C
I
R
C
I
CIRCI
Karyn L. Butler, MD, FACS, FCCM
Chief, Surgical Critical Care
Hartford Hospital
Associate Professor of Surgery
University of Connecticut
Hartford, CT

Background

1940’s:

‘Relative Adrenal Insufficiency”: activation of adrenal response, inadequate for magnitude of insult Pollak H. Lancet 1940

 Adrenalectomised animals exposed to shock had high mortality
(Seyle et al.)
1980’s


Etomidate impairs cortisol synthesis

 Increased mortality 28 to 77% in trauma patients (Watt et al.
Anesthesia 1984)
1990’s
Patients with MSOF improve after GC treatment ( Arch Surg 1993)

….Hydrocortisone did not improve survival or reversal of shock in patients with septic shock.

The etomidate debate is currently in clinical equipoise in which there is genuine uncertainty within the expert medical community.

Key questions
 Terminology?
 How is the diagnosis established?
 When / How to treat?
 Does therapy make a difference?

ADDISON’S DISEASE
RELATIVE ADRENAL
INSUFFICIENCY
CRITICAL ILLNESS
CORTICOSTEROID
INSUFFICIENCY
RAI CIRCI

ACCM Consensus

C ritical
I llness-
R elated
C orticosteroid
I nsufficiency
(
CIRCI
)
 Absolute or Relative adrenal insufficiency should be avoided
 Inadequate cellular corticosteroid activity for the severity of the patient’s illness
 Dynamic / Reversible
Crit Care Med 2008

….the evidence to support its existence as a relevant clinical entity is currently not compelling….We therefore suggest that the terms “RAI” and “critical illness related corticosteroid insufficiency” be abandoned….

Key questions
 Terminology?
 How is the diagnosis established?
 When / How to treat?
 Does therapy make a difference?

Result of stress response?
Potentiate organ dysfunction?

The Stress Response




 Activation of hypothalamic-pituitary-adrenal (HPA) axis essential to maintenance of cellular and organ homeostasis
HPA axis failure common in systemic inflammation
Incidence ~ 20%
60% in septic shock ( Anane et al Am J Resp Crit Care Med 2006)
“Adrenal failure”


CAP
Trauma




Head Injury
Burns
Liver Failure s/p Cardiac Surgery

Cortisol physiology

Cortisol physiology
 Increases blood pressure
 Increases sensitivity to vasopressor agents (increases transcription and expression of receptors)
 Increases endothelial nitric oxide synthetase
(maintaining microvascular perfusion)
 Reduces number and function of immune cells at sites of inflammation


Decreases the production of cytokine/ chemokines
Enhances macrophage migration inhibitory factor

Cortisol physiology
 Major endogenous GC secreted by adrenal cortex
 > 90% bound to CBG
 Decreased CBG during acute illness free cortisol
 Cortisol binds to intracellular receptors


Activates or represses gene transcription
Inhibit NF

B by increasing I

B transcription

Cortisol physiology
 Cortisol binds to intracellular receptors


Activates or represses gene transcription
Inhibits NF

B by increasing I

B transcription

How to establish diagnosis?
 Measure cortisol

Free vs. total



Timing (random vs. other)
Association with severity of illness
Gender differences
 Measure provoked cortisol production

ACTH ‘stim’ test (low vs. high dose)
 Threshold for mortality
?

How to establish diagnosis?
 ACTH stimulation test
SHOULD NOT be used to identify those patients with septic shock or ARDS who should receive GC’s (2B)
 Normal range of free cortisol is unclear
 No test is able to measure GC resistance at the tissue level
 Unclear what level of circulating cortisol is needed to overcome tissue resistance
ACCM consensus Crit Care Med 2008

Key questions
 Terminology?
 How is the diagnosis established?
 When / How to treat?
 Does therapy make a difference?

When / How to treat?
 Hydrocortisone should be considered in patients with septic shock who have responded poorly to fluid resuscitation and vasopressors (2B)
 Meta-analysis of 6 RCT



Hydrocortisone 200-300 mg/day
Greater shock reversal at day 7
No change in mortality
 Methylprednisolone 1 mg/kg/day x 14 days for early severe ARDS (pO
2
/F
I
O
2
< 200)
ACCM consensus Crit Care Med 2008

When / How to treat?
 Dose should be adequate to down-regulate the proinflammatory response without causing immune-paresis or interfering with wound healing
 GC dose reduced slowly to avoid rebound inflammation
 Dexamethasone
NOT indicated
 Immediate and prolonged HPA axis suppression
ACCM consensus Crit Care Med 2008

When / How to treat?
1. IV hydrocortisone 200 mg/day if hemodynamically unstable despite fluid resuscitation and vasopressor support (2C)
2.
Do not use ACTH ‘stim’ test to identify who receives
GC therapy (2B)
3. Taper GC when vasopressors no longer required
(2D)
4. Do not use in sepsis if no shock (1D)
5. Continuous infusion (2D)

Key questions
 Terminology?
 How is the diagnosis established?
 When / How to treat?
 Does therapy make a difference?

Methylprednisolone infusion in early severe ARDS
Results of a Randomized Controlled Trial
Meduri GU, Golden E, Freire AX,
Umberger R et al.
Memphis Lung Research Program
Chest 2007; 131:954 - 963

Study design


Randomized, double blind, placebo controlled
Five ICU’s in Memphis
 91 patients with severe early ARDS (<72h)
 Randomized to MP x 28 days (1mg/kg/d) vs. placebo
 Outcomes


Reduction in lung injury score
Successful extubation by day 7

Results
 MP n=63, Placebo n= 28
 Reduction of LIS: 69.8% vs. 35.7%; P=0.002
 Extubation: 53.9% vs. 25%; P=0.01
 MP: lower CRP levels, decreased MV LOS, decreased
ICU LOS
 Mortality: 20.6% vs. 42.9%; P= 0.03

Conclusions
 Down regulated SIRS
 Improved pulmonary and extrapulmonary organ dysfunction
 Reduced duration of MV and ICU length of stay
 Associated with decreased mortality

Glucocorticoids and CPB
–Moses ML et al. J Sur Res

Glucocorticoids and CPB
 1966: High dose dexamethasone attenuates lysosomal enzyme release after CPB
 Beneficial effects of methylprednisolone 15-30 mg/kg prior to CPB prevented pulmonary vascular and alveolar architectural changes (early 1970’s)

Initial studies from 1970’s to early 2000 not promising

Stress doses of hydrocortisone reduce severe systemic inflammatory response syndrome and improve early outcome in a risk group of patients after cardiac surgery
Kilger E, Weis F, Briegel J, Frey L et al.
University of Munich
Crit Care Med 2003; 31:1068 - 1074

Study design
 Prospective noninterventional trial to identify patients at high risk for SIRS
 Prospective randomized interventional trial of prophylactic hydrocortisone in target population
 Exclusions:



Renal insufficiency Cr > 2 mg/dL
Insulin dependent diabetes mellitus
Body mass index > 30 kg/m 2

Risk Factors
 Duration of CPB > 97 minutes
 EF < 40%
 CABG with 4 or more grafts
 Planned valve + CABG

Methods
 High risk patients randomized to:

Stress dose hydrocortisone: 100 mg bolus before anesthesia, continuous infusion 10 mg/hr tapered over 4 days
 Placebo
 Serum Il-6 levels before anesthesia and 6 hours after
CPB
 Hemodynamic variables
 Length of stay data

Conclusions
 Preoperative risk stratification is pivotal to provide effective anti-inflammatory prophylactic treatment
 Peri-operative continuous hydrocortisone reduces systemic inflammation
 Study not powered to detect reduction in mortality rate at 30 days

Weiss F, Kliger E, Roozendaal B. et al.
University of Zurich, University Munich, UCSF-Irvine
J Thorac Cardiovasc Surg 2006; 131:277-282

Background
 High stress exposure

Increased catecholaminergic activity
 Decreased HPA activity
 Post-operative chronic stress symptoms (PTSD?)
 Impairments in mental health
 Decrease HRQL

Study design
 36 High risk patients

EF < 35%
 CPB > 97 minutes
 Prospective, randomized, double blind trial
 Randomized to stress dose hydrocortisone (4 days) or placebo
 HRQL questionnaire 6 months post-op


Traumatic memories
Chronic stress symptoms

Results

Conclusions (6 months post-op)
Stress dose hydrocortisone in high-risk cardiac surgical patients:
 Reduces peri-operative stress exposure
 Decreases chronic stress symptoms
 Improves Health-related quality of life

Liakopoulos OJ, Schmitto JD, Kazmaier S. et al.
University of Gottingen, Germany
Ann Thorac Surg 2007; 84:110-119

Study design
 Elective CABG
 Exclusion:
 Emergency or concomitant cardiac surgical procedures




Age > 80 years
EF < 30%
AMI < 4 weeks
Renal dysfunction
 Methylprednisolone 15 mg/kg 30 minutes before CPB

Main outcome measures
 Hemodyanmic parameters
 Cytokine, troponin and CRP levels
 Mechanical ventilation, LOS

Conclusions
Glucocorticoid treatment before CPB:
 Attenuates perioperative release of systemic and myocardial inflammatory mediators
 Improves myocardial function
 Potential cardioprotective effect in patients undergoing cardiac surgery
 Surgical practice changed

Halonen J, Halonen P, J
ä rvinen O. et al.
Kuopio University Hospital, Finland
JAMA 2007; 297:1562-1567

Study design






3 University hospitals
241 patients (age 30-85 years)
Exclusion:




AF or flutter
Uncontrolled DM
Infection
Cr >2 mg/dL
Randomized to Hydrocortisone (100 mg) or placebo
 First dose post- op, then q8h x 3 days
All patients received metoprolol according to HR
Sample size based on reduction of AF 30% to 15%

Outcome measures
 Occurrence of AF during the first 84 hours after cardiac surgery
 Study protocol discontinued after first episode of AF
 Meta-analysis of RCT of primary outcome of AF (2 + present study)

Conclusions
 Intravenous hydrocortisone reduced the relative risk of post-op AF by 37%
 Meta-analysis confirmed beneficial effect of corticosteroid treatment over placebo
 No serious complications associated with steroid use

Modifiable
Risk
Factor?
Marker of
Illness
Severity?

Summary
ACCM Consensus 2008
1.
2.
3.
4.
Hydrocortisone ( 200-300 mg/day ) for patients with septic shock despite fluid resuscitation and vasopressors (2B)
ACTH stimulation test
SHOULD
NOT be used to identify who should receive GC’s (2B)
GC dose reduced slowly to avoid rebound inflammation
Methylprednisolone 1 mg/kg/day x
14 days for early severe ARDS
(pO
2
/F
I
O
2
< 200)
1.
2.
3.
4.
5.
Surviving Sepsis 2012
IV hydrocortisone 200 mg/day if hemodynamically unstable despite fluid resuscitation and vasopressor support (2C)
Do not use ACTH ‘stim’ test to identify who receives GC therapy
(2B)
Taper GC when vasopressors no longer required (2D)
Do not use in sepsis if no shock
(1D)
Continuous infusion (2D)