steroids for treating tubercular meningitis date: 94.11.17 ( 四 ) reporter: 張秀美藥師

Steroids for treating tubercular

meningitis

Date: 94.11.17 ( 四 )

Reporter: 張秀美藥師

Background

• Definition--------------Tuberculous meningitis (TBM) is an inflammation of the meninges covering the brain and spinal cord caused by infection with mycobacteria, most usually Mycobacterium tuberculosis.

The condition usually presents with headache, fever, and convulsions and is diagnosed clinically, with confirmation by microscopy and culture of cerebrospinal fluid.

Background

• Incidence--------------TBM is a common cause of admission to neurology and paediatric wards in some hospitals.

In the USA, some researchers have estimated that it accounts for 15% of the tuberculosis (TB) affecting organs other than the lungs.

HIV-infected patients are at higher risk of TB, and this has increased the incidence of TBM in these populations. TBM was the most common cause of meningitis, accounting for more than 25% of cases.

Background

• Incidence--------------

In one study comparing the clinical features, laboratory findings, and mortality rates in patients having TB meningitis with or without HIV infection, cerebral tuberculomas were seen to be more common in the HIV-infected group (60 versus 14 percent); otherwise, co-infection with HIV did not alter the clinical manifestations, CSF findings, or response to therapy.

UpToDate 2005; TB meningitis

Background

• Treatment options (TB Meningitis) ---------------------------

Without drug treatment patients with TBM die. Monotherapy with streptomycin, an early TB drug, reduced the case fatality rate to 63%.

TB drugs (isoniazid, rifampicin, and pyrazinamide) used in combination are associated with better survival, but the mortality remains substantial.

Recent reports estimate fatality rates varying from 20% to 32%, with permanent neurological deficits in 5% to 40% of the survivors.

Background

• Corticosteroids---------------------Corticosteroids for TBM since the 1950s. While some believe corticosteroids improve outcome :

(1) decrease inflammation, especially in the subarachnoid space. (2) reduce cerebral and spinal cord oedema. (3) reduce inflammation of small blood vessels and therefore reduce damage from blood flow slowing to the underlying brain tissue.

Background

• Corticosteroids---------------------It is possible that steroids may harm TBM patients by suppressing the immune mechanism. Steroids may:

(1) suppress the immune response to mycobacteria, making the systemic effects worse;

(2) reduce inflammation of the meninges, reducing drug penetration into the subarachnoid space;

(3) cause gastrointestinal haemorrhage, electrolyte imbalance, hyperglycaemia, infections from fungi or bacteria, and psychosis.

P.I.C.O.

Patients

(P)

Intervention

(I)

Comparison

(C)

Outcome

(O)

tubercular meningitis p’ts

Anti TB drugs+

Steroid

Anti TB drugs Mortality

Disability

Search database

• Cochrane library

key word: tuberculous

Found: 9 results

=> Steroids for treating TB meningitis

=> Interventions for treating TB pericarditis

=> Steroids for treating TB pleurisy

Key word: tuberculous

Search database

• ACP journal Club

key word: steroid, TB meningitis, meningitis

found: no related result

• Bandolier

key word: TB meningitis, meningitis, steroid

found: no related result

Search database

• Ovid Medline

Key word: tuberculosis meningitis, steroid,

dexamethasone

Found: 7 related results

=> Dexamethasone for the treatment of TB

meningitis in adolescents and adults.

Search database

• Pub Med

Key word: tuberculosis meningitis, steroids

Found: 1 related result (systematic review)

Search database

• National Guideline Clearinghouse

frequent search=> tuberculosis

found: 1 related result => Treatment of tuberculosis American Thoracic Society - Medical Specialty Society

Centers for Disease Control and Prevention - Federal Government Agency [U.S.] Infectious Diseases Society of America - Medical Specialty Society. 2003 Jun 20. 77 pages. NGC:003054

• UpToDate

key word: TB meningitis

found: 1 reslut

Search database

Results…..

• Clinical trial---Meta-analysis, RCT

for children, adolescents, adults, with or without HIV

• American Thoracic Society, CDC, IDSA

guideline for TB management• Conclusion

Steroids for treating tuberculous meningitis

K Prasad, J Volmink, GR MenonThe Cochrane Database of Systematic Reviews 2005 Issue 4

Copyright © 2005 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

10.1002/14651858.CD002244 This version first published online: 24 July 2000 in Issue 3, 2000

Date of Most Recent Amendment: 26 May 2005

• Objectives To assess the effects of steroids on death and disability in patients wit

h TBM.

• Selection criteria Randomised controlled trials of steroids in people on TB treatment for

TBM.

• Search strategy Cochrane Infectious Diseases Group specialized trials register (Februar

y 2005), The Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 1, 2005), MEDLINE (1966 to February 2005), EMBASE (1980 to February 2005), LILACS (February 2005).

The Cochrane Database of Systematic Reviews 2005 Issue 4

• Main results

Six trials of 595 patients met the inclusion criteria.

Steroids were associated with fewer deaths (relative risk [RR] 0.79; 95% confidence interval [CI] 0.65 to 0.97) and a reduced incidence of death and severe residual disability (RR 0.58, 95% CI 0.38 to 0.88).

Subgroup analysis suggests an effect on mortality in children (RR 0.77, 95% CI 0.62 to 0.96) but the results in a smaller number of adults are inconclusive (RR 0.96, 95% CI 0.50 to 1.84). There is little evidence that the severity of disease influences the effects of steroids on mortality.


Any steroid vs control

Death


EER: 96/301= 31.89% CER: 116/294= 39.46%

ARR: 39.46%-31.89%= 7.57% NNT: 1/0.0757= 13.2

Any steroid vs control

Death or disabling residual deficits


EER: 23/87= 26.44% CER: 40/88= 45.45%

ARR: 45.45%-26.44%= 19.01% NNT: 1/0.1901= 5.3

Any steroid vs control: stratified by ageDeath

NNT= 14.5


NNT= 10.3

Any steroid vs control: stratified by severityDeath


NNT= 8.6

NNT= 12

• Conclusions

Adjunctive steroids might be of benefit in patients with TBM.

No data are available on the use of steroids in HIV positive persons. Future placebo-controlled studies should include patients with HIV infection and should be large enough to assess both mortality and disability.

Adverse effects were reported in only four small trials, and in these cushingoid facies appear to be the most common. Side effects were more pronounced in studies using high doses of steroids.


Dexamethasone for the Treatment of Tuberculous Meningitis in Adolesce

nts and Adults

Guy E. Thwaites, M.R.C.P., Nguyen Duc Bang, M.D.,

N Engl J Med 351;17: 1741-1751. www.nejm.org october 21, 2004

• Methods

We performed a randomized, double-blind, placebo-controlled trial in Vietnam in patients over 14 years of age who had tuberculous meningitis, with or without HIV infection, to determine whether adjunctive treatment with dexamethasone reduced the risk of death or severe disability after nine months of follow-up. We conducted prespecified subgroup analyses and intention-to-treat analyses.

N Engl J Med 2004; 351(17): 1741-1751.

• Methods

grade I TBM : Glasgow Coma Scale of 15 with no focal neurologic signs (possible range, 3-15, with higher scores indicating better status).

grade II TBM : Glasgow Coma Scale of 11-14, or of 15 with focal neurologic signs.

grade III TBM : Glasgow Coma Scale of 10 or less.

N Engl J Med 2004; 351(17): 1741-1751.

• Methods ----Dexamethasone dosage grade II or III disease:

IV treatment for four weeks

(0.4 mg/kg/day for week 1, 0.3 mg/kg/day for week 2, 0.2 mg /kg/day for week 3, 0.1 mg/kg/day for week 4) and then

oral treatment for four weeks, starting at a total of 4 mg/day and decreasing by 1 mg each week.

grade I disease:

IV therapy for two weeks

(0.3 mg/kg/day for week 1, 0.2 mg/kg/day for week 2) and then oral therapy for four weeks (0.1 mg/kg/day for week 3, then a total of 3 mg/day, decreasing by 1 mg each week).

N Engl J Med 2004; 351(17): 1741-1751.

• Results

A total of 545 patients , age >14 years, were randomly assigned to receive either dexamethasone (274 patients) or placebo (271 patients). Median follow-up was 274 days (range, 28-442 days).

Primary outcome: death or severe disability nine months after randomization. Secondary outcome: coma-clearance time, fever-clearance time, time to discharge from the hospital, time to relapse, the presence of focal neurologic deficit nine months after randomization.

N Engl J Med 2004; 351(17): 1741-1751.

Primary outcome

N Engl J Med 2004; 351(17): 1741-1751.

NNT=10

Primary outcome

N Engl J Med 2004; 351(17): 1741-1751.

Primary outcome

N Engl J Med 2004; 351(17): 1741-1751.

P value 0.44 0.96 0.27 0.01

Secondary Outcome Dexamethasone group Placebo group P value

•Time to fever clearance (days) 9 11 0.03

•Time to coma clearance (days) 9 11 0.23

•Time to hospital discharge (days) 44 54 0.57

•Relapse occurred (%) 15 17.7 0.42

•Time to relapse (days) 41 38 0.12

•Patients who had hemiparesis or paraparesis at baseline

hemiparesis resolved (%) 75 81.1 0.51

paraparesis resolved (%) 67.9 81.8 0.46

•Patients without hemiparesis or paraparesis at baseline

hemiparesis occurred (%) 6.2 4.7 0.48

paraparesis occurred (%) 4.5 4.2 0.89

•Adverse rate (%) 67.9 79.0 0.005

Secondary Outcome with HIV p’t without HIV p’t P value

•Mortality rate (%) 65.3 (64/98) 28.4 (124/436) <0.001

N Engl J Med 2004; 351(17): 1741-1751.

Secondary outcome

N Engl J Med 2004; 351(17): 1741-1751.

• Conclusion

The show that adjunctive treatment with dexamethasone improved survival in patients over 14 years of age with tuberculous meningitis, but when the outcome measure was broadened to death or severe disability, there was no significant benefit.

dexamethasone did not affect the incidence or resolution of hemiparesis, paraparesis, or quadriparesis, which are the most common causes of severe disability due to tuberculous meningitis.

Dexamethasone may improve outcomes by reducing the frequency of adverse events --severe clinical hepatitis.

N Engl J Med 2004; 351(17): 1741-1751.

• Conclusion

The treatment effect of dexamethasone was homogeneous across HIV subsets, and stratified subgroup analysis showed that dexamethasone was associated with a reduction in the risk of death that was not significant (P=0.08).

however, that dexamethasone is safe and may be of benefit in this group of patients.

N Engl J Med 2004; 351(17): 1741-1751.

Treatment of Tuberculosis

American Thoracic Society, CDC, and InfectiousDiseases Society of America

Morbidity and Mortality Weekly Report (MMWR) June 20, 2003 / Vol. 52 / No. RR-11

MMWR 2003; vol. 52:RR-11.

Study Corticosteroid Dosage

Chotmongkol 1996

Prednisolone oral on tapering daily dosage for five weeks (wk 1, 60 mg; wk 2, 45 mg; wk 3, 30 mg; wk 4, 20 mg; wk 5, 10 mg).

Girgis 1991 Dexamethasone given i.m. (12 mg/day to adults and 8 mg/day to children weighing less than 25 kg) for three weeks and then tapered during the next three weeks).

Kumarvelu 1994 Dexamethasone given i.v. 16 mg/day in four divided doses for seven days, then oral tablet 8 mg/day for 21 doses.

Lardizabal 1998 Dexamethasone given at a dose of 16 mg/day for 3 weeks (first 5 days intravenous thereafter orally or via nasogastric tube). After 3 weeks steroid was tapered by 4 mg decrements every 5 days.

O'Toole 1969 Dexamethasone given i.v. for up to four weeks in an adult dose of 9 mg/day during the first week, 6 mg/day during the second week, 3 mg/day during the third week ,and 1.5 mg/day during the fourth week

Corticosteroid for TBM---used dosage

Corticosteroid therapy based upon urgent warning signs:

•Patients who are progressing from one stage to the next at or before the introduction of chemotherapy, especially if associated with any of the conditions listed below.

•Patients with an acute "encephalitis" presentation, especially if the CSF opening pressure is ≧400 mmH2O or if there is clinical or CT evidence of cerebral edema.

•Exacerbation of clinical signs (eg, fever, change in mentation) after beginning antituberculous chemotherapy.

•Spinal block or incipient block (CSF protein >500 mg/dL and rising)•Head CT evidence of marked basilar enhancement (portends an increased risk for infarction of the basal ganglia) or moderate or advancing hydrocephalus

•Patients with intracerebral tuberculoma, where edema is out of proportion to the mass effect and there are any clinical neurologic signs

UpToDate 2005; TB meningitis.

The recommended steroid regimens vary with age:

• Children — Prednisone 2 to 4 mg/kg/day tapered over 4 weeks.

• Adults — Recommended regimens include either:

— Prednisone 60 mg/day tapered gradually over 6 weeks or— Dexamethasone given IV for the first 3 weeks (initially

0.4 mg/kg/day, tapering to 0.1 mg/kg/day) followed by oral administration beginning with 4 mg/day, tapered over 3-4 weeks at the rate of 1 mg decrease in the daily dose each week.

UpToDate 2005; TB meningitis.

院內 Steroid 藥品種類 (inj, oral form)

Glucocorticoid equivalencies, potencies, and half-lifeGlucocorticoid 商品名 /規格 Equivalent

potency dose(mg)*

Anti-inflammatory potency*

Sodium-retaining potency

T1/2 plasma (min)

Short-acting

Cortisone Cortisone 25 mg/tab 25 0.8 2 30

Hydrocortisone Solu-cortef 100 mg/vial 20 1 2 80-118

Intermediate-acting

Prednisone -- 5 4 1 60

Prednisolone Donison 5 mg/tab 5 4 1 115-212

Triamcinolone Kenacort-A 10 mg/vial 4 5 0 200+

Methylprednisolone Solu-Medrol 40, 500 mg/vial

4 5 0 78-188

Long-acting

Dexamethasone Dexamethasone 0.5 mg/tab; Oradexon 5 mg/vial

0.75 20-30 0 110-210

Betamethasone Rinderon 0.5 mg/tab;

Rinderon 2, 4 mg/vial

0.6-0.75 20-30 0 300+

Drug Facts and Comparisons 2005.

總結

由於 Steroid 輔助治療 TBM 可改善 mortality, 且 adverse rate 並未增加 , 故對所有 TBM p’ts (children, adult, with or without HIV) 皆可加入 steroid 輔助治療之 .

Death

( 依 age 區分 )

Cochrane Childern 改善 (P=0.02; NNT=10)

Adult 未改善 (P=0.9)

total P=0.02;

NNT=13

2004 NEJM Age >14 y/o 改善 (P=0.01; NNT=10)

Death or disability

Cochrane 改善 (P=0.01; NNT= 5)

2004 NEJM 未改善 (P=0.22)

Death

( 依疾病嚴重度區分 )

Cochrane Stage I-II 未改善 (P=0.09)

Stage III 改善 (P=0.04; NNT= 8)

total P=0.007;

NNT=12

2004 NEJM Gread I 改善 (P=0.02)

Gread II, III 未改善 (P=0.74; P=0.91)

total

P=0.2

Adverse rate 2004 NEJM 減少 adverse rate (P= 0.005)

尤其 severe hepartitis 明顯降低發生率 (P= 0.004)

Thank you for your attention

steroids for treating tubercular meningitis date: 94.11.17 ( 四 ) reporter: 張秀美 藥師

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steroids for treating tubercular meningitis date: 94.11.17 ( 四 ) reporter: 張秀美藥師