Acute Adrenal Insufficiency

Pathophysiology

• The adrenal gland is divided into the cortex and medulla.
• The adrenal cortex secretes glucocorticoids, mineral corticoids, and androgenic hormones.
• The release of glucocorticoids (cortisol) is regulated by the hypothalamic-pituitary axis (HPA): Hypothalamus. corticotropin-releasing hormone (CRH). pituitary. adrenocorticotropic hormone (ACTH). adrenal cortex. cortisol. end organ sites.
• Mineralocorticoids (aldosterone) are primarily influenced by the renin-angiotensin system and will be secreted despite defects in the HPA axis.
• The adrenal medulla secretes catecholamines and is regulated by the sympathetic nervous system.
• AI will occur in three situations: rapid exogenous steroid withdrawal in a steroid-dependent patient (most common), chronic adrenal insufficiency subjected to severe stress (i.e., trauma, surgery, infection, pregnancy), or acute adrenal failure de novo (rare; i.e., bilateral adrenal hemorrhage).

Diagnosis

The diagnosis of AI requires a high index of suspicion and is based on a constellation of signs and symptoms. Definitive diagnosis is often not possible in the emergency department.

Laboratory/Studies

• Low random cortisol level: < 20 mg/dl in setting of severe stress suggests AI, but levels are often unavailable in the emergency department setting.
• Hypoglycemia occurs in two-thirds of cases and may reach life-threatening levels. Cortisol deficiency impairs gluconeogenesis and glycogenolysis. Treat with dextrose replacement.
• Hyperkalemia and hyponatremia: when seen together, consider AI. Both are usually mild, but may reach severe life-threatening levels, particularly with primary AI. Aldosterone acts on the renal tubules to conserve sodium in exchange for potassium and hydrogen. Aldosterone deficiency leads to hyponatremia, hyperkalemia, and acidosis.
• Hypercalcemia, hypernatremia may be present. Mild elevations are commonly seen; the etiology is unclear.
• Azotemia and elevated hematocrit secondary to dehydration may be found.
• Mild metabolic acidosis secondary to decreased hydrogen ion excretion (aldosterone deficiency) is common.
• CXR/EKG are standard to rule out precipitant pulmonary and cardiac disease.
• Head CT may be needed to rule out CNS pathology in the setting of new altered mental status.
• ACTH stimulation test assures the diagnosis in unclear cases. This is not usually performed in the ED setting. Dexamethasone does not interfere with the ACTH stimulation test.

ED Management

There are five basic components of AI therapy:

1. fluid resuscitation;
2. correct hypoglycemia;
3. glucocorticoid replacement;
4. correct electrolyte abnormalities; and
5. search for and treat underlying disease.

Fluid Resuscitation

• Fluid resuscitation with 0.9% NS as necessary to restore hemodynamic stability is a treatment priority. D5NS at infusion rates of 500-1000 ml/h over the next 3-4 h may be needed to correct dehydration. Close attention must be given to underlying cardiac or renal disease during aggressive hydration.
• It is important to note, that refractory hypotension may be seen in the presence of normovolemia, as cortisol deficiency depresses myocardial contractility and vascular tone. If possible, avoid vasopressors, as they tend to be less effective and precipitate arrhythmias in the setting of AI.

Signs and symptoms of adrenal insufficiency

Symptoms	Signs
Weakness, fatigue	Hypotension
Nausea, vomiting	Tachycardia
Malaise	Orthostasis
Anorexia	Hyper pigmentation
Myalgias	Vitiligo
Abdominal pain	Altered mental status
Lethargy	Sparse axillary and pubic hair
Salt cravings	Auricular cartilage calcification

Abdominal pain of AI may resemble an acute abdomen, but it is important to rule out primary abdominal pathology as the precipitant of AI. Salt cravings seen in primary AI secondary to a deficiency of aldosterone (a salt-retaining hormone regulated by the reninangiotensin system). Aldosterone production remains intact with functional (exogenous steroid-induced), secondary, and tertiary forms of AI. Signs of volume depletion will be more prominent in pituitary AI secondary to aldosterone deficiency. Hyper pigmentation: In primary AI, ACTH is up regulated. Melanocyte stimulating hormone (MSH) is a byproduct of ACTH production. This does not occur with functional, secondary or tertiary forms of AI. Vitiligo: hypo pigmentation is present in 10-20% of patients with Addison’s disease; an autoimmune process.

Correct Hypoglycemia

• Treatment with D50 is given as necessary. It is recommended to add dextrose to the fluids (D5NS) over the early course of the disease.

Glucocorticoid Replacement

• Frequently, the diagnosis and treatment of AI must proceed simultaneously. There is little risk of giving a single dose of steroids when the diagnosis of AI is suspected but not confirmed. In this situation dexamethasone is preferred as it does not interfere with the ACTH stimulation test. Recommended dose: dexamethasone 4-10 mg IV q 6-8 h.
• If the diagnosis of AI is clear (i.e., previously diagnosed or history of abrupt withdrawal of steroids), hydrocortisone is preferred as it has a greater mineralocorticoid (salt-retaining) effect. Recommended dose: hydrocortisone 100 mg IV q 6-8 h.
• When dexamethasone is used Florinef 0.1 mg po (synthetic mineralocorticoid) may need to be added in the setting of primary AI.

Correct Electrolyte Abnormalities

• Electrolyte imbalances usually correct with the administration of fluids and glucocorticoids alone. However, hyperkalemia may be severe, particularly with primary adrenal insufficiency, and may require treatment with calcium, sodium bicarbonate, insulin/ glucose, and kayexalate.

Search for and Treat Underlying Illness

• A thorough history and physical exam is needed, along with appropriate laboratory tests and investigations (CXR, EKG, head CT) as necessary to rule out underlying infection, cardiac, pulmonary, or CNS disease. Treatment should be initiated as necessary.

Admission Criteria

• Most patients with acute adrenal insufficiency require ICU admission. Some mild cases may be appropriate for regular ward.
• Steroid-dependent patients with chronic adrenal insufficiency may be managed as an outpatient for minor illnesses. This is done by doubling their daily steroid dose for ˜ 3 days in consultation with their primary physician. The use of prefilled dexamethasone 4 mg IM syringes at home and medical alert bracelets in case of emergency should be discussed with all AI patients.