Clinical Scenario and PICO question
It’s 3 am, and you’re working another fabulous moonlighting shift in the PED. Little Johnny is brought in by his mother because of concern that he has an ear infection. His mother relates that he has had a fever of 101, responsive to Ibuprofen, but that he has cold sx, and is crying and pulling at his right ear. All symptoms for one day.
ROS: negative for N/V/D, no SOB, +URI sx. Still drinking, normal diapers, no rash, no exposures.
PMH Term, SVD, no recent illness/antibiotics, no medications or allergies, Immunizations are UTD.
Exam: Well appearing 24 month old male, T 38.2, RR 20, HR 100, BP 90/55. Wt. 12 Kg.
HEENT: Profuse rhinorrhea, OP no erythema/exudate. Moist mucous membranes.
Left TM normal, Right TM erythematous, bulging, mild pain with exam. No perforation/otorrhea.
Neck supple, NT, no meningismus, has mild anterior cervical adenopathy bilat.
Lungs CTA, Cor RRR, Abdomen soft and NT, no mass/HSM. Extrem normal cap refill bilat.
Skin no rashes.
Is playful, trying to ingest your stethoscope.
You are about to print out a script for a gallon of Amoxicillin and wish the mother good luck with the diarrhea, when your attending says “Wait a minute. Are you familiar with the 2004 AAFP/AAP guidelines on acute otitis media? Does Little Johnny really need antibiotics tonight?” You think to yourself that Kulstad (either) must be losing it…of course AOM needs antibiotics. And how could you talk a mother into deferring antibiotics? What is this crazy talk? Still, you do have a few minutes to look into it…
PICO
P: Healthy infant >6 months of age meeting the AAP/AAFP diagnosis of AOM
I: Deferring antibiotics for 48 hours after the ED visit
C: Immediate prescription for antibiotic treatment
O: Duration of sx (time to clinical cure), % prescriptions filled, development of complications such as mastoiditis, parental satisfaction, adverse medication effects (diarrhea, rash).
Synopsis
Thanks to Scott and Cindy Altman for hosting, and to Christian DenOuden, Michelle, Dave Cummins, Anna, Gromis and Brad for presenting.
Background: An estimated 15 million antibiotic prescriptions are written annually for the treatment of pediatric acute otitis media (AOM) in the United States. While the vast majority of children in the US receive antibiotics for AOM, prescribing practices differ in Europe; 60% of kids in the UK and only about 30% of kids in the Netherlands are treated with antibiotics. Approximately 80% of children with AOM recover within 3 days without antibiotics. Antibiotic cost, diarrhea/rashes, allergy and growing antibiotic resistance must be weighed against the potential benefits of increased cure rate, shorter symptom duration, and decrease in complications including deafness, meningitis, and mastoiditis. In 2004, joint practice guidelines for the diagnosis and management of AOM were issued by the American Academies of Pediatrics and Family Practice. Besides requiring the presence of 1) acute symptoms and signs, 2) evidence of effusion and 3) evidence of inflammation to make the diagnosis, and a recommendation for treatment with high-dose amoxicillin as the first line antibiotic, these guidelines included a option for 48-72 hour observation without antibiotics for a subset of children. In this journal club, we discussed articles examining a wait-and-see approach to the treatment of AOM, non-treatment with antibiotics, and the effect of antibiotics on rates of mastoiditis.
Article #1: Spiro DM, Tay KY, Arnold DH, et al. Wait-and-See Prescription for the Treatment of Acute Otitis Media. JAMA. 2006;296:1235-1241.
In this RCT, 283 children between the ages of 6 months and 12 years seen in the ED with a clinical diagnosis of AOM were randomized to either receive a wait-and-see prescription (WASP) for antibiotics to be filled in 2 days if the child was not improving or was worsening, or a standard prescription (SP) to be filled and started directly after the ED visit. All participants received complimentary bottles of ibuprofen and otic analgesic drops. Exclusion criteria included recent antibiotics, clinical toxicity, immunocompromise, myringotomy tubes/perforated TM, additional bacterial infection, hospitalization and uncertain access to medical care. The primary outcome was the proportion in each group that filled the antibiotic prescription. Secondary outcomes included clinical course of illness, adverse effects of meds, school/work missed, and unscheduled medical visits. Standardized phone follow-up occurred several times from 4 to 40 days after enrollment (>90% completed at least one follow-up call). Of 776 patients assessed for eligibility, 308 were not enrolled because they did not meet inclusion criteria (27% had been treated with antibiotics in the prior week). Antibiotic prescriptions were not filled for 62% of WASP patients and 13% of SP patients. No serious adverse effects were reported in either group. Of parents reporting otalgia, there were statistically significant but minor differences between the WASP and SP groups in total days of otalgia (2.4 vs. 2.0 respectively, P=.02). There was statistically significant more diarrhea in the SP group (8% vs. 23%, P<.001). There were no significant differences in duration of fever or unscheduled medical visits. The authors conclude that the use of WASP reduced the use of antibiotics by 56% and is a successful strategy for the ED. This study may not be generalizable as it was limited to one urban ED, and there were a number of exclusion criteria (although many kids would qualify). In addition, the half-day of decreased otalgia seen in the SP group might be magnified in situations where parents are not receiving complimentary analgesics. On the other hand, there was a significant increase in diarrhea in the SP group, and no difference between the groups in the rate of unscheduled medical visits (a potential surrogate for treatment failure). This study differs from the AAFP/AAP guidelines in that it includes younger children and does not distinguish between mild vs severe AOM when making decisions about WASP vs SP.
Bottom line: The wait-and-see prescription strategy works in the ED, decreasing filled antibiotic prescriptions by 50%. Additional positive outcome is a significant decrease in diarrhea, but the study found an overall increased duration of otalgia by a half day in the WASP group.
Article #2: Le Saux N, Gaboury I, Baird M, et al. A randomized, double-blind, placebo-controlled noninferiority trial of amoxicillin for clinically diagnosed acute otitis media in children 6 months to 5 years of age. CMAJ. 2005;172:335-41.
These authors took a bolder approach, randomizing 531 children between the ages of 6 months and 6 years with a clinical diagnosis of AOM to either amoxicillin 60 mg/kg/day or placebo for 10 days. Exclusion criteria included recent antibiotics, immunosuppression, comorbid or chronic disease, ear surgery, otorrhea, or recurrent AOM. The study was conducted at three Canadian sites, including one ED. Again all participants received complimentary analgesics. Parents were contacted at 1, 2, 3 days after randomization and again between 10 and 14 days. If at any of the initial three interviews the child was not improving or was worsening, a medical re-assessment was advised. Additional follow-up and tympanometry to assess effusion were performed at 1 and 3 months. The primary outcome was clinical resolution defined as no new antibiotics (other than initial amoxicillin in treatment group). Secondary outcomes included fever and activity level on days 1, 2, 3 as well as rash and diarrhea in the first 2 weeks. Of 1924 children screened, 963 were eligible, 531 proceeded to randomization, and 512 were included in the data analysis. As Dave Cummins noted, a large number of eligible children were not randomized, either because the doctor wanted to treat (were these children different? sicker?) or because parents refused consent (what kinds of parents/kids were in this group?). In the per-protocol analysis, clinical resolution rates at 14 days were 84.2% for the placebo group and 92.8% for the amoxicillin group (absolute difference of 8.6%). Results were similar in the intention-to-treat analysis. Interestingly, there was a smaller difference (6%) in resolution rates between the 2 groups in children <2 years old (more viral AOM? more non-specific fever without a source labeled AOM?). NNT to prevent one treatment failure within 14 days was 11.0 (95% CI 6.83-30.0). Overall, more children in the placebo group had fever and pain in the first 2 days (approximately 10% more children with fever/pain in placebo group during first 2 days). There were no significant differences in activity level, occurrence of rash or diarrhea, recurrent AOM, or middle ear effusions by tympanometry in the 2 groups. Even with free analgesics, the average number of daily analgesic doses administered by parents in each group was 2. I wondered how many children were sent for medical reassessment on Day 1 because they weren’t improving. If a child showed up in the office/ED for reassessment, you could imagine a significant likelihood that the child would leave the reassessment visit with an antibiotic prescription. If those kids instead had been given 2 days before the first follow-up interview and possible trip back to the doctor, I wonder if more of them would have been improving on their own anyway, not been recommended to have a re-assessment, and the resultant differences between the groups may have been smaller. Just guessing, of course.
Finally, to throw in a bit of statistics: the significance level of a hypothesis test is the probability of wrongly rejecting the null hypothesis, if it is in fact true (false positive). It is the probability of a type I error and is set by the investigator in relation to the consequences of such an error. That is, we want to make the significance level as small as possible in order to prevent, as far as possible, the investigator from inadvertently making false claims. Usually, the significance level is chosen to be 0.05 (or equivalently, 5%). As Erik pointed out, in this study, the authors chose a type I error of 10%, giving them a significant (10%) risk of the results of the study being falsely positive.
Bottom line: Although the majority (>80%) of placebo patients were better at 14 days, the NNT to prevent one treatment failure by giving antibiotics was 11.0. Overall, approximately 10% more children in the placebo group than in the antibiotic group had fever and pain in the first 2 days. There were no significant differences in activity level, occurrence of rash or diarrhea, recurrent AOM, or effusions at follow-up in the 2 groups.
Article #3: Thompson PL, Gilbert RE, Long PF, et al. Effect of Antibiotics for Otitis Media on Mastoiditis in Children: A Retrospective Cohort Study Using the United Kingdom General Practice Research Database. Pediatrics. 2009;123:424-430.
Finally, RCTs will never be powered to identify differences in the rates of rare but potentially devastating complications of AOM. This third study examined whether the rates of mastoiditis have increased in the UK in association with the decline in antibiotics prescribed to children for AOM. The authors conducted a retrospective cohort study using the UK General Practice Research Database, representative of practices in the total UK and comprising 6% of children in the UK census population. Children between the ages of 3 months and 15 years with a diagnosis of mastoiditis were identified (n=854), of whom only one third had a diagnosis of AOM in the antecedent 3 months . Although the risk of mastoiditis after AOM was 1.8 per 10,000 episodes after antibiotics compared with 3.8 per 10,000 episodes without antibiotics, 4831 cases of AOM would need to be treated with antibiotics to prevent 1 child from developing mastoiditis. The incidence of mastoiditis remained stable between 1990 and 2006, although the incidence of AOM diagnoses fell by 34% during this time and antibiotic prescribing for AOM declined by 50%. Interestingly, while the incidence of mastoiditis was highest in infants, lowest in 2-year-olds, and increased steadily with age thereafter, the incidence of AOM steadily decreases with increasing age (epidemiology doesn’t match up between the 2 diseases).
Bottom line: While it’s a potentially very serious condition, mastoiditis is rare, and only about a third of patients diagnosed with mastoiditis are treated in the prior 3 months for AOM. While antibiotics decrease the risk of developing mastoiditis, nearly 5,000 children with AOM would need to be treated with antibiotics to prevent one case of mastoiditis (NNT= 5,000…not a sound prevention strategy). Recognizing clinical signs of mastoiditis, especially in older children, is key to early diagnosis and successful treatment.
Wrap-up: Although the majority of folks in the room were willing to try the wait-and-see prescription approach for AOM, a few still prefer to treat all AOM with antibiotics, citing the modest increase in clinical cure rate and small but real decrease in duration of pain. This must be weighed against the long-term effects of antibiotic resistance and increased risk of diarrhea (not inconsequential in this age of community associated Clostridium difficile), as well as cost. It’s an excellent opportunity to involve parents in the decision making process. All in the room agreed that free bottles of ibuprofen and otic analgesic drops for parents to take home at 3 am would be extremely helpful both with patient satisfication and to get buy-in for the wait-and-see approach. Write for generic oticaine otic drops (benzocaine) now that Auralgan has added vinegar to its formulation and is no longer generic!