Adrenal Crisis and Adrenal Cortical Insufficiency INTRODUCTION Background: Adrenal crisis and severe acute adrenocortical insufficiency are often elusive diagnoses, which may result in severe morbidity and mortality when undiagnosed or treated ineffectively. If you’re not looking for adrenocortical insufficiency, I’m certain you’ll never find it; the eye does not see what the mind does not know. Although more than 50 steroids are produced within the adrenal cortex, cortisol and aldosterone are by far the most abundant and physiologically active. In primary adrenocortical insufficiency, both glucocorticoid and mineralocorticoid properties are lost; however, in secondary adrenocortical insufficiency, mineralocorticoid function is preserved. Although suppression of the hypothalamic-pituitary axis from chronic exogenous steroid use is the most common cause of secondary adrenal insufficiency, the possibility of hypopituitarism due to hypothalamic-pituitary disease must be considered. With acute hypopituitarism, adrenal crisis may be recognized and treated appropriately; however, a lack of recognition and treatment of associated endocrine abnormalities resulting from hypofunction of the pituitary-hypothalamic axis may result in clinical deterioration due to other hormone deficiencies. For instance, if patients with pan-hypopituitarism from Sheehan’s syndrome (post-partum pituitary infarction) are only treated for adrenal crisis, they will likely suffer severe cardiovascular compromise from the untreated associated hypothyroidism. If such a deficiency remains undiagnosed, this will ultimately result in death. Adrenocortical insufficiency is a potentially life-threatening entity that every emergency physician should be familiar with. The initial diagnosis and decision to treat is presumptive based on historical, physical examination and, occasionally, laboratory findings. Delays in management from attempts to confirm this diagnosis will result in poor patient outcomes. Pathophysiology: - Normal physiology of the adrenal medullae - The adrenal medullae normally secrete 80% epinephrine and 20% norepinephrine. Sympathetic stimulation results in secretion. The adrenal cortex produces cortisol, aldosterone and androgens. Cortisol isproduced from 2 hydroxylations of 17a-hydroxyprogesterone. It is 90-93% protein-bound (primarily by corticosteroid-binding globulin). It is also known as hydrocortisone. - Physiologic effects of ? - *Stimulates gluconeogenesis *Decreases cellular glucose utilization *Mobilizes amino acids *Mobilizes fatty acids *Inhibits effects of insulin *Ketogenic *Elevate RBC and Platelet levels *Non-specific cardiac stimulation *Release of vasoactive substances *In the absence of corticosteroids, stress will result in hypotension, shock and death *Anti-Inflammatory effects: *Maintains normal vascular response to vasoconstrictors *Opposes the increase in capillary permeability *Inhibits IL-2 production by macrophages *Stimulates PMN leukocytosis *Reduces adherence of macrophages to endothelium *Depletes circulatingeosinophils and lymphocytes *Reduces circulating lymphocytes (primarily T cells) - Aldosterone - *Produced by multiple hydroxylations of deoxycorticosterone *60% protein bound under normal circumstances *Renin-angiotensin system stimulates aldosterone release *Increased K+ stimulates aldosterone production and decreased K+ inhibits production *Chronic ACTH deficiency may inhibit production - Physiologic effects of aldosterone - *Primary action on kidney, gut and salivary and sweat glands *Its purpose is to affect the electrolyte balance *Target organ is the Kidney *Stimulates reabsorption of sodium *Stimulates secretion of potassium *Stimulates secretion of hydrogen ions *Effects on Na+ and K+ are interdependent on the intake of these two cations (i.e. increased Na+ intake = Increased K+ secretion) *Effects on H+ can probably occur independently *Persistent aldosterone excess results in atrial natriuretic factor release and renal hemodynamic changes forcompensation *CHF and cirrhosis with ascites are exceptions which causeprogressive Na+ retention *Excess = Na+ retention, hypokalemia and alkalosis *Deficiency = Na+ loss, hyperkalemia and acidosis *Hyperkalemia stimulates aldosterone release to improve K+ excretion *First line defense against hyperkalemia - Primary adrenal insufficiency - A Anatomic destruction of gland (acute and chronic) *Idiopathic (autoimmune) *Surgical *Infection (TB or Fungal) *Hemorrhage (Waterhouse-Friderichsen Syndrome) *Metastatic destruction B Metabolic failure (insufficient hormone production) *Congenital adrenal hyperplasia *Enzyme inhibitors (metyrapone) *Cytotoxic agents (mitotane) Primary adrenocortical insufficiency is rare. It occurs at any age with a 1:1 male/female ratio. The most common cause being idiopathic. - Secondary adrenal insufficiency - A Hypopituitarism due to hypothalamic-pituitary disease B Suppression of hypothalamic-pituitary axis *Exogenous steroid *Endogenous steroid (i.e. tumor) Secondary adrenocortical insufficiency is relatively common. Extensive therapeutic use of steroids has greatly contributed to the increased incidence. - Acute adrenocortical insufficiency - Adrenal crisis is a rapidly progressive intensification of chronic insufficiency, usually caused by sepsis or surgical stress Adrenal hemorrhage includes Waterhouse-Friderichsen syndrome and anticoagulation complications. Steroid withdrawal (most common) is almost exclusively a glucocorticoid deficiency. Frequency: In the U.S.: Primary adrenocortical insufficiency is an uncommon disorder with an incidence in Western populations near 50/1,000,000. With the advent of widespread corticosteroid use, however, secondary adrenocortical insufficiency secondary to steroid withdrawal is much more common. Approximately 6,000,000 persons in the U.S. are considered to have undiagnosed adrenal insufficiency, which will only be clinically significant during times of physiologic stress. There are multiple etiologies of primary adrenocortical insufficiency with 80% of cases in the U.S. being caused by autoimmune adrenal destruction and glandular infiltration by tuberculosis being the second most frequent etiology. With primary adrenocortical insufficieny due to idiopathic autoimmune lymphocytic infiltration, the presence of other associated endocrine disorders must be considered. Polyglandular autoimmune disorders (PGAs) such as Schmidt’s syndrome should be considered. Schmidt’s syndrome or PGA type II includes adrenal insufficiency, autoimmune thyroid disease and, occasionally, insulin-dependent diabetes mellitus. Adrenal insufficiency usually occurs after age 20 in these patients. Adrenal insufficiency may be the first manifestation of PGA II in approximately 40-50% of these patients. PGA type I includes hypoparathyroidism and mucocutaneous candidiasis inconjunction with adrenal insufficiency. The full triad may only be manifested in 30% of patients with PGA type I. Mortality/Morbidity: Acute adrenocortical insufficiency is a difficult diagnosis to make. Many of the presenting signs and symptoms are non-specific. For instance, a post-operative fever may be presumptively treated as infection or system inflammatory response syndrome, when this may be a subtle indicator of adrenal insufficiency. As this entity rarely occurs without other concomitant injury or illness, it is very challenging to detect; however, the consequences of missed diagnosis are unforgivable. Left untreated, acute adrenal insufficiency carries with it a dismal prognosis for survival. Therefore, treatment at the timeof clinical suspicion is mandatory. Any delays in management waiting for confirmation of this diagnosis cannot be justified. Sex: Although there is an equal male to female ratio for primary adrenocortical insufficiency, women are affected 2-3 times more often by the idiopathic autoimmune form of adrenal insufficiency. Age: In idiopathic autoimmune adrenal insufficiency, the diagnosis is most often discovered in the 3rd-5th decades of life. It is of particular importance, however, to recognize that adrenocortical insufficiency is not limited to any specific age group. CLINICAL History: Weakness (99%) Pigmentation of skin (98%) Weight Loss (97%) Abdominal pain (34%) Salt craving (22%) Diarrhea (20%) Constipation (19%) Syncope (16%) Vitiligo (9%) Causes: Surgery Anesthesia (e.g. Amidate) Volume loss Trauma Asthma Hypothermia Alcohol Myocardial infarction Fever Hypoglycemia Pain Psychoses or depression Exogenous steroid withdrawal DIFFERENTIALS Anorexia nervosa Gastroenteritis Hypercalcemia Hyperkalemia Hypoglycemia Hyponatremia Hypopituitarism Hypothyroidism and Myxedema Coma Metabolic Acidosis WORKUP Lab Studies: Complete blood count Electrolytes Blood urea nitrogen Creatinine Cortisol level Thyroid function tests Other studies as indicated Imaging Studies: Chest radiograph Other Tests: ACTH stimulation test Non-emergent situations only Cosyntropin 250 ug IM Serum Cortisol 0 hr, 1 hr and 6 hrs ACTH/aldosterone level in 30 min High ACTH/Low aldosterone = primary Low ACTH/NL aldosterone = secondary 24-hour urinary cortisol Non-emergent situations only TREATMENT Emergency Department Care: Maintain airway, breathing and circulation. Coma protocol (glucose, thiamine, narcan) Aggressive volume replacement (D5NS) Correct electrolye abnormalities Hypoglycemia (67%), hyponatremia (88%), hyperkalemia (64%), hypercalcemia (6-33%) Dextrose 50% as needed for refractory hypoglycemia Hydrocortisone 100 mg IVP Q 6 hours Fluorocortisol (mineralocorticoid) 0.1 mg QD Always treat the underlying problem. An endocrine specialist should be consulted. ICU admission is recommended. Drug Category: Corticosteroids - These drugs are used primarily to replete glucocorticoids deficiencies. Drug Name Hydrocortisone Adult Dose 100 mg IVP/IM q 6 hrs for 24 hrs Pediatric 1 mg/kg IVP/IM BID or QD Contraindications Systemic fungal infections Interactions Worsens hypokalemia from ampho B. Pregnancy C - Safety for use during pregnancy has not been established MISCELLANEOUS Medical/Legal Pitfalls: Failure to diagnose due to ambiguous presentations or co-morbidity Missed mineralocort deficiency Missed associated endocrine abnormalities Steroids must given before T4. Glucose must given before steroids. Special Concerns: Dexamethasone 4 mg q 6 hrs during ACTH stimulation test 100 times more potent than cortisone Will not alter cortisol levels