Corticosteroids in sepsis:

The use of corticosteroids

in patients with septic
shock has been recently
revisited and the use of
low dose corticosteroids
led to very promising
result

Annane D, Cavaillon JM. Shock; 20 (3) 2003

Learning Objectives
To review adrenal function in
critically ill patients
To review the rationale for
supplementation with
corticosteroids during septic
shock
To review relevant recent
studies evaluating
corticosteroids replacement in
patients with septic shock

Corticosteroids in Septic shock:

Animal Data
Corticosteroids are essential for an
animal to survive shock.
Adrenalectomized dogs injected with
E.coli die. Antibiotics alone do not
prevent death.
Corticosteroid bolus 6 hrs of injection
of endotoxin prevented death
Hinshaw et al Circ Shock:1985:35:139-151

Anti inflammatory activity

Inhibition of production of
pro-inflammatory cytokines.
Free radical
Prostaglandins

Inhibition of chemotaxins and

adhesion molecule expression
Annane D, Cavaillon JM. Shock; 20 (3) 2003

Effects on cardiovascular
system
Increasing mean blood pressure
Increasing pressor sensitivity
Decreasing the duration of use of
catecholamines during septic
shock
Annane D, Cavaillon JM. Shock; 20 (3) 2003

Glucocorticoids
Inhibition of pro - imflammatory
cytokine production
Regulation of anti-inflammatory
cytokine
Inhibition of inflammatory mediators
Modulation of cell markers
Modulation of apoptosis
Annane D, Cavaillon JM. Shock; 20 (3) 2003

Schematic summary of glucocorticoids properties

Annane D, Cavaillon JM. Shock; 20 (3) 2003

Role of Steroids in Septic Shock

Decrease:
Migration of
leukocytes
NO synthesis
Macrophage function
Synthesis of TNF, IL1 and IL-6
Temperature
Amount of pressor
required

Increase:
CO and blood flow by
1 and receptors
Tissue metabolism via
gluconeogenesis
Oxygen dissociation
Synthesis of IL-4 + IL10

Plasma cortisol is often decreased

in patients treated in an ICU.
Rydvall et al. Int Care Med 2000;26:545-551

55 consecutive ICU patients, single ICU

Morning cortisol (median): 550 nmol/l
range was 20-1764 nmol/l
< 400 in 36%
< 500 in 47%

ACTH 250 g stimulation test

cortisol response was < 200 nmol/l in 56%

Potential Explanations of Failed

Interventions in Patients with Severe Sepsis
Bad drugs/concept?
In vivo activity may be different than in vitro

Inappropriate dosing?
Timing issues, tissue penetration

Wrong patients/heterogeneous dilution?

Importance of mechanistic diagnoses

Bad study design?

Sample size, realistic endpoints,
assurance of biologic activity

What is new?

Reversal of late septic shock with

supraphysiologic doses of hydrocortisone.
Bollaert et al. CCM 1998;26:645

Randomized, DB, placebo controlled

Two ICUs
41 pts with septic shock requiring
vasopressors > 48 h
Excluded if post - stim cortisol <495 nml/L
Hydrocortisone 100 mg IV Q8 h for 5 days
Endpoints
reversal of shock (SBP>90 for >24 h
without VP)
mortality

Reversal of late septic shock with

supraphysiologic doses of hydrocortisone.
Bollaert et al. CCM 1998;26:645

Results
Shock reversal in
15/22 (68%) HC pts
4/19 (21%) placebo pts
Mortality:

7/22 (32%) vs 12/19 (63%)

p=.007
p=.09

Response to short corticotropin test did not

predict outcome

Outcome: 7-day Shock Reversal

Abs diff: 47%

NO difference between responders and non-responders

Outcome: 28-day survival

Abs diff: 31%

RRR: 50%

NO difference between responders and non-responders

Stress doses of hydrocortisone

reverse hyperdynamic shock
Briegel et al. CCM 1999;27:723

Randomized, DB, placebo controlled

Single ICU, 40 pts

septic shock requiring pressors

CI > 4 L/min/m2 after fluid resuscitation

Hydrocortisone 100 mg, then 0.18

mg/kg/h for 6 d
ACTH stim test not mentioned
Endpoints
time to cessation of VP
MODS

Stress doses of hydrocortisone

reverse hyperdynamic shock
Briegel et al. CCM 1999;27:723

Results
Median time of VP support
HC pts:
2 days,
placebo pts:
7 days

p=.005

trend to earlier resolution of sepsis-induced

organ dysfunction
No difference in mortality

Time to vasopressor cessation

Median time to vasopressor cessation:
Steroid: 2 days (1,6)
Placebo: 7 days (3,19)

Briegel et al. CCM 1999;27:723

Physiological dose steroid therapy

in sepsis
Yildiz et al. Critical Care 2002;6:251-258

Randomized, DB, placebo controlled

single ICU, 40 pts
Sepsis (14), severe sepsis (17), septic
shock (9)

Prednisolone 5 mg/2.5 mg for 10 days

ACTH stim test
Occult AI = < 250 nmol/l

Endpoint: 28 day mortality

No standardized care

Physiological dose steroid therapy

in sepsis
Yildiz et al. Critical Care 2002;6:251-258

Results

35% of patients had occult AI

Mortality

No difference between responder and nonresponder

40% steroid vs 60% control (NS)

Multivariate analysis
SOFA

OR 2.09

Low doses of hydrocortisone and

fludrocortisone in pts with septic
shock
Annane et al. JAMA 2002;288:862-71
Double blind, placebo controlled
19 ICU, 300 pts
Inclusion criteria
septic shock requiring pressors

250 ug corticotropin test

Hydrocortisone 50 mg Q 6H
Endpoints
28 day survival
time to vasopressor discontinuation

Steroids in Septic Shock with Adrenal

Insufficiency: Study Design
Onset of shock

Randomization

TIME 0
At 8 hours

Hydrocortisone
50 mg IV QID

Eligibility
and
ACTH test

PLACEBO
For 7 days

+
Fludrocortisone PO
50 g/d for 7 days
Annane et al. JAMA 2002;288:862-71.

Patient Selection
Inclusion criteria
>18 years
Documented site
T>38.3 or <35.6c
HR > 90 bpm
SBP<90 mm Hg (fluids &
>5 g/kg/min dopamine)
Mechanical ventilation
PaO2/FiO2 < 280 or urine
output <0.5ml/kg/h or
lactate > 2 mmol/l
ACTH test

Exclusion criteria
Pregnancy
Evidence for AMI, PE
Need for corticosteroids
Contraindication to
steroids

Annane et al. JAMA 2002;288:862-71

Study Endpoints
Primary

28-day Survival in non- responders

Secondary

SURVIVAL in all patients

28-day, ICU, Hospital, 1 yr mortality
Duration of shock and organ dysfunction
Safety

Annane et al. JAMA 2002;288:862-71

Effect of Steroids in Septic Shock

with Adrenal Insufficiency
28-Day Cumulative
Survival in All Patients

Cumulative Survival Rate

28-Day Cumulative Survival in NonResponders

1.00

1.00

0.80

0.80

TREATMENT

TREATMENT
0.60

0.60

0.40

0.40

PLACEBO

0.20

0.20

P = 0.02

P = 0.03

0.00
0

14

Time (days)

21

PLACEBO

28

0.00

14

21

Time (days)

Annane et al. JAMA 2002;288:862-71.

28

Probability of survival

28-day
28-day survival
survival and
and relative
relative adrenal
adrenal
insufficiency
insufficiency
1.00

max > 9 g/dl

0.75
0.50
0.25

max 9 g/dl
0.00

14
Time (days)

21

28

Annane et al. JAMA 2002;288:862-71

Corticosteroids may improve

emotional wellbeing
Retrospective study
Controls matched to steroid group
Post-traumatic stress disorder
5/27 HC patients versus 16/27 (p=.01)

Health related quality of life

Medical outcomes study short-form survey
Mental health index: 68 vs 44 points p=.009
Schelling et al. CCM 1999:27(12);2678

How might steroids be beneficial in

critically ill patients?
Absolute adrenal insufficiency
Relative adrenal insufficiency
Immune response modifier
inhibit migration of leucocytes
inhibit adhesion of neutrophils

Increased CO, regional and coronary blood

flow
Block NO synthesis BP
Effect on tissue metabolism
gluconeogenesis, temperature, shift of
O2 dissociation curve

Steroids in Septic Shock

Conclusions
A short corticotropin test has good
prognostic value and may be helpful in
identifying patients with septic shock
at high risk for death
Modest doses improve 28-day
survival in patients with pressordependent septic shock who are
adrenally insufficient (<250 nm/L )

SUMMARY
Glucocorticoids display wide spectrum of
anti-inflammatory properties
Short courses of high dose corticosteroids
do not affect mortality from severe sepsis
& septic shock
Sepsis and septic shock may be associated
with relative adrenal insufficiency

SUMMARY
In vasopressor dependent septic shock, a
low dose of corticosteroids :
attenuated inflammation
restores vessels reactivity to
vasopressor agents
shortens the time on vasopressor agent
improves survival