Relative Adrenal Insufficiency Syndrome

1. Relative Adrenal Insufficiency Syndrome J.J.M Lightenberg and J.G. Zijlstra By R詹毓哲

2. Introduction • “Physiological” dose of steroid in septic shock => decrease mortality, reduce time to shock reversal. • “Relative adrenal insufficiency syndrom”: • rapid clinical & hemodynamic improvement of catecholamine-dependent patient after 300 mg/day hydrocortisone • Blunted response to corticotropin test • Accuracy of diagnostic tools? • Evidence of cause situated in adrenal cortex?

3. Accuracy of the current tools for diagnosis of the “relative adrenal insufficiency syndrome” ? • Cortisol • Electrolyte disturbances • eosinophilia

4. Cortisol • Critically ill patients: high normal to raised plasma cortisol level: studies: • Prospective study in 40 septic shock: basal cortisol & ACTH test – no differ in survivor (858 nmol/d) vs. non-survivor (1073) => 72 hours: survivor – no rise vs. non-survivor – 1840 • 54 post-OP (abd. aorta) – mod. Increased morning cortisol • 20 young septic shock survivors – basal cortisol increased

5. Cortisol • 159 ICU >7 days cases: cortisol in non-survivor 780 nmol/l > survivor 540. • 52 surgical ICU cases: random cortisol - high-normal range. • 189 cases: mean cortisol 940 at onset of septic shock -> non-survivor higher than survivor: 1076 vs 722 => poorest prognosis: basal cortisol >940, corticotropin stimulated rise <250.

6. Cortisol • Oppert: hydrocortisone Tx (1310-3587 nmol/d) in septic shock P’t => faster weaning from catecholamine infusion with ‘inadequate’ endogenous cortisol production (baseline <1000 & blunted response to ACTH) • Prevalence of absolute: low, 2-3 % • Incidence of relative: unknown – population studied, test methods, definition used; ex: Barquist: relative – basal <400, test stayed <690 => 0.7%

7. Cortisol - conclusion • Hypercortisolism: normal physiological response to acute & prolonged critical illness: ‘high normal’ cortisol level • A relation between mortality rate and cortisol: non-survivor – higher cortisol level • Prevalence of absolute in critical: low • No consensus concerning ‘reference values’ for baseline and stimulated cortisol level.

8. Cortisol – Blunted response • Axis maximally simulated • Feedback be alerted • Adrenal gland already maximally stimulated by increased secretion of peptides with CRH-like activity (eg cytokines); damaged by adrenal hemorrhage, common (eg meningococcal septic shock).

9. Cortisol - summary • Available data – cannot support the use of cortisol level or blunted response as diagnostic tools for relative adrenal insufficiency syndrome, nor in selecting septic shock patients receiving steroid therapy.

10. Electrolyte disturbance • Analogous to diagnosis of absolute adrenal insufficiency – electrolyte disturbance (hyponatremia, hyperkalemia) – indicator of relative • But related factors: volume-expanding solutions, routine potassium supplementation, diuretics => not practical in ICU practice.

11. Eosinophilia • A rise of eosinophilic cells as indicator for adrenocortical dysfunction: • DiPiro: 100 p’ts in trama ICU with sepsis: 1225 vs 446 /ul. • Beishuizen: 612 ICU p’ts: 40 cases eosinophilia >3% • Relative eosinophilia as a warning sign of insufficiency adrenocortical function.

12. Is the Cause of ‘Adreno-cortical Insufficiency Syndrome’ Situated in the Adrenal cortex? • Relative hypofunction of adrenal cortex in prolonged critical illness => ‘exhaustion’ of adrenal cortex. • Decreased secretory activity of anterior pituitary gland => reduced neuroendocrine stimulation.

13. Cortisol levels increased and blunt response to stimulation test => no reference values, consider as a functional adaptation of adrenal cortex instead of a pathological condition.

14. Why should one consider an organ (adrenal cortex) insufficiency when it has been proven to functional adequately, given normal to increased ‘product’ (cortisol) levels? • Evidence: Tx critically ill septic shock patient with hhydrocortisone: benefit • Hypotheses: 1). Hemodynamic effect; 2). Effects on cell activation and subsequent cytokine release. • Corticosteroid – modulate BP, close relations to adrenergic receptors.

15. Attenuate down regulation of adrenergic receptors (prolonged use of catecholamines – down regulation) • Steroid: positive effect on myocardial contractility and exert vasoconstrictive effects by increasing number of a1-adrenoreceptors and B-adrenoreceptors

16. Hypercortisolism: defense mechanism against cascade of cell activation and subsequent cytokine release. • In septic shock, ARDS, Glucocorticoid Tx => significant reduction in proinflammatory cytokines and increase in interleukin(IL)-4 & IL-10 => increase cortisol receptor binding affinity, positively influencing blood pressure!

17. Conclusion • Adrenal cortex function very well in septic shock and must be other explanations why steroid supplementation therapy works.