Cue the Michael Buffer intro… Yes, then age old question surfaces again. This is also probably something that most of us don’t think about on a regular basis. many of our patients’ parents may swear by on or the other (usually Ibuprofen) but is there any evidence to support the superiority of one agent over another? Let’s take a look at the ‘tale of the tape.’

Pharmacology

Cyclooxygenase (COX): Recall that COX converts arachadoinc acid to PGE H2. Why is this important? Because PGE H2 and other chemical cause fevers. COX 1 inhibition leads to platelet aggregation, whereas COX 2 inhibition is involved in antipyresis and antiinflammatory effects

Ibuprofen: a non selective COX 1 & 2 inhibitor

Acetaminophen: Much more selective for COX 2

There are certainly more concerns surrounding the use of ibuprofen, especially in younger patients.

Ibuprofen and the potential for renal injury or GI bleed

Does a single dose of ibuprofen really have the chance to hurt the beans or make you bleed profusely from your gut?

Renal impairment in NSAID users occurs mostly in patients with preexisting renal disease or low intravascular volume or low cardiac output. Ibuprofen inhibits PGE synthesis leading to decreased renal blood flow and glomerular filtration. Acute kidney injury after Ibuprofen overdose is generally because of interstitial nephritis. A ‘dose’ of <200mg/kg is rarely harmful.

Kelly et al. in 1993 noted clinically unimportant increases in BUN in febrile children dosed with ibuprofen versus acetaminophen. Lesko and Allen (Pediatrics, 1997) found no significant difference in renal indices between the two agents. Lesko later noted that there were no adverse outcomes in a cohort of children less than 2 years for 5 and 10mg/kg doses of ibuprofen.

Lesko et al in 1999 conducted a double blinded RCT of 27,065 febrile children < 2 years of age. Follow up was conducted via review of medical records, questionnaires and interviews. They were principally looking at risk of hospitalization with GI bleed or adverse effects (no statistical difference). Though the study was large, doses differed and the ibuprofen group was much larger.

The bottom line is that in single doses you’re fine.

Ibuprofen use in babies less than 6 months of age

What about ibuprofen in the febrile, irritable 4 month old in which acetaminophen has failed to reduce the fever completely?

Well, the FDA has only approved ibuprofen for use in children older than six months of age. In all honesty a single dose in a euvolemic, non septic 4 month old shouldn’t cause kidney injury… But it’s your license  😉

Use as an antipyretic

They both work – that’s the simple answer. But what about the mom who swears that ibuprofen works better? Traditionally you may have learned that they are pretty much the same – though there is some research that would indicate otherwise. Perrott et al in 2004 compared 17 blinded RCTs in children <18 who received either drug for pain or fever. They noted that at 2, 4, and 6 hours post treatment that Ibuprofen (5-10 mg/kg) reduced temperature more than acetaminophen (10-15 mg/kg) (respective weighted-effect sizes: 0.19

[95% CI, 0.05-0.33], 0.31 [95% CI, 0.19-0.44], and 0.33 [95% CI, 0.19-0.47]). Advantage: Ibuprofen

Goldman et al. in 2004 conducted a systematic review looking at reduction of temperature over time and for how long the temperature was reduced in children receiving acetaminophen vs ibuprofen. They noted similar efficacy, with an ever so slightly increased benefit in those getting ibuprofen. Of note, this systematic review included 14 studies, 11 of which were RCTs. Advantage: Ibuprofen

OK, so that’s one review – got any more? Yuuup…

Purssell in 2002 examined 8 studies comparing the two agents and their fever reducing abilities in children 4 months to 13 years and found that there was no benefit for either drug at 1 hour post administration, but that Ibuprofen had a mean temperature reduction of 0.58 C at 6 hours. Advantage: Ibuprofen (for longer duration of activity)

I’ll go through the rest quickly for the tl/dr crowd.

Sarrell et al 2006 Advantage: Push

Wong et al 2001 Advantage: Ibuprofen

OK, so maybe that mom who is adamant about the superiority of ibuprofen wasn’t that far off.

Can I give them both at the onset of fever?

The PITCH (Paracetamol plus ibuprofen for the treatment of fever in children) trial went one step further and compared ibuprofen vs acetaminophen vs both drugs together in a RCT. They noted that both drugs cleared fever 23 minutes faster than acetaminophen alone, but no faster than ibuprofen. The combination when given regularly together over 24 hours also resulted in less time with fever vs either drug alone.

So yes, you can use both simultaneously, but the benefit isn’t startlingly great, and this is a surefire way to get confused about how much medicine you are giving the child.

Alternating them

You can Google this – go ahead dive in if you dare. Many parents also swear by this method. Give Tylenol at 12, ibuprofen at 3, tylenol at 6 and so on forever… But, is it safe and effective? The answer is probably. Kramer et al 2008 found in their prospective randomized double-blind placebo controlled RCT that acetaminophen alone had no significant difference in temperature at 0,3 and 6 hours vs alternating. There were however, significant differences in the temperature at 4 and 5 hours favoring the group who alternated – 4 hours (38.0°C vs 37.4°C; P = .05) and 5 hours (37.1°C vs 37.9°C; P = .0032). Interestingly they noted that parents did not perceive a difference in efficacy.

Alternating the two drugs greatly increases the complexity of the regimen, especially for multiple caregivers. Some reports have indicated that detailed counseling did not occur in 3/5 parents advised to alternate. Clearly the greatest danger is with acetaminophen overdose. So, what do I advise my patients to do? Well, I don’t routinely recommend alternating because of the acetaminophen overdose risk. If parents insist, I caution them to be supremely anal retentive with tracking dose, drus and time of administration, and to reevaluate the need to do this every 12 hours. Yes they can reduce the presence of fever and make their child better – but I ultimately find that most that alternate are doing so because they fear the fever. Thus, time should be spent on counseling on fever phobia, rather than on constructing delicate antipyretic schedules.

Check out this AAP policy for more information.

Conclusion

Still here? Great. So who wins? Well, for a single dose in a child >6 months with fever I prefer ibuprofen alone (by the slimmest of margins). I don’t alternate, nor do I give both at the same time. Ultimately both drugs are safe and effective, and you should be able to answer patient and family questions surrounding both.