The efficacy of repeated courses of ibuprofen in the closure of patent ductus arteriosus in premature infants

The Efficacy of Repeated Courses of Ibuprofen in the Closure of Patent Ductus Arteriosus in Premature Infants Accepted Manuscript The Efficacy of Repeated Courses of Ibuprofen in the Closure of Patent[.]

Accepted Manuscript

The Efficacy of Repeated Courses of Ibuprofen in the Closure of Patent Ductus

Arteriosus in Premature Infants

Ting-An Yen, M.D., MPH, Ching-Chia Wang, M.D., Ph.D.

PII: S1875-9572(17)30022-0

DOI: 10.1016/j.pedneo.2016.12.003

Reference: PEDN 636

To appear in: Pediatrics & Neonatology

Received Date: 28 December 2016

Accepted Date: 28 December 2016

Please cite this article as: Yen T-A, Wang C-C, The Efficacy of Repeated Courses of Ibuprofen in the

Closure of Patent Ductus Arteriosus in Premature Infants, Pediatrics and Neonatology (2017), doi:

10.1016/j.pedneo.2016.12.003.

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The Efficacy of Repeated Courses of Ibuprofen in the Closure of

Patent Ductus Arteriosus in Premature Infants

Ting-An Yen1, M.D., MPH, Ching-Chia, Wang2, M.D., Ph.D

1

Department of Emergency, National Taiwan University Hospital, National Taiwan

University College of Medicine, Taipei, Taiwan

2

Department of Pediatrics, National Taiwan University Hospital, National Taiwan

University College of Medicine, Taipei, Taiwan

Corresponding author:

Ching-Chia, Wang, M.D., Ph.D

Department of Pediatrics,

National Taiwan University Hospital and National Taiwan University College of

Medicine

No 8, Chung-Shan South Road

Taipei, 100, Taiwan

TEL: 886-2-23123456 ext 71616

Fax: 886-2-23278607

E-mail: ccwangy1@ntu.edu.tw

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ACCEPTED MANUSCRIPT Patent ductus arteriosus (PDA) is a common condition in premature infants and is

associated with various prematurity-related morbidities if left untreated.1 A

hemodynamically significant PDA (hsPDA) can decrease systemic flow with left to

right shunting, which is attributable to intraventricular hemorrhage, necrotizing

enterocolitis (NEC), retinopathy of prematurity (ROP), and bronchopulmonary

dysplasia.2 Ibuprofen, a propionic acid derivative and a non-selective cyclooxygenase

(COX) inhibitor, has been reported to be as effective to close a PDA as indomethacin

with less adverse effects, including gastrointestinal, cerebral, and renal hemodynamic

effects Orogastric administration of ibuprofen, compared to intravenous ibuprofen,

was demonstrated to have the same efficacy with fewer adverse effects.3 In addition to

pharmacological management, surgical ligation or percutaneous transcatheter devices

are other treatment choices for PDA closure.2

In most clinical practices, surgical ligation is the alternative treatment following

failure of PDA closure after repeated courses of COX inhibitors Nevertheless,

surgical ligation is associated with an increased risk of neurodevelopment impairment,

chronic lung disease, and severe ROP.4 Therefore, the purpose of the present study

was to research the efficacy and safety of repeated courses of COX inhibitor The

most recent studies with relatively large study populations have demonstrated the

efficacy of repeated courses of ibuprofen.4,5,6 In the study of Richards et al 5,authors

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investigated the rate of PDA closure in a population of infants with <1000 g birth

weight following repeated doses of ibuprofen Although the study did not specify the

route of ibuprofen administration, the overall rate of PDA closure after a single and

second course of ibuprofen was 45% and 40%, respectively With 83% responding to

either one or two courses of treatment, the above study suggests that a second course

of ibuprofen may be effective in closing a PDA in even the most preterm infants

However, the risk of a failed closure by ibuprofen that required surgical ligation was

higher among infants with <26 weeks gestational age and those weighing <750 g

Another retrospective study in 2012, consisting of 164 preterm infants (<32 weeks

gestational age), investigated the efficacy of repeated courses of intravenous

ibuprofen in closure of an hsPDA.4 Unlike the study by Richards et al. 5, this study

demonstrated that the closure rate of PDA after a second (44%) or third (55%) course

of ibuprofen was similar to the closure rate after the first course (66%), with no

additional side effects following multiple courses In addition, the study confirmed the

higher closure rate after the first course of ibuprofen, if started prior to postnatal day 5

In another study by Olgun et al 6, the authors aimed to describe the efficacy and

safety of repeated courses of oral ibuprofen in premature infants with hsPDA The

overall closure rates following the first, second, and third courses of oral ibuprofen

were 71%, 40%, and 35%, respectively Although there is an increasing closure rate

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ACCEPTED MANUSCRIPT following repeated oral ibuprofen administration, a third course did not increase the

closure rate significantly Hence, the study suggested surgical ligation following the

second course of treatment if a patient still has PDA with concomitant signs of severe

heart failure

In general, either oral or intravenous ibuprofen have been proven to be as effective

as indomethacin in closure of PDA with less risk of all-cause mortality, NEC, and

decreased urine output.3 However, oral ibuprofen, compared to intravenous ibuprofen,

seems to be more effective in PDA closure with a significantly decreased risk of

“failure to close PDA after three doses.”3 Furthermore, evidence has demonstrated

that a second course of oral/intravenous ibuprofen may also be helpful after treatment

failure of the initial course To date, no study has demonstrated the outcome of

pharmacological management of PDA with multiple courses of ibuprofen is better or

worse than surgical closure Therefore, a large prospective study may be required to

determine whether pharmacological management of PDA with multiple courses of

ibuprofen is better or worse than surgical closure

References

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ductus arteriosus closure is associated with increased mortality in preterm infants

Pediatrics 2009; 123(1): e138-44.

2 Perez KM, Laughon MM What is new for patent ductus arteriosus management in

premature infants in 2015? Curr Opin Pediatr 2015; 27(2): 158-64

3 Ohlsson A, Walia R, Shah SS Ibuprofen for the treatment of patent ductus

arteriosus in preterm or low birthweight (or both) infants Cochrane Database Syst Rev 2015; 2: CD003481

4 Van der Lugt NM, Lopriore E, Bökenkamp R, Smits-Wintjens VE, Steggerda SJ, Walther FJ Repeated courses of ibuprofen are effective in closure of a patent ductus

arteriosus Eur J Pediatr 2012; 171(11): 1673-77

5 Richards J, Johnson A, Fox G, Campbell M A second course of ibuprofen is

effective in the closure of a clinically significant PDA in ELBW infants Pediatrics

2009; 124(2): e287-93

6 Olgun H, Ceviz N, Kartal İ, Caner İ, Karacan M, Taştekin A, et al Repeated Courses of Oral Ibuprofen in Premature Infants with Patent Ductus Arteriosus:

Efficacy and Safety Pediatr Neonatol 2016; Epub ahead of print