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.     

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.     

Color Doppler flow mapping of the patent ductus arteriosus in very low birthweight neonates: Echocardiographic and clinical findings

Summary Forty-eight preterm infants (mean birthweight 1.0±0.3 kg; mean gestational age 28±3 weeks) underwent serial echocardiograms and physical examinations in order to determine the correlation between color Doppler flow mapping (CDFM) results and physical findings of a patent ductus arteriosus (PDA), the predictive value of early CDFM as an indicator of subsequent requirement for treatment of a PDA, and to determine the direction and duration of ductal shunting and the rate of ductal closure and opening. CDFM analysis and cardiac physical examination of left-to-right ductal shunting were usually concordant in infants with a large PDA shunt, the most reliable physical finding being increased precordial activity. CDFM studies on day 2 or 3 of postnatal life had prognostic value with regard to subsequent need for closing the PDA. Additional findings included the absence of right-to-left PDA shunting in infants <1 kg and <28 weeks gestation and the absence of ductal reopening in infants in whom it had closed spontaneously. After complete PDA closure using indomethacin, subsequent ductal reopening is uncommon, except in infants <25 weeks gestation and <700 g bodyweight.     

Correlation of patent ductus arteriosus shunting with plasma atrial natriuretic factor concentration in preterm infants with respiratory distress syndrome

The concentration of plasma atrial natriuretic factor (ANF) and the mechanism for its secretion were investigated in 17 preterm infants with respiratory distress. Their mean gestational age was 29 wk and wt 1250 g. The infants were followed during the first week of life by sequential Doppler ultrasound studies. Ductal openness versus closure and amount of ductal flow were correlated with plasma ANF concentrations. In a subset of 10 infants, sequential Doppler color flow mapping was used to quantify the ductal flow. During the first 72 h, plasma ANF was high, 361 pg/mL; it decreased to 96 pg/mL by the end of the 1st wk. The ANF level was significantly higher when the ductus was open than closed (393 versus 123 pg/mL, p less than 0.05). In patients with open ductus and bidirectional foramen ovale shunting (n = 3) ANF was 567 pg/mL and in those with left-to-right shunt 355 pg/mL (n 15, NS). The left atrial size, i.e. the left atrial to aortic root ratio, correlated with the amount of ductal shunting (r = 0.63, p less than 0.01) and with ANF concentration (r = 0.46, p less than 0.02). The correlation of ANF values and the magnitude of left-to-right ductal shunting assessed by color flow mapping was highly significant (r = 0.66, p less than 0.001). In these patients, the elevation of ANF is reflective of ductal flow.     

Phototherapy effect on the incidence of patent ductus arteriosus in premature infants: prevention with chest shielding

Patent ductus arteriosus is common among premature neonates, especially those with birth weights less than 1,500 g. In vitro, room light inhibits the contraction of immature piglet's ductal rings. Because phototherapy is used frequently from the first days of life to treat jaundice in preterm neonates, we compared the occurrence of patent ductus arteriosus among premature infants exposed to this intense light source with those whose chests were shielded. Seventy-four babies with respiratory distress syndrome were randomly assigned to either a treatment group (chest shielded with aluminum foil while on phototherapy, 36 babies) or control group (no shield, 38 babies). All were on radiant warmers, received mechanical ventilation for respiratory distress syndrome, and phototherapy (Air Shields model PTU 78-1) from day 1 of life. Irradiance was maintained at greater than 4.0 microW/cm2/nm in all cases. Although both groups had similar birth weights, gestational ages, severity of respiratory distress syndrome, intravenous fluid intake, and duration of phototherapy, the incidence of patent ductus arteriosus was significantly less in the shield group (shield 11/36 v No shield 23/38; P = .009). Patent ductus arteriosus murmurs developed in shielded patients at a later date, they required less vigorous treatment (ie, indomethacin), and they had shorter hospitalizations (74 v 85 days; P less than .05). The significant reduction of patent ductus arteriosus with shielding suggests that phototherapy may play a role in the occurrence of patent ductus arteriosus in premature infants. Shielding may be a practical method to decrease this common complication should this initial observation be confirmed.     

Closure of the ductus arteriosus and mechanics of breathing in preterm infants after surfactant replacement therapy

Treatment of premature infants with exogenous surfactant is thought to increase the incidence of the patent ductus arteriosus (PDA) due to improved mechanics of breathing and the resultant reduced pulmonary vascular resistance. As part of a prospective, blinded, controlled study of human amniotic fluid-derived surfactant, we assessed the time of closure of the PDA, defined by Doppler echocardiographic studies, performed at 6-h intervals, and the mechanics of breathing at 6, 18, and 30 h of age in 61 infants (gestational age, 25-29 wk, and birth wt, 450-1580 g). All infants had respiratory distress syndrome as confirmed by immature surfactant phospholipid profiles determined on either amniotic fluid and/or tracheal aspirate analysis, and chest radiograph, and all had a PDA at 6 h of age. Surfactant treatment was associated with more frequent clinically determined need for treatment of the PDA, but did not prolong the patency of the ductus in infants with spontaneous closure or in those requiring treatment with indomethacin. Infants with spontaneous closure of the PDA had significantly higher dynamic lung compliances and lower oxygen requirements and were treated with lower mean airway pressures than those requiring PDA treatment, although their arterial blood gas status was the same. The dynamic lung compliance of infants with right to left ductal shunting was significantly lower than those with left to right shunting at 6 and 18 h but was not different thereafter. This study suggests that the maturity of the ductus arteriosus, reflected by its tendency to close spontaneously, parallels the maturity of the lungs, reflected by their mechanical stability, and that ductal closing is not significantly altered by surfactant therapy.     

Ductal patency in neonates with respiratory distress syndrome. A randomized surfactant trial

The purpose of this study was to evaluate in a controlled study the effect of exogenous surfactant on various manifestations of ductal patency. Premature infants with respiratory distress syndrome were randomized to receive surfactant (Survanta) (n = 22) or air (n = 14). In neonates receiving surfactant, there was a greater tendency for an audible murmur to develop (13 of 22 vs four of 14). In spite of this, the clinical use of indomethacin was similar for the two groups, 10 (45%) of 22 vs six (43%) of 14. Excluding neonates given indomethacin early, a comparable number of surfactant-treated neonates (9/17 [53%]) vs control neonates (6/12 [50%]) demonstrated spontaneous closure of the ductus within a physiologic time frame (on or before day 4). For the gestational ages studied, the beneficial effects of exogenous surfactant were not associated with either an increased risk for delayed closure of the ductus arteriosus or a greater incidence of indomethacin usage. Utilization of exogenous surfactant does not appear to have an adverse impact on ductal patency.     

极低出生体重儿动脉导管未闭转归的影响因素分析

目的分析极低出生体重儿动脉导管未闭(PDA)转归的影响因素。方法以2012年1月至2014年12月收治的194例极低出生体重儿为研究对象,根据心脏超声检查及治疗转归情况分为无PDA组,PDA自然关闭组、药物关闭组、手术关闭组,分析其临床及超声心动图特征。结果 PDA自然关闭率58.7%。自然关闭组的出生胎龄、出生体重、小于胎龄儿比例均大于药物和手术关闭组,药物及手术关闭组的新生儿呼吸窘迫综合征发生率及肺表面活性物质(PS)应用比例高于自然关闭组(P0.05)。不同时间段自然关闭组的动脉导管直径均明显小于药物和手术关闭组(P0.05)。多因素logistic回归分析示出生胎龄、PS应用及48 h动脉导管直径与PDA转归显著相关。自然关闭组PDA分流类型均以关闭型为主,而药物及手术关闭组在48 h以肺高压型及进展型为主,在4 d、7 d时均以进展型为主。结论极低出生体重儿PDA自然关闭率较高,出生胎龄越小以及应用PS的患儿自然关闭率越低;动脉导管直径越大且分流类型为进展型或脉冲型的PDA不易自然关闭。     

Cerebral blood flow velocity in term newborn infants: changes associated with ductal flow

The effects of ductal closure on range-gated pulsed Doppler cerebral blood flow velocity (CBFV) patterns in the internal carotid, anterior cerebral, and middle cerebral arteries were studied in 10 normal term infants (mean birth weight 3302 +/- 294 g (SD) and mean gestational age 39.6 +/- 1.3 weeks). Pulsatility was calculated from flow velocities and used as an estimate of cerebral blood flow (CBF). Ductal closure was associated with a rise in mean blood pressure from 45.0 +/- 4.2 to 51.3 +/- 6.5 mm Hg (P less than 0.05) and a significant decrease in pulsatility in all three vessels (mean = 0.77 +/- 0.07 vs 0.70 +/- 0.05 (P less than 0.02]. Changes in pulsatility were correlated with changes in mean blood pressure (P less than 0.02), providing evidence that systemic blood pressure may influence postnatal cerebral arterial pulsatility indices. We also noted significant differences in the velocity and pulsatility of individual vessels that were independent of blood pressure, suggesting that Doppler flow studies may be useful in describing regional CBF patterns. The temporal association between ductal closure and decreased pulsatility suggests that CBFV patterns reflect ductal shunting in normal term newborn infants. Diastolic runoff and reduced systemic blood pressure in the presence of ductal shunting appear to reduce diastolic flow velocity and increase CBFV pulsatility in normal term infants during the first days of life. Normal mechanisms of cerebral autoregulation compensate for decreased flow with vasodilation; therefore the increased pulsatility associated with ductal shunting may be due to diastolic runoff rather than increased cerebrovascular resistance.     

Safety and efficacy of ibuprofen versus indomethacin in preterm infants treated for patent ductus arteriosus: a randomised controlled trial

Indomethacin (INDO) and, more recently, ibuprofen (IBU) have been used to treat haemodynamically significant patent ductus arteriosus (PDA) in preterm infants. Both are cyclo-oxygenase blockers, but seem to have a different influence on regional circulation. In a prospective, randomised, controlled study, we compared INDO and IBU with regard to efficacy and safety for the early non-invasive treatment of PDA. Doppler echocardiography was used to study 232 preterm infants (gestational age 23-34 weeks) with respiratory distress syndrome of whom 175 had persistent, haemodynamically significant PDA at 48-72 h of life. They were randomised to receive three intravenous doses of either INDO (0.2 mg/kg, at 12 h intervals) or IBU (a first 10 mg/kg dose followed by two doses of 5 mg/kg at 24 h intervals), recording rate of ductal closure, need for additional treatment, side-effects and clinical course. The efficacy of the pharmacological treatment was similar in the two groups (56/81, 69% INDO; 69/94, 73% IBU). Patients treated with INDO showed a significant increase in serum creatinine (89 +/- 24 versus 82 +/- 20 mmol/l, P = 0.03) and a near-significant tendency for a lower fractional excretion of sodium (3 +/- 3 versus 4 +/- 2%, P = 0.08); moreover, 12/81 (15%) INDO patients versus 1/94 (1%) IBU patients became oliguric (< 1 ml/kg per h) during treatment (P = 0.017). CONCLUSION: Our findings confirm that, by comparison with indomethacin, ibuprofen has fewer effects on renal function in terms of urine output and fluid retention, with much the same efficacy and safety in closing patent ductus arteriosus in preterm infants with respiratory distress syndrome. In particular, no increased incidence of intracranial haemorrhage was observed after ibuprofen treatment.     

Postnatal closure of ductus venosus in preterm infants < or = 32 weeks. An ultrasonographic study

AIM: To assess ultrasonographically the flow pattern and the time of postnatal closure of ductus venosus in preterm infants < or = 32 weeks. METHODS: Thirty-three preterm infants < or = 32 weeks were studied within the first 1 to 5 days of life and followed every second day with ultrasound until no flow was detected either through the ductus venosus or the ductus arteriosus. RESULTS: The ductus venosus was closed in only 9% by day 3, in 40% by day 8 and 88% by day 18. All were closed by day 37. This is significantly later than in healthy term neonates. Closure of the ductus venosus was not significantly correlated with closure of ductus arteriosus. CONCLUSION: The ductus venosus shows a delayed closure in preterm infants, with no significant correlation to the closure of the ductus arteriosus or the condition of the infant. We speculate that immaturity of the ductus venosus and possibly increased levels of dilating prostaglandins leads to a delayed obliteration of the vessel. An open ductus venosus represents a portocaval shunt and may have metabolical and pharmacological consequences.     

Plasma somatostatin and cholecystokinin levels in sick preterm infants during their first six weeks of life

Abstract The present study reports the levels of plasma somatostatin and cholecystokinin in 19 preterm infants with asphyxia [ n =10, GA (median; range) 26; 23–30 weeks] and respiratory distress syndrome ( n = 14, GA 27; 23–29 weeks) compared with preterm infants without any of these conditions (reference group, n = 59, GA 33; 25–36 weeks). In the reference group 37 infants received phototherapy and their peptide levels were compared with those not receiving phototherapy ( n = 22). Plasma somatostatin and cholecystokinin were analysed by specific radioimmunoassays on day 1, day 3–4 and at 6 weeks of life. Plasma somatostatin levels, but not cholecystokinin levels, of reference infants were inversely related to gestational age on day 1 and day 3–4. Asphyxiated infants and infants with respiratory distress syndrome had significantly higher somatostatin levels than reference infants on day 1 and day 3–4. These differences disappeared when the levels were adjusted for gestational age. Plasma cholecystokinin levels were not influenced by respiratory distress syndrome and asphyxia. Phototherapy did not affect plasma somatostatin and cholecystokinin levels.     

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.     

Improved prognosis in severely hypothermic newborn infants treated by rapid rewarming

We introduced a rapid rewarming technique as part of standard therapy in 16 newborn infants with effects of severe environmental hypothermia. On admission, mean rectal temperature was 31.0 +/- 2.7 degrees C, mean gestational age was 33.4 +/- 4.5 weeks, and mean birth weight was 1.76 +/- 0.71 kg. Thirteen infants were admitted within 30 hours of delivery, and the remainder at 2 to 3 weeks of age. Infants were rewarmed under a radiant warmer. The mean time required to reach a rectal temperature of 36.5 degrees C was 3.96 +/- 2.37 hours. Major medical entities encountered included thrombocytopenia (eight patients), metabolic acidosis (eight), respiratory distress (eight), renal failure (six), apnea (four), patent ductus arteriosus (four), seizures (four), intracranial hemorrhage (three), infection (three), and necrotizing enterocolitis (two). No complications could be attributed to the rapid rewarming technique. Of three infants who died, all weighed less than 1.25 kg at birth. This 81% survival is in contrast to the high mortality (25% to 50%) noted previously among infants treated by gradual rewarming.     

Longitudinal changes in the diameter of the ductus arteriosus in ventilated preterm infants: correlation with respiratory outcomes.

This study aimed to examine the early natural history of ductal shunting in ventilated preterm infants (< 1500 g) and to document the association between this shunting and respiratory outcomes. The size of the ductal shunt was assessed in 48 infants using serial echocardiographic measurement of colour Doppler internal ductal diameter and pulsed Doppler postductal aortic diastolic flow (PADF). At all postnatal ages, normal antegrade PADF was invariably seen when the ductal diameter was 1.5 mm or less, and was usually abnormal (absent or retrograde) when more than 1.5 mm. Longitudinal progress of ductal diameter fell into three groups: (i) asymptomatic spontaneous closure (n = 31)--in 20 of these infants closure occurred within 48 hours; (ii) symptomatic PDA which enlarged after a postnatal constriction (n = 9); and (iii) symptomatic PDA that showed minimal postnatal constriction (n = 8). Infants in group 2 were significantly less mature and had PDAs which became symptomatic significantly later than those in group 3. Logistic regression showed that ductal shunting had a significant correlation with mean oxygenation index over the first five days but not with ventilator or oxygen days. Gestation had the most significant association with the latter two variables, with atrial shunting also being related to days in oxygen. The preterm duct displays a wide spectrum of postnatal constrictive activity. Symptomatic PDAs usually showed slower early postnatal constriction. Ductal shunting independently related to short term but not long term respiratory outcomes.     

Factors associated with surfactant treatment response in infants with severe respiratory distress syndrome

In a prospective, randomized study of 18 infants treated with bovine surfactant (surfactant TA, Tokyo Tanabe Co, Tokyo) for severe respiratory distress syndrome, a lasting response was found in 12 infants (66%), a transient response was found in two (11%), and no response was found in four (22%) when arterial to alveolar PO2 ratios were used to define responses during the first 48 hours after treatment. In contrast, three of 23 control infants (13%) had a transient or lasting "response" to sham treatment (Pediatrics 1987;79:31-37). To determine whether maldistribution of surfactant could explain lack of response or a transient response, surfactant TA was mixed with technetium-99m sulfur colloid (approximately 300 mu Ci per infant), and eight infants with severe respiratory distress syndrome were treated six to 58 hours after birth. Scintigraphy of the lungs was performed three to 15 hours after treatment. Although a lasting response was observed in three infants, a transient one in three, and no response in two, no gross maldistribution of the radioactive label was found. Either lung received from 37% to 62% of the total radioactivity. During the past 3 years, in all infants with severe respiratory distress syndrome who were treated with surfactant (n = 29), poor or transient responses were associated with early patent ductus arteriosus and air leaks (pulmonary interstitial emphysema and pneumothoraces). Pathophysiologic conditions associated with respiratory distress syndrome are more likely to explain suboptimal responses after surfactant treatment than gross maldistribution of surfactant in the lungs.     

Neonatal complications of extreme prematurity in mechanically ventilated infants

Previous data have suggested that neonatal complications amongst preterm ventilated infants increase with decreasing gestational age and thus are likely to be greatest among ventilated infants of less than 28 weeks gestational age. The aim of this study was to test that hypothesis, thus we report the neonatal complications of 175 extremely preterm mechanically ventilated infants (gestational age 28 weeks). Of the infants 152 were ventilated because of respiratory distress syndrome (RDS) or respiratory distress of severe prematurity, 41% of these infants died. Amongst infants with RDS or respiratory distress of extreme prematurity, mortality was significantly increased in infants of gestational age 24 weeks and birth weight 1000 g. In this group 20% developed a pneumothorax, and mortality was inversely related to gestational age. In infants with RDS, 43% developed a periventricular haemorrhage and 37% were still oxygen-dependent at 28 days of age; neither of these complications was significantly related to birth weight or gestational age. Of infants with RDS 38% developed a patent ductus arteriosus and 16% developed retinopathy of prematurity. These data suggest that even amongst very immature infants there has been an impressive reduction in the neonatal complications of mechanical ventilation.     

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.     

Hemodynamically significant PDA: An echocardiographic and clinical assessment of incidence,natural history,and outcome in very low birth weight infants maintained in negative fluid balance

Summary Fifty very low birth weight (VLBW) infants (750–1500 g, 27–33 weeks gestational age) were assigned at random to one of two groups of negative fluid balance and underwent prospective clinical and echocardiographic examinations during the first month of life. The purpose was to determine: (a) the effect of fluid restriction on the incidence of ductal shunting, (b) the reliability of the physical examination in diagnosing significant ductal shunting, and (c) the relationship between significant ductal shunting and outcome in such infants. None of the infants had manipulations to close the ductus during the first week of life. Using routine structural and functional echocardiographic indices as criteria for the diagnosis of hemodynamically significant ductal shunting (hsPDA), we found that the two fluid-balance groups (8%–10% weight loss vs 13%–15% weight loss) did not significantly differ in incidence of hsPDA, duration of ventilation, or development of BPD. These two groups were then combined for further analysis: 32 (64%) of 50 VLBW infants had hsPDA during the first week of life. The group of infants with hsPDA did not differ significantly from that without hsPDA in birth weight or gestational age, but had a significantly lower Apgar score (P<0.04) and was significantly more likely to require ventilator support for RDS (P<0.01). Although when present a typical ductal murmur was specific for the development of significant ductal shunting, no murmur was heard in 21 (66%) of 32 infants with early hsPDA. Of the infants requiring ventilator support for RDS, the group with early hsPDA needed ventilation for 13.8±9.4 days, significantly longer than the group without early hsPDA (3.2±2.6 days,P<0.001), and had a higher incidence of BPD and death than the group without early hsPDA (P<0.04). In our study of a large group of prospectively identified VLBW infants, we did not find that significant ductal shunting was altered by more stringent fluid restriction, but we did find that such shunting was frequently inapparent clinically, and was associated with significantly increased morbidity and mortality.This research was supported in part by Children's Hospital Research Foundation; DHHS-USPHS, MCH grant 000174; American Heart Association, SWOC; and by DRR CLINFO grant RR00068-18-52, General Clinical Research Center.     

Early versus late indomethacin treatment for patent ductus arteriosus in premature infants with respiratory distress syndrome

OBJECTIVE: To compare efficacy and side effects of early versus late indomethacin treatment for patent ductus arteriosus (PDA) in premature infants. METHODS: One hundred twenty-seven neonates receiving ventilatory assistance (gestational age: 26-31 weeks) with PDA confirmed by echocardiography were randomly assigned in a prospective multicenter trial to either early (day 3, n = 64) or late (day 7, n = 63) intravenous indomethacin treatment (3 x 0.2 mg/kg every 12 hours). Treatment history and side effects were registered. RESULTS: The PDA closure rate was higher in the early treatment group at both 6 (73% vs 44%, P =.0008) and 9 days of age (91% vs 78%, P =.047). However, there was no significant difference in PDA ligation. Urine output was significantly lower (P <.0001), serum creatinine level was higher (P =.016), and more indomethacin courses were administered in the early treatment group (70 vs 26). Respiratory support, number of deaths, and intraventricular hemorrhages were similar in both groups. However, on the whole, major adverse events (death, necrotizing enterocolitis, and/or localized perforation, extension of hemorrhage, or cystic leukomalacia) occurred more frequently in the early treatment group (P =.017). CONCLUSION: Early indomethacin treatment improves PDA closure but is associated with increased renal side effects and more severe complications and has no respiratory advantage over late indomethacin administration in ventilated, surfactant-treated, preterm infants <32 weeks' gestational age.