儿童急性中耳炎的治疗.ppt

1、Treatment of Acute Otitis Media in Children under 2 Years of Age,2012-3-15,本人制作，仅供分享学习讨论之用,2,SOURCE INFORMATION,N Engl J Med, 2011, 364:105-115(had been cited by 16 articles) From the Department of Pediatrics, University of Pittsburgh School of Medicine, USA. Correspondence author: Dr. Hoberman E-ma

2、il:.,3,美国科学信息所（ISI）公布,4,Introduction of The New England Journal of Medicine (NEJM),1812年创刊，由美国麻州医学协会所出版的同行评审性质之综合性医学期刊。 全科医学周刊，每年52期 出版风格：重要的研究成果、临床发现以及观点。注重文章的实用性，多为指导临床实践。 严格的审稿程序，稿件的处理流程通常需1012周。来稿的刊用率约为7%。,5,BACKGROUND,Acute otitis media(AOM) is the most frequently diagnosed illne

3、ss in children in the US. Most children have routinely been treated with antimicrobial drugs in the US.,1.Tahtinen PA, et al. A placebo-controlled trial of antimicrobial treatment for acute otitis media. N Engl J Med 2011;364:116-126 2.Klein JO. Is acute otitis media a treatable disease? N Engl J Me

4、d 2011;364:168-169,6,A watchful-waiting strategy has long been applied in several countries to minimize the use of antimicrobial drugs. -Netherlands and Scotland4,5 -USA,2004,6,7 -Canada 8,4.Appelman CL, et al. Otitis media acuta: NHG-standaard (eerste herziening). Huisarts Wet 1999;42:362-366 5.Sco

5、ttish Intercollegiate Guidelines Network. Diagnosis and management of childhood otitis media in primary care. Guideline no. 66. Edinburgh: Royal College of Physicians in Edinburgh, 2003. 8.Forgie S, Zhanel G, Robinson J. Management of acute otitis media. Paediatr Child Health (Oxford) 2009;14:457-46

6、4,7,AOM in children aged 6 to 23 months is “nonsevere” 6(mild otalgia and T 39 during the preceding 24 hours) Diagnosis of AOM is uncertain.7,Indications of Watchful Waiting,6.Kaleida PH, et al. Amoxicillin or myringotomy or both for acute otitis media: results of a randomized clinical trial. Pediat

7、rics 1991;87:466-474 7.American Academy of Pediatrics Subcommittee on Management of Acute Otitis Media. Diagnosis and management of acute otitis media. Pediatrics 2004;113:1451-1465,8,The watchful waiting strategy has been based on the results of clinical trials3 that showed relatively high rates of

8、 spontaneous improvement in children with acute otitis media.,Fundament,3.Rosenfeld RM, et al. Clinical efficacy of antimicrobial drugs for acute otitis media: metaanalysis of 5400 children from thirty-three randomized trials. J Pediatr 1994;124:355-367,9,Limitations of earlier trials : -The lack of

9、 stringent diagnostic criteria; -The inclusion of few very young children; -Antimicrobial drug had limited efficacy or was administered in suboptimal doses.9,9.Paradise JL. Short-course antimicrobial treatment for acute otitis media: not best for infants and young children. JAMA 1997;278:1640-1642,T

10、o choose amoxicillinclavulanate(the most effective treatment for AOM) 7,10 in this study.,10.Hoberman A, et al. Large dosage amoxicillin/clavulanate, compared with azithromycin, for the treatment of bacterial acute otitis media in children. Pediatr Infect Dis J 2005;24:525-532,10,Rates of spontaneou

11、s improvement similar to the rates seen in those studies among children receiving placebo have not been found uniformly.6 Therefore, for children with AOM, the circumstances in which immediate antimicrobial treatment is the preferred strategy have remained unclear.,11,OBJECTIVES,To evaluate the exte

12、nt to which antimicrobial treatment(Amoxicillin-clavulanate) and placebo treatment affect the course of both symptoms and signs of AOM in children aged 6 to 23 months .,12,METHODS,Eligibility and Enrollment Randomization Assessment of Symptoms Otoscopic Examination, Overall Assessment, and Managemen

13、t Outcomes Statistical Analysis,13,1.Eligibility and Enrollment,From November 2006 to March 2009 at the Childrens Hospital of Pittsburgh and Armstrong Pediatrics, Pennsylvania. The study protocol was approved by the institutional review board at the University of Pittsburgh; written informed consent

14、 was obtained from a parent of each enrolled child. The protocol is available with the full text of this article at NEJM.org.,14,Inclusion Criteria,Eligible children (1) will be aged 6 to 23 months, (2) have received pneumococcal conjugate vaccine, and (3) have evidence of AOM defined as: Recent (wi

15、thin 48 hours), onset of signs and symptoms and a score of 3 on the AOM-SOS scale. Presence of middle-ear effusion Moderate or marked bulging of the tympanic membrane or slight bulging accompanied by either otalgia or marked erythema of the membrane.,15,AOM-SOS,The Acute Otitis Media Severity of Sym

16、ptoms (AOM-SOS) scale11,12 The AOM-SOS scale consists of seven items: tugging of ears, crying, irritability, difficulty sleeping, diminished activity, diminished appetite, and fever. As “none,” “a little,” or “a lot,” with corresponding scores of 0, 1, and 2 scores range from 0 to 14, with higher sc

17、ores indicating greater severity of symptoms,11.Shaikh N, et al. Development and preliminary evaluation of a parent-reported outcome instrument for clinical trials in acute otitis media. Pediatr Infect Dis J 2009;28:5-8 12.Shaikh N, et al. Responsiveness and construct validity of a symptom scale for

18、 acute otitis media. Pediatr Infect Dis J 2009;28:9-12,16,AOM-SOS,17,Exclusion Criteria,Children(1) had another acute illness (e.g., pneumonia) or a chronic illness (e.g., cystic fibrosis), (2)were allergic to amoxicillin, (3)had received more than one dose of an antimicrobial drug within the previo

19、us 96 hours, (4)had had otalgia for longer than 48 hours, or (5)had perforation of the tympanic membrane.,18,Exclusion Criteria(protocol),(1)certain signs or symptoms (e.g., toxic appearance, otalgia 48 hours, spontaneous perforation of the tympanic membrane and drainage or temperature 105F); (2) cl

20、inical or anatomical characteristics that might obscure response to treatment (e.g., tympanostomy , submucous cleft palate, high-arched palate, or Downs syndrome); (3) underlying systemic problems that might obscure response to infection (e.g., serious underlying disease e.g.,cystic fibrosis, neopla

21、sm, juvenile diabetes), concomitant infection, known renal insufficiency, known hepatic insufficiency, history of immune dysfunction, chronic gastrointestinal conditions , malignancy;,19,(4) sensorineural hearing loss; (5) comedications (e.g., systemic corticosteroids at any point while enrolled in

22、the study, more than one dose of systemic antimicrobial therapy within 96 hours, any investigational drug or vaccine; (6) hypersensitivity to penicillin, amoxicillin or amoxicillin-clavulanate, or phenylketonuria or known hypersensitivity to aspartame; (7) unable to complete the study protocol or no

23、t having access to a telephone; and (8) current enrollment in another study or previously enrolled in this study.,aspartame阿司帕坦; phenylketonuria苯丙酮酸尿,20,2.Randomization,Stratification according to history of recurrent AOM (defined as 3 episodes in 6 months or 4 episodes in 1 year ) and according to

24、their exposure or nonexposure to three or more children for at least 10 hours per week. At each study site, within each stratum, we randomly assigned children in blocks of four, in a 1:1 ratio,21,Amoxicillinclavulanate (Augmentin ES, GlaxoSmithKline), 90/6.4mg/kg/day in 2 divided doses for 10 days.

25、Placebo was similar to Amoxicillinclavulanate in appearance and taste. The parents were unaware of the childrens group assignments. Parents prepared acetaminophen as needed for the relief of symptoms.,22,3.Assessment of Symptoms,Structured interview by telephone every day until the first follow-up v

26、isit and in person at each visit. Parents record their childs AOM-SOS scores and other pertinent clinical information in a diary twice a day for 3 days and once a day thereafter.,23,4.Otoscopic Examination, Overall Assessment, and Management,Otoscopy on day 1, day 4-5, day 10-12, day 21-25.,Slight,O

27、toscopic Photographs,Moderate,marked,bulging of tympanic membrane,24,Overall Assessment,To categorize clinical success or clinical failure at each visit. Clinical failure at or before the day 45 visit: a lack of substantial improvement in symptoms, a worsening of signs on otoscopic examination, or b

28、oth. Clinical failure at the day 1012 visit : the failure to achieve complete or nearly complete resolution of symptoms and of otoscopic signs.,13.Kaleida PH. Assessment of otoscopists accuracy regarding middle-ear effusion: otoscopic validation. Am J Dis Child 1992;146:433-435,25,Management for cli

29、nical failure cases,A standardized 10-day regimen of orally administered amoxicillin, at a dose of 90mg/kg/day, and cefixime, at a dose of 8mg/kg/day. Once a child had met the criteria for clinical failure, he or she remained in that category for the analyses.,26,Relapse at the day 2125 visit: the r

30、eappearance of AOM in a child who had previously been categorized as having met the criteria for clinical success.,27,To obtain nasopharyngeal specimens from the children for culturing, at study entry and at the day 1012 and day 2125 visits.,28,5.Outcomes,The primary outcome measures A.The time to r

31、esolution of symptoms: -The time to the first recording of an AOM-SOS score of 0 or 1 -The time to the second of two successive recordings of that score. B.The symptom burden over time: -The mean AOM-SOS score of each day over the first 7 days of follow-up -The groups weighted mean scores for that p

32、eriod.,29,The secondary outcomes: Overall clinical efficacy The occurrence of adverse events Nasopharyngeal colonization rates The use of acetaminophen The use of health care resources.,30,6.Statistical Analysis,Sample estimates: a sample of 120 children in each study group. All the analyses were ba

33、sed on the intention-to-treat principle, were performed with the use of two-sided tests, and included adjustment for the study stratification variables.,31,To compare the time to the resolution of symptoms between the study groups using life-table plots, and to conduct tests of equal hazard function

34、s using a proportional-hazards model. To compare the mean AOM-SOS scores in the two groups at individual assessments each day over the first 7 days of follow-up using generalized estimating equations, and the groups weighted mean scores for that period using regression analysis.,32,For analyses of c

35、linical success or failure, we used logistic regression. To determine whether variables were prognostic or effect modifiers, we used the proportional-hazards model or logistic-regression models. To used McNemars test for analyses of nasopharyngeal colonization rates.,33,RESULTS,1.Study Population 2.

36、Efficacy of Treatment -Symptomatic Response -Clinical Failure -Prognostic Factors and Effect Modifiers -Relapse and Residual Middle-Ear Effusion 3.Nasopharyngeal Colonization and Other Outcomes 4.Complications and Adverse Events,34,1.Study Population,1385 Children were assessed for eligibility,887 W

37、ere not eligible,498 Were eligible,291 Underwent randomization,207 Had parent who declined participation,144 Were assigned to and received amoxicillinclavulanate,147 Were assigned to and received placebo,35,36,Selected Demographic and Clinical Characteristics(1),1.Age at entry 611 mo 1217 mo 1823 mo

38、 2.Sex Male Female 3.Race White Black Other,4.Maternal level of education Less than high school High-school graduate College graduate 5.Type of health insurance Private Medicaid 6.Exposure to other children Yes No,37,7.AOM-SOS score (1)Baseline score 35 68 911 1214 (2)Mean baseline score (SD) 8.Late

39、rality of acute otitis media Bilateral Unilateral,9.Degree of tympanic membrane bulging in worse ear Slight Moderate Marked,Selected Demographic and Clinical Characteristics(2),There were no significant differences in characteristics between the two study groups.,38,There were no significant differe

40、nces in characteristics between the two study groups.,39,There were no significant differences between enrolled children and children whose parents withheld consent or between the children in the two study groups. There were no significant correlation between childrens AOM-SOS scores at entry and th

41、e degree of bulging of their affected tympanic membranes.,40,2.Efficacy of Treatment: 2.1Symptomatic Response,The proportion of children in whom symptoms had not resolved,41,Day2 Day4 Day7 Group A 35% 61% 80% Group B 28% 54% 74% P=0.14 for the overall comparison,Rates of the first recording of a sco

42、re of 0 or 1,Group A : children who were treated with amoxicillinclavulanate Group B: children who were treated with placebo,42,43,Day2 Day4 Day7 Group A 20% 41% 67% Group B 14% 36% 53% P=0.04 for the overall comparison,Rates of two successive recordings of a score of 0 or 1,In 54% of the instances

43、in which scores fell to 0 or 1, a subsequent score was higher than 1.,44,45,The mean AOM-SOS scores over the first 7 days were lower in the amoxicillinclavulanate group than in the placebo group at each time point (P=0.02) and at the 1012 day visit (1.590.21 vs. 2.460.20; P=0.003).,Group A Group B P

44、 Value *Score8 2.210.16 2.580.19 0.14 Score 8 3.590.27 4.500.28 0.02,* Initial AOM-SOS score at trial entry,The 7-day weighted mean score,46,The 7-day weighted mean (SE) score was lower in the amoxicillinclavulanate group than in the placebo group (2.790.16 vs. 3.420.18; P=0.01).,47,Group A Group B

45、P Value *Day4-5 4% 23% 0.001 Day10-12 16% 51% 0.001,* At or before the day(n),Rates of clinical failure at different time,2.2Clinical Failure,48,n of C.F. n of a score2 % # *Day4-5 39 33 85% Day10-12 95 60 63%,*At or before the day(n) C.F. denotes clinical failure #No difference between the proporti

46、ons.,Proportions of a score2 in all clinical failure at different time,49,No child was categorized as having met the criteria for clinical failure on the basis of symptoms alone.,Mean scores of clinical failure and not clinical failure at different time,Mean score of C.F. Mean score of not C.F. At d

47、ay4-5 5.03.2 2.22.3 At day10-12 3.73.3 1.21.8,C.F. denotes clinical failure,50,2.3 Prognostic Factors and Effect Modifiers,At day 10 to 12 Childrens exposure or nonexposure, (P=0.007) Children with higher AOM-SOS scores at entry and with lower scores (P=0.004) Children with bilateral AOM with unilat

48、eral AOM (P=0.002) Children with more bulging of the tympanic membrane and with less bulging (P0.001),51,52,At day 1012 , the rates of clinical failure in severe and nonsevere conditions initially,Group A Group B * Severe 12/63(19%) 40/66(61%) Nonsevere 11/79(14%) 33/77(43%),* Severe denotes moderat

49、e or severe otalgia or T 39 during the preceding 24 hours,53,Children 18 to 23 months of age who received amoxicillinclavulanate had a higher rate of clinical failure than did children 12 to 17 months of age and children 6 to 11 months of age (38% vs. 12% and 11%, respectively),54,2.4Relapse and Res

50、idual Middle-Ear Effusion,At the day 2125 visit.,55,3.Nasopharyngeal Colonization and Other Outcomes,From day 1 to the day 2125 visit, there were no significant changes in either group in the rates of nasopharyngeal colonization with nonsusceptible Streptococcus pneumoniae.,56,There were no signific

51、ant differences between the study group in either the mean daily number of doses of acetaminophen administered (0.37 and 0.43, respectively; P=0.35) or the use of health care resources.,57,4.Complications and Adverse Events,Mastoiditis developed in one child in the placebo group on day 5. Diarrhea a

52、nd diaper-area dermatitis were more common among children who received amoxicillinclavulanate. Perforation of tympanic membrane Oral thrush Vomiting Rash,58,59,DISCUSSION,Children treated with amoxicillinclavulanate had consistently more favorable short-term outcomes, including: A sustained symptoma

53、tic response, An absence of otoscopic evidence of persistent middle-ear infection, A reduced rate of residual middle-ear effusion.,60,There were no significant between-group differences in the use of analgesic drugs or health care resources.,61,The rates of clinical failure were greatest among child

54、ren who were most severely affected initially.,62,The principal side effects were diarrhea and dermatitis in the diaper area, but the side effects were usually not severe enough to discontinue the treatment of the drugs.,63,In keeping with recent recommendations, 15 The authors chose the resolution

55、of symptoms and the symptom burden over time as the primary outcome of interest. To categorize overall outcomes as either clinical success or clinical failure according to the combination of symptomatic response and middle-ear findings.,15.Guidance for industry acute bacterial otitis media: developi

56、ng drugs for treatment. Revision 1. Rockville, MD: Food and Drug Administration, Center for Drug Evaluation and Research, 2008,64,The differences in symptom scores between the two study groups were modest during the first 10 days; the differences were observed mainly among the children with the most

57、 severe symptoms initially. In contrast, differences in the overall clinical response were substantial, irrespective of the initial severity of AOM.,65,Overall clinical response constitutes the more telling measure of outcome. Among infants and young children, AOM may be entirely asymptomatic16,17 Symptoms may not differentiate AOM from other respiratory illnesses18.,16.Hayden GF, Schwartz RH. Characteristics of earache among children with acute otitis media. Am