Renal Function After Short-term Ibuprofen Use in Infants and Children

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.^1,9 Under these conditions, renal blood flow is regulated by processes involving prostaglandins, and the inhibition of prostaglandin synthesis by NSAIDs may result in reduced renal blood flow and glomerular filtration. Acute renal failure after ibuprofen overdose and interstitial nephritis after ibuprofen used in clinical doses have also been described in patients without preexisting renal disease.^9,10

It is unclear how this adult experience applies to children, who may be more or less susceptible to renal injury by NSAIDs. Children may be at lower risk because they are less likely than adults to have other factors predisposing to acute renal disorders (eg, congestive heart failure, diuretic use, and chronic renal failure). Conversely, they may be at greater risk because some degree of dehydration is likely to accompany fever, the most common indication for ibuprofen use in children, and dehydration may increase the likelihood of renal complications.

A number of reports have linked ibuprofen use to renal complications in children, and three have described renal failure in children younger than 15 years of age after short-term treatment with ibuprofen in therapeutic doses.^2-4 These include acute renal failure with edema in a 10 year old after ibuprofen use for traumatic pain,² and episodes of acute flank pain and non-oliguric renal failure in adolescent girls after ibuprofen use.^3,4In the last of these, interstitial nephritis was documented on renal biopsy.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).¹² Case reports, 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. Spontaneous (case) reports and observational (ie, nonrandomized) studies cannot provide valid estimates of risk when the choice of treatment is influenced by illness severity (ie, when confounding by indication occurs).^6,13 Because ibuprofen was until recently available for use in children only by prescription, children given this medication were likely to be more seriously ill than children treated with acetaminophen. Ibuprofen-treated children therefore may have been at greater risk of renal failure because of the severity of their underlying illness, unrelated to ibuprofen use. Because of this confounding, 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, random).⁶The 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. None of the participants randomized to ibuprofen was hospitalized with renal failure (the observed risk was 0 per 55 785), 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 per 100 000.⁵ However, this estimate does not allow one to assess the risk of lesser degrees of renal impairment, which may be predictive of more serious renal failure.

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. However, in one clinical trial involving 119 febrile children, increases in BUN were observed after administration of a single dose of ibuprofen (5 to 10 mg/kg); the authors describe the increases as being small and clinically unimportant.¹⁴ No differences were observed in creatinine levels and, when multiple testing was taken into account, the increases in mean BUN levels were not statistically significant. In a smaller multi-dose trial described in the same report, neither BUN nor creatinine levels increased significantly among children treated with ibuprofen (2.5 to 10 mg/kg/dose).¹¹ As was the case for renal failure, the randomized, 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, otherwise healthy children. By virtue of its size, this study has power adequate to detect small differences in mean creatinine level (8 μmol/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, we cannot estimate the absolute incidence (rate/1000 courses of treatment) of minor, transient, and undiagnosed impairment in renal function after ibuprofen use, nor can we estimate the relative risk of mild renal effects among children not hospitalized. However, it seems likely that clinically important episodes of renal impairment occurring among participants in the trial were not missed, and that those children at greatest risk for renal failure were hospitalized. As might be expected, elevated BUN and creatinine levels were somewhat more common among children with a discharge diagnosis of dehydration, but there was no evidence of a difference in risk related to antipyretic assignment among these children.

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, those with severe dehydration [≥10% of body weight], preexisting chronic renal, endocrine, or neoplastic disease). Further, 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. However, the diagnoses at enrollment reflect the wide spectrum of febrile illness seen among children in pediatric practice, and because all study participants were seen by a physician, they were likely to have been more seriously ill than most children who are treated with ibuprofen obtained without a prescription.

These data do not exclude the possibility that ibuprofen may cause acute renal failure in some children, 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.