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The Pediatric Infection DiseaseJournal
Volume 23(4) April 2004 pp 355-357
USE OF CORTICOSTEROIDS IN BACTERIAL MENINGITIS
[CONCISE REVIEWS OF PEDIATRIC INFECTIOUS DISEASES®]
Feigin, Ralph D. M.D.; Watson, John T. M.D., M.Sc.; Gerber, Susan I. M.D.
Baylor College of Medicine and Texas Children’s Hospital, Houston, TX
After the introduction of corticosteroids in 1949, interest focused on
the possibility that they might be a helpful supplement to antibiotic
therapy in various life-threatening infections including bacterial
meningitis. In 1957–1958, Lepper and Spies 1 reported in a controlled
study that hydrocortisone was of no value in preventing or modifying
the acute course and immediate neurologic residual damage in patients
with bacterial meningitis. Patients treated with steroids had a worse
prognosis. Eleven years elapsed before the results of additional
studies were reported. 2, 3
deLemos and Haggerty 2 performed a double blind controlled study of
the use of methylprednisolone as an adjunct to treatment of bacterial
meningitis. No significant differences were reported between treated
(59 patients) and placebo (63 patients) groups regarding mortality,
morbidity or ultimate neurologic deficit. The incidence of residual
problems was greater in the steroid-treated patients, but the
difference did not reach statistical significance.
In 1969 Belsey et al. 3 compared dexamethasone-treated patients with
a
placebo-treated group and could not demonstrate a significant effect
of steroids on the course or outcome.
As a result of the three controlled studies showing no beneficial
effect of steroids as adjunctive therapy for bacterial meningitis,
steroid use was largely abandoned; however, hearing loss due to
bacterial meningitis was not measured in these studies.
Newer insights into the pathophysiology of meningitis, in particular
the key roles of inflammatory mediators, sparked a renewed interest in
the possible value of corticosteroid administration in the late 1980s.
The use of corticosteroids was suggested because these drugs may: (1)
modulate the production of cytokines lessening the meningeal
inflammatory response; (2) decrease intracranial pressure by
decreasing meningeal inflammation and brain water content; and (3)
decrease the incidence of various sequelae. 4
Animal studies suggested the efficacy of dexamethasone in reducing
brain water content, cerebrospinal fluid (CSF) pressure, CSF
pleocytosis, CSF lactate concentrations, CSF tumor necrosis factor
activity and other indices of meningeal inflammation. 5
These observations served as the basis for renewed investigations of
steroids for adjunctive therapy of bacterial meningitis in children.
Lebel et al. 6 reported in 1988 that use of dexamethasone was
accompanied by a significant reduction in the number of children who
experienced moderate to severe unilateral or bilateral sensorineural
hearing loss after Haemophilus influenzae type b meningitis. Other
studies, summarized by Kaplan, 7 followed, some of which suggested no
reduction in hearing loss or that steroid-treated patients had worse
outcomes than did control patients.
In an attempt to address these disparate observations, Havens et al.
8
reported the results of a meta-analysis of clinical trials in which
corticosteroids were used as adjunctive therapy for this disease.
Fourteen reports of investigations were found, but five were excluded
from analysis because they did not contain data with endpoints of
interest. The authors concluded that the combined results of evaluable
clinical trials showed no benefit of corticosteroid administration on
risk of mortality, neurologic abnormality at hospital discharge or
neurologic abnormality at follow-up evaluation. The risk of moderate
or more severe bilateral hearing loss was lower in patients treated
with dexamethasone, based on the pooled results of three studies in
which hearing was evaluated (one reporting a beneficial effect of
steroids and two reporting no demonstrable effect; risk difference,
-9%).
In 1995 Wald et al. 9 reported a study in six large children’s
hospitals designed to determine whether children with bacterial
meningitis treated with ceftriaxone and dexamethasone had fewer
hearing losses or other neurologic abnormalities than those receiving
only ceftriaxone. Hearing, developmental and neurologic sequelae were
evaluated during hospitalization, at 6 weeks and 1 year post
discharge.
Unlike all previous studies an evaluation of auditory brainstem
responses was made as soon as possible after hospital admission and in
all cases within 24 h. Thus the investigators could determine whether
the potential beneficial effects of steroids were due to prevention of
progression of a hearing defect or reversal of an already existing
hearing loss. Considerable data suggest that hearing loss from
bacterial meningitis occurs very early in the course of the disease
and is unrelated to duration of symptoms before diagnosis, severity of
illness or initiation of definitive treatment. 10–12 Their
observations support the hypothesis that hearing loss occurs early in
patients with bacterial meningitis. All but one of the children in
this study who had hearing loss had the defect when first evaluated.
This study strongly suggested that if hearing loss is not present on
admission, it is unlikely to develop after initiation of antimicrobial
therapy (±steroids).
Follow-up of children who had bilateral hearing loss at the time of
the first auditory brainstem response demonstrated that a similar
proportion of placebo and dexamethasone recipients improved, recovered
or remained deaf. The authors suggested that differences in outcomes
observed by other investigators may have been due to an uneven
distribution of patients with or without a hearing defect at entry
into the various study arms.
A more detailed analysis of these data reveals a significantly
favorable effect of dexamethasone on patients with H. influenzae type
b meningitis who had bilateral moderate to severe hearing loss on
final audiologic evaluation. Statistical significance is lost when the
data are pooled for all patients regardless of the organism causing
the meningitis. In this study there was no long or short term
beneficial effect of dexamethasone on mortality or other neurologic
problems.
These results coupled with other reports describing no or some
beneficial effect of steroids on the course of bacterial meningitis
prompted another metaanalysis, reported in 1997. 13 Randomized
concurrently controlled trials of dexamethasone therapy in childhood
bacterial meningitis published from 1988 to November 1996 were
included. Because the incidence of severe hearing loss differed
significantly by organism among control subjects, organism-specific
estimates were used. For meningitis caused by H. influenzae type b,
McIntyre et al. 13 concluded that use of dexamethasone was associated
with a reduction in severe hearing loss overall (combined odds ratio,
0.31; 95% confidence interval, 0.14–0.69). Data suggested a possible
benefit for use of dexamethasone in pneumococcal meningitis, but only
if used early. A statistically significant beneficial effect of
dexamethasone on other neurologic sequelae was not achieved.
Many additional articles concerning the use of steroids in bacterial
meningitis have been published over the past 45 years (reviewed in
Refs. 7 and 14). They differ in study design, types of antibiotics
utilized, timing and dosage of dexamethasone or other steroids
administered, as well as the extent of evaluation of each patient
during hospitalization and at follow-up. These factors render attempts
at metaanalysis of the studies difficult, as acknowledged in the
meta-analysis-based reviews. 8, 13
What then might one conclude? The Committee on Infectious Diseases of
the American Academy of Pediatrics states that dexamethasone therapy
should be recommended for treatment of infants and children with H.
influenzae type b meningitis and that it should be considered for
pneumococcal meningitis in infants and children 6 weeks of age and
older. 15
The CSF concentrations of vancomycin, ceftriaxone and rifampin, when
given in the dosage generally recommended for treatment of bacterial
meningitis in children who also are treated with dexamethasone,
usually are adequate to treat meningitis caused by penicillin and
third generation cephalosporin-susceptible and nonsusceptible strains
of Streptococcus pneumoniae. Thus adequate therapy for meningitis
caused by penicillin-resistant S. pneumoniae should be achievable.
Dexamethasone can lead to decreased fever and may cause an impression
of clinical improvement early in some cases in which sterilization of
the CSF has not been achieved.
Dexamethasone should not be used for patients with aseptic or
“partially treated” meningitis or in children with bacterial
meningitis who are <6 weeks of age.
If dexamethasone is used it should be given regardless of clinical
severity of disease and administered as soon as possible in the course
of treatment in a dose of 0.15 mg/kg/dose intravenously every 6 h for
no more than 4 days. One study found no difference in children treated
with dexamethasone for 2 days instead of 4 days using 0.4 mg/kg/dose
every 12 h. 14
As with any therapeutic modality, the use of dexamethasone should be
considered carefully by the clinician caring for the patient with
evaluation of the risk to benefit ratio of such therapy in the
individual patient.
References
1. Lepper MH, et al. The use of intravenous hydrocortisone as
supplemental treatment. . . . Antibiotics Annual 1957–1958. New
York: Medical Encyclopedia, 1958:336. [Context Link]
2. deLemos, RA, et al. Corticosteroids as an adjunct to treatment . .
. Pediatrics 1969;44:30–4. [Context Link]
3. Belsey MA, et al. Dexamethasone in the treatment. . . Pediatrics
1969;44:503–13. [Context Link]
4. Smith AL. Neurologic sequelae of meningitis. N Engl J Med
1988;319:1012–14. Bibliographic Links [Context Link]
5. Feigin RD, et al. Diagnosis and management of meningitis. Pediatr
Infect Dis J 1992;11:785–814. Bibliographic Links [Context Link]
6. Lebel MH, et al. Dexamethasone therapy for bacterial meningitis. .
. N Engl J Med 1988;319:964–71. Bibliographic Links [Context Link]
7. Kaplan SL. Corticosteroids and bacterial meningitis. Scand J Infect
Dis 1990;73(Suppl):43–54. [Context Link]
8. Havens PL, et al. Corticosteroids as adjunctive therapy. . . Am J
Dis Child 1989;143:1051–5. Bibliographic Links [Context Link]
9. Wald ER et al. Dexamethasone therapy for children. . . . Pediatrics
1995;95:21–8. [Context Link]
10. Kaplan SL, et al. Onset of hearing loss in children with. . .
Pediatrics 1984;73:575–8. [Context Link]
11. Vienny H, et al. Early diagnosis and evolution of deafness in. .
.
Pediatrics 1984;73:579–86. [Context Link]
12. Radetsky M. Duration of symptoms and outcome in. . . Pediatr
Infect Dis J 1992;11:694–8. [Context Link]
13. McIntyre PB, et al. Dexamethasone as adjunctive therapy in. . .
JAMA 1997;278:925–31. [Context Link]
14. Feigin RD, et al. Bacterial meningitis beyond the neonatal period.
In: Feigin RD, et al., eds. Textbook of pediatric infectious
diseases. 5th ed. Philadelphia: Lippincott Williams & Wilkins,
2004:413–74. [Context Link]
15. Pickering LK, ed. Red Book: 2003 Report of the Committee on
Infectious Diseases. 26th ed. Elk Grove Village, IL: American
Academy of Pediatrics. 2003:293, 493. [Context Link]
Accession Number: 00006454-200404000-00016
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