pediatric newborn medicine clinical practice …...© department of pediatric newborn medicine,...

© Department of Pediatric Newborn Medicine, Brigham and Women’s Hospital

PEDIATRIC NEWBORN

MEDICINE CLINICAL

PRACTICE GUIDELINES

Assessment and Treatment

for Patent Ductus

Arteriosus

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PEDIATRIC NEWBORN MEDICINE CLINICAL PRACTICE GUIDELINES


Clinical Practice Guideline: Pharmacologic and Surgical Therapy for Patent Ductus

Arteriosus

Points of emphasis/Primary changes in practice:

1. Echocardiography and treatment will be recommended by the Neonatal PDA

SCAMP.

2. Intravenous indomethacin will remain first-line therapy for hemodynamically-

significant PDA.

3. Intravenous or oral acetaminophen may be utilized for infants who fail indomethacin

therapy, who have contraindications to indomethacin therapy, or infants on ≥ 100

mL/kg/day of enteral feedings at the time of diagnosis.

Rationale for change:

To optimize and standardize utilization diagnosis and treatment of PDA.

Questions? Please contact: Terri Gorman, [email protected]

mailto:[email protected]



Clinical Guideline Name Pharmacologic and surgical therapy for patent ductus arteriosus

Implementation Date 1/15/16

Due for CPC Review

Contact Person NICU Medical Director

Approved By Pediatric Newborn Medicine Clinical Practice Council _1/15/16___ CWN SPP __________ SPP Steering _10/21/15_________ Nurse Executive Board/CNO___10/26/15_______

I. Purpose

The purpose of this clinical practice guideline is to address the medical management of the

preterm neonate with hemodynamically significant PDA (hsPDA). Additionally, this guideline

seeks to decrease the unnecessary treatment of non-hemodynamically significant PDA. The

scope of this guideline includes the following aspects of medical management:

(i)Indications for echocardiography

(ii) Interpretation of echocardiography

(iii) Pharmacotherapy for PDA

(iv) Indications for surgical ligation

II. Scope

Inclusion criteria: Neonates ≤ 32 weeks gestation

Exclusion criteria: Gestational age > 32 weeks

Known congenital abnormalities contradicting ductal closure

III. Indications for echocardiography

A large PDA is associated with early pulmonary hemorrhage.1 However, infants at the highest

risk for pulmonary hemorrhage will be captured by the severe IVH prediction algorithm

described above. Therefore, early echocardiography will not be utilized.

Evidence indicates that treatment of moderate or severe ductal shunting detected at 72 hours of

life does not confer a clinical advantage over treatment at 7 days. Importantly, 44% of infants

with moderate or severe ductal shunting at 72 hours of life had a closed PDA at 6 days of life.2

When clinically appropriate, pharmacotherapy for PDA will be deferred to ≥ 7 days of life.



Echocardiography will be performed at the discretion of the medical care team for infants with

clinical score ≥ moderate (Appendix 2).3, 4

Repeat echocardiography will be performed after prophylactic indomethacin only in the setting

of clinical symptoms as described above.

Repeat echocardiography will be performed within 12 hours of the final dose of any course of

pharmacotherapy initiated based on clinical symptoms as described above.5

IV. Interpretation of echocardiography

Indication for treatment will be determined by assessment of the clinical score and ECHO score

(Appendix 2).3, 4

V. Pharmacotherapy for PDA

Indomethacin is relatively contraindicated in the setting of recent IVH (detected within the

previous 24 hours, concern greater after grade III/IV IVH), urine output < 1 mL/kg/hr for the

proceeding 8 hours, SCr > 1.6 mg/dL, platelet count < 50,000/cm3, active clinical bleeding, or

necrotizing enterocolitis.

Indomethacin dosing and monitoring will be guided by the indomethacin Drug Administration

Guideline (abbreviated in Appendix 1).

A repeat course of indomethacin will be initiated immediately after the initial course at the

discretion of the medical care team for persistence of ECHO score > 3 and clinical score ≥

moderate (Appendix 2).

Non-nutritive feedings of up to 15 mL/kg/day of maternal breast milk or donor milk should be

provided during indomethacin therapy, in the absence of specific contraindications.

Neonates with persistence indications for treatment (Appendix 2) after two courses of

indomethacin will receive intravenous acetaminophen per the acetaminophen Drug

Administration Guideline (Appendix 3). .

Acetaminophen will be utilized as first-line therapy in the setting of contraindications to

indomethacin. Intravenous therapy will be utilized for patients receiving < 100 mL/kg/day of

enteral feeding; oral therapy will be utilized for patients receiving > 100 mL/kg/day of enteral



feedings. In the absence of a clear contraindication to enteral feeding advancement (i.e., NEC,

SIP, or vasopressor doses impacting GI perfusion), enteral feeding adjustment should be

continued in the setting of therapy with intravenous or oral acetaminophen.

Oral ibuprofen or oral acetaminophen may be used as first-line therapy for patients receiving >

100 mL/kg/day of enteral feedings at the time of indicated treatment (Appendix 2). Oral

ibuprofen will be utilized per the ibuprofen Drug Administration Guideline (Appendix 4).

VI. Indications for surgical ligation

Consultation with cardiothoracic surgery regarding PDA ligation may be considered for

neonates with ECHO score ≥ 5 and significant/worsening of clinical symptoms after complete

courses of indomethacin and/or acetaminophen.

The short-term and long-term adverse effects of ductal ligation should be weighed against the

potential benefits. Surgical ligation is associated with a high incidence of left vocal cord

paralysis, resulting in prolongation of mechanical ventilation, feeding difficulties, and

respiratory complications persisting into adulthood.6-8 Prospective and retrospective studies

suggest surgical ligation is associated with an increased risk of chronic lung disease and long-

term neurosensory impairment.9-11



Appendix 1 – Abbreviated indomethacin drug administration guideline

Postnatal age

(hours) Dose and interval

< 12 0.1 mg/kg IV q 24 hr x 3

12 – 96 0.2 mg/kg IV q 12 hr x 3 > 96 0.3* mg/kg IV q 12 hr x 3

Generally, hold doses for urine output < 1 mL/kg/hr or serum creatinine increase of 0.5 mg/dL

over baseline

*Dose may be escalated to 0.4-0.5 mg/kg on the basis of serial echocardiography in the absence

of indomethacin toxicity, as described above, at the discretion of the medical care team

Prostaglandin inhibitor for the closure of the ductus arteriosus and prophylaxis of IVH

Administration time and preparation: Infuse dose ≤ 0.3 mg/kg over 60 minutes.

Infuse doses > 0.3 mg/kg over 2 hours.

Compatibility: D5W, NS, furosemide, insulin, potassium chloride, standard UAC fluids

Incompatibilty: D10W, TPN, dobutamine, dopamine, Fentanyl, midazolam

Monitoring: Urine output (notify MD for < 1 mL/kg/hr); platelet count (maintain ≥ 100 x 109/L

during therapy*), serum creatinine before each dose or once daily

*Platelet count of < 50 x 109 utilized as exclusion criteria in the largest trial of indomethacin

prophylaxis (reflected as a relative contraindication above). In a retrospective study, treatment

with a COX inhibitor was associated with an increased incidence of IVH in infants with a

platetlet count of 50– 99 x 109 versus ≥ 100 x 109 (reflected as the desired platelet count above).

Adverse Effects: GI perforation (active corticosteroid therapy is a relative contraindication),

decreased urine output, inhibits platelet aggregation

Evidence

Treatment dosing of INDO varies widely across studies, with the most common approach being

0.2 mg/kg IV q12h x 3 in trials enrolling patients between 12 hour and 96 hours of life.12, 13

The possible utility and safety of dose escalation for older patients has been described in several

large cohort studies.14, 15



Appendix 2 – PDA SCAMP Algorithm


Points Select Score

CPAP with FiO2 ≤ 30% 0 Enter values:

CPAP with FiO2 > 30% OR NIPPV OR ventilator MAP ≤7 1 Patient length (cm)

Ventilator MAP 8-9 2 Paitent weight (g)

Small to moderate pulmonary hemorrhage OR ventilator MAP 10-12 3 PDA diameter (mm)

Ventilator MAP >12 4 BSA (m2) 0.000

PDA diameter ratio #DIV/0!Less than or equal to 26 weeks 0

27-29 weeks 1

Points ScoreUOP ≥1 mL/kg/hour OR Cr ≤ 1.2 0 PDA diameter ratio < 0.5 0

UOP <1 mL/kg/hour OR Cr > 1.2 1 PDA diameter ratio 0.5-1 1

PDA diameter ratio 1.0-1.5 2

No symptoms 0 PDA diameter ratio > 1.5 3

Widened pulse pressure, murmur 1 YES/NO ScoreCardiomegaly or pulmonary edema on CXR 2 Velocity of PDA flow <2m/s (2 m/s ~ 20 mMHg) 0

Hypotension requiring 1 cardiotropic agent 3 Enlargement of the LA without any other etiology 0

Hypotension requiring > 1 cardiotropic agent 4 Enlargement of the LV without any other etiology 0

LA hypertension without any other etiology

pH > 7.25 and/or < -7 (HCO3 11-16) 0 (by flow velocity across PFO or septal bowing left to right)

pH 7.1 - 7.25 and/or BE -7 to -12 (HCO3 11-16) 1 Holodiastolic flow reversal in the abdominal aorta

pH <7.1 and/or BE > -12 (HCO3 <11) 2 (wihtout other etiology)

PDA SCAMP TOOL: CLINICAL SCOREFILL IN EACH RED CELL, DO NOT LEAVE ANY RED CELLS BLANK

PDA SCAMP TOOL: ECHO SCOREFILL IN EACH RED CELL, DO NOT LEAVE ANY RED CELLS BLANK

0 Total ECHO Score #DIV/0!

0

0

Refer to IRCDA SCAMP Data Form to select appropriate pathway you plan to follow

Select YES or NO for any of the following reported on ECHO

PDA Diameter

Total Clinical ScoreMild: 0-3 points; Moderate: 4-7 points; Severe: 8-12 points

IF ECHO ORDERED:

#DIV/0!

ECHO Scoring Table

PDA Ratio Calculator

Clinical Score Calculator:CriterionRespiratory

Renal

Gestational Age

Cardiovascular

Acidosis

Will

automatically

populate from

calculated PDA

diameter ratio

above


Appendix 3 – Abbreviated acetaminophen drug administration guideline

15 mg/kg PO q6h x 3-7 days

Non-narcotic analgesic

Preparation: Commercially-available 32 mg/mL suspension. Do not refrigerate.

Monitoring: Pain scores, temperature

For PDA – Obtain serum concentration, ALT, and bilirubin 4 hours after dose on day 2, 5, and 7

of therapy. Acetaminophen serum concentration requires 0.5 mL of blood in a light green tube

(same tube that is used for electrolytes, bilirubin, chem-7, etc; call x27415 with questions).

Therapeutic range for pain = 10 – 20 mcg/mL

Toxic range > 100 mcg/mL

Therapeutic range for PDA closure is unknown. We will use serum concentrations in our

patients to ensure safety and to develop a pharmacokinetic dose/response curve to inform

future use.

Adverse effects: Liver toxicity after elevated (> 90 mg/kg/day if > 37 wks PMA, > 60 mg/kg/day

if 32-37 wks PMA, > 40 mg/kg/day if < 32 wks PMA) or prolonged dosing (> 48 hours).

Consider obtainment of hepatic transaminases if patient receives elevated dose or scheduled

dosing for > 48 hours.

Evidence

Initially reported by Hammerman et al.16

12 cases series including 88 patients summarized by Le et al.17

Outstanding questions reviewed by Allegaert et al.18

Randomized trials reported by Oncel et al.19 and Dang et al.20



Appendix 4 – Abbreviated ibuprofen drug administration guideline

10 mg/kg PO x 1 dose, then 5 mg/kg PO q24hrs x 2 doses

Higher doses may be utilized for patients > 72 hours of age

Prostaglandin inhibitor for the closure of the ductus arteriosus

Monitoring: Urine output; SCr, platelet count (maintain ≥ 100 x 109/L during therapy) before

each dose or once daily

Adverse Effects: GI perforation, decreased urine output, inhibits platelet aggregation

Evidence

Efficacy equivalent to oral indomethacin in randomized controlled trials with a lower risk of

NEC.21

Efficacy superior to intravenous ibuprofen.21



IX. References

[1] Kluckow M, Evans N. Ductal shunting, high pulmonary blood flow, and pulmonary

hemorrhage. The Journal of pediatrics. 2000;137:68-72.

[2] Van Overmeire B, Van de Broek H, Van Laer P, Weyler J, Vanhaesebrouck P. Early versus

late indomethacin treatment for patent ductus arteriosus in premature infants with respiratory

distress syndrome. The Journal of pediatrics. 2001;138:205-11.

[3] McNamara PJ, Sehgal A. Towards rational management of the patent ductus arteriosus: the

need for disease staging. Archives of disease in childhood Fetal and neonatal edition.

2007;92:F424-7.

[4] Harling S, Hansen-Pupp I, Baigi A, Pesonen E. Echocardiographic prediction of patent

ductus arteriosus in need of therapeutic intervention. Acta paediatrica. 2011;100:231-5.

[5] Carmo KB, Evans N, Paradisis M. Duration of indomethacin treatment of the preterm patent

ductus arteriosus as directed by echocardiography. The Journal of pediatrics. 2009;155:819-22

e1.

[6] Clement WA, El-Hakim H, Phillipos EZ, Cote JJ. Unilateral vocal cord paralysis following

patent ductus arteriosus ligation in extremely low-birth-weight infants. Archives of

otolaryngology--head & neck surgery. 2008;134:28-33.

[7] Benjamin JR, Smith PB, Cotten CM, Jaggers J, Goldstein RF, Malcolm WF. Long-term

morbidities associated with vocal cord paralysis after surgical closure of a patent ductus

arteriosus in extremely low birth weight infants. Journal of perinatology : official journal of the

California Perinatal Association. 2010;30:408-13.

[8] Roksund OD, Clemm H, Heimdal JH, Aukland SM, Sandvik L, Markestad T, et al. Left

vocal cord paralysis after extreme preterm birth, a new clinical scenario in adults. Pediatrics.

2010;126:e1569-77.

[9] Cassady G, Crouse DT, Kirklin JW, Strange MJ, Joiner CH, Godoy G, et al. A randomized,

controlled trial of very early prophylactic ligation of the ductus arteriosus in babies who weighed

1000 g or less at birth. The New England journal of medicine. 1989;320:1511-6.

[10] Chorne N, Leonard C, Piecuch R, Clyman RI. Patent ductus arteriosus and its treatment as

risk factors for neonatal and neurodevelopmental morbidity. Pediatrics. 2007;119:1165-74.

[11] Kabra NS, Schmidt B, Roberts RS, Doyle LW, Papile L, Fanaroff A, et al. Neurosensory

impairment after surgical closure of patent ductus arteriosus in extremely low birth weight

infants: results from the Trial of Indomethacin Prophylaxis in Preterms. The Journal of

pediatrics. 2007;150:229-34, 34 e1.

[12] Van Overmeire B, Smets K, Lecoutere D, Van de Broek H, Weyler J, Degroote K, et al. A

comparison of ibuprofen and indomethacin for closure of patent ductus arteriosus. The New

England journal of medicine. 2000;343:674-81.

[13] Lago P, Bettiol T, Salvadori S, Pitassi I, Vianello A, Chiandetti L, et al. Safety and efficacy

of ibuprofen versus indomethacin in preterm infants treated for patent ductus arteriosus: a

randomised controlled trial. European journal of pediatrics. 2002;161:202-7.

[14] Sperandio M, Beedgen B, Feneberg R, Huppertz C, Brussau J, Poschl J, et al. Effectiveness

and side effects of an escalating, stepwise approach to indomethacin treatment for symptomatic

patent ductus arteriosus in premature infants below 33 weeks of gestation. Pediatrics.

2005;116:1361-6.



[15] McPherson C, Gal P, Ransom JL, Carlos RQ, Dimaguila MA, Smith M, et al. Indomethacin

pharmacodynamics are altered by surfactant: a possible challenge to current indomethacin dosing

guidelines created before surfactant availability. Pediatric cardiology. 2010;31:505-10.

[16] Hammerman C, Bin-Nun A, Markovitch E, Schimmel MS, Kaplan M, Fink D. Ductal

closure with paracetamol: a surprising new approach to patent ductus arteriosus treatment.

Pediatrics. 2011;128:e1618-21.

[17] Le J, Gales MA, Gales BJ. Acetaminophen for Patent Ductus Arteriosus. The Annals of

pharmacotherapy. 2014.

[18] Allegaert K, Naulaers G, Vanhaesebrouck S, Anderson BJ. The paracetamol concentration-

effect relation in neonates. Paediatric anaesthesia. 2013;23:45-50.

[19] Oncel MY, Yurttutan S, Erdeve O, Uras N, Altug N, Oguz SS, et al. Oral paracetamol

versus oral ibuprofen in the management of patent ductus arteriosus in preterm infants: a

randomized controlled trial. The Journal of pediatrics. 2014;164:510-4 e1.

[20] Dang D, Wang D, Zhang C, Zhou W, Zhou Q, Wu H. Comparison of oral paracetamol

versus ibuprofen in premature infants with patent ductus arteriosus: a randomized controlled

trial. PloS one. 2013;8:e77888.

[21] Ohlsson A, Walia R, Shah SS. Ibuprofen for the treatment of patent ductus arteriosus in

preterm and/or low birth weight infants. The Cochrane database of systematic reviews.

2013;4:CD003481.

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