Case discussion

Case
B/O Marianna, day 24 of life, born extreme preterm 25 weeks with
AGA weight 810gram, born via EMLSCS for Chorioamnionitis.
Issues is: 1/ Extreme preterm
2/ RDS grade II - III with evolving BPD surfactant x2 given,
ventilated since birth till now with trial extubation x3 not success.
Latest CXR good expansion 9-10 ribs with cystic changes.
3/ PDA noted at day3 of life, 1st cycle of ibuprofen given at day 6
till day8 total 3 days completed. Repeated echo PDA size 1.1mm from
1.8mm but LA:AO ratio 1.8 to 2.0mm from 1.5mm. Started 2nd cycle of
ibuprofen completed day 23 of life 3 days course.
4/ resolved Acinetobacter baumannii sepsis completed antibiotic
and repeated blood C+S x2 negative.

Case
B/O Mi, born via EMLSCS via severe IUGR with fetal bradycardia, born
late preterm, with good apgar score and symmetrical IUGR .
Issues:
1/ Premature at 32 weeks 2 days with symmetrical IUGR birth weight 1100 gram
2/ compliant chest wall with resolved RDS - no surfactant required/ on CPAP for
11 days then HFNC for 2 days with LFNC for 2 days then RA
3/ PDA hemodynamically stable
Noted murmur at day 7 of life
Received 1 course of ibuprofen day 7 of life till day 9 of life.
Initial Echo PDA size: 2.0 mm ; LA:AO: 2.7 prior start ibuprofen and CXR: cardiomegaly with
pulmonary congestion.
Repeated Echo: 1.3mm, LA/AO ratio: 1.1 mm: CXR post ibuprofen: no cardiomegaly/
congestion. Hemodynamically non significant.

4/ Anemia of prematurity on supplement with FAC and EPO

Baby discharge well at day 36 of life

PDA in prematurity To close or not?

Anatomy
Physiology changes of fetal after birth
What effect of PDA in prematurity?
Should we close or not?
Treatment of choice
Suggestion.

Anatomy of PDA
Patent ductus arteriosus
(PDA), in which there is a
persistent communication
between the descending
thoracic aorta and the
pulmonary artery that results
from failure of normal
physiologic closure of the
fetal ductus.

In fetal life,
Gas exchange occir at the placenta not in the lungs
Only small amount of blood is need for the lung for nutritional and
metabolic requirement. this account for 5-10% of combined
ventricular output (CVO)
Whereas Right ventricle ejects about 65% of CVO, so this duct
account for divert major proportion of blood around 55% of this
CVO away from pulmonary vascular bed to low ressitance
umbilical placental circulation.
This duct is regulate to open by low partial O2 = 18 mmHg, locally
and circulation Prostaglandin E2 and fetal immature ductus
produces more prostaglandin locally to open it. Which also the
endothelial cells of the ductus produces nitric oxide which leads to
ductal patency.

After birth,
A normal term infant, - postnatally closure is in 2 phases
1. Smooth muscle constriction produces functional closure of
lumen within 18 to 24 hours after birth
Due to increase arterial pO2 + drop in circulating PGE2 + drop in pressure
within the ductus lumen as drop in pulmonary vascular resistance.

2. Anatomical closure occurs over few days or weeks.

Due to the initial functional closure loss of the luminal blood flow lead to
hypoxia in the muscle media (local muscle media cell death + stimulate
endothelial proliferation and lead to neointimal thickening, it also leads to
inhibition of endogenous prostaglandin and nitric oxide production) which
cause irreversible anatomical closure with fibrosis - ligamentum
arteriosum in 2 to 3 weeks.

What happen in preterm?

In preterm variation in constriction + pulmonary pressure will be
still sub-systemic at early life. and may lead to failure of closure Patent ductus arteriosus.
In a prospective study Koch et al. observed a rate of spontaneous
closure of the duct in the first 10 days of life in at least 35% of
extremely low birth weight infants and up to 70% in neonates of
more than 28 weeks of GA
Van Overmeire, in a cohort of less immature infants (2631 weeks),
described a 80% rate of spontaneous closure by 7 days of age .
Vanhaesebrouck et al. retrospectively reviewed their conservative
approach to PDA based only on fluid restriction and ventilation
adjustments. They observed that 28% of infants with GA< 30
weeks had a clinical diagnosis of PDA and were subsequently
treated with conservative approach.

Morbidity associated to PDA

PDA has been related particularly to pulmonary problems. It is
believed that a high blood shunt through the ductus is a risk
factor for pulmonary hemorrhage. Kluckow and Evans,
following systematically VLBW infants by echocardiography
showed the association between PDA dimension, the estimated
ductal shunt and pulmonary blood flow with the onset of PH.
Several studies have examined the relationship between a
persistent ductus and the development of chronic lung disease.
In a large multicentric prospective study investigating the risk
factors associated to CLD in the surfactant era, PDA in ventilated
infants was associated with increased risk of CLD regardless of
the timing of the diagnosis of PDA with an OR of 1.9.

Morbidity associated with PDA

An early PDA was correlated to inotrope resistant
hypotension by Sarkar et al. Evaluating 89 infants with
refractory hypotension, in a multivariate analysis of
possible risk factors they found an independent
association of PDA with an OR of 7.6.
PDA has also been considered a risk factor for the
development of NEC. In a population-based study on
6146 very low birth weight infants belonging to the
National Israeli Neonatal Network, the presence of PDA,
adjusted for confounding factors, gave an odds ratio for
developing NEC of 1.8

Morbidity associated with PDA

PDA as a risk factor for intracranial hemorrhage. Evans et al.
showed that preterm infants with a larger PDA and a lower
right ventricular output, (that is an index of systemic
perfusion in presence of PDA), had an increased incidence
of severe IVH.
Noori et al. found an eightfold increase of the adjusted
risk of death for very low birth weight infants when the
ductus remained patent after medical therapy
The redistribution of blood flow to the lung and the diastolic
steal phenomenon lead to systemic hypoperfusion and put
organs like brain, kidney and gut at risk of ischemic injury.

Treatment modalities
Conservative
fluid restriction 100 to 130 cc/kg/day
diuretics for congestive heart failure; - thiazide prefer than
frusemide
use of minimal supplemental oxygen
permissive hypercapnia, & avoidance or correction of
metabolic alkalosis to minimize pulmonary vasodilation
application of continuous distending airway pressure(CPAP or
PEEP - > 5mmHg) to reduce pulmonary blood flow and
increase systemic perfusion

Treatment modalities
Medical therapy - Cyclo-oxygenase inhibitors such as
indomethacin and ibuprofen remain the mainstay of
medical therapy
New emerging Paracetamol.

Surgical therapy surgical ligation or occlusion after

failed medical therapy in a SIGNIFICANT PDA.

To treat or not to treat PDA

Is there a role of prophylaxis? Within 48 hours
Hemodynamically stable/ Non hemodynamically
significant.
Hemodynamically significant.

Patent Ductus Arteriosus in Preterm

Infants: Do We Have the Right
Answers?

Earlier studies have shown that prophylactic indomethacin decreases

the subsequent incidence of symptomatic PDA and IVH in preterm
infants. However, later studies did not show beneficial effect of
prophylactic indomethacin on the rate of survival or long-term
disability.
More recently, prophylactic indomethacin was shown to decrease
cerebral perfusion which may be harmful to the developing brain [105]
and was found to worsen the short-term respiratory outcomes in ELBW
infants

Hindawi Publishing Corporation BioMed Research International Volume 2013, Article ID 676192, 15 pages http://dx.doi.org/10.1155/2013/676192

 However, the use of prophylactic ibuprofen negatively affected the

renal function of preterm infants with no significant differences in
mortality, IVH, or BPD. On the other hand, two trials on oral ibuprofen
had similar results but showed an increased risk of gastrointestinal
bleeding.
Accordingly, authors concluded that prophylactic ibuprofen exposes
many infants to renal and gastrointestinal side effects without any
important short-term benefits and is not recommended. A recent study
compared prophylactic versus expectant ibuprofen for asymptomatic
PDA and found that infants with mild signs of PDA do not benefit from
prophylactic ibuprofen compared with delayed treatment.
A. Ohlsson and S. S. Shah, Ibuprofen for the prevention of patent ductus arteriosus in preterm and/or low birth weight infants,
Cochrane Database of Systematic Reviews, no. 7, p. CD004213, 2011.

 The cumulative evidence supports the conclusion that

early (in the first 2 weeks after birth), routine (as
prophylaxis or for infants with echocardiographic
confirmation of ductal patency with or without clinical
signs) treatment to close the ductus arteriosus does not
improve long-term outcomes for preterm infants.
http://pediatrics.aappublications.org/content/pediatrics/137/1/e20153730.full.pdf

What is the outcome of conservative

therapy and supportive therapy?
. Fluid restriction may decrease circulating blood volume and the overload of the
pulmonary circulation that in turn may improve the respiratory function. In VLBW infants,
retrospective studies have shown an association between increased fluid intake during the
first week of life with a lack of appropriate physiologic weight loss and increase in the
incidence of BPD.
Restricted fluid intake in the first few days of life is associated with a decreased incidence
of PDA and BPD,
Conservative management achieved PDA closure in all infants. Conservative treatment has
the obvious advantage of being devoid of side effects of medication or surgical ligation.
Therefore, it is reasonable to employ conservative PDA management in preterm infants as
the initial management step. However, infants born at 23 to 25 wk gestation were found to
have a lower likelihood of spontaneous PDA closure and a higher risk of treatment failure
with ibuprofen. In this subgroup of infants with significant PDA, treatment with a COX
inhibitor would be acceptable to most clinicians after 48-72 h of life
BUT
Although fluid restriction has been widely recommended in management of PDA [113
116], its benefits to hazards have not been assessed systematically.
J. Wyllie, Treatment of patent ductus arteriosus, Seminars in Neonatology, vol. 8, no. 6, pp. 425432, 2003

 Oxygen therapy has been proposed in the pathogenesis of duct

closure in preterm infants. In a retrospective study including 263
ELBW infants, infants treated with lower oxygen saturation
target range policy (8389% versus 89 94%) had more
incidence of HS-PDA; however, none of these infants required
surgical ligation later on. Suggested O2 saturation 91 to 95 %.

S. Noori, D. Patel, P. Friedlich, B. Siassi, I. Seri, and R. Ramanathan, Effects of low oxygen
saturation limits on the ductus arteriosus in extremely low birth weight infants, Journal of
Perinatology, vol. 29, no. 8, pp. 553557, 2009.

 A neutral thermal environment and adequate oxygenation that minimize

demands on left ventricular (LV) function.
The use of positive end-expiratory pressure (PEEP) to improve gas exchange in
infants with respiratory compromise. In a study in preterm lambs with a PDA,
PEEP decreased left-to-right ductal flow and increased systemic blood flow.
Maintenance of the hematocrit at 35 to 40 percent may increase pulmonary
vascular resistance and reduce left-to-right shunting, although no trials have
evaluated the effect of blood transfusion on PDA closure.
Cotton RB, Lindstrom DP, Kanarek
KS, et al. Effect of positive-end-expiratory-pressure on right ventricular output in lambs with hyaline membrane disease.
Acta Paediatr Scand 1980; 69:603.
Lister G, Hellenbrand WE, Kleinman CS, Talner NS. Physiologic effects of increasing hemoglobin

concentration in left-to-right shunting in infants with ventricular septal defects. N Engl J Med 1982; 306:502 .

Significant PDA
the decision to intervene should be based upon a hemodynamically significant PDA, which if left
untreated leads to pulmonary overcirculation (which increases the risk of developing pulmonary
edema, pulmonary hemorrhage, and BPD), and systemic undercirculation (which increases the risk
of necrotizing enterocolitis [NEC] and systemic hypoperfusion
The size of the PDA measured by echocardiography is generally used to determine whether or not a
PDA is hemodynamically significant in preterm infants. One commonly used measure is a transductal
diameter that exceeds 1.5 mm or 1.4 mm. In one series of mechanically ventilated infants younger
than 30 weeks gestation, a ductal diameter of 1.5 mm or greater at 7 to 31 hours of life predicted a
significant PDA with 83 percent sensitivity and 90 percent specificity for a PDA that was treated.
A proposed staging system to detect clinically significant PDA uses both clinical findings (eg,
oxygenation index, degree of respiratory support, chest radiography, and end-organ function) and
echocardiographic measurements to classify the severity of PDA.
Others have used the PDA:left pulmonary artery (LPA) ratio to define large (1), moderate
(<1 but 0.5), and small (<0.5) PDAs in the first four days of postnatal life to predict which infants
would receive treatment for PDA closure. Those with large or moderate PDAs are 15 times more likely
to receive treatment, and those with small PDAs have a high likelihood of spontaneous resolution.
Sensitivity, specificity, and positive predictive value of a large or moderate PDA:LPA ratio in the first
four days were 80, 86, and 92 percent, respectively, for infants <27 weeks gestation.
There is a strong correlation between the ductal diameter and flow patterns in determining the
severity of PDA, and it is reasonable to use both methods to decide on whether to initiate intervention.
Ramos FG, Rosenfeld CR, Roy L, et al. Echocardiographic predictors of symptomatic patent ductus arteriosus in extr
emely-low-birth-weight preterm neonates. J
Perinatol 2010; 30:535.
Thankavel PP, Rosenfeld CR, Christie L, Ramaciotti
C. Early echocardiographic prediction of ductal closure in neonates 30 weeks gestation. J Perinatol 2013; 33:45.

Outcome with medical therapy

Studies have shown a closure rate of 70-80% with either
indomethacin or ibuprofen in preterm babies <32
weeks. Hence both are equally effective in closing PDA;
however, ibuprofen currently appears to be the superior
option with its better safety profile, especially reduced
NEC rates

Van Overmeire B, Smets K, Lecoutere D, Van de Broek H, Weyler J, De Groote K, et al. A

comparison of ibuprofen and indomethacin for closure of patent ductus arteriosus. N
Engl J Med. 2000;343:674-81

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