Evidence-Based Use of Indomethacin and Ibuprofen in the Neonatal Intensive Care Unit
Section snippets
Pharmacology of indomethacin and ibuprofen
Within the body, synthesis of prostaglandins occurs when arachidonic acid is freed from lipid storage by phospholipase A2. Subsequently, cyclooxygenase (COX) converts arachidonic acid to PGG2 and PGH2. PGH2 is the precursor to multiple types of prostaglandins, including PGE2, PGD2, PGF2α, and PGI2 and thromboxane.13 Prostaglandins are known to play a critical role in the pathophysiology of PDA, thus, inhibiting the production of these vasoactive substances has been the goal of pharmacologic
Efficacy when Treatment is Indicated
NSAIDs are an effective measure to induce PDA closure. Following the initial reports of Friedman and Heymann in the mid-1970s, many studies were published in the early 1980s showing a significant decrease in the presence of PDA after infants were treated with indomethacin compared with control. Rates of initial ductus closure in infants born weighing less than 1750 g range from 60% to 86% after a treatment course of indomethacin.7, 33, 34, 35, 36, 37, 38, 39 By comparison, spontaneous closure
Gastrointestinal Effects
Untoward gastrointestinal events occur with increased frequency in infants treated with NSAIDs. These adverse effects may be greater with indomethacin than ibuprofen and depend on the mode of administration, with rectal and enteral forms having greater toxicity.2, 75
Prophylactic treatment to prevent IVH or hsPDA
Preventive strategies for IVH co-evolved with efforts to effectively treat PDA. Because the smallest preterm infants are at the greatest risk of developing an hsPDA, both indomethacin and ibuprofen have been used in attempts to prevent progression to an hsPDA, reduce left-to-right shunting of blood away from vital organ systems, and avoid surgery.149
Observational treatment of PDA
Justification for PDA treatment was traditionally based on evidence that prolonged exposure to a significant left-to-right shunt was deleterious. Morbidities attributed to the presence of an hsPDA have included BPD, pulmonary hemorrhage, increased RDS severity, NEC, renal impairment, IVH, periventricular leukomalacia, and death.102 However, numerous investigators have challenged the cause-and-effect relationship between PDA and these outcomes and questioned whether exposure to the risks of
Summary
Symptomatic PDA is a well-documented complication of premature birth and is associated with multiple other morbidities. Studies over the past decade have challenged the seemingly foregone conclusion that a symptomatic PDA should be treated on the grounds that short-term morbidities and long-term outcomes may not be improved by PDA closure and infants are unnecessarily exposed to potentially harmful therapies. Yet, no randomized, double-blinded clinical trials comparing the treatment of
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