Patent Ductus Arteriosus

What Do We Already Know?

Dr. R. Adhi Teguh Perma Iskandar

Perinatology Division of Ciptomangunkusumo Hospital

INDONESIAN PICU NICU UPDATE – 2020/2021

 PDA : What do we already know?
1. The younger preterm babies, the higher incidence of PDA
2. All PDA needs to be treated (pro and cons)
3. Heart murmur is the earliest sign of PDA
4. Ductal size and La:Ao ratio determine the necessity of treatment
5. Complication of PDA: lung hemorrhage, heart failure – Hypotension,
IVH, Renal failure, NEC and CLD
6. Treatment for PDA: conservative, pharmacotherapy, surgical therapy
7. Fluid restriction and diuretics are necessary for PDA treatment
8. Indomethacin vs Ibuprofen vs Paracetamol: efficacy and safety

INDONESIAN PICU NICU UPDATE – 2020/2021

 Fetal Ductus Arteriosus
• Fetal circulation → low systemic vascular resistance
(SVR) and high pulmonal vascular resistance (PVR)
• Ductus arteriosus (DA) connects the MPA to the
descending Ao → necessary for fetal survival.
• DA modulates oxygenated blood flow to the lower
part of the body , while foramen ovale to upper part.
• PGE2 & low arterial O2 content → keep fetal DA
remain open

J Pediatr Pharmacol Ther 2007 Vol. 12 No. 3

INDONESIAN PICU NICU UPDATE – 2020/2021

 Neonatal Ductus Arteriosus
• After baby born → inflated lung → low PVR
• DA closes in two phases
• Functional closure
• Anatomic remodeling
• Term babies → DA close in 48 hours
• Preterm DA does not follow the same course as term DA.
• Volume and direction of blood shunting via the duct,
compensation of the heart and target organs will determent
the fate of PDA

J Pediatr Pharmacol Ther 2007 Vol. 12 No. 3

INDONESIAN PICU NICU UPDATE – 2020/2021

 Incidece of Patent Ductus Arteriosus
Birth 72 Hours 1 weeks

Term 100% 0,05%

30-37 w 100% 10% 2%

24-28 w 100% 80% 65%

100% 90% 87%

<24 w

Michelle S.C. Circulation. 1971;43: 323–332

Nemersofsky et al. Am J Perinatol. 2008;25(10):661–666
Claymment et al. Semin Perinatol. 2012;36(2):123–129

INDONESIAN PICU NICU UPDATE – 2020/2021

 Functional Ductal Closure
Intraluminal pressure
PGE2
Favor ductal
closing NO
Potassium Channel
AMPs
cGMP

Oxygen
Endothelin
Calcium channels Do not
Favor
Catecholamine ductal
Rho Kinase closing

INDONESIAN PICU NICU UPDATE – 2020/2021

 Ductus Arteriosus Closure
Mitochondrial derived The medial layer of the Smooth muscle
PaO2
reactive O₂ species DA has smooth muscle senses 02 influx
beside usual elastic
tissue
Activates Rho/Rho kinase
system Activates Developmentally regulated
endothelin system PDA
K⁺ channels open voltage
CLOSURE
regulated Ca2⁺ channels -
Ca2⁺ sensitization and Vasoconstriction
sustained vasoconstriction

Complete anatomical Degrades cAMP and cGMP

↓Production of PGE2 and
closure through which PGE2 and NO
PGI2 and NO
acts

Phosphodiesterase Normal platelet count and

Successful contraction- hypoxic zone-
healthy platelets
transforming growth factor β and
vascular endothelial growth factor
Seri I. Neonatal controversies , Hemodynamic and Cardiology. 2019
INDONESIAN PICU NICU UPDATE – 2020/2021
 Resistance to Ductal Closure in Preterm
• Immature smooth muscle myosin isoforms, with a weaker contractile
capacity
• Decreased Rho kinase expression and activity
• Impaired calcium entry through L-type calcium channels
• Kv Potassium channel → inhibited by increased PaO2
• Increased sensitivity to the vasodilating effects of PGE2 and NO
• Decreased ability of the premature lung to clear circulating PGE2
• The preterm ductus is a much thinner vessel → more difficult to
constrict Brown S. et al. Pediatr Res .2002;51:34-6
Sakurai et al. Eur J Cell Biol.1996;69(2):166-72
INDONESIAN PICU NICU UPDATE – 2020/2021
 Anatomical Closure of Ductus Arteriosus

Intramural tissue pressure obliterate vasa vasorum → ischemic

and hypoxic ductus → inhibit local PGE2 and NO → induced HIF
and VEGF → migration smooth muscle into neo intima →
Waleh N et al. Pediatr Res.2005;57(2):254-62 monocyte and macrophages → remodeling

INDONESIAN PICU NICU UPDATE – 2020/2021

 Risk Factors for PDA
• PDA is related to gens that encode
Angiotensin receptor (ATR) type 1 Transcription factor AP-2B (TFAP2B),
Interferon γ (IFN-γ), PGI synthase SLCO2A1
Estrogen receptor-alpha PvuII, TRAF1 NOS3

• PDA also related to birth factor

Preterm birth Respiratory Distress syndrome
High altitude birth Sepsis
Female: male (1:2) Fluids (>170 mL/kg per day) in the first week
Intrauterine exposure to rubella.
J Pediatr Pharmacol Ther 2007;12:138-146 Mildered et al. Neoreviews. 2018 19(7): e394–e402

INDONESIAN PICU NICU UPDATE – 2020/2021

 Patent Ductus Arteriosus Flow
Q = △P∏r4 Closed ductal
8Lɲ
Shunt Volume (Q)
Ductal diameter(r)
Ductal Length (L)
Blood Viscosity (ɲ)
Pressure gradient (PVR-SVR)△P

PVR>SVR

PVR equal to SVR

Life saving Innocent Pathologic
By stander hs PDA PVR < SVR

Seri I. Neonatal controversies , Hemodynamic and Cardiology. 2019

INDONESIAN PICU NICU UPDATE – 2020/2021
 Pathophysiology of Significant PDA (hsPDA)
PDA with left to right shunt

Pulmonary overflow Systemic hypoperfusion

LA dilatation
diastolic shunting in distal Aorta
Increase LV preload LV diastolic pressure ↑

Increase LVO
Coronary perfusion↓ Retrograde diastolic flow in distal Ao
Poor LV compliance & contractility

Inadequate stroke volume

Compromised organ blood flow
cerebral, mesenteric , renal, etc.
Inadequate systemic perfusion
Seri I. Neonatal controversies , Hemodynamic and Cardiology. 2019
INDONESIAN PICU NICU UPDATE – 2020/2021
Interrelations between hs PDA, IVH, NEC, BPD
Systemic Syst. Pulm. Lung
hypoperfusion Blood Blood Oversirculation
Decrease organ flow RA LA flow
blood flow

RVO RV LV LVO Pulmonary

Brain hypertension

Ductus Pulmonary
Gastrointestinal
Arteriosus over flow Lung hemorrhage
track and kidney
Qp
Lungs
Skin, bone, Lung edema
Qs
skeletal muscle
Body Semin neonatol.2001;6:75-84
INDONESIAN PICU NICU UPDATE – 2020/2021
 Compensation of hs-PDA
Lung overflow
• Increase mean airway pressure by grunting, nasal flaring, work of
breathing etc.

Systemic hypo perfusion

• Increase oxygen extraction ratio
• Increase cardiac output (LVO> 300 mL/Kg/mnt)
• Regional blood flow autoregulation
• Blood flow redistribution from non vital to vital organ
INDONESIAN PICU NICU UPDATE – 2020/2021
 Myocardial adaptation to hs-PDA

Increase LA volume
Increase LV end diastolic volume
Increase LV filling pressure
Increase LV sphericity index

Increase LVO

Adequate organ perfusion

de Wall K. Pediatr cardiol.2016:37;295-303

INDONESIAN PICU NICU UPDATE – 2020/2021

 PDA Symptoms time line
Delivery
Transisition Day 1 Day 2 Day 3 Day 7 Day 28
Resuscitation

Pulmonary Pressure
Symptom of PDA
L→R PDA shunt
L→R PDA shunt

Hipotension
Pulmonary Hemorhage

IVH
BPD/NEC
The clinical sign of PDA are generally apparent
beyond the first natal week but lag behind
Evan N et al. J Pediatr Child Health. 1994;20(50);406-11
Echo diagnosis by nearly 2 days
INDONESIAN PICU NICU UPDATE – 2020/2021
 Clinical Signs of hs-PDA
• Continuous or systolic murmur
• A low diastolic blood pressure
• A wide pulse pressure (due to ductus runoff or steal)
• Hypotension (especially in the most premature infants)
• Tachycardia & Precordial hyperactivity
• Bounding pulses
• Increased serum creatinine concentration or oliguria
• Hepatomegaly
• Pulmonary edema → tachypnea, decreased SpO2 , and
increasing respiratory support
Score > 2 → do the
• Lactic acidosis Echocardiography

Krakauer et al. Neoreviews. 2018 July ; 19(7): e394–e402. Kindler A. Frontier in ped.2017;5:280-5
INDONESIAN PICU NICU UPDATE – 2020/2021
Blood Pressure and hs-PDA
Age in Systolic Diastolic Mean (Calculated)
weeks
Highest Mean Lowest Highest Mean Lowest Highest Mean Lowest
24 14168 infants
49 at a
33 mean46 (SD)29gestation
14 and
53 36 20
25 69
birthweight51 of 26
36 (1.4)
47 weeks
30 and15 952 (235)
54 g37 22
26 70 52 38 48 31 17 55 38 24
27 71 54 40 49 32 18 56 39 25
28 72 55 41 50 33 19 57 40 26
29 73 56 42 51 34 20 58 41 27
30 75 59 43 52 35 21 60 43 28
31 78 61 46 53 36 22 61 44 30
32 80 62 48 54 37 23 63 45 31
33 81 63 50 55 38 24 64 46 33
34 83 66 51 56 39 25 65 48 34
35 84 69 52 57 40 26 66 50 35
36 87 71 55 58 41 27 68 51 36
37 89 72 57 59 42 28 69 52 38
38 90 75 59 60 43 29 70 54 39
39 91 78 60 60 44 30 70 55 40
40 92 80 61 61 44 30 71 56 40

El-Khuffas A et al.J Pediatr.2015;167(6):1364-51

INDONESIAN PICU NICU UPDATE – 2020/2021
How do we differentiate PDA and hsPDA
Biomarker for hs-PDA : BNP

Chen.s et al. Journal of Perinatology (2010) 30, 780–785

INDONESIAN PICU NICU UPDATE – 2020/2021
How do we differentiate PDA and hs-PDA
Biomarker for hs-PDA : Cardiac Troponin T
The median 12-hour cTnT level
was 0.20 g/L (IQR 0.11 to 0.40
g/L). At 48 hours, median cTnT
level was significantly higher in the
PDA group (n 45) than in the
spontaneous closure group (n 35)
(0.43 vs 0.13 g/L; P < .001).

El Khufash et al. J Pediatr 2008;153:350-3)

INDONESIAN PICU NICU UPDATE – 2020/2021

What should we look for from echo report ?

INDONESIAN PICU NICU UPDATE – 2020/2021

Hemodynamic Significant PDA

Noori et al. Congenital heart desease.2018; 1-6

INDONESIAN PICU NICU UPDATE – 2020/2021
 How are neonatologists treating PDA
• Survey in 46 hospitals • Authors’ Conclusion
• Institution specific guidelines No consensus among hospitals
- 29 % Prophylactic indomethacin regrading prophylaxis, NSAID
- 39 % NSAID treatment : treatment or PDA ligation
Indomethacin 37/46
Ibuprofen 6/46
Both 3/46 • What is New
- 27 % Ligation Practice preferences for indomethacib
• Factors influencing starting prophylaxis, NSAID, and surgical PDA
treatment treatment vary both among and within
- Ventilator settings 14/18 institutions. Lack of treatment
- Echocardiographic parameters 14/18 effectiveness and risk of adverse effects
are major concerns
- Clinical 7/14
Slaughter JL et al. Eur J Pediatr 2016
Slaughter
INDONESIAN JL et
PICU al. Eur
NICU J Pediatr
UPDATE 2016
– 2020/2021
 When to treat
Delivery
Transisition Day 1 Day 2 Day 3 Day 7 Day 28
Resuscitation
Prophylactic
Pulmonary Pressure Early targeted

L→R PDA shunt Pre symptomatic

L→R PDA shunt

Hipotension Late symptomatic

Pulmonary Hemorhage
IVH
BPD/NEC
Surgical ligation
Supportive care only

INDONESIAN PICU NICU UPDATE – 2020/2021

 Summary of pro and cons of different treatment
time point
Treatment type Advantage Disadvantage

Prophylactic Most widely study Due to frequency of spontaneous closure,

Decrease IVH, Pulmonary Hemorrhage
Early Asymptomatic Expose fewer baby to the risk of treatment
Symptomatic Expose fewer baby to the risk of treatment
Conservative No initial exposure to medication but risk of
need for later treatment
Exposed large number of infant with side
effect of NSAIDs treatment
Few study, by day 3 the damage have been
done (IVH, Pulmonary hemorrhage)
Few study, closure rate is low, increase the
chance of PDA’s morbidity and mortality
Unproven usefulness and safety profile
No standardized approach

INDONESIAN PICU NICU UPDATE – 2020/2021

 Supportive care treatment
Echo: • Always balance the risk and benefit of
Large PDA PDA treatment
lung overflow, • Supportive treatment instead
systemic hypo pharmacotherapy
perfusion
No clinical • Give the duct more time to closed by
deterioration
> 1 weeks Good
itself
even. compensatory • But Need close and regular observation
Clinically mechanism
improvement (clinical and echo)
• Immediately treat the hs-PDA whenever
echo or clinical deterioration detected
Clayman et al. J. Pediatr.2018;205:1-5

INDONESIAN PICU NICU UPDATE – 2020/2021

 Supportive Management in hs-PDA
Systolic Normal Shunt limitation strategies
Diastolic Low Q = △P∏r4
8Lɲ

↑ PVR Optimizing MAP Promoting O2 delivery

Permissive limiting FiO2 increase PEEP Keep Ht > 45% Avoding blood loss
hypercapnia

Systolic Low Persistent systemic Support systolic without increase

Diastolic Low hypoperfusion diastolic

Rios et al. Frontier in pediatrics.2018;6:e62-8 Dobutamin

INDONESIAN PICU NICU UPDATE – 2020/2021

 Supportive Management in hs-PDA
1. “Mild” restriction (< 130 mL/kg/d), avoid high intakes
(>170mL/kg/d)

2. Concomitant use of diuretics is useless and even contraindicated →

choose Hydrochlorothiazide instead

3. During NSAID treatment, a “normal” fluid intake may prevent renal

damage

Smith A et al. Semin in Fetal Neonatal med.2018

INDONESIAN PICU NICU UPDATE – 2020/2021

How to treat : Pharmacotherapies
Steroid
- Phospholipids
Phospohplipase A2

NSAIDs - Arachidonic Acid

COX

Paracetamol
- Prostaglandin G2
POX + Hydroperoxidase
From leucocyte,
Prostaglandin H2 Thrombocyte

PGF2𝜶 reductase PGE2 synthetase PGI2 synthetase TXA2 synthetase

PGF2𝜶 PGE2 PGI2 TXA2

INDONESIAN PICU NICU UPDATE – 2020/2021

 Indomethacin
• Route : slow infusion 20-30 minutes or oral
• Dose : 0,1-0,2 mg/Kg , 12-24 hours apart for 48-72 hours
Escalation dose 0,4 mg/Kg – 1mg/kg, 12-24 hours apart
• Efficacy : 48%-98,5%, second dose 40-50%
• Prophilactic indomethacin:
• Reduced Symptomatic PDA(RR 0,4; 95% CI 0,38-0,5)
• Reduced P/IVH (RR 0,88; 95% CI 0,80-0,98)
• No improvemnet of Neurodevelopmental outcome

Schmid B et al. J Pediatr.2006;148:730-4

INDONESIAN PICU NICU UPDATE – 2020/2021

 How to treat : Ibuprofen
Cochrane review 20150 – 3 days 10 – 5 – 5 mg/kg
33 studies, 2190 infants,
4 – 6 daysIV and Oral administration
14 – 7 – 7 mg/kg
> 7 days 20 – 10 – 10 mg/kg

- Similar efficacy in ductal closure as compared to indomethacin

- Lower incidence of renal dysfunction (urine output, creat)
- Shorter duration of ventilation : - 2.4d (95% CI -3.7 – 1.0)
- Lower Incidence of NEC (16 studies – 948 infants)
RR : 0.64 ( 95% CI 0,45 – 0.93)
- Lower incidence of NEC if oral administration (7 studies – 249)
RR : 0,41 ( 95% CI 0.27 – 0.64)
- SIP and GIT bleeding do occur
- No difference in ligation rates, IVH , retinopathy, survival
Ohlsson A et al. Cochrane Database of Syst Reviews 2015
INDONESIAN PICU NICU UPDATE – 2020/2021
 How to treat : Paracetamol

Closure of PDA – in 14 uncontrolled studies and case reports :

After 3d : 49 %
After 7 d : 76 %
Safety similar to ibuprofen, minimal side effects ( IVH, NEC, BDP, ROP, renal toxicity,
gastrointestinal bleeding, hyperbilirubinemia)
Conclusions :
1. Comparable efficacy as ibuprofen
2. Higher efficacy if
– GA > 28 w Dosage : ranging from 40 – 60 mg/kg/d
– Postnatal age <7d
– First line therapy
3. Trend to greater effect when given orally
Terrin et al. Arch Dis Child 2016
INDONESIAN PICU NICU UPDATE – 2020/2021
 Adverse effects of PDA’s drug
Indomethacin Ibuprofen Paracetamol
Reduced cerebral blood flow Oliguria Hepatotoxicity
Reduced renal blood flow High bilirubin level Thermodynamic effect
Reduced splanchnic blood flow Gastrointestinal bleeding Hyperosmolar (oral prep)
Impaired platelet aggregation Pulmonary hypertension Alter attention function at 5 yrs
Mucosal injury Hyperkinetic disorder

Seri I, Kluckow M. Hemodinamic & cardiology. 2019

INDONESIAN PICU NICU UPDATE – 2020/2021

 How to treat : Surgical therapy
Therapeutic option for persistent hs-PDA
after unsuccessful medical therapy (usually
three cycle)

Compared with medical treatment, surgical

ligation was associated with increases in NDI
(aOR: 1.54; 95% CI: 1.01–2.33), chronic lung
disease (aOR: 2.51; 95% CI: 1.98–3.18), and
severe retinopathy of prematurity (aOR: 2.23;
95% CI: 1.62–3.08) but with a reduction in
mortality (aOR: 0.54; 95% CI: 0.38–0.77).
MacNamara et al. Pediatrics.2014;133:1024-8

INDONESIAN PICU NICU UPDATE – 2020/2021

 Complication of PDA ligation
Post ligation syndrome
Pneumothorax
Chylothorax
Phrenic nerve paralysis
Injury of adjacent structure
Bleeding
Focal cord paralysis
Residual shunting

INDONESIAN PICU NICU UPDATE – 2020/2021

How to treat : trans catheter closure of PDA
• When surgical closure is contraindicated
• Closured can be achieved by deploying a coil
or an amplatzer duct occluder
• Trans catheter PDA closure can be done via
anterograde (venous) or retrograde (arterial)
• Compared to surgical closure, trans catheter
PDA closure associated with lower risk and
fewer adverse outcome

INDONESIAN PICU NICU UPDATE – 2020/2021

Trans catheter closure of PDA

Francis E. et al. JACC Cardiovasc Interv. 2010;3(5):550-5

INDONESIAN PICU NICU UPDATE – 2020/2021
 Summary
• Early recognition of hs-PDA is important to prevent complications such as
pulmonary hemorrhage, hypotension , heart failure, IVH, NEC, renal failure and
CLD
• Echocardiographic of hemodynamic significance PDA preceded the development of
clinical signs by a mean of 2 days.
• Evaluation of hs-PDA should include the magnitude of ductal shunt and volume, the
ability of the heart to compensate, and the impact to target organs.
• The efficacy of PDA treatment should weigh more than the side effect
• Surgical ligation is an option for large hs-PDA after unsuccessful medical therapy.

INDONESIAN PICU NICU UPDATE – 2020/2021

THANK YOU

INDONESIAN PICU NICU UPDATE – 2020/2021