Comparative efficacy of combined pharmacotherapy (Ibuprofen + Paracetamol) versus monotherapy (Ibuprofen) in the treatment of hemodynamically significant PDA - A Double Blind Randomised Controlled Trial at a level III NICU in LMIC

In fetal life, the ductus arteriosus allows oxygenated blood that returns from the placenta to bypass the lungs and supply the fetal systemic circulation, thereby preventing right ventricular hypertrophy/failure. [1, 2] Several factors, including fluid overload, sepsis [3], and respiratory distress [4], influence ductal closure. Several co-morbidities have been associated with prolonged patency of the ductus in preterm infants (e.g., prolonged ventilator support, pulmonary hemorrhage, bronchopulmonary dysplasia, and impaired renal function). [5]

The optimal medical management of patent ductus arteriosus (PDA) is still debatable, including the choice of medications and timing of PDA treatment.Currently, three medications: indomethacin, ibuprofen, and Paracetamol, have demonstrated efficacy in the closure of a hemodynamically significant PDA. For those infants who fail medical therapy, surgical ligation or insertion of a coil device via cardiac catheterization are management alternatives. [6]

Ibuprofen and Paracetamol inhibit the cyclooxygenase and peroxidases region of prostaglandin synthase, respectively, thus reducing local prostaglandins levels. [7–9] Both medications are metabolized in the liver via different pathways [10], and Paracetamol [11] has a more favorable safety profile than ibuprofen and indomethacin, especially related to markers of renal function and platelet counts. Liebowtiz et al. reported constriction rates for indomethacin, ibuprofen, and Paracetamol to be 62%, 48%, and 27%, respectively in infants < 28 weeks’ gestational age. [12] Paracetamol has been used more widely for PDA management since Hammerman et al. [13] demonstrated ductal closure after treatment with Paracetamol in five preterm infants. After initial reports of Paracetamol use in PDA management, subsequent studies have also demonstrated that oral Paracetamol and oral ibuprofen have similar efficacies in closing the PDA. [14–17]

Despite decades of research and investigation of several pharmacological agents, the failure rate for monotherapy with cyclooxygenase inhibitors (COXi) or Paracetamol for the first treatment course remains unacceptably high, especially in extremely low gestational age neonates. [18-22] Combination therapy, comprising Paracetamol and ibuprofen, is a novel strategy that may facilitate PDA closure via additive or synergistic action on two separate pathways inhibiting prostaglandin production.