1. Acute Adrenal Insufficiency Dr. Sohail Inam FRCP (Ed), FRCP Consultant & Head, Division of Endocrinology Armed Forces Hospital Riyadh

2. CRH AVP Renin substrate Kidney Renin ACTH Angiotensin I Angiotensin II Cortisol Aldosterone Androgens

3. CRH AVP Renin substrate Kidney ACTH Renin Angiotensin I X Angiotensin II Cortisol Aldosterone Androgens

4. CRH AVP Renin substrate Kidney X Renin ACTH Angiotensin I Angiotensin II Cortisol Aldosterone Androgens

5. Acute Adrenal Insufficiency • Previous adrenal insufficiency • Previous normal adrenal function • Acute adrenal injury • Acute pituitary injury • Drug related effect • Functional adrenal insufficiency • Beware of previous corticosteroid use

6. Acute Adrenal InsufficiencyPresentation Non-specific • Hypotension • Postural • Recumbent • Abdominal pain • Electrolyte disturbances • Hypoglycemia

7. Acute Adrenal InsufficiencyPrecipitating factors • Omission of corticosteroids • Increased requirements • Infection • Physical stress • Drugs

8. Diagnosis • Measurement of adrenal hormones Cortisol • Primary versus central ACTH • Determine cause

9. DiagnosisCortisol • Random • 8-9 am level • Level during stress • Stimulated • ACTH • Hypoglycemia • CRH • Metyrapone

10. 100 % chance of adrenal insufficiency 0 <83 650 9 am serum cortisol nmol/l

11. ACTH Stimulation Test • Standard (250 mcg) , Low dose (1mcg) • Can be performed any time though preferably 8-9 am. • 0, 30, 60 minute • Any value  550 nmol/l excludes adrenal insufficiency in non-critically ill patients • Test is abnormal in almost all patients with primary adrenal insufficiency & 90% individuals with central adrenal insufficiency

12. Pituitary Stimulation Tests • Insulin tolerance test (ITT) • Gold standard for central disease • Risk from hypoglycemia • CRH • Metyrapone • Other

13. Suspicion of AIApproach • ACTH stimulation test • ACTH measurement on basal sample

14. Acute AIManagement • Fluids • Glucocorticoids • Treat underlying cause

15. Fluid Therapy • Volume depends upon haemodynamic state & type of AI • Primary AI – hypovolemia (Salt wasting) • Central AI - euvolemia • 0.9% Saline • Beware of rapid change in Na • Dextrose to treat hypoglycemia

16. Steroid Therapy • Hydrocortisone drug of choice • Natural compound • Mineralocorticoid activity • Dose • No need to use large doses • 50 mg 6 hourly (avoid less frequent doses) • Taper dose early • No additional benefit of mineralocorticoids

17. “Low dose regime” 1350 Hydrocortisone 50 mg six hourly Arafah BM, JCEM 2006

18. Electrolyte Disturbance • Hyponatremia • 0.9% saline • Glucocorticoid Beware of rapid change in Na • Hyperkalemia • Fluids & hydrocortisone • Severe cases: NaHCO3, Glucose/insulin

19. Critical Illness Cortisol is a stress hormone and essential for survival • Metabolic effects Provision of energy • Haemodynamic effects • Salt & water retention • Increase presser response • Anti-inflammatory effects

20. CortisolCritical Illness Cortisol levels are elevated (2-3 times) • Increased secretion • Loss of diurnal variation • Decreased negative feedback • Decreased catabolism

21. CortisolCritical Illness Increased availability • Greater increase in Free Cortisol Decreased Binding (CBG, Albumin) • Increased tissue delivery Elastase • Increased tissue effect Up regulation of receptors

22. Neurogenic stimuli Adrenergic stimulation CRH Cytokines AVP ACTH Cortisol Aldosterone Androgens  Tissue action

23. Cortisol in critical illnessDilemmas • How much is good? • Very high levels – deleterious? • Low levels – deleterious • Cortisol measurement? • Changes in free cortisol, hetrophil antibodies • Tissue modulation • No test to measure tissue effect

24. Arafah BM, JCEM 2006

25. Minneci P et al, Ann Intern Med 2004

26. Issues with metanalysis • Small numbers • Measurement of cortisol • Major influence of one study • Almost 80% non-responders • Almost ⅓ had received etomidate • Not designed to test adverse effects • Duration & tapering of steroids

27. CORTICUS study • Non-responders had higher mortality • No difference in mortality between steroid and placebo group • Overall shock reversal rates higher in steroid group- not significant • Rates of super-infection were higher in the steroid group- NS • Hyperglycemia more common on steroids

28. AI in Critical IllnessApproach • Must not miss individuals with true cortisol deficiency • Definitive AI • Relative AI Treating such individuals could be life saving • Avoid unnecessary steroid therapy

29. Adrenal InsufficiencyCritical Illness • Routine testing not recommended • Actively screen those at high risk • ACTH stimulation test • Patients unresponsive to fluids & vasopressors merit trial of steroids

30. Cortisol in critical illnessHigh risk for adrenal insufficiency • Head injury • Known endocrine disease • Previous steroid use • Drugs (etomidate, ketoconazole, Medroxyprogesterone, megestrol) • HIV • Bleeding diathesis

31. Adrenal InsufficiencyCritical Illness Cut off values for cortisol • Basal • Cortisol <400 highly suggestive • Cortisol >810 (930) excludes AI • ACTH stimulation (normal values) • Increase of >250 nmol/l above baseline • Peak cortisol >930 nmol/l?

32. Thank You