Steroids in septic shock: Current status
Bala Venkatesh
Professor of Intensive Care
Wesley & Princess Alexandra Hospitals
The George Institute for Global Health
University of Queensland & NSW
Disclosures
• Recipient of grants from NHMRC
• NHMRC-MRFF Practitioner Fellow
Scope of the presentation
• Magnitude of the problem of sepsis
• History of the steroid usage
• High dose era
• Evolution of low dose era
• Review of 2 recent major RCTS
• Questions arising
• Practice recommendations
N Engl J Med 2017; 377:414-417
Scott WJM J Exp Med 1923
The steroid in sepsis story began in 1923….....
Nature 1936
In 1950, was awarded the Nobel prize for the discovery of hydrocortisone
Hahn et al. J Clin Invest 1951
Annals of Surgery 1976
High dose steroids
were clearly dead in
the water
30mg/kg/day
of methyl-
prednisolone
10000 mg/day
of HC
What about lower dose steroids?
200-300mg / day of HC
Improved pressor
responsiveness
Relative adrenal
insufficiency
Annane et al. JAMA 2002
Sprung et al. N Eng J Med 2008
French 2002 CORTICUS 2008
PATIENTS 299 499
Medical/surgical 66/34 33/66
TREATMENT HC/FC HC
MORTALITY BENEFIT ITT - no ITT-no
Differential treatment
effect in non-
responders to ACTH
Y N
ETOMIDATE Y (24%) Y (19%)
Adverse effects N Y
Debate generated by the 2 RCTs
Power
Divergent
results
Marked global
variability in practice
and uncertainty
Beale et al Critical Care
The ADRENAL study: ADjunctive corticosteroid
tREatment iN criticAlly IlL patients with septic shock
• Bala Venkatesh
• John Myburgh
• Simon Finfer
• Jeremy Cohen
• Yaseen Arabi
• Rinaldo Bellomo
• Laurent Bilott
• Maryam Correa
• Parisa Glass
• Meg Harward
• Chris Joyce
• Qiang Li
• Colin McArthur
• Anders Perner
• Dorrilyn Rajbhandari
• Andy Rhodes
• Kelly Thompson
• Steve Webb
Aim
To determine whether hydrocortisone therapy reduces
mortality in patients admitted to an Intensive Care Unit
(ICU) with septic shock.
Hypothesis
Hydrocortisone, compared to placebo, reduces 90-day
all-cause mortality in patients admitted to an ICU with
septic shock.
Study design
• Trial design – Parallel group, blinded, international
• IC-EC
• Trial treatment: IV infusion of 200mg/day of
hydrocortisone or matched placebo
• Duration- Maximum of 7 days or until ICU discharge or
death if earlier
• Randomization stratified by
• A) participating center and
• B) by medical or surgical admission diagnosis.
Outcomes
• 28 day mortality
• Shock resolution
• Recurrence of shock
• ICU stay
• Hospital stay
• Duration of IPPV
• Re-ventilation
• Bacteraemias/fungemia
• Blood transfusion
• RRT
Primary outcome: 90 day mortality
Secondary outcomes
Sample size
Estimated baseline mortality in septic shock – 33%
(ANZICS-CTG sepsis surveys / CAT study and global data)
5% ARR or 15% RRR, 90% power
Sample size = 3800 patients (1900 each arm)
Size and magnitude of ADRENAL
Annane 2002 – 299 patients
Corticus 2008 - 499 patients
VASST 2007 - 778 patients
APROCCHS 2018 - 1241 patients
ADRENAL 2018 - 3800 patients
Results
2 groups similar at baseline with
respect to
Admission diagnosis
Sources of sepsis
Baseline interventions
Organ failure
Hydrocortisone
(N = 1832) Placebo
(N = 1826) Odds Ratio
Lower 95%CI
Upper 95%CI P-value
Unadjusted
Primary outcome – Day 90 mortality
511 (27.9%)
526 (28.8%)
0.96
0.83
1.10
0.54
Adjusted -
stratification variables
0.95
0.82
1.10
0.50
Adjusted -
additional covariates
0.96
0.82
1.12
0.58
60%
68%
54%
Primary outcome -6 pre-specified subgroups
44%
44%
Analysis of primary outcome by region
23
23
22
28
25
Secondary outcomes
• Hydrocortisone - more rapid resolution of shock (3 vs 4
days**)
• Hydrocortisone - shorter duration of initial episode of
IPPV (6 vs 7 days**)
• Hydrocortisone – earlier time to ICU discharge (10 vs 12
days**)
• Hydrocortisone – reduced frequency of blood transfusion
(37% vs 42%**)
** significant after adjustment for multiplicity
Secondary outcomes
No significant differences between the two groups with respect to;
a) recurrence of shock
b) need for renal replacement therapy
c) recurrence of mechanical ventilation and
d) new onset bacteraemia or fungaemia.
Adverse effects: A small but a slightly higher incidence of adverse
effects in the hydrocortisone group, but these did not impact on patient-
centred outcomes
Adverse events
• 33 total ( 24 hydrocortisone vs 3 placebo)
1.1% (HC) vs 0.3% (Placebo), P =0.009
• Predominantly metabolic (high BSL and hypernatremia)
• Others include GI bleed, haematological and encephalopathy
• SAE – 4 (HC) vs 2 (Placebo)
Summary of principal findings
• Hydrocortisone did not lead to a significant reduction in mortality
at 90 days in patients with septic shock
• This effect on mortality did not differ in any of the six pre-defined
subgroups.
• Hydrocortisone - more rapid resolution of shock,
• Hydrocortisone - shorter duration of initial episode of IPPV
• Hydrocortisone – an earlier time to ICU discharge
• Hydrocortisone – reduced frequency of blood transfusion
Unadjusted 571/1812 (31.5%)
574/1803 (31.8%) 0.99 0.86-1.13 0.83
APROCCHSS - Improvement in 90 day mortality
(43% vs 49%) and secondary outcomes
APROCCHS-ADRENAL key differences
• ADRENAL
• N= 3800
• IC – sepsis / shock definition
• IPPV a requirement
Etomidate - exclusion
• Interventions – HC
• Infusion
• 5 countries
• APROCCHSS
• N=1241
• Septic shock + organ failure
• 0.25mcg/kg/min Norad
• Etomidate – not excluded
• Interventions – HC + FC
• Bolus
• France
1) Was the mortality benefit in APROCCHSS
because of a different trial population?
• Pre-defined subgroups – sicker cohorts
• Geographic regions with a higher mortality
• Applying APROCCHSS criteria
Severity of illness
(N=1625)
(N=1654)
HC Placebo
Geographic regions with a higher mortality
(N=637) HC Placebo
Post hoc-sensitivity analysis – applying
APROCCHS inclusion criteria
Variable
Hydrocortisone
(N = 454)
Placebo
(N = 449)
Odds
Ratio
Lower
CI95%
Upper
CI95% P-value
.
.
Mortality D90 .
Unadjusted 187/453
(41.3%)
200/445
(44.9%)
0.86 0.66 1.12 0.27
Adjusted 0.84 0.60 1.17 0.33
Mortality D28
.
Unadjusted 166/454
(36.6%)
181/449
(40.3%)
0.85 0.65 1.12 0.25
Adjusted 0.84 0.62 1.13 0.28
(N=903)
Post hoc-sensitivity analysis – applying
Sepsis-3 criteria
Variable
Hydrocortisone
(N = 969)
Placebo
(N = 968)
Odds
Ratio
Lower CI
95%
Upper CI
95% P-value
Mortality D90 .
Unadjusted 312/963
(32.4%)
337/958
(35.2%)
0.88 0.73 1.07 0.20
Adjusted 0.86 0.70 1.06 0.19
.
Mortality D28 .
Unadjusted 259/969
(26.7%)
300/968
(31.0%)
0.81 0.67 0.99 0.04
Adjusted 0.80 0.64 0.99 0.06
(N=1937)
Intensive Care Medicine 2018
Generalisability of ADRENAL
• Pragmatic trial
• Did not stipulate a minimum dose of inotropes/pressors
• Results concordant in 5 health care systems
• Results consistent when different inclusion criteria
applied
2) Comparison of the 4 RCTs Ger-Inf-05 CORTICUS ADRENAL APROCCHSS
Sample size 299 499 3800 1241
Inclusion criteria Septic shock Septic shock Septic shock +
IPPV
SS (0.25mcg/kg/min
of Noradrenaline)
Medical/Surgical(%) 66/34 33/66 66/34 80/20
Treatment
Drugs HC/FC HC HC HC/FC
DOSE (mg/mcg) / day 200/50 200 200 200/50
DURATION (days) 7 11 7 7
Administration of HC Bolus Bolus Infusion Bolus
Tapering N Y N N
Ger-Inf-05 CORTICUS ADRENAL APROCCHSS
Mortality(ITT)
In-hospital N N N/A Y
Day-28 N N N N
Day-90 N N/A N Y
6 months N/A N/A N Y
12 months N N N/A N/A
Survival benefit
ACTH non-
responders
Y N N/A N
Other
outcomes
Ger-Inf-05 CORTICUS ADRENAL APROCCHSS
Shock reversal Y Y Y Y
Weaning - IPPV N/A N/A Y Y
LOS - ICU N/A N Y N
LOS -hospital N/A N N N
Adverse
effects with HC
N Y (super-
infections)
Y
(metabolic)
Y
(metabolic)
3) Role of fludrocortisone
• Basis of FC use- Primary insufficiency
• HC at 200 mg sufficient mineralocorticoid activity
• FC – enteric absorption impaired in critically ill patients
• 3 trials have investigated – Ger-Inf-05, COIITSS,
APROCCHSS
Ger-Inf-05 COIITSS APROCCHSS
Mortality benefit
- FC
Intention to treat N N Y ACTH- NR Y N/A N
4) Hydrocortisone - infusion or bolus?
• Bolus administration - widely used method,
• Administration by infusion
- attenuate the inflammatory response,
- reverse shocks
- recommended mode in patients with Addisonian crisis
- may minimize metabolic side effects
- No clear evidence to support one mode or the other
5) Optimal duration of HC therapy?
Ger-Inf-05 – 7 days
CORTICUS – 11 days
ADRENAL - 7 days
APROCCHSS – 7 days
6) Is corticotropin testing required prior
to administration of hydrocortisone?
• Original evidence of benefit -in Ger-Inf-05 trial
• Not replicated in CORTICUS or APROCCHSS trial.
• The corticotropin test has limited utility in critically ill
patients
• A recent international task force meeting on adrenal
insufficiency concluded – no reliable test to diagnose AI
Venkatesh B- Clin Endocrinol (Oxf). 2015;83(3):289-97
Annane D - Intensive Care Med. 2017 43(12):1751-1763.
7) Repeat course of hydrocortisone if
there is a relapse of shock?
• No robust evidence
• Data from Briegel et al
8) Is a 300mg dose of hydrocortisone
superior to 200mg in septic shock?
• One RCT
• No evidence of benefit.
9) Is hydrocortisone useful for the
prevention of septic shock?
1) Corticosteroids did not impact on progression to SS
2) Corticosteroids did not impact on D28 or D90 mortality
3) No differences in weaning /infections/hyperglycemia
10) Does the type of vasopressor influence
responsiveness to hydrocortisone?
11) Does hydrocortisone require the presence of
ascorbic acid and thiamine to be more efficacious?
• Marik et al
• Evidence in a retrospective before-after study
• VICTUS
Etomidate
French 2002 CORTICUS 2008
PATIENTS 299 499
Medical/surgical 66/34 33/66
TREATMENT HC/FC HC
MORTALITY BENEFIT ITT - no ITT-no
Differential treatment
effect in non-
responders to ACTH
Y N
ETOMIDATE Y (24%) Y (19%)
Adverse effects N Y
Areas of future research
• Understanding variability in shock reversal – Only 80%
reversed shock
• Genomics
• Cortisol responders/ non-responders
• Fludrocortisone
Practice recommendations
• HC - Role in improving mortality unclear
• Evidence of benefit - patient-centred secondary outcomes
• Hydrocortisone prescribed in a dose of 200mg/day.
• Recommended duration - 7 days, either infusion or bolus.
• No requirement for dose tapering.
• No requirement to perform a corticotrophin test
• Additional fludrocortisone is not necessary.
• HC used irrespective of which vasopressor is being used
• No role in the prevention of septic shock.