Endocrine disease in critical care - Dr Alex Belcher

1. Endocrine changes
in Critical Care
Alexandra Belcher
ST5

2. Objectives
• HPA axis overview
• Relative adrenal suppression
• Testing in critical care
• Role (or not) for steroids
• Stress Hyperglycaemia
• Sick Euthyroid Syndrome

3. HPA Axis

4. Actions of Cortisol
• Hyperglycaemia: gluconeogenesis,
glycogenolysis
• Free fatty acid and amino acid production
• Catecholamine release, and tissue sensitivity
to catecholamines
• Anti-inflammatory/immunosuppressive

5. Normal Stress Response
• Acute stress stimulates HPA by cytokines (IL-1,
IL-6)
• Loss of diurnal variation in cortisol levels
• Return to baseline and recovery on removal of
stress

6. Cortisol levels in illness
• Rise post-operatively in keeping with extent of surgery
• Higher levels in severe illness (sepsis<other shock
types)
• Hypoproteinaemia common therefore CBG decreased
and free cortisol increased
• AKI can decrease clearance of glucocorticoids
• Decrease in metabolism of cortisol1
1
Boonen et al N Engl J Med 2013; 368:1477-1488

7. Abnormal stress
response
• May occur in:
• states of chronic stress
• Severe illness e.g. septic shock
• Secondary to drugs eg chronic steroid users, phenytoin, etomidate1
• May lead to inhibition of HPA and inadequate cortisol response
• Mediated by TNFα
• Plasma from septic shock patients impairs synthesis of
corticosteroids2
1
Cuthbertson et al Intensive Care Med (2009) 35:1868–1876
2
Keri G, Parameswaran V, Trunkey DD, Ramachandran J: Effects of septic shock plasma on
adrenocortical cell function. Life Sci 28:1917, 1981

8. Assessment of HPA
• Short synacthin test generally not relevant
• Measures total not free cortisol
• Used to identify complete adrenal loss not
relative dysfunction (supraphysiological dose)
• Pts often max stimulated i.e. no reserve
• Response may be linked to outcome1
• Does not relate to likelihood of steroid
response in septic shock2
1
Annane D, Sebille V, Troche G, et al: A three-level prognostic classification in septic
shock based on cortisol levels and cortisol response to corticotropin. JAMA
283:1038, 2000
2
Corticus Study Group N Engl J Med 2008; 358:111-124

9. Other tests
• Baseline cortisol as screen (take at anytime)
• Cut-off value of <6901
• Low dose synacthin
• 1mcg dose
• ?more physiological for relative suppression
• Not enough evidence for its use yet
• CRH to test whole axis
• Not evaluated in critical care
• Not easily available
• Free cortisol
• May be more physiological
1
Malik et al Crit Care Med 2003 31 (1) 141

10. Summary so far…
• Possibility of a relative adrenal suppression in
critical illness
• No complete definition of what this is
• No convincing evidence that treating an
identified RAI is beneficial

11. Is there a role for
steroids??• Steroids first used in 1950s in sepsis with advent of
cortisone
• Older studies used very high dose steroids: increased
mortality
• Two recent RCTs contradicted each other (Annane1
v
CORTICUS)
• BUT steroids may have a role in septic shock requiring
vasopressors2
• Await results of ADRENAL trial
1
Annane et al JAMA. 2002; 288 862-71
2
Annane et al JAMA. 2009;301(22):2362

12. Stress Hyperglycaemia
• Described in 1878 by Claude Bernard
• Usually refers to those without DM, but
process can worsen DM control
• Trials have looked at different values to
intervene, but technically random >11.1

13. Aetiology of SH
• Hyperglycaemia:
• Cortisol-induced gluconeogenesis and
glycogenolysis
• Catecholamine stimulated
• Role for Glucagon and GH
• Glucose Intolerance
• Decreased glucose uptake by peripheral tissues eg
muscle
• Insulin resistance
• Mediated by cytokines (TNFα, IL-1,6) and adipokines

14. Possible adaptive
response to stress
• Increase in GLUT-1 allows non-insulin
dependent uptake in reticulendothelial and
CNS tissue
• Higher serum conc. allows greater diffusion
gradient for glucose to reach tissues with
decreased blood flow
• Macrophages rely upon serum glucose to
function

15. Morbidity of SH
• Consistently associated with harm:
• Trauma1
• TBI2
• Mixed critical care3
• MI4
• No convincing evidence is the cause of harm
1
Sung et al J. Trauma 2005 59(1) 80
2
Jeremitsky et al J. Trauma 2005 58(1) 47
3
Krinsley Mayo Clin Proc 2003 78(12) 1471
4
Capes Lancet 2000 355 (9206) 773

16. Potential
Pathophysiology
• Hyperosmolar damage with fluid shifts
• Increased oxidative stress
• Endothelial dysfunction

17. Sick Euthyroid Syndrome
• Similar hypothalamic-pituitary-thyroid axis to
HPA, with negative feedback
• TSH released by anterior pituitary to induce
release of T3/T4 from thyroid
• 90% secreted from thyroid as T4, bound to TBG
• Peripheral conversion to T3 and rT3 by
monoiodinases in liver and kidney

18. Effect of critical illness
• Decrease in TRH and decrease in TSH response
to TRH
• Secondary to cytokines (TNFα) and dopamine
• Can be overcome by administering TRH
• Reduction of TBG so decrease total T4
• Inhibition of peripheral T4-T3 conversion
• 2nd
to cortisol, f.f.a.s, amiodarone, cytokines
• Conversely increase in rT3

19. Changes in hormone
levels

20. Implications
• Is the body or pituitary “euthyroid”?
• May be increased T4-T3 conversion in pituitary
• Are the tissues functionally hypothyroid?
• If the tissues are hypothyroid, is this an
adaptive mechanism?
• Maybe beneficial if mild decrease
• But, if fT4 decreases, marked increase in
mortality

21. Is it worth treating?
• Small studies in 1980s suggest no benefit
• One study in CABG patients showed no harm,
and increased CI but no benefit
• ?hard to ignore if T3 v low