CRITICAL ILLNESS RELATED CORTICOSTEROID INSUFFICIENCY

CIRCI: Current Status 2013Karyn L. Butler, MD, FACS, FCCM

Chief, Surgical Critical CareHartford Hospital

Associate Professor of SurgeryUniversity 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?

RELATIVE ADRENAL INSUFFICIENCY

RAI CIRCI

CRITICAL ILLNESS CORTICOSTEROID INSUFFICIENCY

ADDISON’S DISEASE

ACCM Consensus Critical Illness-Related Corticosteroid Insufficiency

(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?

CIRCI

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 NFB by increasing IB transcription

Cortisol physiology Cortisol binds to

intracellular receptors

Activates or represses gene transcription

Inhibits NFB by increasing IB 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?

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

How to establish diagnosis?

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 (pO2/FIO2 < 200)

ACCM consensus Crit Care Med 2008

When / How to treat? Dose should be adequate to down-regulate the pro-

inflammatory 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

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)

When / How to treat?

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

1966: “…it is conceivable that such [glucocorticoid] administration before prolonged cardiopulmonary bypass in humans would be of value.” –Moses ML et al. J Sur Res

Glucocorticoids and CPB

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/m2

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

Stress doses of hydrocortisone reduce chronic stress symptoms and improve health-related quality of life in high-risk

patients after cardiac surgery: a randomized study

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)

Reduces peri-operative stress exposure

Decreases chronic stress symptoms

Improves Health-related quality of life

Stress dose hydrocortisone in high-risk cardiac surgical patients:

Cardiopulmonary and systemic effects of methylprednisolone in

patients undergoing cardiac surgery

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

Attenuates perioperative release of systemic and myocardial inflammatory mediators

Improves myocardial function

Potential cardioprotective effect in patients undergoing cardiac surgery

Surgical practice changed

Glucocorticoid treatment before CPB:

Corticosteroids for the prevention of atrial fibrillation

after cardiac surgery: a randomized controlled trial

Halonen J, Halonen P, Järvinen 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?

CIRCI

SummaryACCM Consensus 2008

1. Hydrocortisone (200-300 mg/day) for patients with septic shock despite fluid resuscitation and vasopressors (2B)

2. ACTH stimulation test SHOULD NOT be used to identify who should receive GC’s (2B)

3. GC dose reduced slowly to avoid rebound inflammation

4. Methylprednisolone 1 mg/kg/day x 14 days for early severe ARDS (pO2/FIO2 < 200)

Surviving Sepsis 20121. 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)