The serum T₄ assay is a standard test for evaluation of thyroid gland function (Table 46-1). The total T₄ is elevated in approximately 90% of patients with hyperthyroidism, and it is low in 85% of those who are hypothyroid. The concentration of T₄ is measured by radioimmunoassay (RIA). The serum T₄ concentration is influenced by thyroid hormone protein–binding capacity. An increase or decrease in TBG levels or in protein binding may therefore alter the total T₄ but not the concentration of the free T₄. Because of the effect of TBG on circulating total T₄, the T₄ levels should never be used alone to evaluate thyroid disease. Elevations in the TBG concentration are the most common cause of hyperthyroxinemia in euthyroid patients. Increases in TBG due to acute liver disease, pregnancy, or drugs (oral contraceptives, exogenous estrogens, clofibrate, opioids) may be the causative factor. Because a total T₄ can be misleadingly high in euthyroidism or normal in hypothyroidism, some measure of free thyroid hormone activity (free T₄) must also be used.

The serum T₃ is also measured by RIA. Serum T₃ levels are often determined to detect disease in patients with clinical evidence of hyperthyroidism in the absence of elevations of T₄. T₃ may be the only thyroid hormone produced in excess. T₃ concentrations may be depressed by factors that impair the peripheral conversion of T₄ to T₃ (sick euthyroid syndrome). In 50% of hypothyroid patients, the serum T₃ concentration is low; in the remaining 50%, it is normal.

Because conventional assays measure total hormone levels, which can be affected by protein binding without affecting free hormone levels, it is necessary to find some measure of thyroid-binding proteins to correctly interpret total thyroxine levels. A direct measurement of unbound T₃ and T₄ can be performed by equilibrium dialysis or by unbound immunoassays. Indirect measurement of free hormone levels can be calculated by multiplying the total hormone level by the thyroid hormone binding ratio, which can be calculated from the T₃-resin uptake. This product is the free T₃ or T₄ index. The T₃ uptake test measures the ability of the patient’s serum to bind exogenously introduced T₃ and reflects the amount of TBG and the extent of T₃ saturation on TBG. The T₃ uptake is inversely related to the degree of unsaturation of TBG.

The radioimmunoassay for this hormone is sensitive and specific enough to become the first test in evaluating suspected thyroid dysfunction. It is often higher than 20 μIU/mL in primary hypothyroidism (normal 0.4 to 4.5 μIU/mL). Hyperthyroidism can be suspected from depressed TSH levels. A condition characterized by elevated TSH and normal T₄ may represent subclinical hypothyroidism. A low TSH level in a clinically hypothyroid patient indicates disease at the pituitary or hypothalamic level. The goal of thyroid replacement therapy is to normalize TSH levels.³ Starvation, fever, stress, corticosteroids, and T₃ or T₄ can all depress TSH levels.

The thyroid gland has the ability to concentrate large amounts of inorganic iodide. The oral administration of radioactive iodine (¹³¹I) can be used to indicate thyroid gland activity. Thyroid uptake is elevated in hyperthyroidism unless the hyperthyroidism is caused by thyroiditis, in which case the uptake is low or absent. Because of overlap in values, it is difficult to distinguish euthyroid from hypothyroid people. Radioactive iodide uptake may be increased by a variety of factors, including dietary iodine deficiency, renal failure, and congestive heart failure. Because uptake is under TSH control, elevated free T₄ levels and corticosteroids decrease radioactive iodide uptake. Functioning (“hot”) thyroid tissue is rarely malignant. Nonfunctioning (“cold”) tissue may be malignant or benign.

The most important goal in managing the hyperthyroid patient is to make the patient euthyroid before any surgery, if possible. The drugs propylthiouracil and methimazole are thiourea derivatives that inhibit organification of iodide and the synthesis of thyroid hormone.⁵ Propylthiouracil also decreases the peripheral conversion of T₄ to T₃. Normal thyroid glands usually contain a store of hormone that is large enough to maintain a euthyroid state for several months, even if synthesis is abolished. Therefore, hyperthyroid patients are unlikely to be regulated to a euthyroid state with antithyroid drugs alone in <6 to 8 weeks. Toxic reactions from these drugs are uncommon but include skin rash, nausea, fever, agranulocytosis, hepatitis, and arthralgias.

Inorganic iodide inhibits iodide organification and thyroid hormone release—the Wolff-Chaikoff effect. Iodide is also effective in reducing the size of the hyperplastic gland and has a role in the preparation of the patient for emergency thyroid surgery. Antithyroid drugs should be started before iodide treatment because of the possibility of worsening the thyrotoxicosis.

β-adrenergic antagonists are effective in attenuating the manifestations of excessive sympathetic activity and should be used in all hyperthyroid patients unless contraindicated. β-adrenergic blockade alone does not inhibit hormone synthesis, but specifically propranolol does impair the peripheral conversion of T₄ to T₃ over 1 to 2 weeks. Propranolol given over 12 to 24 hours decreases tachycardia, heat intolerance, anxiety, and tremor. Any β-blocker may be used, and long-acting agents may be more convenient. The combination of propranolol (in doses titrated to effect) plus potassium iodide (2 to 5 drops every 8 hours) is frequently used before surgery to ameliorate cardiovascular symptoms and reduce circulating concentrations of T₄ and T₃. Preoperative preparation usually requires 7 to 14 days.

Heart failure secondary to poorly controlled paroxysmal atrial fibrillation may improve with slowing of the ventricular rate, but abnormalities of left ventricular function secondary to hyperthyroidism may not be corrected with the use of β-antagonists. If a hyperthyroid patient with clinically apparent disease requires emergency surgery, β-adrenergic blockade should be administered to achieve a heart rate <90 beats per minute. β-blockers do not prevent thyroid storm. Glucocorticoids such as dexamethasone (8 to 12 mg/day) are used in the management of severe thyrotoxicosis because they reduce thyroid hormone secretion and the peripheral conversion of T₄ to T₃.

Iopanoic acid, a radiographic contrast agent that decreases peripheral conversion of T₄ and releases iodine that inhibits synthesis, is useful for emergency preparation.

Radioactive iodine therapy is an effective treatment for some patients with thyrotoxicosis.⁶ However, it should not be administered to patients who are pregnant because it crosses the placenta and may destroy the fetal thyroid. A side effect of radioiodine therapy is hypothyroidism; 10% to 60% of cases occur in the first year of therapy and an additional 2% occur per year thereafter.

A variety of anesthetic techniques and drugs have been used for hyperthyroid patients undergoing surgery. All antithyroid medications are continued through the morning of surgery. The goal of intraoperative management in the hyperthyroid patient is to achieve a depth of anesthesia that prevents an exaggerated sympathetic response to surgical stimulation while avoiding the administration of medication that stimulates the sympathetic nervous system. Pancuronium should be avoided. It is best to avoid using ketamine, even when a patient is clinically euthyroid. Hypotension that occurs during surgery is best treated with direct-acting vasopressors rather than a medication that provokes the release of catecholamines. The incidence of myasthenia gravis is increased in hyperthyroid patients; thus, the initial dose of muscle relaxant should be reduced and a twitch monitor should be used to titrate subsequent doses. Regional anesthesia is an excellent alternative when appropriate; however, epinephrine-containing solutions should be avoided.

Thyroid storm is a life-threatening exacerbation of hyperthyroidism that most commonly develops in the undiagnosed or untreated hyperthyroid patient because of the stress of surgery or nonthyroid illness.⁷ Operating on an acutely hyperthyroid gland may provoke thyroid storm, although this is probably not due to mechanical release of hormone.⁸ Its manifestations include hyperthermia, tachycardia, dysrhythmias, myocardial ischemia, congestive heart failure, agitation, and confusion. It must be distinguished from, or considered with, pheochromocytoma,
malignant hyperthermia, and light anesthesia. Although free T₄ levels are often markedly elevated, no laboratory test is diagnostic. Treatment involves large doses of propylthiouracil and supportive measures to control fever and restore intravascular volume. Hemodynamic monitoring (pulmonary artery catheter, arterial catheter) is especially useful in guiding the treatment of patients with significant left ventricular dysfunction (Table 46-3). Again, it is essential to remove or treat the precipitating event.

Thyroidectomy as an alternative to prolonged medical therapy is used less frequently now than in the past. Indications include failed medical therapy, underlying cancer, and symptomatic goiter. It is usually performed under general endotracheal anesthesia, although the use of the laryngeal mask airway is increasing.⁹ Use of a laryngeal mask airway allows real-time visualization of vocal cord function because the patient is allowed to breathe spontaneously. Limited thyroidectomy may also be performed under bilateral superficial cervical plexus block. The anesthesiologist must be prepared to manage an unexpected difficult intubation because the incidence of difficult intubation during goiter surgery is 5% to 8%.¹⁰ Thyroid cancer increases the risk, but the size of the goiter is not predictive. Large goiters, especially if associated with evidence of significant airway obstruction or tracheal deviation, may warrant securing the airway while the patient is awake. Large substernal goiters can behave as anterior mediastinal masses and cause intrathoracic airway obstruction after induction of general anesthesia. Computed tomography (CT) or magnetic resonance imaging (MRI) should be reviewed. The complications after thyroidectomy include recurrent laryngeal nerve (RLN) damage, tracheal compression secondary to hematoma or tracheomalacia, and hypoparathyroidism. Hypoparathyroidism secondary to the inadvertent surgical removal of parathyroid glands is most frequently seen after total thyroidectomy. The symptoms of hypocalcemia develop within 24 to 96 hours after surgery¹¹ (see Chapter 14). Laryngeal stridor progressing to laryngospasm may be one of the first indications of hypocalcemic tetany. Intravenous administration of calcium chloride or calcium gluconate is warranted in this situation. Magnesium levels should also be monitored and corrected if low. Bilateral RLN injury is an extremely rare injury and necessitates reintubation. Unilateral nerve injury is more common and is often transient.¹² Unilateral damage to the RLN is characterized by hoarseness and a paralyzed vocal cord, whereas bilateral injury causes aphonia (see Chapter 27). It is wise to evaluate vocal cord function before and after surgery by laryngoscopy or by asking the patient to phonate by saying the sound for “E.” Routine postoperative visualization of the vocal cords is not warranted. Some surgeons elect to monitor RLN function intraoperatively. A nerve stimulator may be used by the surgeon to stimulate suspicious structures and contraction of the laryngeal muscles noted. Alternatively, the NIM (Nerve Integrity Monitor; Medtronic Xomed) endotracheal tube can be used. This endotracheal tube has two pairs of electrodes embedded in the shaft of the endotracheal tube just above the cuff. When properly positioned, the electrodes will be in contact with the vocal cords and an electromyographic signal can be monitored. Muscle relaxants and topical laryngeal anesthesia must be avoided to obtain appropriate signals. Postoperative extubation of the trachea should be performed under optimal conditions. Intraoperative laryngeal nerve injury or collapse of the tracheal rings from previous weakening may mandate emergency reintubation.

Treatment of symptomatic hypothyroidism is with hormone replacement therapy.¹⁵ Controversy remains regarding the preoperative anesthetic management of the hypothyroid patient. Although it seems logical, given the multisystem effects of thyroid hormone, to recommend that all hypothyroid surgical candidates be restored to a euthyroid state before surgery, such a recommendation is, in general, based on individual case reports. There have been few controlled studies to support the position that most hypothyroid patients are unusually sensitive to anesthetic drugs, have prolonged recovery times, or have a higher incidence of cardiovascular instability or collapse.

No increase in serious complications in patients with mild or moderate hypothyroidism undergoing general anesthesia has been noted.¹⁶ One study noted a higher incidence of intraoperative hypotension and postoperative GI and neuropsychiatric complications in mild and moderately hypothyroid patients undergoing noncardiac surgery, but still noted there were no compelling clinical reasons to postpone surgery in these patients.¹⁷ Surgery in severely hypothyroid patients should be postponed when possible until these patients are at least partially treated.

The management of hypothyroid patients with symptomatic coronary artery disease has been a subject of particular controversy.¹⁸ The need for thyroid hormone replacement therapy must be weighed against the risk of precipitating myocardial ischemia. Several studies and a literature review found no differences in the frequency of intraoperative or postoperative complications when mild or moderately hypothyroid patients underwent cardiac surgery. In symptomatic patients or unstable patients with cardiac ischemia, thyroid replacement should probably be delayed until after coronary revascularization.

There appears to be little reason to postpone elective surgery in patients who have mild or moderate hypothyroidism. However, thyroid replacement therapy is indicated for patients with severe hypothyroidism or myxedema coma and for pregnant patients who are hypothyroid. Untreated hypothyroidism in pregnant patients is associated with an increased incidence of spontaneous abortion and mental and physical abnormalities in the offspring.

A number of anesthetic medications have been used without difficulty in hypothyroid patients. Although ketamine has been proposed as the ideal induction agents, all intravenous induction agents have been used in the hypothyroid patient. The maintenance of anesthesia may be safely achieved with either intravenous or inhaled anesthetics. There appears to be little, if any, decrease in the minimum alveolar concentration for volatile agents. Regional anesthesia is a good choice in the hypothyroid patient, provided the intravascular volume is well maintained. Monitoring is directed toward the early recognition of hypotension, congestive heart failure, and hypothermia. Scrupulous attention should be paid to maintaining normal body temperature.

Myxedema coma represents a severe form of hypothyroidism characterized by stupor or coma, hypoventilation, hypothermia, hypotension, and hyponatremia. This is a medical emergency with a high mortality rate (25% to 50%) and, as such, requires aggressive therapy (Table 46-5). Only lifesaving surgery should proceed in the face of myxedema coma. Intravenous thyroid replacement is initiated as soon as the clinical diagnosis is made. An intravenous loading dose of T₄ (sodium levothyroxine, 200 to 300 μg) is given initially and followed by a maintenance dose of T₄, 50 to 200 μg/day intravenously.¹⁹ Alternatively, T₃ may be used because it has a more rapid onset. Improvements in heart rate, blood pressure, and body temperature may occur within 24 hours. However, replacement therapy with either form of thyroid hormone may precipitate myocardial ischemia. There is also an increased likelihood of acute primary adrenal insufficiency in these patients, and they should receive stress doses of hydrocortisone. Steroid replacement continues until normal adrenal function can be confirmed.

Surgery is the treatment of choice for the patient with symptomatic disease. However, there is considerable controversy surrounding the choice of treatment in the asymptomatic patient. It is not clear whether mild primary hyperparathyroidism decreases longevity. Surgery is often chosen over medical therapy because it offers definitive treatment and is generally safe.

Preoperative preparation focuses on the correction of intravascular volume and electrolyte irregularities. It is particularly important to evaluate the patient with chronic hypercalcemia for abnormalities of the renal, cardiac, or central nervous systems. Emergency treatment of hypercalcemia is undertaken before surgery when the serum Ca²⁺ concentration exceeds 15 mg/dL (7.5 mEq/L). Lowering of the serum Ca²⁺ concentration is initially accomplished by expanding the intravascular volume and establishing a sodium diuresis. This is achieved with the intravenous administration of normal saline and furosemide. Rehydration alone is capable of lowering the serum Ca²⁺ level by ≥2 mg/dL. Hydration dilutes the serum Ca²⁺, and sodium diuresis promotes Ca²⁺ excretion through an inhibition of sodium and Ca²⁺ resorption in the proximal tubule. Hypokalemia and hypomagnesemia may result.

Another element in the treatment of hypercalcemia is the correction of hypophosphatemia. Hypophosphatemia increases GI absorption of Ca²⁺, stimulates the breakdown of bone, and impairs the uptake of Ca²⁺ by bone. Low serum phosphate levels impair cardiac contractility and may contribute to congestive heart failure. Hypophosphatemia also causes skeletal muscle weakness, hemolysis, and platelet dysfunction.

Other medications that have a role in lowering the serum Ca²⁺ include bisphosphonates, mithramycin, calcitonin, and glucocorticoids. Bisphosphonates are pyrophosphate analogs that inhibit osteoclast action. They are the drugs of choice for severe hypercalcemia. Toxic effects include fever and hypophosphatemia. Mithramycin, a cytotoxic agent, inhibits PTH-induced osteoclast activity and can lower the serum Ca²⁺ levels by ≥2 mg/dL in 24 to 48 hours. Toxic effects include azotemia, hepatotoxicity, and thrombocytopenia. Calcitonin is useful in transiently lowering the serum Ca²⁺ level 2 to 4 mg/dL through direct inhibition of osteoclastic bone resorption. The advantages of calcitonin are the mild side effects (urticaria, nausea) and the rapid onset of activity. Calcitonin resistance usually develops within 24 to 48 hours. Glucocorticoids are effective in lowering the serum Ca²⁺ concentration in several conditions (sarcoidosis, some malignancies, hyperthyroidism, vitamin D intoxication) through their actions on osteoclast bone resorption, GI absorption of calcium, and the urinary excretion of calcium. Glucocorticoids are usually of no benefit in the treatment of primary hypercalcemia. Finally, hemodialysis or peritoneal dialysis can be used to lower the serum Ca²⁺ level when alternative regimens are ineffective or contraindicated.

There is no evidence that a specific anesthetic drug or technique has advantages over another. A thorough knowledge of the clinical manifestations attributable to hypercalcemia is of the greatest value in choosing an anesthetic technique. Special monitoring is usually not required. Because of the unpredictable response to neuromuscular blocking drugs in the hypercalcemic patient, a conservative approach to muscle paralysis makes sense. There is an increased requirement for vecuronium, and probably all nondepolarizing muscle relaxants, during onset of
neuromuscular blockade.²² Careful positioning of the osteopenic patient is necessary to avoid pathologic bone fractures.

General anesthesia is most commonly used for parathyroid surgery. Minimally invasive parathyroidectomy is superior to conventional bilateral cervical exploration in patients with sporadic primary hyperparathyroidism²³ and can usually be performed under bilateral cervical plexus block.²⁴ Some centers use an intraoperative rapid PTH assay to help determine when a hyperfunctioning gland has been removed. There is in vitro, but no clinical,²⁵ evidence that propofol can interfere with the assay, so many surgeons prefer that propofol not be used within 15 minutes of an assay. Postoperative complications include RLN injury, bleeding, and transient or complete hypoparathyroidism. Unilateral RLN is characterized by hoarseness and usually requires no intervention. Bilateral RLN injury is a rare complication, producing aphonia and requiring immediate tracheal intubation.

After successful parathyroidectomy, a decrease in the serum Ca²⁺ level should be observed within 24 hours. Patients with significant preoperative bone disease may have hypocalcemia after removal of the PTH-secreting glands. This “hungry bone” syndrome comes as a result of the rapid remineralization of bone. Thus, serum Ca²⁺, magnesium, and phosphorus levels should be closely monitored until stable. The serum Ca²⁺ nadir usually occurs within 3 to 7 days.

The clinical features of hypoparathyroidism are a manifestation of hypocalcemia. Neuronal irritability and skeletal muscle spasms, tetany, or seizures reflect a reduced threshold of excitation. Latent tetany may be demonstrated by eliciting the Chvostek or Trousseau sign. Chvostek sign is a contracture of the facial muscle produced by tapping the facial nerve as it passes through the parotid gland. Trousseau sign is contraction of the fingers and wrist after application of a blood pressure cuff inflated above the systolic blood pressure for approximately 3 minutes. Other common complaints of hypocalcemia include fatigue, depression, paresthesias, and skeletal muscle cramps. The acute onset of hypocalcemia after thyroid or parathyroid surgery may manifest as stridor and apnea. Cardiovascular manifestations of hypocalcemia include congestive heart failure, hypotension, and a relative insensitivity to the effects of β-adrenergic agonists (see Chapter 10). Delayed ventricular repolarization results in a prolonged QT interval on the ECG. Although prolongation of the QT interval may be a reliable sign of hypocalcemia in an individual patient, the ECG is relatively insensitive for the detection of hypocalcemia.

The treatment of hypoparathyroidism consists of electrolyte replacement. The objective is to have the patient’s clinical symptoms under control before anesthesia and surgery. Hypocalcemia caused by magnesium depletion is treated by correcting the magnesium deficit. Serum phosphate excess is corrected by the removal of phosphate from the diet and the oral administration of phosphate-binding resins (aluminum hydroxide). The urinary excretion of phosphate can be increased with a saline volume infusion. Ca²⁺ deficiencies are corrected with Ca²⁺ supplements or vitamin D analogs. Patients with severe symptomatic hypocalcemia are treated with intravenous calcium gluconate (10 to 20 mL of 10% solution) given over several minutes and followed by a continuous infusion (1 to 2 mg/kg/hour) of elemental Ca²⁺. The correction of serum Ca²⁺ levels should be monitored by measuring serum Ca²⁺ concentrations and following clinical symptoms. When oral or intravenous calcium is inadequate to maintain a normal serum–ionized calcium level, vitamin D is added to the regimen.

General considerations for the preoperative preparation of the patient include treating hypertension and diabetes and normalizing intravascular fluid volume and electrolyte concentrations. Diuresis with the aldosterone antagonist spironolactone helps mobilize fluid and normalize potassium concentration. Careful positioning of the osteopenic patient is important to avoid
fractures. Intraoperative monitoring is planned after evaluation of the patient’s cardiac reserve and consideration of the site and extent of the proposed surgery. When either unilateral or bilateral adrenalectomy is planned, glucocorticoid replacement therapy is initiated at a dose equal to full replacement of adrenal output during periods of extreme stress (see “Steroid Replacement During the Perioperative Period”). The total dosage is reduced by approximately 50% per day until a daily maintenance dose of steroids is achieved (20 to 30 mg/day). Hydrocortisone given in doses of this magnitude exerts significant mineralocorticoid activity, and additional exogenous mineralocorticoid is usually not necessary during the perioperative period. After bilateral adrenalectomy, most patients require 0.05 to 0.1 mg/day of fludrocortisone (9-α-fluorohydrocortisone) starting around day 5 to provide mineralocorticoid activity. Slightly higher doses may be needed if prednisone is used for glucocorticoid maintenance because it has little intrinsic mineralocorticoid activity. The fludrocortisone dose is reduced if congestive heart failure, hypokalemia, or hypertension develops. For the patient with a solitary adrenal adenoma, unilateral adrenalectomy may be followed by normalization of function in the contralateral gland over time. Treatment plans should therefore be individualized, and adjustments in dosage may be necessary. The production of glucocorticoids or ACTH by a neoplasm may not be eliminated if the tumor is unresectable. These patients often need continuous medical therapy with steroid inhibitors such as metyrapone to control their symptoms.

There are no specific recommendations regarding the use of a particular anesthetic technique or medication in patients with hyperadrenocorticism. When significant skeletal muscle weakness is present, a conservative approach to the use of muscle relaxants is warranted. Etomidate has been used for temporizing medical treatment of severe Cushing syndrome because of its inhibition of steroid synthesis.

Preoperative preparation for the patient with primary aldosteronism is directed toward restoring the intravascular volume and the electrolyte concentrations to normal. Hypertension and hypokalemia may be controlled by restricting sodium intake and administration of the aldosterone antagonist spironolactone. This diuretic works slowly to produce an increase in potassium levels, with dosages in the range of 25 to 100 mg every 8 hours. Total-body potassium deficits are difficult to estimate and may be in excess of 300 mEq. Whenever possible, potassium should be replaced slowly to allow equilibration between intracellular and extracellular potassium stores. The usual complications of chronic hypertension need to be assessed.

The cardinal symptoms of idiopathic Addison disease include chronic fatigue, muscle weakness, anorexia, weight loss, nausea, vomiting, and diarrhea. Hypotension is almost always encountered in the disease process. Female patients may exhibit decreased axillary and pubic hair growth because of the loss of adrenal androgen secretion. An acute crisis can present as abdominal pain, severe vomiting and diarrhea, hypotension, decreased consciousness, and shock. Diffuse hyperpigmentation occurs in most patients with primary adrenal insufficiency and is secondary to the compensatory increase in ACTH and β-lipotropin. These hormones stimulate an increase in melanocyte production. Mineralocorticoid deficiency is characteristically present in primary adrenal disease; as a result, there is a reduction in urine sodium conservation. Hyperkalemia may be a cause of life-threatening cardiac dysrhythmias. Adrenal insufficiency secondary to pituitary disease is not associated with cutaneous hyperpigmentation or mineralocorticoid deficiency. Salt and water balance is usually maintained unless severe fluid and electrolyte losses overwhelm the subnormal aldosterone secretory capacity. Organic lesions of pituitary origin require a diligent search for coexisting hormone
deficiencies. Acute adrenal insufficiency from inadequate replacement of steroids on chronic steroid therapy is rare and can present as refractory, distributive shock. In critically ill patients, adrenal insufficiency may not present with classic symptoms. The clinical picture may resemble that of sepsis without a source of infection.³⁰ A high degree of suspicion must be maintained if the patient has cardiovascular instability without a defined cause.³¹,³²

The patient’s pituitary–adrenal responsiveness should be determined when the diagnosis of primary or secondary adrenal insufficiency is first suspected. Biochemical evidence of impaired adrenal or pituitary secretory reserve unequivocally confirms the diagnosis. Patients who are clinically stable may undergo testing before treatment is initiated. Those believed to have acute adrenal insufficiency should receive immediate therapy.

Plasma cortisol levels are measured before and 30 and 60 minutes after the intravenous administration of 250 μg of synthetic ACTH. There are multiple determinants for adequate adrenal reserve; usually the plasma cortisol rises at least 500 nmol/L 60 minutes after the injection of the synthetic ACTH.³³ Patients with adrenal insufficiency usually demonstrate little or no adrenal response.

Normal adults secrete about 20 mg of cortisol (hydrocortisone) and 0.1 mg of aldosterone per day. Glucocorticoid therapy is usually given twice daily in sufficient dosage to meet physiologic requirements. A typical regimen in the unstressed patient may consist of prednisone, 5 mg in the morning and 2.5 mg in the evening, or hydrocortisone, 20 mg in the morning and 10 mg in the evening. The daily glucocorticoid dosage is typically 50% higher than basal adrenal output to cover the patient for mild stress. Replacement dosages are adjusted in response to the patient’s clinical symptoms or the occurrence of intercurrent illnesses. Mineralocorticoid replacement is also administered on a daily basis; most patients require 0.05 to 0.1 mg/day of fludrocortisone. The mineralocorticoid dose may be reduced if severe hypokalemia, hypertension, or congestive heart failure develops, or it may be increased if postural hypotension is demonstrated.

Secondary adrenal insufficiency often occurs in the presence of multiple hormone deficiencies. A decrease in ACTH production results in the decreased secretion of cortisol and adrenal androgens, but aldosterone control by more dominant mechanisms remains intact. A liberal salt diet is encouraged. Glucocorticoid substitution follows the same guidelines previously outlined for primary adrenal insufficiency.

Immediate therapy of acute adrenal insufficiency is mandatory, regardless of the etiology, and consists of electrolyte resuscitation and steroid replacement (Table 46-6). Initial therapy begins with the rapid intravenous administration of an isotonic crystalloid solution. A dose of 100 mg of hydrocortisone is administered as an intravenous bolus over several minutes. Steroid replacement is continued during the first 24 hours with 100 mg of intravenous hydrocortisone given every 8 hours. If the patient is stable, the steroid dose is reduced starting on the second day. After adequate fluid resuscitation, if the patient continues to be hemodynamically unstable, inotropic support may be necessary. Invasive monitoring is extremely valuable as a guide to both diagnosis and therapy.

Perioperatively, patients with adrenal insufficiency and those with HPA suppression from chronic steroid use require additional corticosteroids to mimic the increased output of the normal adrenal gland during stress. The normal adrenal gland can secrete up to 100 mg/m² of cortisol per day or more during the perioperative period.³⁴ The pituitary–adrenal axis is usually considered to be intact if a plasma cortisol level of >19 μg/dL is measured during acute stress, but there is no precise threshold. The degree of adrenal responsiveness has been correlated with the duration of surgery and the extent of surgical trauma. The mean maximal plasma cortisol level measured during major surgery (colectomy, hip osteotomy) was 47 μg/dL. Minor surgical procedures (herniorrhaphy) resulted in mean maximal plasma cortisol levels of 28 μg/dL. Adrenal activity may also be affected by the anesthetic technique used. Regional anesthesia is effective in postponing the elevation in cortisol levels during surgery of the lower abdomen and extremities.³⁵ Deep general anesthesia may also suppress the elevation of stress hormones such as ACTH and cortisol during the surgical procedure.