Renal Function After Short-term Ibuprofen Use in Infants and Children Samuel M. Lesko and Allen A.

Mitchell Pediatrics 1997;100;954-957 DOI: 10.1542/peds.100.6.954

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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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5 In the present analysis.8 R enal failure has been reported after nonsteroidal antiinflammatory drug (NSAID) use in adults. Mean blood urea nitrogen levels on admission among children admitted to hospital and assigned ibuprofen 5 mg/kg (n ‫ ؍‬96). blood urea nitrogen. and these groups were preserved throughout the analyses). participants were grouped according to the treatment assigned at study enrollment. Provided by Indonesia:AAP Sponsored on May 7. 41. Study Design. Conclusion. accepted May 12. 2010 . MD. Overall. 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. and discharge diagnosis (comorbidity). both ibuprofen dosage groups were combined). 103. respectively. or ibuprofen (10 mg/kg). double-blind clinical trial designed to assess the safety of ibuprofen suspension when used to treat fever in children. 1997. clinical trial. weight. double-blind acetaminophen-controlled clinical trial.1. Mitchell. Reprint requests to (S.org. ibuprofen.pediatrics. 3. 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).5% overall and did not vary by antipyretic assignment. and only the results of the intention-to-treat analysis are presented here.8. Between-group differences in the prevalences of an abnormal BUN or creatinine level were assessed using the ␹2 test. is small and not significantly greater than that after acetaminophen use. renal function. NSAID. METHODS These data were obtained as part of the Boston University Fever Study. Received for publication Mar 25. RESULTS From the Slone Epidemiology Unit. respectively. Brookline. 97. creatinine. Objective. Boston University School of Medicine. Brookline. Randomized. as reflected by blood urea nitrogen and creatinine levels. To test the hypothesis that short-term use of ibuprofen increases the risk of impaired renal function in children.100:954 –957. blood urea nitrogen. Patients were enrolled into the study from February 1991 through June 1993. and 88 children had been randomized to treatment with acetaminophen.L. ABBREVIATIONS. Descriptive characteristics of these children (including cause of fever at study enrollment) are shown in Table 1.Renal Function After Short-term Ibuprofen Use in Infants and Children Samuel M.5 Renal function tests were performed at the discretion of the attending physician. we found that none of 55 785 children treated with ibuprofen for fever was hospitalized with renal failure. Results. the mean creatinine level was 44 ␮mol/L. PEDIATRICS (ISSN 0031 4005). nonsteroidal antiinflammatory drug. as reflected by elevated blood urea nitrogen (BUN) and creatinine levels. the results were not materially different. Among 83 children hospitalized with dehydration. we sought to determine whether the risk of less severe renal impairment. MPH. MA 02146. Analysis These data were evaluated using an intention-to-treat analysis (ie. these data suggest that for short-term use the risk of less severe renal impairment. and Allen A. Boston University School of Medicine. 6 December 1997 Downloaded from www. The children received a me- 954 PEDIATRICS Vol. ibuprofen (5 mg/kg). nonsteroidal antiinflammatory drugs. of these.1 but only rarely among children exposed to ibuprofen. Among hospitalized children. and the prevalence of an elevated creatinine was 14%. Although renal failure in children has been reported after ibuprofen use. abstractions were performed blindly with respect to antipyretic assignment. Massachusetts. sex.2– 4 In a recently completed randomized clinical trial. neither measure varied by antipyretic assignment. and pneumonia was the most common discharge diagnosis. MD ABSTRACT. 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. BUN.) The Slone Epidemiology Unit. Patients who did not have BUN and creatinine levels obtained within 24 hours of admission were excluded from this analysis.9 mmol/L. 100 No. However. and 3. and 43 ␮mol/L. most hospitalizations were for acute infections or their complications.5–7 Briefly. admission BUN or creatinine levels were available for 288 (36%). The analyses were repeated excluding patients who had received none of the assigned medication (approximately 10% in each assignment group). acetaminophen. 1997. 795 (1%) of the study children were hospitalized in the 4-week follow-up period. for each child hospitalized during follow-up. Statistical Methods Mean admission BUN and creatinine levels were compared using analyses of covariance to control for the potential confounding effects of age. and acetaminophen 12 mg/kg (n ‫ ؍‬87) were 4. The study protocol did not require laboratory measures of renal function to be systematically obtained for all study participants. 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. hospitalization rates did not vary according to antipyretic assignment. Lesko. the methods and principal results of which have been previously described.M. School of Public Health. was associated with short-term use of ibuprofen suspension for the control of fever in children. the three treatment groups were generally similar. respectively. ibuprofen 10 mg/kg (n ‫؍‬ 102). Copyright © 1997 by the American Academy of Pediatrics. the study was a practitionerbased. The prevalence of a creatinine level >62 ␮mol/L was 9. 1371 Beacon St. Pediatrics 1997. The corresponding creatinine levels were 43.

probably streptococcal.4 mmol/L (18 mg/dL) and creatinine values greater than 62 ␮mol/L (0. Descriptive Characteristics of 288 Hospitalized Children With Admission BUN or Creatinine Data According to Antipyretic Assignment Characteristic Acetaminophen (n ϭ 97) Median age.8 17 42 22 21 17 Ibuprofen. 10 mg/kg (n ϭ 88) 22 (6–105) 12 (6. The prevalence of high creatinine levels did not vary significantly by antipyretic group when other creatinine reference values were used (eg. The overall prevalences of BUN levels greater than 6.8–27) 51 61 9. Admission BUN and creatinine values among the 108 children hospitalized with a concomitant diagnosis of dehydration are shown in Table 4.4 mmol/L (18 mg/dL) and creatinine levels greater than 62 ␮mol/L (0. % Upper respiratory tract infection Otitis media Pharyngitis Pneumonia 29 (8–124) 13 (7.1 5. Patients may have reported more than one illness. For example.4 mmol/L (18 mg/dL) and creatinine levels greater than 62 ␮mol/L (0. as was true in the larger group. Provided by Indonesia:AAP Sponsored on May 7. his discharge diagnosis was postinfectious glomerulonephritis.5). 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.1% and 9. months (5th to 95th percentile) Median weight. 35 ␮mol/L or 88 ␮mol/L). 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. neither mean level nor the prevalence of an elevated level of either BUN or creatinine varied significantly by antipyretic assignment. 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. respectively. sex. column totals may exceed 100%. renal blood flow is regulated by processes involving prostaglandins. and discharge diagnosis ( P Ͼ . and the proportion of children with elevated levels did not vary by antipyretic assignment.7 mg/dL) according to antipyretic assignment group are shown in Table 3.2 7.7mg/dL) were 8. and the inhibition of prostaglandin synthesis by NSAIDs may result in reduced renal blood flow and glomerular filtration.1 mg/dL) in mean creatinine level or a 2.7–25) 50 58 9.8 Ibuprofen.7-fold increase in risk of a creatinine level greater than 62 ␮mol/L among all children randomized to ibuprofen (ie.7 mg/dL) were slightly higher among these children than among all hospitalized children. The prevalence of BUN TABLE 2. levels greater than 6.8 7. edema. Downloaded from www. the data had 80% power to detect either a difference of 8 ␮mol/L (0. 2010 ARTICLES 955 . Discharge diagnoses are shown in Table 2.9 Under these conditions.org. both dose groups combined) compared with those randomized to acetaminophen.1.TABLE 1.9 16 38 33 27 13 * Limited to illnesses reported among at least 10% of patients.7 7.7 6.5%. % Race. % White African-American Latino Other Unknown Cause of fever*. One child randomized to receive acetaminophen was admitted with hypertension. 5 mg/kg (n ϭ 103) % 43 28 16 25 7.5 Mean BUN and creatinine levels and the prevalence of BUN values greater than 6.2 4. neither measure varied significantly by treatment group after controlling for age. 5 mg/kg (n ϭ 103) 22 (7–113) 11 (7.3–33) 56 64 6. the number of doses received and duration did not vary by treatment group. column totals may exceed 100%. kg (5th to 95th percentile) Male. However. These data have adequate power to detect small increases in BUN or creatinine. weight. and hematuria. dian of 7 doses of study medication throughout a median duration of 2 days.1 17 43 24 24 19 Antipyretic Assignment Ibuprofen.pediatrics. The mean BUN level was approximately 4 mmol/L and the mean creatinine level was 42 ␮mol/L in each group. Because patients may have more than one discharge diagnosis.

interstitial nephritis was documented on renal biopsy.39) 36 7 (19) 45 (4. However. 5 mg/kg 3.24) 96 11 (11) 43 (2.6.2 and episodes of acute flank pain and non-oliguric renal failure in adolescent girls after ibuprofen use. mmol/L Total Number Number (%) Ͼ6. children given this medication were likely to be more seriously ill than children treated with acetaminophen. and chronic renal failure). increases in BUN were observed after administration of a single dose of ibuprofen (5 to 10 mg/kg). 2010 .4 mmol/L Creatinine Mean (SEM†). 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. 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. 5 mg/kg 4.14 No differences were observed in creatinine levels and.4 per 100 000.96) 87 6 (7) 41 (2. nonrandomized) studies cannot provide valid estimates of risk when the choice of treatment is influenced by illness sever956 ity (ie. † Standard error of the mean.13 Because ibuprofen was until recently available for use in children only by prescription.0 (0. mmol/L Total number Number (%) Ͼ6. unrelated to ibuprofen use. in one clinical trial involving 119 febrile children. Admission BUN and Creatinine Levels Among 288 Hospitalized Children According to Antipyretic Assignment* Test Acetaminophen Antipyretic Assignment Ibuprofen. random). and three have described renal failure in children younger than 15 years of age after short-term treatment with ibuprofen in therapeutic doses. † Standard error of the mean. this estimate does not allow one to assess the risk of lesser degrees of renal impairment.4) 72 5 (7) BUN Mean (SEM†). Ibuprofen-treated children therefore may have been at greater risk of renal failure because of the severity of their underlying illness.5) 67 6 (9) * Patients with unknown BUN (n ϭ 3) or creatinine (n ϭ 66) values were excluded from the respective analysis.1 (0. diuretic use.9 (0. Because of this confounding.12 Case reports. 10 mg/kg 4. Admission BUN and Creatinine Levels Among 108 Children Hospitalized With Dehydration According to Antipyretic Assignment* Test Acetaminophen BUN Mean (SEM†). Children may be at lower risk because they are less likely than adults to have other factors predisposing to acute renal disorders (eg.2) 83 10 (12) Ibuprofen. Conversely.3.9. TABLE 4.4) 26 3 (12) Antipyretic Assignment Ibuprofen. the most common indication for ibuprofen use in children.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 4.10 It is unclear how this adult experience applies to children.84) 27 3 (11) 44 (5. when multiple testing was taken into account. congestive heart failure. when confounding by indication occurs).5 (0. ␮mol/L Total Number Number (%) Ͼ62 ␮mol/L 4. Spontaneous (case) reports and observational (ie. Provided by Indonesia:AAP Sponsored on May 7. and dehydration may increase the likelihood of renal complications.pediatrics. None of the participants randomized to ibuprofen was hospitalized with renal failure (the observed risk was 0 per 55 785). however.8 (0. which may be predictive of more serious renal failure.1) 33 6 (18) Ibuprofen. 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.5 However.4 In the last of these. the increases in mean BUN levels were not RENAL FUNCTIONING AFTER IBUPROFEN USE IN CHILDREN Downloaded from www.36) 43 5 (12) 44 (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.19) 102 6 (6) 43 (2. 10 mg/kg 3.TABLE 3. they may be at greater risk because some degree of dehydration is likely to accompany fever.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).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.org. who may be more or less susceptible to renal injury by NSAIDs.4 mmol/L Creatinine Mean (SEM†).4 (0. A number of reports have linked ibuprofen use to renal complications in children. the authors describe the increases as being small and clinically unimportant.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. clinical doses have also been described in patients without preexisting renal disease.

Youngberg G. MD. Harrington. Anthony R. Shapiro S. those with severe dehydration [Ն10% of body weight]. Michael D. Division of Gastroenterology and Nutrition. 1994. 1979. nor can we estimate the relative risk of mild renal effects among children not hospitalized. and Samuel Shapiro. PharmD. Jr. Pediatr Nephrol. Grazarian M. VT. and Frederick H. Temple.275:986. MB. who coordinated the data collection and supervised our study staff. Renal syndromes associated with nonsteroidal antiinflammatory drugs.6:48 –55 Downloaded from www. 13:15–24 7. 1996. Provided by Indonesia:AAP Sponsored on May 7. MD.39:1– 6 10. or neoplastic disease). 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. Burlington. Kim J. Children’s Hospital. We wish to thank our Advisory Committee for their valuable advice and guidance provided throughout the study: Ralph E.pediatrics. Brune K. MD. PhD. MPH. Alan M. By virtue of its size. and Barbara H. Korberly. Johnson D. Ellis D. but there was no evidence of a difference in risk related to antipyretic assignment among these children. Mitchell AA. As might be expected. An assessment of the safety of pediatric ibuprofen: a practitioner-based randomized clinical trial. McNeil Consumer Products Co. Renal failure in the neonate associated with in utero exposure to non-steroidal antiinflammatory agents. Bernstein J. for technical support. University of Illinois College of Medicine at Peoria. FRCP(E). Medical Affairs. elevated BUN and creatinine levels were somewhat more common among children with a discharge diagnosis of dehydration. Further. MD. JAMA. Feehan T. 2010 ARTICLES 957 . and because all study participants were seen by a physician. McIntire SC. Letter 5.310:563–572 2. Bailie. Drug Saf. Buller GK. Children’s Mercy Hospital. for statistical advice. MD. and undiagnosed impairment in renal function after ibuprofen use. endocrine. Slone D. Kelly MT. Ibuprofen as an over-thecounter drug: is there a risk of renal injury? Clin Nephrol. When a randomized controlled trial is needed to assess drug safety: the case of paediatric ibuprofen. Lesko SM.18: 600 – 602 11. Finkle WD. However. Stolley PD. Drug Invest. Pennsylvania. MD. 1993. Perazella MA. Luft FC. 1995.90: 257–261 14. Pediatrics. 1995. 1984. A unique complication of nonsteroidal antiinflammatory drug use. The liaison to the Advisory Committee consists of: Sumner J. Children’s Hospital. Miettinen OS. Goerig N. MA. Boston. S Afr Med J. Lesko SM. Director of Medical Research.76:34 –35 3. PharmD (McNeil Consumer Products Co). MO. Mitchell AA.8:700 –704 13. 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. Because renal function tests were not performed on all participants. Ann Intern Med. In a smaller multi-dose trial described in the same report. Kauffman. Boston MA. ACKNOWLEDGMENTS This work was supported by McNeil Consumer Products Company. Neuroepidemiology Unit.92:459 – 460 4. Walson PD. Letter 8. Verjee Z. CA: BMDP Statistical Software. Los Angeles. Gilboa N. 1993. the randomized. Mann JFE. Mitchell AA. neither BUN nor creatinine levels increased significantly among children treated with ibuprofen (2. Kansas City. 1991. Can ibuprofen cause acute renal failure in a normal individual? A case of acute overdose. PhD. Children’s Hospital. Restaino I. 1989. William Gerson. 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. Bethesda. Stoff JS. Alan Leviton. These data do not exclude the possibility that ibuprofen may cause acute renal failure in some children. Boston. Leichtner. 1993. they were likely to have been more seriously ill than most children who are treated with ibuprofen obtained without a prescription. Rubenstein RC. Clive DM. 1994. MD. National Institute of Child Health and Human Development. Hintze JL. Acute flank pain and reversible renal dysfunction associated with nonsteroidal antiinflammatory drug use. 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. preexisting chronic renal. otherwise healthy children. Peoria. 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. Acute renal insufficiency in ibuprofen overdose. Pediatrics. REFERENCES 1. Shepard FM. Drug evaluation after marketing: a policy perspective. Pediatric ibuprofen and leukopenia.93:693. Safety of paracetamol and ibuprofen in febrile children. MA. We also wish to thank Richard Vezina. However. Gartner JC. SOLO Statistical System: Power Analysis. Hayes JR. Am J Kidney Dis. Pediatr Emerg Care. Fort Washington. it seems likely that clinically important episodes of renal impairment occurring among participants in the trial were not missed. MD (chair). Reversible renal failure associated with ibuprofen in a child: a case report. for his advice and guidance.org.statistically significant. Medical New Product Development. We are especially grateful to the more than 1700 physicians/investigators without whose participation this study would not have been possible. the diagnoses at enrollment reflect the wide spectrum of febrile illness seen among children in pediatric practice. Edge JH. N Engl J Med. 273:929 –933 6. 1995. Lesko SM. we cannot estimate the absolute incidence (rate/1000 courses of treatment) of minor. David P. Gottlieb RP. Lovejoy. transient. private practice. Kaplan BS. Yaffe. Raval DS. van Biljon G. IL. Mary Joan Denisco. 1992 9. MD. and that those children at greatest risk for renal failure were hospitalized.5 to 10 mg/kg/dose).11 As was the case for renal failure.11:107–108 12.

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