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 Table of Contents  
Year : 2017  |  Volume : 4  |  Issue : 3  |  Page : 114-116

Oral COX inhibitors for closure of hemodynamically significant Patent Ductus Arteriosus in Neonates : A retrospective analysis at a tertiary center in central India

Consultant, Department of Neonatology and Pediatrics Choithram Hospital and Research Centre, Indore, India

Date of Submission25-May-2017
Date of Acceptance15-Jun-2017
Date of Web Publication20-Jul-2017

Correspondence Address:
Jenisha Jain
Department of Neonatology, Mehta Children's Hospital, Chetpet, Chennai
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Source of Support: None, Conflict of Interest: None

DOI: 10.21304/2017.0403.00203

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Background : The efficacy of oral indomethacin/ ibuprofen in the closure of hemodynamically significant PDA is not extensively studied.
Aim : Retrospective analysis of data on the efficacy and safety of oral cyclooxygenase (COX) inhibitors- indomethacin and ibuprofen in patent ductus arteriosus (PDA) closure.
Materials and methods : All preterm (28-36.6weeks) infants born between July 2011- June 2012 who received oral cyclooxygenase inhibitors for closure of PDA were included in the study. The outcome measured was closure rate of PDA.
Results : Of the 162 preterm neonates, 34 received oral COX inhibitors. Of them 27 received oral indomethacin and 7 received syrup ibuprofen. The total closure rate was 91.2% after first course and 8.8% of neonates required a second course with complete closure. No neonate required surgical closure. In the indomethacin group, 5 patients had thrombocytopenia and 1 had NEC. However, none of the cases in ibuprofen group had any significant side effects.
Conclusion : Oral COX inhibitors are an effective therapy for closure of PDA.

Keywords: Patent ductus arteriosus, Neonates, COX inhibitors, Ibuprofen, ductus closure

How to cite this article:
Jain J, Passi GR. Oral COX inhibitors for closure of hemodynamically significant Patent Ductus Arteriosus in Neonates : A retrospective analysis at a tertiary center in central India. J Pediatr Crit Care 2017;4:114-6

How to cite this URL:
Jain J, Passi GR. Oral COX inhibitors for closure of hemodynamically significant Patent Ductus Arteriosus in Neonates : A retrospective analysis at a tertiary center in central India. J Pediatr Crit Care [serial online] 2017 [cited 2023 Jun 8];4:114-6. Available from: http://www.jpcc.org.in/text.asp?2017/4/3/114/281382

  Introduction: Top

Patent Ductus Arteriosus (PDA) is frequently encountered cardiac problem in preterm neonates. Timely closure of PDA is crucial to reduce morbidity and mortality related to complications of PDA like intraventricular hemorrhage, bronchopulmonary dysplasia, necrotizing enterocolitis etc.[1] Intravenous therapy with indomethacin and ibuprofen is the standard medical treatment which has an efficacy of 70-80%[2]. However, it is expensive and not easily available. Oral medical therapy is used as an alternative. However, the safety, efficacy and complications of oral therapy in our setting have not been studied. The present study was undertaken to study these important aspects of treatment.

  Methods: Top

This was a retrospective study conducted at Neonatal Intensive Care Unit of Choithram Hospital and Research Centre from July 2011- June 2012. All preterm neonates with hemodynamically significant PDA who were treated with oral indomethacin or ibuprofen were included for the analysis. Hemodynamically significant PDA was defined as the presence of any of the following signs: systolic or continuous murmur together with widening of pulse pressure or active precordial heave, cardiomegaly and increased pulmonary vascularity on chest radiography.

The diagnosis of PDA was confirmed by echocardiography. The duct size was noted using 2-dimensional image through the parasternal short axis view. Color and pulsed wave spectral Doppler scan was used to assess the direction and velocity of flow. 2D ECHO criteria used for defining significant duct were: ductal diameter >1.4mm/kg, LA: Ao ratio >1.4 and/ retrograde flow in descending aorta > 30%. Echocardiography was repeated 24 hrs. after every treatment course to confirm closure of the ductus. Ductal closure was defined as a ductal diameter of <1mm or a tiny jet of blood. Treatment regimen followed Capsule indomethacin (25 mg) was dissolved in the distilled water to a final concentration of 1mg/ml. Every course consisted of 3 doses at 0.2 mg/kg, repeated at 24 hourly intervals. Ibuprofen was administered as 3 doses in syrup form (100mg/5 ml) at a dosage of 10 mg/kg followed by 2 doses of 5mg/ kg each. The choice of therapy was at the discretion of the treating consultant. In treatment failure cases defined as failure of closure of PDA within 48 hours of the first course, another course of treatment was administered through the same route. The treatment was withheld if any of the following conditions were present: platelet < 50,000/cumm, serum creatinine> 1.8 mg/dl, necrotizing enterocolitis stage II a or more, urine output <1 ml/kg/hour, active bleeding from any site. Surgical ligation was considered if a total of 3 courses failed to close PDA. Data collection the following data was obtained from inpatient files of all neonates in the study group the response to 1st course of therapy (close/open), need for 2nd or 3rd course or surgical ligation and the side effects. Side effects noted were: urine output <1 ml/kg/hr for the following 8 hrs., thrombocytopenia <50,000/cumm, serum creatinine> 1.8 mg/dl post treatment, serum sodium < 130 meq/l or a decrease in serum sodium of more than 5 meq/l if compared from pretreatment values, coffee ground aspirate, and fresh blood from the gastric tube. The side effects were attributed to indomethacin if they occurred during the treatment or within 48 hours after treatment. Other factors like antenatal corticosteroids, surfactant use, mechanical ventilation, culture proven sepsis were noted down.

  Results: Top

A total of 210 babies were admitted to NICU during study period. Of them, 162(77%) were preterm. 34 preterm babies (21%) had hemodynamically significant PDA confirmed by 2D ECHO. 27(79.5%) of them received oral aqueous form of indomethacin and 7(20.5%) received oral ibuprofen in syrup form.

Complete ductal closure was noted in 31/34 (91.2%) infants with first course. 3(8.8%) required 2nd course of treatment. In indomethacin group, 2 neonates required second course for PDA closure and were ventilator dependent for 11 days and 21 days respectively. In ibuprofen group, 1 infant required second course for PDA closure and was oxygen dependent for 10 days. There was no reopening during the hospital stay and none required surgical ligation. There were total 3 mortalities (8.8%, 2 in indomethacin group, 1 in ibuprofen group) due to sepsis. 6 neonates were discharged against medical advice due to financial reason. Apart from upper gastrointestinal hemorrhage (1 case) and thrombocytopenia (5 cases) in indomethacin group, no other side effects were noted with the oral treatment regimens.

  Discussion: Top

The effect of intravenous indomethacin and intravenous ibuprofen is well established in treatment of PDA closure. However, the effects of the enteral form are still controversial, because of high variability of pharmacodynamics in preterm babies. However, in a resource limited setting cost of intravenous indomethacin is a limiting factor (One vial =Rs.1500/-) compared to capsule indomethacin (Rs. 25/capsule). Till now, there are very few studies that have analyzed effectiveness of oral indomethacin. Cook and Pickering [3] reported 5 cases of treatment failure in 7 very low birth weight infants who received oral aqueous form. Evans et al[4] had suggested that absorption of oral indomethacin is low and erratic in preterm neonates with PDA. Studies have shown that in vitro bioavailability of indomethacin is 20%. However, later studies reported 70% closure rate with an aqueous solution and up to 85% closure rate with ethanol based solution [5]. Recently, a saline- ethanol-dextrose based suspension achieved a 98.6% absorption rate in preterm neonates. In this study enteral method used was an aqueous based solution of indomethacin and the closure rate with first course was 92.5%[2]. The efficacy of ibuprofen is comparable to indomethacin in treatment of PDA and the reported ductal closure rate is 62% - 90%.[6] A recent study from India has reported a closure of 65.7% with oral indomethacin and 60 % with oral ibuprofen [7]. In the present study, the ductal closure rates were higher with the first course of oral indomethacin (92.6%) and ibuprofen (85.7%) and only 8.8% of cases required repeat therapy. The discrepancy in the results of various studies points to the need of conducting larger studies to determine appropriate regimens for closure with minimal side effects. Though both agents are cyclooxygenase inhibitors, indomethacin may cause significant reduction in cerebral and gastrointestinal blood flow and may alter platelet function [8] Ibuprofen enhances cerebral blood flow autoregulation, has no changes in gastrointestinal hemodynamics or platelet function [9]. In the current study, the incidence of thrombocytopenia was noted in 5/27 cases in oral indomethacin group and none observed in ibuprofen group. 1 case had upper gastrointestinal hemorrhage in indomethacin group and none in ibuprofen group. No evidence of impaired renal function was observed in any of the cases. Keller and Clyman [10] suggested that additional indomethacin treatment is unlikely to produce ductus closure in premature infants if there is persistent Doppler evidence of ductal flow within 24 hours after an initial short course and earlier surgical ligation is suggested. However, a survey of Neonatal Fellowship Programme Directors in the United States [11] reported that multiple courses of indomethacin (up to 3 courses) are commonly used for persistent PDA. In our study, 2 patients required second course of indomethacin for closure of PDA. We were soon able to extubate the neonates after PDA closure but they were oxygen dependent for longer duration (up to 30 days). 1 patient in ibuprofen group required second course. The present study is a retrospective data on the efficacy and safety of oral COX inhibitors for PDA closure in neonates. The study has limitations based on its retrospective analysis and small sample size. However, it still shows the efficacy of oral formulations as a cost effective treatment modality in our setting. Prospective, large sample studies are warranted to show the true efficacy of the treatment modalities. To conclude, all preterm infants with PDA responded to oral COX inhibitors. Very few side effects were noted in our group. Oral COX inhibitors are effective in closure of PDA. However, large scale studies are needed to confirm our findings.

Conflict of Interest: None

Source of Funding: None

  References Top

Clyman RI. Patent ductus arteriosus in premature infant. In: Tacusch WH, Ballard RA, eds. Avery’s Diseases of the Newborn, 8th edition. Philadelphia: WB Saunders, 2004: 816-23.  Back to cited text no. 1
Tsao PC, Chen SJ, Yang CF, Lee YS, JyJeng M, Soong WJ, et al. Comparison of intravenous and oral indomethacin administration for closure of PDA in extremely low birth babies. J Clin Med Assoc.2010;73(1): 15-20.  Back to cited text no. 2
Cook RW, Pickering D. Poor response to oral indomethacin therapy for persistent patent ductus arteriosus in very low birth weight infants. Br Heart J 1974;41:301-3.  Back to cited text no. 3
Evans M, Bhat R, Vidyasagar D, Patel M, Hastreiter A. A comparison of oral and intravenous indomethacin disposition in the premature infant with patent ductus arteriosus. Pediatr Pharmacol 1981;1:251-8.  Back to cited text no. 4
So LY, Fok TF, Sung RY, Ho JK. Preterm infants with patent ductus arteriosus: treatment with an enteral preparation of indomethacin. Trop Paediatr1992;12:403-8  Back to cited text no. 5
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(4):202-7.  Back to cited text no. 6
Yadav S, Agarwal S, Maria A. Pediatr Cardiol 2014;35: 824. doi:10.1007/s00246-014-0861.  Back to cited text no. 7
Patel J, Roberts I, Azzopardi D, Hamilton P, Edwards AD. Randomized double-blind controlled trial comparing the effects of ibuprofen with indomethacin on cerebral hemodynamics in preterm infants with patent ductus arteriosus. Pediatr Res 2000; 47: 36-42.  Back to cited text no. 8
Clyman RI. Medical treatment of patent ductus arteriosus in premature infants. In: Long WA, ed. Fetal and neonatal cardiology. Philadelphia:WB Saunders, 1990:682-90.  Back to cited text no. 9
Keller RL, Clyman RI. Persistent Doppler flow predicts lack of response to multiple courses of indomethacin in premature infants with recurrent patent ductus arteriosus. Pediatrics. 2003;112:583-7.  Back to cited text no. 10
Amin SB, Handley C, Carter-Pokras O. Indomethacin use for the management of patent ductus arteriosus in preterms: a web-based survey of practice attitudes among neonatal fellowship program directors in the United States. Pediatr Cardiol 2007;28:193-200.  Back to cited text no. 11


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