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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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MD ABSTRACT.L. MPH. was associated with short-term use of ibuprofen suspension for the control of fever in children. accepted May 12. Statistical Methods Mean admission BUN and creatinine levels were compared using analyses of covariance to control for the potential confounding effects of age. and discharge diagnosis (comorbidity). 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 Allen A. Analysis These data were evaluated using an intention-to-treat analysis (ie. 3. most hospitalizations were for acute infections or their complications. ibuprofen. PEDIATRICS (ISSN 0031 4005). admission BUN or creatinine levels were available for 288 (36%). Among hospitalized children. Patients who did not have BUN and creatinine levels obtained within 24 hours of admission were excluded from this analysis. of these. renal function. these data suggest that for short-term use the risk of less severe renal impairment. participants were grouped according to the treatment assigned at study enrollment.5% overall and did not vary by antipyretic assignment. 1997. The children received a me- 954 PEDIATRICS Vol. Overall. respectively. abstractions were performed blindly with respect to antipyretic assignment. Mean blood urea nitrogen levels on admission among children admitted to hospital and assigned ibuprofen 5 mg/kg (n ؍96). 795 (1%) of the study children were hospitalized in the 4-week follow-up period. Provided by Indonesia:AAP Sponsored on May 7.) The Slone Epidemiology Unit.5–7 Briefly. Brookline. The study protocol did not require laboratory measures of renal function to be systematically obtained for all study participants. 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. Between-group differences in the prevalences of an abnormal BUN or creatinine level were assessed using the 2 test.5 In the present analysis. the methods and principal results of which have been previously described. and these groups were preserved throughout the analyses). 100 No.2– 4 In a recently completed randomized clinical trial. The corresponding creatinine levels were 43. as reflected by elevated blood urea nitrogen (BUN) and creatinine levels.1 but only rarely among children exposed to ibuprofen. ibuprofen 10 mg/kg (n ؍ 102). Mitchell.9 mmol/L. for each child hospitalized during follow-up. ABBREVIATIONS. Pediatrics 1997. However. 2010 . MA 02146. acetaminophen. Received for publication Mar 25.pediatrics. 1371 Beacon St. Objective. BUN. 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. Study Design. and the prevalence of an elevated creatinine was 14%. Randomized. Among 83 children hospitalized with dehydration. 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). Descriptive characteristics of these children (including cause of fever at study enrollment) are shown in Table 1. the results were not materially different. NSAID. nonsteroidal antiinflammatory drug. MD. Lesko. double-blind acetaminophen-controlled clinical trial. RESULTS From the Slone Epidemiology Unit. Massachusetts. weight. To test the hypothesis that short-term use of ibuprofen increases the risk of impaired renal function in children. School of Public Health. we sought to determine whether the risk of less severe renal impairment. 6 December 1997 Downloaded from www. both ibuprofen dosage groups were combined). The prevalence of a creatinine level >62 mol/L was 9. ibuprofen (5 mg/kg). we found that none of 55 785 children treated with ibuprofen for fever was hospitalized with renal failure. the mean creatinine level was 44 mol/L. 103. and acetaminophen 12 mg/kg (n ؍87) were 4.8 R enal failure has been reported after nonsteroidal antiinflammatory drug (NSAID) use in adults. as reflected by blood urea nitrogen and creatinine levels. Boston University School of Medicine. Although renal failure in children has been reported after ibuprofen use. respectively. and 88 children had been randomized to treatment with acetaminophen. Results. or ibuprofen (10 mg/kg).M. the study was a practitionerbased. and pneumonia was the most common discharge diagnosis. and 3. Conclusion.org. and only the results of the intention-to-treat analysis are presented here. is small and not significantly greater than that after acetaminophen use. respectively. neither measure varied by antipyretic assignment. 97. Boston University School of Medicine.8. the three treatment groups were generally similar. nonsteroidal antiinflammatory drugs. blood urea nitrogen. METHODS These data were obtained as part of the Boston University Fever Study. double-blind clinical trial designed to assess the safety of ibuprofen suspension when used to treat fever in children. clinical trial.1.Renal Function After Short-term Ibuprofen Use in Infants and Children Samuel M. hospitalization rates did not vary according to antipyretic assignment. blood urea nitrogen. Reprint requests to (S.100:954 –957. Brookline. The analyses were repeated excluding patients who had received none of the assigned medication (approximately 10% in each assignment group).5 Renal function tests were performed at the discretion of the attending physician. Patients were enrolled into the study from February 1991 through June 1993. and 43 mol/L. 1997. creatinine. Copyright © 1997 by the American Academy of Pediatrics. 41. sex.
column totals may exceed 100%. 2010 ARTICLES 955 .5).1 17 43 24 24 19 Antipyretic Assignment Ibuprofen. and the inhibition of prostaglandin synthesis by NSAIDs may result in reduced renal blood flow and glomerular filtration. sex. 5 mg/kg (n ϭ 103) 22 (7–113) 11 (7. The mean BUN level was approximately 4 mmol/L and the mean creatinine level was 42 mol/L in each group. the data had 80% power to detect either a difference of 8 mol/L (0. column totals may exceed 100%.4 mmol/L (18 mg/dL) and creatinine values greater than 62 mol/L (0. kg (5th to 95th percentile) Male. respectively.5%.1 mg/dL) in mean creatinine level or a 2. The prevalence of BUN TABLE 2. The prevalence of high creatinine levels did not vary significantly by antipyretic group when other creatinine reference values were used (eg. For example.3–33) 56 64 6. % Upper respiratory tract infection Otitis media Pharyngitis Pneumonia 29 (8–124) 13 (7.1% and 9. % White African-American Latino Other Unknown Cause of fever*. Patients may have reported more than one illness. months (5th to 95th percentile) Median weight.7 6.TABLE 1. Provided by Indonesia:AAP Sponsored on May 7. and the proportion of children with elevated levels did not vary by antipyretic assignment. The overall prevalences of BUN levels greater than 6.7mg/dL) were 8.1 5.pediatrics. probably streptococcal. Downloaded from www.8 17 42 22 21 17 Ibuprofen. edema.7 mg/dL) were slightly higher among these children than among all hospitalized children.7 mg/dL) according to antipyretic assignment group are shown in Table 3. 35 mol/L or 88 mol/L). as was true in the larger group.7-fold increase in risk of a creatinine level greater than 62 mol/L among all children randomized to ibuprofen (ie. Discharge diagnoses are shown in Table 2. and hematuria. 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. and discharge diagnosis ( P Ͼ .org. One child randomized to receive acetaminophen was admitted with hypertension. neither measure varied significantly by treatment group after controlling for age.9 Under these conditions. levels greater than 6. Because patients may have more than one discharge diagnosis. 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. 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.7 7.4 mmol/L (18 mg/dL) and creatinine levels greater than 62 mol/L (0.1.2 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. both dose groups combined) compared with those randomized to acetaminophen. weight. renal blood flow is regulated by processes involving prostaglandins.5 Mean BUN and creatinine levels and the prevalence of BUN values greater than 6. 5 mg/kg (n ϭ 103) % 43 28 16 25 7. Descriptive Characteristics of 288 Hospitalized Children With Admission BUN or Creatinine Data According to Antipyretic Assignment Characteristic Acetaminophen (n ϭ 97) Median age. neither mean level nor the prevalence of an elevated level of either BUN or creatinine varied significantly by antipyretic assignment. These data have adequate power to detect small increases in BUN or creatinine. the number of doses received and duration did not vary by treatment group. However. 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.8 Ibuprofen.8 7. % Race.2 4. his discharge diagnosis was postinfectious glomerulonephritis. dian of 7 doses of study medication throughout a median duration of 2 days.7–25) 50 58 9.8–27) 51 61 9.
Children may be at lower risk because they are less likely than adults to have other factors predisposing to acute renal disorders (eg.4) 72 5 (7) BUN Mean (SEM†). the increases in mean BUN levels were not RENAL FUNCTIONING AFTER IBUPROFEN USE IN CHILDREN Downloaded from www. and chronic renal failure). diuretic use. this estimate does not allow one to assess the risk of lesser degrees of renal impairment. mmol/L Total number Number (%) Ͼ6. 10 mg/kg 4. 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.TABLE 3.14 No differences were observed in creatinine levels and. Admission BUN and Creatinine Levels Among 288 Hospitalized Children According to Antipyretic Assignment* Test Acetaminophen Antipyretic Assignment Ibuprofen.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). Ibuprofen-treated children therefore may have been at greater risk of renal failure because of the severity of their underlying illness.36) 43 5 (12) 44 (4. 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 mg/kg 3. † Standard error of the mean. 10 mg/kg 3.5 (0.8 (0.9 (0. 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. children given this medication were likely to be more seriously ill than children treated with acetaminophen.4) 26 3 (12) Antipyretic Assignment 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.4 per 100 000.2) 83 10 (12) Ibuprofen. Because of this confounding. and dehydration may increase the likelihood of renal complications.13 Because ibuprofen was until recently available for use in children only by prescription.4 In the last of these. Provided by Indonesia:AAP Sponsored on May 7.1) 33 6 (18) Ibuprofen. which may be predictive of more serious renal failure.0 (0. Spontaneous (case) reports and observational (ie.24) 96 11 (11) 43 (2.4 mmol/L Creatinine Mean (SEM†).19) 102 6 (6) 43 (2.1 (0. in one clinical trial involving 119 febrile children. and three have described renal failure in children younger than 15 years of age after short-term treatment with ibuprofen in therapeutic doses. mmol/L Total Number Number (%) Ͼ6. 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. mol/L Total Number Number (%) Ͼ62 mol/L 4.org.pediatrics. the most common indication for ibuprofen use in children. Admission BUN and Creatinine Levels Among 108 Children Hospitalized With Dehydration According to Antipyretic Assignment* Test Acetaminophen BUN Mean (SEM†). who may be more or less susceptible to renal injury by NSAIDs. however.4 (0.5) 67 6 (9) * Patients with unknown BUN (n ϭ 3) or creatinine (n ϭ 66) values were excluded from the respective analysis.39) 36 7 (19) 45 (4. nonrandomized) studies cannot provide valid estimates of risk when the choice of treatment is influenced by illness sever956 ity (ie. increases in BUN were observed after administration of a single dose of ibuprofen (5 to 10 mg/kg). 2010 . when multiple testing was taken into account.2 and episodes of acute flank pain and non-oliguric renal failure in adolescent girls after ibuprofen use.84) 27 3 (11) 44 (5. clinical doses have also been described in patients without preexisting renal disease. Conversely. † Standard error of the mean.96) 87 6 (7) 41 (2. A number of reports have linked ibuprofen use to renal complications in children. TABLE 4. 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. they may be at greater risk because some degree of dehydration is likely to accompany fever.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. However.3. None of the participants randomized to ibuprofen was hospitalized with renal failure (the observed risk was 0 per 55 785).10 It is unclear how this adult experience applies to children.9.12 Case reports. when confounding by indication occurs).6. 5 mg/kg 4. congestive heart failure.5 However. interstitial nephritis was documented on renal biopsy. unrelated to ibuprofen use. random). mol/L Total number Number (%) Ͼ62 mol/L 4.4 mmol/L Creatinine Mean (SEM†).
1991. Harrington. Children’s Hospital. S Afr Med J. Mitchell AA. Lesko SM. William Gerson. Pediatrics. Bethesda. 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. 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. MA. MD. 2010 ARTICLES 957 . Edge JH. Can ibuprofen cause acute renal failure in a normal individual? A case of acute overdose. van Biljon G. Medical New Product Development. Kaplan BS. Director of Medical Research.8:700 –704 13.275:986. Raval DS. By virtue of its size. 1979.pediatrics. 1989. those with severe dehydration [Ն10% of body weight]. transient. Gartner JC. Hintze JL. PhD.18: 600 – 602 11. We are especially grateful to the more than 1700 physicians/investigators without whose participation this study would not have been possible. MPH. Medical Affairs.statistically significant.11:107–108 12. Drug evaluation after marketing: a policy perspective. Children’s Hospital. A unique complication of nonsteroidal antiinflammatory drug use. Acute flank pain and reversible renal dysfunction associated with nonsteroidal antiinflammatory drug use. Finkle WD. Drug Invest.39:1– 6 10. MD. Michael D. Walson PD. 1995. Anthony R. Kim J. Korberly. for technical support. Lesko SM.93:693. VT.90: 257–261 14. 1994. and because all study participants were seen by a physician. 13:15–24 7. ACKNOWLEDGMENTS This work was supported by McNeil Consumer Products Company. endocrine. and Barbara H. As might be expected. Letter 5. Burlington. McNeil Consumer Products Co. elevated BUN and creatinine levels were somewhat more common among children with a discharge diagnosis of dehydration. Peoria. Los Angeles. Boston. Ann Intern Med. SOLO Statistical System: Power Analysis. Drug Saf. An assessment of the safety of pediatric ibuprofen: a practitioner-based randomized clinical trial. Am J Kidney Dis. MD. Neuroepidemiology Unit. 1995. 1993. Lesko SM. Stoff JS.92:459 – 460 4. 1992 9. otherwise healthy children. Further. Children’s Hospital. but there was no evidence of a difference in risk related to antipyretic assignment among these children. 1995. Alan M. Pediatric ibuprofen and leukopenia. Jr. Provided by Indonesia:AAP Sponsored on May 7.org. MD. Temple.76:34 –35 3. 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. JAMA.11 As was the case for renal failure. Bailie. it seems likely that clinically important episodes of renal impairment occurring among participants in the trial were not missed. Letter 8. Renal syndromes associated with nonsteroidal antiinflammatory drugs. Shepard FM. PhD. Mary Joan Denisco. or neoplastic disease). neither BUN nor creatinine levels increased significantly among children treated with ibuprofen (2. N Engl J Med. Renal failure in the neonate associated with in utero exposure to non-steroidal antiinflammatory agents. Goerig N.310:563–572 2. IL. Kansas City. Pennsylvania. We also wish to thank Richard Vezina. PharmD. MD. Ibuprofen as an over-thecounter drug: is there a risk of renal injury? Clin Nephrol. and that those children at greatest risk for renal failure were hospitalized. 273:929 –933 6. Johnson D. However. Kelly MT. Stolley PD. Miettinen OS. 1994. JAMA. Luft FC. Because renal function tests were not performed on all participants. McIntire SC. the diagnoses at enrollment reflect the wide spectrum of febrile illness seen among children in pediatric practice. Grazarian M. Division of Gastroenterology and Nutrition. Feehan T. MD. and Samuel Shapiro. Bernstein J. Reversible renal failure associated with ibuprofen in a child: a case report. and undiagnosed impairment in renal function after ibuprofen use. and Frederick H. Kauffman. We wish to thank our Advisory Committee for their valuable advice and guidance provided throughout the study: Ralph E. Wattad A. we cannot estimate the absolute incidence (rate/1000 courses of treatment) of minor. FRCP(E). The liaison to the Advisory Committee consists of: Sumner J. 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. Clive DM. Rubenstein RC. David P. Leichtner. Restaino I. Gottlieb RP. PharmD (McNeil Consumer Products Co). Boston. Shapiro S. Buller GK. Slone D. Yaffe. preexisting chronic renal. Mitchell AA. MO. 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. Hayes JR. they were likely to have been more seriously ill than most children who are treated with ibuprofen obtained without a prescription. Brune K. Pediatrics. Ellis D. 1984. CA: BMDP Statistical Software. MD. MD (chair). MA. who coordinated the data collection and supervised our study staff. 1993. Safety of paracetamol and ibuprofen in febrile children. Pediatr Nephrol. for his advice and guidance. MB. However. nor can we estimate the relative risk of mild renal effects among children not hospitalized. Fort Washington. When a randomized controlled trial is needed to assess drug safety: the case of paediatric ibuprofen. Verjee Z. Gilboa N. National Institute of Child Health and Human Development. private practice. Boston MA. Mitchell AA. 1996. Mann JFE. 1993. Youngberg G. Perazella MA. Children’s Mercy Hospital. University of Illinois College of Medicine at Peoria. for statistical advice. REFERENCES 1. the randomized. Acute renal insufficiency in ibuprofen overdose. In a smaller multi-dose trial described in the same report. Pediatr Emerg Care. MD. Alan Leviton. These data do not exclude the possibility that ibuprofen may cause acute renal failure in some children. Lovejoy.6:48 –55 Downloaded from www.5 to 10 mg/kg/dose).
shtml Information about ordering reprints can be found online: http://www.100. can be found at: http://www.pediatrics.org/misc/reprints. Lesko and Allen A.100.org. Provided by Indonesia:AAP Sponsored on May 7.1542/peds. tables) or in its entirety can be found online at: http://www. 4 of which you can access for free at: http://www.pediatrics.org/cgi/collection/therapeutics_and_toxico logy Information about reproducing this article in parts (figures.shtml Citations Subspecialty Collections Permissions & Licensing Reprints Downloaded from www.pediatrics.6.org/cgi/content/full/100/6/954#BIBL This article has been cited by 4 HighWire-hosted articles: http://www.954-957 DOI: 10.pediatrics.pediatrics.954 Updated Information & Services References including high-resolution figures.org/cgi/content/full/100/6/954#otherarticle s This article.Renal Function After Short-term Ibuprofen Use in Infants and Children Samuel M. appears in the following collection(s): Therapeutics & Toxicology http://www.pediatrics.org/cgi/content/full/100/6/954 This article cites 12 articles.pediatrics. 2010 . Mitchell Pediatrics 1997.org/misc/Permissions. along with others on similar topics.
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