SEEKING

CLOSURE FOR
PATENT DUCTUS
ARTERIOSUS
EMILY LETSINGER, PHARMD
PGY1 PHARMACY RESIDENT
ASCENSION ST. VINCENT
Disclosure Statement

This speaker has no relevant financial relationships with ACPE-defined

commercial interest to disclose.

Off-label or non-FDA approved indications may be discussed in this

presentation.

2
Learning Objectives
Seeking Closure for Patent Ductus Arteriosus

1. Recall the symptoms and the clinical presentation associated with a patent ductus arteriosus

2. Identify the role of indomethacin, ibuprofen, and acetaminophen in the treatment of patent
ductus arteriosus.

3. Analyze literature evaluating the efficacy and safety of indomethacin, ibuprofen, and
acetaminophen.

4. Evaluate literature regarding enteral feeding during administration of pharmacologic therapies for
the management patent ductus arteriosus

3
Presentation Overview
Seeking Closure for Patent Ductus Arteriosus

Evolution of Primary
primary literature
Ex-utero and in- Causes and Overview of
literature for the regarding
utero cardiac complications of management
use of enteral feeding
circulation PDA options for PDA
pharmacologic during PDA
therapy in PDA management

4
 Terms and Definitions
• Ductus Arteriosus (DA) – Vessel present in-utero connecting the pulmonary artery with the aorta that allows
circulation to bypass the lungs by shunting most of the blood directly from the right ventricle to systemic
circulation.

• Ductus Venosus (DV) – A vein connecting the umbilical vein to the inferior vena cava of the fetus.

• Foramen Ovale (FO) – An opening in the septum between the two atria of the heart that is normally present
only in-utero.

• Left-to-Right Shunting – A diversion of blood from the systemic circulation to the pulmonary circulation via a
patent ductus arteriosus.

• Patent Ductus Arteriosus (PDA) – An abnormal condition in which the ductus arteriosus fails to close after birth.

• Preterm Infant – A baby born before 37+0 weeks of pregnancy are completed.

• Necrotizing Enterocolitis (NEC) – gastrointestinal disease involving infection and inflammation that leads to
death of intestinal tissue.
5
Merriam-Webster. Dictionary. https://www.merriam-webster.com/.
 REVIEW OF
CIRCULATION
 Normal In-Utero Cardiac Circulation

Ductus
Venosus

Shunts
within
Fetal
Circulation
Ductus Foramen
Arteriosus Ovale

7
American Heart Association. Fetal Circulation.
 Normal Ex-Utero Cardiac Circulation

8
American Heart Association. Heart Valves and Circulation.
UNDERSTANDING
PATENT DUCTUS
ARTERIOSUS
 Causes of PDA

Excess Fluid
Prematurity Family History
Administration

Prenatal
High Altitude
Infection
Birth
(rubella)
10
Schneider DJ, et al. Circulation 2006.
 Mechanisms Underlying Patency of the DA

Factors Promoting DA Closure Factors Promoting DA Patency

Molecular Factors
Increased O2 tension Hypoxia
Decreased vasodilating prostaglandins Increased prostaglandin signaling
Increased endothelin-1 Increased nitric oxide signaling
Physiologic Factors

Decreased pulmonary vascular resistance Prolonged bidirectional or right-to-left blood flow

Increased systemic vascular resistance Low-velocity blood flow

Structural Factors
Mature contractile smooth muscle cells Thin layer or immature smooth muscle
Platelet adherence to lumen Thrombocytopenia or platelet dysfunction

11
Hamrick SEG, et al. Pediatrics 2020.
 Impact and Adverse Effects of PDA

Pulmonary overcirculation
Pulmonary hypertension
Cardiac hypertrophy
Congestive heart failure
Aneurysm of ductus arteriosus
12
Sivanandan S, et al. Pediatr Drugs 2016.
 Symptoms of PDA

Cyanosis

Feeding intolerance

Sweating while feeding

Apnea

Poor weight gain

Difficulty breathing (nasal flaring)

13
Sivanandan S, et al. Pediatr Drugs 2016.
 Clinical Presentation of PDA

Continuous or systolic murmur

Widened pulse pressure (> 30 mmHg)

Hypotension

Tachypnea

Decreased oxygen saturation

Increased serum creatinine or oliguria

Elevated BNP
14
Gillam-Krakauer M, et al. Neoreviews 2018.
 Indications for Treatment of PDA

Asymptomatic left-
Symptomatic from Small PDAs without
to-right shunting
significant left-to- left heart
that is resulting in
right shunting enlargement
heart enlargement

15
Sivanandan S, et al. Pediatr Drugs 2016.
MANAGEMENT OF
PATENT DUCTUS
ARTERIOSUS
 Overview of Management Options for PDA

Watchful Waiting
• May be appropriate if PDA is small to moderate and patient is asymptomatic

Pharmacologic Treatment
• Typically indicated as first-line management for PDAs that meet criteria for treatment
• Indomethacin, Ibuprofen, and Acetaminophen
• Early symptomatic treatment: treatment between 2 and 5 days of age
• Late therapy: treatment between 10-14 days of life
• Response to pharmacologic treatment may decrease beyond 2 weeks of age

Surgical Ligation
• Typically indicated for those that failed and/or have contraindications to pharmacologic therapy
(necrotizing enterocolitis, intestinal perforation, pulmonary hemorrhage, renal impairment)
17
Sivanandan S, et al. Pediatr Drugs 2016.
 Considerations for PDA Management

Watchful Pharmacologic Surgical

Waiting Treatment Ligation

Pros Pros Pros

Minimizes exposure to High success rate when High success rate and strong
pharmacologic agents and administered within alternative to pharmacologic
invasive procedures appropriate time frame treatment

Cons Cons Cons

Delaying treatment decreases
Side effects associated with Associated complications and
response to pharmacologic
pharmacologic agent costs
treatment

18
Sivanandan S, et al. Pediatr Drugs 2016.
Evolution of Pharmacologic PDA Management

1968 1995
First Surgical Ibuprofen
Closure

1976 2011
Indomethacin Acetaminophen

19
 Indomethacin

Mechanism of Action
Non-selective inhibitor of
cyclooxygenase (COX) 1 and 2
Reduces amount of circulating
prostaglandins

20
Sivanandan S, et al. Pediatr Drugs 2016.
Indomethacin

Studied Formulations
• Oral
• Intravenous

Studied Doses
• 0.2 to 0.9 mg/kg Q12H
• Most common: 0.2 mg/kg Q12H x 3 doses

Known Adverse Effects

• Gastrointestinal mucosal injury
• Decreased mesenteric blood flow
• Decreased renal blood flow
21
Indomethacin Literature

Study
Study Sample Patients Interventions Results Adverse Effects
Design
Halliday HL, et Prospective 36 25 to 32 weeks 0.2 to 0.9 mg/kg 24 (67%) with ductus Urine output reduced
al. Pediatrics gestational age; birth (mean 0.4) PO or arteriosus closure by >40% in 24 (67%)
1979. weight 630 to 1490 PR in 1 to 3
gm doses at least Infants older than 14 days Rise in SCr  1.5
eight hours responded less frequently mg/dL in 17 (47%)
apart than those 8 to 14 days old
(33% vs 89%, P = 0.048)
Van Overmeire Prospective, 127 Gestational age <32 Early treatment: Closure at day 6: 47 (73%) in Oliguria occurred in
B, et al. J randomized, weeks; respiratory 3 doses of 0.2 early treatment vs 28 (44%) 14 (22%) in the early
Pediatr 2001. multicenter distress syndrome; mg/kg IV Q12h in late treatment (P = 0.0008) treatment and 3 (5%)
age of 3 days; PDA starting on day 3 in the late treatment
Closure at day 9: 58 (91%) in (P = 0.10)
Late treatment: early treatment vs 49 (78%)
3 doses of 0.2 in late treatment (P = 0.047) NEC in 4 (6%) of the
mg/kg IV Q12h early treatment and 1
starting on day 7 PDAs requiring surgical (2%) of the late
ligation were 4.8% in early treatment (P = 0.18)
treatment vs 6.4% in late
treatment (P = 0.983) 22
Evolution of Pharmacologic PDA Management

1968 1995
First Surgical Ibuprofen
Closure

1976 2011
Indomethacin Acetaminophen

23
 Ibuprofen

Mechanism of Action
Non-selective inhibitor of
cyclooxygenase (COX) 1 and 2
Reduces amount of circulating
prostaglandins

24
Sivanandan S, et al. Pediatr Drugs 2016.
Ibuprofen

Studied Formulations
• Oral
• Intravenous

Studied Doses
• Standard Dose: 10 mg/kg x 1, then 5 mg/kg x 2 Q24H
• High Dose: 20 mg/kg x 1, then 10 mg/kg x 2 Q24H

Known Adverse Effects

• Gastrointestinal mucosal injury
• Decreased renal blood flow

25
Intravenous Ibuprofen Literature
Study
Study Sample Patients Interventions Results Adverse Effects
Design
Overmeire BV, Prospective, 40 Gestational Indomethacin IV PDA closure in 15 (75%) in Urine output decreased
et al. Arch Dis randomized age <33 0.2 mg/kg x3 indomethacin and 16 (80%) significantly on second day of
Child 1997. weeks; RDS; Q12h in ibuprofen groups treatment in indomethacin group
postnatal and not ibuprofen group (P =
age 48-72 Ibuprofen IV 10 7 received second treatment 0.001)
hrs mg/kg x 1 then 5 with indomethacin – those 7
mg/kg x 2 Q24h patients had the lowest No significant difference in
birthweights (940 g, gestation respiratory function
age 27.3)
Overmeire BV, Prospective, 148 Gestational Indomethacin IV PDA closure in 49 (66%) in Oliguria in 14 (19%) indomethacin
et al. New randomized, age <32 0.2 mg/kg x3 indomethacin and 52 (70%) and 5 (7%) in ibuprofen groups (P =
Engl J Med multicenter weeks; age Q12h in ibuprofen groups (P = 0.03)
2000. 2-4 days; 0.41)
PDA; RDS Ibuprofen IV 10 Increase in SCr from day 4 to day 8
mg/kg x 1 then 5 in indomethacin group greater than
mg/kg x 2 Q24h the ibuprofen group (P = 0.04)

NEC in 8 (11%) indomethacin and 4

(5%) in ibuprofen groups (P = 0.37)
26
Oral Ibuprofen Literature

Study Study Design Sample Patients Interventions Results Adverse Effects

Lee CH, et al. Retrospective, 88 Birth weight Indomethacin IV PDA closure in 32 (61.5%) in Oliguria in 33 (37.5%)
Taiwan single-center <1500 g; 0.1-0.25 mg/kg ibuprofen and 62 (70.5%) in in indomethacin and 5
Pediatric postnatal age 48- (based on age) x3 indomethacin groups (P = (9.6%) in ibuprofen
Association 96 hrs; PDA Q12h 0.342) groups (P = 0.002)
2012.
Ibuprofen PO 10 NEC in 10 (11.4%) in
mg/kg x 1 then 5 indomethacin and 2
mg/kg x 2 Q24h (3.8%) in ibuprofen
groups (P = 0.151)
Yang EM, et Retrospective, 48 Birth weight Indomethacin IV Primary closure in 17 Oliguria in 3 (11.5%)
al. J Pediatr single-center <1000 g; PDA 0.1-0.2 mg/kg (65.4%) in indomethacin in indomethacin and 1
2013. (based on age) x3 and 13 (59.1%) in ibuprofen (4.5%) in ibuprofen
Q12h groups (P = 0.44) groups (P = 0.37)

Ibuprofen PO 10 Overall closure in 23

mg/kg x 1 then 5 (88.5%) in indomethacin
mg/kg x 2 Q24h and 18 (81.8%) in ibuprofen
groups (P = 0.40)

27
High-Dose Ibuprofen Literature

Study Adverse
Study Sample Patients Interventions Results
Design Effects
Dani C, et al. Prospective, 70 Gestational Standard: PO Ibuprofen 10 After the 1st treatment course, 37% No significant
Clin randomized, age <29 mg/kg x 1, then 5 mg/kg x of the infants treated with the difference
Pharmacol multicenter weeks; PDA; 2 Q24H standard-dose regimen and 14% of noted in renal
Ther 2012. age 12-24 the infants treated with high-dose function or
hours; RDS High-dose: PO Ibuprofen regimen had persistent PDA (P = bleeding
necessitating 20 mg/kg x 1, then 10 0.03) disorders
respiratory mg/kg x 2 Q24H
support Logistic regression analysis
demonstrated that high-dose
independently decreased risk of
developing refractory PDA
Hiller K, et al. Retrospective, 60 Gestational Standard: IV ibuprofen 10 High-dose ibuprofen was No significant
Journal of multi-center age <37 mg/kg x 1, then 5 mg/kg x associated with a 21% absolute difference
Perinatology weeks; treated 2 Q24H reduction in PDA ligation noted
2020. with IV or PO compared to the use of standard-
ibuprofen; PDA High-dose: PO or IV dose (33.3% vs. 12.5%, P = 0.07)
ibuprofen 20 mg/kg x 1,
then 10 mg/kg x 2 Q24H
28
Evolution of Pharmacologic PDA Management

1968 1995
First Surgical Ibuprofen
Closure

1976 2011
Indomethacin Acetaminophen

29
 Acetaminophen

Mechanism of Action
Inhibits the peroxidase
enzyme, inhibiting the
conversion of PGG2 to PGH2
Reduces amount of circulating
prostaglandins X

30
Sivanandan S, et al. Pediatr Drugs 2016.
Acetaminophen

Studied Formulations
• Oral
• Intravenous
Studied Doses
• IV or PO 15 mg/kg Q6h x 3-7 days
• PO 25 mg/kg x1, then 15 mg/kg BID or TID x 3-7 days
Known Adverse Effects
• Hepatotoxicity

31
Acetaminophen Literature

Study Adverse
Study Sample Patients Interventions Results
Design Effects
Oncel MY, et Prospective, 80 Gestational age  30 Acetaminophen Closure after 1st course in 31 No
al. Jpeds 2014. randomized weeks; birthweight  1250 PO 15 mg/kg Q6h (77.5%) in ibuprofen and 29 statistically
g; postnatal age 48-96 hrs; x 3 days (72.5%) in acetaminophen significant
PDA groups (P = 0.60) difference in
Ibuprofen PO 10 renal function
mg/kg x 1 then 5 Reopening in 7 (24.1%) in or hepatic
mg/kg x 2 Q24h acetaminophen and 5 (16.1%) function
in ibuprofen groups (P = 0.43)
Guimaraes AF, Retrospective, 89 All preterm newborns Acetaminophen Closure after 1st cycle in 54 No adverse
et al. Ann single-center who received PO 25 mg/kg x1, (62%) effects
Pediatr Card acetaminophen for PDA then 15 mg/kg documented
2019. closure, regardless of birth BID (<32 weeks) Overall closure in 65 (74.7%)
weight or age or TID (>32
weeks) for 3-7
51 had contraindications days (determined
to indomethacin by achievement
of PDA closure
38 failed indomethacin via echo)
treatment
32
Evolution of Pharmacologic PDA Management

1968
First Surgical
1995
Ibuprofen
?
Closure

1976 2011
Indomethacin Acetaminophen

33
Newer Literature

Study Adverse
Study Sample Patients Interventions Results
Design Effects
Kumar A, Prospective, 161 Gestational Acetaminophen Closure after 2 courses in 63 (89%) in No
et al. Jpeds randomized, age <32 PO 15 mg/kg Q6h acetaminophen and 65 (89%) in ibuprofen groups difference in
2020. multicenter weeks; PDA x 3 days (P = 0.47) adverse
effects
Ibuprofen PO 10 Closure after 1st course in 52 (64%) in
mg/kg x1, then 5 acetaminophen and 62 (78%) in ibuprofen
mg/kg x2 Q24h groups (P = 0.07)

Time to closure 66 hours in acetaminophen group

and 49 hours in ibuprofen group (P = 0.71)
Dani C, et Prospective, 52 Gestational Acetaminophen IV Closure in 27 (52%) in acetaminophen and 38 No
al. Eur J randomized, age 25 to 32 15 mg/kg Q6h (78%) in ibuprofen groups (P = 0.026) difference in
Pediatr multicenter weeks; adverse
2021. postnatal Ibuprofen IV 10 Constricted DA in 42 (81%) in acetaminophen and effects
age 24-72 mg/kg x1, then 5 44 (90%) in ibuprofen groups (P = 0.202)
hrs; PDA mg/kg x2 Q24h
Reopening within 30 days in 14 (36%) in
acetaminophen and 8 (19%) in ibuprofen groups
(P = 0.078)
34
Newer Literature – Comparisons of all 3 Therapies

Study
Study Sample Patients Interventions Results
Design
El-Mashad Prospective, 300 Gestational IV acetaminophen 15 Closure after 1st course in 80 in acetaminophen, 77 in
AE, et al. Eur randomized age <28 mg/kg Q6h x 3 days ibuprofen, and 81 in indomethacin groups (P = 0.868)
J Pediatr weeks or
2017. birth weight IV ibuprofen 10 mg/kg x1, NEC in 3 in acetaminophen, 6 in ibuprofen, and 9 in
<1500 g in then 5 mg/kg x2 Q24h indomethacin groups (P = 0.074)
first 2 weeks
of life; PDA IV indomethacin 0.2 Rise in Scr, BUN, and oliguria was greatest in
mg/kg x3 Q12h indomethacin group compared to a lower risk in
ibuprofen group and renal function unaffected in the
acetaminophen group
Meena V, et Prospective, 105 Gestational PO indomethacin 0.1- Closure after 1st course in 8 (23%) in indomethacin, 13
al. Ann randomized age <37 0.25 mg/kg (based on (37%) in ibuprofen, and 15 (43%) in acetaminophen
Pediatr Card weeks, age) x3 Q12h groups (P = 0.912)
2020. postnatal age
28 days, PDA PO ibuprofen 10 mg/kg Closure after 2 courses of treatment in 24 (68%) in
x1, then 5 mg/kg x2 Q24h indomethacin, 27 (77%) in ibuprofen, and 25 (71%) in
acetaminophen groups (P = 0.716)
IV acetaminophen 15
mg/kg Q6h x 3 days
35
Key Takeaways

Ibuprofen and Indomethacin have similar efficacy profiles

Ibuprofen has a better adverse effect profile than indomethacin

Acetaminophen MAY have a similar efficacy profile to ibuprofen and indomethacin

• More compelling data with IV acetaminophen

Acetaminophen has a better adverse effect profile than ibuprofen and indomethacin

36
Areas for Future Research

PR
acetaminophen

PO
acetaminophen
vs PO ibuprofen
and
indomethacin

37
Summary of Pharmacologic Agents

Formulations
Medication Available at St. Typical Dosing Side Effects Monitoring
Vincent
• 5 mg/mL PO liquid 0.2 mg/kg Q12H x 3 doses • Gastrointestinal • Urine output
• 0.1 mg/mL IV mucosal injury • Serum creatinine
• Necrotizing enterocolitis • Platelet counts
Indomethacin • Decreased renal blood • Signs/symptoms of bleeding
flow
• Decreases cerebral
blood flow
• 20 mg/mL PO liquid Standard Dose: 10 mg/kg x • Gastrointestinal • Urine output
1, then 5 mg/kg x 2 Q24H mucosal injury • Serum creatinine
Ibuprofen • Decreased renal blood • Platelet counts
High Dose: 20 mg/kg x 1, flow • Signs/symptoms of bleeding
then 10 mg/kg x 2 Q24H
• 160 mg/5 mL PO 15 mg/kg Q6h x 3-7 days • Hepatotoxicity • Liver function
Acetaminophen liquid • Signs/symptoms of bleeding
• 10 mg/mL IV

38
ENTERAL FEEDING AND
MANAGEMENT OF
PATENT DUCTUS
ARTERIOSUS
Rationale for Current Standard of Care

Decreased
gastrointestinal Increased risk Preemptive
blood flow from for discontinuation
PDA and/or gastrointestinal or reduction in
pharmacologic complications enteral feeds
therapies

40
Ibuprofen/Indomethacin and Enteral Feeding

Study
Study Sample Patients Interventions Results
Design
Clyman R, et Prospective, 177 231/7 to 306/7 Pharmacologic therapy: No significant difference in rate of feeding advance
al. J Pediatr randomized weeks gestation; indomethacin or standard- delayed by feeding intolerance or NEC (p=0.103)
2013. 401-1250 g at dose ibuprofen
birth; just No significant difference in rate of NEC/perforation
beginning Feeding regimen: prior to reaching 120 mL/kg/day (p=0.450)
enteral feedings standardized feeding
(receiving  60 advance regimen based No significant difference in rate of NEC/perforation
mL/kg/day); on weight and day of at any time during hospitalization (p=0.963)
about to receive feeding or NPO
pharmacologic
treatment for
PDA closure

41
Indomethacin and Enteral Feeding

Study Study Design Sample Patients Results

Kelleher J, et Retrospective 2-by-2 factorial 15,751 Birth weight 401-1000 g; Risk of spontaneous intestinal perforation
al. Pediatrics cohort study of 2 neonatal survived to at least 12 hours (SIP) did not differ between the I+E+
2014. exposures: after birth; previously (indomethacin and any enteral feeds during
described 2 neonatal the first 3 days) group and the I+E-
1. Prophylactic IV exposures (indomethacin and no feeds during the first
indomethacin initiated 3 days) group (p=0.1467)
during the first 24 hours
after birth Prophylactic indomethacin with early
2. Early enteral nutrition feeding was associated with less death or
defined as any feeding severe neurodevelopmental impairment at
administered during the 18-22-month follow-up compared to the
first 3 days after birth group that received prophylactic
indomethacin but no early feeding.

42
Indomethacin and Enteral Feeding

Study
Study Sample Patients Interventions Results
Design
Louis D, et Single- 415 All preterm Categorized based on enteral Similar rate of NEC  stage IIa between all 3
al. Journal of center, neonates who feed volume (EFV) exposure groups (A: 6.1%, B: 7.8%, and C: 4.6%)
Perinatology retrospective received during treatment:
2016. cohort treatment with Similar rate of feeding intolerance between all
indomethacin Group A: NPO 3 groups (A: 4.9%, B: 10.6%, and C: 9.3%)
for PDA
Group B: EFV  60 mL/kg/day Statistically significant difference in the
number of days to reach enteral feeds of 160
Group C: EFV > 60 mL/kg/day mL/kg/day (A: 29.9, B: 29.4, and C: 23.5)
(p=0.01 for C vs A and p=0.03 for C vs B)

43
Key Takeaways

Limited data is available to guide optimal enteral feeding administration during

PDA management

Enteral feeding is NOT contraindicated during PDA management

Most available literature evaluates enteral feeding with administration of

indomethacin, which is the agent with the greatest impact on mesenteric blood
flow

44
Areas for Future Research

Optimal feeding
advancement
regimen

Enteral feeding
and
acetaminophen

Enteral feeding and high-

dose ibuprofen

45
 SEEKING
CLOSURE FOR
PATENT DUCTUS
ARTERIOSUS
EMILY LETSINGER, PHARMD
PGY1 PHARMACY RESIDENT
ASCENSION ST. VINCENT