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?

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

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 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 (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

When / How to treat? 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)

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 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 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

Kilger E, Weis F, Briegel J, Frey L et al. 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) Stress dose hydrocortisone in high-risk cardiac surgical patients: Reduces peri-operative stress exposure Decreases chronic stress symptoms Improves Health-related quality of life

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 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

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 Modifiable Risk Factor? Marker of Illness Severity?

Summary ACCM Consensus 2008 Surviving Sepsis 2012 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 (pO2/FIO2 < 200) 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)