Low-Dose Intravenous Paracetamol for Patent Ductus Arteriosus in Indomethacin-Resistant or Contraindicated Preterm Infants: Three Cases Reports

Abstract

Maintaining the patency of ductus arteriosus (DA) is essential for fetal circulation and normal development of the fetus. In almost-term infants, the DA constricts and causes intraluminal ischemic hypoxia, which eventually leads to the closure and remodeling of the DA a few days after birth. The occurrence of patent DA (PDA) is inversely related to gestational age and weight, with a higher incidence in preterm infants. 1 PDA is a significant cause of morbidity and mortality in preterm infants, including bronchopulmonary dysplasia, intraventricular hemorrhage, necrotizing enterocolitis, and acute renal failure due to increased pulmonary blood flow and focal organ ischemia. [2][3][4] In Japan, the AbstractBackground Although indomethacin (IND) is the standard treatment for hemodynamically significant patent ductus arteriosus (hsPDA) in Japan, it may be associated with renal impairment and gastrointestinal complications. The use of paracetamol for hsPDA closure has recently increased. Unlike IND, paracetamol does not have a peripheral vasoconstrictive effect and can be given to infants with contraindications to IND. Based on limited data available from randomized trials, paracetamol and IND seem to have similar effects. However, there have been no reports of the use of paracetamol for hsPDA in Japan. Cases Our drug administration protocol was approved by the institutional ethics committee after purchasing a clinical trial insurance. In three premature infants in whom IND was contraindicated or ineffective, a 7.5 mg/kg of paracetamol was intravenously administered every 6 hour for 3 days after obtaining parental consents. A temporary hsPDA closure was observed in two of the three infants. However, all three infants eventually needed surgical closure. No side effects, such as hepatic and renal dysfunctions, and adverse events were reported. Conclusion The intravenous administration of paracetamol was safe and feasible in premature infants with hsPDA. Future clinical trials with optimized dose and timing of administration are needed.

Safety and Feasibility of Intravenous Paracetamol for Patent Ductus Arteriosus in Indomethacin-/Ibuprofen-Resistant or -Contraindicated Preterm Infants: A Case Series

“…In this case series, we confirmed the safety and feasibility of higher-dose intravenous paracetamol (15 mg/kg given every 6 hours for 3 days) for VLBWIs with hsPDA who were indomethacin/ibuprofen-resistant or -contraindicated in Japan, similar to that previously observed in patients with low-dose intravenous paracetamol (7.5 mg/kg, given every 6 hours for 3 days). 13 In our previous study performed using low-dose intravenous paracetamol (7.5 mg/kg given every 6 hours for 3 days), temporary DA closure was observed in two of three (67%) cases with hsPDA and no short-term adverse events occurred during the provision of pharmacological treatment in any cases. However, our protocol of applying low-dose intravenous paracetamol ultimately could not avoid the need for surgical treatment (avoidance rate of surgical ligation: 0%).…”

“…However, all three infants eventually required surgical closure. 13 This treatment failure was thought to be due to an inadequate dose of paracetamol, given that a higher dose (15 mg/kg, given every 6 hours for 3 days) has been used in most studies, elsewhere in which degree of the efficacy of paracetamol on DA closure was observed. [7][8][9][10][11] Therefore, in the present research, we increased the dose of paracetamol up to 15 mg/kg/dose for evaluation in 16 preterm infants who were indomethacin/ibuprofen-resistant or -contraindicated and examined the safety and feasibility outcomes.…”

iPAPP: study protocol for a multicentre randomised controlled trial comparing safety and efficacy of intravenous paracetamol and indomethacin for the treatment of patent ductus arteriosus in preterm infants

“…Paracetamol at 7.5 mg/kg or 15 mg/kg was administered to PDA patients who were refractory to or contraindicated by existing drug therapies. In this pilot study, three patients were administered 7.5 mg/kg and subsequently required surgical closure, but no adverse events were observed 13. In contrast, 16 patients were administered 15 mg/kg and 9 of them did not require surgery, thereby indicating the drug’s efficacy 14.…”

“…In this pilot study, three patients were administered 7.5 mg/kg and subsequently required surgical closure, but no adverse events were observed. 13 In contrast, 16 patients were administered 15 mg/kg and 9 of them did not require surgery, thereby indicating the drug’s efficacy. 14 The neonates who received paracetamol at 15 mg/kg did not present any adverse events as well.…”