Download - Corticosteroids in the ICU
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Corticosteroids in the ICU
Fekri Abroug
CHU F.Bourguiba
Monastir
Tunisia
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Corticosteroids in Sepsis
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Background
Systemic inflammation is the hallmark of sepsis Corticosteroids modulate immune response to
sepsis through genomic and non-genomic effects Cytokines may suppress cortisol production or
access to tissues, inducing corticosteroids insufficiency in almost half of septic shock
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Clinical Question
In patients with sepsis, septic shock, does treatment with corticosteroids replacement-dose improve short-term survival?
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Inclusion Criteria
Types of studies: RCT or quasi-RCT with or without blinding. Types of participants: Children & adults with sepsis, septic shock
(ACCP/SCCM 1992).
Types of interventions- Intervention:
- i.v. of any type of corticosteroid preparation - replacement therapy: ≤300mg HC (equivalent) for ≥5 days
- Control: Standard therapy or placebo. Types of outcome measures
- Primary: 28-day all-cause mortality.
- Secondary: Hospital mortality, shock reversal (day 7), Adverse events.
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Results
26 RCTs
7 RCTsexcluded
Mixed population, n=3Incomplete information, n=3Very short term effects, n=1
19 RCTsincluded
1 Cross over, n=40
18 Parallel groups, n=2,137
CS-Replacement9 RCTsN=570
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Results 28-day Mortality (all trials)
Favors CS Favors ControlP=0.03 RR=0.88 (0.78 to 0.99)
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Results28-day Mortality (Long course of low dose)
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ResultsHospital Mortality (Long course of low dose)
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ResultsShock Reversal
Favors Control Favors CS
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ResultsAdverse Events (long course of low dose)
Favors CS Favors Control
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Corticosteroids in ARDS
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Position of the Problem
Systemic Inflammation is the hallmark of ARDS
both at the early phase and later in the course of the disease
Corticosteroids are the main anti-inflammatory drugs
both at high doses and moderate doses
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Position of the Problem
Theoretically there are 4 therapeutic options
1- High dose CS for early ARDS 2- High dose of CS for late ARDS 3- Low dose CS for early ARDS 4- Low dose CS or late ARDS
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1- High dose CS for early ARDS 2- High dose of CS for late ARDS 3- Low dose CS for early ARDS 4- Low dose CS or late ARDS
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High Dose CS for Early ARDS
CS
(MP30mg/kg)
Placebo P
Weigelt 1985 46% of 39 31% of 42 0.18
Bone 1987 52% of 152 21% of 152 0.004
Luce 1988 58% of 38 54% of 37 ns
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No effect of early high doses and short courses (30mg/kg MP 1-2D)
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1- High dose CS for early ARDS 2- High dose of CS for late ARDS 3- Low dose CS for early ARDS 4- Low dose CS or late ARDS
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NO DATA
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1- High dose CS for early ARDS 2- High dose of CS for late ARDS 3- Low dose CS for early ARDS 4- Low dose CS for late ARDS
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PaO2/FIO2
120
140
160
180
200
220
240
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
PlaceboMethylprednisolone
Day
Rat
io
* P < 0.05
**
*
ARDS net study, ATS05
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Plateau Pressure and Static Compliance
262830323436
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
PlaceboMethylprednisolone
Day
Pla
teau
P
ress
ure
* P < 0.05
*
0,20,30,40,50,60,7
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Sta
tic
Co
mp
lian
ce
* *
* **
ARDS net study, ATS05
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Ventilator-Free Days
VFD @ 28 d (mean)
VFD @ 60 d (mean)
VFD @ 180 d (mean)
6.8
25.5
150
11.1
31.0
159
Placebo MP
0.0007
0.02
0.04
P-Value
ARDS net study, ATS05
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Median OrganFailure-Free Days to Day 28
Cardiovascular
Coagulation
Hepatic
Renal
17
23
24
23
21
23
24.5
25
Variable Placebo Methylprednisolone
0.03
0.84
0.70
0.36
P-Value
ARDS net study, ATS05
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LaSRS: Adverse Events
Total 26 32 NS CNS 0 5 0.028 MS 0 5 0.028
All 9 cases of neuromyopathy reported were in the methylprednisolone group
Placebo MP P Value
ARDS net study, ATS05
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Serious Infections
Placebo 43 in 30 pts Methylprednisolone 25 in 20 pts More suspected/probable pneumonia in the
placebo group (14.3 vs. 5.6%, P=0.049) More septic shock episodes in the placebo
group (17 vs. 15 pts vs 6 in 5 pts; P=0.031)
P=0.135
ARDS net study, ATS05
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Effects of Corticosteroids
Corticosteroids compared to placebo had: Greater decrease in plasma IL-6 Greater decrease in BAL neutrophils
ARDS net study, ATS05
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Low Dose CS for Late ARDSMeduri (Jama 98) ARDS net (ATS05)
n 24 180
Rx MP 2mg/kg 32 d MP 2mg/kg 21 d
P/F Improved Improved
Static compliance Improved Improved
Systemic & lung Inflammation
Reduced Reduced
Time on MV Reduced Reduced
OSF free days Increased Increased
Mortality Decreased Unchanged
Superinfection Decreased Decreased
Muscle weakness ? Increased
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1- High dose CS for early ARDS 2- High dose of CS for late ARDS 3- Low dose CS for early ARDS 4- Low dose CS or late ARDS
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GER-INF-05
300 SEPTIC SHOCK
177 WITH ARDS 123 WITHOUT ARDS
67 PLACEBO 62 STEROIDS
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p
Day-28 mortality 50 (75%) 33 (53%)
Unadjusted hazard ratio 0.60 (0.38-0.93) 0.021
Adjusted hazard ratio 0.57 (0.36-0.89) 0.013
Relative risk 0.71 (0.54-0.94) 0.011
ICU mortality 53 (79%) 36 (58%)
Relative risk 0.73 (0.57-0.94) 0.010
Hospital mortality 53 (79%) 37 (60%)
Relative risk 0.75 (0.59-0.96) 0.016
Placebo(n = 67)
Corticosteroids(n = 62)
Adjusted odds ratio 0.35 (0.15-0.82) 0.016
Adjusted odds ratio 0.35 (0.15-0.82) 0.016
Adjusted odds ratio 0.38 (0.16-0.88) 0.025
NON RESPONDERS
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Low Dose CS for Early ARDS
Meduri et al submitted
Assessed for eligibility (N = 517)
Excluded (N = 212) *Did not meet inclusion criteria (N = 181)Refused to participate (N = 16)
Randomized (n = 91)
Methylprednisolone infusion(N = 63)
Received allocated intervention > 24 h (N = 61)
Received allocated intervention < 24 h (N = 2) †
Protocol violation(N = 5) ‡
Discontinued intervention(N = 1) ||
Day 7 analysis (N = 55)
Exit study after day 7 (N = 4) ¶
Final analysis (N = 51)
Protocol violation(N = 0)
Discontinued intervention(N = 3) ||
Day 7 analysis (N = 24)
Placebo(N = 28)
Received allocated intervention > 24 h (N = 27)
Received allocated intervention < 24 h (N = 1) †
Exit study after day 7 (N = 3) ¶
Final analysis (N = 21)
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Low Dose CS for Early ARDS
Meduri et al submitted
P=0.001
P<0.001
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Low Dose CS for Early ARDS
Meduri et al submitted
P=0.13
P=0.28
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Summary
Low dose of CS consistently showed benefit on both early and late ARDS morbidity
Low Dose of CS may improve survival from ARDS both during the early and late phase. However data remained controversial
Efforts should be made to reduce CS induced muscle weakness – Glucose control?