Download Acetaminophen Use in Patent Ductus Arteriosus (PDA): Should we

Acetaminophen Use in Patent Ductus Arteriosus (PDA)
Should we show a Public Display of Affection for Tylenol®?
Allison Hardy, Pharm.D.
PGY1 Pharmacy Resident
The Children’s Hospital of San Antonio, San Antonio, Texas
Division of Pharmacotherapy, The University of Texas at Austin College of Pharmacy
Pharmacotherapy Education and Research Center
University of Texas Health Science Center at San Antonio
February 26, 2016
Learning Objectives
1. Define patent ductus arteriosus (PDA) and the clinical indications for closure
2. Compare and contrast the adverse effects and contraindications of nonsteroidal anti-inflammatory
drugs (NSAIDs) versus acetaminophen (APAP) treatment for PDA
3. Determine the validity of acetaminophen therapy for PDA closure
I. Fetal Circulation
A. Definitions1,2
1. Ductus arteriosus (DA): shunts blood from the pulmonary artery to the aorta
2. Foramen ovale: shunts blood from the right atrium to the left atrium, bypassing the lungs
Figure 1. Fetal Circulation3
B. Fetal Circulation1
1. Placenta accepts deoxygenated blood from fetus through the umbilical arteries and becomes
oxygenated
2. Oxygenated blood returns to the fetus via the umbilical vein, then enters the right side of the
fetal heart
3. The patent foramen ovale (PFO) allows oxygenated blood to flow from the right atrium to the
left atrium and then continues to the left ventricle and the aorta
4. Deoxygenated blood returning from the fetus enters the right atrium and flows to the right
ventricle
a. After birth, the right ventricle pumps blood to the lungs
b. In the fetus, the right ventricle pumps blood through the DA, bypassing the lungs
5. Deoxygenated and oxygenated blood mix to form partially-oxygenated blood
6. A patent ductus arteriosus is necessary for normal fetal circulation
2|Hardy
Figure 2. Normal Fetal Heart1
II. Patent Ductus Arteriosus
A. Normal Physiology2,4
1. Low fetal systemic arterial oxygen tension (PaO2) and elevated circulating prostaglandins
(PG) from the mother lead to vasodilation
2. Within a few hours after birth, PaO2 increases and circulating PGs decrease leading to
constriction
a. DA develops ischemic hypoxia which transforms the ductus into a non-contractile
ligament and is no longer patent
b. DA begins to close within 72 hours after birth, but may take several days to
completely close
B. Patent Ductus Arteriosus (PDA)2,4
1. In preterm infants, the ductus fails to close or to remain closed within 72 hours following
birth
a. DA fails to develop the profound hypoxic ischemia needed to cause remodeling of
the artery
b. Increased nitric oxide production from the DA causes vasodilation
2. Opening between the aorta and the pulmonary artery allows oxygenated blood to recirculate
into the lungs
3. Left-to-right shunting through the PDA results in pulmonary overcirculation, left heart
volume overload, and pulmonary edema
3|Hardy
Figure 3. Patent Ductus Arteriosus5
C. Incidence Rates4,6
1. Accounts for 6-11% of all congenital heart defects
2. Occurs in 8 out of 1,000 premature births
3. Affects up to 60% of infants < 28 weeks gestation
4. Female to male ratio is 2:1
5. Infants with birth weights < 1000 g
a. 65% will have a PDA at 72 hours
b. 85% out of the 65% will require treatment
D. Risk Factors4,5
1. Prematurity
2. Rubella infection during first trimester of pregnancy
3. Valproic acid exposure
4. Born at high altitude
5. Genetic predisposition
E. Signs and Symptoms5
1. May include:
a. Fatigue
i. Irritability
ii. Crying
b. Increased work of breathing
i. Nasal flaring
ii. Decreased oxygen saturation
c. Feeding intolerance
i. Apnea/bradycardia/hypotension during feedings
ii. Emesis/abdominal distention
d. Failure to thrive
2. May be asymptomatic
3. Depends on the size of the PDA
a. Larger PDAs allows more blood to pass through and overload the lungs
b. Larger PDAs left untreated can allow poorly oxygenated blood to flow in the wrong
direction, weakening the heart muscle and resulting in heart failure
4|Hardy
F. Diagnosis4,7
1. Echocardiogram (echo) is the procedure of choice
a. Confirms diagnosis and characterize PDA
b. Classify the PDA as silent, small, moderate, or large
Type
Silent
Small
Moderate
Large
Table 1. PDA Classification7
Size
< 1.5 mm
1.5-3 mm
3-5 mm
> 5 mm
Murmur Present (Y/N)
N
Y
Y
Y
G. Hemodynamically significant PDA (hsPDA) 4,5,8-11
1. Left atrium-to-aortic root diameter ratio > 1.6
2. DA diameter of > 1.5 mm
3. Left ventricular enlargement
4. Holodiastolic flow reversal in the descending aorta
H. Complications2,4,5
1. Pulmonary hypertension
2. Heart failure
3. Endocarditis
4. Necrotizing enterocolitis (NEC)
5. Metabolic acidosis
6. Intraventricular hemorrhage (IVH)
7. Bronchopulmonary dysplasia (BPD)
8. Respiratory distress syndrome (RDS)
I.
Indications for Closure of PDA4,5,8-11
1. Symptomatic patients
2. Asymptomatic patients with left heart enlargement or volume overload
3. Moderate to large PDAs
4. Pulmonary arterial hypertension (PAH)
5. hsPDA
J. Treatment Options2,4
1. Surgery
2. Pharmacologic Treatment
a. NSAIDs
b. Acetaminophen
III. Surgical Treatment
A. Indicated as treatment of choice for large, symptomatic PDAs, but reserved for infants after
pharmacological failure or with contraindications to pharmacologic therapy4
B. Methods4,12
1. Transcatheter closure
5|Hardy
a. Catheter advanced across the DA from either the pulmonary artery or the aorta
and closure device occludes the ductus
b. Preferred choice of surgical closure over other techniques
c. Success rate: 90-95%
2. Surgical ligation
a. Close the duct by clipping the opening of the DA with a metal device
b. Preferred choice of surgical closure for very large PDAs
c. Success rate: 94-100%
C. Complications4,13
1. Bleeding
2. Pneumothorax
3. Infection
4. Embolization
D. Contraindications12
1. Severe pulmonary hypertension with predominant right-to-left flow
2. Life-threatening infection
3. Septic shock
IV. Pharmacologic Treatment
A. NSAIDs6,8,14-21
1. Mechanism of Action
a. Reversibly inhibits cyclooxygenase-1 and 2 (COX-1 and 2) enzymes
b. Prostaglandin E2 (PGE2) is the most potent ductal relaxant among the five
prostanoids
i. Although COX-2 is the predominant source of PGE2, inhibition of COX-2
does not affect DA diameter
ii. COX-1 inhibitors are equally effective to the non-selective COX inhibitors
Figure 4. Prostaglandin Synthesis14
6|Hardy
2. Indomethacin
a. Considered the gold standard
b. Non-selective COX inhibitor
c. The treatment of choice for PDA since the 1970s
d. Success rate: 60-70%
e. FDA approved for premature neonates weighing 500-1750 g
f. Initial dose: 0.2 mg/kg IV followed by two doses given at 12 and 24 hour intervals
based on postnatal age (PNA) at the time of first dose (Refer to Table 2)
Table 2. Indomethacin Dosing for PDA
PNA
Dose
< 48 hours
0.1 mg/kg
2-7 days
0.2 mg/kg
> 7 days
0.25 mg/kg
g. Adverse Effects
i. Oliguria
ii. Reduces blood-flow velocity to the brain, gut, and kidneys
iii. Renal failure
iv. GI bleeding and perforation
v. Thrombocytopenia
vi. Acute NEC
vii. Hyperbilirubinemia
3. Ibuprofen
a. Neoprofen®: brand name for IV formulation
b. Non-selective COX inhibitor
c. Neoprofen replaced indomethacin as the mainstay of treatment
i. Decreased adverse effects
ii. Similar effectiveness
iii. Success rate: 60-70%
c. FDA approved for neonates without restrictions for gestational age (GA) or weight
d. Evidence-based dosing
GA (weeks)
< 32
> 32
< 34
Table 3. Evidence Based Dosing for Ibuprofen in Neonates
Weight (g)
Initial Dose (mg/kg)
Following Doses (mg/kg)
500-1500
10
5
N/A
10
5
< 1500
10
5
Route
IV
IV
PO
i. High dose: initial dose of 20 mg/kg IV or PO, followed by two doses of 10
mg/kg/dose at 24 and 28 hours
ii. Pourarian, et al (2015): Demonstrated that high dose ibuprofen for PDA in
preterm neonates is more effective than standard dosing with no significant
increase in adverse events
e. Adverse events
iii. Similar to indomethacin but decreased frequency of adverse events
iv. Does not reduce blood-flow velocity to vital organs
7|Hardy
4. Ibuprofen-Related Toxicities
a. Acute Renal Failure
i. Mechanism: glomerular filtration rate (GFR) is lower in preterm infants
a. Considered to be in a state of physiologic renal insufficiency
b. Prolonged half-life in premature infants (~30.5 hrs)
ii. Incidence rate of ibuprofen < indomethacin
b. Hyperbilirubinemia Mechanism: ibuprofen competes with bilirubin for albumin
binding sites and increases circulating bilirubin levels
i. Increased risk for bilirubin encephalopathy and kernicterus due to the need
for PDA treatment plus onset of hyperbilirubinemia in neonatal period
ii. Zecca, et al studied the relationship between ibuprofen and
hyperbilirubinemia (See Table 4)
Table 4. Neonatal Hyperbilirubinemia and Ibuprofen20
Zecca E, Romagnoli C, et al. Does ibuprofen increase neonatal hyperbilirubinemia? Pediatrics.
2009;124:480-484.
To investigate whether ibuprofen exposure was associated with increased
Objective
hyperbilirubinemia in preterm infants < 30 weeks GA
Retrospective cohort study
Trial Design
Ibuprofen group, n=418
Non-ibuprofen group, n=288
Hyperbilirubinemia:
Outcomes
• Total serum bilirubin (TSB) levels
• Need for phototherapy
• Duration of phototherapy
Ibuprofen
Results
Peak TSB level, mean: 9
Need for phototherapy, n: 398 (95.2%)
Phototherapy duration, mean (h): 94.3
Conclusion
Non-ibuprofen
Peak TSB level, mean: 7.3
Need for phototherapy, n: 254 (88.2%)
Phototherapy duration, mean (h): 87.2
Ibuprofen treatment in preterm infants was significantly associated with higher TSB
levels as confirmed by the greater need for phototherapy and the longer duration of
phototherapy in the ibuprofen group
5. Ibuprofen Resistance
a. Approximately 22-30% of preterm infants fail to respond to a single course of
ibuprofen and require further doses and/or surgical ligation
b. In patients with sepsis, serum concentrations of PGs and tumor necrosis factor
alpha (TNF-α) are increased and potentially mediates the drug resistance of PDA
c. Dani, et al studied the characteristics of neonates who failed ibuprofen therapy
versus neonates who had successful closure or spontaneous closure (See Table 5)
8|Hardy
Table 5. Ibuprofen Resistant PDA in Neonates21
Dani C, Bertini G, Corsini I, et al. The fate of ductus arteriosus in infants at 23-27 weeks of
gestation: from spontaneous closure to ibuprofen resistance. Acta Paediatrica. 2008;97:11761180.
To assess if there are clinical characteristics effective as predictive factors for
Objective
spontaneous closure of the DA, development of PDA, and ibuprofen-resistant
PDA in infants < 28 weeks GA with RDS
Prospective observational study
Trial Design
Ibuprofen 10 mg/kg IV followed by 5 mg/kg after 24 and 48 hours
Intervention
Ductal closure verified by echo
Outcomes
Spontaneous closure: 8/34 (24%)
Results
Closure of PDA after first course of ibuprofen: 17/34 (50%)
Failed to respond to the first ibuprofen course: 9/34 (26%)
Conclusion
• Spontaneous closure of PDA was associated with older GA
• Infants responding to the first course of ibuprofen had a older GA, more
frequent occurrence of BPD and IVH, and lower sepsis incidence
• Infants unresponsive to ibuprofen had a higher incidence of sepsis during
the first 3 days of life and a younger GA
B. APAP Treatment11,18,19,22-25
1. Nomenclature
a. Acetaminophen: term used for APAP in United States and Japan
b. Paracetamol: term used for APAP in Canada and European countries
2. Mechanism of Action
a. Inhibits the synthesis of PGs on the peroxidase segment
b. Peroxidase is activated at 10-fold lower peroxide concentrations than cyclooxygenase
c. Acetaminophen-mediated inhibition is facilitated at reduced peroxide concentrations,
such as hypoxia
Figure 5. Acetaminophen Effect on Prostaglandin Synthesis26
9|Hardy
3. Benefits of APAP
a. No known renal adverse effects
b. Lower anti-platelet activity of APAP compared to COX inhibitors may positively
influence the DA closure
a. After ductal closure, platelet aggregation plays a role in the formation of a
thrombus that occludes the ductal lumen
b. With higher anti-platelet activity associated with NSAIDs, the DA may not be
successful in closure
4. Adverse Effect: hepatotoxicity
a. Rare (< 5%)
b. Liver function tests (LFTs) post-treatment are typically normal
C. Pricing (based on Lexi-comp)
Table 6. Pricing of Ibuprofen versus Acetaminophen
Generic (Brand)
Average Wholesale Price
Acetaminophen PO (Tylenol®)
$0.72/473 mL
160 mg/5 mL
®
Acetaminophen IV (Ofirmev )
$42.48/100 mL
10 mg/mL
Ibuprofen PO (Motrin®)
$5.14/120 mL
100 mg/5 mL
Ibuprofen IV (Neoprofen®)
$609/2 mL
10 mg/mL
VI. Acetaminophen Literature Review
Table 7. Dang D, Wang D, Zhang C, et al. Comparison of oral paracetamol versus ibuprofen in
premature infants with patent ductus arteriosus: a randomized controlled trial. Plos One
2013;8(11):1-5.27
Overview
To
evaluate
the
efficacy
and
safety profiles of oral paracetamol to those of standard
Objective
ibuprofen for PDA closure in premature infants
Randomized, non-blinded, parallel-controlled, non-inferiority trial in China
Trial Design
Inclusion Criteria
Exclusion Criteria
Patients
• GA < 34 weeks
• Congenital heart disease with required
PDA to maintain blood flow
• PNA < 14 days
•
Life-threatening infection
• Echo diagnosis of hsPDA
• Recent IVH (grade 3-4)
• Urine output < 1 mL/kg/h
• Serum creatinine (SCr) > 0.88 mg/dL
• Platelet count < 50,000/µL
• Hyperbilirubinemia requiring exchange
transfusion
• Active NEC/intestinal perforation
• Liver dysfunction
10 | H a r d y
Table 7 Continued. Dang D, Wang D, et al. Plos One 2013;8(11):1-5.27
Overview Continued
Primary
Secondary
Outcomes
• Rate of ductal closure for both • Early adverse events (oliguria, IVH,
APAP and ibuprofen
tendency to bleed, NEC,
hyperbilirubinemia, death)
• Late adverse events (BPD, periventricular
leukomalacia [PVL], NEC, retinopathy of
prematurity [ROP], sepsis, death)
Interventions
• Paracetamol group: 15 mg/kg PO every 6 hours for 3 days
• Ibuprofen group: 10 mg/kg PO followed by 5 mg/kg after 24 and 48 hrs
• Between doses of medications, infants received the same volume of dextrose
5% in water (D5W)
• Echo was performed after first course of treatment for both groups
o If only minor shunting was present after two courses without the need
of respiratory support, no further treatment was given
Statistics
• Interim analyses were performed for primary and secondary outcomes at 50%
recruitment
• Non-inferiority analysis
• p < 0.05
Baseline
•
Characteristics •
Primary
Outcomes
Results
80 patients received paracetamol and 80 patients received ibuprofen
No statistical difference between groups
Mean GA (weeks)
Mean birth weight (grams)
Ibuprofen
30.9 + 2.2
1531 + 453.5
Paracetamol
31.2 + 1.8
1591.9 + 348.6
• There was no significant difference between the two treatment groups except
for mean days of closure
Closure Rate of PDA
Paracetamol
Overall closure rate, n (%)
65 (81.2%)
45 (56.3%)
Primary closure rate
Secondary closure rate
20 (25%)
Reopening after closure
5 (7.7%)
Reclosure rate
4 (80%)
Mean days needed for closure
3.22 + 0.14
Ibuprofen
63 (78.8%)
38 (47.5%)
25 (31.3%)
6 (9.5%)
4 (66.7%)
3.71 + 0.16
p value
0.693
0.268
0.379
0.712
0.621
0.020
11 | H a r d y
Table 7 Continued. Dang D, Wang D, et al. Plos One 2013;8(11):1-5.27
Results Continued
Secondary
• No significant differences between the two groups in the incidence of oliguria,
Outcomes
renal failure, NEC, IVH and SCr
• No significant differences between the two groups in adverse events, including
BPD, PVL, NEC, sepsis, ROP, and death
• Significant difference in incidence rates of hyperbilirubinemia
o Paracetamol group, n = 16
o Ibuprofen group, n = 28
o p = 0.03
• Significant difference in incidence rates of gastrointestinal bleeding
o Paracetamol group, n = 2
o Ibuprofen group, n = 8
o p = 0.03
Conclusions
Author’s
• Oral paracetamol is non-inferior to oral ibuprofen in preterm infants with PDA
Conclusions
• The mean days to closure was shorter in the paracetamol group than in the
ibuprofen group
• Paracetamol may be indicated for PDA in preterm infants with
hyperbilirubinemia
Strengths
• Measured ductal diameter and shunt velocity in both groups
• Evaluated adverse events associated with ibuprofen toxicity
Limitations
• Results obtained from single medical center
• Non-blinded (MDs and RNs were not blinded)
• Did not evaluate APAP toxicity, such as LFTs
• Not generalizable to patients > 34 weeks GA
• Paracetamol group was older and larger versus ibuprofen group
• Ibuprofen PO not considered the standard treatment
Take Home
• Paracetamol considered a pharmacological option for PDA closure in neonates
Points
< 34 weeks GA and < 1600 g
12 | H a r d y
Table 8. Oncel MY, Yurttutan S, Erdeve O, et al. Oral paracetamol versus oral ibuprofen in the
management of patent ductus arteriosus in preterm infants: a randomized controlled trial. J
Pediatr 2014;164:510-514.28
Overview
To compare the efficacy and safety of oral paracetamol and oral ibuprofen for the
Objective
pharmacological closure of PDA in preterm infants
Prospective, randomized, controlled study in Turkey
Trial Design
Inclusion Criteria
Exclusion Criteria
Patients
• GA < 30 weeks
• Presence of major congenital abnormalities
• Right-to-left ductal shunting
• Birth weight < 1250 g
• Life-threatening infection
• PNA 48-96 hours
• IVH (grade 3-4)
• Echo diagnosis of hsPDA
• Urine output < 1 mL/kg/h
• SCr > 1.6 mg/dL
• Platelet count < 60,000/µL
• Liver failure
• Hyperbilirubinemia requiring exchange
transfusion
• Persistent pulmonary hypertension
Primary
Secondary
Outcomes
• Success rate, defined as a
• Need for retreatment or surgical ligation
closed duct on echo after the • Mode and duration of ventilation
completed course
• Increase in blood urea nitrogen (BUN),
• Safety
SCr, bilirubin, aspartate amino transferase
(AST), or alanine transaminase (ALT)
levels
• Rates of ductal reopening
• Surfactant treatment
• Pneumothorax
• Pulmonary hemorrhage, NEC, chronic lung
disease (CLD), IVH, GI bleeding, ROP
• Sepsis
• Death
Interventions
• Paracetamol group: 15 mg/kg PO every 6 hours for 3 days
• Ibuprofen group: 10 mg/kg PO followed by 5 mg/kg after 24 and 48 hrs
Statistics
• t-test was used for continuous variables
• χ2 test was used for categorical variables
• Power of 80%
• p < 0.05
Baseline
Characteristics
Results
• 40 patients were assigned to the ibuprofen group and 40 patients were
assigned to the paracetamol group
• No statistical difference between groups
Mean GA (weeks)
Mean birth weight (grams)
Ibuprofen
27.3 + 2.1
973 + 224
Paracetamol
27.3 + 1.7
931 + 217
13 | H a r d y
Table 8 Continued. Oncel MY, Yurttutan S, et al. J Pediatr 2014;164:510-514.28
Results Continued
Primary
• There were no significant differences between the two treatment groups
Outcomes
• Reopening rates between the two groups were not statistically significant
Secondary
Outcomes
Author’s
Conclusions
Closure Rate of PDA
Paracetamol
Ibuprofen
p value
29 (72.5%)
31 (77.5%)
0.6
GA < 30 weeks
17 (73.9%)
11 (57.9%)
0.27
GA < 28 weeks
10 (76.9%)
9 (56.2%)
0.24
GA < 26 weeks
• No significant difference between the two groups for secondary outcomes
•
•
Strengths
Limitations
•
•
•
•
Take Home
Points
•
•
•
Conclusions
Oral paracetamol and ibuprofen were similarly effective for the closure of
PDA with one course of treatment
Both medications were well-tolerated and deemed safe in terms of renal and
liver variables
Measured ductal diameter and shunt velocity in both groups
Evaluated the potential toxicities of both ibuprofen and APAP
Early GA and PNA for inclusion criteria (most infants might have
spontaneously closed the PDA)
Intervention was not completely blinded due to the different number of
doses/day of the different medications
Safety outcomes were not defined prior to the study
Liver failure not defined
Premature infants with GA < 30 weeks and weight < 1250 g with
contraindications to NSAIDs may benefit from paracetamol as a treatment
option for closure of PDA
Table 9. Tekgündüz KS, Ceviz N, Caner I, et al. Intravenous paracetamol with a lower dose is
also effective for the treatment of patent ductus arteriosus in pre-term infants. Cardiol Young
2015;25:1060-1064.29
Overview
To
evaluate
the
efficacy
of
lower-dose IV paracetamol for the treatment of hsPDA
Objective
in pre-term infants with contraindications to oral ibuprofen
Retrospective chart review from October 2012 to November 2013 in Turkey
Trial Design
Inclusion Criteria
Exclusion Criteria
Patients
• Contraindication to oral ibuprofen
• None defined
• Side effects to ibuprofen
• hsPDA
14 | H a r d y
Table 9 Continued. Tekgündüz KS, et al. Cardiol Young 2015;25:1060-1064.29
Overview Continued
Primary
Secondary
Outcomes
• Rate of ductal closure for
• Pre- and post-treatment transaminase
APAP confirmed by echo after
levels
the completed course
• Recanalization after successful closure
• Surgical ligation
1. Paracetamol 15 mg/kg/dose IV every 6 hours OR
Intervention
2. Paracetamol 10 mg/kg/dose IV every 8 hours
Descriptive statistics
Statistics
Baseline
Characteristics
Primary
Outcomes
Secondary
Outcomes
Author’s
Conclusions
Strengths
Limitations
Take Home
Points
Results
• Total number of patients: 13
o 9/13: Feeding intolerance
o 4/13: NEC
• First patient had elevated serum transaminase levels with 15 mg/kg/dose
dosing regimen; remaining patients received 10 mg/kg/dose dosing regimen
• Median GA (weeks): 29
• Median birth weight (g): 950
• Median PNA (days): 3
• Closure rate, including all patients: 76.9% (10/13)
• Closure rate, excluding patient with hepatotoxicity: 83.3% (10/12)
Outcome
Percentage
Pre- and post-treatment transaminase levels
7.69% (1/13)
Recanalization after successful closure
20% (2/10)
Surgical ligation
15.4% (2/13)
Conclusions
• Lower dose paracetamol may be effective for patients with contraindications
to oral ibuprofen
• The closure rate was similar to previously reported rates with oral paracetamol
and suggests that oral and IV administration are not superior to each other in
terms of closure rate and reopening rate
• Transaminase levels should be routinely monitored in these patients due to
increased risk of hepatotoxicity
• Measured transaminase levels in all patients
• Compared low dose to standard dose of paracetamol
• Small sample size
• Retrospective chart review
• No exclusion criteria identified
• Unknown safe and effective dose for paracetamol in premature infants
• Patients only had contraindication to oral ibuprofen, not IV form
• Renal toxicity or hyperbilirubinemia not measured
• Hepatotoxicity and elevated transaminase levels not defined
• Inconclusive evidence on effectiveness of paracetamol on reopened PDAs
• Premature infants with a contraindication to oral ibuprofen, such as NEC or
feeding intolerance, may benefit from low-dose IV paracetamol with a lower
risk of hepatotoxicity
15 | H a r d y
VI. Summary of Evidence
A. Ibuprofen has been the primary option for PDA closure
B. Safety concerns for ibuprofen
1. Renal failure
2. NEC
3. Hyperbilirubinemia
C. Variety of studies examining the role of PO and IV APAP in premature neonates
D. Introduction of APAP
1. Standard dose: 15 mg/kg PO or IV every 6 hours for 3 days
2. Low dose: 10 mg/kg IV every 8 hours for 3 days
E. Efficacy outcomes: APAP vs. Ibuprofen
1. Similar rates of PDA closure
2. No difference between reopening rates
F. Take Home Points
1. APAP considered a pharmacological option for PDA closure in neonates for studied GA
and weight range
2. Premature infants with contraindications to NSAIDs may benefit from paracetamol as a
treatment option for closure of PDA
VII. Conclusions
A. The decision to close PDA with APAP is dependent on several variables
1. Adverse effects and contraindications of NSAIDs
2. Risk of hepatotoxicity
3. Overall benefit of closing hsPDA
B. Future Directions
1. A well-designed superiority trial is essential to determine if APAP is more effective than
NSAIDs
2. Role of APAP in undiscovered ductal-dependent congenital heart defects
VIII. Recommendations
A. Ibuprofen to remain as the first-line treatment until further studies of APAP in PDA are
conducted
B. Recommended Treatment:
1. If contraindications to NSAID/failure of NSAID, trial APAP as second-line option
2. Refer to Figure 6 for proposed algorithm of treatment
C. APAP Monitoring
1. PDA closure via echo
2. LFTs
16 | H a r d y
hsPDA
Contraindication to
NSAIDs/failure of
closure with
NSAIDs
No contraindication
to NSAIDs
GA < 34 weeks
GA < 32 weeks
GA > 32 weeks
Weight
< 1600 g
Weight
500-1500 g
No weight
parameters
APAP
15 mg/kg/dose PO
or IV Q6Hx 3 days
Ibuprofen
10 mg/kg IV
Ibuprofen
10 mg/kg IV
5 mg/kg/dose IV at
24 and 48 hours
5 mg/kg/dose IV at
24 and 48 hours
Figure 6. Proposed Treatment Options for hsPDA in Premature Infants
17 | H a r d y
References
1. American Heart Association. Fetal circulation.
http://www.heart.org/HEARTORG/Conditions/CongenitalHeartDefects/SymptomsDiagnosisofConge
nitalHeartDefects/Fetal-Circulation.Accessed January 25, 2016.
2. De-Sanctis E, Clyman R. Patent ductus arteriosus: pathophysiology and management. J Perinatol.
2006;26:14-18.
3. The Royal Children's Hospital Melbourne. The normal heart.
http://www.rch.org.au/cardiology/parent_info/The_Normal_Heart/. Accessed February 3, 2016.
4. Schneider D, Moore J. Patent ductus arteriosus. Circulation. 2006;114:1873-1882.
5. Mayo Clinic. Patent ductus arteriosus (PDA). http://www.mayoclinic.org/diseases-conditions/patentductus-arteriosus/basics/definition/con-20028530. Accessed January 25, 2016.
6. Overmeire B, Chemtob S. The pharmacologic closure of the patent ductus arteriosus. Semin Fetal
Neonat M. 2005;10:117-184.
7. Fernando R, Koranne K, Loyalka P, et al. Patent ductus arteriosus closure using an amplatzer™
ventricular septal defect closure device. Exp Clin Cardio. 2013;18:50-54.
8. Hamrick S, Hansmann G. Patent ductus arteriosus of the preterm infant. Pediatrics. 2010;125:10201030.
9. Reller M, Lorenz J, Kotagal U, et al. Hemodynamically significant PDA: an echocardiographic and
clinical assessment of incidence, natural history, and outcome in very low birth weight infants
maintained in negative fluid balance. Pediatr Cardiol. 1985;6:17-24.
10. McNamara P, Sehgal A. Towards rational management of the patent ductus arteriosus: the need for
disease staging. Arch Dis Child Fetal Neonatal Ed. 2007;92:424-427.
11. Terrin G, Conte F, Scipione A, et al. Efficacy of paracetamol for the treatment of patent ductus
arteriosus in preterm neonates. Ital J Pediatr. 2014;40:1-4.
12. Ibrahim M, Azab A, Kamal N, et al. Outcomes of early ligation of patent ductus arteriosus in
preterms, multicenter experience. Medicine. 2015;94:1-5.
13. Nadir E, Kassem E, Foldi S, et al. Paracetamol treatment of patent ductus arteriosus in preterm
infants. J Perinatol. 2014;34:748-749.
14. Medscape. NSAIDs, coxibs, and cardio-renal physiology: a mechanism-based evaluation.
http://www.medscape.org/viewarticle/422939. Accessed January 26, 2016.
15. Gulack B, Laughon M, Clark R, et al. Comparative effectiveness and safety of indomethacin versus
ibuprofen for the treatment of patent ductus arteriosus. Early Human Development. 2015;91:725-729.
16. Erdeve O, Sarici S, Sari E, Gok F. Oral-ibuprofen-induced acute renal failure in a preterm infant.
Pediatr Nephrol. 2008;23:1565-1567.
17. Pourarian S, Takmil F, Cheriki S, Amoozgar H. The effect of oral high-dose ibuprofen on patent
ductus arteriosus closure in preterm infants. Am J Perinato. 2015;32:1158-1163.
18. Jasani B, Kabra N, Nanavati R. Oral paracetamol in treatment of closure of patent ductus arteriosus in
preterm neonates. J Postgrad Med. 2013;59:312-314.
19. Yurttutan S, Oncel M, Arayici S, et al. A different first-choice drug in the medical management of
patent ductus arteriosus: oral paracetamol. J Matern Fetal Neonatal Med. 2013;26:825-827.
20. Zecca E, Romagnoli C, Carolis M, et al. Does ibuprofen increase neonatal hyperbilirubinemia?
Pediatrics. 2009;124:480-484.
21. Dani C, Bertini G, Corsini I, et al. The fate of ductus arteriosus in infants at 23-27 weeks of gestation:
from spontaneous closure to ibuprofen resistance. Acta Paediatrica. 2008;97:1176-1180.
22. Hammerman C, Bin-Nun A, Markovitch E, et al. Ductal closure with paracetamol: a surprising new
approach to patent ductus arteriosus treatment. Pedatrics. 2011;128:1618-1621.
23. Sinha R, Negi V, Dalal S. An interesting observation of PDA closure with oral paracetamol in
preterm neonates. J Clin Neonatol. 2013;2:30-32.
24. Allegaert K, Anderson B, Simons S, Overmeire B. Paracetamol to induce patent ductus arteriosus
closure: is it valid? Arch Dis Child. 2013;98:462-466.
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25. Ozdemir O, Dogan M, Kucuktasci K, et al. Paracetamol therapy for patent ductus arteriosus in
premature infants: A change before surgical ligation. Pediatr Cardiol. 2014;35:276-279.
26. Allegaert K. Paracetamol to close the patent ductus arteriosus: from serendipity toward evidence
based medicine. J Postgrad Med. 2013;59:251-252.
27. Dang D, Wang D, Zhang C, et al. Comparison of oral paracetamol versus ibuprofen in premature
infants with patent ductus arteriosus: a randomized controlled trial. Plos One. 2013;8:1-5.
28. Oncel M, Yurttutan S, Erdeve O, et al. Oral paracetamol versus oral ibuprofen in the management of
patent ductus arteriosus in preterm infants: a randomized controlled trial. J Pediatr. 2014;164:510514.
29. Tekgunduz K, Ceviz N, Caner I, et al. Intravenous paracetamol with a lower dose is also effective for
the treatment of patent ductus arteriosus in pre-term infants. Cardiol Young. 2015;25:1060-1064.
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X. Appendix
Appendix A. Acronyms
Name
Patent ductus arteriosus
Patent foramen ovale
Ductus arteriosus
Arterial oxygen tension
Prostaglandin
Echocardiogram
Necrotizing enterocolitis
Intraventricular hemorrhage
Bronchopulmonary dysplasia
Respiratory distress syndrome
Pulmonary arterial hypertension
Hemodynamically significant PDA
Acetaminophen or paracetamol
Nonsteroidal anti-inflammatory drug
Prostaglandin E2
Cyclooxygenase
Aspirin
Postnatal age
Gestational Age
Total serum bilirubin
Glomerular filtration rate
Tumor necrosis factor alpha
Liver function test
Periventricular leukomalacia
Retinopathy of prematurity
Chronic lung disease
Serum creatinine
Aspartate amino transferase
Alanine transaminase
Acronym
PDA
PFO
DA
PaO2
PG
echo
NEC
IVH
BPD
RDS
PAH
hsPDA
APAP
NSAID
PGE2
COX
ASA
PNA
GA
TSB
GFR
TNF-α
LFT
PVL
ROP
CLD
SCr
AST
ALT
20 | H a r d y