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Bacterial meningitis in children: Dexamethasone and other measures to prevent neurologic complications

Bacterial meningitis in children: Dexamethasone and other measures to prevent neurologic complications
Author:
Sheldon L Kaplan, MD
Section Editors:
Morven S Edwards, MD
Douglas R Nordli, Jr, MD
Deputy Editor:
Carrie Armsby, MD, MPH
Literature review current through: Dec 2022. | This topic last updated: May 11, 2022.

INTRODUCTION — Bacterial meningitis can cause substantial morbidity and mortality. The risk of dying or of developing complications depends upon the age and underlying condition of the patient, the causative pathogen, the severity and duration of illness at the time of presentation, and, occasionally, delays in the initiation of antibiotic therapy. (See "Bacterial meningitis in children older than one month: Treatment and prognosis".)

Major neurologic complications of bacterial meningitis include (see "Bacterial meningitis in children: Neurologic complications"):

Cerebral edema

Subdural effusion

Seizures

Hearing loss

Cranial nerve palsy

Motor impairment (eg, hemiparesis, quadriparesis, ataxia)

Cerebrovascular complications (eg, cerebral venous thrombosis)

Hydrocephalus

Neuropsychiatric impairment (eg, intellectual disability, mood disorder, attention deficit)

Hypothalamic dysfunction

Dexamethasone and other measures to prevent neurologic complications of bacterial meningitis in children will be discussed here. Other aspects of treatment of bacterial meningitis in infants and children and details regarding neurologic complications of bacterial meningitis are discussed separately:

(See "Bacterial meningitis in children older than one month: Treatment and prognosis".)

(See "Bacterial meningitis in children: Neurologic complications".)

(See "Bacterial meningitis in the neonate: Treatment and outcome".)

(See "Bacterial meningitis in the neonate: Neurologic complications".)

BACKGROUND — Permanent neurologic sequelae, such as hearing loss and focal neurologic deficits, are common in survivors of bacterial meningitis, particularly patients with pneumococcal meningitis. These complications are as much a consequence of the host response as of the bacterial organisms. (See "Bacterial meningitis in children: Neurologic complications" and "Pathogenesis and pathophysiology of bacterial meningitis".)

Studies in animals demonstrate that hearing loss is temporally associated with inflammatory changes and that neurologic outcome is related to the severity of the inflammatory process [1-3]. These observations led to the evaluation of antiinflammatory agents (usually dexamethasone) as an adjunct to antimicrobial therapy in the treatment of bacterial meningitis (see 'Dexamethasone' below). Antiinflammatory agents have the potential to prevent neurologic complications of bacterial meningitis by decreasing intracranial pressure (through reduction of meningeal inflammation and brain water content) and modulating the production of cytokines [4-11].

Other measures, aimed at preventing vasogenic edema (glycerol) and inflammatory mediators (eg, nitric oxide synthase inhibitors), are less well studied but potentially promising. (See 'Glycerol' below and 'Experimental therapies' below.)

DEXAMETHASONE

Considerations in decision-making — The decision to use dexamethasone in children with suspected bacterial meningitis must be individualized. In addition to the potential benefits and adverse effects described below (see 'Efficacy' below and 'Adverse effects' below), factors to be weighed in this decision include:

The etiologic agent

The feasibility of administering dexamethasone before or at the same time as the first dose of antibiotic therapy

The empiric antibiotic regimen

Etiologic agent — The benefits of dexamethasone therapy vary depending upon the etiologic agent. Dexamethasone appears to be most beneficial in reducing hearing loss in children with Haemophilus influenzae type b (Hib) meningitis [12]. (See 'Efficacy' below.)

Experts continue to debate the efficacy of dexamethasone for children with meningitis caused by other organisms, including pneumococcus [13,14].

Timing — Dexamethasone should be administered before or at the same time as the first dose of antibiotics. It is probably of no benefit if given more than one hour later, although this time interval has not been clearly defined [12,15,16].

Adjuvant dexamethasone may be less beneficial in children with delayed presentation to medical attention. Delay between onset of infection and initiation of appropriate antibiotic therapy may account for the relative lack of efficacy of dexamethasone in children from resource-limited versus resource-rich countries and pneumococcal versus Hib meningitis [17,18]. (See 'Efficacy' below.)

In the Pediatric Multicenter Pneumococcal study on pneumococcal meningitis in eight children's hospitals from 2007 through 2013, dexamethasone was administered to 35 percent (n = 60) of 173 children; timely administration occurred in only 22 patients [19]. The 22 children who received dexamethasone in a timely manner did not differ from the 113 children who did not with respect to severity of illness or complications, including hearing loss.

Antibiotic regimen — The benefits of dexamethasone therapy may depend, to some extent, upon the empiric antibiotic regimen. Patients with possible penicillin-resistant pneumococcal meningitis are typically treated with vancomycin plus either ceftriaxone or cefotaxime, pending results of susceptibility testing. However, there is concern that the entry of vancomycin into the cerebrospinal fluid (CSF) could be reduced in patients who receive adjunctive dexamethasone [20-24].

In a rabbit model of penicillin- and cephalosporin-resistant pneumococcal meningitis, dexamethasone substantially reduced the penetration of vancomycin into the CSF, resulting in a delay in CSF sterilization that was not seen in rabbits not treated with dexamethasone [20]. In comparison, rifampin penetration into the CSF was not affected by dexamethasone and the combination of rifampin and ceftriaxone produced prompt bacteriologic cure.

Whether these experimental findings in rabbits apply to bacterial meningitis in humans is uncertain. Therapeutic CSF concentrations of vancomycin in the CSF were noted in two studies involving 9 children and 13 adults with pneumococcal meningitis who were treated with dexamethasone and vancomycin plus either ceftriaxone or cefotaxime [25,26]. Nonetheless, some experts suggest that if dexamethasone is administered, rifampin should be added to the empiric regimen (which typically consists of vancomycin and either ceftriaxone or cefotaxime [if available]) [16].

Our approach — Our suggested approach is as follows:

Hib meningitis – For children with Hib meningitis, we recommend adjunctive therapy with dexamethasone, provided that it can be administered before or at the same time as the first dose of antimicrobial therapy [27]. In clinical practice, this scenario is fairly uncommon since the causative organism usually is unknown at the time of the initial antibiotic dose. In addition, Hib is a rare cause of bacterial meningitis in immunized children. However, if results of the Gram stain (or other rapid diagnostic test) are readily available and suggest Hib, adjunctive therapy with dexamethasone is recommended. It is unknown if dexamethasone is beneficial for bacterial meningitis due to nontype b H. influenzae meningitis such as types a or f or nontypeable.

Other bacterial pathogens (pneumococcus, meningococcus) – For children with suspected pneumococcal or meningococcal meningitis, and those in whom bacterial meningitis is suspected but the etiology unknown, the benefits of dexamethasone are less certain and the decision is individualized [14].

There is considerable practice variation regarding use of dexamethasone in this setting. The author of this topic review does not routinely administer dexamethasone to children with suspected pneumococcal or meningococcal meningitis. Other experts may choose to use dexamethasone in this setting, particularly in young children (ie, ≥6 weeks to ≤5 years old) and children with sickle cell disease or hyposplenism. In addition, it may be reasonable to use dexamethasone in older adolescent patients since it is a recommended component of therapy for adult patients with suspected bacterial meningitis, as discussed separately. (See "Dexamethasone to prevent neurologic complications of bacterial meningitis in adults".)

In study of 173 children with pneumococcal meningitis treated in the United States from 2007 through 2013, 35 percent received dexamethasone [19].

If dexamethasone is given, it should be administered before or at the same time as the first dose of antimicrobial therapy. If more than one hour has elapsed since the first dose of antimicrobial therapy, administration of dexamethasone is unlikely to improve outcome [16]. (See 'Dose' below and 'Timing' above.)

Nonbacterial or gram-negative enteric meningitisDexamethasone is not indicated in the treatment of patients with suspected aseptic, nonbacterial, or gram-negative enteric meningitis [16]. If initiated before the diagnosis, dexamethasone should be discontinued as soon as a diagnosis of nonbacterial or gram-negative enteric meningitis is confirmed.

Young infants and patients with central nervous system anomaliesDexamethasone is not indicated in the treatment of bacterial meningitis in infants <6 weeks old or in those with congenital or acquired abnormalities of the central nervous system [16].

Tuberculous meningitis – Glucocorticoid therapy appears to be beneficial in selected children and adults with tuberculous meningitis. This issue is discussed separately. (See "Central nervous system tuberculosis: Treatment and prognosis", section on 'Glucocorticoids'.)

Our approach is generally consistent with the guidelines of the Infectious Diseases Society of America and the American Academy of Pediatrics Committee on Infectious Diseases [14,16,27]. In contrast, European guidelines do recommend dexamethasone for adjunctive treatment of bacterial meningitis in children [28]. (See 'Society guideline links' below.)

Dose — If the decision is made to use dexamethasone, it should be given before or concurrently with the first dose of antibiotics. Appropriate dosing for dexamethasone in this setting is as follows:

Dexamethasone (0.15 mg/kg per dose) intravenously every six hours for two to four days [16]; a two-day course appears to be as effective as longer courses and is associated with a lower risk of toxicity [29].

Efficacy — A number of studies have evaluated the use of adjuvant dexamethasone in the treatment of bacterial meningitis in children [12,15,30-43]. Individual studies, performed in various populations and using different antimicrobial regimens, have come to differing conclusions regarding the beneficial effects on survival, hearing, and neurologic sequelae. The issue is complicated by temporal and geographic differences in the microbiology and treatment of bacterial meningitis, as well as the conditions of when and where the individual studies were performed.

Effect on mortality, hearing loss, and other neurologic sequelae – In a 2015 meta-analysis of 18 randomized controlled trials (2511 pediatric patients), mortality was similar in children treated with dexamethasone compared with placebo (13.2 and 14.6 percent, respectively; relative risk [RR] 0.89; 95% CI 0.74-1.07) [12]. The rate of severe hearing loss (generally defined as bilateral hearing loss of ≥60 decibels or requiring bilateral hearing aids) was lower in patients treated with dexamethasone (7.4 versus 11.4 percent; RR 0.67, 95% CI 0.49-0.97; 14 trials, 1524 patients). The effect on hearing loss was largely limited to children with Hib meningitis (3.9 verses 11.9 percent; RR 0.34, 95% CI 0.20-0.59; 10 trials, 756 patients), whereas for other organisms, rates of severe hearing loss were similar in the dexamethasone and placebo groups (9.6 and 10.2 percent, respectively; RR 0.95, 95% CI 0.65-1.39; 13 trials, 860 patients). The incidence of short-term neurologic sequelae other than hearing loss was similar in both groups regardless of the causative organism (18 versus 20 percent; RR 0.90, 95% CI 0.72-1.13; 10 trials, 1271 patients).

An earlier meta-analysis that analyzed individual patient data from five trials (2029 patients) reached similar conclusions, finding that dexamethasone reduced hearing loss among survivors (24.1 versus 29.5 percent; odds ratio [OR] 0.77, 95% CI 0.60-0.99) [43]. Mortality rates were similar (26.5 versus 27.2; OR 0.97, 95% CI 0.79-1.19), as were rates of the combined outcome of death, severe neurologic sequelae, or severe bilateral deafness (42.3 versus 44.3 percent; OR 0.92, 95% CI 0.76-1.11). The effects did not differ according to any of the subgroups that were assessed (etiologic agent, duration of symptoms before treatment, severity of coma at the start of treatment, timing of administration of dexamethasone, and HIV infection status).

Limitations of the evidence – In the available clinical trials, there was considerable heterogeneity with respect to the patient population (age, comorbidities, duration of preadmission symptoms, severity of illness), setting (resource-limited versus resource-rich), and study interventions. Findings from studies in resource-limited countries may not be generalizable to resource-rich settings, since delays in treatment are more common in the resource-limited settings [44] and this likely impacts outcomes [17,45-47]. In particular, there were two studies from Malawi in which the mortality rates were three- to fivefold higher than in the studies from other countries [34,48], raising questions about the generalizability of these effect estimates [12,49]. Other factors that may contribute to increased mortality among patients from Malawi include poor nutrition and increased prevalence of HIV infection. Studies of dexamethasone in adolescents and adults in resource-limited settings are discussed separately. (See "Dexamethasone to prevent neurologic complications of bacterial meningitis in adults", section on 'In developing regions'.)

Another concern about the generalizability of these data is the era in which they were performed. The majority of trials included in the 2015 meta-analysis were published between 1988 and 1995, and the microbiology and treatment of bacterial meningitis have changed considerably since that time [41]. (See "Bacterial meningitis in children older than one month: Clinical features and diagnosis", section on 'Epidemiology'.)

With the widespread use of the Hib vaccine in developed countries, Streptococcus pneumoniae has become an increasingly important pathogen. In contrast, most of the studies of dexamethasone were performed when Hib was the most frequent cause of bacterial meningitis [41,50]. Children with pneumococcal meningitis generally have a longer duration of fever before presentation compared with children with meningitis caused by other bacterial pathogens [18]. The delay between onset of infection and initiation of appropriate antimicrobial therapy may account for the lack of efficacy of dexamethasone in children with pneumococcal compared with Hib meningitis [17]. Retrospective data from 27 tertiary care hospitals in the United States provide additional information about the effect of adjuvant glucocorticoid therapy for bacterial meningitis in developed countries in the post-conjugate vaccine era [51]. Among 2780 children admitted with bacterial meningitis between January 2001 and December 2006, 9 percent received glucocorticoid therapy. The overall mortality rate was 4.2 percent and was not affected by administration of dexamethasone; the results did not change when analyzed according to infecting organism.

In addition, few of the studies of adjuvant dexamethasone therapy were performed with vancomycin, which is now an important component of the empiric treatment for bacterial meningitis (because of the increased incidence of S. pneumoniae nonsusceptible to cephalosporins). The benefits of dexamethasone for patients with bacterial meningitis caused by S. pneumoniae requiring vancomycin therapy are not clear, and there is concern that the entry of vancomycin into the CSF could be reduced in patients who receive adjunctive dexamethasone [52]. (See 'Antibiotic regimen' above and "Bacterial meningitis in children older than one month: Treatment and prognosis", section on 'Empiric therapy'.)

Adverse effects — Adverse effects of dexamethasone include hyperglycemia, behavioral changes, and gastrointestinal effects (gastritis, peptic ulcer, gastrointestinal bleeding). However, most children tolerate short courses of dexamethasone well without serious adverse effects. Other side effects of glucocorticoids more broadly are discussed separately. (See "Major side effects of systemic glucocorticoids".)

A particular downside of dexamethasone therapy in children with bacterial meningitis is that it can interfere with the ability of the clinician to assess clinical response to antibiotic therapy [16,53]. In addition, secondary fever (recurrence of fever after at least 24 hours without fever) may occur after discontinuation of dexamethasone [21].

Patients who receive adjuvant dexamethasone therapy do not appear to have slower clearance of bacteria from the CSF. However, children with meningitis who receive dexamethasone early in their course should be carefully observed throughout therapy. Because dexamethasone can interfere with the ability to interpret the clinical response, repeat LP is suggested in children who have received dexamethasone therapy. This is discussed separately. (See "Bacterial meningitis in children older than one month: Treatment and prognosis", section on 'Repeat lumbar puncture'.)

The effects of dexamethasone on viral meningitis are not fully known; very few studies have examined the long-term outcome of children with viral meningitis who may have received dexamethasone at the time of presentation when bacterial meningitis was a consideration [54].

OTHER INTERVENTIONS TO PREVENT NEUROLOGIC COMPLICATIONS

Fluid management — Careful fluid management is necessary to maintain cerebral perfusion pressure while anticipating the possibility of inappropriate secretion of antidiuretic hormone. There is no "one size fits all" approach to fluid management in children with bacterial meningitis. Decisions should be individualized based upon the child's hemodynamic stability, volume status, serum sodium, and risk for developing cerebral edema. As a general principle, excessive fluid administration and hypotonic fluids (eg, one-half or one-quarter normal saline) should be avoided since they tend to make cerebral edema worse. Fluid management in bacterial meningitis is discussed in greater detail separately. (See "Bacterial meningitis in children older than one month: Treatment and prognosis", section on 'Fluid management'.)

Lack of benefit of hypothermia — Based the available data from studies in adult patients, we suggest not using therapeutic hypothermia in children with bacterial meningitis who are at risk for neurologic sequelae. Based upon studies in adults, hypothermia does not appear to improve outcomes in patients with severe bacterial meningitis and it may be harmful. These studies are described in greater detail separately. (See "Initial therapy and prognosis of bacterial meningitis in adults", section on 'Induced hypothermia'.)

Glycerol — We suggest not routinely using glycerol as adjunctive treatment for children with bacterial meningitis. Glycerol is a hyperosmolar agent and osmotic diuretic that has been used in neurosurgery, neurology, and ophthalmology to reduce raised tissue pressure [42,55-61]. In theory, it also may reduce meningeal inflammation by scavenging free oxygen radicals [42].

Adjunctive therapy with glycerol is appealing, particularly in low-income countries, because it is safe, widely available, inexpensive, does not require special storage, and can be administered orally [33,62,63]. However, additional study is necessary before glycerol can be routinely recommended.

A 2013 meta-analysis of four trials of glycerol in patients with bacterial meningitis did not detect a difference in mortality, neurologic disability, or seizures during treatment; however, the risk of deafness was reduced (relative risk [RR] 0.60, 95% CI 0.38-0.93) [33,42,64-66]. In the only trial in adults, glycerol was associated with an increased mortality [64]. (See "Initial therapy and prognosis of bacterial meningitis in adults", section on 'Reduction of intracranial pressure'.)

Limitations of existing studies include the lack of long-term follow-up for subtle neurologic sequelae, variations in population and environment, use of different methods to assess hearing at different institutions, and lack of provision of information regarding variations from the study protocol or the consistency of results among participating institutions [42,66,67]. Additional studies regarding the effects of adjuvant glycerol therapy for bacterial meningitis in children are warranted before this therapy can be routinely recommended.

Experimental therapies — The search for additional adjunctive agents that target inflammatory mediators or mediator effector molecules is an active area of investigation. Agents that have been studied in animal models include antioxidants [68], nitric oxide synthase inhibitors [69,70], tumor necrosis factor-related apoptosis-inducing ligand [71], melatonin [72], caspase inhibitors [73], adjunctive daptomycin and rifampin (antibiotics that are bacteriocidal but not bacteriolytic) [74-78], and roscovitine (which induces caspase-dependent apoptosis in neutrophils) [79]. These agents are experimental and are not routinely used in clinical practice.

PRIMARY PREVENTION — The best way to eliminate neurologic complications of bacterial meningitis is to prevent bacterial meningitis from occurring in the first place (primary prevention) [67,80,81]. Primary prevention of bacterial meningitis through vaccines and chemoprophylaxis is discussed separately. (See "Prevention of Haemophilus influenzae type b infection" and "Pneumococcal vaccination in children" and "Meningococcal vaccination in children and adults" and "Treatment and prevention of meningococcal infection", section on 'Antimicrobial chemoprophylaxis'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Bacterial meningitis in infants and children".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword[s] of interest.)

Basics topic (see "Patient education: Bacterial meningitis (The Basics)")

SUMMARY AND RECOMMENDATIONS

Rationale – Antiinflammatory agents (chiefly dexamethasone) have been proposed as an adjunct to antimicrobial therapy in the treatment of bacterial meningitis to reduce the inflammatory response, with the aim of preventing neurologic complications. (See 'Background' above.)

Clinical use of dexamethasone – In children with bacterial meningitis caused by Haemophilus influenzae type b (Hib), dexamethasone appears to reduce the risk of hearing loss. It is unclear if dexamethasone has similar benefit in patients with more common pathogens (eg, pneumococcus, meningococcus). Dexamethasone does not appear to reduce the risk of other neurologic sequelae or mortality. (See 'Efficacy' above.)

Our suggested approach is as follows (see 'Our approach' above):

Suspected Hib meningitis – For children with known or strongly suspected Hib meningitis (eg, on the basis of the Gram stain or other rapid diagnostic test), we recommend adjunctive therapy with dexamethasone, provided that it can be administered before or at the same time as the first dose of antimicrobial therapy (Grade 1B). In clinical practice, this scenario is uncommon. (See 'Our approach' above and 'Efficacy' above.)

Pneumococcal or meningococcal meningitis or unknown etiology – Decisions regarding the use of dexamethasone in children with suspected pneumococcal or meningococcal meningitis or in patients with bacterial meningitis of unknown etiology should be individualized. The author of this topic review does not routinely administer dexamethasone to children with suspected pneumococcal or meningococcal meningitis. In the same patients, other experts may choose to use dexamethasone. (See 'Our approach' above.)

Nonbacterial or gram-negative enteric meningitis – There is no role for adjunctive dexamethasone therapy in aseptic, nonbacterial, or gram-negative enteric meningitis. (See 'Our approach' above.)

Young infants and patients with central nervous system abnormalities – There is no role for adjunctive dexamethasone therapy in the treatment of bacterial meningitis in infants <6 weeks old and in those with congenital or acquired abnormalities of the central nervous system. (See 'Our approach' above.)

Timing and dosing regimen – If dexamethasone is given, it should be administered before or at the same time as the first dose of antibiotics. It is probably of no benefit if given more than one hour later, although this time interval has not been clearly defined. (See 'Timing' above.)

Appropriate dosing for dexamethasone in this setting is 0.15 mg/kg per dose given intravenously every six hours for two to four days. (See 'Dose' above.)

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