• Cushing's disease refers specifically to hypercortisolism caused by adrenocorticotropic hormone (ACTH)-secreting pituitary tumors, usually microadenomas
• Cushing's syndrome, however, is the constellation of symptoms resulting from high levels of circulating cortisol in the body; it refers to hypercortisolism from all causes. The syndrome was first described in 1912 by Dr. Harvey Cushing.
• Patients with Cushing's syndrome commonly present to the operating room for corrective surgery to remove pituitary tumors, lung tumors, adrenal tumors or adrenalectomies, or may present for surgical procedures unrelated to the syndrome.

• Chronic exogenous corticosteroid therapy
• ACTH oversecretion from tumor-related syndromes is responsible for 80–85% of cases. They most commonly result from pituitary adenomas (Conn's syndrome) but can also be seen with oat cell lung cancers or other ACTH or corticotrophin-releasing hormone (CRH) producing tumors.
• ACTH-independent tumors are responsible for 15–20% of cases and may be from unilateral or bilateral adrenal adenoma or carcinoma.

• CRH release is triggered by stressors such as fever, surgery, burns, exercise, psychological stress, and hypotension. CRH, stimulates ACTH release from the pituitary gland into the bloodstream; in turn, ACTH stimulates cortisol release by the adrenal glands.
• Cortisol has a normal diurnal variation, highest from 5 to 9 am and lowest from 6 pm to midnight.
• Cortisol affects gluconeogenesis as well as fat and protein metabolism; suppresses the immune system; increases myocardial contractility and output; and enhances the catecholamine pressor effect.
• Abnormally elevated cortisol levels can cause (1)
  • BP elevation from deoxycorticosterone and increased vascular sensitivity to circulating vasopressors.
  • Vascular disease; prolonged hypertension may lead to vascular functional abnormalities.
  • Increased gastric acid secretion via increased pepsin levels.
  • Decreased collagen synthesis
  • Osteoporosis; inhibits osteoblast function and intestinal calcium absorption.
  • Hyperglycemia; increases glycogen synthase that increases hepatic glucose output and also decreases insulin sensitivity.
  • Hypokalemia can result from potassium wasting secondary to the triggering of a mineralocorticoid response in the kidneys.
  • Water retention from an increase in mineralocorticoids.
  • Muscle weakness; induces catabolic changes in muscle and decreases muscle protein synthesis as well as type II muscle fibers.
  • Hypercoagulability may be partially due to alterations of von Willebrand factor and hyperresponsiveness of platelets (3).
  • Immune suppression: may cause leukocytopenia and can inhibit the immune/inflammatory response to injury.

• Assess for concomitant diseases including diabetes mellitus and cardiac or vascular disease (4).
• Difficulty with ventilation or intubation may be encountered; perform a careful airway exam (4).
• In patients with Cushing's syndrome from exogenous steroid use, evaluate the underlying disease for anesthetic implications (e.g., cervical spine instability in patients with rheumatoid arthritis, electrolyte imbalances and dehydration in Crohn's and ulcerative colitis, etc).
• Perioperative thrombus risk is increased due to hypercoagulability.

• Frequent infections due to a relatively immunocompromised state (high levels of cortisol and elevated blood sugar)
• Edema due to sodium and water retention
• Rapid onset of weight gain

"Stress dose" steroids may be necessary in patients undergoing surgery and who have been on chronic steroid therapy.

• Patients with Cushing's syndrome are often on medications to inhibit adrenal steroid production (4).
• Ketoconazole: Midazolam levels and effects may be increased; fentanyl levels may be increased and result in delayed emergence or other adverse effects; and lidocaine systemic levels may be increased.
• Metyrapone: Not as frequently used in the US but is quite common elsewhere. May cause edema and neurologic side effects.
• Mitotane: The effects of benzodiazepines, opioids, and inhaled anesthetics may be potentiated; can result in increased CNS depression or other side effects.
• Bromocriptine: Can inhibit ACTH release. When combined with phenylephrine or other sympathomimetics may cause hypertension, ventricular tachyarrhythmias, or seizures.

• Vascular and cardiac disease
• Diabetes mellitus
• Hypertension
• Hypercoagulability

• Uncontrolled hyperglycemia
• Abnormal EKG that may require further cardiac workup
• Hypertensive crisis
• Severe hypokalemia

Telemetry or intensive care unit (ICU) for adrenal gland removal may be considered depending on blood loss, intraoperative events, or other comorbidities.

• Close monitoring of BP and blood glucose are recommended.
• If surgery is for removal of a pituitary adenoma, postoperative steroid replacement must be given for 3–14 months after surgery or until endogenous steroid synthesis normalizes.
• Endocrinology consult may be warranted for evaluation and treatment postoperatively.

• Hypercortisolism causes hypercoagulability and DVT risk is higher in patients with Cushing's syndrome (4).
• Diabetes insipidus is a possible complication of pituitary resection.
• New neurological deficits or pituitary hormonal insufficiency are possible.
• Postoperative mortality from pituitary surgery may reach 2% (4).

• Diabetes Mellitus
• Hypokalemia
• Cortisol
• Hypertension

255.0 Cushing's syndrome

E24.9 Cushing's syndrome, unspecified

Matthew D. Cohen , DO