Adjunctive Steroids in the Treatment of Adults with suspected Bacterial Meningitis
1) Dexamethasone in Adults with Bacterial Meningitis
De Gans, et al, NEJM Nov 14, 2002;347:1549-1556.
RCT, Europe, 301 patients, >16 yo, suspected bacterial meningitis, primary outcome Glasgow Outcome Scale at 8 weeks (death/disability), secondary outcomes death, focal neuro abnormalities, hearing loss, GI bleed, fungal infection, zoster, hyperglycemia. Significant reduction in mortality and risk of unfavorable outcome using dexamethasone 10 mg IV q 6 hours for 4 days (mortality 7%) vs. placebo (mortality 15%), both groups received IV Amoxicillin or empiric antibiotics based on local resistance patterns (yes, Amox works well in Holland). No beneficial effect seen in dex group with regards to neuro sequelae including hearing loss.
Points of interest for comparison: Confirmed meningitis (in this study defined by CSF culture pos = 78%, probable meningitis CSF culture neg = 22%). Median duration of symptoms 24 hours. Breakdown of bacterial etiologies when known: S. pneumoniae 36%, N. meningitidis 32%, other bacteria 10%, including H. flu 1%. In this study patients who had received prior antibiotics were excluded. Low risk of adverse events/no sig. difference in rates of steroid associated adverse effects between groups. Interesting point made in article about neuro sequelae; although no benefit seen in steroid group, neuro sequelae seen predominantly in the most severely ill patients, and proportion of severely ill who survived to be tested was larger in dex group. Also very interesting that positive steroid effects (death/disability) appear to be significant only in S. pneumoniae group (other bacterial etiologies NS).
2) Corticosteroids for Bacterial Meningitis in Adults in Sub-Saharan Africa
Scarborough et al, NEJM Dec 13, 2007;357:2441-2450.
RCT, Malawi, 465 patients, >16 yo, suspected bacterial meningitis, primary outcome mortality at 40 days, secondary outcomes time to death, combined death/disability at day 40, hearing impairment at day 40, death at 10 days, death at 6 months. No difference in either primary or secondary outcomes (40 day mortality 56% dex, 53% placebo) using dexamethasone 16 mg IV bid for 4 days vs. placebo, both groups received 2 gm IV or IM ceftriaxone bid for 10 days (route independently being evaluated in study, no difference in mortality).
Points of interest for comparison: Confirmed meningitis 70%, probable meningitis 22%. Breakdown of bacterial etiologies when known: S. pneumoniae 59% of total patients, N. meningitidis 4%, other gram neg 5% (including <1% H. flu), Crypto 4%, TB 1.5%. Breakdown of HIV status available for 93% of total patients, and 90% were HIV +, median CD4 count 102. Prior antibiotics 37%, including 20% having received prior parenteral antibiotics, but analysis of prior antibiotic + patients still with no steroid advantage. Median length of illness 3 days (more than Europe, same as Vietnam). Low risk of adverse events/no sig. difference in rates of steroid associated adverse effects between groups. Huge mortality, in population with extremely high rate of advanced HIV disease, and therefore may already have an attenuated host response (steroids may not confer additional anti-inflammatory benefit).
3) Dexamethasone in Vietnamese Adolescents and Adults with Bacterial Meningitis
Mai et al, NEJM Dec 13, 2007;357:2431-2440.
RCT, Vietnam, 435 patients, >14 yo, suspected bacterial meningitis, primary outcome mortality at one month, secondary outcome death/disability at 6 months. No difference in either outcome (one month mortality 10.1% dex, 12.4% placebo) using dexamethasone 0.4 mg/kg IV q 12 hours for 4 days vs. placebo, both groups received 2 gm IV ceftriaxone q 12 hours for 10-14 days. There was a significant benefit from dex in reducing deafness overall and in subgroups. For patients with confirmed meningitis (69%), both outcomes were significantly improved with dexamethasone, while for probable cases (28%), dex was associated with an increased risk of death at one month. Why? Proposed explanation that some patients in “probable meningitis” group ended up diagnosed with TB meningitis but TB meds were delayed, and more of these patients received dex; TB with high mortality anyway, and will do worse if given dex and no TB drugs.
Points of Interest for comparison: Breakdown of etiologies of meningitis when known: Streptococcus suis 27% of total patients, S. pneumoniae 13%, all others each <5% (Neisseria 4%, H. flu 2%). S. suis common in Asia, and although less likely to kill you, is highly associated with deafness. Also important when comparing studies: low rate of HIV (<1%), high rate of prior antibiotics (65%), and no mortality difference in dex/placebo groups who had received prior antibiotics. Median duration of illness 3-4 days. Low risk of adverse events/no sig. difference in rates of steroid associated adverse effects between groups.
Bottom line:
Vast majority at journal club would give the vignette patient (young adult, healthy, CSF with pus) steroids and then antibiotics. Based on first study and decrease in mortality 15% → 7% with steroids, and lower risk of negative outcome. Most vocal contrarian: Erik Kulstad, who pointed out that cognitive function may be negatively impacted by steroids, and therefore need to weigh mortality benefit vs. potential cognitive harm. This brought out the importance of discussing potentially controversial treatment plans with family/patients; not only is patient preference the third pillar of EBM, but documenting these discussions of risk/benefit can also help protect you from a medico-legal standpoint (is it more important for your patient to survive, or to be a brainiac?). Also important to remember that although no significant increase in GI bleeding, studies were relatively small-might see more negative outcomes with larger studies. There was clear consensus in the room NOT to treat patients with meningitis and advanced HIV with steroids (Malawi study). Also important to realize the heterogeneity of the studies and our patients-different bacteria, different chronic medical conditions/genetics of patients, different antibiotic choices (vanco/blood brain barrier), time to antibiotics-- all may factor into decision process.