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Mitchell Pediatrics 1997;100;954-957 DOI: 10.1542/peds.100.6.954
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://www.pediatrics.org/cgi/content/full/100/6/954
PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 1997 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.
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The final data included information on 83 915 children treated for febrile illnesses who were randomly assigned to receive suspensions of either acetaminophen (12 mg/kg) or ibuprofen in one of two dosages (5 or 10 mg/kg) and followed for 4 weeks. Brookline.) The Slone Epidemiology Unit. accepted May 12. respectively. as reflected by blood urea nitrogen and creatinine levels. and pneumonia was the most common discharge diagnosis. Post hoc power analyses were performed for both continuous and dichotomous variables comparing children assigned to treatment with acetaminophen to all children assigned to ibuprofen (ie. and the prevalence of an elevated creatinine was 14%. blood urea nitrogen. most hospitalizations were for acute infections or their complications. and 3. abstractions were performed blindly with respect to antipyretic assignment. respectively. Pediatrics 1997. creatinine. METHODS These data were obtained as part of the Boston University Fever Study. hospitalization rates did not vary according to antipyretic assignment. Massachusetts. Children with a febrile illness were enrolled from outpatient pediatric and family medicine practices and randomly assigned to receive either acetaminophen suspension or one of two dosages of ibuprofen suspension (5 mg/kg or 10 mg/kg) for fever control. nonsteroidal antiinflammatory drug. the study was a practitionerbased. 1371 Beacon St. Statistical Methods Mean admission BUN and creatinine levels were compared using analyses of covariance to control for the potential confounding effects of age. Copyright © 1997 by the American Academy of Pediatrics. RESULTS From the Slone Epidemiology Unit. Reprint requests to (S. PEDIATRICS (ISSN 0031 4005). ibuprofen 10 mg/kg (n ؍ 102). Randomized. or ibuprofen (10 mg/kg).8.9 mmol/L. 2010 . Brookline. both ibuprofen dosage groups were combined). is small and not significantly greater than that after acetaminophen use. was associated with short-term use of ibuprofen suspension for the control of fever in children. nonsteroidal antiinflammatory drugs. Boston University School of Medicine. MD ABSTRACT. BUN. and discharge diagnosis (comorbidity). NSAID. double-blind clinical trial designed to assess the safety of ibuprofen suspension when used to treat fever in children. respectively. Overall.L. sex. Mitchell. MD. and 88 children had been randomized to treatment with acetaminophen. The corresponding creatinine levels were 43. MA 02146. 6 December 1997 Downloaded from www. the results were not materially different. Boston University School of Medicine. The prevalence of a creatinine level >62 mol/L was 9. we sought to determine whether the risk of less severe renal impairment. 3.5 Renal function tests were performed at the discretion of the attending physician. Lesko. Among 83 children hospitalized with dehydration.Renal Function After Short-term Ibuprofen Use in Infants and Children Samuel M. and these groups were preserved throughout the analyses). blood urea nitrogen. The study protocol did not require laboratory measures of renal function to be systematically obtained for all study participants. 41. However. Patients were enrolled into the study from February 1991 through June 1993. of these. Descriptive characteristics of these children (including cause of fever at study enrollment) are shown in Table 1.5–7 Briefly. MPH. The children received a me- 954 PEDIATRICS Vol. The analyses were repeated excluding patients who had received none of the assigned medication (approximately 10% in each assignment group). Among hospitalized children. for each child hospitalized during follow-up. clinical trial. Results. 103. 795 (1%) of the study children were hospitalized in the 4-week follow-up period. we found that none of 55 785 children treated with ibuprofen for fever was hospitalized with renal failure. Although renal failure in children has been reported after ibuprofen use.5% overall and did not vary by antipyretic assignment. we obtained the hospital record and abstracted the admission BUN and creatinine levels (or the first value of each reported within 24 hours of admission). and 43 mol/L. 1997. ABBREVIATIONS. Conclusion. 97. these data suggest that for short-term use the risk of less severe renal impairment. Provided by Indonesia:AAP Sponsored on May 7.org. the methods and principal results of which have been previously described.5 In the present analysis.1. acetaminophen. 1997. and only the results of the intention-to-treat analysis are presented here. double-blind acetaminophen-controlled clinical trial. ibuprofen (5 mg/kg). admission BUN or creatinine levels were available for 288 (36%).1 but only rarely among children exposed to ibuprofen. School of Public Health. To test the hypothesis that short-term use of ibuprofen increases the risk of impaired renal function in children. Objective. as reflected by elevated blood urea nitrogen (BUN) and creatinine levels. renal function.M. the mean creatinine level was 44 mol/L. ibuprofen. neither measure varied by antipyretic assignment. Analysis These data were evaluated using an intention-to-treat analysis (ie. the three treatment groups were generally similar. Patients who did not have BUN and creatinine levels obtained within 24 hours of admission were excluded from this analysis. Study Design.2– 4 In a recently completed randomized clinical trial. Mean blood urea nitrogen levels on admission among children admitted to hospital and assigned ibuprofen 5 mg/kg (n ؍96). Between-group differences in the prevalences of an abnormal BUN or creatinine level were assessed using the 2 test.8 R enal failure has been reported after nonsteroidal antiinflammatory drug (NSAID) use in adults. 100 No. weight. participants were grouped according to the treatment assigned at study enrollment.100:954 –957.pediatrics. and acetaminophen 12 mg/kg (n ؍87) were 4. Received for publication Mar 25. and Allen A.
For example. sex. The prevalence of high creatinine levels did not vary significantly by antipyretic group when other creatinine reference values were used (eg. the number of doses received and duration did not vary by treatment group. weight. dian of 7 doses of study medication throughout a median duration of 2 days. and hematuria. % White African-American Latino Other Unknown Cause of fever*. renal blood flow is regulated by processes involving prostaglandins.3–33) 56 64 6.8 17 42 22 21 17 Ibuprofen. DISCUSSION Renal impairment in adult NSAID users occurs primarily among patients with preexisting renal disease or other conditions associated with low intravascular volume or low cardiac output. respectively. However. and the inhibition of prostaglandin synthesis by NSAIDs may result in reduced renal blood flow and glomerular filtration.1 17 43 24 24 19 Antipyretic Assignment Ibuprofen. The prevalence of BUN TABLE 2.1 mg/dL) in mean creatinine level or a 2. his discharge diagnosis was postinfectious glomerulonephritis. column totals may exceed 100%. 5 mg/kg (n ϭ 103) 22 (7–113) 11 (7. 5 mg/kg (n ϭ 103) % 43 28 16 25 7.1% and 9.5). 2010 ARTICLES 955 . Because patients may have more than one discharge diagnosis. months (5th to 95th percentile) Median weight.7–25) 50 58 9. neither measure varied significantly by treatment group after controlling for age. levels greater than 6.9 Under these conditions.7 6. as was true in the larger group.7 mg/dL) according to antipyretic assignment group are shown in Table 3.1. and discharge diagnosis ( P Ͼ . % Upper respiratory tract infection Otitis media Pharyngitis Pneumonia 29 (8–124) 13 (7.4 mmol/L (18 mg/dL) and creatinine levels greater than 62 mol/L (0.9 16 38 33 27 13 * Limited to illnesses reported among at least 10% of patients. Downloaded from www.4 mmol/L (18 mg/dL) and creatinine levels greater than 62 mol/L (0.2 7. Descriptive Characteristics of 288 Hospitalized Children With Admission BUN or Creatinine Data According to Antipyretic Assignment Characteristic Acetaminophen (n ϭ 97) Median age. edema.8 Ibuprofen.2 4. and the proportion of children with elevated levels did not vary by antipyretic assignment.7 mg/dL) were slightly higher among these children than among all hospitalized children. column totals may exceed 100%.5%. Admission BUN and creatinine values among the 108 children hospitalized with a concomitant diagnosis of dehydration are shown in Table 4. 10 mg/kg (n ϭ 88) 22 (6–105) 12 (6.7-fold increase in risk of a creatinine level greater than 62 mol/L among all children randomized to ibuprofen (ie.pediatrics. The mean BUN level was approximately 4 mmol/L and the mean creatinine level was 42 mol/L in each group. These data have adequate power to detect small increases in BUN or creatinine.8 7.TABLE 1. both dose groups combined) compared with those randomized to acetaminophen. The overall prevalences of BUN levels greater than 6. probably streptococcal. Acute renal failure after ibuprofen overdose and interstitial nephritis after ibuprofen used in Discharge Diagnoses Among 288 Hospitalized Children According to Antipyretic Assignment* Diagnosis Acetaminophen (n ϭ 97) % Antipyretic Assignment Ibuprofen. Provided by Indonesia:AAP Sponsored on May 7.8–27) 51 61 9. kg (5th to 95th percentile) Male.7 7. the data had 80% power to detect either a difference of 8 mol/L (0. One child randomized to receive acetaminophen was admitted with hypertension. Patients may have reported more than one illness.4 mmol/L (18 mg/dL) and creatinine values greater than 62 mol/L (0. 10 mg/kg (n ϭ 88) % 31 22 27 17 13 Dehydration Gastroenteritis Pneumonia Otitis media Asthma/bronchiolitis 38 27 16 15 15 * Limited to diagnoses reported among at least 10% of patients.1 5. Discharge diagnoses are shown in Table 2. neither mean level nor the prevalence of an elevated level of either BUN or creatinine varied significantly by antipyretic assignment.org.7mg/dL) were 8.5 Mean BUN and creatinine levels and the prevalence of BUN values greater than 6. 35 mol/L or 88 mol/L). % Race.
36) 43 5 (12) 44 (4. TABLE 4. mmol/L Total Number Number (%) Ͼ6.4) 24 3 (13) Total 106 15 (14) 83 12 (14) * Patients with unknown BUN (n ϭ 2) or creatinine (n ϭ 25) values were excluded from the respective analysis. Spontaneous (case) reports and observational (ie.10 It is unclear how this adult experience applies to children.4) 72 5 (7) BUN Mean (SEM†).1 (0. the most common indication for ibuprofen use in children.2 and episodes of acute flank pain and non-oliguric renal failure in adolescent girls after ibuprofen use.4 mmol/L Creatinine Mean (SEM†). Because of this confounding. the increases in mean BUN levels were not RENAL FUNCTIONING AFTER IBUPROFEN USE IN CHILDREN Downloaded from www. in one clinical trial involving 119 febrile children.13 Because ibuprofen was until recently available for use in children only by prescription. increases in BUN were observed after administration of a single dose of ibuprofen (5 to 10 mg/kg). who may be more or less susceptible to renal injury by NSAIDs. interstitial nephritis was documented on renal biopsy. A number of reports have linked ibuprofen use to renal complications in children.4) 26 3 (12) Antipyretic Assignment Ibuprofen. unrelated to ibuprofen use. which may be predictive of more serious renal failure.3.19) 102 6 (6) 43 (2.14 No differences were observed in creatinine levels and. None of the participants randomized to ibuprofen was hospitalized with renal failure (the observed risk was 0 per 55 785). congestive heart failure. 10 mg/kg 4. mmol/L Total number Number (%) Ͼ6.0 (0. when multiple testing was taken into account. they may be at greater risk because some degree of dehydration is likely to accompany fever. 2010 . nonrandomized) studies cannot provide valid estimates of risk when the choice of treatment is influenced by illness sever956 ity (ie. when confounding by indication occurs). Ibuprofen-treated children therefore may have been at greater risk of renal failure because of the severity of their underlying illness.5 However. neither prove causation (none of the affected children was rechallenged with ibuprofen) nor do they provide estimates of the rate at which renal failure occurs among otherwise healthy children receiving short-term treatment with ibuprofen. random).pediatrics.9 (0.2) 83 10 (12) Ibuprofen.4 mmol/L Creatinine Mean (SEM†).8 (0. 10 mg/kg 3.4 In the last of these. and dehydration may increase the likelihood of renal complications. this estimate does not allow one to assess the risk of lesser degrees of renal impairment.39) 36 7 (19) 45 (4. Provided by Indonesia:AAP Sponsored on May 7. † Standard error of the mean.12 Case reports. mol/L Total Number Number (%) Ͼ62 mol/L 4.4 per 100 000. children given this medication were likely to be more seriously ill than children treated with acetaminophen. However. an unbiased estimate of the risk of renal failure requires that the choice of antipyretic be independent of the severity of the underlying febrile illness (ie.5) 67 6 (9) * Patients with unknown BUN (n ϭ 3) or creatinine (n ϭ 66) values were excluded from the respective analysis.1) 33 6 (18) Ibuprofen.6 The experience of 55 785 children in the present report provides one such estimate of the risk of complete renal failure after ibuprofen use in children. † Standard error of the mean. Randomized clinical trials designed to test the efficacy of ibuprofen in children have typically been too small to detect even modest differences in the risk of mild renal impairment.5 (0. and three have described renal failure in children younger than 15 years of age after short-term treatment with ibuprofen in therapeutic doses.6.96) 87 6 (7) 41 (2. diuretic use.org. the authors describe the increases as being small and clinically unimportant.2– 4 These include acute renal failure with edema in a 10 year old after ibuprofen use for traumatic pain.TABLE 3. Conversely. Admission BUN and Creatinine Levels Among 108 Children Hospitalized With Dehydration According to Antipyretic Assignment* Test Acetaminophen BUN Mean (SEM†).9. Children may be at lower risk because they are less likely than adults to have other factors predisposing to acute renal disorders (eg. however.24) 96 11 (11) 43 (2.4 Renal failure has also been reported in a healthy two year old after an overdose with ibuprofen11 and in newborns after in utero exposure to NSAIDs (1 infant was exposed to ibuprofen). mol/L Total number Number (%) Ͼ62 mol/L 4. and chronic renal failure). clinical doses have also been described in patients without preexisting renal disease. and the upper bound of the 95% confidence interval around this estimate allows one to conclude that the true risk is likely to be no greater than 5.4 (0. Admission BUN and Creatinine Levels Among 288 Hospitalized Children According to Antipyretic Assignment* Test Acetaminophen Antipyretic Assignment Ibuprofen. 5 mg/kg 4.84) 27 3 (11) 44 (5. 5 mg/kg 3.
the diagnoses at enrollment reflect the wide spectrum of febrile illness seen among children in pediatric practice. Am J Kidney Dis. In a smaller multi-dose trial described in the same report. As might be expected. Can ibuprofen cause acute renal failure in a normal individual? A case of acute overdose. However.93:693. Luft FC. Lesko SM. Ellis D. 1984. for his advice and guidance. Burlington. We are especially grateful to the more than 1700 physicians/investigators without whose participation this study would not have been possible. CA: BMDP Statistical Software. Drug Invest. Bethesda. for statistical advice. 1993. Pediatric ibuprofen and leukopenia. N Engl J Med. William Gerson. Pennsylvania. Mitchell AA. otherwise healthy children. Los Angeles. Reversible renal failure associated with ibuprofen in a child: a case report. and because all study participants were seen by a physician. preexisting chronic renal. National Institute of Child Health and Human Development. 1991. MA. University of Illinois College of Medicine at Peoria. Buller GK. Pediatrics. Bernstein J. Children’s Hospital. An assessment of the safety of pediatric ibuprofen: a practitioner-based randomized clinical trial. Letter 8. 1994.310:563–572 2. 1993. Stoff JS. MD (chair). Pediatr Nephrol. Clive DM. those with severe dehydration [Ն10% of body weight]. Renal syndromes associated with nonsteroidal antiinflammatory drugs. Kauffman. Kelly MT. van Biljon G. Perazella MA. but they do suggest that the risk of acute renal complications after short-term use for fever reduction is small and cannot easily be differentiated from the risk among children given acetaminophen for the same indication. MD. Boston. MD. Gottlieb RP. nor can we estimate the relative risk of mild renal effects among children not hospitalized. Leichtner. it is possible that the children in this study are not representative of all patients seen by the participating physicians because these physicians may not have enrolled their sickest patients. 13:15–24 7. These data provide no information on the risk of renal impairment in children after long-term use of ibuprofen or among children ineligible for the clinical trial (eg. 1995.org. Kim J. FRCP(E). MD. Pediatr Emerg Care. it seems likely that clinically important episodes of renal impairment occurring among participants in the trial were not missed. Restaino I. Renal failure in the neonate associated with in utero exposure to non-steroidal antiinflammatory agents. Raval DS. Anthony R. Walson PD. McIntire SC. Neuroepidemiology Unit. Letter 5. Mary Joan Denisco. 1996. Children’s Hospital.11 As was the case for renal failure. Stolley PD. PhD. Kansas City. Children’s Hospital. who coordinated the data collection and supervised our study staff. Mann JFE. Mitchell AA. VT. JAMA. Feehan T. ACKNOWLEDGMENTS This work was supported by McNeil Consumer Products Company. Boston. Drug evaluation after marketing: a policy perspective. MA. Boston MA.6:48 –55 Downloaded from www. Goerig N. Mitchell AA. Because renal function tests were not performed on all participants. David P. Rubenstein RC. we cannot estimate the absolute incidence (rate/1000 courses of treatment) of minor. Youngberg G. These data do not exclude the possibility that ibuprofen may cause acute renal failure in some children. Lovejoy.275:986. McNeil Consumer Products Co. 1994. Lesko SM. and that those children at greatest risk for renal failure were hospitalized. Medical New Product Development. 1989. Director of Medical Research. Division of Gastroenterology and Nutrition. Ann Intern Med.statistically significant. 1995. or neoplastic disease). MD. By virtue of its size. 273:929 –933 6. MD. Harrington. Acute renal insufficiency in ibuprofen overdose. Children’s Mercy Hospital. Yaffe. SOLO Statistical System: Power Analysis.11:107–108 12. private practice.18: 600 – 602 11. Lesko SM.pediatrics. Jr. S Afr Med J. Verjee Z. Michael D. IL. Ibuprofen as an over-thecounter drug: is there a risk of renal injury? Clin Nephrol. MPH. Finkle WD. 1992 9. elevated BUN and creatinine levels were somewhat more common among children with a discharge diagnosis of dehydration. A unique complication of nonsteroidal antiinflammatory drug use. Pediatrics. Provided by Indonesia:AAP Sponsored on May 7.8:700 –704 13. MO. neither BUN nor creatinine levels increased significantly among children treated with ibuprofen (2. but there was no evidence of a difference in risk related to antipyretic assignment among these children. they were likely to have been more seriously ill than most children who are treated with ibuprofen obtained without a prescription. Drug Saf. MD. and undiagnosed impairment in renal function after ibuprofen use. When a randomized controlled trial is needed to assess drug safety: the case of paediatric ibuprofen. Shapiro S. The liaison to the Advisory Committee consists of: Sumner J. the randomized. Temple. Acute flank pain and reversible renal dysfunction associated with nonsteroidal antiinflammatory drug use. Grazarian M. We wish to thank our Advisory Committee for their valuable advice and guidance provided throughout the study: Ralph E. Safety of paracetamol and ibuprofen in febrile children. PharmD (McNeil Consumer Products Co).39:1– 6 10. Edge JH. double-blind design of the present study permits an unbiased estimation of the risk of mild degrees of renal impairment (as reflected by elevated serum BUN and creatinine levels) after short-term ibuprofen use for fever in relatively unselected. and Samuel Shapiro. PhD. Brune K. We also wish to thank Richard Vezina. Korberly. Shepard FM.76:34 –35 3.90: 257–261 14. Kaplan BS. for technical support. Johnson D. Peoria. Wattad A. this study has power adequate to detect small differences in mean creatinine level (8 mol/L) and can effectively rule out a 3-fold or greater relative risk of an elevated creatinine level among ibuprofen-treated children compared with those treated with acetaminophen. Further. MB. Fort Washington.92:459 – 460 4. Hayes JR. However. Slone D. 1979. MD. 1993. 1995. Miettinen OS. Bailie. JAMA.5 to 10 mg/kg/dose). and Barbara H. MD. 2010 ARTICLES 957 . Medical Affairs. Gartner JC. REFERENCES 1. PharmD. Alan M. transient. Gilboa N. and Frederick H. Alan Leviton. Hintze JL. endocrine.
org/cgi/collection/therapeutics_and_toxico logy Information about reproducing this article in parts (figures.954 Updated Information & Services References including high-resolution figures.shtml Information about ordering reprints can be found online: http://www. can be found at: http://www.org. 2010 . Mitchell Pediatrics 1997. along with others on similar topics.Renal Function After Short-term Ibuprofen Use in Infants and Children Samuel M.pediatrics.100.org/cgi/content/full/100/6/954 This article cites 12 articles. appears in the following collection(s): Therapeutics & Toxicology http://www.pediatrics. tables) or in its entirety can be found online at: http://www.pediatrics.pediatrics. Lesko and Allen A. Provided by Indonesia:AAP Sponsored on May 7.1542/peds.pediatrics.100.org/misc/reprints.org/misc/Permissions.pediatrics. 4 of which you can access for free at: http://www.6.shtml Citations Subspecialty Collections Permissions & Licensing Reprints Downloaded from www.org/cgi/content/full/100/6/954#otherarticle s This article.org/cgi/content/full/100/6/954#BIBL This article has been cited by 4 HighWire-hosted articles: http://www.pediatrics.954-957 DOI: 10.
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