Do corticosteroids prevent hearing loss in pediatric bacterial meningitis? An analysis of the evidence.

Abstract

We reviewed the MEDLINE database of articles published from January 1966 through December 2001 in search of data on the ability of the corticosteroid dexamethasone to protect against sensorineural hearing loss in children with meningitis. We found 1,034 articles that matched our keyword entries, and after various exclusions, we winnowed this number down to 16 articles that contained adequate data regarding audiometric evaluation and follow-up. The 16 articles included reports of 11 randomized controlled trials (only 10 are considered in this analysis), two meta-analyses, two retrospective case series, and two consensus statements. Of the 10 clinical trials (all of which contained level I evidence), four showed that dexamethasone had a protective effect and six showed that it did not. The authors of the two meta-analyses (both level I) concluded that there was a protective effect, and the authors of the two retrospective case series (both level IV) concluded that there was not. Both consensus statements (both level V) recommended the use of dexamethasone only in Haemophilus influenzae meningitis. We conclude that well-designed studies with level I evidence have shown that the benefit of dexamethasone in preventing hearing loss in children with meningitis remains unclear. Significant variables in treatment response include the specific pathogen, the type of antibiotic, and the timing of dexamethasone administration.

Introduction

Bacterial meningitis affects approximately 15,000 infants and children in the United States each year. (1) Despite the availability of potent antimicrobial agents, 1.5 to 5% of children with bacterial meningitis die; among the survivors, 15 to 20% have significant long-term neurologic sequelae, such as epilepsy, motor dysfunction, and retardation. (2-4) These sequelae are more common in patients who have more severe disease at presentation, as is frequently seen in developing countries. (5-8)

By far, the most common long-term effect of bacterial meningitis in children is sensorineural hearing loss (SNHL), which is often severe or profound and bilateral. (2,9,10) The reported incidence of SNHL ranges from 5% to more than 20%, depending on the type of audiologic surveillance. (11)

During the past 2 decades, several excellent randomized trials have been conducted to investigate the effectiveness of the corticosteroid dexamethasone in preventing the sequelae of bacterial meningitis in infants and children. (12-21) However, results have been conflicting. (22,23) The aim of our review was to evaluate the quality of the evidence in these studies in the hope of arriving at a definitive conclusion about the ability of dexamethasone to protect against SNHL in children with bacterial meningitis.

Materials and methods

We searched the MEDLINE database of articles published from January 1966 through December 2001 using the MESH terms meningitis, hearing loss, and dexamethasone. The search identified 1,034 articles that matched the keyword entries. Of these, 170 articles were relevant to the protective effect of dexamethasone in bacterial meningitis. The abstracts of these articles were reviewed by 5 individuals: 3 senior otolaryngology faculty members, 1 pediatric otolaryngology fellow, and 1 senior resident. The reviewers categorized each report according to the 5-point grading system for data class developed by the Oxford Centre for Evidence-Based Medicine. After excluding reviews, case reports, non-English-language publications, editorial comments, etc., we were left with 65 articles that addressed the issue of dexamethasone and meningitis. Of these, 16 contained adequate data regarding audiometric evaluation and follow-up, and these articles served as the foundation of this evidence-based analysis.

Results

The 16 articles included 11 randomized controlled trials (only 10 of which are included in this analysis), (12-21) two meta-analyses, (22,23) two retrospective case series, (24,25) and two consensus statements (1,26) (tables 1 and 2). The evidence contained in all the clinical trials and both meta-analyses was rated as level I. The 2 case series were rated level IV, and the two consensus statements were rated level V.

Of the level I reports, four randomized controlled trials (13,17,20,21) and both meta-analyses showed that dexamethasone did confer some beneficial effect in preventing SNHL, and six randomized controlled trials (12,14-16,18,19) showed that it did not (table 1).

The authors of the two retrospective case series concluded that dexamethasone conferred no protective benefit. (24,25) Both consensus statements recommend the use of dexamethasone only in patients with Haemophilus influenzae meningitis. (1,26)

We conclude, therefore, that the benefit of dexamethasone in preventing SNHL in children with meningitis remains unclear, despite the publication of well-designed studies with level I evidence. Significant variables affecting treatment response include the specific pathogen, the type of antibiotic, and the timing of dexamethasone administration.

Discussion

Two strategies have evolved to reduce the disease burden in patients with bacterial meningitis: (1) active immunization against the most common pathogens and (2) reduction of central nervous system inflammation with anti-inflammatory therapy. (18) Immunization is highly effective, and it has already significantly reduced the number of meningitis cases caused by H influenzae. (27-29)

Steroids are the only anti-inflammatory agents that have been extensively studied in clinical trials for the prevention of neurologic complications of meningitis, including SNHL. There is good evidence that the inflammatory cascade induced by bacterial products during bacterial lysis is initiated and maintained by cytokines--tumor necrosis factor alpha (TNF-[alpha]) and interleukin- 1-beta (IL-1[beta]) in particular. (30-32) Studies in rabbits have shown that pretreatment with a steroid prior to intrathecal injection with H influenzae results in a reduction in concentrations of TNF-[alpha] and IL-1[beta]. (33-35) Similar findings have been seen in animal models of pneumococcal meningitis. (36,37)

The modern era of steroid use in bacterial meningitis trials began in Dallas with a report of two double-blind, randomized trials by Lebel et al in 1988. (21) The first trial showed that patients who received adjunctive dexamethasone had a significantly lower rate of SNHL than did patients who received antibiotic alone. However, the antibiotic used in the first trial was cefuroxime, an agent that is not often used because it requires a relatively long time to sterilize the cerebrospinal fluid (CSF). (38,39) Additionally, most of the patients in that trial (77%) had H influenzae type b meningitis, which is believed to be more responsive to dexamethasone. Therefore, we did not include the results of that first study in this analysis. In the second arm of this study, which is included in this analysis, the authors used ceftriaxone, which is a much more effective agent and rapidly sterilizes CSE Dexamethasone was found to be protective in this study, as well.

The reasons for the lack of definitive findings in these level I trials can be attributed to three variables: (1) the specific pathogen, (2) the type of antibiotic administered, and (3) the timing of dexamethasone administration.

Pathogen. The three most common causative bacteria are H influenzae, Streptococcus pneumoniae, and Neisseria meningitidis. Dexamethasone was most protective in patients who had H influenzae meningitis. Those who had Spneumoniae or N meningitidis meningitis either did not respond to the steroid or their numbers were too small to allow for a meaningful conclusion. (1,24-26)

Type of antibiotic. Ceftriaxone is more effective than both cefotaxime and cefuroxime in treating meningitis. (38,39) Studies in which cefotaxime and cefuroxime were used are potentially biased because these drugs enhance the protective effect of steroids. These two cephalosporins take a longer time to sterilize CSF in meningitis, and therefore the period of inflammation is extended. (40,41) There are no conclusive data on CSF sterilization with ampicillin plus chloramphenicol or with other antibiotics that have been studied.

Timing of the steroid dosage. In the four studies that showed that dexamethasone had a protective effect against SNHL, the steroid was administered either before the antibiotic, (13,21) concurrently with the antibiotic, (20) or within 4 hours of antibiotic administration. (17)

A power analysis was not performed in any of the clinical trials. The only such analysis was conducted by Geiman and Smith in their meta-analysis. (23) Their power analysis showed that bilateral SNHL occurred with greater frequency in patients who did not receive a steroid. This was significant in view of the number of patients who were included in the analysis. However, one of the studies in this meta-analysis included adults.

In the meta-analysis by McIntyre et al, the authors reached a similar conclusion without a power analysis. (22) However, the beneficial effect of dexamethasone was seen only in patients who had H influenzae b infection. Also, in patients with S pneumoniae meningitis, the meta-analysis found that dexamethasone had a protective effect only when it was administered prior to antibiotic administration.

No statistically significant incidence of steroid-related side effects in the treatment of meningitis has been reported. (23,25) The duration of steroid treatment does not influence its protective effect, as shown by Syrogiannopoulos et al in a comparison of 2- and 4-day regimens. (42)

Audiometric follow-up in the 16 studies varied widely, and the stability of SNHL was not examined. However, experience gained during two other studies indicates that SNHL after meningitis can be progressive in patients with H influenzae and Spneumoniae infections. (43,44) An additional consideration is ossification of the labyrinth in children with SNHL after meningitis; in a retrospective study (level IV) reported by Hartnick et al in 2001, dexamethasone was shown to have a protective effect against cochlear ossification after meningitis. (45)

In conclusion, the current literature suggests that there is grade B evidence in favor of the use of dexamethasone in patients with H influenzae-associated meningitis and grade C evidence for its use in patients with other bacteria. (A grade of B indicates consistent results in level II or III studies or extrapolations from level I studies; a grade of C indicates data from level IV studies or extrapolations from level II or III studies.)

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(22.) McIntyre PB, Berkey CS, King SM, et al. Dexamethasone as adjunctive therapy in bacterial meningitis. A meta-analysis of randomized clinical trials since 1988. JAMA 1997;278:925-31.

(23.) Geiman BJ, Smith AL. Dexamethasone and bacterial meningitis. A meta-analysis of randomized controlled trials. West J Med 1992;157:27-31.

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(35.) Bakhiet M, Mustafa M, Zhu J, et al. Induction of cytokines and anti-cytokine autoantibodies in cerebrospinal fluid (CSF) during experimental bacterial meningitis. Clin Exp Immunol 1998;114: 398-402.

(36.) Tauber MG, Khayam-Bashi H, Sande MA. Effects of ampicillin and corticosteroids on brain water content, cerebrospinal fluid pressure, and cerebrospinal fluid lactate levels in experimental pneumococcal meningitis. J Infect Dis 1985;151:528-34.

(37.) Ramilo O, Saez-Llorens X, Mertsola J, et al. Tumor necrosis factor alpha/cachectin and interleukin 1 beta initiate meningeal inflammation. J Exp Med 1990;172:497-507.

(38.) Lebel MH, McCracken GH Jr. Delayed cerebrospinal fluid sterilization and adverse outcome of bacterial meningitis in infants and children. Pediatrics 1989;83:161-7.

(39.) Schaad UB, Suter S, Gianella-Borradori A, et al. A comparison of ceftriaxone and cefuroxime for the treatment of bacterial meningitis in children. N Engl J Med 1990;322:141-7.

(40.) Kaplan SL. Adjuvant therapy in meningitis. Adv Pediatr Infect Dis 1995;10:167-86.

(41.) Kaplan SL. Dexamethasone for children with bacterial meningitis. Should it be routine therapy? Am J Dis Child 1989;143:290-2.

(42.) Syrogiannopoulos GA, Lourida AN, Theodoridou MC, et al. Dexamethasone therapy for bacterial meningitis in children: 2- versus 4-day regimen. J Infect Dis 1994;169:853-8.

(43.) Bhatt SM, Lauretano A, Cabellos C, et al. Progression of hearing loss in experimental pneumococcal meningitis: Correlation with cerebrospinal fluid cytochemistry. J Infect Dis 1993;167:675-83.

(44.) Silkes ED, Chabot J. Progressive hearing loss following Haemophilus influenzae meningitis. Int J Pediatr Otorhinolaryngol 1985:9:249-56.

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From the Department of Otolaryngology--Head and Neck Surgery, Columbia University College of Physicians and Surgeons, New York City.

Reprint requests: Spiros Manolidis, MD, Department of Otolaryngology--Head and Neck Surgery, Columbia University, HP813, 180 Fort Washington, New York, NY 10032. Phone: [phone]; fax: [phone]; e-mail: [e-mail]

Spiros Manolidis MD; Romaine Johnson, MD

Table 1. Summary of the 16 articles
                                                               Evidence
Authors        Description                                      level

Daoud          (RCT) examined the effects of dexamethasone        I
et al, (12)    on neurologic sequelae in
1999           neonates with bacterial meningitis.
               N = 52

Kulahli        RCT compared adjunctive dexamethasone              I
et al, (13)    with placebo in reducing the risk of
               SNHL in bacterial meningitis in children.
               Dexamethasone was given 20 minutes
               prior to parenteral antibiotics at a dose of
               0.6 mg/kg/day for 4 doses.
               N=50

Qazi et        RCT compared dexamethasone's effects               I
al, (14)       on hearing loss and neurologic and
1996           developmental outcomes in children with
               bacterial meningitis. Dexamethasone was
               given prior to parenteral antibiotics at 0.6
               mg/kg/day in four doses.
               N = 89

Kilpi et       RCT measured the effects of                        I
al, (15)       dexamethasone and glycerol in the
1995           treatment of bacterial meningitis in infants
               and children.
               N = 122

Kanra et       RCT compared dexamethasone with                    I
al, (16)       placebo in children older than 2 years
1995           who had pneumococcal meningitis.
               Dexamethasone was given 20 minutes
               prior to parenteral antibiotics at 0.6 mg/
               kg/day in four doses.
               N=60

Wald et        Multicenter RCT was conducted to                   I
al, (17)       assess the efficacy of dexamethasone
1995           as an adjunctive therapy for bacterial
               meningitis in children. Dexamethasone
               was given at a dose of 0.15 mg/kg/day
               for 4 days within 4 hours of the antibiotic
               dose.
               N = 173

Schaad et      RCT examined the use of dexamethasone              I
al, (18)       in children with bacterial meningitis.
1993           Dexamethasone was given 10 minutes
               prior to a parenteral antibiotic at a dose
               of 0.4 mg/kg/day for 2 days.
               N=115

Odio et        RCT assessed the effects of adjuvant               I
al, (19)       dexamethasone in bacterial meningitis in
1991           children. The steroid was given 15 to 20
               minutes prior to a parenteral antibiotic
               for 4 days at a dose of 0.6 mg/kg/day.
               N= 101

Girgis et      RCT assessed ampicillin and                        I
al, (20)       chloramphenicol with and without
1989           dexamethasone given on a nonselective
               alternating basis to children and adults
               (8 mg for patients younger than 12 years
               and 12 mg for those older) for 3 days. The
               steroid was given concomitantly with the
               antibiotics.
               N = 429

Lebel et       Two RCTs compared the efficacy of an               I
al (21)        antibiotic with and without adjunctive
1988           dexamethasone in the treatment
               of bacterial meningitis in children.
               Dexamethasone was given at a dose of
               0.15 mg/kg/day for 4 days.
               N = 200

McIntyre et    Meta-analysis included 11 RCTs published           I
al, (22)       from January 1988 through November
1997           1996 on the use of dexamethasone as an
               adjunctive therapy for bacterial meningitis.

Geiman and     Meta-analysis evaluated 5 RCTs in children         I
Smith,         and 1 study with children and adults to
(23) 1992      evaluate the effect of dexamethasone as
               an adjunctive therapy for the treatment
               of bacterial meningitis. Studies were
               published between 1989 and 1991.

Arditi et      Retrospective case series looked at                IV
al, (24)       children with pneumococcal meningitis.
1998           Some 40 children (22%) were treated with
               dexamethasone.
               N = 180

Kennedy et     Retrospective case series reviewed                 IV
al, (25)       patients admitted and treated for
1991           pneumococcal meningitis and given
               steroids. Some patients were part of
               clinical trials of dexamethasone therapy.

               N=97

British        Consensus statement addressed the                  V
Paediatric     efficacy and safety of dexamethasone in
Immunology     children with bacterial meningitis.
and
Infectious
Diseases
Group,
(26) 1992

American       Consensus statement addressed                      V
Academy of     dexamethasone therapy for bacterial
Pediatrics,    meningitis in infants and children,
(1) 1990

Authors        Summary

Daoud          The dexamethasone group had 2 infants
et al, (12)    with SNHL, compared with 1 in the control
1999           group (7.4 vs. 4%). The difference was not
               statistically significant. No power analysis
               was performed.

Kulahli        Fewer patients in the dexamethasone
et al, (13)    group developed mild and severe persistent
               hearing loss (19 vs. 38%). No power
               analysis was performed. No p values for
               cumulative hearing loss data were reported.

Qazi et        Authors found no statistically significant
al, (14)       difference in outcomes between the
1996           dexamethasone group and the placebo
               controls with respect to hearing loss at 1
               and 12 months postinfection. Authors used
               multivariate analysis to control for factors
               other than dexamethasone use, including
               duration of illness prior to admission.

Kilpi et       Some 10% of study participants
al, (15)       developed SNHL. Hearing loss was more
1995           common in patients who were not given
               dexamethasone, although the difference
               did not reach statisical significance
               (p=0.14). No power analysis was performed.

Kanra et       The incidence of both unilateral and
al, (16)       bilateral SNHL was lower in the
1995           dexamethasone-treated group, but the
               difference was not statistically significant
               (7.4 vs. 23%; p = 0.11). No power analysis
               was performed.

Wald et        Overall, no difference in audiometric
al, (17)       outcomes between the dexamethasone
1995           group and the placebo controls was
               observed. However, patients with
               Hib-induced meningitis who were treated with
               dexamethasone had a significantly lower
               rate of SIN HL (p=0.02).

Schaad et      Authors found a higher incidence of SNHL
al, (18)       in the placebo group, but the difference
1993           did not reach statistical significance (5 vs.
               15%; p = 0.11). No power analysis was
               performed.

Odio et        SNHL was more common in the placebo
al, (19)       controls, but the difference did not reach
1991           statistical significance (6 vs. 16%; p=
               0.18). No power analysis was performed.

Girgis et      The incidence of SNHL was lower among
al, (20)       those who received dexamethasone, but
1989           the advantage was statistically significant
               only in patients who had Streptococcus
               pneumoniae infections (p = 0.05).

Lebel et       Children who received dexamethasone
al (21)        were significantly less likely to experience
1988           SNHL than were placebo controls (3 vs.
               15.5%; p < 0.01). *
               * Second arm of this study.

McIntyre et    Dexamethasone provided protection
al, (22)       against SNHL in patients with Hib
1997           meningitis and pneumococcal infection
               when given prior to parenteral antibiotics.

Geiman and     Placebo controls had a higher relative
Smith,         risk of bilateral SNHL and the need for
(23) 1992      hearing aids (relative risks: 4.12 and 20.94,
               respectively). The difference between
               groups in unilateral hearing loss was not
               statistically significant (relative
               risk: 1.09).

Arditi et      The incidence of SNHL was higher in
al, (24)       dexamethasone patients than in placebo
1998           controls (46 vs. 23%). However, the
               authors noted a trend toward giving the
               steroid to sicker children; when this trend
               was taken into account, the difference
               in SNHL was no longer statistically
               significant.

Kennedy et     Moderate or worse bilateral hearing loss
al, (25)       was less common in the steroid-treated
1991           patients, but not significantly so
               (p = 0.13).

British        Children with Hib meningitis probably
Paediatric     benefit from dexamethasone in terms of
Immunology     SNHL, but there is no current evidence
and            that children with pneumococcal meningitis
Infectious     have better outcomes when they are
Diseases       treated with steroids.
Group,
(26) 1992

American       Dexamethasone probably prevents SNHL
Academy of     in patients with Hib meningitis, and it
Pediatrics,    should be considered on an individual
(1) 1990       basis. The steroid should be administered
               at the time of the first dose of antibiotic.
               Its utility for treatment of pneumococcal or
               meningococcal meningitis is not known.

Key: RCT = randomized controlled trial; SNHL = sensorineural
hearing loss; Hib = Haemophilus influenzae type b

Table 2. Additional data on the 10 randomized
controlled trials and 2 case series

                                                       Timing of
Authors               Bacteria (% of cases)            steroid dose

Daoud et al, (12)     Klebsiella pneumoniae, 44%       Before
1999                  Enterobacter spp., 17%           antibiotic
                      Staphylococcus aureus, 4%

Kulahli et al, (13)   Streptococcus pneumoniae, 20%    Before
1997                  Neisseria meningitidis, 20%      antibiotic
                      Haemophilus influenzae, 12%

Qazi et al, (14)      H influenzae type b, 45%         Before
1996                  N meningitidis, 17%              antibiotic
                      S pneumoniae, 13%

Kilpi et al, (15)     H influenzae type b, 53%         Concomitantly
1995                  N meningitides, 33%
                      S pneumoniae, 10%

Kanra et al, (16)     S pneumoniae, 100%               Before
1995                                                   antibiotic

Wald et al, (17)      H influenzae type b, 58%         Within
1995                  S pneumoniae, 23%                4 hours of
                      N meningitides, 17%              antibiotic

Schaad et al, (18)    H influenzae type b, 58%         Before
1993                  N meningitidis, 24%              antibiotic
                      S pneumoniae, 9%

Odio et al, (19)      H influenzae type b, 78%         Before
1991                  N meningitidis, 8%               antibiotic
                      S pneumoniae, 2%

Girgis et al, (20)    N meningitidis, 60%              Concomitantly
1989                  S pneumoniae, 25%
                      H influenzae type b, 13%

Lebel et al, (21)     H influenzae type b, 77%         Before
1988                  N meningitides, 8%               antibiotic
                      S pneumoniae, 8%

Arditi et al, (24)    S pneumoniae, 100%               Before
1998                                                   antibiotic

Kennedy et al, (25)   S pneumoniae, 100%               Not
1991                                                   reported

                                                       Audiometric
Authors               Antibiotic                       follow-up

Daoud et al, (12)     Cefotaxime plus                  Year 2
1999                  ampicillin

Kulahli et al, (13)   Penicillin G                     Days 2 and 10,
1997                  Chloramphenicol                  week 8

Qazi et al, (14)      Ampicillin                       Months 1, 4,
1996                  Chloramphenicol                  and 12

Kilpi et al, (15)     Ceftriaxone                      2 months
1995                                                   postdischarge

Kanra et al, (16)     Ampicillin/                      Week 6, month
1995                  sulbactam                        3, year 1

Wald et al, (17)      Ceftriaxone                      Admission,
1995                                                   week 6, month
                                                       12

Schaad et al, (18)    Ceftriaxone                      Days 2 and
1993                                                   4, discharge,
                                                       months 3 and 9

Odio et al, (19)      Cefotaxime                       Discharge,
1991                                                   months 4 and
                                                       24

Girgis et al, (20)    Ampicillin                       When awake,
1989                  Chloramphenicol                  months 1
                                                       through 6

Lebel et al, (21)     Ceftriaxone *                    Within 6 weeks
1988                  * Second
                      arm of this
                      study

Arditi et al, (24)    Cefotaxime                       Not reported
1998                  Ceftriaxone
                      Penicillin
                      Vancomycin
                      Meropenem
                      Clindamycin

Kennedy et al, (25)   Cefotaxime                       End of therapy,
1991                  Ceftriaxone                      months 2
                      Cefuroxime                       through 6
                      Ampicillin
                      Penicillin