Original Article
The Effect of Oral High-dose Ibuprofen on Patent Ductus Arteriosus Closure in Preterm Infants Shahnaz Pourarian, MD1
Faranak Takmil, MD2
Sirous Cheriki, MD3
1 Neonatology Research Center, Shiraz University of Medical Sciences,
Shiraz, Iran 2 Department of Pediatrics, Shiraz University of Medical Sciences, Shiraz, Iran 3 Neonatology and Cardiac Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
Hamid Amoozgar, MD3
Address for correspondence Faranak Takmil, MD, Department of Pediatric, Nemazee Hospital, Nemazee Square, Shiraz, Iran (e-mail: [email protected]).
Am J Perinatol 2015;32:1158–1163.
Abstract
Keywords
► Premature PDA HighDose Ibuprofen
Objective The aim of this study is to compare the efficacy and possible adverse effects of the oral high-dose ibuprofen regimen to that of standard regimen in closing patent ductus arteriosus (PDA). Study Design This clinical trial study was performed from April 2012 to May 2013 on preterm infants with gestational age < 37 weeks and postnatal age 3 to 7 days with echocardiographic diagnosis of hemodynamically significant PDA. These neonates were randomly assigned to two treatment groups that respectively received high dose (20–10–10 mg/kg/d) and standard dose (10–5–5 mg/kg/d) oral ibuprofen regimen for 3 days. Effect of ibuprofen therapy was evaluated by echocardiography and neonates were followed for renal dysfunction, gastrointestinal complication, bleeding, and hyperbilirubinemia. Results From a total of 60 enrolled infants, 30 cases received the high dose of ibuprofen and the remaining 30 received the standard dose. Complete ductal closure was observed in 20 (70%) infants treated with high-dose regimen in comparison with 11 (36.7%) in the standard-dose regimen group (p ¼ 0.010). No gastrointestinal, renal, or hematological adverse effects were reported. Conclusion The high-dose oral ibuprofen seems to be more effective than the current standard dose regimen for PDA closure in premature neonates without increasing the adverse effects.
Patent ductus arteriosus (PDA) is one of the most common cardiovascular diseases in premature infants and its closure has a significant effect on management of respiratory and circulatory disorders. Natural ductal closure is inversely related to gestational age and birth weight. The prevalence of a hemodynamically significant shunt because of the PDA has been reported as high as 66% for infants with gestational age less than 28 weeks, and 20% for those with gestational age more than 32 weeks.1,2 The PDA at birth may cause several complications such as cardiac and pulmonary disorders,3 or even an increase in the mortality rate.4 Therefore, offering
treatments toward closing this duct is of crucial importance and many studies have been conducted on this subject to date. Several studies have revealed that, compared with indomethacin, in the pharmacological closure of PDA, oral ibuprofen has shown the same therapeutic effects with even fewer side effects5–8; however, other studies seem to suggest a reduction in the success of the treatment by using the standard dose of ibuprofen. As a result, recent studies have focused on using the high-dose intravenous ibuprofen regimen for PDA closure.9,10 Moreover, studies have revealed
received August 20, 2014 accepted after revision March 13, 2015 published online May 22, 2015
Copyright © 2015 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
DOI http://dx.doi.org/ 10.1055/s-0035-1551671. ISSN 0735-1631.
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that increasing the drug dosage does not result in an increase in side effects.10,11 In spite of lack of intravenous ibuprofen accessibility in Iran, no studies have been conducted on the effect of high-dose oral ibuprofen. This study is therefore aimed at using oral ibuprofen for PDA closure in premature infants to improve ibuprofen efficacy.
Patients and Methods Patients This randomized trial study was performed in the neonatal intensive care units of the Nemazee and Hafez Hospitals, affiliated hospitals of Shiraz University of Medical Sciences, Shiraz, Iran, from April 2012 to May 2013. The study was approved by the Medical Ethics Committee of each center. Neonates were enrolled after a written informed consent was obtained from their parents. Enrollment criteria were as follows: preterm infants with gestational age 37 weeks; postnatal age of 3 to 7 days and echocardiographic diagnosis of hemodynamically significant PDA. Exclusion criteria were major congenital anomalies, congenital heart defects, persistent pulmonary hypertension, life-threatening infections, severe bleeding, death before administration of the first course of ibuprofen, infants with decreased urine output less than 1 mL/kg of body weight per hour, and those with impaired renal function with a serum creatinine concentration 1.8 mg/dL (129 µmol/L), platelet count 50,000/mm3 or a tendency to bleed, as hematuria, or blood in the endotracheal aspirate, oozing of blood from sampling site, and gastrointestinal bleeding. Neonates meeting any single exclusion criterion were excluded from the study.
Study Design Enrolled neonates were then randomly divided into two groups by means of cards in sealed opaque envelopes. The first group consisted of those who were treated with highdose regimen of oral ibuprofen. Using a 24-hour interval, three doses of oral suspension (100 mg/5 mL; Hakim Pharmaceutical, Tehran, Iran, 75-HM-30) were administered to these infants. The first dose of the high-dose regimen was 20 mg/kg followed by two 10 mg/kg doses. Using the same interval, the second group was also given three doses of standard regimen oral ibuprofen with an initial dose of 10 mg/kg, followed by two doses of 5 mg/kg each, 24 and 48 hours later. Whenever the ductus arteriosus was yet patent after the randomly assigned treatment in a patient in either group, a second course of ibuprofen at high dose (20–10–10 mg/kg/d) was given as nonrandomized treatment, starting 24 hours after the last dose of the first course. In this trial study, neonatologist and nurses were not blind. All infants were closely monitored for any side effects of the drug such as oliguria and gastrointestinal bleeding, or any bleeding tendency during and after treatment. Serum creatinine, blood urea nitrogen, and platelet count were recorded before and after treatment and also 24-hour urine output was
Pourarian et al.
measured during treatment. Oliguria was defined as a urine output of 1 mL/kg/h or less during a 24-hour collection period. Necrotizing enterocolitis (NEC) was diagnosed by the presence of clinical signals and radiographic findings of pneumatosis intestinalis, hepatobiliary gas, or free intraperitoneal air.12 Total serum bilirubin levels, the need for and the duration of phototherapy were evaluated during treatment. A tendency to bleed was defined according to the criteria used for exclusion from the study. Doppler echocardiography was performed with a Mindray M7 (Shenzhen, People's Republic of China) echocardiography machine using 7 MHz probes. This was performed twice during the study. First, the day before treatment for identifying neonates with PDA and also to rule out the possibility of other congenital heart disease and the existence of pulmonary hypertension; and second, 24 hours after receiving the last dose of the drug for evaluation of the neonates’ responses to the treatment. The cardiologist was unaware of the infants’ treatment assignments. The patient’s demographic data and drug dosage along with echocardiographic parameters such as size of PDA end systolic and diastolic pressure gradients and left atrial to aortic ratio were recorded on a demographic form which was designed by the neonatologist and pediatric cardiologist.
Statistical Analysis Assuming a closure rate of 80%13 with the standard regimen oral ibuprofen, with a 95% confidence interval (CI) and a power of 80%, it was calculated that a study group of 60 neonates would be necessary for the study to be able to detect a difference of at least 20 percentage points in the closure rate between the standard- and high-regimen oral ibuprofen groups. The data were presented as mean SD for continuous or number (percent) for categorical variables. To compare categorized and continuous variables between the two groups, the chi-square or Fisher exact test and student t test were used, respectively. The p value of 0.05 or less was considered statistically significant. Data were analyzed by SPSS statistical software, v.18 (SPSS Inc, Chicago, IL).
Results Demographic Data A total of 85 premature neonates were assessed for eligibility in this study (►Fig. 1). A total of 60 neonates with hemodynamically significant PDA, confirmed by Doppler echocardiography were enrolled and randomized into two groups of 30 cases each to receive either standard-dose oral ibuprofen regimen (10–5–5 mg/kg/d) or a high-dose oral regimen (20–10–10 mg/kg/d). No significant differences were found between the two groups in terms of birth weight, sex, gestational age, and method of delivery, age at start of treatment, maternal factors, and predictable complication of prematurity (►Table 1). Of the 60 neonates, 41 cases had hyperbilirubinemia before the onset of treatment and received phototherapy; none American Journal of Perinatology
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Oral High-Dose Ibuprofen and PDA Closure
Oral High-Dose Ibuprofen and PDA Closure
Pourarian et al.
Fig. 1 Number of infants who were eligible for the study and randomly assigned to treatment groups. PDA, patent ductus arteriosus.
of them required exchange transfusion during or after therapy. There were no significant differences in total serum bilirubin levels, the requirement for and duration of phototherapy between the two groups.
Efficacy Complete ductal closure was seen in 21 (70%) infants treated with the high-dose regimen in comparison to 11 (36.7%) infants in the standard-dose regimen group (p ¼ 0.010)
(►Table 1). No reopening of the ductus after closure was observed. The second high-dose regimen (20–10–10 mg/kg/d) resulted in ductal closure in 16 of the total 28 cases of PDA refractory to the first pharmacologic closure treatment (standard- and high-dose regimen) (►Table 1). With the exception of infant’s sex, there were almost similar clinical characteristics between infants with PDA closure and those with PDA refractory to the first course of
Table 1 Clinical characteristics and incidence of PDA closure in the standard- and high-dose ibuprofen regimen groups Variable
High-dose regimen (n ¼ 30)
Standard-dose regimen (n ¼ 30)
p Value
Gestational age (wk)
30 2.6
31.3 2.1
0.376
Birth weight (g)
1,339 542
1,493 346
0.540
Sex (no. of male)
14 (46.7%)
12 (40%)
0.602
Cesarean delivery
19 (63.3%)
20 (66.7%)
0.787
Antenatal steroid
23 (76%)
17 (56%)
0.100
Mechanical ventilation
17 (55.6%)
17 (55.6%)
1.000
Respiratory distress syndrome
22 (73.3%)
22 (73.3%)
1.000
Surfactant therapy
23 (76.7%)
17 (56.7%)
0.100
Sepsis
5 (16%)
4 (13%)
1.000
Closure rate after first course of ibuprofen
21 (70%)
11 (36.7%)
0.010
Closure rate after second course of ibuprofena
5/9 (55.6%)
11/19 (57.8%)
1.000
Abbreviation: PDA, patent ductus arteriosus. a High dose in both the groups. American Journal of Perinatology
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Table 2 Clinical characteristics of infants with PDA responding or refractory to the first course of high-dose ibuprofen PDA responding to ibuprofen (n ¼ 21)
PDA refractory to ibuprofen (n ¼ 9)
p Value
Gestational age (wks)
30 2.4
30 1.9
1.000
Birth weight (g)
1,291 556
1,452 522
0.449
Sex (male)
6 (26%)
8 (88%)
0.004
Cesarean delivery
13 (61%)
6 (66%)
1.000
Antenatal steroids
17 (81%)
6 (66.7%)
0.640
Mechanical ventilation
13 (61%)
4 (44.4%)
0.443
Surfactant treatment
15 (71.4%)
8 (88.8%)
1.000
Asphyxia
0
2 (22.2%)
0.080
Abbreviation: PDA, patent ductus arteriosus.
Safety There were no significant differences in the level of serum blood urea nitrogen and creatinine before and after treatment between the two groups. As demonstrated by the similar urine output and oliguria, renal function was similar in the two groups. No neonate in either group had renal toxicity. The incidence of NEC and gastrointestinal bleeding did not differ between the two groups, nor did the occurrence of bleeding tendency and thrombocytopenia (< 50,000 mm3) (►Table 3).
Discussion PDA is a common problem in preterm infants. Persistent PDA is associated with various neonatal morbidities and mortalities such as chronic lung disease and bronchopulmonary dysplasia.3,4 Thus, early detection and treatment may be preventive and of considerable importance. PDA can be treated effectively with nonselective cyclooxygenase (COX) inhibitors, namely, intravenous indomethacin and intravenous ibuprofen. Both agents are equally efficacious, leading to successful closure of a PDA6–8,14; however, indomethacin affects the renal and cerebral perfusion and may lead to renal impairment. In contrast, ibuprofen appears to be as effective as indomethacin but with fewer renal and cerebral complications.15,16 Regarding ibuprofen safety, a very recent report has shown that renal and mesenteric tissue oxygenation and oxygen extraction are preserved in
Table 3 Markers of potential side effects and complications of preterm birth in the first course of standard- and high-dose ibuprofen groups Standard-dose regimen (n ¼ 30)
High-dose regimen (n ¼ 30)
p Value
Serum creatinine (mg/dL) before treatment
0.5 0.16
0.6 0.25
0.219
Serum creatinine (mg/dL) after treatment
0.5 0.32
0.6 0.27
0.433
Serum BUN (mmol/L) before treatment
11.6 5.6
14 7
0.070
Serum BUN (mmol/L) after treatment
10.4 6.3
10.7 5.7
0.862
Urine output (mL/kg/h) before treatment
3.8 1.6
3.3 1.2
0.176
Urine output (mL/kg/h) after treatment
3.5 2.8
3.9 1.1
0.469
Oliguria
0
1 (3.3%)
1
Gastrointestinal bleeding
1 (3.3%)
2 (6.7%)
1
Necrotizing enterocolitis after treatment
5 (16.7%)
4 (13.3%)
1
9
Platelets ( 10 /L) before treatment
217 187
229 83
0.613
Platelets ( 109/L) after treatment
283 100
254 80
0.324
Bleeding disorders
2 (6%)
1 (3.3%)
1
Mortality rate
1 (33%)
2 (6.7%)
1
Abbreviation: BUN, blood urea nitrogen. American Journal of Perinatology
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high-dose regimen. Among the neonatal variables studied, gender was found to significantly affect the PDA response to treatment (p ¼ 0.004). The male infants seemed to be more unresponsive to treatment than females. There were two neonates with asphyxia among those in the refractory group (►Table 2).
Oral High-Dose Ibuprofen and PDA Closure
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preterm infants with significant PDA treated with oral ibuprofen.17 Several studies have revealed that oral ibuprofen is as effective as the intravenous form.18,19 As the parenteral preparation type of the drug is not available in Iran, our study is conducted in the oral form. This study showed that high-dose oral ibuprofen regimen is more effective than the standard dose oral ibuprofen regimen in closing PDA in premature infants. This outcome was achieved without increasing any significant adverse effect. Few studies have been conducted on the specific dose of ibuprofen for PDA closure and to date, no optimal dose has been determined. Desfrere et al10 studied the current dose regimen of intravenous ibuprofen. They showed that this regimen (10–5–5 mg/kg/d) appeared to be less effective, especially with higher failure rate for PDA closure in gestational ages less than 27 weeks. They also mentioned that the current dose regimen was based on limited pharmacokinetic data20,21 and recommended the high-dose regimen (20–10–10 mg/kg/d) for PDA closure in preterm neonates, which is in total agreement with this study criterion. However, they were unable to extend the idea to a large group and thus suggested that more studies were needed to investigate the safety of the high-dose regimen. As demonstrated in Dani et al9 the higher rate of PDA closure was achieved with the high-dose intravenous form of ibuprofen in extremely premature infants. In agreement with Dani et al, we found that the oral form with high-dose regimen is more successful in PDA closure in premature infants, while in comparison to their study, the oral form is more accessible and less expensive. In this study, in agreement with Dani et al9 and also with Richards et al,22 it is revealed that a second course of ibuprofen can lead to PDA closure of a great number of those refractory to the first course, as well as resulting in reduction of the requirement for further invasive treatment. This response to the second course applies similarly to both refractory cases to either high or standard first course regimen of medication. Increasing postnatal age at the time of the second course of medication might have an effect on the final response of PDA to ibuprofen. This theory has also been demonstrated by a pharmacokinetic study by Hirt et al on 66 infants with PDA who were treated with standard-dose regimen of ibuprofen, which revealed that ibuprofen plasma clearance progressed with increasing postnatal age. Therefore, higher dose of ibuprofen for neonates older than 70 hours was recommended.11 In this study, infants 3 to 7 days old were treated by ibuprofen and because of the increasing clearance of medication according to the previous study, a higher dose of ibuprofen was prescribed. In addition, no relationship was detected between the final response of PDA to the second course of ibuprofen and the dose of the first course. This result is also in agreement with Dani et al suggesting that more randomized controlled studies are needed to assess the efficacy of the second course of highdose regimen after the failure of the first course.9 High-dose oral ibuprofen was not associated with any adverse effect such as gastrointestinal bleeding or renal American Journal of Perinatology
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impairment in our study. This outcome is also in accordance with Dani et al9 who demonstrated similar mean value of serum creatinine and urine output between standard- and high-regimen groups, although neonates in that study had less gestational age than in ours and were therefore more prone to adverse effects. From the point of pharmacokinetic study, Hirt et al11 also found no relationship between the increase in the ibuprofen area under the concentration–time curve or the serum creatinine variation; they stated that a high-dose regimen would rarely lead to an increase in ibuprofen toxicity. Other studies have also shown that in preterm infants, ibuprofen does not significantly reduce mesenteric blood flow velocity23 and cerebral blood flow.15 Therefore, the results of the aforementioned studies could explain why high-dose regimen ibuprofen, in spite of its greater therapeutic effect, does not have more side effects than the low-dose regimen. Female neonates were more responsive to treatment than males in our study, thus raising the question of sex effects on drug response. This fact may suggest a noticeable gender effect in drug response in the neonatal period. As many studies in adults have reported gender differences in drug response both in pharmacodynamics and pharmacokinetics,24,25 sex seems to be a variable that cannot be ignored. However, further investigation is necessary to elucidate this role and consequently improve drug efficacy. A limitation of our trial may be the range of patients’ gestational age, which is wider and also higher than previous studies. This also limited the power of the study in detecting those side effects which are higher in extremely preterm infants; therefore, high-dose ibuprofen should be applied with more caution to the very low-birth-weight infants.
Conclusion High-dose oral ibuprofen is more effective than the current standard-dose regimen for PDA closure in premature neonates, without the increased side effects. The second course of high-dose regimen causes the PDA closure in a great number of those refractory to first course of ibuprofen, however, the final fate of PDA is not influenced by the dose of the first course. Therefore, using a high-dose regimen of ibuprofen for PDA closure and also using the second high-dose regimen in those with persistent PDA after the first course and before choosing the invasive approach can be recommended. However, high-dose ibuprofen should be applied with more caution to the very low-birth-weight infants that could be more vulnerable to organ injury by nonsteroidal anti-inflammatory drugs. In addition, more studies are of course needed to investigate the efficacy of a second course of high-dose ibuprofen.
Contributor’s Statements All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
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Oral High-Dose Ibuprofen and PDA Closure
Funding Source No external funding was secured for this study. Conflict of Interest The authors have no conflicts of interest to disclose.
Acknowledgments This article was extracted from the thesis written by Faranak Takmil and was financially supported by Shiraz University of Medical Sciences grant no: 4292. The authors thank the staff of the neonatal intensive care unit for their cooperation. The authors thank Dr. O. Khalilpour from Center for Development of Clinical Research of Nemazee Hospital for editorial assistance.
9 Dani C, Vangi V, Bertini G, et al. High-dose ibuprofen for patent
10
11
12
13 14
15
16
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Prevalence of spontaneous closure of the ductus arteriosus in neonates at a birth weight of 1000 grams or less. Pediatrics 2006; 117(4):1113–1121 Ellison RC, Peckham GJ, Lang P, et al. Evaluation of the preterm infant for patent ductus arteriosus. Pediatrics 1983;71(3): 364–372 Rojas MA, Gonzalez A, Bancalari E, Claure N, Poole C, Silva-Neto G. Changing trends in the epidemiology and pathogenesis of neonatal chronic lung disease. J Pediatr 1995;126(4):605–610 Jones RW, Pickering D. Persistent ductus arteriosus complicating the respiratory distress syndrome. Arch Dis Child 1977;52(4): 274–281 Supapannachart S, Limrungsikul A, Khowsathit P. Oral ibuprofen and indomethacin for treatment of patent ductus arteriosus in premature infants: a randomized trial at Ramathibodi Hospital. J Med Assoc Thai 2002;85(4, Suppl 4):S1252–S1258 Pourarian Sh, Pishva N, Madani A, Rastegari M. Comparison of oral ibuprofen and indomethacin on closure of patent ductus arteriosus in preterm infants. East Mediterr Health J 2008;14(2):360– 365 Lee CH, Chen HN, Tsao LY, Hsiao CC, Lee ML. Oral ibuprofen versus intravenous indomethacin for closure of patent ductus arteriosus in very low birth weight infants. Pediatr Neonatol 2012;53(6): 346–353 Yadav S, Agarwal S, Maria A, et al. Comparison of oral ibuprofen with oral indomethacin for PDA closure in Indian preterm neonates: a randomized controlled trial. Pediatr Cardiol 2014;35(5): 824–830
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ductus arteriosus in extremely preterm infants: a randomized controlled study. Clin Pharmacol Ther 2012;91(4):590–596 Desfrere L, Zohar S, Morville P, et al. Dose-finding study of ibuprofen in patent ductus arteriosus using the continual reassessment method. J Clin Pharm Ther 2005;30(2):121–132 Hirt D, Van Overmeire B, Treluyer J-M, et al. An optimized ibuprofen dosing scheme for preterm neonates with patent ductus arteriosus, based on a population pharmacokinetic and pharmacodynamic study. Br J Clin Pharmacol 2008;65(5):629–636 Gregory KE, Deforge CE, Natale KM, Phillips M, Van Marter LJ. Necrotizing enterocolitis in the premature infant: neonatal nursing assessment, disease pathogenesis, and clinical presentation. Adv Neonatal Care 2011;11(3):155–164, quiz 165–166 Sasi A, Deorari A. Patent ductus arteriosus in preterm infants. Indian Pediatr 2011;48(4):301–308 Yang EM, Song ES, Choi YY. Comparison of oral Ibuprofen and intravenous indomethacin for the treatment of patent ductus arteriosus in extremely low birth weight infants. J Pediatr (Rio J) 2013;89(1):33–39 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(1):36–42 Van Overmeire B, Smets K, Lecoutere D, et al. A comparison of ibuprofen and indomethacin for closure of patent ductus arteriosus. N Engl J Med 2000;343(10):674–681 Guzoglu N, Sari FN, Ozdemir R, et al. Renal and mesenteric tissue oxygenation in preterm infants treated with oral ibuprofen. J Matern Fetal Neonatal Med 2014;27(2):197–203 Neumann R, Schulzke SM, Bührer C. Oral ibuprofen versus intravenous ibuprofen or intravenous indomethacin for the treatment of patent ductus arteriosus in preterm infants: a systematic review and meta-analysis. Neonatology 2012;102(1):9–15 Erdeve O, Yurttutan S, Altug N, et al. Oral versus intravenous ibuprofen for patent ductus arteriosus closure: a randomised controlled trial in extremely low birthweight infants. Arch Dis Child Fetal Neonatal Ed 2012;97(4):F279–F283 Aranda JV, Varvarigou A, Beharry K, et al. Pharmacokinetics and protein binding of intravenous ibuprofen in the premature newborn infant. Acta Paediatr 1997;86(3):289–293 Van Overmeire B, Touw D, Schepens PJ, Kearns GL, van den Anker JN. Ibuprofen pharmacokinetics in preterm infants with patent ductus arteriosus. Clin Pharmacol Ther 2001;70(4):336–343 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–e293 Pezzati M, Vangi V, Biagiotti R, Bertini G, Cianciulli D, Rubaltelli FF. Effects of indomethacin and ibuprofen on mesenteric and renal blood flow in preterm infants with patent ductus arteriosus. J Pediatr 1999;135(6):733–738 Soldin OP, Chung SH, Mattison DR. Sex differences in drug disposition. J Biomed Biotechnol 2011;2011:187103 Whitley H, Lindsey W. Sex-based differences in drug activity. Am Fam Physician 2009;80(11):1254–1258
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Financial Disclosure There are no financial relationships relevant to this article to disclose.
Pourarian et al.
The Effect of Oral High-dose Ibuprofen on Patent Ductus Arteriosus Closure in Preterm Infants Shahnaz Pourarian, MD1
Faranak Takmil, MD2
Sirous Cheriki, MD3
1 Neonatology Research Center, Shiraz University of Medical Sciences,
Shiraz, Iran 2 Department of Pediatrics, Shiraz University of Medical Sciences, Shiraz, Iran 3 Neonatology and Cardiac Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
Hamid Amoozgar, MD3
Address for correspondence Faranak Takmil, MD, Department of Pediatric, Nemazee Hospital, Nemazee Square, Shiraz, Iran (e-mail: [email protected]).
Am J Perinatol 2015;32:1158–1163.
Abstract
Keywords
► Premature PDA HighDose Ibuprofen
Objective The aim of this study is to compare the efficacy and possible adverse effects of the oral high-dose ibuprofen regimen to that of standard regimen in closing patent ductus arteriosus (PDA). Study Design This clinical trial study was performed from April 2012 to May 2013 on preterm infants with gestational age < 37 weeks and postnatal age 3 to 7 days with echocardiographic diagnosis of hemodynamically significant PDA. These neonates were randomly assigned to two treatment groups that respectively received high dose (20–10–10 mg/kg/d) and standard dose (10–5–5 mg/kg/d) oral ibuprofen regimen for 3 days. Effect of ibuprofen therapy was evaluated by echocardiography and neonates were followed for renal dysfunction, gastrointestinal complication, bleeding, and hyperbilirubinemia. Results From a total of 60 enrolled infants, 30 cases received the high dose of ibuprofen and the remaining 30 received the standard dose. Complete ductal closure was observed in 20 (70%) infants treated with high-dose regimen in comparison with 11 (36.7%) in the standard-dose regimen group (p ¼ 0.010). No gastrointestinal, renal, or hematological adverse effects were reported. Conclusion The high-dose oral ibuprofen seems to be more effective than the current standard dose regimen for PDA closure in premature neonates without increasing the adverse effects.
Patent ductus arteriosus (PDA) is one of the most common cardiovascular diseases in premature infants and its closure has a significant effect on management of respiratory and circulatory disorders. Natural ductal closure is inversely related to gestational age and birth weight. The prevalence of a hemodynamically significant shunt because of the PDA has been reported as high as 66% for infants with gestational age less than 28 weeks, and 20% for those with gestational age more than 32 weeks.1,2 The PDA at birth may cause several complications such as cardiac and pulmonary disorders,3 or even an increase in the mortality rate.4 Therefore, offering
treatments toward closing this duct is of crucial importance and many studies have been conducted on this subject to date. Several studies have revealed that, compared with indomethacin, in the pharmacological closure of PDA, oral ibuprofen has shown the same therapeutic effects with even fewer side effects5–8; however, other studies seem to suggest a reduction in the success of the treatment by using the standard dose of ibuprofen. As a result, recent studies have focused on using the high-dose intravenous ibuprofen regimen for PDA closure.9,10 Moreover, studies have revealed
received August 20, 2014 accepted after revision March 13, 2015 published online May 22, 2015
Copyright © 2015 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
DOI http://dx.doi.org/ 10.1055/s-0035-1551671. ISSN 0735-1631.
Downloaded by: University of British Columbia. Copyrighted material.
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that increasing the drug dosage does not result in an increase in side effects.10,11 In spite of lack of intravenous ibuprofen accessibility in Iran, no studies have been conducted on the effect of high-dose oral ibuprofen. This study is therefore aimed at using oral ibuprofen for PDA closure in premature infants to improve ibuprofen efficacy.
Patients and Methods Patients This randomized trial study was performed in the neonatal intensive care units of the Nemazee and Hafez Hospitals, affiliated hospitals of Shiraz University of Medical Sciences, Shiraz, Iran, from April 2012 to May 2013. The study was approved by the Medical Ethics Committee of each center. Neonates were enrolled after a written informed consent was obtained from their parents. Enrollment criteria were as follows: preterm infants with gestational age 37 weeks; postnatal age of 3 to 7 days and echocardiographic diagnosis of hemodynamically significant PDA. Exclusion criteria were major congenital anomalies, congenital heart defects, persistent pulmonary hypertension, life-threatening infections, severe bleeding, death before administration of the first course of ibuprofen, infants with decreased urine output less than 1 mL/kg of body weight per hour, and those with impaired renal function with a serum creatinine concentration 1.8 mg/dL (129 µmol/L), platelet count 50,000/mm3 or a tendency to bleed, as hematuria, or blood in the endotracheal aspirate, oozing of blood from sampling site, and gastrointestinal bleeding. Neonates meeting any single exclusion criterion were excluded from the study.
Study Design Enrolled neonates were then randomly divided into two groups by means of cards in sealed opaque envelopes. The first group consisted of those who were treated with highdose regimen of oral ibuprofen. Using a 24-hour interval, three doses of oral suspension (100 mg/5 mL; Hakim Pharmaceutical, Tehran, Iran, 75-HM-30) were administered to these infants. The first dose of the high-dose regimen was 20 mg/kg followed by two 10 mg/kg doses. Using the same interval, the second group was also given three doses of standard regimen oral ibuprofen with an initial dose of 10 mg/kg, followed by two doses of 5 mg/kg each, 24 and 48 hours later. Whenever the ductus arteriosus was yet patent after the randomly assigned treatment in a patient in either group, a second course of ibuprofen at high dose (20–10–10 mg/kg/d) was given as nonrandomized treatment, starting 24 hours after the last dose of the first course. In this trial study, neonatologist and nurses were not blind. All infants were closely monitored for any side effects of the drug such as oliguria and gastrointestinal bleeding, or any bleeding tendency during and after treatment. Serum creatinine, blood urea nitrogen, and platelet count were recorded before and after treatment and also 24-hour urine output was
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measured during treatment. Oliguria was defined as a urine output of 1 mL/kg/h or less during a 24-hour collection period. Necrotizing enterocolitis (NEC) was diagnosed by the presence of clinical signals and radiographic findings of pneumatosis intestinalis, hepatobiliary gas, or free intraperitoneal air.12 Total serum bilirubin levels, the need for and the duration of phototherapy were evaluated during treatment. A tendency to bleed was defined according to the criteria used for exclusion from the study. Doppler echocardiography was performed with a Mindray M7 (Shenzhen, People's Republic of China) echocardiography machine using 7 MHz probes. This was performed twice during the study. First, the day before treatment for identifying neonates with PDA and also to rule out the possibility of other congenital heart disease and the existence of pulmonary hypertension; and second, 24 hours after receiving the last dose of the drug for evaluation of the neonates’ responses to the treatment. The cardiologist was unaware of the infants’ treatment assignments. The patient’s demographic data and drug dosage along with echocardiographic parameters such as size of PDA end systolic and diastolic pressure gradients and left atrial to aortic ratio were recorded on a demographic form which was designed by the neonatologist and pediatric cardiologist.
Statistical Analysis Assuming a closure rate of 80%13 with the standard regimen oral ibuprofen, with a 95% confidence interval (CI) and a power of 80%, it was calculated that a study group of 60 neonates would be necessary for the study to be able to detect a difference of at least 20 percentage points in the closure rate between the standard- and high-regimen oral ibuprofen groups. The data were presented as mean SD for continuous or number (percent) for categorical variables. To compare categorized and continuous variables between the two groups, the chi-square or Fisher exact test and student t test were used, respectively. The p value of 0.05 or less was considered statistically significant. Data were analyzed by SPSS statistical software, v.18 (SPSS Inc, Chicago, IL).
Results Demographic Data A total of 85 premature neonates were assessed for eligibility in this study (►Fig. 1). A total of 60 neonates with hemodynamically significant PDA, confirmed by Doppler echocardiography were enrolled and randomized into two groups of 30 cases each to receive either standard-dose oral ibuprofen regimen (10–5–5 mg/kg/d) or a high-dose oral regimen (20–10–10 mg/kg/d). No significant differences were found between the two groups in terms of birth weight, sex, gestational age, and method of delivery, age at start of treatment, maternal factors, and predictable complication of prematurity (►Table 1). Of the 60 neonates, 41 cases had hyperbilirubinemia before the onset of treatment and received phototherapy; none American Journal of Perinatology
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Fig. 1 Number of infants who were eligible for the study and randomly assigned to treatment groups. PDA, patent ductus arteriosus.
of them required exchange transfusion during or after therapy. There were no significant differences in total serum bilirubin levels, the requirement for and duration of phototherapy between the two groups.
Efficacy Complete ductal closure was seen in 21 (70%) infants treated with the high-dose regimen in comparison to 11 (36.7%) infants in the standard-dose regimen group (p ¼ 0.010)
(►Table 1). No reopening of the ductus after closure was observed. The second high-dose regimen (20–10–10 mg/kg/d) resulted in ductal closure in 16 of the total 28 cases of PDA refractory to the first pharmacologic closure treatment (standard- and high-dose regimen) (►Table 1). With the exception of infant’s sex, there were almost similar clinical characteristics between infants with PDA closure and those with PDA refractory to the first course of
Table 1 Clinical characteristics and incidence of PDA closure in the standard- and high-dose ibuprofen regimen groups Variable
High-dose regimen (n ¼ 30)
Standard-dose regimen (n ¼ 30)
p Value
Gestational age (wk)
30 2.6
31.3 2.1
0.376
Birth weight (g)
1,339 542
1,493 346
0.540
Sex (no. of male)
14 (46.7%)
12 (40%)
0.602
Cesarean delivery
19 (63.3%)
20 (66.7%)
0.787
Antenatal steroid
23 (76%)
17 (56%)
0.100
Mechanical ventilation
17 (55.6%)
17 (55.6%)
1.000
Respiratory distress syndrome
22 (73.3%)
22 (73.3%)
1.000
Surfactant therapy
23 (76.7%)
17 (56.7%)
0.100
Sepsis
5 (16%)
4 (13%)
1.000
Closure rate after first course of ibuprofen
21 (70%)
11 (36.7%)
0.010
Closure rate after second course of ibuprofena
5/9 (55.6%)
11/19 (57.8%)
1.000
Abbreviation: PDA, patent ductus arteriosus. a High dose in both the groups. American Journal of Perinatology
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Table 2 Clinical characteristics of infants with PDA responding or refractory to the first course of high-dose ibuprofen PDA responding to ibuprofen (n ¼ 21)
PDA refractory to ibuprofen (n ¼ 9)
p Value
Gestational age (wks)
30 2.4
30 1.9
1.000
Birth weight (g)
1,291 556
1,452 522
0.449
Sex (male)
6 (26%)
8 (88%)
0.004
Cesarean delivery
13 (61%)
6 (66%)
1.000
Antenatal steroids
17 (81%)
6 (66.7%)
0.640
Mechanical ventilation
13 (61%)
4 (44.4%)
0.443
Surfactant treatment
15 (71.4%)
8 (88.8%)
1.000
Asphyxia
0
2 (22.2%)
0.080
Abbreviation: PDA, patent ductus arteriosus.
Safety There were no significant differences in the level of serum blood urea nitrogen and creatinine before and after treatment between the two groups. As demonstrated by the similar urine output and oliguria, renal function was similar in the two groups. No neonate in either group had renal toxicity. The incidence of NEC and gastrointestinal bleeding did not differ between the two groups, nor did the occurrence of bleeding tendency and thrombocytopenia (< 50,000 mm3) (►Table 3).
Discussion PDA is a common problem in preterm infants. Persistent PDA is associated with various neonatal morbidities and mortalities such as chronic lung disease and bronchopulmonary dysplasia.3,4 Thus, early detection and treatment may be preventive and of considerable importance. PDA can be treated effectively with nonselective cyclooxygenase (COX) inhibitors, namely, intravenous indomethacin and intravenous ibuprofen. Both agents are equally efficacious, leading to successful closure of a PDA6–8,14; however, indomethacin affects the renal and cerebral perfusion and may lead to renal impairment. In contrast, ibuprofen appears to be as effective as indomethacin but with fewer renal and cerebral complications.15,16 Regarding ibuprofen safety, a very recent report has shown that renal and mesenteric tissue oxygenation and oxygen extraction are preserved in
Table 3 Markers of potential side effects and complications of preterm birth in the first course of standard- and high-dose ibuprofen groups Standard-dose regimen (n ¼ 30)
High-dose regimen (n ¼ 30)
p Value
Serum creatinine (mg/dL) before treatment
0.5 0.16
0.6 0.25
0.219
Serum creatinine (mg/dL) after treatment
0.5 0.32
0.6 0.27
0.433
Serum BUN (mmol/L) before treatment
11.6 5.6
14 7
0.070
Serum BUN (mmol/L) after treatment
10.4 6.3
10.7 5.7
0.862
Urine output (mL/kg/h) before treatment
3.8 1.6
3.3 1.2
0.176
Urine output (mL/kg/h) after treatment
3.5 2.8
3.9 1.1
0.469
Oliguria
0
1 (3.3%)
1
Gastrointestinal bleeding
1 (3.3%)
2 (6.7%)
1
Necrotizing enterocolitis after treatment
5 (16.7%)
4 (13.3%)
1
9
Platelets ( 10 /L) before treatment
217 187
229 83
0.613
Platelets ( 109/L) after treatment
283 100
254 80
0.324
Bleeding disorders
2 (6%)
1 (3.3%)
1
Mortality rate
1 (33%)
2 (6.7%)
1
Abbreviation: BUN, blood urea nitrogen. American Journal of Perinatology
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high-dose regimen. Among the neonatal variables studied, gender was found to significantly affect the PDA response to treatment (p ¼ 0.004). The male infants seemed to be more unresponsive to treatment than females. There were two neonates with asphyxia among those in the refractory group (►Table 2).
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preterm infants with significant PDA treated with oral ibuprofen.17 Several studies have revealed that oral ibuprofen is as effective as the intravenous form.18,19 As the parenteral preparation type of the drug is not available in Iran, our study is conducted in the oral form. This study showed that high-dose oral ibuprofen regimen is more effective than the standard dose oral ibuprofen regimen in closing PDA in premature infants. This outcome was achieved without increasing any significant adverse effect. Few studies have been conducted on the specific dose of ibuprofen for PDA closure and to date, no optimal dose has been determined. Desfrere et al10 studied the current dose regimen of intravenous ibuprofen. They showed that this regimen (10–5–5 mg/kg/d) appeared to be less effective, especially with higher failure rate for PDA closure in gestational ages less than 27 weeks. They also mentioned that the current dose regimen was based on limited pharmacokinetic data20,21 and recommended the high-dose regimen (20–10–10 mg/kg/d) for PDA closure in preterm neonates, which is in total agreement with this study criterion. However, they were unable to extend the idea to a large group and thus suggested that more studies were needed to investigate the safety of the high-dose regimen. As demonstrated in Dani et al9 the higher rate of PDA closure was achieved with the high-dose intravenous form of ibuprofen in extremely premature infants. In agreement with Dani et al, we found that the oral form with high-dose regimen is more successful in PDA closure in premature infants, while in comparison to their study, the oral form is more accessible and less expensive. In this study, in agreement with Dani et al9 and also with Richards et al,22 it is revealed that a second course of ibuprofen can lead to PDA closure of a great number of those refractory to the first course, as well as resulting in reduction of the requirement for further invasive treatment. This response to the second course applies similarly to both refractory cases to either high or standard first course regimen of medication. Increasing postnatal age at the time of the second course of medication might have an effect on the final response of PDA to ibuprofen. This theory has also been demonstrated by a pharmacokinetic study by Hirt et al on 66 infants with PDA who were treated with standard-dose regimen of ibuprofen, which revealed that ibuprofen plasma clearance progressed with increasing postnatal age. Therefore, higher dose of ibuprofen for neonates older than 70 hours was recommended.11 In this study, infants 3 to 7 days old were treated by ibuprofen and because of the increasing clearance of medication according to the previous study, a higher dose of ibuprofen was prescribed. In addition, no relationship was detected between the final response of PDA to the second course of ibuprofen and the dose of the first course. This result is also in agreement with Dani et al suggesting that more randomized controlled studies are needed to assess the efficacy of the second course of highdose regimen after the failure of the first course.9 High-dose oral ibuprofen was not associated with any adverse effect such as gastrointestinal bleeding or renal American Journal of Perinatology
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impairment in our study. This outcome is also in accordance with Dani et al9 who demonstrated similar mean value of serum creatinine and urine output between standard- and high-regimen groups, although neonates in that study had less gestational age than in ours and were therefore more prone to adverse effects. From the point of pharmacokinetic study, Hirt et al11 also found no relationship between the increase in the ibuprofen area under the concentration–time curve or the serum creatinine variation; they stated that a high-dose regimen would rarely lead to an increase in ibuprofen toxicity. Other studies have also shown that in preterm infants, ibuprofen does not significantly reduce mesenteric blood flow velocity23 and cerebral blood flow.15 Therefore, the results of the aforementioned studies could explain why high-dose regimen ibuprofen, in spite of its greater therapeutic effect, does not have more side effects than the low-dose regimen. Female neonates were more responsive to treatment than males in our study, thus raising the question of sex effects on drug response. This fact may suggest a noticeable gender effect in drug response in the neonatal period. As many studies in adults have reported gender differences in drug response both in pharmacodynamics and pharmacokinetics,24,25 sex seems to be a variable that cannot be ignored. However, further investigation is necessary to elucidate this role and consequently improve drug efficacy. A limitation of our trial may be the range of patients’ gestational age, which is wider and also higher than previous studies. This also limited the power of the study in detecting those side effects which are higher in extremely preterm infants; therefore, high-dose ibuprofen should be applied with more caution to the very low-birth-weight infants.
Conclusion High-dose oral ibuprofen is more effective than the current standard-dose regimen for PDA closure in premature neonates, without the increased side effects. The second course of high-dose regimen causes the PDA closure in a great number of those refractory to first course of ibuprofen, however, the final fate of PDA is not influenced by the dose of the first course. Therefore, using a high-dose regimen of ibuprofen for PDA closure and also using the second high-dose regimen in those with persistent PDA after the first course and before choosing the invasive approach can be recommended. However, high-dose ibuprofen should be applied with more caution to the very low-birth-weight infants that could be more vulnerable to organ injury by nonsteroidal anti-inflammatory drugs. In addition, more studies are of course needed to investigate the efficacy of a second course of high-dose ibuprofen.
Contributor’s Statements All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
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Funding Source No external funding was secured for this study. Conflict of Interest The authors have no conflicts of interest to disclose.
Acknowledgments This article was extracted from the thesis written by Faranak Takmil and was financially supported by Shiraz University of Medical Sciences grant no: 4292. The authors thank the staff of the neonatal intensive care unit for their cooperation. The authors thank Dr. O. Khalilpour from Center for Development of Clinical Research of Nemazee Hospital for editorial assistance.
9 Dani C, Vangi V, Bertini G, et al. High-dose ibuprofen for patent
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11
12
13 14
15
16
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Financial Disclosure There are no financial relationships relevant to this article to disclose.
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