endocrine changes in critical care
TRANSCRIPT
Objectives
• HPA axis overview• Relative adrenal suppression• Testing in critical care• Role (or not) for steroids
• Stress Hyperglycaemia
• Sick Euthyroid Syndrome
Actions of Cortisol
• Hyperglycaemia: gluconeogenesis, glycogenolysis
• Free fatty acid and amino acid production
• Catecholamine release, and tissue sensitivity to catecholamines
• Anti-inflammatory/immunosuppressive
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
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
1Boonen et al N Engl J Med 2013; 368:1477-1488
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
2Keri G, Parameswaran V, Trunkey DD, Ramachandran J: Effects of septic shock plasma on adrenocortical cell function. Life Sci 28:1917, 1981
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
1Annane 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
2Corticus Study Group N Engl J Med 2008; 358:111-124
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
1Malik et al Crit Care Med 2003 31 (1) 141
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
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
2Annane et al JAMA. 2009;301(22):2362
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
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
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
Morbidity of SH
• Consistently associated with harm:• Trauma1
• TBI2
• Mixed critical care3
• MI4
• No convincing evidence is the cause of harm1 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
Potential Pathophysiology
• Hyperosmolar damage with fluid shifts
• Increased oxidative stress
• Endothelial dysfunction
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
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
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