jeremy cohen on steroids

‘ROIDS IN SEPSIS

Jeremy Cohen, Royal Brisbane Hospital

Queensland, Australia

Monday, 2 September 13

Monday, 2 September 13

The Steroid Controversy

Monday, 2 September 13

Hippocrates

Description of Sepsis

Girolamo Frascatoro

Concept of Contagion

SEPSIS TIMELINE

430 BC 1546

Anthony van Leeuwenhoek

Description of Bacteria

1683

Monday, 2 September 13

Ignaz Semmelweiss

Hand Disinfection

Robert Koch & Louis Pasteur

Germ Theory

1847 1870

SEPSIS TIMELINE

Monday, 2 September 13

Gram negative Sepsis

Multiple Organ Failure

1909

Host Response

1912 1975

SEPSIS TIMELINE

1951

32 Studies on Steroids in Infection

1944

Monday, 2 September 13

Bone et al

NEJM

Annane et al

JAMA

Sprung et al

NEJM

1987 2002 2008

SEPSIS TIMELINE

Monday, 2 September 13

0

15

30

45

60

Poland Germany Belgium Other

Europe

Perc

enta

ge u

se o

f LDS

0

15

30

45

60

Brazil Chile Peru ArgentinaMexico Other

Latin America

Perc

enta

ge u

se o

f LDS

0

15

30

45

60

India Singapore Phillipines Israel Malaysia Other

Asia

Perc

enta

ge u

se o

f LDS

18.0

28.5

39.0

49.5

60.0

N.America Australia Other

Rest of World

Perc

enta

ge u

se o

f LDS

Low Dose Corticosteroid Use By Region

Adapted from Beale at al CC 2010

Monday, 2 September 13

Monday, 2 September 13

Monday, 2 September 13

Patient with Septic Shock

Short Synacthen Test

Overall

Randomised to Steroid or Placebo

Non -Responders

Responders

Monday, 2 September 13

Use of Etomidate

Statistical Analysis

Outcomes reported as time to death rather than mortality

Mortality only significant after using adjusted model

Monday, 2 September 13

Overall

Non Responders

Responders

28 Day Mortality(steroids vs placebo) p value

82 (55%) vs 91(61%)

22 (61%) vs 18(53%)

60 (53%) vs 73 (63%)

0.09

0.96

0.04

0.24

0.63

0.11

Monday, 2 September 13

Patients not as sick

Underpowered

Did not reach recruitment target

Monday, 2 September 13

Severe  Stress

Moderate  Stress

Mild  Stress

Monday, 2 September 13

0

1000

2000

3000

4000

Rothwell Annane Schein Sibbald Bollaert Sam Bouachour Schroeder Beishuizen Aygen Jarek De Jong Dimopoulou Oppert

Cor

tisol

nm

ol/l

Survivors Non Survivors

Cortisol values in Sepsis

Monday, 2 September 13

“There is no greater tragedy in Science than to witness the slaying of a beautiful hypothesis by an ugly fact” Thomas Huxley

Monday, 2 September 13

Annane et al,JAMA 2000

Cortisol < 940, Delta > 250

Cortisol < 940, Delta < 250Cortisol > 940, Delta > 250

Cortisol > 940, Delta < 250

Monday, 2 September 13

Good Outcome

Intermediate Outcome

Bad OutcomeCortisol > 940, Delta < 250

Cortisol < 940, Delta > 250

Cortisol < 940, Delta < 250Cortisol > 940, Delta > 250

Monday, 2 September 13

Monday, 2 September 13

Monday, 2 September 13

250µg 1-24 ACTH

Baseline

IncrementPeak

Time

30 min 60 min0 min

Monday, 2 September 13

Peak vs. Increment

Up to 1/3 healthy controls fail to increase cortisol by 250 n mol/l. Widmer at al JCEM 2005

Increment dependent upon basal concentration May and Carey, Am.J.Med 1985

Increments in repeated tests inversely related to response of the previous challenge

Arvat et al, JCEM 2000Monday, 2 September 13

Correlation vs Causation

Monday, 2 September 13

Baseline:

Peak

Increment

600

900

300

1000

1200

200

Normal InsufficientMonday, 2 September 13

Reproducibility of ACTH tests in Sepsis

Loisa et al 2005

Monday, 2 September 13

Patient 1

Patient 2

Patient 3

Patient 4

Patient 5

Patient 6

Patient 7

Patient 8

Patient 9

HPLC RAI AAI RAI RAI AAI AAI RAI AAI AAI

Centaur RAI RAI RAI RAI RAI RAI RAI AAI NORMAL

TDx NORMAL RAI RAI RAI RAI NORMAL RAI AAI NORMAL

Immulite NORMAL RAI RAI RAI RAI NORMAL RAI AAI NORMAL

Adrenal Status by Assay

Monday, 2 September 13

!

Monday, 2 September 13

Monday, 2 September 13

Cohen et al, Shock 2011

Monday, 2 September 13

Cohen et al, Shock 2011

Monday, 2 September 13

Free Cortisol Values in Survivors and Non Survivors

0

50

100

150

Free Cortisol

Co

nce

ntr

atio

n n

mo

l/

Baseline + 30 Minutes + 60 Minutes

Total Cortisol Values in Survivors and Non Survivors

0

200

400

600

800

1000

Co

nce

ntr

atio

n n

mo

l/Baseline + 30 Minutes + 60 Minutes

Total Cortisol

Comparison of Outcomes

**

DiedSurvived

Free Cortisol Total Cortisol

Cohen et al, Shock 2011

Monday, 2 September 13

ADRENALAdjunctive Corticosteroid Treatment in Critically Ill

Patients with Septic Shock

3800 patients200mg hydrocortisone by infusion for 7 days90 day mortality

Monday, 2 September 13

Queensland  Princess  Alexandra  Royal  Brisbane  &  Womens  Ipswich  Logan  Mater  Health-­‐Public    Mater  Private  HospitalNambour  RedcliffeToowoombaWesley

NSWBlacktownCalvary  Mater  –  NewcastleJohn  HunterLiverpoolNepeanPrince  of  WalesRoyal  North  shoreRoyal  Prince  AlfredSt  GeorgeSt  Vincent’s  SydneyTamworthWoollongong

Northern  TerritoryDarwin

New  ZealandAuckland  DCCMAuckland  CVICUChristchurchMiddlemoreNorth  ShoreTaurangaWellington

Western  AustraliaFremantleRoyal    Perth

TasmaniaHobart

South  AustraliaLyell  McEwinQueen  Elizabeth

VictoriaAusUnBendigoDandenongGeelongMonashNorthernRoyal  MelbourneSt  Vincent’s  MelbourneWestern

ADRENAL

Monday, 2 September 13

United  KingdomSt  Georges  NHS  +  7  sites Denmark

Righospitalet

IndiaChris8an  Medical  College  Manipal  HospitalColumbia  Asia

Saudia  ArabiaKing  Abdul  Aziz  Medical  City

Republic  of  IrelandCork  University  Hospital Norway

ADRENAL

Monday, 2 September 13