**3.2 Combination therapy**

Another strategy that has been attempted, is combining acetaminophen with NSAIDs specifically ibuprofen which may provide a synergetic effect on the reduction of prostaglandin production, resulting in PDA closure. In a small randomized controlled trial (RCT), Hochwald et al. compared the combination of intravenous ibuprofen and intravenous acetaminophen versus intravenous ibuprofen alone. There was a trend towards increased efficacy with combination therapy but without a statistical difference (83% vs. 42%, p = 0.08); also, there was no increase in the side effects [30]. In an observational study by Yurttutan et al., combination therapy with oral ibuprofen and oral acetaminophen was successful in closing the ductus in 9 out of 12 infants who had failed two previous courses with no increase in the side effects [31]. A retrospective cohort by Kimani et al. did not demonstrate any increased adverse effects in the combination group [32].

## **3.3 Other strategies**

Diuretics have been used as an adjunct agent to facilitate ductal closure. While diuretics help with symptomatic management of pulmonary over circulation, it appears that it compromises the systemic blood flow and may not provide a significant increase in the closure rates [48]. This is similar to a fluid restriction which may help managing the symptoms of chronic lung disease, but it would worsen the systemic blood flow [49, 50].
