Rev. Assoc. Med. Bras. vol.58 número3 en v58n3a11

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ORIGINAL ARTICLE

319

SUMMARY

Objective: To evaluate the eicacy of the association of corticosteroids with the standard treatment of bacterial meningitis in pediatric patients. Methods: A systematic review of the literature was conducted through the MEDLINE database. Only randomized con-trolled trials comparing dexamethasone with placebo in the treatment of pediatric pa-tients with bacterial meningitis were included. Results: Eight articles met the inclusion criteria and were selected for analysis. here were no diferences in mortality (p = 0.86), and incidence of neurological (p = 0.41), and auditory (p = 0.48) sequelae between the groups. Conclusion: here are no beneits in associating corticosteroids with the stan-dard treatment of bacterial meningitis in pediatric patients.

Keywords: Bacterial meningitis; dexamethasone; mortality.

Study conducted at Academic Center of Studies and Research in Evidence-Based Medicine, Faculdade de Medicina de Santos, Centro Universitário Lusíada (UNILUS), Santos, SP, Brazil

Submitted on: 10/10/2011

Approved on: 01/20/2012

Correspondence to:

Wanderley Marques Bernardo Rua Oswaldo Cruz, 179 Boqueirão Santos – SP, Brazil CEP:11045-101 Tel: (13) 3221-3252 wmbernardo@usp.com

Conflict of interest: None.

Effectiveness of the association of dexamethasone with antibiotic

therapy in pediatric patients with bacterial meningitis

WANDERLEY MARQUES BERNARDO1, FELIPE TOYAMA AIRES2, FERNANDO PEREIRADE SÁ3

1_{PhD, Medical School, Universidade de São Paulo (USP); Coordinator of the ABM/CFM Guidelines Project; Professor of Evidence–Based Medicine, Faculdade de Medicina de Santos,}

Centro Universitário Lusíada (UNILUS), Santos, SP, Brazil

2_{Medical Student, UNILUS, Santos, SP, Brazil}

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WANDERLEY MARQUES BERNARDOETAL.

320 Rev Assoc Med Bras 2012; 58(3):319-322

INTRODUCTION

Bacterial meningitis is an important cause of death and permanent neurological disability despite advances in antimicrobial therapy and diagnostic techniques, and the improvement in general care. he physiopathology of neu-rological lesions in meningitis correlates with the severity of inlammation in the cerebrospinal luid (CSF), which can be alleviated with the use of systemic corticosteroids.

he adjunct therapy with dexamethasone is based on the observation that the host’s inlammatory response, es-pecially ater the start of antibiotic therapy, can prevent ad-verse results. Its use is controversial in patients older than two months, and it is banned in patients younger than this age.

he objective of this study is to evaluate the efective-ness of the association of corticosteroids with the standard treatment for bacterial meningitis in pediatric patients.

METHODS

A systematic review of the literature was conducted through MEDLINE, EMBASE and LILACS databases. he following combination of keywords was used through the Clinical Queries interface (herapy/Narrow): meningitis AND (adrenal cortex hormones OR dexamethasone). he survey was inished on October 8, 2011. Articles were se-lected based on their respective titles and abstracts.

Only randomized controlled trials comparing dexa-methasone with placebo in the treatment of pediatric patients with bacterial meningitis were included. he an-alyzed outcomes were mortality and incidence of neuro-logical and auditory complications.

he assessment of the methodological quality of the in-cluded studies was carried out using the criteria proposed by Jadad et al.1_{. hese criteria assess the description of} ran-domization, adequacy of ranran-domization, description of blinding, adequacy of blinding, and description of follow-up losses in a scale ranging from zero to ive points. Only studies with a score ≥ 3 were included in this review.

Univariate analysis of the dichotomous data was per-formed using a 2 × 2 table and compared by the chi-square test (Mantel-Haenzel) and the level of the null hypothesis rejection was set at 0.05. All data were analyzed by inten-tion to treat. Moreover, the power of each study was calcu-lated, adopting a minimum value of 80% as signiicant. A meta-analysis of the obtained data was performed for all outcomes.

RESULTS

A total of 73 articles were retrieved through the search strategy. Ten articles met the inclusion criteria and were selected for the analysis2-11_{. Of these, two studies were} ex-cluded because they were classiied as Jadad < 35,8_{. hus,} this review included data from eight primary studies,

totaling 1,460 patients (743 in the dexamethasone group and 717 in the control group).

All studies adequately described the sequence of pa-tient allocation, as well as the description of blinding and follow-up losses. hus, they received a Jadad score of 5.

he patients’ ages ranged between two months and 16 years of age. he antibiotic schemes included cefo-taxime 200 mg/kg/day2_{, ampicillin 200 mg/kg/day +} sulbactam 100 mg/kg/day6_{, ampicillin 300 mg/kg/day +} chloramphenicol 100 mg/kg/day7_{, benzathine/penicillin} 200,000 IU/kg/day + chloramphenicol 100 mg/kg/day9_, and cetriaxone 80-100 mg/kg/day3,4,10,11_{. he dose of} dexamethasone ranged from 0.6 to 0.8 mg/kg/ day for 2-4 days.

he diagnosis was conirmed by culture of the CSF in all tests. Regarding the etiologic agents, 180 cases (12%) were caused by Neisseria meningitidis, 429 cases (29%) by

Streptococcus pneumoniae, 535 cases (37%) by Haemoph-ilus inluenzae type B, 239 cases (16%) had no isolated agents, and 77 cases (5%) had other microorganisms as infection agents.

MORTALITY

he mortality rate in the study group was 18.0% (134 of 743 patients), whereas in the control group it was 17.6% (126 of 717 patients). here was no statistical diference between the groups (p = 0.86; I2 _{= 0%; Figure 1).}

NEUROLOGICAL SEQUELAE

he incidence of neurological sequelae in the interven-tion group was 16.8% (104 of 618 patients), whereas in the control group it was 18.5% (110 of 595 patients). here was no statistical diference between the groups (p = 0.41; I2 _{= 18%; Figure 2).}

AUDITORYSEQUELAE

he incidence of auditory sequelae in the interven-tion group was 28.2% (174 of 618 patients), whereas in the control group it was 29.9% (178 of 595 patients). here was no statistical diference between the groups (p = 0.48; I2 _{= 45%; Figure 3).}

POWER (TYPE II ERROR)

None of the primary studies included in this review had power > 80% capable of demonstrating diferences be-tween groups.

DISCUSSION

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EFFECTIVENESSOFTHEASSOCIATIONOFDEXAMETHASONEWITHANTIBIOTICTHERAPYINPEDIATRICPATIENTSWITHBACTERIALMENINGITIS

Figure 1 – Meta-analysis of the incidence of mortality evaluating the association of dexamethasone with antibiotic therapy in pediatric patients with bacterial meningitis.

Figure 2 – Meta-analysis on the incidence of neurological sequelae evaluating the association of dexamethasone with antibiotic therapy in pediatric patients with bacterial meningitis.

Figure 3 – Meta-analysis on the incidence of auditory sequelae evaluating the association of dexamethasone with antibiotic therapy in pediatric patients with bacterial meningitis.

Dexamethasone Control Risk difference Risk difference Study n Total n Total Weight M-F, Fixed, 95% CI M-F, Fixed, 95% CI

Kanra GY, 19956 ₂ ₂₉ ₁ ₂₇ _3.8% _{0.03 [-0.08; 0.15]}

Molyneux EM, 20029 ₉₅ ₃₀₇ ₉₂ ₂₉₅ _41.3% _{-0.00 [-0.08; 0.07]}

Odio CM, 19912 ₁ ₅₂ ₁ ₄₉ _6.9% _{-0.00 [-0.06; 0.05]}

Peltola H, 200710 ₂₃ ₁₆₆ ₂₆ ₁₆₃ _22.6% _{-0.02 [-0.10; 0.06]}

Qazi SA, 19967 ₁₂ ₄₈ ₅ ₄₁ _6.1% _{0.13 [-0.03; 0.29]}

Sankar J, 200711 ₀ ₁₂ ₁ ₁₃ _1.7% _{-0.08 [-0.27; 0.12]}

Schaad UB, 19933 ₀ ₆₀ ₀ ₅₅ _7.9% _{0.00 [-0.03; 0.03]}

Wald ER, 19954 ₁ ₆₉ ₀ ₇₄ _9.8% _{0.01 [-0.02; 0.05]}

Total (95% CI) 743 717 100.0% 0.00 [-003; 0.04]

Total of events 134 126 Heterogeneity: Chi2_{= 4.08; df = 7 (p = 0.77); I} 2 _{= 0%}

Overall effect test: Z = 0.17 (p = 0.86)

Dexamethasone

-0.5 -0.25 0 0.25 0.5 Control

Kanra GY, 19956 ₁ ₂₇ ₁ ₂₆ _4.4% _{-0.00 [-0.10; 0.10]}

Molyneux EM, 20029 ₆₉ ₂₀₉ ₅₆ ₂₀₂ _33.9% _{0.05 [-0.04; 0.14]}

Odio CM, 19912 ₄ ₅₁ ₁₂ ₄₈ _8.2% _{-0.17 [-0.31; -0.03]}

Peltola H, 200710 ₁₄ ₁₄₃ ₂₁ ₁₃₇ _23.1% _{-0.06 [-0.13; 0.02]}

Qazi SA, 19967 ₉ ₄₈ ₈ ₄₁ _7.3% _{-0.01 [-0.17; 0.16]}

Sankar J, 200711 ₀ ₁₂ ₁ ₁₂ _2.0% _{-0.08 [-0.29; 0.12]}

Schaad UB, 19933 ₃ ₆₀ ₅ ₅₅ _9.5% _{-0.04 [-0.13; 0.05]}

Wald ER, 19954 ₄ ₆₈ ₆ ₇₄ _11.7% _{-0.02 [-0.11; 0.06]}

Total (95% CI) 618 595 100.0% -0.02 [-006; 0.02]

Dexamethasone

-0.2 -0.1 0 0.1 0.2 Control

Kanra GY, 19956 ₂ ₂₇ ₆ ₂₆ _4.4% _{-0.16 [-0.35; 0.03]}

Molyneux EM, 20029 ₁₂₃ ₂₀₉ ₁₁₀ ₂₀₂ _33.9% _{0.04 [-0.05; 0.14]}

Odio CM, 19912 ₄ ₅₁ ₁₁ ₄₈ _8.2% _{-0.15 [-0.29; -0.01]}

Peltola H, 200710 ₁₈ ₁₄₃ ₁₈ ₁₃₇ _23.1% _{-0.01 [-0.08; 0.07]}

Qazi SA, 19967 ₁₁ ₄₈ ₅ ₄₁ _7.3% _{0.11 [-0.05; 0.26]}

Sankar J, 200711 ₃ ₁₂ ₃ ₁₂ _2.0% _{0.00 [-0.35; 0.35]}

Schaad UB, 19933 ₃ ₆₀ ₈ ₅₅ _9.5% _{-0.10 [-0.20; 0.01]}

Wald ER, 19954 ₁₀ ₆₈ ₁₇ ₇₄ _11.7% _{-0.08 [-0.21; 0.04]}

Total (95% CI) 618 595 100.0% -0.02 [-006; 0.02]

Dexamethasone

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WANDERLEY MARQUES BERNARDOETAL.

he rationale for the use of corticosteroids is the in-hibition of inlammatory cytokines in the CSF luid and, when administered 15-20 minutes before the antimicro-bial agents, the inhibition of the inlammatory response ater bacterial lysis by these drugs. However, experi-mental studies in vitro have demonstrated that cortico-steroids may be toxic to cultures of cortical and hippo-campal neurons. In animals, hippohippo-campal and striatal neurons are particularly vulnerable to dexamethasone. Corticosteroid therapy increases hippocampal apoptosis and also learning deicit12_{. Several studies published in} recent years have evaluated the beneit of dexamethasone in patients with bacterial meningitis, but the adjunct use of steroids remains controversial. Two meta-analyses of placebo-controlled studies have reached diferent conclu-sions. Havens et al.13_{demonstrated that dexamethasone} did not reduce mortality or neurologic abnormalities at hospital discharge and late follow-up, whereas Geiman and Smith14_{found that dexamethasone did not reduce} mortality, but decreased neurological sequelae and bi-lateral hearing loss up to six weeks ater discharge. he diference in neurological sequelae in the groups treated with dexamethasone was maintained six months ater discharge.

Some explanations for the inconsistent results are dis-cussed in the literature, and include: (i) diferent patient populations, (ii) various antibiotic regimens, (iii) lack of standardization of diagnostic tests to evaluate hearing loss in infants, and (iv) duration of disease and antimi-crobial treatment before admission.

None of the included studies had suicient power to detect a signiicant diference in mortality and morbid-ity between patients treated with adjunct dexamethasone and those treated with placebo.

hese data should be considered by pediatricians, in-tensivists, neurologists, and all those who treat patients with meningitis regarding the decision-making of pre-scribing or not prepre-scribing corticosteroids.

CONCLUSION

Based on the results of this review, it can be inferred that there are no beneits in the association of corticosteroids with the standard treatment of bacterial meningitis in pe-diatric patients.

REFERENCES

1. Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996;17(1):1-12.

2. Odio CM, Faingezicht I, Paris M, Nassar M, Baltodano A, Rogers J, et al. he beneicial efects of early dexamethasone administration in infants and chil-dren with bacterial meningitis. N Engl J Med. 1991;324(22):1525-31. 3. Schaad UB, Lips U, Gnehm HE, Blumberg A, Heinzer I, Wedgwood J.

Dexa-methasone therapy for bacterial meningitis in children. Swiss Meningitis Study Group. Lancet. 1993;342(8869):457-61.

4. Wald ER, Kaplan SL, Mason EO Jr, Sabo D, Ross L, Arditi M, Wiedermann BL, Barson W, Kim KS, Yogov R, et al. Dexamethasone therapy for children with bacterial meningitis. Meningitis Study Group. Pediatrics. 1995;95(1):21-8. 5. Ciana G, Parmar N, Antonio C, Pivetta S, Tamburlini G, Cuttini M.

Efective-ness of adjunctive treatment with steroids in reducing short-term mortality in a high-risk population of children with bacterial meningitis. J Trop Pediatr. 1995;41(3):164-8.

6. Kanra GY, Ozen H, Seçmeer G, Ceyhan M, Ecevit Z, Belgin E. Beneicial ef-fects of dexamethasone in children with pneumococcal meningitis. Pediatr Infect Dis J. 1995;14(6):490-4.

7. Qazi SA, Khan MA, Mughal N, Ahmad M, Joomro B, Sakata Y, et al. Dexameth-asone and bacterial meningitis in Pakistan. Arch Dis Child. 1996;75(6):482-8. 8. Daoud AS, Batieha A, Al-Sheyyab M, Abuekteish F, Obeidat A, Mahafza T.

Lack of efectiveness of dexamethasone in neonatal bacterial meningitis. Eur J Pediatr. 1999;158(3):230-3.

9. Molyneux EM, Walsh AL, Forsyth H, Tembo M, Mwenechanya J, Kayira K, Bwanaisa L, Njobvu A, Rogerson S, Malenga G. Dexamethasone treatment in childhood bacterial meningitis in Malawi: a randomized controlled trial. Lan-cet. 2002;360(9328):211-8.

10. Peltola H, Roine I, Fernández J, Zavala I, Ayala SG, Mata AG, et al. Adjuvant glycerol and/or dexamethasone to improve the outcomes of childhood bacte-rial meningitis: a prospective, randomized, double-blind, placebo-controlled trial. Clin Infect Dis. 2007;45(10):1277-86.

11. Sankar J, Singhi P, Bansal A, Ray P, Singhi S. Role of dexamethasone and oral glycerol in reducing hearing and neurological sequelae in children with bacte-rial meningitis. Indian Pediatr. 2007;44(9):649-56.

12. Weisfelt M, Hoogman M, van de Beek D, de Gans J, Dreschler WA, Schmand BA. Dexamethasone and long-term outcome in adults with bacterial meningi-tis. Ann Neurol. 2006;60(4):456-68.

13. Havens PL, Wendelberger KJ, Hofman GM, Lee MB, Chusid MJ. Corticoste-roids as adjunctive therapy in bacterial meningitis. A meta-analysis of clinical trials. Am J Dis Child. 1989;143(9):1051-5.