Combination of Acetaminophen and Ibuprofen in the Management of Patent Ductus Arteriosus
Condition: Patent Ductus Arteriosus; Neonate
MeSH terms: Ductus Arteriosus, Patent
Study type: Interventional
Phase: Phase 1

Summary: 
      Patent ductus arteriosus or PDA is a blood vessel that connects the right and left side of
      the heart that usually closes after birth but remains open in some premature infants born
      before 30 weeks' gestation. When this blood vessel remains open for a long time, it may cause
      problems such as bleeding in the lung and brain, lung injury due to prolonged need of
      ventilator, and poor kidney function. It sometimes becomes necessary to close this blood
      vessel in the preterm infant. Currently, this blood vessel can be closed either by medication
      or surgery. Pain medications such as Ibuprofen and Indomethacin are routinely used
      medications to close PDA. However, in the last 5 year, acetaminophen has been found as an
      alternative medication to close PDA in preterm infants. In multiple studies, acetaminophen is
      found to be a safe alternative medication with lower side effects than current standard
      management. Intravenous Ibuprofen is approved by FDA to treat PDA in preterm infants.
      Although not approved by FDA, oral ibuprofen is being used for the management of PDA.
      However, the success rate of a single medication is approximately 70%. Both medications have
      been used in the previous clinical studies to treat the same condition in the preterm infants
      and fewer side effects were reported. Mechanism of both medications to close PDA is different
      and may work more effectively together than single medication alone. In this study, the
      investigator are going to use these two medications (Ibuprofen and Acetaminophen) at the same
      time if the child needs treatment and is eligible to participate in this study. This study is
      based on the assumption that by using both medications at the same time, investigator can
      close this blood vessel more effectively than with either drug alone.
    

Detailed description: 
      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.
    

Intervention name(s): Acetaminophen; ibuprofen
Intervention type(s): Drug; Drug
Intervention description(s): Oral acetaminophen [160 mg/5ml concentration] will be administered every 6 hours with dose of 15 mg/kg/dose for a total of twelve doses; Oral ibuprofen [100 mg/5 ml] at 10 mg/kg/dose on first day followed by 5 mg/kg/dose at 24 and 48 hours for a total of three doses
Other intervention name(s): Tylenol; Motrin
Intervention MeSH terms: Acetaminophen; Ibuprofen
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment