Effects of prolonged versus acute indomethacin therapy in very low birth-weight infants with patent ductus arteriosus. Prolonged indomethacin therapy for the prevention of recurrences of patent ductus arteriosus. Prolonged low dose indomethacin for persistent ductus arteriosus of prematurity. Randomized trial of prolonged low-dose versus conventional-dose indomethacin for treating patent ductus arteriosus in very low birth weight infants. Short versus prolonged indomethacin therapy for patent ductus arteriosus in preterm infants.
Indomethacin has proven effective in closing the patent ductus arteriosus (PDA) in most low birth weight (LBW) neonates with this disorder. Early reopening of the ductus is a problem and often leads to the need for surgery. Prolonged use of indomethacin for several days has been suggested as a means to alleviate this problem. The present study was designed to determine if prolonged therapy over 5 days is more effective than a two-dose regimen in preventing reopening of the PDA. Seventy neonates were randomized for either prolonged therapy over 1 week or to receive two doses of indomethacin. All infants were given two doses of indomethacin 0.15 mg per kg, 12h apart. The maintenance group received an additional 0.1 mg per kg daily for 5 days. Ten days after the infants' initial dose of indomethacin, 6 of 22 in the nonmaintenance group as compared to 0 of 22 in the maintenance group had reopening of their ductus arteriosus. Ten infants in the maintenance group eventually had the ductus reopen at a median of 29, range 11-66 days compared to a median of 3, range 2-44 days in the nonmaintenance group. Significantly fewer babies in the maintenance group had a grade II-IV intraventricular hemorrhage compared to the nonmaintenance group. There was no other significant difference in the two groups in the incidence of necrotizing enterocolitis, retrolental fibroplasia or death. Indomethacin given over 5 days is effective for closure of the ductus arteriosus and will prevent reopening until after the acute clinical course in babies under 1500 g; however, the overall incidence of reopening was not different. 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. A total of 121 infants who required indomethacin for persistent ductus arteriosus in Liverpool and Cambridge over a four year period were randomised to receive either 0.1 mg/kg daily for six days or 0.2 mg/kg every 12 hours for three doses. The groups were of similar birth weight and gestational and postnatal age, though those treated with a low dose were by chance receiving a higher percentage of oxygen at the start of treatment and there were more deaths from bronchopulmonary dysplasia in this group. Of 59 infants treated with the prolonged course 53 (90%) responded initially to indomethacin compared with 48 of 62 (77%) treated conventionally--a difference of 13% (95% confidence interval for the difference 0 to 26%). Of the 53 responders 11 (21%) relapsed after low dose indomethacin, whereas after the shorter course 19 of 48 (40%) relapsed. This difference was significant (95% confidence intervals 3 to 37%). Side effects, mainly gastrointestinal haemorrhage, were similar in both groups. Significantly fewer infants experienced a rise in serum creatinine or urea concentration after treatment with low dose indomethacin. A prolonged low dose course of indomethacin offers advantages over conventional treatment. Indomethacin is used for closing the patent ductus arteriosus in premature infants. Prolonged low-dose indomethacin given over 6 days could potentially improve closure rates because ductal constriction is maintained long enough for more effective anatomic closure. We compared the efficacy of this regimen to conventional dosing in a cohort of very low birth weight infants.
                In a 2-arm clinical trial, 140 infants were randomized to either conventional dose (0.2 mg/kg/dose every 12 hours for 3 doses) or prolonged low-dose indomethacin (0.1 mg/kg/dose daily for 6 doses). The primary outcome measure was ductal closure rate, and the secondary outcomes were the need for a second course of treatment, surgical ligation rates, and side effects.
                Ductal closure after 1 course of indomethacin was similar between the 2 groups: 68% for the conventional dose group and 72% for the prolonged low dose (mean difference -4%; 95% confidence interval: -19% to 11%). The incidence of transient oliguria was higher in the conventional dose group, 31% versus 9%. There was a trend toward more necrotizing enterocolitis in the prolonged low-dose group, 7.0% versus 1.4%.
                There was no difference in efficacy between the 2 dosing regimens. In view of this and with its higher incidence of necrotizing enterocolitis, we do not recommend using prolonged low-dose indomethacin for closing the patent ductus arteriosus in very low birth weight infants. 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.