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

Study Overview
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Brief Summary
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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
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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.

Official Title
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Combination of Acetaminophen and Ibuprofen in the Management of Patent Ductus Arteriosus in Premature Infants: A Pilot Study

Conditions
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Patent Ductus Arteriosus, Neonate

Intervention / Treatment
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* Drug: Acetaminophen
* Drug: ibuprofen


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 23 Weeks
Maximum Age: 30 Weeks

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Interventional Group<br>Preterm infants who met the eligibility criteria will receive both oral acetaminophen and ibuprofen. 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 and 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 | Drug: Acetaminophen<br>* 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<br>* Other names: Tylenol;Drug: ibuprofen<br>* 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<br>* Other names: Motrin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ductal closing rate | To determine the ductal closure rate on echocardiography after completion of a first treatment course. | within 24-48 hrs after completion of treatment. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of ductal reopening | Echocardiographic evidence of closure followed by later re-opening of ductus if further echocardiogram is indicated. | From birth until discharge / 36 weeks post menstrual age | 
| Neonatal outcomes - Sepsis | late-onset sepsis duration of hospital stay and death. Late onset sepsis: Defined as clinical signs of sepsis associated with a positive blood culture after 3 days of age. | until discharge / 36 weeks post menstrual age | 
| Neonatal outcomes - Necrotizing Enterocolitis | Necrotizing Enterocolitis (NEC): defined as stage 2 or greater duration of hospital stay and death. | until discharge / 36 weeks post menstrual age | 
| Neonatal outcomes - Bronchopulmonary Dysplasia | Late-onset bronchopulmonary dysplasia (BPD) is defined as oxygen requirement at 36 weeks or discharge for less than 32 weeks gestational infants duration of hospital stay and death. | until discharge / 36 weeks post menstrual age | 
| neonatal outcomes - Ventilator days | The number of days that ventilator support is needed during hospitalization. | until discharge / 36 weeks post menstrual age | 
| Neonatal outcomes- Intraventricular Hemorrhage | Late-onset severe intraventricular hemorrhage (IVH): IVH grade 3 and 4 both duration of hospital stay and death. | until discharge / 36 weeks post menstrual age | 
| Neonatal outcomes - Periventricular Leukomalacia | late-onset periventricular leukomalacia information will be derived from routine head ultra sounds (US) at 36 weeks / discharge as a standard of care duration of hospital stay and death. | until discharge / 36 weeks post menstrual age | 
| Neonatal outcomes - Retinopathy of Prematurity | Retinopathy of prematurity (ROP): severity of ROP will be derived from eye examination by pediatric ophthalmologist duration of hospital stay and death | until discharge / 36 weeks post menstrual age | 
| Nutritional status - Weight | Weight in grams at birth and discharge or 36 weeks post menstrual age converted to percentile or Z score by using Fenton 2013 growth chart. | until discharge / 36 weeks post menstrual age | 
| Nutritional status - Length | length in centimeters (cm) at birth and discharge or 36 weeks post menstrual age converted to either percentile or Z score by using Fenton 2013 growth chart. | until discharge / 36 weeks post menstrual age | 
| Nutritional status - Head Circumference | Head circumference (HC) in cm at birth and discharge or 36 weeks post menstrual age converted to either percentile or Z score by using Fenton 2013 growth chart. | until discharge / 36 weeks post menstrual age |