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

Corticosteroids in Sepsis

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

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

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.

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

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

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

Results Hospital Mortality (Long course of low dose)

Results Shock Reversal Favors Control Favors CS

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

Corticosteroids in ARDS

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

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

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

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

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

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

NO DATA

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

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

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

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

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

LaSRS: Adverse Events P Value Placebo MP 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 ARDS net study, ATS05

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

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

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 ?

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

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

Day-28 mortality ICU mortality Hospital mortality NON RESPONDERS   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%) 0.73 (0.57-0.94) 0.010 Hospital mortality 37 (60%) 0.75 (0.59-0.96) 0.016 Placebo (n = 67) Corticosteroids (n = 62) Adjusted odds ratio 0.35 (0.15-0.82) 0.38 (0.16-0.88) 0.025

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

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

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

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?