Physiology

The adrenal glands consist of two functionally distinct areas: the adrenal cortex and the adrenal medulla. The adrenal cortex has three zones, each secreting a different hormone: mineralocorticoids, glucocorticoids, and androgens. The adrenal medulla secretes catecholamines which will be discussed next.

1. Mineralocorticoids

   Aldosterone is the principal hormone of this class and a major regulator of extracellular fluid volume and potassium homeostasis. Its production is regulated by the renin–angiotensin–aldosterone system, blood K+ concentration, and, to a lesser extent, pituitary adrenocorticotropic hormone (ACTH). Increased renin, as a result of decreased renal blood flow, decreased sodium level, or sympathetic activation, promotes the conversion of angiotensinogen to angiotensin I. Angiotensin-converting enzyme (ACE) cleaves angiotensin I to generate angiotensin II. Angiotensin II then stimulates aldosterone secretion. Aldosterone causes reabsorption of Na+ and subsequently water, as well as excretion of K+ and H+ in the distal tubule of the nephron.

2. Glucocorticoids

   Cortisol is the principal hormone of this class. It is produced daily in a diurnal manner in response to ACTH from the anterior pituitary, which can be augmented during stress. Cortisol has anti-inflammatory and immunosuppressive properties. It raises blood glucose levels by stimulating gluconeogenesis and promoting insulin resistance. It also has multiple effects on carbohydrate, protein, and fatty acid metabolism. Cortisol is required for converting norepinephrine to epinephrine in the adrenal medulla. Cortisol raises blood pressure by various mechanisms.

3. Androgens

   Abnormalities in androgen secretion are rarely pertinent to anesthetic management.

Synthetic steroids are used mainly for their immunosuppressive effect in inflammatory diseases and exhibit different potencies, duration of action, and ratios of glucocorticoid to mineralocorticoid effect.

1. Hydrocortisone (100 to 200 mg IV) is the name of the hormone cortisol as a medication and has the most balanced glucocorticoid to mineralocorticoid effect ratio.

2. Fludrocortisone has 10 times more mineralo- than glucocorticoid effect and is used to reverse the electrolyte dysfunctions in patients with primary hypoaldosteronism.

3. Other drugs, such as prednisone, prednisolone, methylprednisolone, and dexamethasone have a marked glucocorticoid anti-inflammatory effect. In the operating room, methylprednisolone (125 to 250 mg IV) and

   dexamethasone (4 to 8 mg) are the most commonly used, to treat allergic reactions, bronchoconstriction, for immunosuppression during organ transplantation and (controversially) for stress-dose steroid supplementation. Dexamethasone, especially, is also routinely used to prevent postoperative nausea and vomiting (PONV), among other beneficial effects.

Primary hyperaldosteronism: Conn syndrome

1. Conn syndrome is caused by either aldosterone-producing adrenal adenomas or from bilateral adrenal hyperplasia. Clinical features include hypertension, mild hypernatremia, hypokalemic metabolic alkalosis, hypokalemia-related muscle weakness, and increased incidence of metabolic syndrome. The recommended treatment for unilateral aldosterone-producing adrenal adenoma or hyperplasia is adrenalectomy. The treatment for bilateral disease is with a mineralocorticoid receptor antagonist, such as spironolactone or eplerenone.

2. Anesthesia considerations

   1. Mineralocorticoid receptor antagonist therapy should be continued perioperatively.

   2. Consider checking serum sodium, potassium, and pH perioperatively. However, due to chronic nature, aggressive correction is rarely necessary.

   3. Avoid hyperventilation as this can worsen alkalosis.

   4. Ensure adequate reversal of neuromuscular blockade as hypokalemia increases effects of nondepolarizing neuromuscular blockers.

Glucocorticoid excess and Cushing syndrome

1. Cushing syndrome is usually caused by excess exogenous steroid administration, excess pituitary ACTH secretion, ectopic ACTH secretion, and excess cortisol secretion. Clinical features include truncal obesity, moon face, gastroesophageal reflux disease, peptic ulcers, hypertension, hypernatremia, hypervolemia, hyperglycemia, hypokalemia, red or purple cutaneous striae, poor wound healing, muscle wasting and weakness, osteopenia/porosis, hypercoagulability, mental status changes, emotional lability, aseptic osteonecrosis, pancreatitis, benign intracranial hypertension, cataracts, and glaucoma. Treatment includes surgical resection, in the case of ACTH-secreting tumor (pituitary or ectopic) or cortisol-secreting adrenal adenoma. Medical therapy with adrenal enzyme inhibitors (eg, ketoconazole, etomidate) and glucocorticoid receptor antagonists (eg, mifepristone) can be considered in nonresectable disease. In refractory cases, bilateral adrenalectomy is the definitive therapy.

2. Anesthesia considerations

   1. Beware of difficult mask ventilation and intubation, given central obesity and increased incidence of OSA.

   2. Patients often exhibit hypertension refractory to treatment.

   3. Unrecognized coronary artery disease is also possible. Consider preoperative cardiac evaluations.

   4. Patients may have unrecognized insulin resistance. Monitor serum glucose levels and treat as needed.

   5. Osteoporosis and skin fragility make careful positioning necessary.

   6. Consider venous thrombosis prophylaxis given hypercoagulability.

   7. Glucocorticoid replacement should begin postoperatively for both unilateral and bilateral adrenalectomies. Mineralocorticoid replacement is necessary only after bilateral adrenalectomy.

   8. Excess ACTH secretion is treated by excision of the secreting tumor, usually via transsphenoidal pituitary surgery (Chapter 30: Anesthesia for Head and Neck Surgery).

Adrenal cortical hypofunction and Addison disease

1. Adrenal cortical hypofunction may be due to dysfunction of the adrenal gland (primary, aka Addison disease), pituitary gland (secondary), or hypothalamus (tertiary), which have different pathologies, manifestations, and anesthesia concerns.

2. Anesthetic considerations in patients with Addison disease

   1. Primary adrenal insufficiency (Addison disease) is associated with low cortisol and aldosterone levels. In the United States, 80% of primary adrenocortical insufficiency results from autoimmune adrenalitis; other causes include tuberculosis (the most common cause worldwide), various viral conditions [HIV, cytomegalic virus (CMV)], hemorrhage (often from anticoagulants), tumor metastasis, and sepsis.

   2. The main manifestations are hyponatremia and hyperkalemia, which lead to psychiatric changes, weakness, fatigue, weight loss, nausea/vomiting, abdominal pain, myalgias, arthralgias, postural hypotension, salt craving, hyperpigmentation, and, frequently, anemia.

   3. Acute adrenal insufficiency (adrenal crisis) primarily presents as shock and is a life-threatening emergency. The precipitant is usually a physiologic stressor (eg, surgery, trauma, infection), but can also be inadequate daily doses of mineralocorticoid and/or glucocorticoid, a missed dose, or reduced drug absorption from vomiting or diarrhea.

   4. Treatment of adrenal crisis includes:

      1. Elective surgery should be delayed if there is concern for uncorrected adrenal insufficiency.

      2. Identification and correction of hyperkalemia, hyponatremia, and hypoglycemia

      3. Patients with adrenal hypofunction may exhibit marked sensitivity to sedative, anesthetic, or vasodilator drugs. Titrate drug doses carefully to avoid cardiovascular depression.

      4. Avoid etomidate given the potential for further adrenal suppression.

      5. Steroid replacement. Hydrocortisone 100 mg IV followed by 50 mg IV every 6 hours, usually no more than 200 mg daily are necessary; other parental glucocorticoids may be used in equivalent dosages. In primary adrenal insufficiency, daily fludrocortisone is required once the daily hydrocortisone dose is <50 mg.

      6. Stress-dose steroids. Surgery is a known activator of hypothalamic–pituitary–adrenal axis (HPAA) and physiologic cortisol production increases by 5- to 20-fold during surgery. An additional steroid dose (100 to 200 mg hydrocortisone) is probably indicated in patients with known primary adrenal insufficiency. It is controversial whether this is also necessary in patients with chronic high-dose steroid use, which, in principle may suppress HPAA, as discussed below.

      7. Unexplained or exaggerated episodes of intra- or postoperative hypotension should prompt further administration of hydrocortisone (keeping in mind, however, that the effect is nonspecific).

      8. It is important to aggressively identify and treat precipitating events (infection, organ ischemia, internal bleeding) that could be life threatening in themselves.

3. Anesthetic considerations in patients with secondary and tertiary adrenal insufficiency

   1. Secondary and tertiary adrenal insufficiency are caused by pituitary or hypothalamic dysfunction, damage, or tumors and are rare. Secondary

      adrenal insufficiency results in low cortisol levels and normal serum aldosterone because aldosterone production is relatively independent of ACTH. Patients may have panhypopituitarism with symptoms of low TSH, growth hormone (GH), and/or gonadotropin levels. Tertiary adrenal insufficiency is typically due to iatrogenic administration of glucocorticoids. In these patients, the basal steroid treatment should be continued perioperatively. It is controversial whether an additional “stress dose” is indicated in patients on chronic steroid therapy as discussed in the text box (Box 7.2).