critical illness related corticosteroid insufficiency circi: current status 2013 karyn l. butler,...
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CRITICAL ILLNESS RELATED CORTICOSTEROID INSUFFICIENCY
CIRCI: Current Status 2013
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?
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
Summary
ACCM Consensus 20081. 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)
