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Corticosteroid Replacement
in Critically Ill Patients
Steroid Physiology
 Basal Cortisol Production = 8-25 mg in 24hrs
 Production can be increased 6-fold in stress
 Diurnal pattern of cortisol production lost in stress
situations
 Cortisol T1/2 = 70-120 minutes

 Bound to circulating CBG, albumin, 1-acid

glycoprotein
 10% free = biologically active
 CBG decreases rapidly in critically ill pts  increased
free cortisol
 Adrenal Insufficiency (AI)
 1. Primary Adrenal Insufficiency (Addison’s)
– >90% destruction of adrenal cortex
– Causes: thrombosis, hemorrhage (septic shock with
DIC), necrosis from ischemia

– Sxs: truncal pain, fever, shaking chills, hypotension,

shock, abdominal rigidity or rebound, dehydration,
hyponatremia, hyperkalemia, elevated BUN
– Failure to recognize and tx severe adrenal
insufficiency (addisonian crisis) can be fatal within
6-48 hours
 Adrenal Insufficiency (AI)
 2. Secondary Adrenal Insufficiency
– Pituitary or hypothalamic abnormalities
– Causes: empty sella syndrome, tumors,
hypopituitarism, head trauma, postpartum
pituitary necrosis, exogenous glucocorticoid use

– Sxs: similar to primary AI but with preserved

aldosterone (no Na, K abnormalities)
 Adrenal Insufficiency (AI)
 3. Relative or Functional AI (1)
– Reported in critically ill pts
– Subnormal adrenal corticosteroid production
– Hypoadrenal state without clearly defined defects in
hypothalamic-pituitary-adrenal axis

– Difficult to define based on serum cortisol concentrations as

cortisol production may be inadequate to control
inflammatory response or meet an elevated metabolic
demand
– Characteristic rapid improvement on HC thx
 Diagnosis of Adrenal
Insufficiency
 High-dose corticotropin stimulation test
– Can be done at any time of day
– Baseline cortisol  250g cosyntropin 
measure cortisol at 30 and 60 minutes
– Nonstressed pt: increase to 18 g /dL r/o AI

– Hi sensitivity & specificity for primary AI

using threshold value of 15 g /dL
– Less sensitive for secondary AI
Diagnostic Clues in Critically
Ill Patients
 Persistent hypotension despite adequate
volume resuscitation
 Hyperdynamic circulation and low SVR
 Ongoing e/o inflammation w/o obvious
source that does not respond to empiric
treatment
 Lab test difficulties in
critical illness
 Cortisol level interpretation complicated by:
– Hard to define “normal” ranges as expected
levels vary based on disease & severity
– Reduced CBG
– Changes in tissue resistance to cortisol
– Local release of free cortisol
– Etomidate use for intubation
 Random Cortisol Level
 Poor prognosis in septic shock patients: (4)
– extremely HIGH (>34g/dL) total cortisol
– extremely LOW (<25g/dL) total cortisol

 Interpretation of Baseline Cortisol = Controversial

– Cortisol level <15g/dL suggested to ID pts with clinical
features of AI or who would benefit from replacement (2)
– Others suggest that a pt w/ septic shock on vasopressors
should have baseline cortisol of >25 g/dL if measured w/i
48 hrs of admit (3)
 Cosyntropin Stimulation

 Advocated as standard of diagnosis of AI in

critically ill pts (5)
– Failure to increase cortisol concentration at least 9
g/dL to value >20 g/dL associated w/
 Increased mortality
 Lack response to catecholamines

 Disagreement on threshold of basal

concentration and change in cortisol with
stimulation necessary to diagnose relative AI
Outcome of steroid replacement
 Cochrane Database Meta-analysis in 2004 (6)
– 15 trials  no significant reduction in all-cause mortality at
28 days w/ steroid replacement in septic shock
– 4 trials  reduced mortality & increased shock reversal
with long courses of low dose steroids

 Another Meta-analysis in 2004 (7)

– Short courses of high-dose steroids decreased survival
during sepsis
– But a 5- to 7-day course of physiologic hydrocortisone
doses with subsequent tapering increased survival rate
and shock reversal in patients with vasopressor-
dependent septic shock
 Conclusion
 Patients with septic shock should have:
– Baseline cortisol measured
– Undergo corticotropin-stimulation testing

 Patients with inadequate cortisol response

(baseline <15-25g/dL and failure to increase by
9g/dL) benefit from glucocorticoid replacement

 HC at 200-300 mg/d recommended with

intermittent or continuous IV infusion
 Steroids tx for 5-7days followed by taper (total
treatment time of 10days)
 References
1. Bollaert PE. 2000. Stress doses of glucocorticoids in catecholamine dependency: a
new therapy for a new syndrome?. Intensive care medicine 26 (1): 3-5.
2. Cooper MS, Stewart PM. 2003. Corticosteroid insufficiency in acutely ill patients. The New
England journal of medicine 348 (8): 727-734.
3. Marik PE, Zaloga GP. 2003. Adrenal insufficiency during septic shock. Critical care
medicine 31 (1): 141-145.
4. Marik PE, Zaloga GP. 2002. Adrenal insufficiency in the critically ill: a new look at an old
problem. Chest 122 (5): 1784-1796.
5. Jacobi J. 2006. Corticosteroid replacement in critically ill patients. Critical care clinics 22
(2): 245-53, vi.
6. Annane D, Bellissant E, Bollaert PE, Briegel J, Keh D, Kupfer Y. 2004. Corticosteroids for
severe sepsis and septic shock: a systematic review and meta-analysis. BMJ 329 (7464):
480-480.
7. Minneci PC, Deans KJ, Banks SM, Eichacker PQ, Natanson C. 2004. Meta-analysis: the
effect of steroids on survival and shock during sepsis depends on the dose. Annals of
internal medicine 141 (1): 47-56.