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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 Outcome (C) (O) tubercular Anti TB drugs Anti TB drugs Mortality + meningitis Disability Steroid p’ts 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 Search database • UpToDate key word: TB meningitis found: 1 reslut 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 Menon The 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 with TBM. • Selection criteria Randomised controlled trials of steroids in people on TB treatment for TBM. • Search strategy Cochrane Infectious Diseases Group specialized trials register (February 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. The Cochrane Database of Systematic Reviews 2005 Issue 4 Any steroid vs control Death EER: 96/301= 31.89% ARR: 39.46%-31.89%= 7.57% CER: 116/294= 39.46% NNT: 1/0.0757= 13.2 The Cochrane Database of Systematic Reviews 2005 Issue 4 Any steroid vs control Death or disabling residual deficits EER: 23/87= 26.44% ARR: 45.45%-26.44%= 19.01% CER: 40/88= 45.45% NNT: 1/0.1901= 5.3 The Cochrane Database of Systematic Reviews 2005 Issue 4 Any steroid vs control: stratified by age Death NNT= 10.3 NNT= 14.5 The Cochrane Database of Systematic Reviews 2005 Issue 4 Any steroid vs control: stratified by severity Death NNT= 8.6 NNT= 12 The Cochrane Database of Systematic Reviews 2005 Issue 4 • 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. The Cochrane Database of Systematic Reviews 2005 Issue 4 Dexamethasone for the Treatment of Tuberculous Meningitis in Adolescents 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 NNT=10 N Engl J Med 2004; 351(17): 1741-1751. Primary outcome N Engl J Med 2004; 351(17): 1741-1751. Primary outcome P value 0.44 0.96 0.27 0.01 N Engl J Med 2004; 351(17): 1741-1751. Secondary outcome 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 paraparesis resolved (%) 67.9 81.1 81.8 0.51 0.46 •Patients without hemiparesis or paraparesis at baseline hemiparesis occurred (%) 6.2 paraparesis occurred (%) 4.5 4.7 4.2 0.48 0.89 •Adverse rate (%) 79.0 0.005 67.9 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. 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 Infectious Diseases Society of America Morbidity and Mortality Weekly Report (MMWR) June 20, 2003 / Vol. 52 / No. RR-11 MMWR 2003; vol. 52:RR-11. MMWR 2003; vol. 52:RR-11. Corticosteroid for TBM---used dosage 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 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-life Glucocorticoid 商品名/規格 Equivalent potency dose(mg)* Antiinflammatory potency* Sodiumretaining 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 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 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+ Intermediate-acting Long-acting Drug Facts and Comparisons 2005. 總 結 Death Cochrane (依age區分) 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) Stage I-II 未改善 (P=0.09) Death Cochrane (依疾病嚴重 Stage III 改善 (P=0.04; NNT= 8) 度區分) 2004 NEJM Gread I 改善 (P=0.02) Gread II, III 未改善 (P=0.74; P=0.91) Adverse rate total P=0.007; NNT=12 total P=0.2 2004 NEJM 減少adverse rate (P= 0.005) 尤其severe hepartitis明顯降低發生率 (P= 0.004) 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. 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