**3. Non-steroidal anti-inflammatory drugs (NSAIDs)**

It was known early on that NSAIDs induce ductal constriction and closure [25, 33–35]; this is even in infants who are born prematurely [36, 37]. Early treatment with indomethacin induces ductal closure, however, with concerns about compromising renal function [38]. This is probably due to the vasoconstrictive effects of those agents contributing to the development of renal hypoperfusion, NEC and spontaneous intestinal perforation (SIP), as well as platelet dysfunction and hyperbilirubinemia [39, 40].

A meta-analysis by Ohlsson et al. show that ibuprofen is equal to indomethacin in terms of efficacy in closing PDA with fewer side effects on the kidneys as well as reduced risk for NEC [41]. Rectal ibuprofen has been used as well with similar efficacy to oral ibuprofen [42]. It appears that indomethacin, the most widely used agent, is more prevalent in North America, and ibuprofen is more commonly used in Europe and Asia [43].

Repeated courses of NSAIDs are a common practice when initial treatment wasn't completely successful in closing the PDA, keeping in mind, decreased efficacy with repeated courses [44, 45].

A higher dose of ibuprofen has been attempted as well, and this includes a loading dose of 20 mg/kg, followed by two subsequent doses of 10 mg/kg, 24 hours apart; this is in comparison to the standard dosing regimen which is a loading dose of 10 mg/kg, followed by two subsequent doses of 5 mg/kg, 24 hours apart. It appears that a higher dose of ibuprofen is more effective in closing the PDA, without an obvious increase in the side effects [41, 46].

## **3.1 Acetaminophen**

Hammerman et al. reported the first case series of the use of acetaminophen as a therapeutic agent to facilitate ductal closure [27]. Acetaminophen inhibits the POX receptors on the prostaglandin synthesis pathway [29]. In a recent systematic review, Ohlsson et al. included 916 infants in eight studies comparing oral or intravenous acetaminophen to ibuprofen and found similar efficacy for acetaminophen with lower gastrointestinal bleeds, lower serum levels of creatinine, lower serum levels of bilirubin, and higher platelet count but no difference in the neurological outcomes between 18 and 24 months [28].

It is possible that acetaminophen may increase pulmonary vascular resistance [47].
