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

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

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

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

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

Acute Adrenal Insufficiency Presentation Non-specific Hypotension Postural Recumbent Abdominal pain Electrolyte disturbances Hypoglycemia

Acute Adrenal Insufficiency Precipitating factors Omission of corticosteroids Increased requirements Infection Physical stress Drugs

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

Diagnosis Cortisol Random Stimulated 8-9 am level Level during stress ACTH Hypoglycemia CRH Metyrapone

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

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

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

Suspicion of AI Approach ACTH stimulation test ACTH measurement on basal sample

Acute AI Management Fluids Glucocorticoids Treat underlying cause

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

Steroid Therapy Hydrocortisone drug of choice Dose 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

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

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

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

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

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

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

Cortisol in critical illness Dilemmas 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

Arafah BM, JCEM 2006

Minneci P et al, Ann Intern Med 2004

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

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

AI in Critical Illness Approach Must not miss individuals with true cortisol deficiency Definitive AI Relative AI Treating such individuals could be life saving Avoid unnecessary steroid therapy

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

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

Adrenal Insufficiency Critical 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?

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