Abstract
Background aim of the study
Patent ductus arteriosus (PDA), a common finding among premature infants, is conventionally treated by intravenous indomethacin. Intravenous ibuprofen was recently shown to be as effective and to have fewer adverse reactions in preterm infants. If equally effective, then oral ibuprofen for PDA closure would have several important advantages over the intravenous route. This study was designed to determine whether oral ibuprofen treatment is efficacious and safe in closure of a PDA in premature infants.
Patients and methods
Thirty-three premature group I (study group) were treated with ibuprofen 10 mg/kg administered through a feeding tube. Thirty-three premature group II (control group) receive placebo the two imaging procedures were again performed 24 h after each ibuprofen dose. When the PDA was still hemodynamically significant, as demonstrated by echocardiography, and there was no evidence of deterioration in brain ultrasonography, a second dose of ibuprofen 5 mg/kg (placebo for control) was administered. A third equivalent dose was given after another 24 h if necessary. Cranial ultrasound was repeated 1 week after the last ibuprofen dose and again before discharge from the ward. Hematochemical analysis was preformed daily in the unit during the first days of life.
Results
In the study group the rate of PDA closure was 93.9% (31 of 33 cases) while in the control group the rate of PDA closure was 30.3% (10 of 33 cases) with significant difference in between. There was no reopening of the ductus after closure had been achieved. No infant required surgical ligation of the ductus in study group while in the control group 24.2% (8 of 33 cases) were required surgical ligation (Table 2). Twenty-one newborns were treated with 1 dose of ibuprofen, 9 were treated with 2 doses, and the remaining 3 were treated with 3 doses.
Conclusion
Oral ibuprofen is an effective and safe alternative to intravenous ibuprofen for PDA closure in premature infants.
Keywords: PDA closure, Patent ductus arteriosus, Premature newborn, Oral ibuprofen, Echocardiography
1. Introduction
The incidence of patent ductus arteriosus (PDA) in premature infants who weigh between 500 and 1500 g at birth is approximately 30% on the third day of life (The Vermont-Oxford Trials, 1993).
PDA is associated with increased risks of intraventricular hemorrhage (IVH), necrotizing enterocolitis (NEC), chronic lung disease (CLD), and death Gersony et al., 2004; Cotton et al., 2001. Therefore, closure of a hemodynamically significant PDA is indicated.
Intravenous indomethacin is the conventional pharmacologic treatment for promoting closure of a patent ductus in premature infants. However, concern remains regarding the safety of indomethacin, which affects renal, gastrointestinal, and cerebral perfusion and may lead to complications such as transient or permanent renal dysfunction (Krueger et al., 2002; Hammerman et al., 2005), necrotizing enterocolitis, gastrointestinal hemorrhage (Van Bel et al., 2005), and reduced cerebral intracellular oxygenation (Varvarigou et al., 2006).
Intravenous ibuprofen was recently shown to be as effective for the closure of patent ductus arteriosus in premature infants (Chemtob et al., 2004, 2000, 2007), without reducing mesenteric, renal (Mosca et al., 2006), or cerebral (Malcolm et al., 2005) blood flow. However, the intravenous form of ibuprofen is not available in Saudi Arabia, whereas, the oral suspension form is widely used for antipyretic treatment in children. Therefore, we investigated the possibilities of using oral ibuprofen for the treatment of PDA in premature newborn infants. Oral ibuprofen for PDA closure would have several important advantages over the intravenous route. (1) Intravenous ibuprofen is not available in the Saudi Arabia and many other countries, (2) the required oral dose is of minimal volume (0.25–0.5 mL for infants who weigh 500–1000 g), (3) oral administration is extremely simple, and (4) the oral form of the drug is less expensive than the intravenous one. This study was designed to determine whether oral ibuprofen treatment is efficacious and safe in closure of a PDA in premature infants.
2. Patients and methods
Sixty-six premature newborns that were treated at the neonatal intensive care unit at Al-Jedaani Hospital, Saudi Arabia between November 2006 and April 2008 were recruited prospectively. The infants were enrolled in the study only after written parental consent had been obtained and divided into two groups
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•
Group I study group that receive ibuprofen.
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Group II control group receive placebo.
Neonates who were admitted to the study were enrolled when the following criteria were met:
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(1)
Gestational age <32 weeks and <1500 g.
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(2)
Postnatal age between 48 and 96 h.
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(3)
RDS on chest radiograph necessitating treatment with surfactant, mechanical ventilation, and need for oxygen supplementation above 25%.
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(4)
Echocardiographic evidence of hemodynamically significant PDA (left atrium/aortic root diameter ratio >1.4 or ductal size >1.5 mm) (de Vries et al., 2002).
Exclusion criteria included:
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(1)
Presence of major congenital anomalies.
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(2)
IVH of grade 3 according to the classification by Papile et al. (1998) within the previous 24 h.
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(3)
Serum creatinine level ⩾1.5 mg%.
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(4)
Serum urea nitrogen concentration >50 mg%.
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(5)
Platelet count ⩽60,000/mL3.
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(6)
A tendency to bleed (defined by the presence of hematuria, blood in the endotracheal aspirate, gastric aspirate, or stools and/or oozing from puncture sites).
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(7)
Hyperbilirubinemia necessitating exchange transfusion.
3. Study design
Sixty-six infants who were born between November 2006 and April 2008 and met the entry criteria first underwent echocardiography and cranial ultrasonography, after which 33 premature group I (study group) were treated with ibuprofen 10 mg/kg administered through a feeding tube. Thirty-three premature groups II (control group) receive placebo the two imaging procedures were again performed 24 h after each ibuprofen dose. When the PDA was still hemodynamically significant, as demonstrated by echocardiography, and there was no evidence of deterioration in brain ultrasonography, a second dose of ibuprofen 5 mg/kg (placebo for control) was administered. A third equivalent dose was given after another 24 h if necessary. Cranial ultrasound was repeated 1 week after the last ibuprofen dose and again before discharge from the ward. Hematochemical analysis was preformed daily in the unit during the first days of life.
RDS was treated with respiratory support (intermittent mechanical ventilation), oxygen supplements, and surfactant 100 mg/kg. Treatment of PDA in preterm infants with RDS is indicated before a significant left-to-right shunting occurs (Gersony et al., 2004; Hammerman et al., 2005). Surfactant was administered during the first 24 h on the basis of the need for oxygen and respiratory support, i.e., fraction of inspired oxygen ⩾40% and mean airway pressure of ⩾8, and chest radiographs compatible with the diagnosis of RDS. Prophylactic antibiotics were started on admission and stopped after 5 days if blood cultures were negative. Birth weight, gestational age, and clinical outcomes were recorded prospectively.
4. Echocardiography
Color Doppler echocardiography was performed on all infants who were clinically suspected of having PDA, using SSD-Alpha 7 Aloka color Doppler ultrasound machine equipped with UST 52108 pediatric cardiac probe having frequency 1–15 MHz with tissue harmonic imaging technology, all infants underwent a complete 2D, M-mode and color Doppler imaging. This was conducted by a cardiologist who was blind to the child’s name and the treatment being given. Patients with clinical signs of PDA such as tachycardia (>160 beats/min), presence of a murmur, and bounding pulses were eligible for the study and underwent an echocardiographic evaluation before entry to the study (Mahony et al., 1999). PDA was considered echocardiographically significant when the ductal size was >1.5 mm or the left atrial-to-aortic root ratio was >1.4. We evaluated these parameters before the first dose and 24 h after each dose of ibuprofen, never exceeding 3 doses in total.
5. Cranial ultrasonography
Cranial ultrasound scans were performed by radiologist using SSD-Alpha 7 Aloka color Doppler ultrasound machine equipped with UST 9120 pediatric transcranial electronic convex probe having frequency 1–15 MHz before treatment was started, after each dose of ibuprofen, before any additional doses, 1 week after the last dose, and before discharge from the ward. The study infants were assessed for IVH (grades 1–4) Papile et al., 1998; Van Overmeire et al., 2007.
5.1. Statistical analysis
Continuous data, such as weight, gestational age, various treatment modalities, IVH, and age at start of treatment, were presented as mean ± standard deviation. Changes in serum creatinine concentrations were compared using t-test.
6. Results
A total of 250 premature infants at gestational age <32 weeks and birth weight <1500 g were admitted in the Al-Jedaani Neonatal Intensive Care Unit during the study period. Sixty-six premature of them were legible for entry in the study and underwent an echocardiographic-Doppler ultrasound evaluation at the age of 48–96 h, and divided into two groups:
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•
Group I study group that receive ibuprofen.
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•
Group II control group receive placebo.
Fluid intake began at 70–80 mL/kg/d and was increased by 20–30 mL/kg/d to a maximum of 160 mL/kg/d by the end of the first week, adjusted according to body weight. Most patients received packed red blood cells as well as fresh-frozen plasma transfusion. Hypotension was treated with fluid replacement. Dopamine was used in cases in which fluid treatment failed. Furosemide was not used during the first week of life.
The baseline characteristics of the 66 studied premature infants are presented in Table 1. In the study group the rate of PDA closure was 93.9% (31 of 33 cases) while in the control group the rate of PDA closure was 30.3% (10 of 33 cases) with significant difference in between. There was no reopening of the ductus after closure had been achieved. No infant required surgical ligation of the ductus in study group while in the control group 24.2% (8 of 33 cases) were required surgical ligation (Table 2). Twenty-one newborns were treated with 1 dose of ibuprofen, 9 were treated with 2 doses, and the remaining 3 were treated with 3 doses.
Table 1.
Baseline characteristics of the study infants.
| Diseased group (no. = 33) | Control group (no. = 33) | p-Value | |
|---|---|---|---|
| Birth weight (g) | 1035 ± 353 (range: 680–1500) | 1047 ± 403 | >0.05⁎ |
| Gestational age (week) | 28.8 ± 2.8 (range: 27–32) | 28.9 ± 2.7 | >0.05⁎ |
| Antenatal indomethacin (n) | 0 | 0 | |
| Antenatal glucocorticoids (n) | 14 | 15 | >0.05⁎ |
| Surfactant treatment (n) | 16 | 17 | >0.05⁎ |
| 1 Dose | 6 | 7 | >0.05⁎ |
| 2 Doses | 10 | 11 | >0.05⁎ |
| 3 Doses | 3 | 2 | >0.05⁎ |
| Mechanical ventilation (n) | 9 (27.3%) | 10 (30.3%) | >0.05⁎ |
| Mean airway pressure (cm H2O) | 10.4 ± 2.3 | 10.5 ± 2.4 | >0.05⁎ |
| Inspired oxygen (%) | 40 ± 13 (range: 25–70) | 41 ± 14 (range: 26–70) | >0.05⁎ |
| IVH (n) grade 1 | 5 (15.2%) | 4 (12.1%) | >0.05⁎ |
| IVH (n) grade 2 | 3 (9%) | 2 (6.1%) | >0.05⁎ |
| IVH (n) grade 3 | 3 (9%) | 2 (6.1%) | >0.05⁎ |
| Ductal diameter (mm) | 2.3 ± 0.83 | 2.2 ± 0.87 | >0.05⁎ |
| Degree of ductal shunting (n) | |||
| Moderate | 26 (78.8%) | 27 (81.9%) | >0.05⁎ |
| Severe | 7 (21.2%) | 6 (18.1%) | >0.05⁎ |
Insignificant.
Table 2.
Efficacy of treatment by ibuprofen.
| Variable | Study group (no. = 33) | Control group (no. = 33) | p-Value |
|---|---|---|---|
| Age at start of treatment (d) | 2.5 ± 0.6 | 2.4 ± 0.9 | >0.05⁎ |
| Number of closed PDA (%) | 31/33 (93.9%) | 10/33 (30.3%) | <0.001⁎⁎ |
| Number of ibuprofen doses | 1.45 ± 0.67 (range: 1–3) | ||
| Surgical ligation | 0 | 8/33 (24.2%) | <0.001⁎⁎ |
Insignificant.
Significant.
7. Outcome and side effects
The survival rate at 1 month was 87.9% (29 of 33) in study group I and 81.8% (27 of 33) in control group II with significant differences in between P-value <0.001 (Table 3). The rate of survival to discharge was 87.94% (29 of 33; Table 3). No bronchopulmonary dysplasia (oxygen support at 36 weeks of age) was observed in the study group, and there was no case of tendency to bleed.
Table 3.
Outcome of the study infants (n = 22).
| Variable | Study group (no. = 33) | Control group (no. = 33) | p-Value |
|---|---|---|---|
| Death within 30 d (n) | 4/33 (12.1%) | 6/33 (18.2%) | <0.001⁎⁎ |
| NEC (n) | 1/33 (3.03%) | 1/33 (3.03%) | >0.05⁎ |
| Localized bowel perforation | 0 | 0 | |
| Sepsis (n) | 6/33 (18.2%) | 6/33 (18.2%) | >0.05⁎ |
| Extension of IVH during treatment (n) | |||
| Change from grade 1 to grade 2 | 0 | 0 | |
| Change from grade 2 to grade 3 | 1/33 (3.03%) | 1/33 (3.03%) | >0.05⁎ |
| Change from grade 2 to grade 4 | 0 | 0 | |
| Change from grade 0 to grade 1 or higher | 4/33 (12.1%) | 5/33 (15.4%) | >0.05⁎ |
| PVL (n) | 4/33 (12.1%) | 5/33 (15.4%) | >0.05⁎ |
| Grade 1 (flaring after day 7) | 1/33 (3.03%) | 1/33 (3.03%) | >0.05⁎ |
| Grade 2 | 3/33 (9.1%) | 3/33 (9.1%) | >0.05⁎ |
| Grade 3 (cystic) | 0 | 1/33 (3.03%) | <0.001⁎⁎ |
| Respiratory outcome | |||
| BPD (n) | 0 | 1/33 (3.03%) | <0.001⁎⁎ |
| IPPV (d) | Mean 11 | 12 | >0.05⁎ |
| CPAP (d) | 0 | 0 | >0.05⁎ |
| Time to regain birth weight (d) | 15.6 ± 4.8 | 19 ± 6.4 | <0.001⁎⁎ |
| Time to full enteral feeding (d) | 20.2 ± 7.2 | 25 ± 8.3 | <0.001⁎⁎ |
PVL, periventricular leukomalacia; BPD, broncopulmonary dysplasia; IPPV, intermittent positive pressure ventilation; CPAP, continuous positive airway pressure.
Insignificant.
Significant.
8. Renal function
There were no significant differences in the levels of serum creatinine before and after treatment with oral ibuprofen in both study and control groups (P = .35; Table 4).
Table 4.
Changes in serum creatinine (mg/dL).
| Study group (no. = 33) | Control group (no. = 33) | p-Value | |
|---|---|---|---|
| Day 1 (24 h after ibuprofen administration) | 0.88 ± 0.16 | 0.85 ± 0.18 | >0.05⁎ |
| Day 2 (48 h after ibuprofen administration) | 0.91 ± 0.15 | 0.89 ± 0.26 | >0.05⁎ |
| Day 3 (72 h after ibuprofen administration) | 0.8 ± 0.14 | 0.81 ± 0.35 | >0.05⁎ |
| Pretreatment increase in serum creatinine from day 1 to day 3 | p = 0.35⁎ | p = 0.36⁎ | |
| Comparison of creatinine between day 1 and day 2 | p = 0.44⁎ | p = 0.46⁎ | |
| Comparison of creatinine between day 2 and day 3 | p = 0.37⁎ | p = 0.38⁎ |
Insignificant.
9. Discussion
The primary objective of the current study was to determine whether orally administered ibuprofen treatment is efficacious in PDA closure in premature infants with RDS. Our results showed oral ibuprofen to be effective and safe in PDA closure, with 31 of our 33 (93.9%) study infants achieving a successful outcome. This frequency of closure is in agreement with the study done by Ohlsson et al. (2008) who done meta analysis of 15 studies including 740 infants compared the effectiveness of ibuprofen to indomethacin for the closure of a PDA. And they find there is no statistically significant difference in the effectiveness of ibuprofen compared to indomethacin in closing a PDA was found. Also, ibuprofen compared with indomethacin reduces the risk of oliguria and is associated with lower serum creatinine levels following treatment (Ohlsson et al., 2008).
Also, our result in agreement with the study done by Cherif et al., they were studied 40 premature. Thirty-eight patients (95%) achieved pharmacological closure. Two patients did not respond to the treatment: One required surgical ligation of the ductus, and the other patient received and well tolerated ductal shunting (Cherif et al., 2007).
Also, in agreement with other study that done by Gimeno Navarro and Zhongguo Dang and they were fined oral ibuprofen is as effective as indomethacin for the treatment of PDA in preterm infants (100%). Oral ibuprofen therapy is associated with a lower incidence of NEC (Gournay et al., 2008; Gimeno Navarro et al., 2005).
Our results higher than the 70% figure reported by Van Overmeire’s group (Mahony et al., 1999) where ibuprofen was administered intravenously, and also significantly higher compared with other studies in which indomethacin was administered for PDA closure with a reported ductal closure rate of between 71% and 77% (Gersony et al., 2004; Coceani et al., 1998) and this explained by small number of studied cases.
Ibuprofen was administered orally in our study; therefore, there are theoretical concerns about direct gastrointestinal irritability. In our study, the drug was given undiluted through a feeding tube in a very small volume and followed by flushing with distilled water before final dilution in the stomach. The osmolarity of the ibuprofen suspension used in our study was 320 mosmol/L, and the pH was 5.5, both of which are not associated with gastrointestinal irritation. Most of the preterm infants in our study (n = 21) received only 1 dose of ibuprofen, 9 patients received 2 doses, and only 3 infants received 3 doses. The administration of several doses of ibuprofen as an antipyretic as presented and studied in other studies (Lesko and Mitchell, 2005, 2004) was not associated with significant gastrointestinal tract problems.
Treatment with oral ibuprofen is both effective and safe, and then it would have the advantages of more widespread availability, simpler administration, and decreased cost.
The pharmacokinetics of oral ibuprofen among preterm infants and infants older than 3 months have been studied and reported (Kauffman and Nelson, 2002; Raju et al., 2007). The findings indicate that ibuprofen is absorbed rapidly after oral administration, and peak concentrations in plasma are observed after 1–2 h. Among infants older than 3 months, the age of the child does not significantly influence the rate of absorption of ibuprofen, the plasma concentration of the drug, or its rate of elimination. With oral administration of ibuprofen, a small inter-individual variability in the pharmacokinetics of the drug is observed (Kauffman and Nelson, 2002; Raju et al., 2007).
Serum creatinine levels in our patients were within normal range at all times, and no significant differences between study and control group so there was no contraindication for a second or third dose of ibuprofen when it was needed. This might be an explanation for the higher rate of pharmacologic ductal closure observed in our study.
The infant who died as a result of extreme prematurity (24th gestational week) and extreme low birth weight (580 g) had no deterioration in serum creatinine or in brain sonography.
IVH was observed in 7 infants (Table 1). The classification was changed from grade 2 to grade 3 in 1 and from grade 0 to grade 1 or higher in 3 others (Table 3). IVH is a common complication during the first days of life in premature infants, and its presence or extension therefore might be the natural history of IVH or a complication of PDA in premature infants, and not necessarily related to ibuprofen treatment as we see no significant differences between study and control groups.
10. Conclusion
Oral ibuprofen is an effective and safe alternative to intravenous ibuprofen for PDA closure in premature infants.
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