High-Dose Ibuprofen for Patent Ductus Arteriosus in Extremely Preterm Infants: A Randomized Controlled Study

Transcription

1 nature publishing group High-Dose Ibuprofen for Patent Ductus Arteriosus in Extremely Preterm Infants: A Randomized Controlled Study C Dani 1, V Vangi 1, G Bertini 1, S Pratesi 1, I Lori 1, F Favelli 1, R Ciuti 2, A Bandinelli 2, C Martano 3, P Murru 3, H Messner 4, F Schena 5 and F Mosca 5 Our aim was to assess the hypothesis that a high-dose of ibuprofen is more effective than the standarddose in closing patent ductus arteriosus (PDA) without increasing adverse effects. Infants of gestational age <29 weeks, with respiratory distress syndrome (RDS) and echocardiographic evidence of significant PDA at h of life, were randomized to receive a standard ( mg/kg/day) or high-dose ( mg/kg/day) course of ibuprofen. We studied 70 infants, 35 of whom received the standard dose of ibuprofen and the other 35 the high dose. Of the infants treated with the standard-dose, 37% had persistent PDA as compared with 14% of those treated with the highdose (P = 0.03). No differences in the occurrence of adverse effects were observed between the two groups. The high-dose ibuprofen is more effective than the standard-dose in closing PDA in preterm infants <29 weeks of gestation without increasing the adverse effect rate. The patency of ductus arteriosus (PDA) is a frequent complication in preterm infants with respiratory distress syndrome (RDS), and 60 70% of preterm infants of <28 weeks gestation receive medical or surgical therapy for PDA. 1 Neonates with a left-to-right shunt through the ductus as a complication of RDS have higher respiratory failure rates, lower survival rates, and increased risk of intracranial hemorrhage, bronchopulmonary dysplasia, and necrotizing enterocolitis. 2 Therefore, it is critical to effect closure of PDA before a significant left-to-right shunting occurs. PDA can be treated effectively with intravenous indomethacin and ibuprofen, leading to permanent ductal closure in 60 80% of infants. 3 5 However, preterm infants treated with ibuprofen have lower serum creatinine values, higher urine output, and fewer undesirable effects (such as decreased organ blood flow and vasoconstrictive adverse effects) than infants treated with indomethacin. 4 Recently, Sperandio et al. reported that high doses of indomethacin (1 mg/kg: five times the usual dose) were safe and effective in closing PDA in 98.5% of infants of gestational age <33 weeks, and demonstrated that the closure rate of PDA was related to the cumulative dose of indomethacin administered. 6 Moreover, Desfrere et al. demonstrated that the currently recommended dose of ibuprofen ( mg/kg/day) is associated with a low estimated probability (30.6%) of closing PDA in infants, whereas a high-dose ( mg/kg/ day) might be associated with a greater, although still unsatisfactory, probability (54.8%) of closing PDA, without relevant side effects. 7 In addition, Hirt et al., on the basis of pharmacokinetic findings, proposed increasing the dose of ibuprofen during the postnatal period from mg/kg/day in preterm infants <70 h of age to mg/kg/day in infants h of age and mg/kg/day in infants h of age. 8 These studies 6 8 suggest that the failure of pharmacologic treatment of PDA closure might be due to the inadequacy of the standard-dose, given the large interindividual variations in the pharmacokinetics and pharmacodynamics of drugs in premature infants. 9,10 We hypothesized that the early treatment of PDA with ibuprofen doses higher than those now recommended might increase the closure rate in preterm infants of gestational age <29 weeks without increasing the occurrence of associated adverse effects. In order to assess this hypothesis, we planned a multicenter, randomized, controlled study to compare the effectiveness of 1 Department of Surgical and Medical Critical Care, Section of Neonatology, Careggi University Hospital of Florence, Florence, Italy; 2 Central Laboratory of Chemical-Clinical Analysis, Careggi University Hospital of Florence, Florence, Italy; 3 Division of Neonatology of Turin University, OIRM-Sant Anna Hospital of Turin, Turin, Italy; 4 Neonatal Intensive Care Unit of Ospedale Regionale, Bolzano, Italy; 5 Neonatal Intensive Care Unit, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico-Department of Mother and Infant Sciences, University of Milan, Milan, Italy. Correspondence: C Dani (cdani@unifi.it) Received 5 July 2011; accepted 8 October 2011; advance online publication 16 November doi: /clpt VOLUME 91 NUMBER 4 APRIL

2 the current ibuprofen with that of a high-dose in closing PDA. Results Subject demographics and clinical characteristics The study was carried out between July 2007 and June Figure 1 shows the number of newborns who were assessed for eligibility, the number of eligible newborns, and the number of newborns who were randomly assigned to each treatment group. A total of 70 infants were enrolled and randomized into two groups to receive either the current intravenous ibuprofen ( mg/kg/day; n = 35) or a high-dose intravenous ( mg/kg/day; n = 35). The two groups were comparable in maternal and obstetric factors (Table 1) and also with respect to clinical characteristics except for the ibuprofen plasma level, which was higher in the high-dose ibuprofen group after both the first and third doses (Table 2). Efficacy After the first course of ibuprofen, 37% of the infants treated with the standard-dose had persistent PDA in comparison with 14% in the high-dose group (P = 0.03). The second course of ibuprofen ( mg/kg/day) resulted in a similar observation of PDA refractory to pharmacologic closure treatment (6 vs. 3%). The reopening of DA was observed in two patients in the first group (at 12 and 14 days of life after one and two courses of ibuprofen, respectively) and in four patients in the second group (at 12, 26, 33, and 15 days of life, after a single course of ibuprofen in three cases and after two courses in the last case). Surgical closure of PDA was needed in two patients in the standard-dose group (in one patient the second course of ibuprofen failed, and another experienced DA reopening at 12 days of life after a single course of ibuprofen) and in two patients in the high-dose group (these patients experienced DA reopening at 12 and 26 days of life, respectively, after a single course of ibuprofen). None of the patients had PDA at the time of discharge (Table 3). Infants with PDA that responded to the first course of ibuprofen and those with PDA that was refractory to the treatment had similar clinical characteristics; however, those in whom PDA closure was achieved had higher ibuprofen plasma levels (Table 4). Logistic regression analysis demonstrated that FiO 2 <0.40 was the highest value (relative risk 0.42; 95% confidence interval: ) and that the high-dose ibuprofen (relative risk 0.38; 95% confidence interval: ) independently decreased the risk of developing a refractory PDA. Safety Renal function was similar in the two groups, as demonstrated by similar mean values of serum creatinine and urine output and similar rates of occurrence of serum creatinine levels >1.5 mg/dl and oliguria. None of patients had to discontinue the treatment because of renal toxicity. Bleeding disorders and platelet counts did not differ between the groups, nor did the occurrence of prematurity complications, mortality, and duration of hospital stay (Table 5). The peak total serum bilirubin levels and the requirement for and duration of phototherapy during the first week of life were similar in the two groups (Table 5). Discussion The optimal dose of ibuprofen for closing PDA is an area of uncertainty, and this study is the first randomized controlled trial attempting to examine the efficacy and side effects of different doses of ibuprofen. We found that a single course of ibuprofen with a high-dose is more effective than the standard in closing PDA in extremely preterm infants without the occurrence of significant short-term adverse effects. We also found that, as an independent factor, the treatment reduces the risk of developing a refractory PDA, with a number needed to treat of four. The question of the most effective dose of ibuprofen for ductal closure was raised by Desfrere et al., 7 who pointed out that the dose used in most studies ( mg/kg for 3 days) 157 assessed for eligibility 95 underwent randomization 62 excluded 34 did not meet inclusion criteria: 30 no significant PDA 4 congenital malformations 19 consent not given 9 other reasons 48 allocated to standard ibuprofen 11 died before 1st course completion 2 incomplete data 47 allocated to standard ibuprofen 9 died before 1st course completion 3 incomplete data 35 were followed until discharge or death and were analyzed 35 were followed until discharge or death and were analyzed Figure 1 Number of infants who were eligible for the study and randomly assigned to treatment groups. PDA, patent ductus arteriosus. Clinical pharmacology & Therapeutics VOLUME 91 NUMBER 4 APRIL

3 Table 1 Comparison between infants in the standard and high-dose ibuprofen groups according to obstetrical and maternal factors (n = 35) (n = 35) P Hypertensive disorders 3 (9) 5 (15) Antenatal steroids 25 (71) 28 (80) Preterm premature rupture 4 (11) 5 (15) of membranes Preterm noninduced labor 16 (46) 14 (40) IUGR 9 (26) 11 (31) Abruptio placentae 2 (6) 2 (6) Cesarean section 19 (54) 20 (57) Other 3 (9) 2 (6) Rate and (%). IUGR, intrauterine growth restriction. is based on very sparse pharmacokinetic data. 8,9,11 They suggested that a high-dose of mg/kg for 3 days might achieve a higher closure rate in more immature infants (<27 weeks), but they were able to administer this dose to only a single patient and advocated further studies to assess the tolerability and safety of this dose in a larger population. More recently, Hirt et al. demonstrated that when postnatal age increases from 1 to 8 days, ibuprofen plasma clearance also increases, leading to a decrease in its half-life (42.2 h at 3 days vs h at 5 days). 8 This is probably the result of the postnatal maturation of the cytochrome P450 complex and, more specifically, of the CYP2C9 and CYP2C8 subfamily that metabolizes ibuprofen. 12 They therefore suggested increasing the dose during the postnatal period; although all their patients had received the standard, the authors of the study concluded that their assumptions about the proper ibuprofen needed to be tested prospectively. 8 Our data have now confirmed the speculations raised in previous studies 7,8 regarding the effectiveness of the first course of ibuprofen at a high dose, 7 and the beneficial effect of a second course of ibuprofen at a high dose in infants with PDA that is resistant to the first course. 8 In agreement with Richards et al., we found that a second course of ibuprofen is effective in closing PDA. 13 Nonetheless, our study demonstrates that the second course of ibuprofen (always given as a high-dose ) is followed by the occurrence of persistent PDA and the need for surgical closure to a similar extent in infants who received the first course of ibuprofen at the standard dose and in those who received the first course at the high dose. This finding might suggest that the final fate of PDA is not affected by the dose of the first ibuprofen course, provided that, in persistent PDA, a second course of ibuprofen is given at a high dose. Therefore, a rational approach to the early treatment of PDA with ibuprofen in extremely preterm infants would be to administer a first course at standard dose followed by a second at high dose in nonresponder infants. This approach takes into account the Table 2 Clinical characteristics of infants in the standard and high-dose ibuprofen groups (n = 35) (n = 35) P Gestational age (weeks) 26.0 ± ± Birth weight (g) 835 ± Male 14 (40) 13 (37) 1 Highest FiO ± ± Highest MAP 12.0 ± NCPAP 34 (97) 34 (97) Duration (days) 19 ± ± Mechanical ventilation PTV 17 (49) 15 (43) 0.81 HFOV 14 (40) 17 (49) 0.63 Duration (days) 14 ± ± Surfactant 33 (94) 34 (97) 1 Number of doses 2 (1-4) 2 (1-5) 1 Fluid intake (ml/kg) DOL ± ± DOL ± ± DOL ± ± DOL ± ± DOL ± ± DOL ± ± DOL ± ± Vasoactive drug Dopamine 10 (29) 10 (29) Dobutamine 7 (20) 6 (17) 1 Plasma transfusion during 25 (71) 28 (80) the 1st week Ibuprofen plasma level (mg/l) a 15 min after 1st dose 47.1 ± ± 27.2* < h after 3rd dose 46.2 ± ± 26.0 < Mean ± SD, rate and (%), or median and (range). DOL, day of life; FiO 2, fraction of inspired oxygen; HFOV, high-frequency oscillatory ventilation; MAP, mean airway pressure; NCPAP, nasal continuous positive airway pressure; PTV, patient-triggered ventilation. a Measured in 10 patients per group. *P = vs. 24-h value. consideration that the first days of life are particularly critical for renal function and, as mentioned above, the metabolization of ibuprofen increases postnatally. It is worth noting, however, that infants in the high-dose group in the first course required a second course of ibuprofen less frequently (14 vs. 37%) than infants who were administered the standard dose in the first course. Still, our study was not designed to evaluate whether the dose of the first course can affect the success rate of the second course, and the size of our population was insufficient to draw conclusions on this issue. A further study, with patients randomized between groups of standard-dose and high-dose second course of ibuprofen (if the first course of ibuprofen fails 592 VOLUME 91 NUMBER 4 APRIL

4 Table 3 Incidence of PDA in the standard and high-dose ibuprofen groups PDA occurrence (n = 35) (n = 35) First course of ibuprofen After 1st dose 25 (71) 29 (83) 0.19 After 2nd dose 16 (46) 15 (43) 0.50 After 3rd dose a 13 (37) 5 (14) 0.03 Second course of ibuprofen a After 4th dose 6 (17) 3 (9) 0.23 After 5th dose 2 (6) 1 (3) 0.50 After 6th dose 2 (6) 1 (3) 0.50 Reopening 2 (6) b 4 (12) c 0.33 Surgical closure 2 (6) d 2 (6) e 0.39 PDA at discharge Rate and (%). PDA, patent ductus arteriosus. a in both groups. b At 12 and 14 days of life. c At 12, 26, 33, and 15 days of life. d One patient failed 2nd course of ibuprofen, one patient had DA reopening at 14 days of life. e These patients had DA reopening at 12 and 26 days of life. to close the PDA), could elucidate the answer to this relevant question. It is interesting that the difference in efficacy between the standard-dose and high-dose groups emerges after the third dose of the first course and disappears after the first dose of the second course: this could indicate an effect of ibuprofen cumulative dose in addition to its peak level, as suggested by Sperandio et al., 6 but our data cannot support this hypothesis. As expected, we found that the plasma ibuprofen level was higher in infants who were treated with the high-dose than in infants who were treated with the standard. Interestingly, we found that the ibuprofen level was higher in infants in whom the PDA responded to ibuprofen than in infants with refractory PDA; this finding was in disagreement with that by Desfrere et al. 7 and Van Overmeire et al., 9 both of whom found no significant relationship between plasma ibuprofen concentrations and ductal closure. These differences probably reflect the variations in study design and time points of blood sampling. Another relevant finding of our study is that the high-dose of ibuprofen was well tolerated and not associated with the development of adverse effects. In particular, we did not observe any major impairment of renal function or coagulation during the first week of life or any change in the rate of prematurityrelated complications. These results are in agreement with those of Desfrere et al., 7 who did not find major adverse effects of ibuprofen on renal function at any dose level, although subgroup analysis showed mild renal side effects. Altogether, these findings confirm the assumption by Hirt et al., 8 who considered it unlikely that a high dose of ibuprofen would lead to an increase in toxicity; in their study on the effects of optimizing the ibuprofen dose, they did not find any relationship between the increase in the ibuprofen area under the concentration time curve and serum creatinine levels. Nevertheless, the possible nephrotoxic effect of ibuprofen remains controversial and it may not be considered P Table 4 Clinical characteristics of infants with PDA responding or refractory to the 1st course of ibuprofen PDA responding to Ibuprofen (n = 52) PDA refractory to Ibuprofen (n = 18) P Gestational age (weeks) 26.1 ± ± Birth weight (g) 841 ± ± Cesarean section 29 (56) 10 (56) Male 18 (35) 9 (50) Antenatal steroids 42 (81) 11 (61) Surfactant treatment 50 (96) 17 (94) NCPAP 50 (96) 18 (100) Duration (days) 20 ± ± Mechanical ventilation PTV 23 (44) 9 (50) HFOV 24 (46) 7 (39) Duration (days) 18 ± ± Highest FiO ± ± Highest MAP 11.5 ± ± Vasoactive drug Dopamine 15 (29) 5 (28) Dobutamine 9 (17) 4 (22) Plasma transfusions 40 (77) 13 (72) during the 1st week Fluid intake (ml/kg) DOL ± ± DOL ± ± DOL ± ± DOL ± ± DOL ± ± DOL ± ± DOL ± ± PDA surgical ligature 2 (4) 2 (11) PDA reopening 4 (8) 2 (11) PDA at discharge 0 0 N/A Sepsis 21 (40) 6 (33) Bronchopulmonary 17 (33) 9 (50) dysplasia Necrotizing enterocolitis 6 (12) 1 (6) ROP: All grades 5 (10) 3 (17) >Grade 2 2 (4) 1 (6) ICH: All grades 7 (13) 3 (17) Grade (10) 1 (6) PVL (all grades) 4 (8) 1 (6) 0.82 Mortality 8 (15) 3 (17) Ibuprofen plasma level (mg/l) a 15 min after 1st dose 88.4 ± ± 35.2 < h after 3rd dose 65.3 ± ± 22.1 < Mean ± (SD), rate and (%). a Measured in 14 and 6 patients in the responding and refractory group. DOL, day of life; FiO 2, fraction of inspired oxygen; HFOV, high-frequency oscillatory ventilation; ICH, intracranial hemorrhage; MAP, mean airway pressure; NCPAP, nasal continuous positive airway pressure; PDA, patent ductus arteriosus; PTV, patienttriggered ventilation; PVL, periventricular hemorrhage; ROP, retinopathy of prematurity. Clinical pharmacology & Therapeutics VOLUME 91 NUMBER 4 APRIL

5 Table 5 Markers of potential side effects and complications of preterm birth in the standard and high-dose ibuprofen groups (n = 35) (n = 35) P Serum creatinine 0 (0) 1 (3) 1 >1.5 mg/dl Serum creatinine (mg/dl) DOL ± DOL ± ± DOL ± ± CrCl (ml/min/1.73 m 2 ) DOL ± DOL ± ± DOL ± 13.4* 41.4 ± 10.9* Urine output (ml/kg/h) DOL ± DOL ± ± DOL ± ± DOL ± ± DOL ± ± DOL ± ± DOL ± ± Oliguria 2 (6) 3 (9) 1 Bleeding disorders 13 (37) 13 (37) Platelets ( 10 9 /l) DOL 1 190,830 ± 73, ,250 ± 68, DOL 2 153,070 ± 72, ,210 ± 84, DOL 3 231,250 ± 136, ,320 ± 110, Peak total serum bilirubin (mg/dl) 8.0 ± ± Need of phototherapy 30 (86) 31 (89) 1 Duration of phototherapy (days) 2.4 ± ± ICH: All grades 6 (17) 4 (11) Grade (11) 2 (6) PVL (all grades) 2 (6) 3 (9) 1 ROP: All grades 4 (11) 4 (11) >Grade 2 1 (3) 2 (6) 1 Necrotizing enterocolitis Bronchopulmonary dysplasia 3 (9) 4 (11) 1 10 (29) 16 (46) Sepsis 14 (40) 13 (37) 1 Mortality 5 (14) 6 (17) 1 Hospital stay (days) 81 ± ± Mean ± SD and rate and (%). CrCl, creatinine clearance; DOL, day of life; ICH, intracranial hemorrhage; PVL, periventricular hemorrhage; ROP, retinopathy of prematurity. *P < th DOL vs. 1st DOL. exempt from causing adverse renal effects. 14 Interestingly and reassuringly, we did not observe any differences in peak serum bilirubin levels and/or need of phototherapy between the infants exposed to the two ibuprofen s; however, we were not able to measure the levels of unbound bilirubin. 15 A limitation of our study may be that it does not exclude the possibility that other factors have relevant roles in the outcome of treatment of PDA in infants These possible factors include the wide use of gentamicin (which, like other aminoglycosides, has been reported to have vasodilatory properties in the ductus in animal models) 16 and genetics. 17 In fact, it has recently been demonstrated that preterm PDA is highly familial (genetic plus environmental factors), and, although the effect is mainly environmental, 18 the magnitude of the genetic contribution warrants additional investigation. 19 A better understanding of the genetic background of this developmental process may help to develop new strategies to manipulate the DA in premature infants. Another limitation is that our study does not include data on the long-term outcome of our patients. In conclusion, we demonstrated that the early treatment of PDA with high-dose ibuprofen is more effective than the current dose in closing PDA in preterm infants of <29 weeks gestation, without increasing the adverse effect rate. Furthermore, we found that the ultimate outcome of PDA is not affected by the dose of the first ibuprofen course, provided that, if PDA persists, a second course of ibuprofen is given at high dose. Further randomized controlled studies are warranted to evaluate the efficacy of a second course of highdose ibuprofen if the first course fails to close the PDA. Methods Subject selection and study design. Four tertiary neonatal intensive care units participated in the trial (the Careggi University Hospital, Florence, Italy; the Sant Anna University Hospital, Turin, Italy; the Regional Hospital, Bozen, Italy, and the IRCCS Ospedale Maggiore Policlinico, Milan, Italy). The study was approved by the medical ethics committee of each center. Neonates were enrolled after written informed consent had been obtained from their parents. The criteria for enrolment were gestational age <29 weeks; echocardiographic evidence of significant PDA; age h; and RDS necessitating respiratory support. The exclusion criteria were major congenital anomalies; life-threatening infection (complicated by a multiple organ dysfunction and failure syndrome) or hydrops fetalis; pulmonary hypertension, diagnosed by means of heart ultrasound when the presence of a right-to-left shunt through the foramen ovale or ductus arteriosus was demonstrated, or when the estimated pulmonary pressure, in terms of the tricuspid regurgitation jet, was greater than two-thirds of the systemic arterial pressure; death before the conclusion of the first course of ibuprofen; urine output <1 ml/kg of body weight/h during the preceding 12 h (with the exception of the first dose); a serum creatinine concentration 1.5 mg/dl (129 μmol/l); platelet count 50,000/mm 3 ; or a tendency to bleed, as revealed by hematuria, or blood in the endotracheal aspirate, gastric aspirate, or stools, or oozing of blood from puncture sites. The infants in each unit were randomly assigned to treatment groups by means of cards in sealed opaque envelopes. Each infant received three doses of intravenous ibuprofen (Pedea; Orphan Europe, Paris, France), either according to the standard (an initial dose of 10 mg/kg, followed by two doses of 5 mg/kg each, after 24 and 48 h) or per a high-dose (an initial dose of 20 mg/kg, followed by two doses of 10 mg/kg each, after 24 and 48 h). The treatment was started at h of age, and the medication was infused continuously over a period of 15 min. 594 VOLUME 91 NUMBER 4 APRIL

6 Wherever the ductus arteriosus was still patent after the randomly assigned treatment in a patient in either group, a second course of ibuprofen at high dose ( mg/kg/day) was given as nonrandomized treatment, starting 24 h after the last dose of the first course. If there was a contraindication to the second pharmacologic treatment, or if this therapy also failed to promote ductal closure, subsequent pharmacologic, and/or surgical treatment of PDA was left to the discretion of physicians at each center. The plasma ibuprofen concentration was measured in blood samples (400 μl) obtained 15 min after the first dose of ibuprofen and 24 h after the last dose, 7 using high-pressure liquid chromatography as previously described. 20 Plasma samples (200 μl) were obtained by centrifugation for 5 min at 3,700g and were stored at 20 C awaiting analysis. Echocardiography. The first heart ultrasound examination was performed at h of age to confirm the normalcy of cardiac anatomy, to rule out the possibility of congenital heart disease with ductus-dependent pulmonary or systemic blood flow and pulmonary hypertension, and to evaluate the PDA (Careggi University Hospital; HP Sonos 7500, Philips, Amsterdam, The Netherlands; Sant Anna University Hospital; ATL HDI 3500; Philips; Regional Hospital of Bozen; Acuson Sequoia 512; Siemens, Munich, Germany; the IRCCS Ospedale Maggiore Policlinico; Acuson Sequoia 512; Siemens). The diagnosis of hemodynamically significant PDA requiring treatment was made by echocardiographic demonstration of a ductal left-to-right shunt, with a left atrium-to-aortic root ratio >1.3 or a ductal size >1.5 mm (the minimal ductal size within the course of the ductus was measured). 21 In the enrolled patients, echocardiography was repeated after each dose of ibuprofen (12 24 h after the last dose of the assigned treatment) and also every time a clinical reopening of PDA was suspected (at least at 7 ± 1, 15 ± 2, and 30 ± 2 days of life). All echocardiographic studies were performed by physicians (cardiologists or neonatologists trained in neonatal cardiology (Careggi University Hospital, n = 3; Sant Anna University Hospital, n = 2; Regional Hospital of Bozen, n = 2; and the IRCCS Ospedale Maggiore Policlinico, n = 4)) who were blinded as to the infants treatment assignments. Concomitant treatments. Daily clinical care was performed by attending physicians in accordance with the common practices at each center. Fluid intake was guided by body weight, serum sodium concentrations, and serum osmolality. Daily fluid intake started with ml/kg and was increased by ml/kg/day up to 150 ml/kg at the end of the first week of life. When there was hypotension that was refractory to fluid-replacement therapy, dopamine, and/or dobutamine infusion was started. For treatment of RDS, the infants received oxygen therapy, respiratory supports (nasal continuous positive pressure, patient-triggered ventilation, or high-frequency oscillatory ventilation), and rescue surfactant treatment (Curosurf; Chiesi Farmaceutici Spa, Parma, Italy, first dose: 200 mg/kg; following dose: 100 mg/kg). Prophylactic antibiotics (generally piperacillin or ampicillin plus gentamicin) were administered from the time of admission to the neonatal intensive care unit and were stopped after 3 4 days if the results of the bacterial cultures (of blood, tracheal aspirate, and urine) remained negative. Clinical course and outcome. Gestational age, birth weight, sex, type of delivery, antenatal steroid treatment, and main maternal pregnancy pathologies (preterm noninduced labor, hypertensive disorders, premature rupture of membranes, abruptio placentae, intrauterine growth restriction), highest FIO 2 and mean airway pressure values, type and duration of respiratory support, the need for a surfactant, daily fluid intake during the first week of life, and the need for dopamine/dobutamine or plasma infusion for hypotension were recorded for each infant. Serum creatinine was measured at 1, 3, and 7 days of life, while daily urine output was measured during the first week of life. Oliguria was defined as urine output 1 ml/kg/h during a 24-h collection period. In addition, platelet count was measured at 1, 3, and 7 days of life and bleeding disorders (as revealed by hematuria, blood in the endotracheal aspirate, gastric aspirate, or stools, and oozing of blood from puncture sites) were recorded during the first week of life. We also recorded the peak total serum bilirubin levels and the need for and duration of phototherapy during the first week of life for each infant. Serial echoencephalography was performed at 1, 3, 7 ± 1, 15 ± 2, and 30 ± 2 days of life, and at 40 weeks postconception to evaluate possible brain damage and, in particular, intracranial hemorrhage and periventricular hemorrhage, which were graded according to standard classification systems. 22,23 Bronchopulmonary dysplasia was defined as oxygen requirement at 36 weeks postconception. 24 Retinopathy of prematurity was graded according to the international classification of retinopathy of prematurity. 25 Necrotizing enterocolitis was diagnosed in terms of the presence of abdominal distention, gastric residuals with or without bile-stained vomiting and bloody diarrhea or stools, hypotension, and suggestive abdominal radiogram (dilated and thickened bowel loops, parietal pneumatosis ± perforation, portal or hepatic venous air). 26 Diagnosis of sepsis was based on clinical and laboratory data (total neutrophil count, immature-to-total neutrophil ratio, C-reactive protein concentration) and confirmed by positive blood cultures. 27 Finally, mortality and duration of hospitalization were reported. Study registration. The trial was registered with ClinicalTrials.gov ( under identifier NCT Outcome measures Efficacy: The primary end point of our study was to evaluate the success rate in closing PDA using ibuprofen at high or standard dose. We defined failure of ibuprofen treatment as the failure to effect PDA closure at the end of the first course of ibuprofen, in both the standard and high-dose groups. The secondary end points were the evaluation of the effectiveness of a high-dose second ibuprofen course in closing PDA refractory to the first ibuprofen course; possible associations among dose, occurrence of adverse effects, and plasma ibuprofen level; and comparison of the incidence of intracranial hemorrhage, periventricular hemorrhage, retinopathy of prematurity, necrotizing enterocolitis, bronchopulmonary dysplasia, sepsis, death, and hospital-stay duration in the two groups. Safety: Safety end-point measures included incidence, severity, and causality of spontaneously reported treatment-emergent adverse events; changes in occurrence of the common complications associated with prematurity; and clinical laboratory test assessments. Statistical methodology. On the basis of our data, and in agreement with data from the literature, 3 5 we assumed a failure rate of 25% in the group treated with the standard ibuprofen. Therefore, to detect as being statistically significant a decrease in failure rate of 20% (to 5%) in the group treated with the high ibuprofen, we calculated that a sample size of at least 34 infants in each group was necessary for a power of 0.80 and α-value of The clinical characteristics of the two groups were described in terms of mean values and SD, median values and range, or rate and percentage. The t-test, Wilcoxon rank-sum test, and Fisher s exact test were used to compare continuous normally distributed data, nonparametric continuous data, and categorical data, respectively. Multiple logistic regression analysis was performed to assess the influence of predictive factors on the rate of PDA after the first ibuprofen course; the factors we analyzed were: gestational age, sex, birth weight, use or nonuse of antenatal glucocorticoid, highest FIO 2 and mean airway pressure values, and assignment to standard or high-dose ibuprofen group. Effect estimates are expressed as relative risk with profile likelihood-based 95% confidence limits. The reported relative risks represent the effect of gestational age vs weeks, birth weight <800 vs. 800 g, antenatal steroid treatment, FiO 2 <0.40 vs. 0.40, mean airway pressure <9 cm H 2 O vs. 9 cm H 2 O, and standard vs. high-dose ibuprofen. Clinical pharmacology & Therapeutics VOLUME 91 NUMBER 4 APRIL

7 Conflict of Interest The authors declared no conflict of interest American Society for Clinical Pharmacology and Therapeutics 1. Van Overmeire, B. et al. A comparison of ibuprofen and indomethacin for closure of patent ductus arteriosus. N. Engl. J. Med. 343, (2000). 2. Hamrick, S.E. & Hansmann, G. Patent ductus arteriosus of the preterm infant. Pediatrics 125, (2010). 3. Itabashi, K., Ohno, T. & Nishida, H. Indomethacin responsiveness of patent ductus arteriosus and renal abnormalities in preterm infants treated with indomethacin. J. Pediatr. 143, (2003). 4. Ohlsson, A., Walia, R. & Shah, S.S. Ibuprofen for the treatment of patent ductus arteriosus in preterm and/or low birth weight infants. Cochrane Database Syst. Rev. CD (2010). 5. Gournay, V. et al. Prophylactic ibuprofen versus placebo in very premature infants: a randomised, double-blind, placebo-controlled trial. Lancet 364, (2004). 6. Sperandio, M. et al. Effectiveness and side effects of an escalating, stepwise approach to indomethacin treatment for symptomatic patent ductus arteriosus in premature infants below 33 weeks of gestation. Pediatrics 116, (2005). 7. Desfrere, L. et al. Dose-finding study of ibuprofen in patent ductus arteriosus using the continual reassessment method. J. Clin. Pharm. Ther. 30, (2005). 8. Hirt, D. et al. An optimized ibuprofen dosing scheme for preterm neonates with patent ductus arteriosus, based on a population pharmacokinetic and pharmacodynamic study. Br. J. Clin. Pharmacol. 65, (2008). 9. Van Overmeire, B., Touw, D., Schepens, P.J., Kearns, G.L. & van den Anker, J.N. Ibuprofen pharmacokinetics in preterm infants with patent ductus arteriosus. Clin. Pharmacol. Ther. 70, (2001). 10. Seyberth, H.W., Knapp, G., Wolf, D. & Ulmer, H.E. Introduction of plasma indomethacin level monitoring and evaluation of an effective threshold level in very low birth weight infants with symptomatic patent ductus arteriosus. Eur. J. Pediatr. 141, (1983). 11. Aranda, J.V. et al. Pharmacokinetics and protein binding of intravenous ibuprofen in the premature newborn infant. Acta Paediatr. 86, (1997). 12. Treluyer, J.M., Gueret, G., Cheron, G., Sonnier, M. & Cresteil, T. Developmental expression of CYP2C and CYP2C-dependent activities in the human liver: in-vivo/in-vitro correlation and inducibility. Pharmacogenetics 7, (1997). 13. Richards, J., Johnson, A., Fox, G. & Campbell, M. A second course of ibuprofen is effective in the closure of a clinically significant PDA in ELBW infants. Pediatrics 124, e287 e293 (2009). 14. Fanos, V., Antonucci, R. & Zaffanello, M. Ibuprofen and acute kidney injury in the newborn. Turk. J. Pediatr. 52, (2010). 15. Ahlfors, C.E. Effect of ibuprofen on bilirubin-albumin binding. J. Pediatr. 144, (2004). 16. Reese, J., Veldman, A., Shah, L., Vucovich, M. & Cotton, R.B. Inadvertent relaxation of the ductus arteriosus by pharmacologic agents that are commonly used in the neonatal period. Semin. Perinatol. 34, (2010). 17. Bökenkamp, R., DeRuiter, M.C., van Munsteren, C. & Gittenberger-de Groot, A.C. Insights into the pathogenesis and genetic background of patency of the ductus arteriosus. Neonatology 98, 6 17 (2010). 18. Bhandari, V. et al. Genetic contribution to patent ductus arteriosus in the premature newborn. Pediatrics 123, (2009). 19. Dagle, J.M. et al. Determination of genetic predisposition to patent ductus arteriosus in preterm infants. Pediatrics 123, (2009). 20. Rey, E. et al. Stereoselective disposition of ibuprofen enantiomers in infants. Br. J. Clin. Pharmacol. 38, (1994). 21. Varvarigou, A., Bardin, C.L., Beharry, K., Chemtob, S., Papageorgiou, A. & Aranda, J.V. Early ibuprofen administration to prevent patent ductus arteriosus in premature newborn infants. JAMA 275, (1996). 22. Papile, L.A., Burstein, J., Burstein, R. & Koffler, H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm. J. Pediatr. 92, (1978). 23. de Vries, L.S., Eken, P. & Dubowitz, L.M. The spectrum of leukomalacia using cranial ultrasound. Behav. Brain Res. 49, 1 6 (1992). 24. Ehrenkranz, R.A. et al.; National Institutes of Child Health and Human Development Neonatal Research Network. Validation of the National Institutes of Health consensus definition of bronchopulmonary dysplasia. Pediatrics 116, (2005). 25. International Committee for the Classification of Retinopathy of Prematurity. The International Classification of Retinopathy of Prematurity revisited. Arch. Ophthalmol. 123, (2005). 26. Bell, M.J. et al. Neonatal necrotizing enterocolitis. Therapeutic decisions based upon clinical staging. Ann. Surg. 187, 1 7 (1978). 27. American Academy of Pediatric s Committee on drugs, Committee on fetus and newborn and Committee on Infectious Diseases. Pediatrics 65, (1980). 28. Brissaud, O. & Guichoux, J. Patent ductus arteriosus in the preterm infant: a survey of clinical practices in French neonatal intensive care units. Pediatr. Cardiol. 32, (2011). 596 VOLUME 91 NUMBER 4 APRIL