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Thursday, November 13, 2014

Tiny Tylenol Tidbit: The Loading Dose

I work at an institution with a Children’s Hospital attached to it, which means that we encounter a fair amount of pediatric patients in the emergency department (ED). One of the most common complaints of children presenting to the ED is fever.

Acetaminophen is a routinely administered medication in this population. I recently had the opportunity to review a policy of standing orders for triage nurses in our ED that may be carried out before a provider sees the patient. One such order included administration of a loading dose of acetaminophen (30 mg/kg orally or 45 mg/kg per rectum) for children presenting to the ED with a fever.

Historically, it has been theorized that acetaminophen loading doses may be administered in order to achieve higher serum levels of drug and thus a more rapid pharmacodynamic effect. As you might expect, pharmacokinetic data from pediatric populations demonstrate that a 20-30 mg/kg oral dose of acetaminophen results in approximately a 2-fold higher serum concentration than a single 10-15 mg/kg dose.1-3 But is there evidence to correlate higher serum concentrations with better antipyresis?

The first of these studies was published by Treluyer and colleagues.4 Subjects in this study (n = 121) were outpatient children ranging from 4 months to 9 years of age, and had to have an initial rectal temperature of 39° C to 40.5° C. They were randomized to receive a single dose of acetaminophen either 30 mg/kg or 15 mg/kg, and the primary outcome was time to rectal temperature below 38.5° C. Other outcomes included maximum temperature decrease, time to maximum temperature decrease, and number of patients requiring “rescue” temperature-altering treatment (a tepid water bath or a repeat dose of 15 mg/kg acetaminophen). Although the authors were able to find a statistically significant difference in the primary outcome of time to temperature less than 38.5° C, this difference was only 19 minutes, and the clinical significance is questionable. Additionally, the maximum temperature decrease was found to be statistically significant but only about 0.5° C.

Treluyer and colleagues’ results have not been replicated. Scolnik et al. compared standard and high dose rectal acetaminophen (15 mg/kg and 30 mg/kg) and the standard 15 mg/kg oral dose in 70 febrile children.5 They found no difference in temperature change between groups. These findings were replicated in an evaluation by Nabulsi and colleagues.6 This study compared antipyretic effectiveness of two rectal acetaminophen doses (15 mg/kg and 35 mg/kg) and the standard oral dose of 15 mg/kg. Among the 51 febrile children randomized in this study, there were no significant differences in time to maximum antipyresis, time to fever reduction by at least 1° C, or mean hourly temperature for 6 hours after study drug administration.

Some unpublished data is available that confirms the lack of a significant difference in terms of antipyretic efficacy between the standard (15 mg/kg) and 20-30 mg/kg dosing regimens. Temple and colleagues summarize this unpublished data in a review, where they found a mean change in temperature at 4 hours was 1.5° C with a 10-15 mg/kg dose, and 1.9° C with a 20-30 mg/kg dose.7

The American Academy of Pediatrics has a guideline statement addressing the care of the febrile child.8 They specifically recommend against the routine administration of acetaminophen loading doses, citing a lack of consistent evidence and mounting concern for harm.

Wait a second, harm? What harm could come from a single dose of acetaminophen? The toxic threshold for most patients is 150 mg/kg, surely a dose of 30 mg/kg orally or 45 mg/kg rectally can’t cause a problem.

The concern that the American Academy of Pediatrics cites in their hesitancy to recommend loading doses of acetaminophen is related to hepatotoxicity with supratherapeutic dosing.4 In fact, many agree that the total dose of acetaminophen in children should not exceed 75 mg/kg/day because of the risk of hepatic injury.9 If a child received any acetaminophen at home prior to coming to the hospital, then starts receiving doses of 30 mg/kg at a time in the ED, the 75 mg/kg/day threshold may easily be exceeded.

So what to do about the loading dose? If a higher dose isn’t any better than the traditional dose in terms of fever reduction, what are you left with? Many pediatric providers are hesitant to routinely recommend acetaminophen for reasons other than making the patient comfortable in the setting of a febrile illness. Furthermore, when thinking about the (1) apparent lack of benefit of high-dose over conventional dosing and (2) the potential risk of hepatotoxicity with increasing/cumulative doses then the idea of the loading dose becomes much less attractive.

If you’ve decided that your febrile pediatric patient does indeed require a dose of acetaminophen to make them more comfortable, I’d stick to the recommended 15 mg/kg orally and leave the loading doses for vancomycin.

Meghan E. Groth, Pharm.D., BCPS (@EMPharmGirl)
Emergency Medicine Clinician, Fletcher Allen Health Care

Reviewed by: Craig Cocchio, Pharm.D., BCPS and Nadia Awad, Pharm.D., BCPS

References:
  1. McNeil Protocol 1-224 Issued September 1981. A double-blind study of the comparative antipyretic effectiveness and safety of a single 10 mg/kg, 20 mg/kg, or 30 mg/kg dose of acetaminophen. Study terminated; no report but data listings [Meta-Analysis Code P81224].
  2. McNeil Protocol 2-227 Issued October 1982. A double-blind study of the comparative antipyretic effectiveness and safety of a single 15 mg/kg, 30 mg/kg, or 40 mg/kg dose of acetaminophen. Study terminated; no report but data listings [Meta-Analysis Code P82227].
  3. Gelotte CK. Pharmacokinetic and pharmacodynamics modeling of acetaminophen in febrile children: evaluation of three products. Protocol 93-308. Report #003221. McNeil Consumer Products Company 1994 [Meta-Analysis Code P93308].
  4. Treluyer JM, Tonnelier S, d’Athis P, et al. Antipyretic efficacy of an initial 30 mg/kg loading dose of acetaminophen versus a 15 mg/kg maintenance dose. Pediatrics 2001; 108:e73.
  5. Scolnik D, Kozer E, Jacobson S, et al. Comparison of oral versus normal and high-dose rectal acetaminophen in the treatment of febrile children. Pediatrics 2002; 110:553-6.
  6. Nabulsi M, Tamim H, Sabra R, et al. Equal antipyretic effectiveness of oral and rectal acetaminophen: a randomized controlled trial. BMC Pediatr 2005; 5:35.
  7. Temple AR, Temple BR, and Kuffner EK. Dosing and antipyretic efficacy of oral acetaminophen in children. Clin Ther 2013; 35:1361-75.
  8. Sullivan JE, Farrar HC, et al. Fever and antipyretic use in children. Pediatrics 2011; 127:580-7.
  9. Kozer E, Greenberg R, Zimmerman DR, et al. Repeated supratherapeutic doses of paracetamol in children-a literature review and suggested clinical approach. Acta Pediatrica 2006; 95:1165-71.

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