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Effects of indomethacin and ibuprofen on mesenteric and renal blood flow in preterm infants with patent ductus arteriosus
E
Effects of indomethacin and ibuprofen on mesenteric
and renal blood flow in preterm infants with patent ductus arteriosus
Marco Pezzati, MD, Venturella Vangi, MD, Roberto Biagiotti, MD, Giovanna Bertini, MD, Domenico Cianciulli, MD, and Firmino F. Rubaltelli MD
Objective: To evaluate the effect of intravenous ibuprofen and indomethacin for treatment of patent ductus arteriosus (PDA) on mesenteric and renal blood flow velocity in preterm infants. Study design: Seventeen mechanically ventilated preterm infants (<33 weeks’ gestation) with PDA received either 0.2 mg/kg indomethacin (n = 8) or 10 mg/kg ibuprofen (n = 9), infused over 15 minutes. Mesenteric and renal blood flow velocity were measured by using Doppler ultrasonography. Results: Indomethacin caused a significant reduction in mesenteric and renal blood flow velocity 30 minutes after drug administration; mesenteric and renal blood flow velocity did not return to the pretreatment values by 120 minutes. Ibuprofen did not alter blood flow 30 minutes after treatment, and blood flow increased 120 minutes after treatment. Mesenteric and renal blood flow velocity changes were significantly different between the 2 treatment groups. Conclusions: Compared with indomethacin, ibuprofen did not significantly reduce mesenteric and renal blood flow velocity.(J Pediatr 1999;135:733-8)
A hemodynamically significant patent ductus arteriosus in preterm infants with respiratory distress syndrome may lead to an increased risk for intraventricular cerebral hemorrhage, necrotizing enterocolitis, bronchopulmonary dysplasia, and death.1 ConseFrom the Department of Pediatrics, Division of Neonatology, and the Department of Obstetrics and Gynecology, University of Firenze School of Medicine, Firenze, Italy.
Submitted for publication Aug 25, 1998; revisions received May 27, 1999, and July 28, 1999; accepted Aug 13, 1999. Reprint requests: Marco Pezzati, MD, Division of Neonatology, Careggi University Hospital, Viale Morgagni 85, 50134 Firenze, Italy. Copyright © 1999 by Mosby, Inc. 0022-3476/99/$8.00 + 0 9/21/102410
quently, in these patients treatment is indicated before important left-to-right shunting occurs.2 Indomethacin, a prostaglandin synthesis inhibitor, has been widely used in the prophylaxis and treatment of hemodynamically significant PDA.3-5 However, this drug induces a significant reduction in cerebral,6,7 mesenteric,8,9 and renal10 blood flow velocity measured by Doppler ultrasonography. More recently, the use of a different nonsteroidal anti-inflammatory drug, ibuprofen, has demonstrated good efficacy and apparent safety in the prophylaxis of PDA in preterm infants.11 Mosca et al12 demonstrated that compared with indomethacin, ibuprofen does not significantly reduce cerebral perfusion in
preterm human infants. Moreover, ibuprofen, in contrast to indomethacin, does not affect intestinal or renal hemodynamics,13,14 probably because indomethacin acts in part through mechanisms other than inhibition of prostaglandin synthesis.11,13 The effects of ibuprofen on mesenteric and renal BFV have not been previously evaluated with Doppler ultrasonography. We therefore performed a clinical trial to compare the effects of ibuprofen and indomethacin as treatment for PDA on mesenteric and renal BFV in human preterm infants.
BFV EDV MV PDA PSV RA RVR SMA
Blood flow velocity End-diastolic velocity Mean velocity Patent ductus arteriosus Peak-systolic velocity Renal artery Relative vascular resistance Superior mesenteric artery
PATIENTS AND METHODS We studied a group of 17 preterm infants <33 weeks’ gestational age, who were receiving mechanical ventilation because of respiratory distress syndrome and had evidence of hemodynamically significant PDA on the second day of life. Infants were excluded if they had malformations, renal or gastrointestinal abnormalities, hypotension or hypertension, infection, anemia (hemoglobin <10 g/dL), poly733
PEZZATI ET AL
THE JOURNAL OF PEDIATRICS DECEMBER 1999
Fig 1. Doppler measurements (PSV, MV, and EDV) and RVR in superior mesenteric artery before and at 30, 60, and 120 minutes after either indomethacin (■) or ibuprofen () administration (*P < .05 vs pretreatment; **P < .05 vs 30 minutes; §P < .0001 vs indomethacin at the same time). All values are expressed as mean ± SD.
Table. Characteristics of the study population at entry
Variables
Indomethacin (n = 8)
Ibuprofen (n = 9)
P value
Birth weight (g) Gestational age (wk) Age at treatment (h) FIO2 (%) MAP (cm H2O)
1277 ± 440 (630-1890) 29.5 ± 2.6 (26- 32) 33.2 ± 5.4 (26-42) 39.7 ± 8.8 (28-55) 8.8 ± 1.3 (7-11)
1151 ± 426 (580-1810) 29.1 ± 2.1 (26-32) 31.9 ± 4.5 (27-40) 38.5 ± 8.0 (29-54) 8.7 ± 1.2 (7-11)
NS NS NS NS NS
All values are expressed as mean ± SD with ranges in parentheses. NS, Not significant; FIO2 , fraction of inspired oxygen; MAP, mean airway pressure
cythemia (venous hemoglobin >22 g/dL), platelet count <50,000/mm3, or intraventricular hemorrhage of grade 2 or higher according to the classification of Papile et al.15 A weight loss of 734
5% to 10% was allowed during the first postnatal days. All mothers had received betamethasone, 12 mg per dose, 2 times before delivery. Because mesenteric and renal BFV may be
specifically affected by several factors, we excluded the following groups from the study: (1) infants with perinatal asphyxia, because BFV parameters show a significant reduction, directly correlated to the severity of asphyxia16; (2) infants with intrauterine growth retardation, because their BFV parameters are significantly modified during the first days of life17,18; (3) infants with postnatal age <24 hours and >48 hours, because BFV parameters significantly change during the first week of life19,20; and (4) infants receiving phototherapy, because mesenteric and renal perfusion are significantly reduced during phototherapy.21,22 To exclude the possible influence of postprandial changes on
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THE JOURNAL OF PEDIATRICS VOLUME 135, NUMBER 6
Fig 2. Doppler measurements (PSV, MV, and EDV) and RVR in renal artery before and at 30, 60, and 120 minutes after either indomethacin (■) or ibuprofen () administration (*P < .05 vs pretreatment; **P < .05 vs 30 minutes; §P < .0001 vs indomethacin at the same time). All values are expressed as mean ± SD.
intestinal blood supply,23,24 all the infants were studied at least 3 hours after a feed, and they were fed orally only after the last blood flow determination. The patients were fed with very small quantities of human milk, which would probably not modify the results (feeding volumes were 3.0 ± 1.5 mL in the indomethacin group and 3.1 ± 1.4 mL in the ibuprofen group). Informed consent was obtained from the parents, and the study was approved by our institutional review board. Infants were randomly assigned to receive either intravenous indomethacin (0.2 mg/kg) or intravenous ibuprofen (10 mg/kg). Both drugs were continuously infused over
15 minutes. Regardless of the ductus closure after the first dose, all patients received a second and third dose of indomethacin (0.1 mg/kg) or ibuprofen (5 mg/kg) at 24-hour intervals. We measured superior mesenteric artery and renal artery peak-systolic velocity, SMA and RA mean velocity, and SMA and RA end-diastolic velocity. The measurements were made within 10 minutes of drug administration and repeated at 30, 60, and 120 minutes after treatment. At the same times, we recorded heart rate, arterial oxygen saturation, and mean arterial pressure. Examinations of mesenteric and renal BFV were performed by using a realtime computed ultrasound scanner
(Toshiba Sonolayer SSH 140A) with a microconvex 7 MHz transducer. PSV, MV, and EDV were automatically calculated by the instrument software from 5 sequential cardiac cycles of optimal quality. The newborns were examined by the same sonography technician, blinded to treatment. For the study of mesenteric BFV, the transducer was positioned on the mid abdomen just above the umbilicus in the sagittal plane; for the study of renal BFV, the transducer was positioned below the costal margin in the dorsolateral area of the right flank. The sample volume of the Doppler system was set a few millimeters distal to the origin of the SMA and RA; an angle correc735
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THE JOURNAL OF PEDIATRICS DECEMBER 1999
Fig 3. Urine output and serum creatinine in indomethacin (solid bars) and ibuprofen (open bars) treatment groups. (*P < .05; **P < .02). tion was performed if the angle of incidence was greater than 15 degrees. The patency of PDA was initially diagnosed with pulsed Doppler echocardiography to demonstrate a detectable flow through the duct. PDA was considered hemodynamically significant as determined by 2-dimensional ultrasound imaging of the ductus when the left atrium/aortic root diameter ratio was greater than 1:4.25 Mean arterial pressure was measured by the standard oscillometric method (Escort 300 A, Medical Data Electronics) at the end of each blood flow study. At the same time, heart rate was recorded by electrocardiogram, and arterial oxygen saturation of the right hand was measured with a pulse oximeter (Biox 3740, Ohmeda). We calculated the mean arterial blood pressure/MV ratio as an estimate of SMA and RA relative vascular resistance. To evaluate the effects of indomethacin and ibuprofen on renal function, we calculated urine flow rates and serum creatinine values daily for the first week of life. We tested all stools for the presence of occult blood and recorded abdominal girth and 736
number and volume of gastric residuals daily to evaluate feeding intolerance and identify necrotizing enterocolitis. Analysis of variance for repeated measures and unpaired t test were used for statistical analysis. The Sheffé test was used to compare all possible pairs of mean values within each treatment group. A P value of <.05 was considered to be statistically significant. Computer software used was SPSS for Microsoft Windows, version 6.0.
RESULTS There were no significant differences in birth weight, gestational age, amount of feeding, or postnatal age at the start of therapy (Table). All infants were receiving conventional mechanical ventilation, and there were no significant differences in fraction of inspired oxygen or mean airway pressure. Heart rate, mean arterial blood pressure, and arterial oxygen saturation were comparable at the beginning of the study in the 2 groups; no significant changes were observed at any time after treatment with either drug. Before treatment, we did not observe
any differences in mesenteric and renal Doppler PSV, MV, EDV, and RVR (Figs 1 and 2). After indomethacin administration, we found significant reductions in PSV, MV, and EDV at 30 minutes; mesenteric and renal BFV parameters did not return to pretreatment values by 120 minutes. RVR increased significantly at 30 minutes and decreased from 30 to 120 minutes without reaching pretreatment values. In contrast, after treatment with ibuprofen, we did not find significant decreases in PSV, MV, or EDV at 30 minutes; and mesenteric and renal BFV increased significantly from 30 to 120 minutes (except for mesenteric PSV values). RVR significantly increased at 30 minutes and returned to pretreatment values at 60 minutes. Mesenteric and renal BFV changes in PSV, MV, EDV, and RVR were significantly different between the 2 treatment groups. In the indomethacin treatment group, ductal closure was observed in 7 infants after the first dose of the drug and in 1 infant after the second dose. No reopening was observed. In the ibuprofen treatment group, ductal clo-
PEZZATI ET AL
THE JOURNAL OF PEDIATRICS VOLUME 135, NUMBER 6 sure occurred in 7 infants after the first dose of the drug and in 2 infants after the second dose. No reopening of the ductus was observed. Urine output and serum creatinine values were significantly affected by indomethacin; on the contrary, no changes were observed with ibuprofen treatment (Fig 3). In the indomethacin group urine output decreased significantly on the first, second, and third days after indomethacin administration to a minimal value of 1.7 mL/kg/h on the third day and increased again to pretreatment values by 7 days. In the ibuprofen group we observed a significant decrease in urine output after drug administration only during the first day. A significant difference in urine output between the 2 groups was observed on days 2 and 3 after treatment. In the indomethacin group serum creatinine values increased significantly on the first, second, and third days, whereas no significant difference was observed for the ibuprofen group. A significant difference in serum creatinine values between the 2 groups was seen on days 1, 2, 3, and 7. No significant difference in daily fluid intake was observed between the 2 groups. Diuretics were not used in either group during the first days of life. There was no necrotizing enterocolitis in either group.
DISCUSSION Indomethacin has been the drug of choice for the treatment of PDA, but significant reductions in cerebral, mesenteric, and renal perfusion have been reported.6-10 A continuous infusion of indomethacin over 24 hours minimized the reduction of cerebral perfusion.4 More recently, ibuprofen was used with the same efficacy to close the duct and was associated with fewer side effects.14,26,27 In comparison with indomethacin, ibuprofen did not reduce cerebral BFV in preterm human infants.12 Ibuprofen, in con-
trast to indomethacin, does not affect renal or intestinal hemodynamics,11,13,14 although these effects have not been evaluated by Doppler ultrasonography. The results of our Doppler sonographic study confirm that pharmacologic closure of the ductus arteriosus with ibuprofen did not significantly reduce mesenteric and renal perfusion. Because mean arterial blood pressure did not change, the reduction in mesenteric and renal BFV with indomethacin was a direct vasoconstrictive effect on the resistance vessels, as has been proposed for cerebral perfusion.12 The lack of effect on urine flow rate and serum creatinine values in the ibuprofen treatment group confirms the results of Van Overmeire et al.14 A similar trend was observed by the same authors in a subsequent and larger trial,28 even though differences were not statistically significant. Our findings suggest that ibuprofen does not strongly influence renal perfusion. This difference between the 2 groups may be due to the fact that indomethacin acts in part through mechanisms other than inhibition of prostaglandin synthesis13; another possibility is that both drugs inhibit the cyclooxygenase enzyme system in the neonatal kidneys to a different extent14 or that serum indomethacin concentrations remain high enough to influence both the ductus and renal function, whereas those of ibuprofen are sufficiently high to close the duct but lack the potential to impair renal function.14 We conclude that ibuprofen administration, when used to treat PDA in preterm infants, does not significantly reduce mesenteric and renal BFV.
REFERENCES 1. Cotton RB, Stahlman MT, Kovar I, Catterton WZ. Medical management of small preterm infants with symptomatic patent ductus arteriosus. J Pediatr 1979;2:467-73. 2. Stefano JL, Abbasi S, Pearlman SA,
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Spear ML, Esterly KL, Bhutani VK. Closure of the ductus arteriosus with indomethacin in ventilated neonates with respiratory distress syndrome: effects on pulmonary compliance and ventilation. Am Rev Respir Dis 1991; 143:236-9. Krueger E, Mellander M, Bratton D, Cotton R. Prevention of symptomatic ductus arteriosus with a single dose of indomethacin. J Pediatr 1987;111: 749-54. Hammerman C, Glaser J, Schimmel MS, Ferber B, Kaplan M, Eidelman AI. Continuous versus multiple rapid infusions of indomethacin: effects on cerebral blood flow velocity. Pediatrics 1995;95:244-8. Clyman RI. Recommendations for the postnatal use of indomethacin: an analysis of four separate treatment strategies. J Pediatr 1996;128:601-7. Austin NC, Pairaudeau PW, Haames TK, Hall M. Regional blood flow velocity changes after indomethacin infusion in preterm infants. Arch Dis Child 1992;67:851-4. Van Bel F, Van De Bor M, Stijnen T, Baan J, Ruys JH. Cerebral blood flow velocity changes in preterm infants after a single dose of indomethacin: duration of its effects. Pediatrics 1989; 84:802-7. Coombs RC, Morgan MEI, Durbin GM, Booth IW, McNeisc AS. Gut blood flow velocities in the newborn: effects of patent ductus arteriosus and parenteral indomethacin. Arch Dis Child 1990;65:1067-71. Van Bel F, Van Zoeren D, Schipper J, Guit GL, Baan J. Effect of indomethacin on superior mesenteric artery blood flow velocity in preterm infants. J Pediatr 1990;116:965-70. Van Bel F, Guit GL, Schipper J, van de Bor M, Baan J. Indomethacininduced changes in renal blood flow velocity waveform in premature infants investigated with color Doppler imaging. J Pediatr 1991;118:621-6. Varvarigou A, Bardin CL, Beharry K, Chemtob S, Papageorgiou A, Aranda J. Early ibuprofen administration to prevent patent ductus arteriosus in premature newborn infants. JAMA 1996;275:539-44. Mosca F, Bray M, Lattanzio M, Fumagalli M, Tosetto C. Comparative evaluation of the effects of indomethacin and ibuprofen on cerebral perfusion and oxygenation in preterm infants with patent ductus arteriosus. J Pediatr 1997;131:549-54. 737
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THE JOURNAL OF PEDIATRICS DECEMBER 1999
13. Malcolm DD, Segar JL, Robillard E, Chemtob S. Indomethacin compromises hemodynamics during positive-pressure ventilation, independently of prostanoids. J Appl Physiol 1993;74:1672-8. 14. Van Overmeire B, Follens I, Hartmann S, Creten WL, Van Acker KJ. Treatment of patent ductus arteriosus with ibuprofen. Arch Dis Child 1997; 76:179-84. 15. Papile LS, Burstein J, Burstein R, Keffler H. Incidence and evaluation of the subependymal intraventricular hemorrhage: a study of infants weighing less than 1500 grams. J Pediatr 1978;92:529-34. 16. Akinbi H, Abbasi S, Hilpert PL, Bhutani VK. Gastrointestinal and renal blood flow velocity profile in neonates with birth asphyxia. J Pediatr 1994;125:625-7. 17. Kempley ST, Gamsu HR, Nicolaides KH. Renal artery blood flow velocity in very low birthweight infants with intrauterine growth retardation. Arch Dis Child 1993;68:588-90. 18. Martinussen M, Mari Brubakk AM, Vik T, Yao AC. Relationship between intrauterine growth retardation and
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early postnatal superior mesenteric artery blood flow velocity. Biol Neonate 1997;71:22-30. Cleary GM, Higgins ST, Merton DA, Cullen JA, Gottlieb RP, Baumgart S. Developmental changes in renal artery blood flow velocity during the first three weeks of life in preterm neonates. J Pediatr 1996;129:251-7. Pezzati M, Danesi G, Pozzessere A, Biagioli Cosenza E, Rubaltelli FF. Renal blood flow velocity in preterm and term neonates during the fourth day of life: changes in relation to gestational age and birth weight. Biol Neonate 1998;73:19-23. Benders MJNL, van Bel F, van de Bor M. The effect of phototherapy on renal blood flow velocity in preterm infants. Biol Neonate 1998;73:228-34. Yao AC, Martinussen M, Johansen OJ, Brubakk AM. Phototherapy-associated changes in mesenteric blood flow response to feeding in term neonates. J Pediatr 1994;124:309-12. Hsu CH, Lee HC, Huang FY. Duplex ultrasonography assessment of gut blood flow velocity: effect of meal composition in normal full-term newborns
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after first feed. J Ultrasound Med 1994;13:15-8. Coombs RC, Morgan ME, Durbin GM, Booth IW, McNeish AS. Doppler assessment of human neonatal gut blood flow velocities: postnatal adaptation and response to feeds. J Pediatr Gastroenterol Nutr 1992;15:6-12. Johnson GL, Breart GL, Gewitz MH, Brenner JI, Lang P, Dooley KJ, et al. Echocardiographic characteristics of premature infants with patent ductus arteriosus. Pediatrics 1983;72:864-71. Aranda J, Varvarigou N, Beharry K, Modanlou H, Bardin C, Papageorgiou A. The effect of early intravenous ibuprofen on renal function in premature newborns [abstract]. Pediatr Res 1994;37:361A. Patel J, Marks KA, Roberts I, Azzopardi D, Edwards AD. Ibuprofen treatment of patent ductus arteriosus [letter]. Lancet 1995;346:255. Van Overmeire B, Langhendries JP, Vanhaesebrouck P, Lecoutere D, Van de Broek H. Ibuprofen for early treatment of patent ductus arteriosus, a randomized multicenter trial [abstract]. Pediatr Res 1998;43:200A.
BOUND VOLUMES AVAILABLE TO SUBSCRIBERS Bound volumes of the 1999 issues of The Journal of Pediatrics are available to subscribers (only) from the Publisher, at a cost of $100.00 for domestic, $125.19 for Canadian, and $117.00 for international subscribers, for Vol. 134 (January-June) and Vol. 135 (July-December), shipping charges included. Each bound volume contains subject and author indexes, and all advertising is removed. Copies are shipped within 60 days after publication of the last issue in the volume. The binding is durable buckram, with the Journal name, volume number, and year stamped in gold on the spine. Payment must accompany all orders. Contact Mosby, Inc., Subscription Services, 11830 Westline Industrial Dr., St. Louis, MO 63146-3318, USA/800-4534351, or 314-453-4351. Subscriptions must be in force to qualify. Bound volumes are not available in place of a regular Journal subscription.
738
Effects of indomethacin and ibuprofen on mesenteric
and renal blood flow in preterm infants with patent ductus arteriosus
Marco Pezzati, MD, Venturella Vangi, MD, Roberto Biagiotti, MD, Giovanna Bertini, MD, Domenico Cianciulli, MD, and Firmino F. Rubaltelli MD
Objective: To evaluate the effect of intravenous ibuprofen and indomethacin for treatment of patent ductus arteriosus (PDA) on mesenteric and renal blood flow velocity in preterm infants. Study design: Seventeen mechanically ventilated preterm infants (<33 weeks’ gestation) with PDA received either 0.2 mg/kg indomethacin (n = 8) or 10 mg/kg ibuprofen (n = 9), infused over 15 minutes. Mesenteric and renal blood flow velocity were measured by using Doppler ultrasonography. Results: Indomethacin caused a significant reduction in mesenteric and renal blood flow velocity 30 minutes after drug administration; mesenteric and renal blood flow velocity did not return to the pretreatment values by 120 minutes. Ibuprofen did not alter blood flow 30 minutes after treatment, and blood flow increased 120 minutes after treatment. Mesenteric and renal blood flow velocity changes were significantly different between the 2 treatment groups. Conclusions: Compared with indomethacin, ibuprofen did not significantly reduce mesenteric and renal blood flow velocity.(J Pediatr 1999;135:733-8)
A hemodynamically significant patent ductus arteriosus in preterm infants with respiratory distress syndrome may lead to an increased risk for intraventricular cerebral hemorrhage, necrotizing enterocolitis, bronchopulmonary dysplasia, and death.1 ConseFrom the Department of Pediatrics, Division of Neonatology, and the Department of Obstetrics and Gynecology, University of Firenze School of Medicine, Firenze, Italy.
Submitted for publication Aug 25, 1998; revisions received May 27, 1999, and July 28, 1999; accepted Aug 13, 1999. Reprint requests: Marco Pezzati, MD, Division of Neonatology, Careggi University Hospital, Viale Morgagni 85, 50134 Firenze, Italy. Copyright © 1999 by Mosby, Inc. 0022-3476/99/$8.00 + 0 9/21/102410
quently, in these patients treatment is indicated before important left-to-right shunting occurs.2 Indomethacin, a prostaglandin synthesis inhibitor, has been widely used in the prophylaxis and treatment of hemodynamically significant PDA.3-5 However, this drug induces a significant reduction in cerebral,6,7 mesenteric,8,9 and renal10 blood flow velocity measured by Doppler ultrasonography. More recently, the use of a different nonsteroidal anti-inflammatory drug, ibuprofen, has demonstrated good efficacy and apparent safety in the prophylaxis of PDA in preterm infants.11 Mosca et al12 demonstrated that compared with indomethacin, ibuprofen does not significantly reduce cerebral perfusion in
preterm human infants. Moreover, ibuprofen, in contrast to indomethacin, does not affect intestinal or renal hemodynamics,13,14 probably because indomethacin acts in part through mechanisms other than inhibition of prostaglandin synthesis.11,13 The effects of ibuprofen on mesenteric and renal BFV have not been previously evaluated with Doppler ultrasonography. We therefore performed a clinical trial to compare the effects of ibuprofen and indomethacin as treatment for PDA on mesenteric and renal BFV in human preterm infants.
BFV EDV MV PDA PSV RA RVR SMA
Blood flow velocity End-diastolic velocity Mean velocity Patent ductus arteriosus Peak-systolic velocity Renal artery Relative vascular resistance Superior mesenteric artery
PATIENTS AND METHODS We studied a group of 17 preterm infants <33 weeks’ gestational age, who were receiving mechanical ventilation because of respiratory distress syndrome and had evidence of hemodynamically significant PDA on the second day of life. Infants were excluded if they had malformations, renal or gastrointestinal abnormalities, hypotension or hypertension, infection, anemia (hemoglobin <10 g/dL), poly733
PEZZATI ET AL
THE JOURNAL OF PEDIATRICS DECEMBER 1999
Fig 1. Doppler measurements (PSV, MV, and EDV) and RVR in superior mesenteric artery before and at 30, 60, and 120 minutes after either indomethacin (■) or ibuprofen () administration (*P < .05 vs pretreatment; **P < .05 vs 30 minutes; §P < .0001 vs indomethacin at the same time). All values are expressed as mean ± SD.
Table. Characteristics of the study population at entry
Variables
Indomethacin (n = 8)
Ibuprofen (n = 9)
P value
Birth weight (g) Gestational age (wk) Age at treatment (h) FIO2 (%) MAP (cm H2O)
1277 ± 440 (630-1890) 29.5 ± 2.6 (26- 32) 33.2 ± 5.4 (26-42) 39.7 ± 8.8 (28-55) 8.8 ± 1.3 (7-11)
1151 ± 426 (580-1810) 29.1 ± 2.1 (26-32) 31.9 ± 4.5 (27-40) 38.5 ± 8.0 (29-54) 8.7 ± 1.2 (7-11)
NS NS NS NS NS
All values are expressed as mean ± SD with ranges in parentheses. NS, Not significant; FIO2 , fraction of inspired oxygen; MAP, mean airway pressure
cythemia (venous hemoglobin >22 g/dL), platelet count <50,000/mm3, or intraventricular hemorrhage of grade 2 or higher according to the classification of Papile et al.15 A weight loss of 734
5% to 10% was allowed during the first postnatal days. All mothers had received betamethasone, 12 mg per dose, 2 times before delivery. Because mesenteric and renal BFV may be
specifically affected by several factors, we excluded the following groups from the study: (1) infants with perinatal asphyxia, because BFV parameters show a significant reduction, directly correlated to the severity of asphyxia16; (2) infants with intrauterine growth retardation, because their BFV parameters are significantly modified during the first days of life17,18; (3) infants with postnatal age <24 hours and >48 hours, because BFV parameters significantly change during the first week of life19,20; and (4) infants receiving phototherapy, because mesenteric and renal perfusion are significantly reduced during phototherapy.21,22 To exclude the possible influence of postprandial changes on
PEZZATI ET AL
THE JOURNAL OF PEDIATRICS VOLUME 135, NUMBER 6
Fig 2. Doppler measurements (PSV, MV, and EDV) and RVR in renal artery before and at 30, 60, and 120 minutes after either indomethacin (■) or ibuprofen () administration (*P < .05 vs pretreatment; **P < .05 vs 30 minutes; §P < .0001 vs indomethacin at the same time). All values are expressed as mean ± SD.
intestinal blood supply,23,24 all the infants were studied at least 3 hours after a feed, and they were fed orally only after the last blood flow determination. The patients were fed with very small quantities of human milk, which would probably not modify the results (feeding volumes were 3.0 ± 1.5 mL in the indomethacin group and 3.1 ± 1.4 mL in the ibuprofen group). Informed consent was obtained from the parents, and the study was approved by our institutional review board. Infants were randomly assigned to receive either intravenous indomethacin (0.2 mg/kg) or intravenous ibuprofen (10 mg/kg). Both drugs were continuously infused over
15 minutes. Regardless of the ductus closure after the first dose, all patients received a second and third dose of indomethacin (0.1 mg/kg) or ibuprofen (5 mg/kg) at 24-hour intervals. We measured superior mesenteric artery and renal artery peak-systolic velocity, SMA and RA mean velocity, and SMA and RA end-diastolic velocity. The measurements were made within 10 minutes of drug administration and repeated at 30, 60, and 120 minutes after treatment. At the same times, we recorded heart rate, arterial oxygen saturation, and mean arterial pressure. Examinations of mesenteric and renal BFV were performed by using a realtime computed ultrasound scanner
(Toshiba Sonolayer SSH 140A) with a microconvex 7 MHz transducer. PSV, MV, and EDV were automatically calculated by the instrument software from 5 sequential cardiac cycles of optimal quality. The newborns were examined by the same sonography technician, blinded to treatment. For the study of mesenteric BFV, the transducer was positioned on the mid abdomen just above the umbilicus in the sagittal plane; for the study of renal BFV, the transducer was positioned below the costal margin in the dorsolateral area of the right flank. The sample volume of the Doppler system was set a few millimeters distal to the origin of the SMA and RA; an angle correc735
PEZZATI ET AL
THE JOURNAL OF PEDIATRICS DECEMBER 1999
Fig 3. Urine output and serum creatinine in indomethacin (solid bars) and ibuprofen (open bars) treatment groups. (*P < .05; **P < .02). tion was performed if the angle of incidence was greater than 15 degrees. The patency of PDA was initially diagnosed with pulsed Doppler echocardiography to demonstrate a detectable flow through the duct. PDA was considered hemodynamically significant as determined by 2-dimensional ultrasound imaging of the ductus when the left atrium/aortic root diameter ratio was greater than 1:4.25 Mean arterial pressure was measured by the standard oscillometric method (Escort 300 A, Medical Data Electronics) at the end of each blood flow study. At the same time, heart rate was recorded by electrocardiogram, and arterial oxygen saturation of the right hand was measured with a pulse oximeter (Biox 3740, Ohmeda). We calculated the mean arterial blood pressure/MV ratio as an estimate of SMA and RA relative vascular resistance. To evaluate the effects of indomethacin and ibuprofen on renal function, we calculated urine flow rates and serum creatinine values daily for the first week of life. We tested all stools for the presence of occult blood and recorded abdominal girth and 736
number and volume of gastric residuals daily to evaluate feeding intolerance and identify necrotizing enterocolitis. Analysis of variance for repeated measures and unpaired t test were used for statistical analysis. The Sheffé test was used to compare all possible pairs of mean values within each treatment group. A P value of <.05 was considered to be statistically significant. Computer software used was SPSS for Microsoft Windows, version 6.0.
RESULTS There were no significant differences in birth weight, gestational age, amount of feeding, or postnatal age at the start of therapy (Table). All infants were receiving conventional mechanical ventilation, and there were no significant differences in fraction of inspired oxygen or mean airway pressure. Heart rate, mean arterial blood pressure, and arterial oxygen saturation were comparable at the beginning of the study in the 2 groups; no significant changes were observed at any time after treatment with either drug. Before treatment, we did not observe
any differences in mesenteric and renal Doppler PSV, MV, EDV, and RVR (Figs 1 and 2). After indomethacin administration, we found significant reductions in PSV, MV, and EDV at 30 minutes; mesenteric and renal BFV parameters did not return to pretreatment values by 120 minutes. RVR increased significantly at 30 minutes and decreased from 30 to 120 minutes without reaching pretreatment values. In contrast, after treatment with ibuprofen, we did not find significant decreases in PSV, MV, or EDV at 30 minutes; and mesenteric and renal BFV increased significantly from 30 to 120 minutes (except for mesenteric PSV values). RVR significantly increased at 30 minutes and returned to pretreatment values at 60 minutes. Mesenteric and renal BFV changes in PSV, MV, EDV, and RVR were significantly different between the 2 treatment groups. In the indomethacin treatment group, ductal closure was observed in 7 infants after the first dose of the drug and in 1 infant after the second dose. No reopening was observed. In the ibuprofen treatment group, ductal clo-
PEZZATI ET AL
THE JOURNAL OF PEDIATRICS VOLUME 135, NUMBER 6 sure occurred in 7 infants after the first dose of the drug and in 2 infants after the second dose. No reopening of the ductus was observed. Urine output and serum creatinine values were significantly affected by indomethacin; on the contrary, no changes were observed with ibuprofen treatment (Fig 3). In the indomethacin group urine output decreased significantly on the first, second, and third days after indomethacin administration to a minimal value of 1.7 mL/kg/h on the third day and increased again to pretreatment values by 7 days. In the ibuprofen group we observed a significant decrease in urine output after drug administration only during the first day. A significant difference in urine output between the 2 groups was observed on days 2 and 3 after treatment. In the indomethacin group serum creatinine values increased significantly on the first, second, and third days, whereas no significant difference was observed for the ibuprofen group. A significant difference in serum creatinine values between the 2 groups was seen on days 1, 2, 3, and 7. No significant difference in daily fluid intake was observed between the 2 groups. Diuretics were not used in either group during the first days of life. There was no necrotizing enterocolitis in either group.
DISCUSSION Indomethacin has been the drug of choice for the treatment of PDA, but significant reductions in cerebral, mesenteric, and renal perfusion have been reported.6-10 A continuous infusion of indomethacin over 24 hours minimized the reduction of cerebral perfusion.4 More recently, ibuprofen was used with the same efficacy to close the duct and was associated with fewer side effects.14,26,27 In comparison with indomethacin, ibuprofen did not reduce cerebral BFV in preterm human infants.12 Ibuprofen, in con-
trast to indomethacin, does not affect renal or intestinal hemodynamics,11,13,14 although these effects have not been evaluated by Doppler ultrasonography. The results of our Doppler sonographic study confirm that pharmacologic closure of the ductus arteriosus with ibuprofen did not significantly reduce mesenteric and renal perfusion. Because mean arterial blood pressure did not change, the reduction in mesenteric and renal BFV with indomethacin was a direct vasoconstrictive effect on the resistance vessels, as has been proposed for cerebral perfusion.12 The lack of effect on urine flow rate and serum creatinine values in the ibuprofen treatment group confirms the results of Van Overmeire et al.14 A similar trend was observed by the same authors in a subsequent and larger trial,28 even though differences were not statistically significant. Our findings suggest that ibuprofen does not strongly influence renal perfusion. This difference between the 2 groups may be due to the fact that indomethacin acts in part through mechanisms other than inhibition of prostaglandin synthesis13; another possibility is that both drugs inhibit the cyclooxygenase enzyme system in the neonatal kidneys to a different extent14 or that serum indomethacin concentrations remain high enough to influence both the ductus and renal function, whereas those of ibuprofen are sufficiently high to close the duct but lack the potential to impair renal function.14 We conclude that ibuprofen administration, when used to treat PDA in preterm infants, does not significantly reduce mesenteric and renal BFV.
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