1. Corticosteroids in the ICU
Fekri Abroug
CHU F.Bourguiba
Monastir
Tunisia

2. Corticosteroids in Sepsis

3. 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

4. Clinical Question
In patients with sepsis, septic shock, does treatment with corticosteroids replacement-dose improve short-term survival?

5. 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.

6. Results Mixed population, n=3 Incomplete information, n=3
26 RCTs
7 RCTs
excluded
Mixed population, n=3
Incomplete information, n=3
Very short term effects, n=1
19 RCTs
included
1 Cross over, n=40
18 Parallel groups, n=2,137
CS-Replacement
9 RCTs
N=570

7. Results 28-day Mortality (all trials)
RR=0.88 (0.78 to 0.99)
P=0.03
Favors CS
Favors Control

8. Results 28-day Mortality (Long course of low dose)

9. Results Hospital Mortality (Long course of low dose)

10. Results Shock Reversal
Favors Control
Favors CS

11. Results Adverse Events (long course of low dose)
Favors CS
Favors Control

12. Corticosteroids in ARDS

13. 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

14. 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

15. 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

16. High Dose CS for Early ARDS
(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

17. No effect of early high doses and short courses (30mg/kg MP 1-2D)

18. 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

19. NO DATA

20. 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

21. PaO2/FIO2
* P < 0.05
Ratio * * *
Day
ARDS net study, ATS05

22. Plateau Pressure and Static Compliance* * *
Compliance
Static * * *
Day
* P < 0.05
ARDS net study, ATS05

23. Ventilator-Free Days Placebo MP P-Value VFD @ 28 d (mean)
6.8
25.5
150
11.1
31.0
159
0.0007
0.02
0.04
ARDS net study, ATS05

24. Median Organ Failure-Free Days to Day 28
Variable
Placebo
Methylprednisolone
P-Value
Cardiovascular
Coagulation
Hepatic
Renal 17 23 24 21 23
24.5 25
0.03
0.84
0.70
0.36
ARDS net study, ATS05

25. LaSRS: Adverse Events P Value Placebo MP Total 26 32 NS CNS 0 5 0.028MS
All 9 cases of neuromyopathy reported were in the methylprednisolone group
ARDS net study, ATS05

26. 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)
ARDS net study, ATS05

27. Effects of Corticosteroids
Corticosteroids compared to placebo had:
Greater decrease in plasma IL-6
Greater decrease in BAL neutrophils
ARDS net study, ATS05

28. Low Dose CS for Late ARDS
Meduri (Jama 98)
ARDS net (ATS05) n 24
180 Rx
MP 2mg/kg 32 d
MP 2mg/kg 21 d
P/F
Improved
Static compliance
Systemic & lung Inflammation
Reduced
Time on MV
OSF free days
Increased
Mortality
Decreased
Unchanged
Superinfection
Muscle weakness ?

29. 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

30. GER-INF-05 300 SEPTIC SHOCK 177 WITH ARDS 123 WITHOUT ARDS 67 PLACEBO
62 STEROIDS

31. Day-28 mortality ICU mortality Hospital mortality NON RESPONDERSp
Day-28 mortality
50 (75%)
33 (53%)
Unadjusted hazard ratio
0.60 ( )
0.021
Adjusted hazard ratio
0.57 ( )
0.013
Relative risk
0.71 ( )
0.011
ICU mortality
53 (79%)
36 (58%)
0.73 ( )
0.010
Hospital mortality
37 (60%)
0.75 ( )
0.016
Placebo
(n = 67)
Corticosteroids
(n = 62)
Adjusted odds ratio
0.35 ( )
0.38 ( )
0.025

32. Low Dose CS for Early ARDS
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)
(N = 0)
(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)
Meduri et al submitted

33. Low Dose CS for Early ARDS
P=0.001
P<0.001
Meduri et al submitted

34. Low Dose CS for Early ARDS
P=0.13
P=0.28
Meduri et al submitted

35. 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?