corticosteroids in the icu

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

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

Results 28-day Mortality (all trials)

Favors CS Favors ControlP=0.03 RR=0.88 (0.78 to 0.99)

Results28-day Mortality (Long course of low dose)

ResultsHospital Mortality (Long course of low dose)

ResultsShock Reversal

Favors Control Favors CS

ResultsAdverse 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

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

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

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

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

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

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

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

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

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 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

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

  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

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)

Low Dose CS for Early ARDS

Meduri et al submitted

P=0.001

P<0.001

Low Dose CS for Early ARDS

Meduri et al submitted

P=0.13

P=0.28

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?