Combination of Acetaminophen and Ibuprofen in the Management of Patent Ductus Arteriosus

The ductus arteriosus is an essential blood vessel that connects the pulmonary artery and the aorta in the fetus. The patent ductus arteriosus (PDA) allows oxygenated blood that returns from the placenta to bypass the lungs and supply the fetal systemic circulation. In fetal life, ductus remains open due to low partial pressure of oxygen, circulating or locally produced prostaglandins and local nitric oxide production. Constriction of ductal vascular smooth muscle (functional closure) occurs within few hours of delivery due to decrease level of prostaglandin and rising oxygen concentrations. Closure of ductus can be affected by several perinatal and postnatal factors such as growth restriction, sepsis, and fluid overload. Spontaneous PDA closure occurs in > 34% extreme premature infants compared to > 95% in infants with birth weight more than 1500 grams. In a prospective study, 65 infants less than 1500 g birth weight were closely followed by serial echocardiograms. Sensitivity of ductal tissue to oxygen and prostaglandin differs in preterm compared to term infants. Without sufficient physiologic hypoxia, the ductus may fail to close or may reopen after initial constriction. Several co-morbidities have been associated with prolonged patency of the ductus in preterm infants (e.g., prolonged ventilator support, bronchopulmonary dysplasia, pulmonary hemorrhage, impaired renal function, intraventricular hemorrhage and cerebral palsy). Preterm infants with uncomplicated respiratory course, PDA is commonly managed conservatively. Currently hemodynamically significant PDA are managed medically (indomethacin and ibuprofen) and surgically. Recently, acetaminophen has gained attention as an alternative for PDA management due to its low cost, wide availability and the potential for fewer side effects. In two randomized controlled trials comparing acetaminophen with ibuprofen, authors have shown comparable closure rate of PDA with acetaminophen.

To our knowledge, a combination of the drugs has not been used to treat PDA in preterm infants and prospective study has not been conducted or published to determine the effectiveness of a combination of ibuprofen and acetaminophen in the treatment of PDA. As both medications are metabolized through different organs (hepatic and renal), the investigator assume that incidence of adverse events should not be affected. The Investigator hypothesize that the combination of oral ibuprofen and oral acetaminophen will be more effective, because the mechanisms of action differ for the two medications and hence may produce therapeutic synergy.

Inclusion criteria

• Infant with gestational age 23 to 30 weeks at birth and birth weight between 500 - 1000 grams
• Postnatal age less than equal to 14 days
• Hemodynamically significant PDA as defined by any of the following:

• Increased ventilator support attributed by the clinician to be due to PDA
• Hypotension and/or widening pulse pressure requiring vasopressors
• Signs of congestive heart failure such as pulmonary congestion
• Echocardiographic criteria:

• Ratio of the smallest ductal diameter to the ostium of the left pulmonary artery > 0.5

Exclusion criteria

• PDA-dependent congenital heart disease
• Prior treatment with prophylactic indomethacin
• Significant hyperbilirubinemia requiring exchange transfusion
• Active or suspected necrotizing enterocolitis (NEC) and/or intestinal perforation
• Abnormal liver enzymes
• Platelets count < 50000 /l and / or active intracranial or gastrointestinal bleeding or from any other site
• Major congenital anomalies such as neural tube defect, chromosomal abnormality and gastrointestinal defect