Failure of prophylactic indomethacin to improve the outcome of the very low birth weight infant. Indomethacin prophylaxis for patent ductus arteriosus (PDA) in infants with a birth weight of less than 1250 grams. 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. Prevention of symptomatic patent ductus arteriosus with a single dose of indomethacin. Short versus prolonged indomethacin therapy for patent ductus arteriosus in preterm infants.
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. 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. 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. 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. 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.
Implications for practiceProlonged indomethacin course does not appear to have a significant effect on improving important outcomes, such as PDA treatment failure, CLD, IVH, or mortality. The reduction of transient renal impairment does not outweigh the increased risk of NEC associated with the prolonged course. Based on these results, a prolonged course of indomethacin cannot be recommended for the routine treatment of PDA in preterm infants. 
Implications for researchThere is a paucity of data on optimal dosing and duration of indomethacin therapy for the treatment of PDA, in particular for extremely low birth weight infants (ELBW) premature infants. It is likely that a single standard indomethacin regime is not the ideal for every premature infant. Therefore, individual patient response should be considered and evaluated, in particular in ELBW infants. Future randomized clinical trials should include this high risk population and investigate the effect of tailoring dose and duration of therapy to individual response in terms of echocardiographic findings and/or prostaglandin levels, focusing on clinically significant outcomes, including long-term neurodevelopmental outcomes. In addition, factors that may influence treatment effect, such as birth weight, gestational age, age at the time of randomization, total fluid intake, feeding practice, and severity of PDA, need to be taken into account when designing such studies.