Prophylactic Ibuprofen for the Prevention of Intraventricular Hemorrhage Among Preterm Infants: A Multicenter, Randomized Study
http://www.100md.com
《小儿科》
Prophylactic Ibuprofen for the Prevention of Intraventricular Hemorrhage Among Preterm Infants: A Multicenter, Randomized Study
Carlo Dani, MD, Giovanna Bertini, MD, Marco Pezzati, MD, Chiara Poggi, MD, Pietro Guerrini, MD, Claudio Martano, MD, Firmino F. Rubaltelli, MDand the IntraVentricular Ibuprofen Study Group
Department of Surgical and Medical Critical Care, Section of Neonatology, Careggi University Hospital of Florence, Florence, Italy
Division of Neonatology, Sant'Anna University Hospital of Ferrara, Ferrara, Italy
Division of Neonatology, Sant'Anna University Hospital of Turin, Turin, Italy
ABSTRACT
Objective. Ibuprofen enhances cerebral blood flow autoregulation and was shown to protect neurologic functions after oxidative stresses in an animal model. For these reasons, we hypothesized that the prophylactic use of ibuprofen would reduce the occurrence of intraventricular hemorrhage (IVH) and its worsening toward grades 2 to 4 among preterm infants. To confirm this hypothesis, we planned the present prospective study.
Methods. This was a double-blind, randomized, controlled trial in which preterm infants with gestational ages of <28 weeks received ibuprofen or placebo within the first 6 hours of life. The infants were assigned randomly, at 7 neonatal care units, to receive ibuprofen (10 mg/kg, followed by 5 mg/kg after 24 and 48 hours) or placebo. Serial echoencephalography was performed 24 and 48 hours after the initial cerebral ultrasound study, on postnatal days 7, 15, and 30, and at 40 weeks' postconceptional age. Grade 1 IVH or no IVH was considered a successful outcome, whereas grade 2 to 4 IVH represented failure. The rates of ductal closure, side effects, and complications were recorded.
Results. We studied 155 infants. Grade 2 to 4 IVH developed for 16% of the ibuprofen-treated infants and 13% of the infants in the placebo group. The occurrence of patent ductus arteriosus was less frequent only on day 3 of life in the ibuprofen group. There were no significant differences with respect to other complications or adverse effects.
Conclusions. Our study demonstrated that prophylactic ibuprofen is ineffective in preventing grade 2 to 4 IVH and that its use for this indication cannot be recommended.
Key Words: ibuprofen intraventricular hemorrhage patent ductus arteriosus infants
Abbreviations: IVH, intraventricular hemorrhage PDA, patent ductus arteriosus CBF, cerebral blood flow iRDS, infant respiratory distress syndrome ROP, retinopathy of prematurity OR, odds ratio CI, confidence interval PVL, periventricular leukomalacia PPHN, persistent pulmonary hypertension of the newborn
Despite improvements in the assistance and treatment of preterm infants, intraventricular hemorrhage (IVH) remains a frequent complication among these patients.1 This point is crucial because the most severe IVH cases are related to a high risk of neurodevelopmental handicaps. In fact, mental retardation, seizures, and cerebral palsy have been reported for 45% to 86% of preterm infants with parenchymal IVH involvement.2–5
Previous clinical trials demonstrated that indomethacin, a cyclooxygenase inhibitor of prostaglandin synthesis that is used commonly for the closure of patent ductus arteriosus (PDA), decreased the incidence of IVH among very low birth weight infants.6–10 Indomethacin was shown to decrease baseline cerebral blood flow (CBF), to modulate CBF changes in response to hypercarbic insults, to decrease serum prostaglandin levels, and to promote germinal matrix maturation in animal models.11–14 However, indomethacin prophylaxis for IVH has never been used widely, because of the adverse effects of indomethacin on renal function and the gastrointestinal tract.10,15–19
In contrast, experimental20 and preliminary clinical21–24 studies demonstrated that ibuprofen (another cyclooxygenase inhibitor of prostaglandin synthesis) was effective in closing PDA without reducing CBF25 or affecting cerebral vasoreactivity to arterial carbon dioxide tension26 or intestinal27,28 or renal29 hemodynamics. Furthermore, ibuprofen enhances CBF autoregulation30 and was shown to protect neurologic functions after oxidative stresses in an animal model.31
For these reasons, we hypothesized that the prophylactic use of ibuprofen would reduce the occurrence of IVH and its worsening toward grades 2 to 4 among preterm infants. To confirm this hypothesis, we planned a double-blind, randomized, controlled trial in which preterm infants with gestational age of <28 weeks received ibuprofen or placebo within the first 6 hours of life.
METHODS
Patient Population
A multicenter, double-blind, prospective study, approved by local ethics committees, was conducted in 7 tertiary neonatal care units (Careggi University Hospital of Florence, Sant'Anna University Hospital of Ferrara, Clinica Mangiagalli of Milan, Children's Hospital "V. Buzzi" of Milan, San Gerardo Hospital of Monza, Regional Hospital of Bolzano, and Sant'Anna Hospital of Turin, all in Italy). Inclusion criteria were gestational age of <28 weeks and postnatal age of <6 hours. Exclusion criteria were the presence of major congenital malformations; hydrops fetalis; persistent pulmonary hypertension of the newborn (PPHN); grade 2 to 4 IVH; platelet count of <50000 platelets per mm3; tendency to bleed, as revealed by hematuria, blood in the endotracheal aspirate, gastric aspirate, or stools, or oozing from puncture sites; or serum creatinine concentration of >1.5 mg/dL. Neonates were enrolled after written informed consent was obtained from their parents.
Study Design
The infants in each unit were assigned randomly to a treatment group with the sealed-envelope technique; envelopes were prepared at Careggi University Hospital of Florence and then distributed to participating centers. Each infant received 3 doses of ibuprofen lysine (Arfen; Lisapharma, Erba, Italy; 10 mg/kg within 6 hours after birth, followed by 5 mg/kg after 24 and 48 hours) or indistinguishable placebo. The medications were infused continuously in a period of 15 minutes. The doses and dosing intervals were the same as those used for newborn infants in previous studies.21–23
When the ductus arteriosus was still patent after the randomly assigned treatment for a patient of either group, ibuprofen was administered as a nonrandomized rescue treatment. If this therapy also failed to promote ductal closure or if there was a contraindication to repeated pharmacologic treatment, then surgical ligation of the ductus arteriosus was performed.
Echographic Study
All patients for whom study permission was requested underwent cerebral ultrasonography within the first 6 hours of life, to exclude grade 2 to 4 IVH. Serial echoencephalography was performed 24 and 48 hours after the first study, on postnatal days 7, 15, and 30, and at 40 weeks' postconceptional age. The images were obtained with a high-resolution (7.5-MHz), real-time, sector scanner, in both coronal and sagittal projections through the anterior fontanel.
The grading system for hemorrhage was adapted from that described by Papile et al,32 as follows: grade 1, blood in the periventricular germinal matrix regions or germinal matrix hemorrhage; grade 2, blood within the lateral ventricular system without ventricular dilation; grade 3, blood acutely distending the lateral ventricles; grade 4, blood within the ventricular system and parenchyma. Hemorrhage was considered to have extended if an intraventricular or parenchymal component developed from a germinal matrix hemorrhage or a second hemorrhage was not in the hemisphere opposite that with an existing hemorrhage. The echoencephalographic studies were also evaluated for the presence of periventricular leukomalacia (PVL). All infants identified as having PVL had cystic areas on the 40-week cerebral ultrasound scans; earlier scans of the same infants showed parenchymal echodensities. PVL was graded from grade 1 to grade 3 according to the classification described by De Vries et al.33
Echocardiographic examinations were performed for all patients before enrollment and on postnatal days 2, 3, 5, 7, and 21 (or more frequently, if indicated). The initial evaluation included 2-dimensional, M-mode, pulsed Doppler and color flow evaluations of cardiac flow dynamics, performed to ascertain the normality of cardiac anatomic features and to rule out the possibility of congenital heart disease with "ductus-dependent" pulmonary or systemic blood flow or PPHN. Two-dimensional studies were performed for direct observation of the PDA, and left-to-right shunts were documented with pulsed Doppler echocardiography and color flow mapping. A diagnosis of significant PDA was made with echocardiographic demonstration of a ductal left-to-right shunt, with a left atrium/aortic root ratio of >1.3 or a ductal size of >1.5 mm.21 All echographic studies were performed by physicians who were unaware of the infants' treatment assignments.
Concomitant Treatment
Daily clinical care was performed by attending physicians, in accordance with common practices. Fluid intake was based essentially on changes in body weight, serum electrolyte concentrations, and serum osmolality; we started with 70 mL/kg, which was increased 10 to 20 mL each day to reach 150 mL/kg at the end of the first week of life. Infants could receive human milk from donors (and then from their own mothers) from the first day of life. When dextrose infusion was indicated, its concentration was set to maintain appropriate plasma glucose levels. Electrolytes were added after the first day of life, whereas intravenous administration of amino acids and lipids was initiated generally by the second day of life.
When hypotension was refractory to fluid-replacement therapy (with plasma, packed red cells, or more rarely saline), dopamine and/or dobutamine infusion was started. For infant respiratory distress syndrome (iRDS), infants received oxygen therapy, respiratory support (nasal continuous positive pressure, synchronized mechanical ventilation, or high-frequency oscillatory ventilation), and early rescue surfactant treatment (Curosurf; Chiesi, Parma, Italy; 200 mg/kg plus 100 mg/kg after 12 hours). The objective of assisted ventilation was to maintain an arterial partial pressure of oxygen of 50 to 70 mm Hg, arterial partial pressure of carbon dioxide of <65 mm Hg, pH of >7.20, and oxygen saturation of 90% to 95%.
Infants who underwent mechanical ventilation, had signs of sepsis, or were predisposed to infection because of maternal factors were given antibiotics after appropriate studies. Antibiotic therapy was stopped after 3 or 4 days if the bacterial cultures (of blood, tracheal aspirate, and urine) remained negative. Postnatal steroid treatment (12 days of tapering doses of dexamethasone34) was started for infants with severe respiratory failure who were receiving maximal ventilatory and oxygen support and for infants who, after 2 weeks of life, were still undergoing mechanical ventilation and were considered at high risk of developing chronic lung disease.
Clinical Courses and Outcomes
For each newborn infant, gestational age, birth weight, gender, type of delivery, Apgar scores at 1 and 5 minutes, pH of umbilical artery blood, prenatal and postnatal steroid treatment, main maternal pregnancy pathologic conditions, length of stay in the hospital, and death were recorded. To evaluate the severity of iRDS, initial (at the first blood gas analysis) and highest values of the oxygenation index (mean airway pressure x fraction of inspired oxygen x 100/arterial partial pressure of oxygen) and the ventilatory index (oxygenation index x arterial partial pressure of carbon dioxide) were measured for patients undergoing mechanical ventilation.
Serum creatinine levels and platelet counts were measured at 1, 3, and 5 days of life. Urine output was measured every day during the first 5 days of life, by collecting urine in adhesive bags, and oliguria was defined as a urinary output of <1 mL/kg per hour during a 24-hour collection period; fluid intake was recorded every day during the first week of life. To evaluate bleeding tendencies, hematuria, gastric bleeding, blood in the endotracheal aspirate or stools, and oozing from puncture sites were assessed.
Our patients were also monitored for complications such as sepsis, bronchopulmonary dysplasia, necrotizing enterocolitis, and retinopathy of prematurity (ROP). Diagnoses of sepsis were based on clinical and laboratory data (total neutrophil counts, immature/total neutrophil ratios, and C-reactive protein concentrations) and confirmed with positive blood cultures.35 Diagnosis of bronchopulmonary dysplasia was based on the requirement for supplemental oxygen to maintain adequate oxygenation at 36 weeks' postconceptional age.36 Necrotizing enterocolitis was diagnosed in the presence of abdominal distension, gastric residuals with or without bile-stained vomiting and bloody diarrhea or stools, hypotension, and suggestive abdominal radiographs (showing dilated and thickened bowel loops, parietal pneumatosis with or without perforation, or portal or hepatic venous air).37 The incidence of ROP, staged according to the international classification,38 was also recorded. All clinical and biological data were reported on data sheets designed for this study.
Statistical Analyses
In our study, we considered as successful outcomes grade 1 IVH or no IVH at 7 days of life, whereas grade 2 to 4 IVH represented failure. We assumed a failure rate 20% higher in the placebo group than in the ibuprofen group. Therefore, at a power of 0.80 and = .05, the estimated sample size was 74 infants in each group.
Clinical characteristics of the 2 groups were described with mean values and SDs or rates and percentages. Statistical analyses were performed with Student's t test for parametric continuous variables, the 2-sample Wilcoxon rank-sum test for nonparametric continuous variables, and Fisher's exact test for categorical variables such as frequencies. P < .05 was considered statistically significant.
Multiple stepwise logistic regressions were conducted to determine which maternal, neonatal, or perinatal factors would influence the risk for development of grade 2 to 4 IVH. Effect estimates are expressed as odds ratios (ORs) with profile, likelihood-based, 95% confidence intervals (CIs).
RESULTS
Two hundred fifty patients were eligible for the study, but 80 were excluded because of the presence of cardiac malformations (n = 4), hydrops fetalis (n = 3), PPHN (n = 15), grade 2 IVH (n = 20), platelet counts of <50000 platelets per mm3 or bleeding tendency (n = 25), or serum creatinine concentrations of >1.5 mg/dL (n = 13). Among the remaining 170 infants, 10 were excluded because of a lack of parental consent and 5 were excluded after randomization because of incomplete data collection (4 in the ibuprofen group and 1 in the placebo group). Therefore, we studied 155 infants, 77 of whom were assigned to the ibuprofen group and 78 to the placebo group. The initial dose of the drug was administered at 5.2 ± 0.6 hours and 5.4 ± 0.5 hours in the ibuprofen and placebo groups, respectively. The groups had comparable proportions of maternal and obstetric factors (Table 1); they were also comparable in clinical characteristics except for gestational age (Table 2).
The proportions of infants with grade 1 IVH at enrollment were similar in the ibuprofen (n = 4, 5%) and placebo (n = 5, 6%) groups. Two of these infants in each group experienced progression of hemorrhage; the 2 infants in the ibuprofen group developed grade 2 IVH, whereas 1 infant in the placebo group developed grade 2 IVH and another developed grade 3 IVH. Grade 2 to 4 IVH developed for 21% of the ibuprofen-treated infants and for 17% in the placebo group (Table 3). The incidences of grade 1, grade 2, grade 3, and grade 4 IVH were similar in the ibuprofen and placebo groups. We considered the possibility that the occurrence of IVH could differ between the groups at different times. For this reason, we compared the IVH rates at baseline and at 24 hours, 48 hours, and 7 days of life, but we did not find any difference between the ibuprofen group and the placebo group (Table 4).
The infant survival rates were similar in the 2 groups (Table 5). The most frequent causes of death were refractory respiratory failure and sepsis. There was no significant difference between the groups in the occurrence of iRDS or its severity, the requirement for or type of mechanical ventilation, or the need for surfactant treatment (Table 2). The rates of sepsis, bronchopulmonary dysplasia, necrotizing enterocolitis, ROP (all grades), and PVL (all grades) and the lengths of stay in the hospital were similar in the ibuprofen and placebo groups (Table 5). The occurrence of PDA was less frequent on day 3 of life in the ibuprofen group (Table 5). The incidences of serum creatinine levels of >1.5 mg/dL, mean serum creatinine levels, urine outputs, rates of oliguria, bleeding tendency, and platelet counts of <50000/mm3, and mean platelet counts did not differ between the ibuprofen and placebo groups (Table 5).
Logistic-regression analysis included all variables in Tables 1 and 2 and also the occurrence of grade 1 IVH at enrollment, bleeding tendency, thrombocytopenia, and PDA in the day 3 of life. We found that the following factors had significant predictive values for the development of grade 2 to 4 IVH: male gender (OR: 2.3; 95% CI: 1.76–2.84) and prenatal steroid treatment (OR: 0.30; 95% CI: –1.66 to –0.71).
DISCUSSION
The anomalies of cerebral perfusion play an important role in the development of cerebral injury among preterm infants. Prostaglandins, especially prostaglandin E2 and F2, are determinants in the control of the upper range of CBF autoregulation; they exert a minimal vasoconstrictor activity, which could prevent an increase in CBF when systemic blood pressure increases.30 Ibuprofen was reported to enhance CBF autoregulation among newborn piglets,30 and Li et al39 demonstrated that its effect was secondary to the up-regulation of prostaglandin E2 and F2 receptors induced by inhibition of the isoenzyme cyclooxygenase-2. Therefore, with stabilization of cerebral perfusion, a reduction in the incidence of IVH among preterm infants might be expected. Varvarigou et al21 reported a trend toward a decrease in the incidence of IVH among preterm infants, although this was not statistically significant and was not confirmed in other studies.39
Unfortunately, our study demonstrated that ibuprofen was ineffective in preventing grade 2 to 4 IVH, confirming the results of a recent meta-analysis study of the prevention of PDA with ibuprofen prophylaxis.40 This result suggests that the action of ibuprofen in improving CBF autoregulation among preterm infants is insufficient to limit brain injuries. We wondered why ibuprofen is ineffective in reducing the occurrence of IVH whereas indomethacin, which is also a cyclooxygenase inhibitor, is effective.6–10 We found that several authors observed decreased CBF after indomethacin administration, both in newborn animals12,41 and among newborn infants,25,42 but not after ibuprofen treatment.12,25,42,43 Therefore, we concluded that indomethacin can affect cerebral circulation through mechanisms different from cyclooxygenase blockade and prostaglandin synthesis,43 such as direct action on vascular endothelium44 and the increase in the circulating level of endothelins,45 which likely can explain also the more frequent occurrence of adverse effects after indomethacin treatment, rather than after ibuprofen treatment. In other words, it is probable that the ineffectiveness of ibuprofen in preventing grade 2 to 4 IVH and the lower occurrence of adverse effects after its administration are secondary to more-selective inhibition of cyclooxygenase isoforms, compared with indomethacin, which permits the closure of PDA but is not sufficient to compensate for inadequate CBF autoregulation among preterm infants.
Another possible explanation is that we used an inadequate ibuprofen dose. However, it is difficult to suggest increasing this dose, because in a previous study21 it was found to be associated with a plasma ibuprofen level 2.5-fold higher than that generated among adults with arthritis receiving similar doses46 and there are no studies of ibuprofen pharmacokinetics among newborn infants.
In the present study, we monitored the possible adverse effects of ibuprofen treatment, in particular on renal function and the clotting system, but we did not find any difference between the ibuprofen and placebo groups. This confirms previous studies,40 except that Van Overmeire et al24 found serum creatinine levels to be increased on day 3 of life among ibuprofen-treated infants. The recorded complications of prematurity also showed similar rates in the 2 groups, except for the incidences of PDA on day 3 of life (9% in the treated group and 29% in the placebo group), which confirmed that prophylactic treatment with ibuprofen reduced PDA occurrence among preterm infants with iRDS at 3 days of life.23 However, among patients in the placebo group who demonstrated PDA at 3 days of life, 83% (19 of 23 patients) experienced closure of the ductus arteriosus after the first cycle of ibuprofen, as reported previously.19,23,24
A final issue in our study was the possible occurrence of PPHN among our patients after ibuprofen administration, as reported by Gournay et al.47 None of our patients demonstrated PPHN47 after ibuprofen treatment; we think this was because all infants with PPHN were excluded from the study. In fact, it is our opinion that the reported PPHN was preexisting, not caused by ibuprofen, and that PDA closure only worsened and manifested it.
CONCLUSIONS
Our study demonstrated that prophylactic ibuprofen was ineffective in preventing grade 2 to 4 IVH and its use for this purpose cannot be recommended. We confirmed that ibuprofen therapy for PDA closure is safe and effective. Because ibuprofen cannot represent an alternative to indomethacin and indomethacin treatment might be followed by several adverse effects, the question of pharmacologic IVH prevention among preterm infants remains crucial and additional efforts are necessary to identify other potentially effective drugs.
ACKNOWLEDGMENTS
The IntraVentricular Ibuprofen Study Group includes G.L. Lista, MD (Milan, Italy); Hubert Messner, MD (Bolzano, Italy); Fabio Mosca, MD (Milan, Italy); and Paolo Tagliabue, MD (Monza, Italy).
FOOTNOTES
Accepted Oct 4, 2004.
No conflict of interest declared.
REFERENCES
Rubaltelli FF, Dani C, Reali MF, et al. Acute neonatal respiratory distress in Italy: a one year prospective study. Acta Paediatr. 1998;87 :1261 –1268
Krishnamooorthy KS, Shannon DC, DeLong GR, Todres ID, Davis KR. Neurologic sequelae in the survivors of neonatal intraventricular hemorrhage. Pediatrics. 1979;64 :233 –237
Shinnar S, Molteni RA, Gammon K, D'Souza BJ, Altman J, Freeman JM. Intraventricular hemorrhage in the premature infant. N Engl J Med. 1982;306 :1464 –1468
McMenamin JB, Shackelford GD, Volpe JJ. Outcome of neonatal intraventricular hemorrhage with periventricular echodense lesions. Ann Neurol. 1984;15 :285 –290
Szymonowicz W, Yu VYH, Bajuk B, Astbury J. Neurodevelopmental outcome of periventricular hemorrhage and leukomalacia in infants 1250 g or less at birth. Early Hum Dev. 1986;14 :1 –7
Banstra ES, Montalvo BM, Goldberg RN. Prophylactic indomethacin for prevention of intraventricular hemorrhage in premature infants. Pediatrics. 1984;74 :1107 –1112
Bada HS, Green RS, Pourcyrous M, et al. Indomethacin reduced the risks of severe intraventricular hemorrhage. J Pediatr. 1989;115 :631 –637
Ment LR, Duncan CC, Ehrenkrnaz RA. Randomized indomethacin trial for prevention of intraventricular hemorrhage in very low birth weight neonates. J Pediatr. 1985;107 :937 –943
Ment LR, Oh W, Ehrenkrnaz RA, et al. Low-dose indomethacin and prevention of intraventricular hemorrhage: a multicenter randomized trial. Pediatrics. 1994;93 :543 –550
Fowlie PW, Davis PG. Prophylactic intravenous indomethacin for preventing mortality and morbidity in preterm infants. Cochrane Database Syst Rev. 2002;(3) :CD000174
Leffler CW, Busija DW, Fletcher AM, Beasley DG, Hessler JR, Green RS. Effects of indomethacin upon cerebral hemodynamics of newborn pigs. Pediatr Res. 1985;19 :1160 –1164
Chemtob S, Beharry K, Barna T, Varma DR, Aranda JV. Difference in the effects in the newborn piglet of various non-steroidal anti-inflammatory drugs on cerebral blood flow but not on cerebrovascular prostaglandins. Pediatr Res. 1991;30 :106 –111
Dahlgren N, Nilsson B, Sakabe T. The effect of indomethacin on cerebral blood flow and oxygen consumption in the rat at the normal and increased carbon dioxide tension. Acta Physiol Scand. 1982;3 :475 –485
Ment LR, Stewart WB, Ardito TA, Huang E, Madri JA. Indomethacin promotes germinal matrix microvessel maturation in the newborn beagle pup. Stroke. 1992;23 :1132 –1137
Betkerur MV, Yeh TF, Miller K, Glasser RJ, Pildes RS. Indomethacin and its effects on renal function and urinary kallikrein excretion in premature infants with patent ductus arteriosus. Pediatrics. 1981;68 :99 –102
Van Bel F, Guit GL, Schipper J, Van de Bor M, Baan J. Indomethacin-induced changes in renal blood flow velocity waveform in premature infants investigated with color Doppler imaging. J Pediatr. 1991;118 :621 –626
Grosfeld JL, Chaedt M, Molinari F. Increased risk of necrotizing enterocolitis in premature infants with patent ductus arteriosus treated with indomethacin. Ann Surg. 1996;224 :350 –357
Ojala R, Ikonen S, Tammela O. Perinatal indomethacin treatment and neonatal complications in preterm infants. Eur J Pediatr. 2000;159 :153 –155
Lago P, Bettiol T, Salvadori S, et al. Safety and efficacy of ibuprofen versus indomethacin in preterm infants treated for patent ductus arteriosus: a randomized control trial. Eur J Pediatr. 2002;161 :202 –207
Coceani F, White E, Bodach E, Olley PM. Age-dependent changes in the response of the lamb ductus arteriosus to oxygen and ibuprofen. Can J Physiol Pharmacol. 1979;57 :825 –831
Varvarigou A, Bardin LC, Beharry K, Chemtob S, Papageorgiu A, Aranda JV. Early ibuprofen administration to prevent patent ductus arteriosus in premature newborn infants. JAMA. 1996;275 :539 –544
Van Overmeire B, Follens I, Hartmann S, Creten WL, van Acker KJ. Treatment of patent ductus arteriosus with ibuprofen. Arch Dis Child. 1997;76 :F179 –F184
Dani C, Bertini G, Reali MF, et al. Prophylaxis of patent ductus arteriosus with ibuprofen in preterm infants. Acta Paediatr. 2000;89 :1369 –1374
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 :674 –681
Mosca F, Bray M, Lattanzio M, Fumagalli M, Tosetto C. Comparative evaluation of the effect of indomethacin and ibuprofen on cerebral perfusion and oxygenation in preterm infants with patent ductus arteriosus. J Pediatr. 1997;131 :549 –554
Mosca F, Bray M, Colnaghi MR, Fumagalli M, Compagnoni G. Cerebral vasoreactivity to arterial carbon dioxide tension in premature infants: effect of ibuprofen. J Pediatr. 1999;135 :644 –646
Grosfeld JL, Kamman K, Gross K, Cikrit D, Ross D, Wolfe M. Comparative effects of indomethacin, prostaglandin E1 and ibuprofen on bowel ischemia. Pediatr Surg. 1983;18 :738 –742
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 :733 –738
Malcom DD, Segar JL, Robillard E, Chemtob S. Indomethacin compromises hemodynamics during positive-pressure ventilation independently of prostanoids. J Appl Physiol. 1993;74 :1672 –1678
Chemtob S, Beharry K, Barna T, Varma DR, Aranda JV. Prostanoids determine the range of cerebral blood flow autoregulation of newborn piglets. Stroke. 1990;21 :777 –784
Chemtob S, Roy M-S, Abran D, Ferandez H, Varma DR. Prevention of post-asphyxial increase in lipid peroxides and retinal function deterioration in the newborn pig by inhibition of cyclooxygenase activity and free radical generation. Pediatr Res. 1993;33 :336 –340
Papile LA, Burstein J, Burstein R, Keffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birthweight less than 1500 grams. J Pediatr. 1978;92 :529 –534
De Vries LS, Eken P, Dubowitz LM. The spectrum of leukomalacia using cranial ultrasounds. Behav Brain Res. 1992;49 :1 –6
Rastogi A, Akintorin SM, Bez ML, Morales P, Pildes PS. A controlled trial of dexamethasone to prevent bronchopulmonary dysplasia in surfactant-treated infants. Pediatrics. 1996;98 :204 –210
American Academy of Pediatric, Committee on Drugs, Committee on Fetus and Newborn, and Committee on Infectious Diseases. Prophylaxis and treatment of neonatal gonococcal infections. Pediatrics. 1980;65 :1047 –1048
Shennan AT, Dunn MS, Ohlsson A, Lennox K, Hoskins EM. Abnormal pulmonary outcomes in premature infants: prediction from oxygen requirement in the neonatal period. Pediatrics. 1988;82 :527 –532
Bell MJ, Ternberg JL, Feigin RD, Keating JP, Marshall R, Barton L, Brotherton T. Neonatal necrotizing enterocolitis: therapeutic decisions based upon clinical staging. Ann Surg. 1978;187 :1 –12
Committee for the Classification of Retinopathy of Prematurity. An international classification of retinopathy of prematurity. Arch Ophthalmol. 1984;102 :1130 –1134
Li DY, Hardy P, Abran D, et al. Key role for cyclooxygenase-2 in PGE2 and PGF2 receptor regulation and cerebral blood flow of the newborn. Am J Physiol. 1997;273 :R1283 –R1290
Shah SS, Ohlsson A. Ibuprofen for the prevention of patent ductus arteriosus in preterm and/or low birth weight infants. Cochrane Database Syst Rev. 2003;(2) :CD004213
Pappius HM, Wolfe LS. Effects of indomethacin and ibuprofen on cerebral metabolism and blood flow in traumatized brain. J Cereb Blood Flow Metab. 1983;3 :448 –459
Patel J, Robert I, Azzopardi D, Hamilton P, Edwards AD. Randomized double-blind controlled trial comparing the effects of ibuprofen with indomethacin on cerebral hemodynamics in preterm infants with patent ductus arteriosus. Pediatr Res. 2000;47 :36 –42
Pellicer A, Aparicio M, Cabanas F, Valverde E, Quero J, Stiris TA. Effects of the cyclo-oxygenase blocker ibuprofen on cerebral blood flow during normocarbia and hypercarbia in newborn piglets. Acta Paediatr. 1999;88 :82 –88
Siesjo BK. Cerebral circulation and metabolism. J Neurosurg. 1984;60 :883 –908
Therkelsen K, Jensen KA, Freundlich M, Thorshange H, Bunemann L, Bogeskov-Nielsen L. Endothelin-1 and cerebral blood flow: influence of hypoxia, hypercapnia, and indomethacin on circulating endothelin levels in healthy volunteers. Scand J Clin Lab Invest. 1994;54 :441 –451
Gallo JM, GalI IP, Gillespie WR, Albert KS, Perrier D. Ibuprofen kinetics in plasma and synovial fluid of arthritic patients. J Clin Pharmacol. 1986;26 :65 –70
Gournay V, Savagner C, Thiriez G, Kuster A, Rozé JC. Pulmonary hypertension after ibuprofen prophylaxis in very preterm infants. Lancet. 2002;259 :1486 –1488(Carlo Dani, MD, Giovanna )
Carlo Dani, MD, Giovanna Bertini, MD, Marco Pezzati, MD, Chiara Poggi, MD, Pietro Guerrini, MD, Claudio Martano, MD, Firmino F. Rubaltelli, MDand the IntraVentricular Ibuprofen Study Group
Department of Surgical and Medical Critical Care, Section of Neonatology, Careggi University Hospital of Florence, Florence, Italy
Division of Neonatology, Sant'Anna University Hospital of Ferrara, Ferrara, Italy
Division of Neonatology, Sant'Anna University Hospital of Turin, Turin, Italy
ABSTRACT
Objective. Ibuprofen enhances cerebral blood flow autoregulation and was shown to protect neurologic functions after oxidative stresses in an animal model. For these reasons, we hypothesized that the prophylactic use of ibuprofen would reduce the occurrence of intraventricular hemorrhage (IVH) and its worsening toward grades 2 to 4 among preterm infants. To confirm this hypothesis, we planned the present prospective study.
Methods. This was a double-blind, randomized, controlled trial in which preterm infants with gestational ages of <28 weeks received ibuprofen or placebo within the first 6 hours of life. The infants were assigned randomly, at 7 neonatal care units, to receive ibuprofen (10 mg/kg, followed by 5 mg/kg after 24 and 48 hours) or placebo. Serial echoencephalography was performed 24 and 48 hours after the initial cerebral ultrasound study, on postnatal days 7, 15, and 30, and at 40 weeks' postconceptional age. Grade 1 IVH or no IVH was considered a successful outcome, whereas grade 2 to 4 IVH represented failure. The rates of ductal closure, side effects, and complications were recorded.
Results. We studied 155 infants. Grade 2 to 4 IVH developed for 16% of the ibuprofen-treated infants and 13% of the infants in the placebo group. The occurrence of patent ductus arteriosus was less frequent only on day 3 of life in the ibuprofen group. There were no significant differences with respect to other complications or adverse effects.
Conclusions. Our study demonstrated that prophylactic ibuprofen is ineffective in preventing grade 2 to 4 IVH and that its use for this indication cannot be recommended.
Key Words: ibuprofen intraventricular hemorrhage patent ductus arteriosus infants
Abbreviations: IVH, intraventricular hemorrhage PDA, patent ductus arteriosus CBF, cerebral blood flow iRDS, infant respiratory distress syndrome ROP, retinopathy of prematurity OR, odds ratio CI, confidence interval PVL, periventricular leukomalacia PPHN, persistent pulmonary hypertension of the newborn
Despite improvements in the assistance and treatment of preterm infants, intraventricular hemorrhage (IVH) remains a frequent complication among these patients.1 This point is crucial because the most severe IVH cases are related to a high risk of neurodevelopmental handicaps. In fact, mental retardation, seizures, and cerebral palsy have been reported for 45% to 86% of preterm infants with parenchymal IVH involvement.2–5
Previous clinical trials demonstrated that indomethacin, a cyclooxygenase inhibitor of prostaglandin synthesis that is used commonly for the closure of patent ductus arteriosus (PDA), decreased the incidence of IVH among very low birth weight infants.6–10 Indomethacin was shown to decrease baseline cerebral blood flow (CBF), to modulate CBF changes in response to hypercarbic insults, to decrease serum prostaglandin levels, and to promote germinal matrix maturation in animal models.11–14 However, indomethacin prophylaxis for IVH has never been used widely, because of the adverse effects of indomethacin on renal function and the gastrointestinal tract.10,15–19
In contrast, experimental20 and preliminary clinical21–24 studies demonstrated that ibuprofen (another cyclooxygenase inhibitor of prostaglandin synthesis) was effective in closing PDA without reducing CBF25 or affecting cerebral vasoreactivity to arterial carbon dioxide tension26 or intestinal27,28 or renal29 hemodynamics. Furthermore, ibuprofen enhances CBF autoregulation30 and was shown to protect neurologic functions after oxidative stresses in an animal model.31
For these reasons, we hypothesized that the prophylactic use of ibuprofen would reduce the occurrence of IVH and its worsening toward grades 2 to 4 among preterm infants. To confirm this hypothesis, we planned a double-blind, randomized, controlled trial in which preterm infants with gestational age of <28 weeks received ibuprofen or placebo within the first 6 hours of life.
METHODS
Patient Population
A multicenter, double-blind, prospective study, approved by local ethics committees, was conducted in 7 tertiary neonatal care units (Careggi University Hospital of Florence, Sant'Anna University Hospital of Ferrara, Clinica Mangiagalli of Milan, Children's Hospital "V. Buzzi" of Milan, San Gerardo Hospital of Monza, Regional Hospital of Bolzano, and Sant'Anna Hospital of Turin, all in Italy). Inclusion criteria were gestational age of <28 weeks and postnatal age of <6 hours. Exclusion criteria were the presence of major congenital malformations; hydrops fetalis; persistent pulmonary hypertension of the newborn (PPHN); grade 2 to 4 IVH; platelet count of <50000 platelets per mm3; tendency to bleed, as revealed by hematuria, blood in the endotracheal aspirate, gastric aspirate, or stools, or oozing from puncture sites; or serum creatinine concentration of >1.5 mg/dL. Neonates were enrolled after written informed consent was obtained from their parents.
Study Design
The infants in each unit were assigned randomly to a treatment group with the sealed-envelope technique; envelopes were prepared at Careggi University Hospital of Florence and then distributed to participating centers. Each infant received 3 doses of ibuprofen lysine (Arfen; Lisapharma, Erba, Italy; 10 mg/kg within 6 hours after birth, followed by 5 mg/kg after 24 and 48 hours) or indistinguishable placebo. The medications were infused continuously in a period of 15 minutes. The doses and dosing intervals were the same as those used for newborn infants in previous studies.21–23
When the ductus arteriosus was still patent after the randomly assigned treatment for a patient of either group, ibuprofen was administered as a nonrandomized rescue treatment. If this therapy also failed to promote ductal closure or if there was a contraindication to repeated pharmacologic treatment, then surgical ligation of the ductus arteriosus was performed.
Echographic Study
All patients for whom study permission was requested underwent cerebral ultrasonography within the first 6 hours of life, to exclude grade 2 to 4 IVH. Serial echoencephalography was performed 24 and 48 hours after the first study, on postnatal days 7, 15, and 30, and at 40 weeks' postconceptional age. The images were obtained with a high-resolution (7.5-MHz), real-time, sector scanner, in both coronal and sagittal projections through the anterior fontanel.
The grading system for hemorrhage was adapted from that described by Papile et al,32 as follows: grade 1, blood in the periventricular germinal matrix regions or germinal matrix hemorrhage; grade 2, blood within the lateral ventricular system without ventricular dilation; grade 3, blood acutely distending the lateral ventricles; grade 4, blood within the ventricular system and parenchyma. Hemorrhage was considered to have extended if an intraventricular or parenchymal component developed from a germinal matrix hemorrhage or a second hemorrhage was not in the hemisphere opposite that with an existing hemorrhage. The echoencephalographic studies were also evaluated for the presence of periventricular leukomalacia (PVL). All infants identified as having PVL had cystic areas on the 40-week cerebral ultrasound scans; earlier scans of the same infants showed parenchymal echodensities. PVL was graded from grade 1 to grade 3 according to the classification described by De Vries et al.33
Echocardiographic examinations were performed for all patients before enrollment and on postnatal days 2, 3, 5, 7, and 21 (or more frequently, if indicated). The initial evaluation included 2-dimensional, M-mode, pulsed Doppler and color flow evaluations of cardiac flow dynamics, performed to ascertain the normality of cardiac anatomic features and to rule out the possibility of congenital heart disease with "ductus-dependent" pulmonary or systemic blood flow or PPHN. Two-dimensional studies were performed for direct observation of the PDA, and left-to-right shunts were documented with pulsed Doppler echocardiography and color flow mapping. A diagnosis of significant PDA was made with echocardiographic demonstration of a ductal left-to-right shunt, with a left atrium/aortic root ratio of >1.3 or a ductal size of >1.5 mm.21 All echographic studies were performed by physicians who were unaware of the infants' treatment assignments.
Concomitant Treatment
Daily clinical care was performed by attending physicians, in accordance with common practices. Fluid intake was based essentially on changes in body weight, serum electrolyte concentrations, and serum osmolality; we started with 70 mL/kg, which was increased 10 to 20 mL each day to reach 150 mL/kg at the end of the first week of life. Infants could receive human milk from donors (and then from their own mothers) from the first day of life. When dextrose infusion was indicated, its concentration was set to maintain appropriate plasma glucose levels. Electrolytes were added after the first day of life, whereas intravenous administration of amino acids and lipids was initiated generally by the second day of life.
When hypotension was refractory to fluid-replacement therapy (with plasma, packed red cells, or more rarely saline), dopamine and/or dobutamine infusion was started. For infant respiratory distress syndrome (iRDS), infants received oxygen therapy, respiratory support (nasal continuous positive pressure, synchronized mechanical ventilation, or high-frequency oscillatory ventilation), and early rescue surfactant treatment (Curosurf; Chiesi, Parma, Italy; 200 mg/kg plus 100 mg/kg after 12 hours). The objective of assisted ventilation was to maintain an arterial partial pressure of oxygen of 50 to 70 mm Hg, arterial partial pressure of carbon dioxide of <65 mm Hg, pH of >7.20, and oxygen saturation of 90% to 95%.
Infants who underwent mechanical ventilation, had signs of sepsis, or were predisposed to infection because of maternal factors were given antibiotics after appropriate studies. Antibiotic therapy was stopped after 3 or 4 days if the bacterial cultures (of blood, tracheal aspirate, and urine) remained negative. Postnatal steroid treatment (12 days of tapering doses of dexamethasone34) was started for infants with severe respiratory failure who were receiving maximal ventilatory and oxygen support and for infants who, after 2 weeks of life, were still undergoing mechanical ventilation and were considered at high risk of developing chronic lung disease.
Clinical Courses and Outcomes
For each newborn infant, gestational age, birth weight, gender, type of delivery, Apgar scores at 1 and 5 minutes, pH of umbilical artery blood, prenatal and postnatal steroid treatment, main maternal pregnancy pathologic conditions, length of stay in the hospital, and death were recorded. To evaluate the severity of iRDS, initial (at the first blood gas analysis) and highest values of the oxygenation index (mean airway pressure x fraction of inspired oxygen x 100/arterial partial pressure of oxygen) and the ventilatory index (oxygenation index x arterial partial pressure of carbon dioxide) were measured for patients undergoing mechanical ventilation.
Serum creatinine levels and platelet counts were measured at 1, 3, and 5 days of life. Urine output was measured every day during the first 5 days of life, by collecting urine in adhesive bags, and oliguria was defined as a urinary output of <1 mL/kg per hour during a 24-hour collection period; fluid intake was recorded every day during the first week of life. To evaluate bleeding tendencies, hematuria, gastric bleeding, blood in the endotracheal aspirate or stools, and oozing from puncture sites were assessed.
Our patients were also monitored for complications such as sepsis, bronchopulmonary dysplasia, necrotizing enterocolitis, and retinopathy of prematurity (ROP). Diagnoses of sepsis were based on clinical and laboratory data (total neutrophil counts, immature/total neutrophil ratios, and C-reactive protein concentrations) and confirmed with positive blood cultures.35 Diagnosis of bronchopulmonary dysplasia was based on the requirement for supplemental oxygen to maintain adequate oxygenation at 36 weeks' postconceptional age.36 Necrotizing enterocolitis was diagnosed in the presence of abdominal distension, gastric residuals with or without bile-stained vomiting and bloody diarrhea or stools, hypotension, and suggestive abdominal radiographs (showing dilated and thickened bowel loops, parietal pneumatosis with or without perforation, or portal or hepatic venous air).37 The incidence of ROP, staged according to the international classification,38 was also recorded. All clinical and biological data were reported on data sheets designed for this study.
Statistical Analyses
In our study, we considered as successful outcomes grade 1 IVH or no IVH at 7 days of life, whereas grade 2 to 4 IVH represented failure. We assumed a failure rate 20% higher in the placebo group than in the ibuprofen group. Therefore, at a power of 0.80 and = .05, the estimated sample size was 74 infants in each group.
Clinical characteristics of the 2 groups were described with mean values and SDs or rates and percentages. Statistical analyses were performed with Student's t test for parametric continuous variables, the 2-sample Wilcoxon rank-sum test for nonparametric continuous variables, and Fisher's exact test for categorical variables such as frequencies. P < .05 was considered statistically significant.
Multiple stepwise logistic regressions were conducted to determine which maternal, neonatal, or perinatal factors would influence the risk for development of grade 2 to 4 IVH. Effect estimates are expressed as odds ratios (ORs) with profile, likelihood-based, 95% confidence intervals (CIs).
RESULTS
Two hundred fifty patients were eligible for the study, but 80 were excluded because of the presence of cardiac malformations (n = 4), hydrops fetalis (n = 3), PPHN (n = 15), grade 2 IVH (n = 20), platelet counts of <50000 platelets per mm3 or bleeding tendency (n = 25), or serum creatinine concentrations of >1.5 mg/dL (n = 13). Among the remaining 170 infants, 10 were excluded because of a lack of parental consent and 5 were excluded after randomization because of incomplete data collection (4 in the ibuprofen group and 1 in the placebo group). Therefore, we studied 155 infants, 77 of whom were assigned to the ibuprofen group and 78 to the placebo group. The initial dose of the drug was administered at 5.2 ± 0.6 hours and 5.4 ± 0.5 hours in the ibuprofen and placebo groups, respectively. The groups had comparable proportions of maternal and obstetric factors (Table 1); they were also comparable in clinical characteristics except for gestational age (Table 2).
The proportions of infants with grade 1 IVH at enrollment were similar in the ibuprofen (n = 4, 5%) and placebo (n = 5, 6%) groups. Two of these infants in each group experienced progression of hemorrhage; the 2 infants in the ibuprofen group developed grade 2 IVH, whereas 1 infant in the placebo group developed grade 2 IVH and another developed grade 3 IVH. Grade 2 to 4 IVH developed for 21% of the ibuprofen-treated infants and for 17% in the placebo group (Table 3). The incidences of grade 1, grade 2, grade 3, and grade 4 IVH were similar in the ibuprofen and placebo groups. We considered the possibility that the occurrence of IVH could differ between the groups at different times. For this reason, we compared the IVH rates at baseline and at 24 hours, 48 hours, and 7 days of life, but we did not find any difference between the ibuprofen group and the placebo group (Table 4).
The infant survival rates were similar in the 2 groups (Table 5). The most frequent causes of death were refractory respiratory failure and sepsis. There was no significant difference between the groups in the occurrence of iRDS or its severity, the requirement for or type of mechanical ventilation, or the need for surfactant treatment (Table 2). The rates of sepsis, bronchopulmonary dysplasia, necrotizing enterocolitis, ROP (all grades), and PVL (all grades) and the lengths of stay in the hospital were similar in the ibuprofen and placebo groups (Table 5). The occurrence of PDA was less frequent on day 3 of life in the ibuprofen group (Table 5). The incidences of serum creatinine levels of >1.5 mg/dL, mean serum creatinine levels, urine outputs, rates of oliguria, bleeding tendency, and platelet counts of <50000/mm3, and mean platelet counts did not differ between the ibuprofen and placebo groups (Table 5).
Logistic-regression analysis included all variables in Tables 1 and 2 and also the occurrence of grade 1 IVH at enrollment, bleeding tendency, thrombocytopenia, and PDA in the day 3 of life. We found that the following factors had significant predictive values for the development of grade 2 to 4 IVH: male gender (OR: 2.3; 95% CI: 1.76–2.84) and prenatal steroid treatment (OR: 0.30; 95% CI: –1.66 to –0.71).
DISCUSSION
The anomalies of cerebral perfusion play an important role in the development of cerebral injury among preterm infants. Prostaglandins, especially prostaglandin E2 and F2, are determinants in the control of the upper range of CBF autoregulation; they exert a minimal vasoconstrictor activity, which could prevent an increase in CBF when systemic blood pressure increases.30 Ibuprofen was reported to enhance CBF autoregulation among newborn piglets,30 and Li et al39 demonstrated that its effect was secondary to the up-regulation of prostaglandin E2 and F2 receptors induced by inhibition of the isoenzyme cyclooxygenase-2. Therefore, with stabilization of cerebral perfusion, a reduction in the incidence of IVH among preterm infants might be expected. Varvarigou et al21 reported a trend toward a decrease in the incidence of IVH among preterm infants, although this was not statistically significant and was not confirmed in other studies.39
Unfortunately, our study demonstrated that ibuprofen was ineffective in preventing grade 2 to 4 IVH, confirming the results of a recent meta-analysis study of the prevention of PDA with ibuprofen prophylaxis.40 This result suggests that the action of ibuprofen in improving CBF autoregulation among preterm infants is insufficient to limit brain injuries. We wondered why ibuprofen is ineffective in reducing the occurrence of IVH whereas indomethacin, which is also a cyclooxygenase inhibitor, is effective.6–10 We found that several authors observed decreased CBF after indomethacin administration, both in newborn animals12,41 and among newborn infants,25,42 but not after ibuprofen treatment.12,25,42,43 Therefore, we concluded that indomethacin can affect cerebral circulation through mechanisms different from cyclooxygenase blockade and prostaglandin synthesis,43 such as direct action on vascular endothelium44 and the increase in the circulating level of endothelins,45 which likely can explain also the more frequent occurrence of adverse effects after indomethacin treatment, rather than after ibuprofen treatment. In other words, it is probable that the ineffectiveness of ibuprofen in preventing grade 2 to 4 IVH and the lower occurrence of adverse effects after its administration are secondary to more-selective inhibition of cyclooxygenase isoforms, compared with indomethacin, which permits the closure of PDA but is not sufficient to compensate for inadequate CBF autoregulation among preterm infants.
Another possible explanation is that we used an inadequate ibuprofen dose. However, it is difficult to suggest increasing this dose, because in a previous study21 it was found to be associated with a plasma ibuprofen level 2.5-fold higher than that generated among adults with arthritis receiving similar doses46 and there are no studies of ibuprofen pharmacokinetics among newborn infants.
In the present study, we monitored the possible adverse effects of ibuprofen treatment, in particular on renal function and the clotting system, but we did not find any difference between the ibuprofen and placebo groups. This confirms previous studies,40 except that Van Overmeire et al24 found serum creatinine levels to be increased on day 3 of life among ibuprofen-treated infants. The recorded complications of prematurity also showed similar rates in the 2 groups, except for the incidences of PDA on day 3 of life (9% in the treated group and 29% in the placebo group), which confirmed that prophylactic treatment with ibuprofen reduced PDA occurrence among preterm infants with iRDS at 3 days of life.23 However, among patients in the placebo group who demonstrated PDA at 3 days of life, 83% (19 of 23 patients) experienced closure of the ductus arteriosus after the first cycle of ibuprofen, as reported previously.19,23,24
A final issue in our study was the possible occurrence of PPHN among our patients after ibuprofen administration, as reported by Gournay et al.47 None of our patients demonstrated PPHN47 after ibuprofen treatment; we think this was because all infants with PPHN were excluded from the study. In fact, it is our opinion that the reported PPHN was preexisting, not caused by ibuprofen, and that PDA closure only worsened and manifested it.
CONCLUSIONS
Our study demonstrated that prophylactic ibuprofen was ineffective in preventing grade 2 to 4 IVH and its use for this purpose cannot be recommended. We confirmed that ibuprofen therapy for PDA closure is safe and effective. Because ibuprofen cannot represent an alternative to indomethacin and indomethacin treatment might be followed by several adverse effects, the question of pharmacologic IVH prevention among preterm infants remains crucial and additional efforts are necessary to identify other potentially effective drugs.
ACKNOWLEDGMENTS
The IntraVentricular Ibuprofen Study Group includes G.L. Lista, MD (Milan, Italy); Hubert Messner, MD (Bolzano, Italy); Fabio Mosca, MD (Milan, Italy); and Paolo Tagliabue, MD (Monza, Italy).
FOOTNOTES
Accepted Oct 4, 2004.
No conflict of interest declared.
REFERENCES
Rubaltelli FF, Dani C, Reali MF, et al. Acute neonatal respiratory distress in Italy: a one year prospective study. Acta Paediatr. 1998;87 :1261 –1268
Krishnamooorthy KS, Shannon DC, DeLong GR, Todres ID, Davis KR. Neurologic sequelae in the survivors of neonatal intraventricular hemorrhage. Pediatrics. 1979;64 :233 –237
Shinnar S, Molteni RA, Gammon K, D'Souza BJ, Altman J, Freeman JM. Intraventricular hemorrhage in the premature infant. N Engl J Med. 1982;306 :1464 –1468
McMenamin JB, Shackelford GD, Volpe JJ. Outcome of neonatal intraventricular hemorrhage with periventricular echodense lesions. Ann Neurol. 1984;15 :285 –290
Szymonowicz W, Yu VYH, Bajuk B, Astbury J. Neurodevelopmental outcome of periventricular hemorrhage and leukomalacia in infants 1250 g or less at birth. Early Hum Dev. 1986;14 :1 –7
Banstra ES, Montalvo BM, Goldberg RN. Prophylactic indomethacin for prevention of intraventricular hemorrhage in premature infants. Pediatrics. 1984;74 :1107 –1112
Bada HS, Green RS, Pourcyrous M, et al. Indomethacin reduced the risks of severe intraventricular hemorrhage. J Pediatr. 1989;115 :631 –637
Ment LR, Duncan CC, Ehrenkrnaz RA. Randomized indomethacin trial for prevention of intraventricular hemorrhage in very low birth weight neonates. J Pediatr. 1985;107 :937 –943
Ment LR, Oh W, Ehrenkrnaz RA, et al. Low-dose indomethacin and prevention of intraventricular hemorrhage: a multicenter randomized trial. Pediatrics. 1994;93 :543 –550
Fowlie PW, Davis PG. Prophylactic intravenous indomethacin for preventing mortality and morbidity in preterm infants. Cochrane Database Syst Rev. 2002;(3) :CD000174
Leffler CW, Busija DW, Fletcher AM, Beasley DG, Hessler JR, Green RS. Effects of indomethacin upon cerebral hemodynamics of newborn pigs. Pediatr Res. 1985;19 :1160 –1164
Chemtob S, Beharry K, Barna T, Varma DR, Aranda JV. Difference in the effects in the newborn piglet of various non-steroidal anti-inflammatory drugs on cerebral blood flow but not on cerebrovascular prostaglandins. Pediatr Res. 1991;30 :106 –111
Dahlgren N, Nilsson B, Sakabe T. The effect of indomethacin on cerebral blood flow and oxygen consumption in the rat at the normal and increased carbon dioxide tension. Acta Physiol Scand. 1982;3 :475 –485
Ment LR, Stewart WB, Ardito TA, Huang E, Madri JA. Indomethacin promotes germinal matrix microvessel maturation in the newborn beagle pup. Stroke. 1992;23 :1132 –1137
Betkerur MV, Yeh TF, Miller K, Glasser RJ, Pildes RS. Indomethacin and its effects on renal function and urinary kallikrein excretion in premature infants with patent ductus arteriosus. Pediatrics. 1981;68 :99 –102
Van Bel F, Guit GL, Schipper J, Van de Bor M, Baan J. Indomethacin-induced changes in renal blood flow velocity waveform in premature infants investigated with color Doppler imaging. J Pediatr. 1991;118 :621 –626
Grosfeld JL, Chaedt M, Molinari F. Increased risk of necrotizing enterocolitis in premature infants with patent ductus arteriosus treated with indomethacin. Ann Surg. 1996;224 :350 –357
Ojala R, Ikonen S, Tammela O. Perinatal indomethacin treatment and neonatal complications in preterm infants. Eur J Pediatr. 2000;159 :153 –155
Lago P, Bettiol T, Salvadori S, et al. Safety and efficacy of ibuprofen versus indomethacin in preterm infants treated for patent ductus arteriosus: a randomized control trial. Eur J Pediatr. 2002;161 :202 –207
Coceani F, White E, Bodach E, Olley PM. Age-dependent changes in the response of the lamb ductus arteriosus to oxygen and ibuprofen. Can J Physiol Pharmacol. 1979;57 :825 –831
Varvarigou A, Bardin LC, Beharry K, Chemtob S, Papageorgiu A, Aranda JV. Early ibuprofen administration to prevent patent ductus arteriosus in premature newborn infants. JAMA. 1996;275 :539 –544
Van Overmeire B, Follens I, Hartmann S, Creten WL, van Acker KJ. Treatment of patent ductus arteriosus with ibuprofen. Arch Dis Child. 1997;76 :F179 –F184
Dani C, Bertini G, Reali MF, et al. Prophylaxis of patent ductus arteriosus with ibuprofen in preterm infants. Acta Paediatr. 2000;89 :1369 –1374
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 :674 –681
Mosca F, Bray M, Lattanzio M, Fumagalli M, Tosetto C. Comparative evaluation of the effect of indomethacin and ibuprofen on cerebral perfusion and oxygenation in preterm infants with patent ductus arteriosus. J Pediatr. 1997;131 :549 –554
Mosca F, Bray M, Colnaghi MR, Fumagalli M, Compagnoni G. Cerebral vasoreactivity to arterial carbon dioxide tension in premature infants: effect of ibuprofen. J Pediatr. 1999;135 :644 –646
Grosfeld JL, Kamman K, Gross K, Cikrit D, Ross D, Wolfe M. Comparative effects of indomethacin, prostaglandin E1 and ibuprofen on bowel ischemia. Pediatr Surg. 1983;18 :738 –742
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 :733 –738
Malcom DD, Segar JL, Robillard E, Chemtob S. Indomethacin compromises hemodynamics during positive-pressure ventilation independently of prostanoids. J Appl Physiol. 1993;74 :1672 –1678
Chemtob S, Beharry K, Barna T, Varma DR, Aranda JV. Prostanoids determine the range of cerebral blood flow autoregulation of newborn piglets. Stroke. 1990;21 :777 –784
Chemtob S, Roy M-S, Abran D, Ferandez H, Varma DR. Prevention of post-asphyxial increase in lipid peroxides and retinal function deterioration in the newborn pig by inhibition of cyclooxygenase activity and free radical generation. Pediatr Res. 1993;33 :336 –340
Papile LA, Burstein J, Burstein R, Keffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birthweight less than 1500 grams. J Pediatr. 1978;92 :529 –534
De Vries LS, Eken P, Dubowitz LM. The spectrum of leukomalacia using cranial ultrasounds. Behav Brain Res. 1992;49 :1 –6
Rastogi A, Akintorin SM, Bez ML, Morales P, Pildes PS. A controlled trial of dexamethasone to prevent bronchopulmonary dysplasia in surfactant-treated infants. Pediatrics. 1996;98 :204 –210
American Academy of Pediatric, Committee on Drugs, Committee on Fetus and Newborn, and Committee on Infectious Diseases. Prophylaxis and treatment of neonatal gonococcal infections. Pediatrics. 1980;65 :1047 –1048
Shennan AT, Dunn MS, Ohlsson A, Lennox K, Hoskins EM. Abnormal pulmonary outcomes in premature infants: prediction from oxygen requirement in the neonatal period. Pediatrics. 1988;82 :527 –532
Bell MJ, Ternberg JL, Feigin RD, Keating JP, Marshall R, Barton L, Brotherton T. Neonatal necrotizing enterocolitis: therapeutic decisions based upon clinical staging. Ann Surg. 1978;187 :1 –12
Committee for the Classification of Retinopathy of Prematurity. An international classification of retinopathy of prematurity. Arch Ophthalmol. 1984;102 :1130 –1134
Li DY, Hardy P, Abran D, et al. Key role for cyclooxygenase-2 in PGE2 and PGF2 receptor regulation and cerebral blood flow of the newborn. Am J Physiol. 1997;273 :R1283 –R1290
Shah SS, Ohlsson A. Ibuprofen for the prevention of patent ductus arteriosus in preterm and/or low birth weight infants. Cochrane Database Syst Rev. 2003;(2) :CD004213
Pappius HM, Wolfe LS. Effects of indomethacin and ibuprofen on cerebral metabolism and blood flow in traumatized brain. J Cereb Blood Flow Metab. 1983;3 :448 –459
Patel J, Robert I, Azzopardi D, Hamilton P, Edwards AD. Randomized double-blind controlled trial comparing the effects of ibuprofen with indomethacin on cerebral hemodynamics in preterm infants with patent ductus arteriosus. Pediatr Res. 2000;47 :36 –42
Pellicer A, Aparicio M, Cabanas F, Valverde E, Quero J, Stiris TA. Effects of the cyclo-oxygenase blocker ibuprofen on cerebral blood flow during normocarbia and hypercarbia in newborn piglets. Acta Paediatr. 1999;88 :82 –88
Siesjo BK. Cerebral circulation and metabolism. J Neurosurg. 1984;60 :883 –908
Therkelsen K, Jensen KA, Freundlich M, Thorshange H, Bunemann L, Bogeskov-Nielsen L. Endothelin-1 and cerebral blood flow: influence of hypoxia, hypercapnia, and indomethacin on circulating endothelin levels in healthy volunteers. Scand J Clin Lab Invest. 1994;54 :441 –451
Gallo JM, GalI IP, Gillespie WR, Albert KS, Perrier D. Ibuprofen kinetics in plasma and synovial fluid of arthritic patients. J Clin Pharmacol. 1986;26 :65 –70
Gournay V, Savagner C, Thiriez G, Kuster A, Rozé JC. Pulmonary hypertension after ibuprofen prophylaxis in very preterm infants. Lancet. 2002;259 :1486 –1488(Carlo Dani, MD, Giovanna )