Paracetamol Treatment of the Borderline Significant PDA

Study Overview
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Brief Summary
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The therapeutic approach to the patent ductus arteriosus (PDA) in the premature neonate remains controversial. Currently it is generally accepted to treat only hemodynamically significant PDAs. The current investigation aims to study the effect of treatment on PDAs of borderline significance via a prospective, randomized controlled trial of paracetamol in this group.

Detailed Description
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In the neonatal intensive care unit of the Shaare Zedek Medical Center, preterm babies <30 wks. GA, are studied echocardiographically on day of life 3-4. Pending parental informed consent, those diagnosed with a PDA of borderline significance will be randomized to receive either paracetamol or placebo for three days, followed by a repeat echocardiogram. If the PDA remains of borderline significance, the treatment will be continued for an additional 4 days (1 week total). Paracetamol levels and liver functions will be assessed after the third day. Babies will be followed until discharge for subsequent PDA pathology; respiratory distress and chronic lung disease [CLD]; necrotizing enterocolitis [NEC]; retinopathy of prematurity [ROP]. The investigators' primary goal is to demonstrate a decrease in the composite outcome of death or severe morbidity chronic lung disease [CLD], as shown by decreased time on supplemental oxygen and assisted ventilation. Secondary goals: To demonstrate a decrease in subsequently diagnosed hs PDA, including Decrease in the need for subsequent therapy for PDA closure Decrease in surgical PDA ligations To demonstrate a decrease in necrotizing enterocolitis (NEC) and/or ROP with treatment. To demonstrate no adverse effect on blood flow in anterior cerebral, superior mesenteric and renal arteries.

Official Title
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TIME TO RE-EVALUATE THE KINDER GENTLER APPROACH TO PATENT DUCTUS ARTERIOSUS (PDA) IN THE PRETERM NEONATE

Conditions
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Patent Ductus Arteriosus

Intervention / Treatment
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* Drug: Paracetamol drops
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Preterm neonates < 30 weeks' gestational age PDA of borderline significance Exclusion Criteria: Infants not deemed likely to survive more than one week Infants with congenital heart malformations Infants with pulmonary hypertension and right to left ductal shunting

Ages Eligible for Study
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Minimum Age: 3 Days
Maximum Age: 6 Days

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Control Group<br>Treatment with placebo at a volume of 2.25 cc/kg/dose x 4/day to be given with feeds, or in place of feed when baby is receiving <2 cc/kg/feed. | Other: Placebo<br>* 2.25 ml/kg/dose x 4/day of sterile water to be given for three days<br>|
| Active Comparator: Treatment Group<br>Treatment with paracetamol drops at 15 mg/kg/dose x 4/day. Drops will be diluted 1:15 in order to reduce osmolality. This will yield a dose of 2.25 ml/kg/dose, to be given with feeds, or in place of feed when baby is receiving <2 cc/kg/feed. | Drug: Paracetamol drops<br>* 15 mg/kg/dose x 4/day diluted 1:15 yielding dose of 2.25 ml/kg/dose to be given for three days<br>* Other names: Novimol;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite outcome of death or severe morbidity chronic lung disease [CLD] | Chronic lung disease will be assessed by time on supplemental oxygen and assisted ventilation. | Day of life 3 until 40 weeks post-conception | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Subsequently diagnosed hs PDA | Will be assessed by subsequent need for medical or surgical intervention for closure of PDA | Completion of study intervention until 40 weeks post-conception | 
| Subsequent incidence of necrotizing enterocolitis (NEC) and/or retinopathy of prematurity (ROP) | Study infants will be followed clinically and any occurrence of NEC or ROP will be recorded with its level of significance (Bell staging for NEC and Stage of ROP) | Completion of study intervention until 40 weeks post-conception |