Pharmacokinetics of intra-arterial indomethacin treatment for patent ductus arteriosus

Summary We present pharmacokinetic data of prolonged, intra-arterial indomethacin treatment (i.e. induction plus maintenance dose) for symptomatic patent ductus arteriosus (sPDA) in 26 ventilated premature infants. sPDA was assessed by two-dimensional and pulsed Doppler echocardiography. Permanent ductal closure occurred in 20 (76%) infants. Plasma levels of indomethacin were 1.18±0.74; 1.8±1.0; 1.51±0.93 and 1.25±0.98 g/ml (mean±SD) at 12, 24, 48 and 72 h after initial dose administration. All except one patient who responded with ductal closure, showed plasma levels above 0.25 g/ml throughout the 3 day treatment period and no case of sPDA reopening was noted. Although target concentrations over time were not defined, the data indicate that the maintenance levels measured were within the therapeutic range. A negative correlation was found for plasma drug levels and postnatal age (r=0.52;P<0.01). Volume of drug distribution was 0.23±0.18l/kg, total clearance 0.1±0.11 ml/min and elimination constant 0.06±0.05h^–1 (mean±SD). The great variation in pharmacokinetic data reflects the heterogeneity of the population studied with respect to extracellular fluid space, cardiovascular status, serum protein and other parameters.     

Intestinal perforation associated with indomethacin treatment in premature infants

Within 9 months we observed intestinal perforations in three very low birth weight (VLBW) infants undergoing indomethacin treatment for symptomatic patent ductus arteriosus (sPDA). The three patients exhibited striking similarities in their clinical courses and predisposing factors. Although clinical and histological criteria did not differentiate the perforations from necrotising enterocolitis (NEC), a well-known entity in premature infants, these events were remarkable to us since we had observed no other cases of NEC in recent years. From animal experiments and pathophysiological data, a role for indomethacin in gastrointestinal ischaemic damage must be considered. This communication is not meant to discredit indomethacin treatment. However, awareness of potential complications and careful monitoring during treatment is warranted.Abbreviations NEC necrotising enterocolitis - VLBW very low birth weight - sPDA symptomatic patent ductus arteriosus - RDS respiratory distress syndrome     

Effect of prolonged indomethacin therapy on renal function and selected vasoactive hormones in very-low-birth-weight infants with symptomatic patent ductus arteriosus

Renal function and changes in the activity of selected vasoactive hormones during prolonged indomethacin therapy (1 week) were studied in 11 very-low-birth-weight infants with symptomatic patent ductus arteriosus. The initiation of indomethacin therapy was associated with a reduction in diuresis, a transient decrease in creatinine clearance, and an increase in body weight (P less than 0.01). Furthermore, there was a transient trend toward hyponatremia and hyperkalemia. This acute renal dysfunction was compatible with a complex picture of renal hypoperfusion associated with a fall of plasma renin activity from high levels prior to indomethacin treatment, with a transient rise in the plasma level of arginine vasopressin and with suppressed renal and systemic prostaglandin synthesis. During treatment, an effective circulatory volume was restored by closing the ductus. In parallel, PRA and AVP plasma concentrations returned to nearly normal values. Subsequently, kidney function was not further impaired despite continued indomethacin therapy. These observations suggest that prolonged indomethacin therapy for prevention of sPDA relapse probably constitutes no further risk to kidney function after successful pharmacologically induced ductal constriction.     

Effects of highly overdosed indomethacin in a preterm infant with symptomatic patent ductus arteriosus

We describe a preterm infant with severe idiopathic respiratory distress syndrome (iRDS, hyaline membrane disease) who needed artificial ventilation with high inspiratory pressure, high frequencies, 100% oxygen and developed a symptomatic patent ductus arteriosus (sPDA) in the course of the disease. The infant was given indomethacin to induce constriction of sPDA. Due to an error in drug dilution the patient received a 100-fold overdose of indomethacin. Compared to the normal study protocol side-effects such as renal failure were not observed probably due to sufficient fluid intake and good clinical condition prior to treatment and to the rapid and persistent ductal closure.     

Atrial natriuretic peptide in the diagnosis of patent ductus arteriosus

The aim of this study was to measure plasma atrial natriuretic peptide in preterm infants with a patent ductus arteriosus before and after closure with indomethacin. Atrial natriuretic peptide was measured in 28 preterm infants with clinical and echocardiographic evidence of a patent ductus arteriosus and in eight preterm infants who did not develop clinical evidence of a patent ductus arteriosus. Plasma concentration of atrial natriuretic peptide was measured by radioimmunoassay. In 18 infants the patent ductus arteriosus closed after one course of indomethacin; atrial natriuretic peptide levels decreased from median 1240 pg/ml (range 201-5483 pg/ml) to 266 pg/ml (range 62-1108 pg/ml). In four infants the patent ductus arteriosus closed after two courses of indomethacin and two infants had surgical ligation after indomethacin treatment failed. The patent ductus arteriosus closed spontaneously in four infants (atrial natriuretic peptide median level 152 pg/ml, range 61-495 pg/ml). In the eight infants without patent ductus arteriosus, atrial natriuretic peptide level was median 224 pg/ml (range 38-876 pg/ml). Measurement of plasma atrial natriuretic peptide concentration has a role in predicting when indomethacin treatment is indicated.     

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.     

Prolonged indomethacin treatment in preterm infants with symptomatic patent ductus arteriosus: efficacy,drug level monitoring,and patient selection

Indomethacin treatment for 1 week monitored by drug level determinations was evaluated in 32 preterm infants with symptomatic patent ductus arteriousus (sPDA). Inter- and intra-individual indomethacin dispositions varied considerably with the need for marked dosage adjustments to maintain the drug level within the proposed therapeutic range. The overall success rate of this prolonged treatment was 63%. There were no significant differences between the groups of responders (n=20), relapsers (n=5) and non-responders (n=7) with respect to postnatal age, sex, total indomethacin dose, and indomethacin serum concentrations. The responders, however, had significantly higher birth weights. Eighty-five percent of infants weighing more than 1000g (n=20) were treated successfully. Only four of these children experienced adverse reactions. The benefit-to-risk ratio was lowest in the group of infants weighing 1000 g or less (n=12) with a success rate of only 25% and, potentially, severe adverse reactions in ten infants. In conclusion, prolonged indomethacin treatment is an alternative to conventional short-term treatment and appears to be particularly efficacious and safe in infants weighing more than 1000 g. In infants weighing 1000 g or less and suffering from severe pulmonary diseases, this treatment cannot generally be recommended. The advantage of on-line drug level monitoring during indomethacin treatment deserves further investigation.     

Clinical aspects of very‐low‐birthweight infants showing reopening of ductus arteriosus

Background: Indomethacin is used to treat the hemodynamically significant patent ductus arteriosus in premature infants. Some infants show ductus arteriosus reopening after effective constriction by the drug. The purpose of this study was to examine the clinical characteristics of such infants. Methods: We studied 57 very‐low‐birthweight infants with effective constriction of patent ductus arteriosus by the initial course of indomethacin. They were classified into the reopened group if they developed hemodynamically significant patent ductus arteriosus again or into the closed group if they showed complete closure. Clinical characteristics were compared between the two groups. Results: Ductus arteriosus reopening was shown in 15 (26%) of the 57 infants. These 15 infants had successful clinical ductal closure after a subsequent course of indomethacin or oral mefenamic acid treatment or surgical ligation without any severe complications. Infants in the reopened group showed significantly higher rates of developing chronic lung disease at 36 weeks of gestation than those in the closed group (53% vs 18%; P= 0.009). Furthermore, multivariate logistic regression analysis revealed ductus arteriosus reopening was the only independent risk factor for developing chronic lung disease at 36 postconceptional weeks in this population (adjusted odds ratio, 6.1; 95% confidence interval, 1.4–31.2; P= 0.02). Conclusions: Incomplete closure of the ductus arteriosus is associated with recurrence of a clinically significant patent ductus arteriosus and reopening of the ductus after initial closure with indomethacin is associated with chronic lung disease.     

Diastolic flow velocity of the left pulmonary artery of patent ductus arteriosus in preterm infants

BACKGROUND: The usefulness of diastolic pulmonary flow velocity determined by echocardiography in the assessment of symptomatic patent ductus arteriosus (sPDA) in preterm infants has not been confirmed. METHODS: Echocardiography was performed daily in infants ranging from 23 to 31 gestational weeks of age, and diastolic flow velocity of the left pulmonary artery (DFLPA) was measured. The DFLPA data before indomethacin administration for sPDA were compared with data obtained after indomethacin administration. The normal range of DFLPA was also determined from serial measurements performed in infants who did not develop sPDA during the first 7 days of life. Then, this range was compared with data from infants who did develop sPDA during this time. RESULTS: In infants who underwent indomethacin treatment, DFLPA increased with the development of sPDA and decreased when the symptoms of sPDA disappeared. On the basis of results from serial DFLPA measurement, the sensitivity and specificity of DFLPA for assessing sPDA was found to be 0.82 and 0.83, respectively. CONCLUSIONS: Measurement of DFLPA by echocardiography is a useful method for assessing sPDA in preterm infants.     

Inflammatory changes in the lungs of premature infants with symptomatic patent ductus arteriosus

BACKGROUND: The aim of the study was to observe the inflammatory changes during the therapy for symptomatic patent ductus arteriosus (sPDA). METHODS: We investigated biochemically the sample of the tracheobroncheal aspirates (TA) from 11 intubated premature infants. Three i.v. doses of indomethacin (0.2 mg/kg)were administered with 24-h intervals. The samples were divided into two groups, the effective occasions (n = 10)and non-effective occasions (n = 6). The amounts of myeloperoxidase (MPO), soluble L-selectin (sL-selectin)in TA, and the polymorphonuclear leukocytes (PMN) of peripheral blood stream and TA were analyzed before and after treatment ofsPDA with indomethacin. RESULTS: In effective occasions, there were significant decreases of peripheral PMN and MPO and PMN in TA. However, this group had a significant increase of sL-selectin. In non-effective occasions, five out of six samples had decreases of MPO and PMNin TA, but not significantly. In contrast, there was a significant decrease of sL-selectin. CONCLUSION: These data suggested that anti-inflammatory change after closure of sPDA may be caused by not only indomethacin itself, but also ductal closure itself. However, further study is necessary to clarify the relationship between the closure of the ductus itself and anti-inflammatory action in the lung.     

In vivo constriction of the fetal and neonatal ductus arteriosus by a prostanoid EP4-receptor antagonist in rats

Indomethacin is used to constrict the patent ductus arteriosus in premature infants. To clarify possible prostanoid receptor antagonists that can constrict the ductus, we studied in vivo constriction of the fetal and neonatal ductus arteriosus by AE3-208, a prostanoid EP4-receptor antagonist, in rats. Following quick cesarean section of near-term pregnant rats (21 d), neonates were incubated in room air at 33 degrees C. The inner diameter of the ductus was measured with a microscope and a micrometer following rapid whole-body freezing of the fetus and neonate, and sectioning of the thorax in the frontal plane on a freezing microtome. In the control, the ductus arteriosus constricted quickly after birth, and the inner diameter was 0.80 mm in the fetus and 0.06 mm at 90 min after birth. AE3-208, administered orogastrically to the dam, constricted the fetal ductus dose dependently. Maximal ductal constriction was observed 4 h after administration, and the ductal diameters were 0.06 mm and 0.26 mm after administration of 10 mg/kg and 10 ng/kg of AE3-208, respectively. In neonatal rats, AE3-208 injected subcutaneously at 30 min after birth, inhibited dilatation of the ductus by PGE1 dose dependently. PGE1 (10 microg/kg) was injected subcutaneously to the 1-h-old neonatal rat, and the ductal diameters were 0.53 mm and 0.19 mm without and with pretreatment of AE3-208 (10 microg/kg), respectively. These results indicate the major role of EP4 in the fetal and neonatal ductus and show that an EP4 antagonist can be used to constrict the patent ductus of premature infants.     

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

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

Effectiveness of Prostaglandin E<Subscript>1</Subscript> in Relieving Obstruction in Coarctation of the Aorta Without Opening the Ductus Arteriosus

The two main theories regarding the pathogenesis of coarctation of the aorta are the Skodaic hypothesis of ductal tissue constricting the aorta at the level of the insertion of the ductus arteriosus and the flow theory of decreased ascending aortic blood flow in the fetus, which results in associated isthmic narrowing and a localized shelf. To document that ectopic ductal tissue constriction can cause coarctation of the aorta in the absence of a patent ductus arteriosus, we report three cases of infants presenting with critical coarctation who responded to prostaglandin E₁ infusion without opening the ductus arteriosus.     

血N端脑钠肽前体在早产儿症状性动脉导管未闭诊治中的应用价值

目的探讨血浆N端脑钠肽前体(NT-pro BNP)在早产儿症状性动脉导管未闭(s PDA)诊治中的临床应用价值。方法选取2013年10月—2014年9月入住新生儿重症监护病房、胎龄28~32周、出生体质量??1 500 g的早产儿107例,分别于生后第4、7天检测NT-pro BNP,采血后30 min内行超声心动图检查。根据生后第4天超声心动图检查结果分PDA组(39例)与对照组(68例);PDA组根据有无超声血流动力学显著改变及临床表现分为症状性PDA(s PDA组,20例)和无症状性PDA(as PDA组,19例);s PDA组再根据是否服用布洛芬分为治疗组(13例)与非治疗组(7例)。结果生后第4天,s PDA组患儿血浆NT-pro BNP水平高于as PDA组,as PDA组高于对照组,差异均有统计学意义(P??0.05);生后第7天,s PDA组患儿血浆NT-pro BNP水平高于as PDA组和对照组,差异有统计学意义(P??0.05),as PDA组与对照组的差异则无统计学意义(P??0.05)。治疗组生后第7天血浆NT-pro BNP水平较第4天显著下降,差异有统计学意义(P??0.05);非治疗组生后第7天与第4天血浆NT-pro BNP水平的差异无统计学意义(P??0.05)。PDA患儿生后第4天血浆NT-pro BNP水平与动脉导管(DA)直径、左心房/主动脉根部内径比值(LA/AO)及DA直径与左肺动脉内径比值(TDD/LPA)呈正相关(r=0.498~0.670,P均??0.05)。生后第4天血浆NT-pro BNP水平预测s PDA的ROC曲线下面积(AUC)为0.969(95%CI:0.938~1.000),NT-pro BNP水平在13 964 pg/m L时,诊断s PDA的灵敏度为95%,特异度为95.4%。结论 s PDA早产儿血浆NT-pro BNP水平明显增高,治疗后下降。第4天血浆NT-pro BNP是预测s PDA的敏感指标,动态监测血浆NT-pro BNP水平变化对指导早产儿PDA治疗策略的选择有重要临床价值。     

氨基末端脑钠肽前体预测早产儿症状性动脉导管未闭的价值

目的 探讨氨基末端脑钠肽前体(NT-proBNP)预测早产儿症状性动脉导管未闭(sPDA)的价值。方法 选择2014年6月至2015年4月出生、胎龄≤32周、48 h内超声心动图确定存在动脉导管的早产儿为研究对象,监测其临床表现,于生后3 d及5 d检测血清NT-proBNP水平并行超声心动图检查,根据患儿临床表现、超声心动图结果分为sPDA组及非症状性动脉导管未闭(asPDA)组,分析血清NT-proBNP水平与超声指标的关系,比较两组间相同日龄血清NT-proBNP水平,ROC曲线确定血清NT-proBNP水平预测sPDA的敏感性、特异性。结果 共69例早产儿纳入研究,其中sPDA组13例,asPDA组56例。血清NT-proBNP水平与动脉导管管径、左房内径与主动脉根部内径比值(LA/AO)呈正相关关系(分别r=0.856、0.713,均 PPCI:0.892~1.000,PCI:0.848~1.000,P结论 NT-proBNP可能是动脉导管分流量的量化指标;生后3 d 及5 d血清NT-proBNP水平的检测均有助于早期预测sPDA。     

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.     

The silent ductus: Its precursors and its aftermath

Summary Prophylactic closure of the patent ductus arteriosus has been recommended as a means of decreasing the morbidity of the very low birth weight neonate. This study was undertaken in order to determine potential risk factors involved in the development of the silent ductus, its impact upon both the early cardiorespiratory symptomatology and the subsequent morbidity of the premature neonate, and finally the potential benefit to be derived from prophylatic closure in this presymptomatic stage. Infants with birth weights of 1000 g or less were studied on days 2–3 of life echocardiographically, clinically, and with determination of plasma dilator prostaglandin levels. On entry to the study, those infants with early evidence of silent left-to-right patent ductus arteriosus (PDA) shunting were randomized to receive either prophylactic indomethacin or placebo therapy. Those infants with no evidence of ductal shunting were not treated at all. Infants with silent PDAs had elevated levels of the dilator prostaglandin metabolite 6-keto PGF_1α on admission, although they had no echocardiographic abnormalities. No other risk factors for PDA development could be identified. Silent PDA infants had an increased incidence of subsequent symptomatic PDAs, and overall morbidity and mortality when compared with those with no evidence of PDA (silent or symptomatic). Prophylactic ductal closure decreased the incidence of subsequent PDA development, but had no effect on overall morbidity and/or mortality.     

Prolonged low-dose indomethacin therapy for patent ductus arteriosus in very low birthweight infants

To determine the efficacy and side-effects of prolonged low-dose indomethacin therapy in very low birthweight (VLBW; <1500 g) infants with a haemodynamically significant patent ductus arteriosus (hsPDA).

Methodology:

Very low birthweight infants admitted over a 16 month period were studied (6 months, retrospectively and 10 months, prospectively). Cross-sectional and M-Mode echocardiograms with pulsed-wave and colour Doppler were performed to assess the significance of ductal patency.

Results:

Forty-one (28%) of 148 VLBW infants were diagnosed to have hsPDA. Indomethacin therapy was successful in 90% after the first course, increasing to 95% after the second course. The recurrence rate after the first course was 3%. Minor and transient complications included oliguria, urea retention, hyponatraemia and thrombocytopenia. Although three infants had focal bowel perforation and the fourth had bowel perforation associated with necrotizing enterocolitis, the incidence of gastrointenstinal pathology was not significantly different from infants without hsPDA and not given indomethacin.

Conclusions:

Very low birthweight infants with hsPDA have a high response rate and low recurrence rate to prolonged lowdose indomethacin therapy. Side-effects were mild and transient. However, it is prudent to be cautious when administering indomethacin in critically ill infants <1000 g with hsPDA who manifest clinical features of bowel ischaemia.     

Patent ductus arteriosus, indomethacin and necrotizing enterocolitis in very low birth weight infants: a population-based study

BACKGROUND: Patent ductus arteriosus is a risk factor for the development of necrotizing enterocolitis. The use of indomethacin to treat patent ductus arteriosus in preterm infants may either decrease the incidence of necrotizing enterocolitis by stabilizing or closing the ductus arteriosus or increase its incidence by a direct constricting effect on mesenteric blood vessels. The authors sought to evaluate the interrelationship between patent ductus arteriosus, treatment with indomethacin and the risk of necrotizing enterocolitis in very low birth weight infants. METHOD: The Israel National database includes prospectively collected data on 99% of all very low birth weight infants in Israel. The study population comprised 6146 infants of 24-34 weeks' gestation born between 1995 and 2000. The effect of patent ductus arteriosus on necrotizing enterocolitis was assessed using multiple regression analysis. RESULTS: Necrotizing enterocolitis occurred in 5.5% (n = 343) of all infants, in 9.4% of infants with patent ductus arteriosus and in 8.9% of infants who received indomethacin. The occurrence of necrotizing enterocolitis was independently associated with the presence of patent ductus arteriosus among infants not treated with indomethacin (odds ratio, 1.85) and those who received indomethacin therapy (odds ratio, 1.53). Indomethacin therapy in absence of patent ductus arteriosus was not associated with an increased risk of necrotizing enterocolitis (odds ratio, 0.72). CONCLUSIONS: Patent ductus arteriosus is an independent risk factor for the development of necrotizing enterocolitis in very low birth weight infants. Therapy with indomethacin did not have a significant effect on the risk for necrotizing enterocolitis.     

Indomethacin treatment for symptomatic patent ductus arteriosus: a double-blind control study

A double-blind control study was designed to determine the efficacy and safety of indomethacin treatment of patients with symptomatic patent ductus arteriosus. Infants with severe respiratory distress syndrome and symptomatic patent ductus arteriosus were eligible for the prospective study if the ratio of left atrial/aortic root diameter remained greater than or equal to 1.3:1 following a 24-hour period of medical management. Thirty-nine eligible infants were randomly assigned to the control or indomethacin group and given 0.2 mg/kg of enteral indomethacin or placebo in a double-blind manner. Second and third doses were administered at 24-hour intervals in phase 1 (17 patients), and at eight-hour intervals in phase 2 (22 patients). The 75% patent ductus arteriosus closure rate with indomethacin treatment in phase 1 was not statistically significant due to a 44% spontaneous closure rate in the control group. In phase 2, however, 85% of the indomethacin group demonstrated patent ductus arteriosus closure vs only 11% in the matched control group (P less than .01). Although no indomethacin side effects occurred in phase 1, in phase 2 indomethacin administration was associated with minimal, but statistically significant, transient impaired renal function and, in three infants (23%), mild upper gastrointestinal bleeding. In summary, enteral administration of three 0.2 mg/kg indomethacin doses at eight-hour intervals thus appears to be a safe and effective alternative to surgical closure.