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• Hypoadrenal state without clearly defined defects in HPA axis
• Difficult to define based on serum cortisol concentrations:
– Although cortisol level may be normal, it may remain inadequate for the patient’s metabolic demands
• Rapid improvement on Hydrocortisone therapy
Relative Adrenal Insufficiency
0%
10%
20%
30%
40%
50%
60%
70%
Septic Shock Other ICU Patients
CABG
Dissecting AAA
JCEM (2006) 91: 105–114
Incidence of Relative Adrenal Insufficiency
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CORTISOL
ACTH
CRH
STRESS:
Physical stress
Emotional stress
Hypoglycemia
Cold exposure
Pain
Adrenal Cortex
Anterior Lobe of
Pituitary Gland
Hypothalamus
• Increased sensitivity to pressors
• Anti-inflammatory effect on immune
system
• Maintenance of vascular tone &
endothelial integrity
• Modulation of angiotensinogen synthesis
• Reduction of NO-mediated vasodilation
Cortisol Action
Classical regulators of the axis continue to
be operable in critically ill patients but with significant alterations:
– Hypothalamic hormones
– CRH
– Vasopressin
– Inflammatory cytokines: IL-1, IL-6,TNF-α
– ANS
modulators of HPA function
Anesthesiology (1993) 77: 426–431
HPA Alteration During Critical Illness
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• Impaired hepatocellular
function
• Impaired hepatic blood
flow
• Impaired renal/thyroid
function
J Clin Invest (1958) 37: 1791–1798
• Increased steroid production
•Decreased steroid clearance
Increased Serum Cortisol
(free cortisol level)
Stress
• ACTH and cortisol responsiveness to exogenous CRH is enhanced during critical illnesses
• ACTH = dominant factor stimulating cortisol secretion throughout the critical illness → other factors play a significant modulating influence on the axis
J Inflamm (1996) 47: 39–51
Arginine Vasopressin
Endothelin
Atrial Natriuretic Factor
(ANF)
Variety of Cytokines
(IL-6)
Type & Severity of Illness • Acute phase of illnesscortisol levels proportionate to
degree of stress
• Cortisol levels: major surgery vs sepsis SIMILAR ELEVATION
• Cortisol elevations in sepsis: -wide range
-? don’t correlate with APACHE
-highest levels highest mortality
• Sepsis vs Trauma patients: -similar cortisol elevation
-levels markedly higher in:
– Sepsis,
– Progression to ARDS
– Patients who didn’t survive
• Glucocorticoid resistant patients have higher levels
JCEM (2001) 86: 2811–2816 Intensive Care Med (2001)27: 1584-1591 Clin Endocrinol (2004) 60:29-35.
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Short-Term Stressors vs. Protracted Critical Illness
• Initial phase is characterized by:
» ↑ACTH
» ↑Cortisol
• Protracted critical illness:
» ↓ACTH
» ↑Cortisol
cortisol secretion is being regulated and stimulated by
alternative pathways other than the classical hypothalamic CRH
JCEM (1998)83: 1827-34
J Trauma (1987)27: 384-392
Persistent Hypercortisolism Observed in Protracted Critical Illness
J Trauma (1987) 27: 384–392
Benefits Related To Long Term Complications
Providing energy Hyperglycemia
Maintaining volume Myopathy
Minimizing inflammation Psychiatric alterations
Poor wound healing
Diagnostic Clues in Critically Ill Patients
• persistent hypotension despite
adequate volume resuscitation
• hyperdynamic circulation and low SVR
• ongoing inflammation w/o obvious
source that does not respond to empiric
treatment
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High-Dose ACTH Stimulation Test:
• Can be done at any time of day
• Baseline cortisol 250g ACTH measure cortisol at 30 and 60 minutes
• Non-stressed pt: increase to 18 g /dL R/O AI
• High sensitivity & specificity for primary AI using
threshold value of 15 g /dL
• Less sensitive for secondary AI
Critical Care Clinics (2006) 22 (2): 245-53
Random Cortisol Level
Poor prognosis in septic shock patients:
– extremely HIGH (>34g/dL) total cortisol
– extremely LOW (<25g/dL) total cortisol
N Engl J Med (2003) 348 (8): 727-734 Chest (2002) 122 (5): 1784-1796 Critical care medicine (2003) 31 (1): 141-145
• Unstressed subjects, AI:
– ACTH stimulated cortisol 18-20 ug/dl
• Critically illness, AI:
– random cortisol <15 or 25 ug/dl (if on pressors)
– cortisol increment after ACTH stimulation < 9ug/dl
• Severe hypoproteinemia, AI:
– serum free cortisol < 2 ug/dl or
– ACTH stimulated value < 3.1 ug/dl
N Engl J Med (1996) 335: 1206-1212 N Engl J Med (2003) 348: 727–734