prostaglandin metabolism it became apparent that in about 80% of these infants the activity of PGI2 and/or PGE2 was increased. In parallel to weaning infants from the respirator a decrease in prostaglandin activity was observed which was associated with ductal closure. The inhibition of prostaglandin synthesis with indomethacin had the same effect. Considering the various lines of evidence that an artificially ventilated lung is releasing vasodilatory prostaglandins into the circulation we postulated the following sequence of events in the pathogenesis of PDA in preterm infants: development of RDS or other pulmonary lesions which require artificial ventilation; this mechanical intervention causes permanent shear stress and barotrauma on the pulmonary tissue; this stress causes release of arachidonic acid from phospholipids; subsequently vasodilatory prostanoids, such as PGI2 and PGE2 are released and reach the pulmonary circulation and the ductus arteriosus. As a consequence the left-to-right shunt causes pulmonary hypercirculation with further need to continue artificial ventilation. A vicious circle is established. This circle can be broken by ductus ligation, by indomethacin treatment, by less traumatic artificial ventilation or by early weaning from the respirator with theophylline.     

Early functional closure of the ductus arteriosus associated with decreased severity of respiratory distress syndrome in preterm infants

It has been shown that a patent ductus arteriosus may complicate the course of the respiratory distress syndrome (RDS) in preterm infants. In this study, an attempt is made to answer the question: Is there any relationship between RDS and patency of the ductus arteriosus in preterm infants, that is, do preterm infants without the RDS have early functional closure of the ductus arteriosus? Clinical observations were made on 144 preterm infants 25 to 34 weeks' gestation. Infants were included in the study if the status of the ductus arteriosus (open or closed) could be established either by clinical examination or retrograde aortography. The ductus arteriosus was closed in 59 infants within 48 hours of birth and open in 85. None of the infants with a closed ductus had severe RDS and only three had mild RDS. In contrast, 50% (43 of 85) of infants with open ductus had severe RDS. These findings suggest that early functional closure of the ductus can occur even in very immature infants, and this early closure appears to be associated with a decreased incidence of RDS.     

Long-term variability of heart rate increases with successful closure of patent ductus arteriosus in preterm infants.

Long-term variability (LTV) of heart rate was calculated continuously by a microprocessor in 25 preterm infants undergoing indomethacin treatment for closure of patent ductus arteriosus (PDA), in 24 preterm infants without signs of PDA, and in 10 neonates treated with prostaglandin E1 for cyanotic heart malformation. In infants with patent ductus arteriosus, LTV was lower than in controls. Following indomethacin, LTV increased most markedly (from 1.5 to 3.2; p less than 0.01) in infants with improved ventilation. The increase was less marked (from 1.8 to 2.5; p less than 0.05) in infants whose degree of respiratory failure did not change. LTV remained largely unchanged in infants who deteriorated. In 9 out of the 10 neonates treated with prostaglandin E1, LTV increased. We conclude that LTV corresponds to brain stem oxygenation and may be a useful tool to monitor treatment of PDA.     

Incidence and clinical features of patent ductus arteriosus in low-birthweight infants: a prospective analysis of 150 consecutively born infants.

The incidence of persistent patency of the ductus arteriosus beyond the third day of life was prospectively determined in 100 preterm infants with birthweights of 2,000 gm or less and 50 infants with birthweights of 2,001 to 2,500 gm. The overall incidence was 21% and was inversely related to increasing gestational age and birthweight. The data suggest that immaturity is the major determinant of the persistent patency of the ductus arteriosus. Spontaneous delayed closure of the ductus occurred in 79% of patients that survived the immediate neonatal period. There was a high degree of association between the presence of a patent ductus arteriosus (PDA) and respiratory distress syndrome (RDS). Eight infants with severe RDS and PDA developed heart failure and four required surgical ligation of the ductus. None of the infants with birthweights greater than 2,000 gm who had PDA developed heart failure or required surgical ligation of the ductus arteriosus.     

Comparison of ibuprofen and indomethacin therapy for patent ductus arteriosus in preterm infants

BACKGROUND: Patent ductus arteriosus (PDA) is commonly found in very low-birthweight (VLBW) infants. The presence of respiratory distress syndrome (RDS) is also associated with increased frequency of significant PDA. Intravenous indomethacin has been used to treat and to prevent PDA in premature infants since 1976. However, concern remains regarding the safety of indomethacin, which affects renal, gastrointestinal and cerebral perfusion. Intravenous ibuprofen has recently been used to treat and to prevent PDA premature infants with PDA without reducing cerebral blood flow or affecting intestinal or renal hemodynamics. The aim of the present study is to compare intravenous ibuprofen and indomethacin with regard to efficacy and safety for the early treatment of PDA in preterm infants. METHODS: A total of 63 preterm infants with RDS who had a birthweight of < or =1500 g and gestational age of < or =32 weeks, were enrolled in the present study. All patients were treated with nasal continuous positive airway pressure with additional oxygen supply in inspired air>30%, or with mechanical ventilation. The patients' serum platelet counts were>100,000/uL, and serum creatinine values were <1.5 mg/dL. There were no 3-4 grade intraventricular hemorrhages before randomization, and all patients were aged 2-7 days and had echo-cardio-graphic evidence of significant PDA. Patients were randomized into two groups: the first group of neonates (group A, n = 32) received intravenous ibuprofen lysine 10 mg/kg, followed by 5 mg/kg after 24 and 48 h; the second group (group B, n = 31) received intravenous indomethacin 0.2 mg/kg every 12 h for three doses. RESULTS: Patent ductus arteriosus closed in 27 patients from the ibuprofen group (84.4%) and in 25 patients from the indomethacin group (80.6%). PDA reopened in three patients from the ibuprofen group (9.4%) and in three patients from the indomethacin group (9.7%). One patient in the ibuprofen group and two patients in the indomethacin group required ductal ligation. Serum creatinine and blood urea nitrogen (BUN) concentrations were lower in the ibuprofen group than in the indomethacin group. Urine output and creatinine clearance values were higher in the ibuprofen group than in the indomethacin group. CONCLUSIONS: Ibuprofen therapy is as efficacious as indomethacin for the treatment of PDA in preterm infants. Infants treated with ibuprofen have higher creatinine clearance and urine output and lower serum creatinine and BUN values than infants treated with indomethacin.     

Late closure of the ductus arteriosus using indomethacin in the preterm infant

Several studies have shown a lack of effect of indomethacin therapy for the closure of a patent ductus arteriosus (PDA) in premature infants over 14 days of postnatal age. In this report we describe two cases in which a hemodynamically significant PDA was closed with indomethacin in preterm infants over 20 days of age. The response to indomethacin may be more related to postconceptual age than to actual postnatal age. We suggest that intravenous indomethacin therapy should be attempted before surgical ligation is performed in those premature infants under 34 weeks postconceptual age who have a hemodynamically significant patent ductus arteriosus.     

EARLY CLOSURE OF PATENT DUCTUS ARTERIOSUS WITH INDOMETHACIN IN PRETERM INFANTS WITH IDIOPATHIC RESPIRATORY DISTRESS SYNDROME

ABSTRACT. Thirty-seven preterm infants with idiopathic respiratory distress syndrome were prospectively studied for the effect of the early closure of patent ductus arteriosus with indomethacin on the course of idiopathic respiratory distress syndrome. Serial retrograde aortograms were performed in all infants in order to visualize the ductus arteriosus, apart from three patients, who died early and were evaluated aortographically only once. The ductus was initially open in 27 infants and closed in 10 infants. The infants with open ductus arteriosus were randomly divided into two groups. The first group consisted of 13 infants, in whom the ductus was closed with indomethacin at a median age of 18 hours. The other 14 infants served as controls. Total time on assisted ventilation and duration of exposure to additional oxygen were significantly shorter in medicated infants than in controls. Oxygenation of infants with an initially closed ductus was better from birth and duration of their ventilatory assistance and oxygen exposure were shorter than in infants with initial ductal shunting. The data suggest that the early closure of the patent ductus arteriosus with indomethacin in distressed preterm infants has a favourable effect on the course of idiopathic respiratory distress syndrome.     

Pulmonary function in preterm infants following treatment with intravenous indomethacin

Pulmonary function tests, including measurements of arterial blood gas levels, total pulmonary compliance, and arterial-alveolar oxygen ratios, were performed in 38 ventilator-dependent preterm infants with respiratory distress syndrome who weighed less than 1500 g at birth. Twenty-seven had a physiologically significant patent ductus arteriosus (PDA). Twelve were assigned at random to receive three doses of intravenous indomethacin, 0.2 mg/kg per dose, on the fourth day of life. This treatment resulted in ductal closure in seven infants by the seventh day of life. Another concurrently observed group of 15 infants with PDA received no indomethacin. A third group of 11 infants lacked evidence of a PDA. Pulmonary function in the infants who received indomethacin did not differ significantly from that in the other two groups.     

Closure of the patent ductus arteriosus with ligation and indomethacin: a consecutive experience.

This report summarizes a consecutive experience with 59 preterm infants with clinical, radiographic, and echocardiographic findings of a large patent ductus arteriosus. Thirty-five infants who met defined criteria received indomethacin, and 24 infants underwent PDA ligation. Analysis of the clinical course of these infants revealed no selective indomethacin morbidity and suggests that infants undergoing ligation require more prolonged ventilator therapy with increased exposure to FiO2 greater than or equal to 0.3. Mortality rates between ligated and pharmacologically treated groups were similar. This study documents that inhibition of prostaglandin synthesis to constrict and close the PDA in the premature infant is an effective alternative to operative closure.     

Response of the patent ductus arteriosus to indomethacin treatment

The purposes of this study were to examine the response of the patent ductus arteriosus (PDA) to indomethacin, using serial two-dimensional and pulsed Doppler echocardiographic studies, and to correlate the response to treatment with serum indomethacin levels. Nineteen preterm infants (gestational age, 26 to 31 weeks [mean, 28 weeks]; weight, 600 to 1680 g [mean, 1060 g]) were treated with indomethacin. Two-dimensional and pulsed Doppler echocardiograms were obtained before administration of indomethacin and daily thereafter until the day after the last dose. Ductal responses to treatment were graded as open, constricted, or closed, and serum indomethacin levels were obtained 24 hours after the last dose. The PDA initially closed in 11 (58%) of 19 infants; however, in four of the 11, PDA reopened and three of four required surgical ligation. In seven (37%) of 19 patients, the PDA initially constricted, but five of seven subsequently reopened and required ligation. In one patient, indomethacin had no effect on the PDA. The mean indomethacin level for the whole group was 622 ng/mL. There was no difference in indomethacin level between the group with initial closure vs those with constriction (580 vs 590 ng/mL), nor between those who eventually required ligation and those who did not. This study demonstrates that the majority of premature infants respond to indomethacin treatment with ductal constriction or closure but that reopening occurs frequently. The initial response does not mean that the ductus will remain constricted or closed, and surgical intervention may still be necessary. A serum indomethacin level of more than 250 ng/mL does not ensure ductal closure.     

Cardiocirculatory effects of patent ductus arteriosus in extremely low-birth-weight infants with respiratory distress syndrome

BACKGROUND: Cardiocirculatory effects of hemodynamically significant patent ductus arteriosus (hsPDA) have not been systematically studied in extremely low-birth-weight (ELBW) infants with respiratory distress syndrome (RDS). The objective of the present study was to evaluate the effects of hsPDA on the left ventricular output (LVO) and organ blood flows in ELBW infants with RDS. METHODS: Extremely low-birth-weight infants (birth-weight <1000 g) treated with surfactant for RDS were studied by serial Doppler flow examinations. Doppler flow variables in 19 infants in whom hsPDA developed (hsPDA group) were compared with those in 19 infants without hsPDA matched for gestational age, birth-weight, and postnatal age (non-hsPDA group). All infants in the hsPDA group had pharmacologic closure of ductus arteriosus when hsPDA developed. RESULTS: Before pharmacological closure of PDA, the hsPDA group had significantly higher LVO, lower blood flow volume of the abdominal aorta, and lower mean blood flow velocities in the celiac artery, superior mesenteric artery, and renal artery than the non-hsPDA group. These alterations in the hsPDA group reverted to the levels in the non-hsPDA group after the closure of PDA and had no deleterious effects on the cardiorespiratory status. No significant differences between the groups were found in mean blood flow velocities of the anterior cerebral artery throughout the study period. CONCLUSION: These results indicate that although LVO is increased, the splanchnic and renal blood flows are decreased when hsPDA develops in ELBW infants with RDS. The effects of these alterations of LVO and organ blood flows on the cardiorespiratory course seem to be minor when early pharmacologic closure of PDA is done.     

Indomethacin and cerebral blood flow in premature infants treated for patent ductus arteriosus

Central blood flow (CBF) was estimated by an intravenous 133-xenon technique in six preterm infants before and after administration of indomethacin for closure of patent ductus arteriosus. CBF fell in all infants (range 12%–40%), the mean fall was 24% (P<0.005). Though none of the infants showed signs of impaired cerebral function during or following the injections, the results do not indicate whether or not the use of indomethacin is a potential hazard.Abbreviations PDA patent ductus arteriosus - CBF cerebral blood flow - PaCO₂ arterial carbon dioxide tension - MAP mean arterial blood pressure     

Patent ductus arteriosus treated with ligation or indomethacin: a follow-up study.

The course and complications of fifty-two infants with patent ductus arteriosus requiring closure were assessed prospectively. Twenty-six infants with a PDA received indomethacin for pharmacologic closure of the PDA, and 26 underwent ligation. The current study analyzes and compares the longitudinal follow-up with respect to somatic growth, neurologic function, psychomotor and mental development, and renal, ophthalmologic, and audiologic function in 21 infants in each group who entered the follow-up. No selective morbidity was attributable to PDA closure with indomethacin when compared to surgically treated infants.     

The fate of ductus arteriosus in infants at 23-27 weeks of gestation: from spontaneous closure to ibuprofen resistance

BACKGROUND: Some extremely preterm infants experience spontaneous closure of the ductus arteriosus. On the other side, a high percentage (22-30%) of preterm infants born at the lower gestational age fail to respond to a single course of ibuprofen. AIM: To assess if there are clinical characteristics effective as predictive factors for spontaneous closure of the ductus arteriosus, development of patent ductus arteriosus (PDA) and ibuprofen-resistant PDA. METHODS: A cohort of inborn infants less than 28 weeks of gestation were prospectively studied. We distinguished infants who had spontaneous closure of ductus arteriosus, who developed PDA and who developed ibuprofen-resistant PDA. RESULTS: We studied 34 infants. Eight infants (24%) had spontaneous closure of PDA, 17 infants (50%) had a closure of PDA following the first ibuprofen course, while 9 infants (26%) failed to respond to the first ibuprofen course. Infants born at 23-25 weeks of gestation were found to have lower likelihood of PDA spontaneous closure, and higher risk of developing PDA refractory to ibuprofen therapy. Sepsis was found to increase significantly the risk of ibuprofen failure in closing PDA. CONCLUSION: An important percentage of extremely preterm infants exhibited spontaneous closure of PDA. Among clinical characteristics lowest gestational ages predict PDA and ibuprofen-resistant PDA, while sepsis predicts only ibuprofen-resistant PDA.     

The fate of ductus arteriosus in infants at 23–27 weeks of gestation: from spontaneous closure to ibuprofen resistance

Background: Some extremely preterm infants experience spontaneous closure of the ductus arteriosus. On the other side, a high percentage (22–30%) of preterm infants born at the lower gestational age fail to respond to a single course of ibuprofen.
Aim: To assess if there are clinical characteristics effective as predictive factors for spontaneous closure of the ductus arteriosus, development of patent ductus arteriosus (PDA) and ibuprofen-resistant PDA.
Methods: A cohort of inborn infants less than 28 weeks of gestation were prospectively studied. We distinguished infants who had spontaneous closure of ductus arteriosus, who developed PDA and who developed ibuprofen-resistant PDA.
Results: We studied 34 infants. Eight infants (24%) had spontaneous closure of PDA, 17 infants (50%) had a closure of PDA following the first ibuprofen course, while 9 infants (26%) failed to respond to the first ibuprofen course. Infants born at 23–25 weeks of gestation were found to have lower likelihood of PDA spontaneous closure, and higher risk of developing PDA refractory to ibuprofen therapy. Sepsis was found to increase significantly the risk of ibuprofen failure in closing PDA.
Conclusion: An important percentage of extremely preterm infants exhibited spontaneous closure of PDA. Among clinical characteristics lowest gestational ages predict PDA and ibuprofen-resistant PDA, while sepsis predicts only ibuprofen-resistant PDA.     

A meta-analysis of ibuprofen versus indomethacin for closure of patent ductus arteriosus

Ibuprofen (IBU) has previously been shown to be as effective as indomethacin (INDO) in closing the patent ductus arteriosus (PDA) of preterm infants, without severely affecting renal hemodynamics or basal cerebral blood flow. We conducted a meta-analysis of randomized trials to compare the efficacy and safety of IBU and INDO for treatment of PDA. Data from the nine relevant trials ( n =566), showed no significant difference in the efficacy of IBU and INDO in PDA closure ( P =0.70). However, five trials ( n =443) provided serum creatinine concentration data that revealed a significantly lower increase favoring IBU ( P < 0.001), and urine output data that showed a significantly lower decrease favoring IBU ( P < 0.001). In two trials ( n =188) the proportion of infants who required postnatal oxygen therapy at 28 days (defined as chronic lung disease) was significantly higher with IBU (52/94; 55.3%) than with INDO (38/94; 40.4%, P < 0.05). No statistically significant differences were found in mortality, intraventricular hemorrhage, necrotizing enterocolitis, surgical ligation, sepsis, retinopathy of prematurity, periventricular leukomalacia, length of hospital stay, gastrointestinal bleeding, re-opening of PDA, back-up treatment, surfactant therapy, or days on a ventilator. Conclusion:ibuprofen and indomethacin have similar efficacy in patent ductus arteriosus closure, but preterm infants treated with ibuprofen experience lower serum creatinine values, higher urine output, and less undesirable decreased organ blood flow and vasoconstrictive adverse effects.     

Oral medications regarding their safety and efficacy in the management of patent ductus arteriosus

Patent ductus arteriosus (PDA) is a common clinical condition in preterm infants which is inversely related to birth weight and gestational age. Cyclooxygenase inhibitors such as indomethacin and ibuprofen which block the prostaglandin conversion from arachidonic acid are the most commonly used drugs for ductal closure. This review focuses on the safety and efficacy oral medications in the management of PDA in preterm infants. Ibuprofen seems to be the first choice due to its higher safety profile, as it is associated with fewer gastrointestinal and renal side effects when compared to indomethacin. PDA closure rates are better with oral than with intravenous ibuprofen probably due to the pharmacokinetic of the drug. However, these medications were reported to be associated with several adverse including transient renal failure, gastrointestinal bleeding and perforation, hyperbilirubinemia and platelet dysfunction. Paracetamol seems be an alternative to PDA therapy with lower adverse events and side effects.     

Patent ductus arteriosus in preterm infants

Patent ductus arteriosus (PDA) is a major morbidity in preterm infants, especially in extremely premature infants less than 28 weeks. The clinical signs and symptoms of PDA in preterm infants are non specific and insensitive for making an early diagnosis of significant ductal shunting. Functional echocardiography is emerging as a new valuable bedside tool for early diagnosis of hemodynamically significant ductus, even though there are no universally accepted criteria for grading the hemodynamic significance. Echocardiography has also been used for early targeted treatment of ductus arteriosus, though the long term benefits of such strategy are debatable. The biomarkers like BNP and N-terminal pro-BNP are currently under research as diagnostic marker of PDA. The primary mode of treatment for PDA is pharmacological closure using cyclo-oxygenase inhibitors with closure rate of 70–80%. Oral ibuprofen is emerging as a better alternative especially in Indian scenario where parenteral preparations of indomethacin are unavailable and side effects are comparatively lesser. Though pharmacological closure of PDA is an established treatment modality, there is still lack of evidence for long term benefits of such therapy as well as there is some evidence for the possible adverse effects like increased ROP and BPD rates, especially if treated prophylactically. Hence, it is prudent to reserve treatment of PDA to infants with clinically significant ductus on the basis of gestation, birth weight, serial echocardiography and clinical status to individualize the decision to treat.     

Patent ductus arteriosus in infants <29 weeks gestation — outcomes and factors affecting closure

Objective  

To determine Patent ductus arteriosus (PDA) closure rates for extremely preterm infants in a tertiary care centre, factors affecting response to indomethacin and outcomes of these infants relative to their PDA status.     

Use of indomethacin and its relationship to retinopathy of prematurity in very low birthweight infants.

The relationship between the use of indomethacin, a prostaglandin inhibitor, for closure of patent ductus arteriosus (PDA) and the occurrence of retinopathy of prematurity was investigated retrospectively. 63 preterm infants less than or equal to 1500 g who were less than or equal to 32 weeks'' gestational age, appropriate weight for gestational age, with a diagnosis of PDA, and admitted during the first 24 hours of life were studied. Diagnosis of retinopathy was made by retinal examination when each infant was about 4 weeks. Diagnosis of PDA was made by clinical, radiological, and echocardiographic findings. 15 patients were treated with indomethacin because of severe congestive heart failure. There were no differences between gestational ages, birthweights, duration of oxygen therapy, or incidence of retinopathy in treated and untreated patients. We suggest that the use of indomethacin for PDA closure does not increase the incidence of retinopathy in very low birthweight infants.