| Summary of treatment modalities for patent ductus arteriosus in preterm infants
A network meta-analysis of treatment modalities for patent ductus arteriosus in preterm infants included 68 RCTs of 4802 infants including 14 different variations of indomethacin, ibuprofen, acetaminophen and placebo. The overall PDA closure rate was 67.4% (2867 of 4256 infants).
A high dose of oral ibuprofen [20 mg/kg followed by ibuprofen 10 mg/kg for two doses] was associated with a significantly higher odds of PDA closure versus a standard dose of intravenous ibuprofen (OR 3.59; 95% CI 1.64-8.17; RD 199, 95%CI, 95-258 more per 1000 infants) and a standard dose of intravenous indomethacin (OR 2.35, 95%CI 1.08-5.31; RD 124, 95%CI 14-188 more per 1000 infants). Based on the ranking statistics, a high dose of oral ibuprofen ranked as the best pharmacotherapeutic option for PDA closure and to prevent surgical PDA ligation. There was no significant difference in the odds of mortality, necrotizing enterocolitis, or intraventricular hemorrhage with use of placebo or no treatment compared with any of the other treatment modalities. For side effects, a continuous infusion of intravenous ibuprofen was associated with the lowest incidence of oliguria, whereas high dose ibuprofen was associated with the highest incidence of oliguria. [22]
Conclusion: A high dose of oral ibuprofen was associated with a higher likelihood of hemodynamically significant PDA closure compared to standard doses of intravenous ibuprofen or intravenous indomethacin. However, high dose ibuprofen was associated with a higher likelihood of oliguria. Placebo or no treatment did not significantly change the likelihood of mortality, necrotizing enterocolitis, or intraventricular hemorrhage. [22]
Safety
Compared to placebo, prophylactic use of ibuprofen is associated increased risks for oliguria, increase in serum creatinine levels, and increased risk of gastrointestinal haemorrhage.[5]
Ibuprofen for treatment of a PDA was associated with increased oliguria and increased creatinine. [6]
Compared to treatment of a PDA with indomethacin, ibuprofen was associated with reduced NEC, reduced oliguria and was associated with lower creatinine levels 72 hours after initiation of treatment. [6]
Compared to paracetamol (acetaminophen), ibuprofen was associated with a high rate of gastrointestinal bleeding (RR 3.57, 95% CI 1.45 to 8.33; NNTH 17, 95% CI 11 to 50), higher creatinine and bilirubin levels, and lower platelet counts and daily urine output. [7]
A single study (111 infants) reported use of a continuous infusion of ibuprofen of 10 mg, 5 mg and 5 mg given over 24 hours compared to IV ibuprofen of 10 mg 5 mg and 5 mg administered over 15 minutes did not have an effect on PDA closure or reopening, reduced surgical ligation of the ductus (RR 0.28, 95% CI 0.08, 0.94) and was not associated with other benefits or harms. [23] [LOE II, GOR D]
In clinical trials, pulmonary hypertension was observed in only three infants after the prophylactic use of ibuprofen [5], in one case after ibuprofen treatment, and in additional case reports for the treatment of a PDA. [6] In a cohort study, 732 infants had a PDA diagnosis, with persistent pulmonary hypertension of the newborn occurring in 19 of 306 ibuprofen treated infants (6%) and in 32 of 426 indomethacin treated infants (8%). [8]
Ibuprofen may displace bilirubin from albumin at high concentrations in vitro (200 micromol/L)[9]. This does not appear to occur in vivo at the concentrations associated with recommended doses (up to 100 micromol/L). [10] [Note 1 µg/mL = 4.85 µmol/L].
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