Pediatr Cardiol DOI 10.1007/s00246-014-0861-2
ORIGINAL ARTICLE
Comparison of Oral Ibuprofen with Oral Indomethacin for PDA Closure in Indian Preterm Neonates: A Randomized Controlled Trial Sanju Yadav • Sheetal Agarwal • Arti Maria • Ajay Dudeja • N. K. Dubey • Puneet Anand • Dinesh Kumar Yadav
Received: 29 July 2013 / Accepted: 2 January 2014 Ó Springer Science+Business Media New York 2014
Abstract Oral ibuprofen is being used as an alternative to indomethacin in medical management of patent ductus arteriosus (PDA), but limited data exist on oral efficacy of these drugs for PDA closure in India. To assess and compare the efficacy of oral ibuprofen and oral indomethacin for PDA closure in preterm Indian neonates, we designed a randomized controlled study on clinically diagnosed and echocardiographically confirmed hemodynamically significant PDA in preterm neonates. Patients were assigned to receive either oral ibuprofen at a dosage of 10, 5, 5 mg/kg every 24 h or three doses of oral indomethacin (0.20–0.25 mg/kg every 24 h) starting on the third day of life or when diagnosed. A second course of ibuprofen/ indomethacin was given, if PDA failed to close within 48 h after the first course. Patients were monitored for complications like oliguria, bleeding, necrotizing enterocolitis, intraventricular hemorrhage, oxygen dependency, and
S. Yadav N. K. Dubey Department of Pediatrics, PGIMER & Associated Dr RML Hospital, New Delhi, India S. Agarwal P. Anand D. K. Yadav Division of Pediatric Cardiology, Department of Pediatrics, PGIMER & Associated Dr RML Hospital, New Delhi, India A. Maria Division of Neonatalogy, Department of Pediatrics, PGIMER & Associated Dr RML Hospital, New Delhi, India A. Dudeja Department of Pediatrics & Neonatalogy, LHMC & KSCH, New Delhi, India D. K. Yadav (&) Abhay Khand- I, H. No 169 Indirapuram, Ghaziabad, Uttar Pradesh, India e-mail: [email protected]
gastrointestinal side effects. The baseline characteristics were comparable in both groups. Of the 83 children enrolled, 57.8 % received oral ibuprofen and 42.1 % received oral indomethacin. The overall closure rate of PDA was 60 and 65.7 % in the ibuprofen and indomethacin groups, respectively. Closure rate was significantly higher when the drugs were administered at an early postnatal age (\8 days) (83.3 % [p = 0.02] in the indomethacin group and 75 % [p = 0.03] in the ibuprofen group) in neonates [28 weeks (ibuprofen group 66.7 % [p = 0.02]; indomethacin group 65.5 % [p = 0.04]) and in babies with birth weight [1,000 g (ibuprofen group 62.2 %; indomethacin group 70 % [p = 0.04 in both groups]). Complications were similar in both groups. The efficacy of both drugs was similar. Poor closure in our study could be because of genetic differences in pharmacokinetics of drug metabolism in the Indian population. Regimens with higher doses or increased duration of treatment may increase the frequency of closure. Studies with larger numbers of subjects with evaluation of pharmacokinetic parameters are therefore required. Keywords Oral ibuprofen Indomethacin PDA closure Preterm
Introduction The ductus arteriosus is a dynamic vascular structure functioning as a prenatal bypass between the pulmonary artery and aorta, which usually closes in term infants by 48–96 h after birth [3]. However, the ductus fails to close in as many as 30 % of very low birth weight (VLBW) neonates [28]. A significant left-to-right shunt at the level of ductus and the associated ‘steal phenomenon’ results in complications like congestive cardiac failure, apnea,
123
Pediatr Cardiol
chronic lung disease, necrotizing enterocolitis (NEC), renal failure, and intraventricular hemorrhage (IVH), thus increasing morbidity and mortality [6, 12]. Indomethacin is a non-steroidal anti-inflammatory drug (NSAID) that has been conventionally used for pharmacological closure of patent ductus arteriosus (PDA) since the late 1970s [6, 12, 28]. However, it is associated with significant side effects such as hyponatremia, worsening of NEC, gastrointestinal hemorrhage, renal impairment, and transient platelet dysfunction [7, 12, 13]. For the last 5–10 years, ibuprofen has also been used as an alternative to indomethacin, apparently because of its relatively superior safety profile and similar efficacy [15, 27]. Most of these studies were conducted with the intravenous form of ibuprofen, which is not widely available. The oral suspension form of ibuprofen has been shown to be as efficacious and safe as the intravenous form in the treatment of symptomatic PDA, with several advantages such as easy availability, ease of administration and being relatively less expensive than the intravenous form [25, 26]. This is even more important for third-world countries, where economics and availability of the drug become limiting factors in management. There is no study comparing the efficacy of the oral preparation of indomethacin and ibuprofen for PDA closure in preterm babies from India. Hence, the present study was designed with the objective of assessing the efficacy and safety of oral ibuprofen therapy for PDA closure in preterm babies and comparing it with oral indomethacin.
Materials and Methods The study was conducted in two tertiary care institutes in New Delhi, northern India, from March 2010 until May 2012. All preterm neonates (\37 weeks, birth weight \ 2,500 g) with hemodynamically significant PDA, diagnosed clinically and confirmed by echocardiographic criteria in the neonatal period (up to 28 days) were enrolled in the study. The closest gestational age was assessed clinically. Exclusion criteria included: ductal-dependent congenital heart disease, severe pulmonary hypertension, hydrops fetalis, multiple congenital anomalies, maternal prenatal infection, critical illness, IVH grade III/IV, platelet count \ 50,000/cu mm, abnormal coagulogram, serum creatinine C 1.5 mg/dl, or guardians denying consent. The study was approved by the institutional review board. Randomization was carried out by investigators not involved in the study. Eligible neonates were randomized into two groups (oral ibuprofen [study group] or oral indomethacin [control group]) using computer-generated random numbers. Allocation concealment was achieved by
123
using sequentially numbered opaque sealed envelopes containing the code for intervention. The envelopes were exclusively accessed by the principal investigator. Patients were assigned to the study and control groups starting on the 3rd day of life or later in those who were more than 3 days old at admission. Patients in the ibuprofen group were given three doses of oral ibuprofen suspension at a dosage of 10, 5, 5 mg/kg every 24 h. The drug was given via the orogastric route, followed by 0.5 ml of distilled water. Patients in the indomethacin group were given three doses (0.20–0.25 mg/kg every 24 h) depending on the gestational age (initial dose was 0.2 mg/kg, subsequent doses 2–7 days of age were 0.2 mg/kg/dose every 24 h for two doses, [7 days of age 0.25 mg/kg/dose every 24 h for two doses). The oral preparation was made by suspending a 25 mg capsule of indomethacin in 10 ml of distilled water. If PDA failed to close within 48 h after one course (three doses) of treatment, a second course was administered of the same treatment regimen. If PDA did not close after two courses of treatment, surgical ligation of PDA was considered. Echocardiographic evaluation was performed on a PHILIPS HD11XE advanced version with M-mode, 2D and color Doppler facility by a pediatric cardiologist at 24–48 h of life (institutional deliveries) or later in referred cases when PDA was suspected. He was blinded to the group allocation and treatment being administered to the study subjects. PDA was confirmed on Echo color Doppler and was evaluated for ‘hemodynamic significance’, i.e. size [ 1.5 mm, systolic and diastolic pressure gradients, left atrium-to-aorta ratio (LA/Ao) [ 1.4, and PDA flow pattern (hypertensive, growing, pulsatile). Significant PDA Doppler flow patterns were defined from the high left parasternal view. In the pulmonary hypertension pattern, a right-to-left shunt in early systole is followed by a small left-to-right shunt throughout the diastole. In the growing pattern, a bi-directional shunt is still present, but the right-to-left shunt decreases and a growing left-to-right shunt is seen. It represents a growing left-to-right shunt through a large ductus subsequent to decrease in pulmonary vascular resistance. The pulsatile pattern is characterized only by left-to-right shunt, as shown by a rhythmic pulsatile flow of peak velocity of about 1.5 m/s [21]. Repeat echo was performed within 24–48 h after the last dose of the drug was given. A third echocardiographic evaluation was performed to evaluate the effect of the second course of drug if given or whenever ductal reopening was suspected. The primary outcome measure was PDA closure in preterm babies by oral ibuprofen and its comparison with oral indomethacin. Secondary outcome variables included the need for a
Pediatr Cardiol
repeat of the second course of medications (after 48 h of the third dose of treatment), reopening of the duct, need for surgical closure (after two courses of treatment), and complications such as oliguria, gastrointestinal bleed, NEC, IVH, derangement of renal functions, and development of pulmonary hypertension. The babies were followed-up throughout hospitalization for these complications. Sample Size A sample size of 35 was calculated for each group, using a power of 80 % with two-tailed alpha value of 0.05 after considering a clinically relevant difference of 25 % in evaluating the efficacy of oral ibuprofen and indomethacin therapy. Statistical Analysis The comparison of normally distributed continuous variables between the groups was performed using Student’s t test and within the groups using paired t test. Nominal categorical data between the groups were compared using the Chi squared test or Fisher’s exact test as appropriate. Non-normal distribution continuous variables were compared using the Mann–Whitney U test or the Wilcoxon rank sum test. p \ 0.05 was considered statistically significant. All statistical analysis was performed using statistical package SPSS 17.0 (IBM, Armomk, NY, USA).
Table 1 Baseline characteristics of the study population Clinical characteristics
Ibuprofen group (N = 48)
Sex (M/F)
26/22
17/18
0.614
Gestational age (week)
29.65 ± 3.15
30.29 ± 3.14
0.363
15 (31.3 %) 33 (68.8 %)
9 (25.7 %) 26 (64.3 %)
0.583 0.567
\28 [28 Mean birth weight (g)
Indomethacin p value group (N = 35)
1,440 ± 450
1,380 ± 450
0.58
\1,000
11 (22.9 %)
5 (14.3 %)
0.325
[1,000
37 (77.1 %)
30 (85.7 %)
0.257
10.08 ± 6.09
9.83 ± 6.04
0.68
Mean age of drug administration (days) Antenatal steroid
16 (33.3 %)
15 (42.9 %)
0.376
Surfactant administration
12
6
0.391 0.37
Number of courses 1
15
15
2
33
20
Results During the study period, a total of 83 subjects with hemodynamically significant PDA were recruited; none of them had another co-existing left-to-right shunt. The enrolled subjects were randomly assigned to either the study (ibuprofen, N = 48) or control (indomethacin, N = 35) group. The baseline characteristics of both the groups were similar (Table 1). All the patients were from lower socioeconomic strata (middle/lower middle and upper lower group, Kuppuswamy’s Socioeconomic Status Scale) [18] and from the plains (altitude 293 m above sea level). The overall closure rate of PDA was 65.7 % in the indomethacin group and 60 % in the ibuprofen group. A second course of drug administration was required in 20 (57.1 %) babies in the indomethacin group and 32 (66.7 %) in the ibuprofen group (p = 0.376). The closure rate was significantly higher in both groups when the drugs were administered at an early postnatal age (\8 days) (83.3 % [p = 0.02] in the indomethacin group and 75 % [p = 0.03] in the ibuprofen group) (Fig. 1). The closure rate was higher in neonates [28 weeks in both the groups (ibuprofen 66.7 % [p = 0.02]; indomethacin
Fig. 1 Closure in relation to postnatal age of drug administration
group 65.5 % [p = 0.04]). Similarly, the closure rate was higher in babies with birth weight [1,000 g (62.2 and 70 % in the ibuprofen and indomethacin groups, respectively [p = 0.04 in both groups]) (Figs. 2, 3). There was a statistically significant reduction in size of PDA in both groups after the first and second course of treatment (indomethacin: pre 2.54 ± 0.71, post 1.76 ± 0.42; ibuprofen: pre 2.56 ± 0.67, post 1.92 ± 0.51, p \ 0.001). Similarly, there was a significant decrease (p \ 0.001) in the LA/Ao ratio in both the groups between pre (ibuprofen 1.65 ± 0.18 mm, indomethacin 1.66 ± 0.20 mm) and first course (ibuprofen 1.44 ± 0.30 mm, indomethacin 1.33 ±
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Pediatr Cardiol
0.32 mm) as well as in those patients requiring a second course (ibuprofen 1.33 ± 0.33 mm, indomethacin 1.38 ± 0.27 mm), with no statistically significant difference noted between the groups (see Fig. 4). 100.00% 90.00%
Ibuprofen Indomethacin
80.00% 70.00% 60.00% 50.00% 40.00% 30.00% 20.00% 10.00% 0.00% < 1000 g
1000 - 1499 g 1500 - 2499 g
Fig. 2 Closure in relation to birth weight
100.00%
The rate of closure of PDA after the first course was 29 and 37 % in the ibuprofen and indomethacin groups, respectively, and 45.4 and 50 %, respectively, after the second course. Twelve (25 %) babies in the ibuprofen group and 7 (20 %) in the indomethacin group required surgical ligation; the difference was not statistically significant. Of these, it was found that ten (83.3 %) and five (71.4 %) babies in the ibuprofen and indomethacin groups, respectively, had received the drug after 8 days of postnatal age (p = 0.01 and 0.03, respectively). There were no statistically significant differences in median blood urea levels between the ibuprofen and indomethacin groups after the first and second course of treatment (p [ 0.05). There was a statistically significant fall in blood urea levels after treatment in both ibuprofen and indomethacin groups. One baby in the ibuprofen group had a reopening of the duct, which was not hemodynamically significant. There was no statistically significant difference in other complications like oliguria, NEC, IVH, gastrointestinal bleed, and mortality in both the groups (Table 2).
90.00% 80.00% 70.00%
Discussion
60.00% 50.00% 40.00% 30.00% 20.00% 10.00% 0.00% < 28 weeks
28 - 32 weeks
>32-
ORIGINAL ARTICLE
Comparison of Oral Ibuprofen with Oral Indomethacin for PDA Closure in Indian Preterm Neonates: A Randomized Controlled Trial Sanju Yadav • Sheetal Agarwal • Arti Maria • Ajay Dudeja • N. K. Dubey • Puneet Anand • Dinesh Kumar Yadav
Received: 29 July 2013 / Accepted: 2 January 2014 Ó Springer Science+Business Media New York 2014
Abstract Oral ibuprofen is being used as an alternative to indomethacin in medical management of patent ductus arteriosus (PDA), but limited data exist on oral efficacy of these drugs for PDA closure in India. To assess and compare the efficacy of oral ibuprofen and oral indomethacin for PDA closure in preterm Indian neonates, we designed a randomized controlled study on clinically diagnosed and echocardiographically confirmed hemodynamically significant PDA in preterm neonates. Patients were assigned to receive either oral ibuprofen at a dosage of 10, 5, 5 mg/kg every 24 h or three doses of oral indomethacin (0.20–0.25 mg/kg every 24 h) starting on the third day of life or when diagnosed. A second course of ibuprofen/ indomethacin was given, if PDA failed to close within 48 h after the first course. Patients were monitored for complications like oliguria, bleeding, necrotizing enterocolitis, intraventricular hemorrhage, oxygen dependency, and
S. Yadav N. K. Dubey Department of Pediatrics, PGIMER & Associated Dr RML Hospital, New Delhi, India S. Agarwal P. Anand D. K. Yadav Division of Pediatric Cardiology, Department of Pediatrics, PGIMER & Associated Dr RML Hospital, New Delhi, India A. Maria Division of Neonatalogy, Department of Pediatrics, PGIMER & Associated Dr RML Hospital, New Delhi, India A. Dudeja Department of Pediatrics & Neonatalogy, LHMC & KSCH, New Delhi, India D. K. Yadav (&) Abhay Khand- I, H. No 169 Indirapuram, Ghaziabad, Uttar Pradesh, India e-mail: [email protected]
gastrointestinal side effects. The baseline characteristics were comparable in both groups. Of the 83 children enrolled, 57.8 % received oral ibuprofen and 42.1 % received oral indomethacin. The overall closure rate of PDA was 60 and 65.7 % in the ibuprofen and indomethacin groups, respectively. Closure rate was significantly higher when the drugs were administered at an early postnatal age (\8 days) (83.3 % [p = 0.02] in the indomethacin group and 75 % [p = 0.03] in the ibuprofen group) in neonates [28 weeks (ibuprofen group 66.7 % [p = 0.02]; indomethacin group 65.5 % [p = 0.04]) and in babies with birth weight [1,000 g (ibuprofen group 62.2 %; indomethacin group 70 % [p = 0.04 in both groups]). Complications were similar in both groups. The efficacy of both drugs was similar. Poor closure in our study could be because of genetic differences in pharmacokinetics of drug metabolism in the Indian population. Regimens with higher doses or increased duration of treatment may increase the frequency of closure. Studies with larger numbers of subjects with evaluation of pharmacokinetic parameters are therefore required. Keywords Oral ibuprofen Indomethacin PDA closure Preterm
Introduction The ductus arteriosus is a dynamic vascular structure functioning as a prenatal bypass between the pulmonary artery and aorta, which usually closes in term infants by 48–96 h after birth [3]. However, the ductus fails to close in as many as 30 % of very low birth weight (VLBW) neonates [28]. A significant left-to-right shunt at the level of ductus and the associated ‘steal phenomenon’ results in complications like congestive cardiac failure, apnea,
123
Pediatr Cardiol
chronic lung disease, necrotizing enterocolitis (NEC), renal failure, and intraventricular hemorrhage (IVH), thus increasing morbidity and mortality [6, 12]. Indomethacin is a non-steroidal anti-inflammatory drug (NSAID) that has been conventionally used for pharmacological closure of patent ductus arteriosus (PDA) since the late 1970s [6, 12, 28]. However, it is associated with significant side effects such as hyponatremia, worsening of NEC, gastrointestinal hemorrhage, renal impairment, and transient platelet dysfunction [7, 12, 13]. For the last 5–10 years, ibuprofen has also been used as an alternative to indomethacin, apparently because of its relatively superior safety profile and similar efficacy [15, 27]. Most of these studies were conducted with the intravenous form of ibuprofen, which is not widely available. The oral suspension form of ibuprofen has been shown to be as efficacious and safe as the intravenous form in the treatment of symptomatic PDA, with several advantages such as easy availability, ease of administration and being relatively less expensive than the intravenous form [25, 26]. This is even more important for third-world countries, where economics and availability of the drug become limiting factors in management. There is no study comparing the efficacy of the oral preparation of indomethacin and ibuprofen for PDA closure in preterm babies from India. Hence, the present study was designed with the objective of assessing the efficacy and safety of oral ibuprofen therapy for PDA closure in preterm babies and comparing it with oral indomethacin.
Materials and Methods The study was conducted in two tertiary care institutes in New Delhi, northern India, from March 2010 until May 2012. All preterm neonates (\37 weeks, birth weight \ 2,500 g) with hemodynamically significant PDA, diagnosed clinically and confirmed by echocardiographic criteria in the neonatal period (up to 28 days) were enrolled in the study. The closest gestational age was assessed clinically. Exclusion criteria included: ductal-dependent congenital heart disease, severe pulmonary hypertension, hydrops fetalis, multiple congenital anomalies, maternal prenatal infection, critical illness, IVH grade III/IV, platelet count \ 50,000/cu mm, abnormal coagulogram, serum creatinine C 1.5 mg/dl, or guardians denying consent. The study was approved by the institutional review board. Randomization was carried out by investigators not involved in the study. Eligible neonates were randomized into two groups (oral ibuprofen [study group] or oral indomethacin [control group]) using computer-generated random numbers. Allocation concealment was achieved by
123
using sequentially numbered opaque sealed envelopes containing the code for intervention. The envelopes were exclusively accessed by the principal investigator. Patients were assigned to the study and control groups starting on the 3rd day of life or later in those who were more than 3 days old at admission. Patients in the ibuprofen group were given three doses of oral ibuprofen suspension at a dosage of 10, 5, 5 mg/kg every 24 h. The drug was given via the orogastric route, followed by 0.5 ml of distilled water. Patients in the indomethacin group were given three doses (0.20–0.25 mg/kg every 24 h) depending on the gestational age (initial dose was 0.2 mg/kg, subsequent doses 2–7 days of age were 0.2 mg/kg/dose every 24 h for two doses, [7 days of age 0.25 mg/kg/dose every 24 h for two doses). The oral preparation was made by suspending a 25 mg capsule of indomethacin in 10 ml of distilled water. If PDA failed to close within 48 h after one course (three doses) of treatment, a second course was administered of the same treatment regimen. If PDA did not close after two courses of treatment, surgical ligation of PDA was considered. Echocardiographic evaluation was performed on a PHILIPS HD11XE advanced version with M-mode, 2D and color Doppler facility by a pediatric cardiologist at 24–48 h of life (institutional deliveries) or later in referred cases when PDA was suspected. He was blinded to the group allocation and treatment being administered to the study subjects. PDA was confirmed on Echo color Doppler and was evaluated for ‘hemodynamic significance’, i.e. size [ 1.5 mm, systolic and diastolic pressure gradients, left atrium-to-aorta ratio (LA/Ao) [ 1.4, and PDA flow pattern (hypertensive, growing, pulsatile). Significant PDA Doppler flow patterns were defined from the high left parasternal view. In the pulmonary hypertension pattern, a right-to-left shunt in early systole is followed by a small left-to-right shunt throughout the diastole. In the growing pattern, a bi-directional shunt is still present, but the right-to-left shunt decreases and a growing left-to-right shunt is seen. It represents a growing left-to-right shunt through a large ductus subsequent to decrease in pulmonary vascular resistance. The pulsatile pattern is characterized only by left-to-right shunt, as shown by a rhythmic pulsatile flow of peak velocity of about 1.5 m/s [21]. Repeat echo was performed within 24–48 h after the last dose of the drug was given. A third echocardiographic evaluation was performed to evaluate the effect of the second course of drug if given or whenever ductal reopening was suspected. The primary outcome measure was PDA closure in preterm babies by oral ibuprofen and its comparison with oral indomethacin. Secondary outcome variables included the need for a
Pediatr Cardiol
repeat of the second course of medications (after 48 h of the third dose of treatment), reopening of the duct, need for surgical closure (after two courses of treatment), and complications such as oliguria, gastrointestinal bleed, NEC, IVH, derangement of renal functions, and development of pulmonary hypertension. The babies were followed-up throughout hospitalization for these complications. Sample Size A sample size of 35 was calculated for each group, using a power of 80 % with two-tailed alpha value of 0.05 after considering a clinically relevant difference of 25 % in evaluating the efficacy of oral ibuprofen and indomethacin therapy. Statistical Analysis The comparison of normally distributed continuous variables between the groups was performed using Student’s t test and within the groups using paired t test. Nominal categorical data between the groups were compared using the Chi squared test or Fisher’s exact test as appropriate. Non-normal distribution continuous variables were compared using the Mann–Whitney U test or the Wilcoxon rank sum test. p \ 0.05 was considered statistically significant. All statistical analysis was performed using statistical package SPSS 17.0 (IBM, Armomk, NY, USA).
Table 1 Baseline characteristics of the study population Clinical characteristics
Ibuprofen group (N = 48)
Sex (M/F)
26/22
17/18
0.614
Gestational age (week)
29.65 ± 3.15
30.29 ± 3.14
0.363
15 (31.3 %) 33 (68.8 %)
9 (25.7 %) 26 (64.3 %)
0.583 0.567
\28 [28 Mean birth weight (g)
Indomethacin p value group (N = 35)
1,440 ± 450
1,380 ± 450
0.58
\1,000
11 (22.9 %)
5 (14.3 %)
0.325
[1,000
37 (77.1 %)
30 (85.7 %)
0.257
10.08 ± 6.09
9.83 ± 6.04
0.68
Mean age of drug administration (days) Antenatal steroid
16 (33.3 %)
15 (42.9 %)
0.376
Surfactant administration
12
6
0.391 0.37
Number of courses 1
15
15
2
33
20
Results During the study period, a total of 83 subjects with hemodynamically significant PDA were recruited; none of them had another co-existing left-to-right shunt. The enrolled subjects were randomly assigned to either the study (ibuprofen, N = 48) or control (indomethacin, N = 35) group. The baseline characteristics of both the groups were similar (Table 1). All the patients were from lower socioeconomic strata (middle/lower middle and upper lower group, Kuppuswamy’s Socioeconomic Status Scale) [18] and from the plains (altitude 293 m above sea level). The overall closure rate of PDA was 65.7 % in the indomethacin group and 60 % in the ibuprofen group. A second course of drug administration was required in 20 (57.1 %) babies in the indomethacin group and 32 (66.7 %) in the ibuprofen group (p = 0.376). The closure rate was significantly higher in both groups when the drugs were administered at an early postnatal age (\8 days) (83.3 % [p = 0.02] in the indomethacin group and 75 % [p = 0.03] in the ibuprofen group) (Fig. 1). The closure rate was higher in neonates [28 weeks in both the groups (ibuprofen 66.7 % [p = 0.02]; indomethacin
Fig. 1 Closure in relation to postnatal age of drug administration
group 65.5 % [p = 0.04]). Similarly, the closure rate was higher in babies with birth weight [1,000 g (62.2 and 70 % in the ibuprofen and indomethacin groups, respectively [p = 0.04 in both groups]) (Figs. 2, 3). There was a statistically significant reduction in size of PDA in both groups after the first and second course of treatment (indomethacin: pre 2.54 ± 0.71, post 1.76 ± 0.42; ibuprofen: pre 2.56 ± 0.67, post 1.92 ± 0.51, p \ 0.001). Similarly, there was a significant decrease (p \ 0.001) in the LA/Ao ratio in both the groups between pre (ibuprofen 1.65 ± 0.18 mm, indomethacin 1.66 ± 0.20 mm) and first course (ibuprofen 1.44 ± 0.30 mm, indomethacin 1.33 ±
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Pediatr Cardiol
0.32 mm) as well as in those patients requiring a second course (ibuprofen 1.33 ± 0.33 mm, indomethacin 1.38 ± 0.27 mm), with no statistically significant difference noted between the groups (see Fig. 4). 100.00% 90.00%
Ibuprofen Indomethacin
80.00% 70.00% 60.00% 50.00% 40.00% 30.00% 20.00% 10.00% 0.00% < 1000 g
1000 - 1499 g 1500 - 2499 g
Fig. 2 Closure in relation to birth weight
100.00%
The rate of closure of PDA after the first course was 29 and 37 % in the ibuprofen and indomethacin groups, respectively, and 45.4 and 50 %, respectively, after the second course. Twelve (25 %) babies in the ibuprofen group and 7 (20 %) in the indomethacin group required surgical ligation; the difference was not statistically significant. Of these, it was found that ten (83.3 %) and five (71.4 %) babies in the ibuprofen and indomethacin groups, respectively, had received the drug after 8 days of postnatal age (p = 0.01 and 0.03, respectively). There were no statistically significant differences in median blood urea levels between the ibuprofen and indomethacin groups after the first and second course of treatment (p [ 0.05). There was a statistically significant fall in blood urea levels after treatment in both ibuprofen and indomethacin groups. One baby in the ibuprofen group had a reopening of the duct, which was not hemodynamically significant. There was no statistically significant difference in other complications like oliguria, NEC, IVH, gastrointestinal bleed, and mortality in both the groups (Table 2).
90.00% 80.00% 70.00%
Discussion
60.00% 50.00% 40.00% 30.00% 20.00% 10.00% 0.00% < 28 weeks
28 - 32 weeks
>32-
