Endocrine changes in Critical Care

Alexandra BelcherST5

Objectives

• HPA axis overview• Relative adrenal suppression• Testing in critical care• Role (or not) for steroids

• Stress Hyperglycaemia

• Sick Euthyroid Syndrome

HPA Axis

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

Changes in hormone levels

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

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