PEDIATRICS Vol. 108 No. 5 November 2001, pp. 1236-1237

Alternating Antipyretics: Is This an Alternative?

To the Editor.

We read with interest the article by Mayoral et al.¹ We would like to describe a case of acute renal failure that may add to the general discussion regarding alternating antipyretics. A 14-month-old previously healthy girl was admitted to Bryn Mawr Hospital for febrile status epilepticus. Initial laboratory studies revealed a normal head computed tomography scan, normal cerebrospinal (CSF) studies, and negative bacterial cultures of the blood, urine, and CSF. Initial electrolytes were normal, and initial blood urea nitrogen (BUN) and creatinine were 16 mg/dL and 0.5 mg/dL, respectively. The patient received the following anticonvulsants: lorazepam, phenytoin, and phenobarbital. After initial control of the seizures, the patient was maintained on phenobarbital without additional seizure activity. The only other drug initially administered was ceftriaxone, which was continued for 72 hours pending negative bacterial cultures. The patient's initial course was one of general improvement, but she continued to have fever. On hospital day 6 the patient spiked a temperature to 105.0, and additional evaluation was undertaken but was unrevealing. At this same time, given the height of the fever, the patient received an alternating regimen of acetaminophen and ibuprofen. The patient had some loose stools during this same interval, but did not receive parenteral fluids. On day 8 of hospitalization the patient had further laboratory evaluation that revealed a BUN of 63 mg/dL and creatinine of 3.4 mg/dL. The patient had an extensive renal evaluation, including a pediatric nephrology consultation, without discovering a definite cause for the acute renal failure. The patient had no features of hemolytic-uremic syndrome, systemic lupus, obstructive uropathy, or sickle cell disease. The patient was treated with careful medical management and she gradually recovered. She was discharged on hospital day 15 with a BUN of 15 mg/dL and creatinine of 0.9 mg/dL. She has gone on to have a full recovery. We believe that the acute renal failure was attributable to the additive and synergistic renal toxicities of acetaminophen and ibuprofen, in a patient who was moderately dehydrated. McIntire et al² pointed out that acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs) may cause renal failure synergistically by oxidative metabolites of acetaminophen accumulating in the renal medulla during renal ischemia, which can be caused by NSAIDs. We would like to suggest an additional mechanism for toxicity from the combination of acetaminophen and ibuprofen. Eguia and Materson³ point out that acetaminophen inhibits urinary prostaglandin synthesis, just as NSAIDs do. Thus, you have an additive effect of this toxicity. In the normal participants, this decrease in prostaglandin synthesis does not seem to be clinically relevant, but in impaired individuals can lead to renal injury. We suggest that the synergistic and additive toxicities of acetaminophen and ibuprofen in a mildly to moderately dehydrated child can lead to acute renal failure. Although the clinical event of acute renal failure may be quite rare in the above circumstances, we believe it should be taken into account before prescribing the combination of these antipyretics.

Michael T. Del Vecchio, MD
Department of Pediatrics
Temple University Children's Medical Center
Temple University School of Medicine
Philadelphia, PA 19140

Eric R. Sundel, MD
Department of Pediatrics
Bryn Mawr Hospital
Bryn Mawr, PA 19010

REFERENCES

1. Mayoral C, Marino R, Rosenfeld W, Greensher J Alternating antipyretics: is this an alternative? Pediatrics. 2000; 105:1009-1012 [Abstract/Free Full Text]
2. McIntire S, Rubenstein R, Gartner J, Gilboa N, Ellis D Acute flank pain and reversible renal dysfunction associated with nonsteroidal anti-inflammatory drug use. Pediatrics. 1993; 92:459-460 [Abstract/Free Full Text]
3. Eguia L, Materson B Acetaminophen-related acute renal failure without fulminant liver failure. Pharmacotherapy. 1997; 17:363-370 [Medline]

To the Editor.

In support of the recent article by Mayoral on "Alternating Antipyretics: Is This an Alternative?"¹ I would add emphasis to their statement that:

"There is presently no scientific evidence that this combination [acetaminophen and ibuprofen] is safe or achieves faster antipyresis than either agent alone." It has been postulated that they may even "act synergistically and produce tubular toxicity."

Back in 1991, within a 2-year time frame after the approval of prescription ibuprofen for children in the United States, Robert J. Walker wrote in the article "Paracetamol [acetaminophen], Nonsteroidal Anti-inflammatory Drugs (NSAIDs) and Nephrotoxicity"² as follows:

"Renal metabolism ... is related to generation of nontoxic and toxic paracetamol metabolites ... The accumulation of paracetamol in the medulla is important in the subsequent generation of chronic nephrotoxicity."

"Under conditions of ... intravascular volume depletion, paracetamol concentrations will increase in the inner medulla."

"NSAIDs may have a synergistic effect with paracetamol in producing cell toxicity by the reduction in renal blood flow particularly into the medulla. The reduced oxygen gradient that already exists in the renal medulla would be further compromised and hence increase the risk of cellular damage. These potential interactions await experimental confirmation."

Subsequently, in 1993 McIntire and colleagues³ from Children's Hospital of Pittsburgh reported that:

"... concomitant acetaminophen use [with an NSAID] was present in both cases and its role is more problematic. Acetaminophen accumulates in the renal medulla ... Oxidative metabolites of acetaminophen can result in medullary cellular necrosis in the absence of reduced glutathione, the production of which is inhibited by agents that inhibit renal prostaglandin synthesis."

"Thus, the tubular toxicity of NSAIDs and acetaminophen are, at least theoretically, synergistic ... The practice of alternating doses of acetaminophen and NSAIDs for fever control theoretically increases the risk of nephrotoxicity."

In view of the preceding comments and observations, it appears prudent to avoid alternating or simultaneous administration of acetaminophen with ibuprofen. Engaging in wishful thinking may tempt possibly synergistic adverse events.

The individual utility of ibuprofen or of acetaminophen, separately, for fever control and associated improved comfort of children, is well-known. The safety record of each is a matter of record, and I would refer colleagues to my letter on ibuprofen safety published in Pediatrics in January 1992.⁴

Alternating or combining the two medications is not recommended.

Jonathan B. Rosefsky, MD, FAAP
Havenford, PA 19041

REFERENCES

1. Mayoral CE, Marino RV, Rosenfeld W, Greensher J Alternating antipyretics: is this an alternative? Pediatrics. 2000; 105:1009-1012
2. Walker RJ. Paracetamol, nonsteroidal anti-inflammatory drugs and nephrotoxicity. N Z Med J. 1991;182-183
3. McIntire SC, Rubenstein RC, Gartner JC, Gilboa N, Ellis D Acute flank pain and reversible renal dysfunction associated with nonsteroidal anti-inflammatory drug use. Pediatrics. 1993; 92:459-460
4. Rosefsky JB. Ibuprofen safety [letter]. Pediatrics. 1992;166-167

In Reply.

We welcome Dr Rosefsky's support of our admonition against the use of combination therapy for the management of fever in children.

Despite the lack of scientific knowledge regarding the use of acetaminophen and ibuprofen in combination or in an alternating regime, physicians have not been dissuaded from practicing this method of antipyresis.

Acetaminophen and ibuprofen act via similar mechanism: they both inhibit cyclooxygenase activity and therefore the formation and release of prostaglandin.¹ In certain settings, such as hypovolemia, inhibition of prostaglandin synthesis may impair renal perfusion.² McIntire et al present two cases where patients developed acute flank pain and reversible renal dysfunction after use of nonsteroidal anti-inflammatory agents. In both cases, acetaminophen was also ingested. McIntire suggests that in states of renal ischemia, acetaminophen metabolites may accumulate in the renal medulla and lead to medullary cellular necrosis. Theoretically these two products may act synergistically and cause tubular toxicity.²

Dr Del Vecchio and Dr Sundel provide the first documentation of acute renal failure in a patient who also received combination therapy for fever management. This example adds support to our concerns about the safety of this method of antipyresis. There is presently no scientific evidence that the use of this combination achieves faster antipyresis or has greater efficacy than either agent used alone. Because of the lack of evidence regarding the safety of this combination and until properly controlled studies have assessed the risk of combining or alternating these 2 products, we believe it would be prudent for physicians to advise parents to use one single agent during the management of the febrile child.

Clara E. Mayoral, MD
General Pediatrics
South Nassau Communities Hospital
Oceanside, NY 11570

Warren Rosenfeld, MD
Ronald V. Marino, DO
Joseph Greensher, MD
Department of Pediatrics
Winthrop University Hospital
Mineola, NY 11501

REFERENCES

1. Gilman AG, Rall TW. Goodman and Gilman's the Pharmacologic Basis of Therapeutics. 8th ed. New York, NY: Pergamon Press; 1990
2. McIntire SC, Rubenstein RC, Gartner JC, Gilboa N, Ellis D Acute flank pain and irreversible renal dysfunction associated with nonsteroidal anti-inflammatory Drug use. Pediatrics. 1993; 92:459