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:

1. Infant with gestational age 23 to 30 weeks at birth and birth weight between 500 -
1000 grams

2. Postnatal age less than equal to 14 days

3. Hemodynamically significant PDA as defined by any of the following:

1. Increased ventilator support attributed by the clinician to be due to PDA

2. Hypotension and/or widening pulse pressure requiring vasopressors

3. Signs of congestive heart failure such as pulmonary congestion

4. Echocardiographic criteria:

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

Exclusion Criteria:

1. PDA-dependent congenital heart disease

2. Prior treatment with prophylactic indomethacin

3. Significant hyperbilirubinemia requiring exchange transfusion

4. Active or suspected necrotizing enterocolitis (NEC) and/or intestinal perforation

5. Abnormal liver enzymes

6. Platelets count < 50000 /l and / or active intracranial or gastrointestinal bleeding
or from any other site

7. Major congenital anomalies such as neural tube defect, chromosomal abnormality and
gastrointestinal defect