Hearing Impairment in Childhood Bacterial Meningitis Is Little Relieved by Dexamethasone or Glycerol. abstract ARTICLES

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1 ARTICLES Hering Impirment in Childhood Bcteril Meningitis Is Little Relieved by Dexmethsone or Glycerol AUTHORS: Heikki Peltol, MD, Irmeli Roine, MD, b Josefin Fernández, MD, c Antonio González Mt, MD, d Inés Zvl, MD, e Silvi Gonzlez Ayl, MD, f Antonio Arbo, MD, g Ros Bologn, MD, h José Goyo, MD, i Edurdo López, MD, j Gret Miño, MD, k Solnge Dourdo de Andrde, MD, l Seppo Srn, PhD, m nd Tpni Juhiinen, MD n Division of Peditric Infectious Diseses, Hospitl for Children nd Adolescents, nd n Deprtment of Audiology, Helsinki University Centrl Hospitl, Helsinki, Finlnd; b Division of Peditric Infectious Diseses, Universidd Diego Portles, Fcultd de Ciencis de l Slud, Sntigo, Chile; c Division of Peditric Infectious Diseses, Clinic Infntil Dr Robert Reid Cbrl, Snto Domingo, Dominicn Republic; d Division of Peditric Infectious Diseses, Hospitl Peditrico Dr Agustin Zubillg, Brquisimeto, Venezuel; e Division of Peditric Infectious Diseses, Hospitl de Niños Dr Roberto Gilbert, Guyquil, Ecudor; f Division of Peditric Infectious Diseses, Hospitl de Niños Sor Mri Ludovic, L Plt, Argentin; g Division of Peditric Infectious Diseses, Instituto de Medicin Tropicl, Universidd Ncionl de Asunción, Asunción, Prguy; h Division of Peditric Infectious Diseses, Hospitl de Peditrí Dr Jun P. Grrhn, Buenos Aires, Argentin; i Division of Peditric Infectious Diseses, Hospitl Universitrio de los Andes, Mérid, Venezuel; j Division of Peditric Infectious Diseses, Hospitl de Niños Dr Ricrdo Gutiérrez, Buenos Aires, Argentin; k Division of Peditric Infectious Diseses, Hospitl del Niño Dr Frncisco de Icz Bustmnte, Guyquil, Ecudor; l Institute for Tropicl Diseses, Mnus, Brzil; nd m Deprtment of Public Helth, University of Helsinki, Helsinki, Finlnd KEY WORDS dexmethsone, glycerol, meningitis, hering impirment, defness ABBREVIATIONS Hib Hemophilus influenze type b CSF cerebrospinl fluid BERA brinstem evoked response udiometry OR odds rtio CI confidence intervl This tril hs been registered t (identifier ISRCTN ). doi: /peds Accepted for publiction Jul 10, 2009 Address correspondence to Heikki Peltol, MD, Helsinki University Centrl Hospitl, Hospitl for Children nd Adolescents, 11 Stenbäck St, PO Box 281, HUS Helsinki, Finlnd. E-mil: heikki.peltol@hus.fi PEDIATRICS (ISSN Numbers: Print, ; Online, ). Copyright 2009 by the Americn Acdemy of Peditrics FINANCIAL DISCLOSURE: Modest remunertion of enrolling ptients ws obtined by the liison persons in the institutions prticipting the study. All this money cme from the sources tht re listed in Acknowledgments. The uthors hve occsionlly received trvel costs to prticipte in the scientific meetings or grnts from vrious phrmceuticl compnies, none of which hd ny role in this study. Dr Peltol is currently clinicl scientific consultnt for Serum Institute of Indi, Ltd. WHAT S KNOWN ON THIS SUBJECT: Adjuvnt dexmethssone is believed to prevent or relieve hering impirment, especilly in Hib meningitis if instituted before ntimicrobil tretment, but no single study hs documented this effect. All informtion derives from metnlyses in which profoundly different popultions hve been combined. WHAT THIS STUDY ADDS: This rndomized, double-blind clinicl tril, the lrgest in peditrics, reveled no significnt relief in hering impirment by djuvnt intrvenous dexmethsone, orl glycerol, or their combintion. Insted, the child s presenting sttus nd ge were the most importnt predictors of hering loss. bstrct OBJECTIVE. Severl studies hve evluted dexmethsone for prevention of hering loss in childhood bcteril meningitis, but results hve vried. We compred dexmethsone nd/or glycerol recipients with plcebo recipients, nd mesured hering t 3 threshold levels. METHODS. Children ged 2 months to 16 yers with meningitis were treted with ceftrixone but were double-blindly rndomly ssigned to receive djuvnt dexmethsone intrvenously, glycerol orlly, both gents, or neither gent. We used the Glsgow com scle to grde the presenting sttus. The end points were the better er s bility to detect sounds of 40 db, 60 db, nd 80 db, with these thresholds indicting ny, moderte-to-severe, or severe impirment, respectively. All tests were interpreted by n externl udiologist. Influence of covrites in the tretment groups ws exmined by binry logistic regression. RESULTS: Of the 383 children, mostly with meningitis cused by Hemophilus influenze type b or Streptococcus pneumonie, 101 received dexmethsone, 95 received dexmethsone nd glycerol, 92 received glycerol, nd 95 received plcebo. Only the presenting condition nd young ge predicted impirment independently through ll threshold levels. Ech lowering point in the Glsgow scle incresed the risk by 15% to 21% (odds rtio: 1.20, 1.21, nd 1.15 [95% confidence intervl: , , nd ]; P.005,.003, nd.039) for ny, moderte-to-severe, or severe impirment, respectively. Ech incresing month of ge decresed the risk by 2% to 6% (P.0001,.0007, nd.041, respectively). Neither dexmethsone nor glycerol prevented hering loss t these levels regrdless of the custive gent or timing of ntimicrobil gent. CONCLUSIONS: With bcteril meningitis, the child s presenting sttus nd young ge re the most importnt predictors of hering impirment. Little relief is obtined from current djuvnt medictions. Peditrics 2010;125:e1 e8 PEDIATRICS Volume 125, Number 1, Jnury 2010 e1

2 A child who survives bcteril meningitis but is left with serious hering impirment is lwys trgedy, but especilly so if chnces for rehbilittion nd hving hering device do not exist. This is the relity for most of the world s children. In resource-poor setting, def child, unble yet to spek, remins socilly isolted, nd the long-term survivl is unlikely. 1,2 The best solution would be to implement lrge-scle Hemophilus influenze type b (Hib) nd Streptococcus pneumonie vccintions, 3,4 but globlly, few children re privileged to those. Hering impirment occurs erly in meningitis, 5,6 nd once developed, llevites little in time, if t ll. 6 8 Overll, impirment is reported in 30% to 50% in pneumococcl, in 10% to 30% in Hib, nd in 5% to 25% in meningococcl meningitis Almost certinly these estimtes re too low, becuse most dt rrive from the best centers. Worldwide, most survivors re dischrged without relible informtion on hering. Furthermore, hering impirment hs been defined dissimilrly in different studies. Childhood hering impirment is no doubt n understted nd growing problem, especilly in developing countries. 18 Becuse modern ntimicrobil gents such s third-genertion cephlosporins hve not improved the sitution, 19 ptients hve sought relief from djuvnt medictions. Dexmethsone hs well documented fvorble biochemicl effects in Hib meningitis, but no single peditric study which hs used n optiml ntimicrobil gent hs reched significnce, when hering impirment hs been exmined s n outcome of its own. Distinguishing different outcomes is, however, importnt, becuse hering is likely impired by other mechnisms thn those leding to neurologic sequele or deth. 25,26 Animl studies 21 suggest tht the timing of dexmethsone versus the institution of ntimicrobil gents is crucil (dexmethsone should be given first or, t the ltest, with ntimicrobil gents). However, even tking this requirement into ccount, the first sufficiently powered (N 598) humn study from Mlwi did not find dexmethsone beneficil. 27 Unfortuntely, economic constrints hindered routine use of third-genertion cephlosporins in tht pivotl tril. A Cochrne nlysis 28 concluded tht dt support the use of djunctive corticosteroids in children in high-income countries, but the popultions included were profoundly dissimilr, different thresholds for hering were used, nd the child s presenting condition ws totlly neglected despite the presenting sttus is the single most importnt predictor of deth nd/or severe neurologic sequele, 29 nd likely, of hering impirment. Obviously, the finl sttus of djuvnt dexmethsone in childhood meningitis remins still unsettled. In Peditrics more thn 30 yers go, Herson nd Todd 30 reported tht glycerol (1-propnetriol, 2-propnetriol, nd 3-propnetriol), n essentil compound of humn metbolism, hyperosmolr gent, nd n osmotic diuretic might be of some benefit in the prevention of sequele in Hib meningitis. The results of our pilot study in Finlnd 36 greed with this view, becuse they hinted tht glycerol my equl intrvenous dexmethsone in the prevention of hering loss. However, the size of tht study ws too smll to llow conclusions. Therefore, we lunched much lrger tril in Ltin Americ. One of the min lessons from tht mjor undertking 25 ws tht neither dexmethsone nor glycerol prevented defness, this being defined s the better er s hering threshold level t 80 db. Although tht messge ws cler, 2 questions remined unnswered: first, would dexmethsone, glycerol, or their combintion relieve milder impirment (moderte or more severe impirment hs been exmined in most previous trils)? Second, could the erlier studies fvoring dexmethsone in Hib meningitis be explined by their too smll smple size, nd/or by confounding covrites (ptient chrcteristics)? METHODS Setting nd Ptients The study setup hs been described erlier. 25 In short, the tril ws prospective, rndomized, nd double-blind, comprising children ged 2 months to 16 yers with bcteril meningitis from 10 institutions (listed in the uthor ffilitions) of Argentin, Brzil, Dominicn Republic, Ecudor, Prguy, nd Venezuel in The study ws pproved by the ethicl committees of the institutions, nd legl gurdins consent ws required. The tril ws designed, conducted, nd nlyzed independently of ny phrmceuticl compnies. The min im ws to exmine whether the dismloutcomesofbcterilmeningitis deth, severe neurologic sequele, nd/or hering impirment could be prevented with djuvnt dexmethsone, orl glycerol, or their combintion. A child t n pproprite ge ws included in the study if the results of the cerebrospinl fluid (CSF) culture proved positive, or, if the results of the blood culture were positive, he or she hd comptible symptoms nd signs of meningitis. If the results of both cultures proved negtive, child with clinicl meningitis ws still included if t lest 3 of the following 4 criteri were fulfilled: CSF showed pleocytosis ( 1000 leukocytes per L); decresed CSF glucose level ( 40 mg/dl); incresed CSF protein concentrtion e2 PELTOLA et l

3 ARTICLES ( 40 mg/dl); or serum C-rective protein level ws incresed ( 40 mg/l). The exclusion criteri were history of recent hed injury, previous neurosurgicl procedure (eg, intrcrnil shunt plcement), previous neurologic disese (eg, cerebrl plsy nd Down syndrome), immunosuppression, nd known hering impirment. Predmission ntimicrobil therpy ws registered in detil but did not prevent study enrollment. Ceftrixone, with dose of 80 to 100 mg/kg once dily for 7 to 10 dys intrvenously ws given to ll children who were rndomly ssigned to receive lso djuvnt dexmethsone intrvenously (0.15 mg/kg dministered every 6 hours for 48 hours, 38 first dose 15 minutes before ceftrixone, whenever possible) nd plcebo orlly; 85% of ptients received glycerol orlly (1.5 g [1.5 ml] per kg every 6 hours for 48 hours, the mximum per dose being 25 ml for 48 hours) nd plcebo intrvenously; both gents; or neither gent. Dexmethsone, glycerol, nd their plcebo preprtion (sline nd crboxymethylcellulose, respectively) were delivered in identicl mpoules or bottles, nd were lbeled with study code. No person treting the child or being otherwise involved in the study ws wre of child s specific tretment until the code ws broken. Becuse ll children received drug or plcebo orlly nd vi intrvenous line nd the preprtions looked similr, the pproch ws entirely doubleblind. The Glsgow com scle, djusted for ge, ws used to grde the presenting sttus. 37 Among other registered covrites were the potentil use of pretretment ntimicrobil gents, signs of incresed intrcrnil pressure, convulsions, nd severl blood nd CSF indices. Audiology The dt on profound defness, better er s bility to detect sounds of 80 db, hve been published erlier. 25 Here we give more detiled informtion becuse, resources permitting, 3 different thresholds of hering were used, 40 db, 60 db, nd 80 db, with these end points indicting ny moderteto-severe, or severe impirment, respectively. Brinstem evoked response udiometry (BERA) (uditory brinstem response) ws pplied, unless the child ws old enough for trditionl pure tone udiometry. Before testing, otitis medi or other benign resons for reduced hering were excluded with otoscopy or tympnometry. The test personnel were kept unwre of ll tretment detils. A copy of the test curves ws sent to n externl udiologist (Dr Juhiinen, former hed of Deprtment). Kept blinded of ll other detils, he gve written interprettion for ech child. In pure tone threshold udiometry, the men threshold vlue (0.5, 1.0, nd 2.0 khz) ws used. A test result of BERA ws interpreted only if the threshold level showed n indisputbly detectble wve V response t the minimum level of coustic stimultion. Recordings of only the supr-threshold stimultion led to the exclusion of the child becuse of unrelible extrpolting of such result into sensorineurl hering impirment. Becuse hering defect begins to trouble the child t 40 db, ll findings up to this level were deemed norml. The impirment ws considered mild t thresholds 41 to 59 db, moderte t 60 to 79 db, nd severe t 80 db. In ddition, we checked how mny children filed to respond to tones of 100 db (totl defness, would need cochler implnt). Smple Size nd Sttisticl Anlysis The smple size for the whole study 25 ws bsed on the ssumption tht given djuvnt therpy versus plcebo would decrese the sequel rte from 20% to 5%. Accepting n error of 5% in 2-tiled test, nd power of 80%, t lest 88 ptients in ech rm were required. For compring mens, Student s t test ws used, 2 being dopted for proportions. To identify fctors potentilly ssociting with the udiologicl outcomes, ll covrites registered on dmission were exmined 1 by 1 in univrite binry logistic nlysis. The 3 dependent vribles were s follows: (1) ny degree (better er s threshold 40 db) of hering impirment; (2) t lest moderte hering loss ( 60 db); nd (3) severe impirment ( 80 db). All vribles with P vlue of.1 were included together s independent vribles in multivrite logistic models, by using the sme dependent vribles s before. When exmining the 3 different tretment groups, the plcebo recipients served s the reference group. Thus, ech tretment s effects on hering could be individulized, nd the vribles predicting hering loss could be independently identified. Becuse the strongest evidence for dexmethsone in peditric meningitis stems from Hib meningitis without pretretment ntimicrobil gents nd with dexmethsone instituted before or simultneously with the first dose of n ntimicrobil gent, preplnned subgroup nlysis ws performed for ptients with these chrcteristics. The results re expressed s odds rtios (ORs) with 95% confidence intervls (CIs) nd P vlues, of which those.05 were considered significnt. RESULTS Ptient Chrcteristics Figure 1 shows the tril profile. Of the 654 children entering the study, 87 (13%) died, but of them, hering ws tested in 4 cses. Testing ws not done or ws defectively performed in 33 PEDIATRICS Volume 125, Number 1, Jnury 2010 e3

4 FIGURE 1 Study profile. In ll, 87 ptients (13%) died in the study, but hering could be tested in 4 of these children. DXM indictes dexmethsone; PLA, plcebo; GLY, glycerol. cses, nd of 155 children, only the loclly mesured 80 db test result ws vilble. Thus, 383 children remined for our detiled nlysis. The 188 excluded ptients did not differ from the 383 included ptients in ge (37 43 vs months; P.13), the Glsgow com score ( vs ; P.23), djuvnt tretment (Fig 1; P.35), or the frequency of the 80 db hering defect mesured loclly (10 of 155 vs 33 of 383; P.40). They did differ in country of origin (84 of 155, vs 81 of 383 [P.0001] were from Argentin, where only the 80 db threshold ws frequently used), in etiology (more meningococcus [55 of 188 vs 54 of 383; P.0001] nd less cses cused by other gents [5 of 188 vs 7 of 383; P.0001]), use of predmission ntimicrobil gents (41 of 156 vs 145 of 360; P.002), nd the time of the Glsgow score to return to 15 (2.5 vs 3.5 dys; P.002). Two children hd only 1 er tested (norml); they were included in nlysis. Of the 383 children, 91 were from Venezuel, 87 from Dominicn Republic, 81 from Argentin, 74 from Ecudor, 40 from Prguy, nd 10 from Brzil. The series comprised 146 cses of Hib, 70 of pneumococcl, 54 of meningococcl, nd 7 of other type of meningitis; 106 cses remined bcteriologiclly unidentified. The 4 tretment groups distributed evenly (Fig 1): 101 children hd received dexmethsone only; 95 children received the dexmethsoneglycerol combintion; 92 children received glycerol only; nd 95 children received plcebo only. Audiology Two of 3 children (n 248 [66%]) recovered without meningful hering loss. Mild impirment ws detected in 44 children (11% of ll 383 children, 33% of 132 impired children), moderte-to-severe impirment ws detected in 46 children (12%, 35%), nd severe impirment ws detected in 27 children (7%, 20%); 15 children (4%, 11%) becme totlly def. The results for ll meningitides, nd for Hib, pneumococcl, nd non-hib nonpneumococcl meningitis re presented in Tble 1. Regrdless of the threshold level, no tretment differed from ech other or plcebo. Deletoriousness of Hib nd non-hib nonpneumococcl meningitides ws striking, being close to tht of pneumococcl meningitis. Ineffectiveness of ll djuvnt medictions TABLE 1 Hering Sttus After Any Type of Meningitis nd Specificlly After Hib, S pneumonie, or Non-Hib, Non S pneumonie Meningitis (Better Er Recording) Threshold db Dexmethsone Dexmethsone Glycerol Glycerol Plcebo n % n % n % n % All meningitides (N 383) n Hib meningitis (N 146) n S pneumonie meningitis (N 70) n Non-Hib, non S pneumonie meningitis (N 167) n The series comprises cses cused by N meningitidis (n 54) nd by other bcteri (n 7); 106 cses remined without etiology disclosed. e4 PELTOLA et l

5 ARTICLES TABLE 2 Influence of Ptient Chrcteristics (Covrites) on Hering t Vrious Threshold Levels (Univrite Binry Logistic Model) Vrible n 40 db 60 db 80 db OR 95% CI P OR 95% CI P OR 95% CI P Age Mle ptients Incresed intrcrnil pressure for 24 h No convulsions Previous ntimicrobil gents b Ech point 15 c in Glsgow com scle Systolic blood pressure, mm Hg Pulse, frequency per min Cpillry filling time, s CSF Leukocytes per L Glucose, mg/dl Protein, g/dl Blood Leukocytes per L Hemoglobin, g/dl Sodium, mmol/l Glucose, g/dl Etiology Hib S pneumonie N meningitidis Irritbility, vomiting, bsent look, neck rigidity, or convulsions observed by mother. b During 72 hours before the dignosis of bcteril meningitis. c Mximum score is 15. remined essentilly the sme when cses with nd without proven etiology were exmined. Six covrites were ssocited with poorer hering through ll threshold levels: low ge; low Glsgow com score; low CSF glucose concentrtion; low blood leukocyte count; low hemoglobin level; nd the Hib etiology (Tble 2). To lesser extent, impirment ws ssocited with convulsions, pretretment ntimicrobil gents, low CSF glucose concentrtion, blood leukocyte count, nd the pneumococcl etiology. Meningococcl meningitis left often hering undmged. Effects of the 3 djuvnt medictions versus plcebo re presented in Tble 3. Dexmethsone showed some tendency towrd protection ginst hering loss, but significnce ws not reched t ny prticulr level. Nor ws difference found in the 130 cses of nonpretreted Hib meningitis in which ceftrixone ws instituted only fter dexmethsone (Tble 4). The most fvorble result for dexmethsone ws t the level of 80 db, ll meningitides combined (OR: 0.40 [95% CI: ]; P.075). Once the significnt covrites were submitted to multivrite logistic model, the picture becme even clerer (Tble 5): the child s presenting condition nd ge were the only fctors tht independently predicted hering impirment through ll threshold levels. Notbly, ech lowering point in the Glsgow scle, strting from the mximum score of 15, incresed the risk significntly; OR vried from 1.20 for ny impirment (95% CI: ; P.005) to 1.15 for defness (95% CI: ; P.039). Inversely, ech incresing month of ge decresed the risk of hering impirment by 2% to 6% for ny, moderte-to-severe, nd severe im- TABLE 3 Bilterl Hering Impirment in the 3 Adjuvnt Mediction Groups Versus Plcebo Recipients t Vrious Threshold Levels (All Meningitides Combined, Univrite Logistic Model) Threshold, db Dexmethsone (N 101) Dexmethsone Glycerol (N 95) Glycerol (N 92) n OR 95% CI P n OR 95% CI P n OR 95% CI P Number of children. PEDIATRICS Volume 125, Number 1, Jnury 2010 e5

6 TABLE 4 Bilterl Hering Impirment in Hib Meningitis in the 3 Adjuvnt Mediction Groups Versus 38 Plcebo Recipients t Vrious Threshold Levels Threshold, db Dexmethsone (N 33) Dexmethsone Glycerol (N 28) Glycerol (N 31) n OR 95% CI P n OR 95% CI P n OR 95% CI P No previous ntimicrobil gent ws given, nd dexmethsone ws instituted before or, t the ltest, with the first dose of ceftrixone. Univrite logistic model ws used. Number of children. pirment (OR: 0.97, 0.96, nd 0.98 [95% CI: , , nd ]; P.0001,.0007, nd.041, respectively). Pretretment ntimicrobil gents incresed the risk of severe hering impirment, OR: 2.25 (95% CI: ; P.039). Also blood leukocyte count below / L incresed the risk of severe impirment (OR: 2.32 [95% CI: ]; P.043), but overll, the effects of these 2 cofctors were much smller thn those of the presenting sttus nd low ge (Tble 5). Surprisingly, etiology per se plyed less prominent role. Our expert of udiology greed very well with the locl interprettions, becuse his dignosis of defness ws the sme in 97% of ptients (373 of 383). In 2.5% of ptients (11 of 383), the externl udiologist detected defness which ws not found loclly. Exmined vice vers, our expert disgreed on the locl interprettion of defness in only 0.5% of ptients (2 of 383). DISCUSSION The comprehensiveness of our series, being mnifold to ll previous childhood meningitis trils except tht from Mlwi, 27 llowed us to relte hering impirment to number of covrites, not only to the custive gent or timing of ntimicrobil gents. As 3 threshold levels were used, we believe tht it is difficult to rech better ccurcy from children who were mostly infnts or t toddler ge. The rndomized, double-blind design, nd the test results interpreted by n independent expert with decdes-long experience in peditric udiology dd to the relibility of dt. The on-dmission chrcteristics of ptients 25,29 were comprble to those in privileged country, nd previous informtion from the sme institutions 13,17,39 shows tht the outcomes in these centers compete well to those in the industrilized world. Insufficient funding in this study, which sought for simple nd inexpensive tretment modlities, ws mjor obstcle. Therefore, economic constrints hindered full udiologicl testing in ll cses. The possibility tht this shortcoming bised the results cnnot be excluded, but we deem it very unlikely becuse ll nontesting occurred t rndom. The min lesson lerned ws tht, insted of the custive gent or timing of ntimicrobil gents, it were fundmentlly the child s presenting sttus nd young ge tht ffected the TABLE 5 Risk of Bilterl Hering Impirment t Vrious Threshold Levels in the 3 Adjuvnt Mediction Versus Plcebo Groups 40 db (N 281) 60 db (N 307) 80 db (N 319) OR 95% CI P OR 95% CI P OR 95% CI P Age, ech incresing mo Etiology Hib S pneumonie N meningitidis Previous ntimicrobil gents No previous convulsions Blood leukocytes / L Blood hemoglobin 7 g/dl CSF glucose 20 mg/dl Ech point 15 in Glsgow com scle Pulse frequency 120/min Cpillry filling time 3 s Adjuvnt mediction Dexmethsone Dexmethsone glycerol Glycerol Multivrite logistic model ws used, including covrites reching P.1 in univrite nlysis. Number of children with ll dt for multivrite nlysis. e6 PELTOLA et l

7 ARTICLES udiologicl outcome. The effect of the clinicl condition ws so drmtic tht ech lowering point in the Glsgow com scle incresed the risk of hering impirment by 15% to 20% (Tble 5). No djuvnt mediction bted this effect, not even if the dt were sorted gentwise or ccording to the timing of ntimicrobil therpy. Thus, the experience 8 10 (lbeit not demonstrted by this study) tht pneumococcl meningitis in survivors is more deletorious to the hering orgn thn other meningitides, seems to be more ssocited with the ptient s frequently poor clinicl condition in this type of meningitis 29 thn with the gent per se s such n interesting finding. Neither djuvnt prevented hering impirment, but becuse dexmethsone showed tendency towrd protection when ll meningitides were combined, there seems to be subset of ptients which sometimes benefits from dexmethsone. They re, however, not strightforwrdly those with Hib meningitis who hve not received pretretment ntimicrobil gents. For the time being, we simply re unble to identify these few ptients. Studies nd met-nlyses in which sttisticl significnce for n djuvnt mediction hs been reched by combining different outcomes should not be tken s proof of tht tretment s benefit regrding hering. Also, neglecting key issue, the presenting condition, 29 in such vrible disese s bcteril meningitis is shortcoming which blurs well-blnced interprettion of the results from dissimilr studies. A direct comprison is founded only if the disese severity is scored with the sme criteri, nd ll the mjor covrites ffecting the outcomes re tken into ccount. We foresee tht the future met-nlyses will look different from those which re currently cited. Although the results of this study were rther negtive, it is of specil note tht our udiologist greed very well with the locl interprettions. An overll 97% ccordnce ws reched, lthough our expert confined himself in indisputble observtions, used stringent criteri, nd ccepted only the responses one recognized beyond doubt. Possibly our results were so negtive becuse, for the first time, hering impirment ws quntittively relted to series of covrites some of which ffected the hering more thn one previously hs relized. We underline the need of n externl expert to interpret ll test results with the sme criteri. In Mlwi, n expert visited the site from the United Kingdom, 27 but we cnnot esily compre the results, becuse in Mlwi lso behviorl distrction test ws used. Here we rrive t nother problem in meningitis studies: udiology is mesured with dissimilr methods, nd where the methods re the sme (preferbly BERA), different thresholds re used. We should soon strt using methodology tht llows direct comprisons between studies. And in those studies, the presenting sttus nd the ge should be tken into ccount. CONCLUSIONS Neither intrvenous dexmethsone nor orl glycerol (or their combintion) prevented hering impirment in bcteril meningitis of childhood, when the effects were studied t the threshold levels of 40, 60, nd 80 db. Meningitis being cused by Hib, nonreceipt or pretretment ntimicrobil gents, nd the djuvnt strted before ntimicrobil therpy did not chnge the results. To sve child from hering loss in meningitis, better gents thn dexmethsone or glycerol should be sought. ACKNOWLEDGMENTS We re especilly indebted to Dr Rlf Clemens, then with GlxoSmithKline, who orgnized the first grnt for this non profit-mking study. Additionl support ws obtined from the Alfred Kordelin, Päivikki nd Skri Sohlberg, nd Sigfrid Jusélius Funds, nd the Foundtion for Peditric Reserch, Finlnd. Frmci Ahumd, Sntigo de Chile, donted glycerol nd the plcebo preprtions. Lbortorio de Chile, Sntigo, prtly donted ceftrixone. The following collegues performed the udiologicl tests loclly: Snto Domingo: Dr Clemente Teorero; Brquisimeto: Dr Beil Pire; Guyquil: Dr Pedro Toledo; Asunción: Dr Arturo Cmpos; nd Buenos Aires: Dr Mrí E. Prieto. The following collegues prticipted ctively in the study by enrolling nd following up the ptients: Snto Domingo: Drs Jesús Feris-Iglesis nd Chbel Peñ; Guyquil: Drs Mriell Chng nd Ruth Flor; L Plt: Dr Mrí Ros Agosti; Brquisimeto: Drs Mirim Mitin nd Lesbi Colin; Asunción:Dr Dolores Lover; Buenos Aires: Drs Mrí Teres Rosnov, Ilse Villroel, nd Mri Crmen Cifró; Mérid: Dr Mgdlen Corre; nd Mnus: Drs Mrcos Fernndes nd Vni Przeres. Bcteriology ws directed by the following collegues: Snto Domingo: Dr Jcqueline Snchez; Brquisimeto: Dr Rfel Ros; Asunción: Dr Wilm Bsuldo; Buenos Aires: Dr Mri del Crmen Ceinos; nd Mnus: Dr Rossiclei Monte. The formul for the plcebo of glycerol ws developed by Dr Pedro Vlor, PhD, Buenos Aires. PEDIATRICS Volume 125, Number 1, Jnury 2010 e7

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