seminar PDA

Welcome to Seminar
Dr. Shimul Mandal (Year 3)
Dr. Md. Sazzadul Alam (year 4)
Resident
Department of Neonatology
BSMMU

Case summary
• S/O Jannatul Preterm(29 weeks) LBW(1600 gm)
AGA ,baby developed repeated apnea,
desaturation from 75 hours of age on CPAP then
put on mechanical ventilation. At day 7 there was
systolic murmur in left upper chest with high
pulse volume & normal blood pressure, other
parameter was normal on MV support.
• What may be possibilities behind these scenario?

Contents
• History
• Definition
• Embryology
• Fetal circulation
• New adaptation after birth
• Incidence
• Classification
• Risk factor
• Pathophysiology
• Diagnosis
• Management
• Literature
• Prognosis

History
 In the early first century(181 AD) Galen initially described
the ductus arteriosus
 Harvey undertook further physiologic study in fetal
circulation
 In 1888 Munro conducted the dissection & ligation of the
ductus arteriosus in an infant cadaver
 In 1938 Robert E. Gross successfully ligated a PDA in a 7
years old child
 Catheter based closure first performed in 1971
 In 1998 Amplatzer duct occluder(ADO) was introduced
 Amplatzer duct occluder II additional size(ADO II AS) are
currently being used.

INTRODUCTION
 The ductus arteriosus is a large
vessel that connects the main
pulmonary trunk (or proximal
left pulmonary artery) with the
descending aorta, some 5–10
mm distal to the origin of the
left subclavian artery.
 Patent ductus arteriosus
(PDA) refers to the failure of
the closure process and
continued patency of this fetal
channel.
Tricia Lacy Gomella 7th edition

Embryology
In normal cardiovascular
development the distal
portion of the left sixth
aortic arch persists as the
ductus arteriosus,
connecting the left
pulmonary artery with
the left dorsal aorta. This
transformation is
complete by 8 weeks of
fetal life.

Fetal
circulation
PDA : R-L shunting
Pulmonary vascular
resistance : High
Systemic vascular
resistance : Low

Major changes in infant circulation occurs
following birth:
• Pulmonary Circulation:
Lungs expand,
Pulmonary Vasodilation,
Drop in pulmonary vascular resistance
• Systemic Circulation:
↑resistance with placental removal
• PDA:
Flow reverses to L→R shunting,
Begins to functionally close due to ↑PaO2 and ↓PGE2
levels

PATENT DUCTUS ARTERIOSUS
 The ductus arteriosus is patent in
all newborns at the time of
delivery.
 In full-term healthy newborns,
functional closure of the ductus
occurs in almost half of full-term
infants by 24 hours of age, in 90%
by 48 hours after birth.
 A ductus open beyond 72 h can be
considered to be a persistently
patent ductus arteriosus.
Rennie & Roberton’s Text book of Neonatology 5th edition

Physiology of closure of DA
Functional closure(10-15 hrs after birth):
Within few hours of birth increased PaO2 & decreased
circulating prostaglandins
Constriction of inner smooth muscle of the DA
Anatomical closure(by 2-3 weeks):
DA become ischaemic & hypoxic
Formation of vascular endothelial growth factor & other
growth factors
Transforming the DA into a non-contractile ligament
(Ligamentum arteriosum)
A comprehensive approach to congenital heart diseases: IB Vijayalaksmi

Incidence
 In term neonate: 1/2000 live birth(5% to 10% of all CHD)
 In preterm neonate: 8/1000 live birth(20-42%)
 In preterm neonates PDA is inversely related to
gestational age & maturity.
 In preterm neonates weighing less than 1000gm: 80%
 F>M (2:1)
 A PDA is seen in 10% of patients with other congenital
heart lesions .

• Title: Patent Ductus Arteriosus: An Overview
• James E. Dice, PharmD and Jatinder Bhatia, MBBS
• Source: J Pediatr Pharmacol Ther. 2007 Jul-Sep; 12(3): 138–146
• They reported incidence of PDA in term neonates is only 1 in
2,000 births, accounting for 5%–10% of all congenital heart
disease. The incidence of PDA in preterm neonates is far
greater, with reports ranging from 20%–60% (depending on
population and diagnostic criteria).Gestational age and weight
are intimately linked to PDA in preterm neonates. Specifically,
PDA is present in 80% of infants weighing less than 1,200 g at
birth, compared to 40% of infants weighing less than 2,000 g
at birth. Furthermore, symptomatic PDA is present in 48% of
infants with a birth weight of less than 1,000 g.

Classification of PDA
A. Depending on the size (size of the internal ductal
diameter in the lateral angiographic view ):
 Silent : ˂ 1 mm
 Very small : ≤ 1.5 mm
 Small : 1.5-3 mm
 Moderate : 3-5 mm
 Large : >5 mm

Type A - conical duct with well
defined aortic ampulla and
constriction near the
pulmonary artery end.
Type B - window like structure
which is very short in length.
B. According to Shape

Type C - tubular duct without any
constriction.
Type D - complex duct with multiple
constrictions.
Type E - elongated duct with
constriction remote from the edge of
the trachea (as viewed on lateral
angiography).

Risk Factors
Factors associated with increased incidence of PDA
1. Prematurity: The incidence is inversely related to
gestational age. PDA is found in ~45% of infants <1750 g &
80% in infants weighing <1000 g
2. Respiratory distress syndrome (RDS)
3. Fluid administration
4. Asphyxia
5. Congenital syndromes: PDA is present in 60–70% of
infants with congenital rubella syndrome. Trisomy 13,
trisomy 18.
6. High altitude
7. Congenital heart disease: A PDA may occur as part of a
congenital heart disease

Factors associated with decreased incidence of PDA:
1. Antenatal steroid administration
2. Intrauterine growth restriction
3. Prolonged rupture of membranes

Pathophysiology
Left-to-Right Shunting:
The magnitude of shunt depends
on :
 The diameter and length of
the ductus arteriosus.
 The pressure difference
between the aorta and the
pulmonary artery
 The systemic and pulmonary
vascular resistances.

Cont…
 Left-to-right shunt through the ductus arteriosus
results in pulmonary over-circulation and left heart
volume overload.
 If the PDA is small, pressures within the pulmonary
artery, the right ventricle and the right atrium are
normal.
 In Moderate or large PDA pulmonary artery pressure
may be elevated to systemic levels during both
systole and diastole, causes decreased lung
compliance, which results in increased work of
breathing.

Cont…
 Neuroendocrine adaptations also occur, with
increased sympathetic activity and circulating
catecholamines that result in increased contractility
and heart rate.
 Long-standing left-to-right shunt causes increased
pulmonary vascular resistance. When this resistance
approaches and exceeds systemic vascular
resistance, leads to reversal of the shunt and
develops Eisenmenger’s syndrome.

What makes the PDA hemodynamically
significant?
Pulmonary Overcirculation:
 Oxygenation failure
 Increased ventilation
requirements
 Pulmonary Edema
 Cardiomegaly
Systemic Hypoperfusion:
 Systemic Hypotension
 End-Organ
Hypoperfusion
 Renal Insufficiency
 NEC
 IVH
 Acidosis(Metabolic,
Lactic)

Congenital malformation of cardiovascular system in BSMMU
from 01/07/18 to 30/06/19
Birth Defect type Male Female Total
ASD 19 10 29
VSD 6 8 14
PDA 5 4 9
Double inlet ventricle 0 2 2
Common atrium 1 2 3
Atrioventricular septal defect 1 1 2
Patent/persistent foramen ovale 1 0 1
Sinus venosus defect 1 0 1
Congenital pulmonary valve stenosis 1 0 1
Ebstein’s anomaly 1 0 1
Hypoplastic left heart syndrome 0 1 1
Congenital mitral stenosis 2 0 2
Dextrocardia 2 0 2
Other cong. Malformation of heart 2 1 3
Total 42 29 71

History
 Risk factor
 Prematurity
 Respiratory distress with surfactant
 Fluid administration
 Asphyxia
 Sex
 Congenital syndromes
 Genetic factor
 No Antenatal steroid
 Frusemide Tricia Lacy Gomella 7th edition
Mildred T et al

Clinical Presentation
– Usually 1-4 days of age, may at birth
– Respiratory deterioration
– Apnea
– Tachypnea

Clinical complication
– Metabolic Acidosis
– Intracranial haemorrhage
– NEC
– Pulmonary oedema
– Haemorrhage

Hypotension
Crackles
Hepatomegaly

Investigation
• Echocardiography : Gold standard
– Direct visualization
• Shunt:
o Size
o Shape
– Direction of flow
– Secondary effect
– Contractility

Shape of PDA

Biomarker
– Natriuretic peptide
• ANP
• BNP
• N –terminal pro BNP
Care of the Newborn Revised 8th edition:Maharban singh

Predict the development of symptom
• Birth wt <1500 gm & <10 days of age, PDA 1.5
mm
• Left atrial : aortic root > 1.5 after 1st day
• Doppler wave form(Closing pattern)
• Pulsatile pattern

Indications for treatment(Preterm)
• hsPDA with one of the following
– Features of CHF
– Prolong respiratory support
– Unexplained/↑ O2 requirement
– Recurrent apnea requiring respiratory
support(CPAP/MV) attributed to PDA.
AIIMS Protocol: 1st edition 2015

Treatment
• 1st line :
– Respiratory support
• O2 Support
• Ventilator support
– Fluid restriction
– ↑ Hematocrit
– Diuretic therapy

Drug therapy
• Duct closure therapy by drug
• Usually tried 1st unless contraindication
• Contraindication:
– GIT/Renal anomaly
– Suspected CHD
– Suspected/Active necrotising endocarditis
– Active bleeding/PLT <50000/cmm
– U/O <0.6ml/kg/hr
– S.Creatinine ↑
– Active infection

Drug therapy
– Indomethacin
– Ibuprofen
– Acetaminophen(Not approved by FDA)

Indomethacin
• Prophylactic
– Criteria
• All infants <1250 gm with surfactant for RDS
(Before any clinical sign)
– Dose: 0.1 mg/kg
– Route : I/V
– Duration: Daily for day 6(From 1st day)

Indomethacin
• Early symptomatic
– Dose: I/V
– O hrs: 0.2 mg/kg
– 12 hrs : 0.1 mg/kg
– 36 hrs: 0.1 mg/kg
BW >1250 gm
or
PNA >7 days
2nd & 3rd dose 0.2 mg/kg
BW <1250 gm
PNA <7 days

Indomethacin
• Late symptomatic
– Dose :0.25 mg/kg
– When sign of congestive cardiac failure
– Usually 7-10 days

Indomethacin
• Complication:
– Renal effect
– GIT bleeding
– Thrombocytopenia

Ibuprofen
• Within 1st wk
– Dose :
• 0 hrs : 10 mg/kg
• 24 hrs: 5 mg/kg
• 48 hrs: 5 mg/kg
• At 2nd wk
– Dose :
• 0 hrs : 18mg/kg
• 24 hrs :9 mg/kg
• 48 hrs :9 mg/kg
Advantage comparision with indomethacin
Not ↓ Mesenteric blood flow
Not ↓ Renal blood flow
↑Urine ourput
↓ S.Creatinine

Surgery
• Surgery: Significant PDA
– Contraindication of indomethacin
– Indomethacin ineffective
– Relapse after 2nd short course
– Failure of medical therapy
– Intractable congenital heart failure with
progressive cardiomegaly & deteriorating
pulmonary compliance
Care of the Newborn Revised 8th edition:Maharban singh

PDA in Term Baby
• Term neonates with PDA should not be
treated with indomethacin/ ibuprofen and
should have a detailed echo to rule out an
underlying congenital heart defect. They
would require surgery for closure of an
isolated patent ductus arteriosus.
AIIMS- NICU protocols 2007

Cont…
• Selection criteria Randomised or quasi-randomised controlled
trials of ibuprofen for the treatment of a PDA in preterm, low birth
weight, or both preterm and low-birth-weight newborn infants
• Ibuprofen (IV or oral) compared with indomethacin (IV or oral):
Twenty-four studies (1590 infants) comparing ibuprofen (IV or oral)
with indomethacin (IV or oral) found no significant differences in
failure rates for PDA closure
There was a statistically significant reduction in the proportion of
infants with oliguria in the ibuprofen group (6 studies,576 infants)
The serum/plasma creatinine levels 72 hours after initiation of
treatment were statistically significantly lower in the ibuprofen group
(11 studies, 918 infants)

Cont…
• Ibuprofen (oral) compared with indomethacin (IV or
oral): Eight studies (272 infants) reported on failure
rates for PDA closure in a subgroup of the above
studies comparing oral ibuprofen with indomethacin
(IV or oral). There was no significant difference
between the groups
The risk of NEC was reduced with oral ibuprofen
compared with indomethacin (IV or oral) (7 studies, 249
infants
There was a decreased risk of failure to close a PDA
with oral ibuprofen compared with IV ibuprofen (5
studies, 406 infants;

Cont…
• Conclusions
Ibuprofen is as effective as indomethacin in
closing a PDA. Ibuprofen reduces the risk of NEC
and transient renal insufficiency. Therefore, of
these two drugs, ibuprofen appears to be the
drug of choice.

The Role of Paracetamol for Closing Patent Ductus Arteriosus. A
Challenging Alternative for Ductal Closure?

Paracetamol Accelerates Closure of the Ductus Arteriosus after
Premature Birth: A Randomized Trial
• Source :The journal of paediatrics
• Published :2016
• From the PEDEGO Research Center, and MRC Oulu, University of Oulu, and the
Department of Children and Adolescents, Oulu University Hospital, Oulu,
Finland
• Study design :In a controlled, double-blind, phase I-II trial, very
low gestational age (<32 weeks) infants requiring intensive
care were randomly assigned to intravenous paracetamol or
placebo (0.45% NaCl). A loading dose of 20 mg/kg was given
within 24 hours of birth, followed by 7.5 mg/kg every 6
hours for 4 days. Daily cardiac ultrasound examinations of
ductal calibers were performed before the first dose, and until
1 day after the last dose. The main outcome was a decrease in
the ductal caliber without side effects

Cont…
• Results Of 63 screened infants, 48 were randomized: 23
were assigned to paracetamol and 25 to placebo. Before
the intervention, their ductal calibers were similar. During
the intervention, the ductus closed faster in the
paracetamol group (hazard ratio 0.49, 95% CI 0.25-0.97, P =
.016). The mean (95% CI) postnatal ages for ductal closure
were 177 hours (31.1-324) for the paracetamol-treated vs
338 hours (118-557) for controls (P = .045). Paracetamol
serum levels were within the therapeutic range, and no
adverse effects were evident.
• Conclusions Prophylactic paracetamol induced early
closure of the ductus arteriosus without detectable side
effects. Further trials are required to determine whether
intravenous paracetamol may safely prevent symptomatic
patent ductus arteriosus.

Comparative study of the efficacy and safety of paracetamol,
ibuprofen, and indomethacin in closure of patent ductus
arteriosus in preterm neonates
• Source:Eur J Pediatr
• Published: 12 December 2016
• Pediatric Department, Tanta University Hospital,
Elgeish street, Tanta, Egypt
• Inclusion criteria :Preterm neonates with
gestational age less than 28 weeks or birth
weight less than 1500 g in the first 2 weeks of
life with hs-PDA diagnosed with
echocardiography and clinical examination

Cont…
• Study design:This prospective study, we compared
the efficacy and side effects of indomethacin, ibuprofen,
and paracetamol in patent ductus arteriosus (PDA) closure
in preterm neonates. Three hundred preterm neonates
with hemodynamically significant PDA (hs-PDA) admitted
at our neonatal intensive care unit were enrolled in the
study. They were randomized into three groups. Group I
(paracetamol group) received 15 mg/kg/6 h IV
paracetamol infusion for 3 days. Group II (ibuprofen group)
received 10 mg/kg IV ibuprofen infusion followed by 5
mg/kg/day for 2 days. Group III (indomethacin group)
received 0.2 mg/kg/12 h indomethacin IV infusion for
three doses.

Cont…
• There was no significant difference between all
groups regarding efficacy of PDA closure (P = 0.868).
There was a significant increase in serum creatinine
levels and serum blood urea nitrogen (BUN) in the
ibuprofen and indomethacin groups (P < 0.001). There
was a significant reduction in platelet count and urine
output (UOP) in both ibuprofen and indomethacin
groups (P < 0.001). There was a significant increase in
bilirubin levels in only the ibuprofen group (P = 0.003).
No significant difference of hemoglobin (HB) level or
liver enzymes in all groups (P > 0.05).

Cont…
• Conclusion: Paracetamol is as effective as
indomethacin and ibuprofen in closure of PDA
in preterm neonates and has less side effects
mainly on renal function, platelet count, and
GIT bleeding

Cont…
• Results: They included eight studies that reported on 916
infants. One of these studies compared paracetamol to
both ibuprofen and indomethacin.
• Five studies compared treatment of PDA with paracetamol
versus ibuprofen and enrolled 559 infants. Therewas no
significant difference between paracetamol and ibuprofen
for failure of ductal closure after the first course of drug
administration
• Four studies (n = 537) reported on gastrointestinal bleed
which was lower in the paracetamol group versus the
ibuprofen group
• Platelet counts and daily urine output were higher in the
paracetamol group compared with the ibuprofen group.

Cont…
• Two studies compared prophylactic administration of
paracetamol for a PDA with placebo or no intervention in
80 infants. Paracetamol resulted in a lower rate of failure
of ductal closure after 4 to 5 days of treatment compared
to placebo or no intervention which was of borderline
significance
• Two studies (n = 277) compared paracetamol with
indomethacin. There was no significant difference in the
failure to close a PDA
Serum creatinine levels were significantly lower in the
paracetamol group compared with the indomethacin group
and platelet counts and daily urine output were
significantly higher in the paracetamol group.

Cont…
• Conclusions: Moderate-quality evidence
according to GRADE suggests that
paracetamol is as effective as ibuprofen; low-
quality evidence suggests paracetamol to be
more effective than placebo or no
intervention; and low-quality evidence
suggests paracetamol as effective as
indomethacin in closing a PDA.

Oral Paracetamol versus Intravenous Paracetamol in
the Closure of Patent Ductus Arteriosus: A Proportion
Meta-Analysis
Source: Journal of clinical neonatology
Published: 2nd august 2018
Author: Jesmin Hossain, Mohammad Kamrul
Hassan Shabuj
Study:They included 14 studies with 454
premature infants having PDA.
Conclusion: Events of closure of hsPDA in
premature infants with oral and IV paracetamol
were comparable in pooled proportion, and any
route of administration can be used

Prognosis
• Isolated PDA : Excellent
• PT <30 wk: Spontaneous closure 72%
• Conservative treatment with medication
closure rate 94%

seminar PDA

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