Transcript Steroids for treating tuberculous meningitis

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.
Thank you for your
attention