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.