Acetaminophen vs Indomethacin in Treating hsPDA

The study will be a randomized, controlled, non-inferiority trial, and we plan to enroll
premature infants <32 weeks, <1500g, and who are < 21 days of age at Regional One Health,
LeBonheur Children's Hospital, and Methodist Germantown NICUs in Memphis, TN. A study group
of 42 patients for each group will be needed to allow a maximum difference of 25% to consider
non-inferiority in the closure rate between IV acetaminophen and IV indomethacin (with power
of 80% and alpha of 0.05).2 Our goal will be to enroll 50 infants for each treatment group,
to help with an expected 20% drop out rate either due to complications or parents removal of
consent. Dosages: IV acetaminophen 15mg/kg/dose every 6 hours for 12 doses,6 IV indomethacin
dose will depend on age.IV indomethacin will be given every 12 hours for 3 doses. The infants
will be eligible for the study after primary attending has made the decision to treat the
hsPDA. The goal will be 50 infants in the IV acetaminophen group and 50 infants in the IV
indomethacin group.

Informed consent will be obtained from the parent after ECHO has been obtained and the
primary attending has decided to treat PDA in the infant who meets inclusion criteria without
any of the exclusion criteria. We will use block randomization and stratify by site to
generate 140 random values of either 0 for acetaminophen or 1 for indomethacin. The goal will
be 50 infants randomized to acetaminophen group and 50 infants randomized to indomethacin
group. The numbers will be placed in opaque envelope and opened after consent is obtained.
The primary team will not be blinded given the different frequencies of administration of
acetaminophen and indomethacin. The first ECHO will be read by staff pediatric cardiologist.
A pediatric cardiologist will retrospectively go back and read all ECHOs blinded for
standardization.

Prior to induction of treatment, we will record complete blood count (CBC) and complete
metabolic panel (CMP) with AST/ALT. After treatment, we will record AST/ALT within 48 hours,
and we will record follow-up ECHO reports that occur within seven days of initiation of
treatment. The decision to repeat treatment will be left to primary attending's discretion.
The primary attending will determine any additional medical or surgical treatment if
indicated. Data regarding ROP, IVH, and BPD will be collected from patient's chart prior to
discharge.

Primary outcome will be the rate of successful PDA treatment by ECHO in each group.
Successful PDA treatment will be defined as no longer meeting ECHO criteria for hsPDA.
Secondary outcome data will be recorded and include the following: retreatment, surgical
closure, days on invasive mechanical ventilation, duration of supplemental oxygen
requirement, respiratory support at 36 weeks post-menstrual age (PMA), NEC, ROP, days to full
feeds, gastrointestinal perforation, length of stay, renal dysfunction defined by UOP <
1cc/kg/hr in an 8 hour period, creatinine elevation greater than 1.5 mg/dL, and discharge
disposition.

Inclusion Criteria:

- Gestational age at birth 22 weeks to 31 6/7 weeks.

- Birth weight ≤ 1500 grams

- Day of life ≤ 21 days

- ECHO findings:

Left-to-right ductal flow AND 2 of the following 3:

- Ductal size > 1.5mm at smallest diameter

- Reversal of flow in descending aorta

- Left atrial size to aortic root ratio >1.5

- Platelet count > 50,000

Exclusion Criteria:

- Ductal dependent congenital heart disease

- Major congenital anomaly

- Life-threatening infection

- Urine output < 1cc/kg/hr in prior 8 hours

- Serum creatinine > 1.8 mg/dL

- Hyperbilirubinemia requiring exchange transfusion

- Active NEC Stage 2 or 3 using Bell's staging criteria

- Active intestinal perforation

- Liver dysfunction [2x upper limit of normal for aspartate aminotransferase(AST) and/or
alanine aminotransferase (ALT)]

- Active GI bleeding

- Concurrent hydrocortisone use

- Known IVH Grade 3 or 4