Enteral Paracetamol or Intravenous Indomethacin For Closure of PDA In Preterm Neonates:RCT

Dr. Zaheen Zehra N
1st Year MD PAEDIATRICS
JOURNAL CLUB

Enteral Paracetamol or Intravenous
Indomethacin For Closure of PDA In
Preterm Neonates: A Randomised
Control Trial.
 Indian Pediatrics.
Received: August 06, 2014;
Initial review: October 04, 2014;
Accepted: April 21, 2015.

Indian Pediatrics
 The official publication of the Indian Academy of Paediatrics
(IAP),
 Indexed by leading international services including Index
Medicus.
 The journal began publication in 1963.
 Indian Paediatrics has a permanent Editorial Office situated at
New Delhi, India.
 It is published monthly and has a current circulation of about
23,000.
 The journal gives priority to reports of outstanding clinical and
experimental work as well as important contributions related to
common and topical problems in India and the developing
countries

AUTHORS
 Swarup Kumar Dash, Nandkishor S Kabra,
Bhupendra S Avasthi, Shobha R Sharma,
Phalguni Padhi and Javed Ahmed
From Department of Neonatology,
Surya Children’s Hospital.
Correspondence to: Dr Nandkishor S Kabra,
Department of Neonatology,
Surya Children’s Hospital.

OBJECTIVE
 To compare the efficacy of enteral
paracetamol and intravenous
indomethacin for closure of patent
ductus arteriosus (PDA) in preterm
neonates.

OUTCOMES
 Primary Outcome: PDA closure rate assessed by
echocardiography.
 Secondary Outcome:
Need for surgical closure of PDA
Renal impairment
Gastrointestinal bleed
Necrotising enterocolitis
Hepatotoxicity
Pulmonary hemorrhage
Sepsis
Hypothermia
Retinopathy of prematurity
Intraventricular hemorrhage
Bronchopulmonary dysplasia
Mortality.

METHODOLOGY
 Study Design: Randomized controlled trial.
 Setting: Level III neonatal intensive care unit.
 Participants: 77 preterm neonates

SELECTION CRITERIA
 Inclusion Criteria:
1. Preterm infant with birth weight <1500 grams
2. Echocardiography performed within the first 48
hours of life
3. Demonstrating PDA size1.5 mm at the
narrowest diameter
4. Left to right shunt across the duct and ratio of
the diameter of the left atrium to that of the aortic
root (LA:AO) >1.5:1

 Exclusion Criteria:
1.Inability to administer the study drug within 48
hours of birth
2.Structural duct-dependent congenital heart
disease, renal disease (such as multicystic
dysplastic kidney and polycystic disease of kidney)
3.Dysmorphic features or congenital anomalies
likely to affect life-expectancy or neurologic
development
4.Maternal tocolytic therapy with indomethacin or
another prostaglandin inhibitor within 72 hrs prior to
delivery
5.Overt clinical bleeding at more than one site
6. Platelet count <50×109/L
7. Hydrops fetalis

INTERVENTION DONE
 Paracetamol drops through the infant feeding
tube 15mg/kg/dose 6 hourly for 7 days
or
 intravenous indomethacin
0.2 mg/kg/dose once daily for 3 days.

Grouping of Subjects
 All eligible neonates were randomized into two
groups, using a 1:1 ratio.
 Random sequence generation was performed by
using random allocation software in variable
blocks of 2 or 4.
 Allocation concealment was done by sequentially
numbered sealed opaque envelopes.

ADMINISTRATION OF
PARACETAMOL
 Patients received paracetamol drops (Calpol drops,
100 mg/mL, Glaxo SmithKline) through the infant
feeding tube.
 At a dose of 15 mg/kg/dose four times daily for 7
days
 Total of 28 doses.

ADMINISTRATION OF
INDOMETHACIN
 IV indomethacin (1mg/mL, Lygacin IV, Alliance
Overseas).
 At a dose of 0.2 mg/kg/dose, diluted with normal
saline to make 5 mL solution and infused over 20
minutes by syringe pump once daily for three
days.
 Two additional extra doses of indomethacin were
allowed in the indomethacin group, if clinical
evaluation after three doses showed persistence
of PDA as demonstrated by clinical signs and
symptoms such as tachycardia, wide pulse
pressure and persistent murmur.

SCREENING- Primary
Outcome
 Closure of PDA:
ECHO:
1. 1st within 48 hours.
2. Follow up echo-completion of 7 days.
3. The PDA was considered to be closed if
there was no evidence of any flow in the ductus
arteriosus on echocardiographic and doppler flow
assessment.

SCREENING- SECONDARY
OUTCOMES
 Renal Impairment:
1. Oliguria (urine output of < 0.5 mL/kg/hr) over
a 6 hour period
2.Serum creatinine levels more than twice the
normal value
 GI Bleed:
1.Presence of blood- stained or coffee ground
brown gastric aspirates.
2. Mild gastric aspirate - blood-stained or altered
brownish blood in the aspirate.
3. Major GI bleeding - frank blood in the gastric
aspirate.

CONTD
 Hepatotoxicity:
1.If the hepatic enzymes were elevated more
than twice of
the normal reference values.
2. LFT was measured at the day 7 of life.
 Pulmonary Hemorrhage:
1. Pulmonary hemorrhage was diagnosed if a
blood tinged tracheal aspirate was obtained.
 Hypothermia:
1. Temperature <36º celsius during the therapy
period.

 Sepsis:
1. Positive C-reactive protein (CRP) before and
after first 72 hours of life.
2. Early-onset sepsis was defined as isolation of
pathogenic organism from a blood culture
collected in first 72 hours of life.
3. Late onset sepsis was defined as isolation of
pathogenic organism from a blood culture
collected after first 72 hours of life.
4. All blood cultures were collected in
BacT/ALERT 3D (Bio-merieux) blood culture
bottles

 Retinopathy of Prematurity:
1. Based on International classification of ROP.

 Intraventricular Hemorrhage:
1. Neuro-sonography was performed at least
twice.
2. First sonography between day 5 to 7 of life.
3. Second sonography between days 21 to 28 of
life.
4. A third cranial ultrasonography at 36 weeks
corrected gestational age.
5. Grading of intraventricular hemorrhage (IVH)
was performed according to the Papile grading
system.

 BronchoPulmonary Dysplasia:
Bronchopulmonary dysplasia (BPD)
/chronic lung disease (CLD) was defined by the
need for supplemental oxygen at 36 weeks of
postmenstrual age.

Statistical Methods
 The estimated sample size was 77 (38 in
Paracetamol and 39 in indomethacin)
 To compare the outcome variables on continuous
and ordinal scale:
Two sample t tests or the Mann Whitney test
were used.
 To compare the outcome variables on nominal
type of data:
Fisher exact test was used.
 Analysis was performed by using IBM SPSS 21
software.

Comparison of PDA Closure Rate and Adverse Events
With Paracetamol and Indomethacin

Result
 Enteral paracetamol is safe but not superior to
intravenous indomethacin.
 No significant Difference in Secondary Outcomes.

Limitations Of The Study
 Lack of blinding of the caregivers to the study
intervention.
 Spontaneous PDA closure during the first 7 days.
 Only evaluated short-term outcomes, in a
selected group of premature infants, mainly SGA.

Conclusion
 Oral paracetamol is safe but not superior to
intravenous indomethacin in closure of PDA.
 In developing countries, where intravenous
indomethacin use is constrained by scarcity, high
cost and difficulty in monitoring the side effects,
oral paracetamol may be considered as an
alternative.

Enteral Paracetamol or Intravenous Indomethacin For Closure of PDA In Preterm Neonates:RCT

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