Pharmacotherapy of PDA involves the use of COX inhibitors, which have been shown to be safe and effective in the majority of treated infants. COX inhibitors block the conversion of arachidonic acid to various prostaglandins that are involved in maintaining the patency of the ductus arteriosus in the fetus. By inhibiting this conversion, COX inhibitors block the production of prostaglandins, thereby allowing the ductus to close. There are two isoforms of COX inhibitors (COX 1 and 2) described. The two available pharmacological agents approved by the Food and Drug Administration (FDA) in the United States are IV indomethacin (Indocin) and IV ibuprofen lysine (NeoProfen). These drugs are chemically different and inhibit COX 1 and 2 isoforms to different degrees. Indomethacin has stronger COX 1 inhibition, which has been attributed to undesirable gastrointestinal, cerebral and renal side effects. Ibuprofen lysine has less COX 1 inhibition, resulting in less vasoconstrictive side effects on these vital organs. Both drugs are highly protein bound and eliminated primarily by the liver. Both drugs are equally effective in closing the PDA in preterm infants.
Differences exist in the effect on cerebral and renal blood flow when using these two drugs. Indomethacin decreases cerebral blood flow and oxygen consumption to a greater degree than ibuprofen lysine. This is associated with a preventative effect in the occurrence of IVH when given prophylactically in low-birth-weight infants, whereas ibuprofen lysine has no such protective effect. Indomethacin more profoundly decreases renal blood flow compared to ibuprofen lysine, resulting in significant oliguria and an increase in serum creatinine levels. Studies comparing these drugs reveal no significant differences in the incidence of NEC, BPD at 36 weeks or neurodevelopmental outcome at 18 months of age. Because these drugs are highly protein bound, they can potentially compete with bilirubin for albumin binding sites and increase the risk of bilirubin encephalopathy. Studies have shown that at the recommended therapeutic dose of ibuprofen, the serum drug levels achieved do not increase free bilirubin levels. A few incidents of persistent pulmonary hypertension have been reported with alternative ibuprofen preparations but this has not been seen with ibuprofen lysine, which is the only form of ibuprofen approved by the FDA in the United States.
Several clinical studies comparing indomethacin to placebo showed significant PDA closure rates and protective effects on IVH status when given as a prophylaxis for presymptomatic and symptomatic PDA. One study showed no differences in neurodevelopmetal outcome between both groups. Ibuprofen lysine when given as prophylaxis compared to placebo showed significant PDA closure rates but did not have an effect on the incidence of IVH. Studies comparing indomethacin and ibuprofen lysine showed equal efficacy rates in ductal closure. In these comparative trials, the indomethacin group had statistically significant higher incidence of oliguria and elevated creatinine levels. There were no differences in the incidence of NEC, BPD or short-term neurological outcomes in patients receiving either of these COX inhibitors. Several comparison studies have reconfirmed these observations. Recent analysis of children at 4 ½ and 8 years of age who were treated with indomethacin prophylaxis at birth showed favorable neurodevelopmental outcome vs those treated with placebo. Long-term neurological outcome in infants who received ibuprofen lysine is not yet available since it has only been approved for use since 2006.
The optimal time to treat the PDA is when treatment with COX inhibitors will be most effective while avoiding treatment of infants who may have spontaneous closure of the ductus. Therefore, prophylaxis treatment is only indicated in situations where the risk of IVH is very high. If prophylaxis is desired, indomethacin is the treatment of choice, as ibuprofen lysine has not been shown to have an effect on IVH. The current trend is to treat early presymptomatic therapeutic PDA at 2 to 7 days of age after echocardiogram confirmation. This will minimize the number of babies exposed to COX inhibitors whose ductus will close spontaneously and at the same time benefit those babies who will respond most favorably to COX inhibitors. Indomethacin and ibuprofen lysine have been shown to be equally effective in closure rates when given at this time. However, ibuprofen lysine will be preferable because of its better toxicity profile. Medical therapy should still be attempted for PDA closure beyond 7 days of age with the knowledge that treatment may be ineffective, as nonprostaglandin mechanisms are involved in keeping ductal patency by this age. Surgical ligation should be reserved for resistant symptomatic PDA that did not respond to medical and pharmacologic therapy.
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