Prolonged indomethacin therapy for the prevention of recurrences of patent ductus arteriosus. Prevention of symptomatic patent ductus arteriosus with a single dose of indomethacin. Failure of prophylactic indomethacin to improve the outcome of the very low birth weight infant. Short versus prolonged indomethacin therapy for patent ductus arteriosus in preterm infants. Indomethacin prophylaxis for patent ductus arteriosus (PDA) in infants with a birth weight of less than 1250 grams. [Ibuprofen versus indomethacin in the treatment of patent ductus arteriosus in preterm infants]. Prophylactic indomethacin therapy in the first twenty-four hours of life for the prevention of patent ductus arteriosus in preterm infants treated prophylactically with surfactant in the delivery room. Ibuprofen versus continuous indomethacin in premature neonates with patent ductus arteriosus: is the difference in the mode of administration? Oral ibuprofen and indomethacin for treatment of patent ductus arteriosus in premature infants: a randomized trial at Ramathibodi Hospital. Continuous versus multiple rapid infusions of indomethacin: effects on cerebral blood flow velocity. Comparison of ibuprofen and indomethacin therapy for patent ductus arteriosus in preterm infants.
We tested the hypothesis that prolonged maintenance indomethacin therapy would allow more effective closure of patent ductus arteriosus (PDA) and thereby decrease the recurrence rate. Thirty-nine low birthweight neonates (less than 1500 gm) with confirmed PDA were randomly assigned in a double-blind fashion to receive standard indomethacin therapy (three doses), followed either by maintenance indomethacin therapy (0.2 mg/kg/day) for 5 days or by an equivalent volume of placebo for 5 days. Of the 20 infants who received maintenance indomethacin therapy, two (10%) required additional therapy and one of these required surgical ligation. Of the 19 infants who received only the first three indomethacin doses, nine (47%) required additional therapy for PDA (p less than 0.05) and seven of these had a ligation (p less than 0.05). We conclude that maintenance indomethacin therapy, in comparison with short-term indomethacin therapy, decreases the incidence of surgical PDA ligations, eliminates most PDA recurrences, and does not increase toxic effects of indomethacin in the low birth weight infant with PDA. To determine the efficacy of indomethacin to prevent the occurrence of symptomatic patent ductus arteriosus (PDA), a randomized clinical trial was conducted involving 32 preterm infants weighing 750 to 1500 g at birth who had hyaline membrane disease. By random assignment, 15 infants were given a single dose of indomethacin, 0.2 mg/kg intravenously, 24 hours after birth. Seventeen infants composed a control group for which indomethacin was reserved as treatment for symptomatic PDA. Birth weight, gestational age, male/female ratio, black/white ratio, and severity of disease were similar for both groups. Only one of the 14 survivors who received prophylactic indomethacin had symptomatic PDA, compared with nine of the 16 survivors in the control group (P = 0.007). There was no difference between the groups in development of bronchopulmonary dysplasia, duration of time endotracheal intubation, was required, duration in oxygen, duration to reach full feedings and regain birth weight, and duration of hospital stay. There was no difference between the two groups in incidence of intraventricular hemorrhage, and none developed necrotizing enterocolitis. These results indicate that the use of prophylactic indomethacin is beneficial in prevention of symptomatic PDA; the lack of differences in pulmonary sequelae or other complications may have been related to a population sample size not large enough to impart sufficient statistical power. Prophylactic closure of the patent ductus arteriosus (PDA) has been recommended as a means of decreasing early respiratory distress, and thereby chronic respiratory sequelae in the very low birth weight (VLBW) neonate. This study was undertaken to evaluate some possible mechanisms for the observed failure of early indomethacin therapy to achieve such improvement. 24 VLBW infants with echocardiographic evidence of PDA were randomized to receive either indomethacin or placebo at 48 h of life; and then they were studied for clinical, metabolic and laboratory signs of ductal constriction and/or reopening. Early indomethacin conferred no improvement in respiratory sequelae. However, this was not secondary to a short-term therapeutic failure. Prophylactic indomethacin, even in the VLBW infant, was successful in decreasing dilator prostaglandin production, and probably in closing the PDA and in decreasing the number of recurrences. The implications are that even with effective ductal constriction, overall morbidity is not affected. To evaluate whether a prolonged low-dose course of indomethacin would produce an improved closure rate and have fewer side effects compared with a short standard dosage schedule in the management of patent ductus arteriosus (PDA) in preterm infants.
                Sixty-one infants of gestational ages 24 to 32 weeks with a PDA confirmed with echocardiography were randomized to receive 0.2 to 0.1 to 0.1 mg/kg indomethacin in 24 hours (short course, n = 31) or 0.1 mg/kg every 24 hours 7 times (long course, n = 30). Echocardiography was done 3, 9, and 14 days after the treatment was started, and side effects were monitored.
                Primary PDA closure occurred more often in the short course group (94% vs 67%, P =.011), but the sustained closure rates were not different (74% vs 60%). Surgical PDA ligations were less frequent in the short course group than in the long course group. The short course group had a shorter duration of oxygen supplementation, less frequent symptoms of necrotizing enterocolitis, and a lower rate of urea retention. Mortality and other neonatal morbidity rates were similar.
                A prolonged low-dosage indomethacin regimen offers no advantage compared with a standard-dosage short course in the management of a hemodynamically significant PDA in preterm infants. Very low birth weight (VLBW, less than 1500 g) and extremely low birth weight infants (ELBW, less than 1000 g) are the premature infants that are most likely to develop symptomatic PDA. Intravenous indomethacin has proven effective in prevention of PDA in many prospective trials. This strategy will be a useful adjunctive therapy for premature infants in Thailand.
                To answer the following questions: 1. Will multiple doses of intravenous indomethacin, given to VLBW infants within the first day of life, effectively prevent the occurrence of symptomatic PDA? Are there any side effects or complications? 2. Will this strategy be more beneficial in ELBW?
                The study included thirty VLBW infants born at Ramathibodi Hospital, with birth weights ranging from 630 to 1230 g. They were randomized into 2 groups of 15 infants each. One group received 3 doses of intravenous indomethacin at the dosage of 0.2 mg/kg initially and then 0.1 mg/kg every 12 hours for 2 more doses; the second group received a placebo. The study was performed by a double blind control.
                Sixteen infants developed symptomatic PDA, 4 in the indomethacin group and 12 in the placebo group. The decrease in incidence of PDA is statistically significant. But when the data was analyzed separately for the VLBW and ELBW groups. The effects were only significantly different in ELBW but not yet significant in the VLBW group. There was a statistically significant difference in the incidence of severe intraventricular hemorrhage (IVH) (grade 3 or higher) in the ELBW infants.
                Intravenous indomethacin therapy given to VLBW infants with a birth weight of less than 1250 g decreased incidence of symptomatic PDA with no significant permanent side effects. The effect was markedly noticeable in ELBW infants. Incidence of severe IVH was also markedly decreased in the ELBW infants who received indomethacin. Persistent patent ductus arteriosus (PDA) is a common entity in preterm infants. The most commonly used pharmacological treatment to close the ductus is indomethacin but it can affect cerebral, renal and mesenteric blood flow. Ibuprofen has recently been shown to be effective in closing PDA with fewer hemodynamic effects. In this study we compared the safety and efficacy of ibuprofen and indomethacin in the treatment of PDA in preterm infants.
                A randomized trial was performed. Premature infants with symptomatic PDA confirmed by echocardiography in the first week of life and who required respiratory support were included. The patients were randomly assigned to receive either intravenous indomethacin or ibuprofen. The rate of ductal closure, need for additional treatment, complications, and clinical course were evaluated.
                Twenty-four patients were treated with indomethacin and 23 with ibuprofen. The clinical characteristics before treatment were similar in both groups. Both treatments were effective in closing PDA (87.5% in the indomethacin group and 82.6% in the ibuprofen group). The two cohorts did not differ in the rate of reopening, need for a second pharmacologic treatment, or surgical ductal ligation. No patient in the ibuprofen group developed gastrointestinal adverse effects, but two infants in the indomethacin group had isolated bowel perforation and one had necrotizing enterocolitis. Transient renal dysfunction developed in seven patients (29%) in the indomethacin group versus two (9%) in the ibuprofen group. Transient renal insufficiency was found in one patient in the indomethacin group and in none in the ibuprofen group. The rate of other complications was similar in both groups.
                In our trial ibuprofen was as effective as indomethacin in closing PDA. No significant differences were found in the incidence of complications but fewer renal complications and no gastrointestinal complications were found in the ibuprofen group. To determine whether a course of low-dose indomethacin therapy, when initiated within 24 hours of birth, would decrease ductal shunting in premature infants who received prophylactic surfactant in the delivery room.
                Ninety infants, with birth weights of 600 to 1250 gm, were entered into a prospective, randomized, controlled trial to receive either indomethacin, 0.1 mg/kg per dose, or placebo less than 24 hours and again every 24 hours for six doses. Echocardiography was performed on day 1 before treatment and on day 7, 24 hours after treatment. A hemodynamically significant patent ductus arteriosus (PDA) was confirmed with an out-of-study echocardiogram, and the nonresponders were treated with standard indomethacin or ligation.
                Forty-three infants received indomethacin (birth weight, 915 +/- 209 gm; gestational age, 26.4 +/- 1.6 weeks; 25 boys), and 47 received placebo (birth weight, 879 +/- 202 gm; gestational age, 26.4 +/- 1.8 weeks; 22 boys) (P = not significant). Of 90 infants, 77 (86%) had a PDA by echocardiogram on the first day of life before study treatment; 84% of these PDAs were moderate or large in size in the indomethacin-treated group compared with 93% in the placebo group. Nine of forty indomethacin-treated infants (21%) were study-dose nonresponders compared with 22 (47%) of 47 placebo-treated infants (p < 0.018). There were no significant differences between both groups in any of the long-term outcome variables, including intraventricular hemorrhage, duration of oxygen therapy, endotracheal intubation, duration of stay in neonatal intensive care unit, time to regain birth weight or reach full caloric intake, incidence of bronchopulmonary dysplasia, and survival. No significant differences were noted in the incidence of oliguria, elevated plasma creatinine concentration, thrombocytopenia, pulmonary hemorrhage, or necrotizing enterocolitis.
                The prophylactic use of low doses of indomethacin, when initiated in the first 24 hours of life in low birth weight infants who receive prophylactic surfactant in the delivery room, decreases the incidence of left-to-right shunting at the level of the ductus arteriosus. Ibuprofen has been proposed as a preferential alternative to indomethacin in treating patent ductus arteriosus (PDA), because it is purported to have less renal, mesenteric, and cerebral vasoconstrictive effects. However, short and long-term safety concerns regarding ibuprofen remain. Continuous slow infusion of indomethacin also eliminates peripheral vasoconstriction and may thus offer similar benefits to ibuprofen without safety concerns. In this study, our objective was to show that treating a PDA with continuous indomethacin is similar to ibuprofen in its effect on urine output, renal function, and blood flow velocities in the renal, superior mesenteric, and anterior cerebral arteries. Sixty four prematures with PDA were randomly, prospectively assigned to either treatment. PDA closure rates were similar (74 versus 59%; p = 0.123). Nine indomethacin-treated babies (29%) versus twelve ibuprofen babies (38%) underwent repeated therapy (p = 0.656). Two indomethacin and four ibuprofen infants required surgical ligation (p = 0.672). Serum creatinine, oliguria, estimated glomerular filtration rate, and fractional excretion of sodium were similar in both groups, as were blood flow velocity parameters in the vessels studied. There were no differences in necrotizing enterocolitis, BPD, intraventricular hemorrhage, and/or retinopathy of prematurity. In conclusion, PDA treatment with either continuous indomethacin infusion or ibuprofen was equally devoid of adverse renal effects and/or peripheral vasoconstrictive effects. Ibuprofen given intravenously to premature newborn infants is a proven treatment for patent ductus arteriosus (PDA). The efficacy of ibuprofen is comparable to indomethacin in many clinical trials with fewer renal side effects. However, the intravenous form of ibuprofen is not available in Thailand, whereas, the oral suspension form is widely used for antipyretic treatment in children. Therefore, the authors investigated the possibilities of using oral ibuprofen for the treatment of PDA in premature newborn infants.
                To assess whether oral ibuprofen at 10 mg/kg/dose daily for 3 days was as effective as indomethacin to treat symptomatic PDA in premature infants and to compare the side effects of oral ibuprofen to indomethacin.
                Eighteen premature infants with gestational ages less than 34 weeks born at Ramathibodi Hospital who developed symptomatic PDA were randomly assigned to receive three doses of either indomethacin (oral or intravenous administration 0.2 mg/kg/dose for three doses given at 12 hourly intervals or oral ibuprofen (10 mg/kg/dose for three doses given at 24 hourly intervals). The rates of ductal closure, infants' clinical courses, side effects and complications were recorded.
                Birth weight, gestational age, gender, age onset and number of infants who had respiratory distress syndrome were similar in both groups, PDA was closed in 7 of 9 infants given ibuprofen (78%) and in 8 of 9 infants given indomethacin (89%) (p > 0.05). The mean plasma concentration of ibuprofen was 28.05 microg/ml at 1 hour after the third dose. Neonates in the ibuprofen group had more urine output. However, the increment of serum BUN and creatinine were not significantly different in both groups. There were no significant differences in duration of ventilator support as well as number of patients with bronchopulmonary dysplasia, intraventricular hemorrhage, necrotizing enterocolitis and death in both groups.
                Oral ibuprofen therapy is as effective as indomethacin for the treatment of PDA in premature infants and seems to have fewer renal side effects. Therapeutic administration of indomethacin for patent ductus arteriosus (PDA) closure has been documented to decrease cerebral blood flow velocity which may be harmful to the vulnerable premature neonate. We have therefore compared the effects of administering indomethacin by rapid injection versus slow, continuous indomethacin infusion at the same total therapeutic dose on middle cerebral artery (MCA) systolic and diastolic flow velocity, resistance index, and cerebral blood flow (as reflected by the integrated area under the curve).
                Premature neonates (< 1750 g) documented echocardiographically to have a PDA were randomized to receive indomethacin either by three rapid injection doses or by continuous intravenous infusion over the ensuing 36 hours, providing an equivalent total dose. Echocardiograms and transcranial color flow mapping of the MCA flow velocity were measured at baseline and serially following initiation of therapy in both groups. Effects on cerebral blood flow velocity are presented.
                Eighteen infants [rapid injection-1.2 +/- 0.3 kg (n = 9) and continuous-1.1 +/- 0.2 kg (n = 9)] were studied. In the rapid injection treated infants decreased flow velocity in the MCA as manifested by abrupt, significant decreases in systolic (to 70 +/- 8% baseline) and diastolic (to 65 +/- 13% baseline) flow velocity and area under the curve (to 60 +/- 10% of baseline) were evident by 4 minutes and progressed to 30 minutes after treatment initiation. These changes were not observed in the group treated with continuous indomethacin. Both therapeutic modalities were equally successful in closing the ductus, although the numbers are too small to definitively determine therapeutic efficacy.
                Slow, continuous infusion eliminated the decrease in cerebral flow velocity and appears to be effective in closing the PDA. 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.
                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.
                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.
                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.
This review demonstrates a significant decrease in the incidence of symptomatic PDA following treatment of an asymptomatic PDA with indomethacin. There is also a small but statistically significant decrease in the duration of requirement for supplemental oxygen. There are no reported long term outcomes in the included trials, and so it is not possible to comment on possible long term effects. Further studies are required to determine the long term benefits or harms of closing a PDA prior to the onset of symptoms.