Effect of oral ibuprofen on patent ductus arteriosus in premature newborns
Article Outline
- Abstract
- 1. Introduction
- 2. Patients and methods
- 3. Study design
- 4. Echocardiography
- 5. Cranial ultrasonography
- 6. Results
- 7. Outcome and side effects
- 8. Renal function
- 9. Discussion
- 10. Conclusion
- References
- Copyright
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 24h 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 5mg/kg (placebo for control) was administered. A third equivalent dose was given after another 24h if necessary. Cranial ultrasound was repeated 1week 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, nine were treated with 2 doses, and the remaining three 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 1500g 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., 2000, Chemtob et al., 2004, Chemtob et al., 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 (0.25–0.5mL for infants who weigh 500–1000g). (3) Oral administration is extremely simple. (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-Jeddaani 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 in two groups:
Neonates who were admitted to the study were enrolled when the following criteria were met:weeks and <1500g.h.mm) (de Vries et al., 2002).
Exclusion criteria included:h.mg%.mg%.
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 10mg/kg administered through a feeding tube. Thirty-three premature groups II (control group) receive placebo the two imaging procedures were again performed 24h 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 5mg/kg (placebo for control) was administered. A third equivalent dose was given after another 24h if necessary. Cranial ultrasound was repeated 1week 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 100mg/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 24h 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 5days 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 1–15MHz 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 (>160beats/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 >1.5mm or the left atrial-to-aortic root ratio was >1.4. We evaluated these parameters before the first dose and 24h after each dose of ibuprofen, never exceeding three 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 1–15MHz before treatment was started, after each dose of ibuprofen, before any additional doses, 1week 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 <32weeks and birth weight <1500g were admitted in the Al-Jeddaani 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 48–96h, and divided in two groups:
Fluid intake began at 70–80mL/kg/d and was increased by 20–30mL/kg/d to a maximum of 160mL/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⁎ |
| No. of closed PDA (%) | 31/33 (93.9%) | 10/33 (30.3%) | <0.001⁎⁎ |
| No. 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 1month 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 36weeks 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 30d (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⁎⁎ |
⁎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=0.35; Table 4).
Table 4. Changes in serum creatinine (mg/dL).
| Study group (no.=33) | Control group (no.=33) | p-Value | |
|---|---|---|---|
| Day 1 (24h after ibuprofen administration) | 0.88±0.16 | 0.85±0.18 | >0.05⁎ |
| Day 2 (48h after ibuprofen administration) | 0.91±0.15 | 0.89±0.26 | >0.05⁎ |
| Day 3 (72h 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 et al. (2005) and Fakhraee et al. (2007) 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 320mosmol/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, Lesko and Mitchell, 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 3months 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 1–2h. Among infants older than 3months, 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 (580g) 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.
References
- . Prostanoids determine the range of cerebral blood flow autoregulation of newborn piglets. Stroke. 2000;21:777–784
- . Effects of prostaglandins and indomethacin on cerebral blood flow and oxygen consumption of conscious newborn piglets. Dev. Pharmacol. Ther. 2004;14:1–14
- . Differences in the effect in the newborn piglet of various nonsteroidal antiinflammatory drugs on cerebral blood flow but not on cerebrovascular prostaglandins. Pediatr. Res. 2007;30:106–111
- . Oral ibuprofen in early curative closure of patent ductus arteriosus in very premature infants. Am. J. Perinatol. 2007;24(6):339–345
- . Age-dependent changes in the response of the lamb ductus arteriosus to oxygen and ibuprofen. Can. J. Physiol. Pharmacol. 1998;57:825–831
- . Medical management of small preterm infants with symptomatic patent ductus arteriosus. J. Pediatr. 2001;2:467–473
- . The spectrum of leukomalacia using cranial ultrasound. Behav. Brain Res. 2002;49:1–6
- . Effects of indomethacin in premature infants with patent ductus arteriosus: results of a national collaborative study. J. Pediatr. 2004;102:895–906
- . Ibuprofen versus indomethacin in the treatment of patent ductus arteriosus in preterm infants. Ann. Pediatr. (Barc). 2005;63(3):212–218
- . Pulmonary hypertension after ibuprofen prophylaxis in very preterm infants. Lancet. 2008;359:1486–1488
- . Continuous versus multiple rapid infusion of indomethacin: effects on cerebral blood flow velocity. Pediatrics. 2005;95:244–248
- . Effect of age on ibuprofen pharmacokinetics and antipyretic response. J. Pediatr. 2002;121:969–973
- . Prevention of symptomatic ductus arteriosus with single dose of indomethacin. J. Pediatr. 2002;111:749–754
- . The safety of acetaminophen and ibuprofen among children younger than two years old. Pediatrics. 2004;104(1):
- . An assessment of the safety of pediatric ibuprofen: a practitioner-based randomized clinical trial. JAMA. 2005;273:929–933
- . Prophylactic indomethacin therapy for patent ductus arteriosus in very low birth weight infants. New Engl. J. Med. 1999;306:506–510
- . Indomethacin compromises hemodynamics during positive-pressure ventilation, independently of prostanoids. J. Appl. Physiol. 2005;74:1672–1678
- . Comparative evaluation of the effects of indomethacin and ibuprofen on cerebral perfusion and oxygenation in preterm infants with patent ductus arteriosus. J. Pediatr. 2006;131:549–554
- Ohlsson,A., Walia,R., Shah,S., 2008. Ibuprofen for the treatment of patent ductus arteriosus in preterm and/or low birth weight infants. Cochrane Database Syst. Rev. 1, CD003481. ISSN:1469-493X.
- . Incidence and evolution of the subependymal intraventricular hemorrhage: a study of infants weighing less than 1500g. J. Pediatr. 1998;92:529–534
- . Ibuprofen use to reduce the incidence and severity of bronchopulmonary dysplasia: a pilot study. J. Perinatol. 2007;1:13–16
- The Vermont-Oxford Trials Network: very low birth weight outcomes for 1990. Pediatrics 1993;91:540–545.
- . Indomethacin-induced changes in renal blood flow velocity waveform in premature infants investigated with color Doppler imaging. J. Pediatr. 2005;118:621–626
- . A comparison of ibuprofen and indomethacin for closure of patent ductus arteriosus. New Engl. J. Med. 2007;343:674–681
- . Early ibuprofen administration to prevent patent ductus arteriosus in premature infants. JAMA. 2006;275:539–544
- . Comparison of oral ibuprofen and indomethacin therapy for patent ductus arteriosus in preterm infants. Zhongguo Dang Dai Er Ke Za Zhi. 2007;9(5):399–403
PII: S1319-9218(10)00003-7
doi:10.1016/j.jsha.2010.01.002
© 2010 Published by Elsevier Inc.
