Diseases of The Endocrine System

C H A P T E R
13
Diseases of the Endocrine System
SHAMSUDDIN AKHTAR, MBBS n
n If rapid parathyroid hormone assay is contemplated intra-

Parathyroid Glands operatively (to determine effectiveness of resection), pro-
Physiology
pofol use is discouraged and should be stopped at least 5
Hypercalcemia
minutes before the assay is drawn.
Hypocalcemia
n Before thyroid surgery the anesthesiologist must know
Thyroid Gland the gland's functional status; hyperthyroidism and
Physiology
hypothyroidism have significant preoperative implica-
Hyperthyroidism
tions. Imaging studies delineate anatomy, determine
Hypothyroidism
if other structures are involved, and help plan surgical
Thyroid Nodules and Carcinoma
management.
Anesthetic Considerations
n The major considerations regarding anesthesia for
Pituitary Gland patients with thyroid disorders are (1) attainment of a
Physiology
euthyroid state preoperatively, (2) preoperative prepara-
Anterior Pituitary Disease: Hypopituitarism and
tion and attention to disease characteristics, and (3) nor-
Hyperpituitarism
malization of cardiovascular function and temperature
Posterior Pituitary Disorders: Diabetes Insipidus and SIADH
perioperatively.
Adrenal Cortex
n Thyroid storm is a medical emergency with significant
Physiology
mortality. Therapy includes blocking the synthesis of thy-
Excessive Adrenocortical Hormones: Hyperplasia,
Adenoma, and Carcinoma roid hormones with antithyroid drugs.
Adrenocortical Hormone Deficiency n Myxedema coma is a rare complication associated with
Perioperative Stress and Corticoid Supplementation profound hypothyroidism and occasionally accompanied
Adrenal Medulla by pericardial effusion and congestive heart failure.
Pheochromocytoma n Pituitary adenomas are three to five times more com-
Pancreas mon than previously reported (5%-20% of primary CNS
Physiology tumors). Pituitary surgery treats the hyperfunctioning
Hypoglycemia and Hyperinsulinism (Islet Cell Tumors gland, cancer, or mass effect.
of Pancreas) n Pituitary surgical complications include temperature
Diabetes Mellitus dysregulation and abnormalities of endocrine function,
requiring immediate treatment of steroid deficiency,
hypoglycemia, and excessive or deficient secretion of
vasopressin.
n Abnormalities of vasopressin (ADH) function that affect
KEY POINTS
perioperative management involve a relative or absolute
n Anesthetic management of endocrine surgical patients lack or an excess of vasopressin.
should consider not only the organ of interest but also the n Special preoperative considerations for patients with
end-organ consequences of the endocrine dysfunction and Cushing's syndrome include regulating diabetes and hyper-
possible rare syndromes. tension, ensuring normal intravascular fluid volume and
n Severe symptomatic hypercalcemia (especially > 14 mg/dL) electrolyte concentrations, and careful patient positioning.
constitutes a medical emergency, often mandating treat- n Withdrawal of steroids or suppression of their adre-
ment before completing the diagnosis. nal synthesis by steroid therapy is the leading cause
401
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402 ANESTHESIA AND UNCOMMON DISEASES
of underproduction of corticosteroids. If not stressed,

TABLE 13-1 n Syndromes Associated with Parathyroid
glucocorticoid-deficient patients usually have no periop- Gland Tumors
erative problems.
n Pheochromocytoma and paragangliomas are c atecholamine- Syndrome Clinical Features
producing nervous system tumors. Preoperative α-blockade Multiple endocrine Primary hyperparathyroidism
alleviates symptoms, with β-blockade and phenoxy- neoplasia type I (MEN-I) Enteropancreatic tumors
benzamine for patients with persistent dysrhythmias or Pituitary tumors
tachycardia. Thymic or bronchial endocrine
n Signs and symptoms in patients with insulinomas usually tumors
Adrenocortical tumors
are directly related to prolonged hypoglycemic states.
n Surgical mortality rates for diabetic patients average MEN-IIA Medullary thyroid carcinoma
five times higher than for nondiabetic patients. Acute Pheochromocytoma
Parathyroid hyperplasia
diabetic complications include hypoglycemia, diabetic
ketoacidosis, and hyperglycemic hyperosmolar nonke- Hereditary Primary hyperparathyroidism
totic coma. hyperparathyroidism– Parathyroid carcinoma
n For management of hyperglycemia in the ICU, recom- jaw tumor syndrome Ossifying fibromas of jaw
Renal cysts
mended threshold to initiate insulin infusion is 180 mg/dL, Renal solid tumors
then 140 to 180 mg/dL as the target range. Glucose control Uterine fibromas
by insulin infusion is recommended preoperatively and for
Familial isolated Associated with MEN-I
critically ill patients.
hyperparathyroidism
Neonatal severe Occurs in childhood

The endocrine system directly or indirectly influences many hyperparathyroidism Extreme hypercalcemia caused by:
Diffuse chief cell hyperplasia
critical functions of the body, especially energy homeostasis, Demineralization and pathologic
metabolism, and the cardiovascular system. Electrolyte and fractures
fluid balance and immune system function are intricately con- Multiglandular parathyroid
trolled by hormones. Disorders involving the endocrine sys- hyperplasia vs. adenoma
tem can present as primary disorders of the endocrine organ Familial hypocalciuric Mild to moderate hypercalcemia
(common) or can be part of a syndrome (rare). The man- hypercalcemia (FHH) Most common cause of hereditary
agement of a patient who presents for surgery on endocrine hypercalcemia
organs should not only focus on the organ of interest, but Histologically, parathyroid glands
removed from FHH patients are
also consider the end-organ consequences of the endocrine
normal or occasionally hyperplastic.
dysfunction and its possible relationship to rare syndromes.
Perioperative outcome in many of these patients also involves
the anesthesiologist's understanding of the surgery and the hyperparathyroidism, neonatal severe hyperparathyroidism,
potentially dramatic pathophysiologic effects of removing the and familial hypocalciuric hypercalcemia (Table 13-1). To
endocrine organ. appreciate perioperative considerations for patients undergo-
ing parathyroid surgery, it is important to know about calcium
metabolism.
PARATHYROID GLANDS
Parathyroid glands are intricately involved in calcium and
Physiology
phosphate metabolism. Disorders of serum calcium concen-
tration are relatively common and often serve as a harbinger The calcium ion (Ca++) plays a critical role in diverse cellu-
of underlying parathyroid disease. However, many diseases lar functions such as cardiac contractility, hormone secretion,
can cause hypercalcemia or hypocalcemia.1 Most surgeries blood coagulation, and neuromuscular signaling. Total (bound
on the parathyroid gland are performed for primary hyper- and free) serum calcium concentration is maintained at the
parathyroidism. However, surgery may also be needed for sec- normal level of 9.5 to 10.5 mg/dL through a series of feedback
ondary hyperparathyroidism, inherited parathyroid diseases, mechanisms that involve parathyroid gland, bone, kidney, and
or familial hyperparathyroidism syndromes. Patients with gastrointestinal (GI) tract5 (Fig. 13-1). Approximately 50%
primary carcinoma of the parathyroid gland, multiple endo- of the serum calcium is bound to serum proteins (albumin),
crine neoplasia type I (MEN-I, parathyroid hyperplasia with 40% is ionized, and the remaining 10% is bound to such che-
lesions of pancreas and pituitary), and MEN-IIA (medullary lating agents as citrate. If the serum protein concentration
thyroid cancer, pheochromocytoma, and primary hyperpara- decreases, the total serum calcium concentration will also
thyroidism) may also present for parathyroid surgery.2-4 Other decrease. The rule of thumb is that for every 1-g decrement
parathyroid syndromes that may require surgery include in albumin, a 0.8-mg/dL decrement in total serum calcium
hereditary hyperparathyroidism–jaw tumor, familial isolated concentration occurs. Likewise, if the serum proteins increase
Chapter 13 Diseases of the Endocrine System 403
increasing calcium reabsorption from bone and by promot-

Increased Decreased
extracellular calcium extracellular calcium ing synthesis of 1,25(OH)2D3, which in turn enhances calcium
reabsorption from the gut. Finally, PTH directly increases cal-
Intestines cium reabsorption from the renal tubule. Thus, PTH accel-
1,25(OH)2D3 erates the breakdown of bone by a complex mechanism that
absorption includes a fast component and a slow component (involving
protein synthesis and cellular proliferation). In addition, PTH
Kidney Bone Parathyroid has an anabolic effect on bone formation, and in tissue culture
absorption resorption glands it increases the number of active osteoblasts, the maturation of
cartilage, and osteoid formation within the bone shaft.
Increased PTH
Hypercalcemia
FIGURE 13-1 Factors involved in extracellular calcium
homeostasis. 1,25[OH]2D3, 1,25-dihydroxycholecalciferol; PTH, Etiology. The many causes of hypercalcemia can be grouped
parathyroid hormone (parathormone). pathophysiologically into six broad categories (Fig 13-2).
Excessive PTH production is seen in (1) primary hyperpara-
thyroidism, caused by adenoma, hyperplasia, or rarely carci-
(as in myeloma), total serum calcium will increase. Acidosis
noma; (2) tertiary hyperparathyroidism, caused by long-term
tends to increase the ionized calcium, whereas alkalosis tends
stimulation of PTH secretion in renal insufficiency; (3) ecto-
to decrease it. Serum calcium tends to decrease slightly with
pic PTH secretion (rare); (4) inactivation mutations at the cal-
age, with a concomitant elevation of the serum parathyroid
cium sensor receptor (CaSR), as seen in familial hypocalciuric
hormone (PTH, parathormone), perhaps contributing to the
hypercalcemia (FHH); and (5) alteration in CaSR function, as
osteoporosis associated with the aging process.6
seen with lithium therapy.
When the ionized calcium concentration decreases or
Parathyroid hyperplasia, usually involving all four para-
the serum phosphate level rises, release of PTH is stimulated
thyroid glands, may be a major cause of the hyperparathyroid
through activation of the calcium sensor receptor on para-
syndrome. Carcinoma of the parathyroid glands is extremely
thyroid cells. PTH is secreted by the four parathyroid glands,
rare. All adenomas might begin as hyperplasia;8 therefore, for
which are usually located posterior to the upper and lower
the individual patient, where surgery occurs in the natural his-
poles of the thyroid gland. PTH increases tubular reabsorption
tory of the disease may determine whether hyperplasia or an
of calcium and decreases tubular reabsorption of phosphate
adenoma is found. Hypercalcemia can also be seen in solid
to raise the serum calcium concentration. PTH also increases
malignancies caused by overproduction of PTH-related pep-
the resorption from the bone. Another effect of PTH on the
tide (PTHrP) or lytic skeletal metastases, as seen in myeloma
kidney is the increase in active form of vitamin D, which in
or breast cancer. Excessive 1,25(OH)2D3 production can also
turn increases the absorption of calcium from the intestines.
cause hypercalcemia. This is typically observed with lym-
A renal phosphate leak is the result of excessive PTH secretion.
phomas, granulomatous diseases, or vitamin D intoxication.
Vitamin D plays an important role in calcium homeosta-
Primary increase in bone resorption, as seen with immobi-
sis. Cholecalciferol is synthesized in the skin by the effects
lization, Paget's disease, and hyperthyroidism, can also lead
of ultraviolet light. Cholecalciferol is hydroxylated in the
to hypercalcemia. Excessive calcium intake, which can occur
liver to form 25-hydroxycholecalciferol. The 25-hydroxy
with total parenteral nutrition (TPN) and milk-alkali syn-
derivative is further hydroxylated in the kidney to form
drome, can also cause hypercalcemia. Hypercalcemia also
1,25-dihydroxycholecalciferol (1,25[OH]2D3). 1,25(OH)2D3
results from other endocrine disorders (e.g., adrenal insuf-
stimulates absorption of both calcium and phosphorus from
ficiency, pheochromocytoma, VIPomas) and medications
the GI tract.7 Thus, vitamin D provides the substrates for the
(e.g., antiestrogens, vitamin A, thiazides). Thiazides increase
formation of mineralized bone. 1,25(OH)2D3 may also directly
renal tubular reabsorption of calcium and may even enhance
enhance mineralization of newly formed osteoid matrix in
the PTH effects on the renal tubule. Most patients with sig-
bone. Vitamin D derivatives also seem to work synergisti-
nificant hypercalcemia associated with thiazide diuretics have
cally with PTH to increase resorption of bone. This is clinically
hyperparathyroidism.
important because immobilization alone increases bone resorp-
tion, and if the patient is receiving a vitamin D derivative, bone Clinical Presentation. Patients with hypercalcemia present
resorption may be increased further. with a variety of symptoms. The level of blood calcium is fre-
Hydroxylation of 25-hydroxycholecalciferol is controlled quently related to the degree and severity of symptoms. Mild
in the kidney by PTH and the phosphorus level. Elevated hypercalcemia (up to 11-11.5 mg/dL) is usually asymptomatic
PTH and hypophosphatemia tend to accentuate the synthe- and detected on routine calcium measurement. Patients may
sis of 1,25(OH)2D3, whereas low levels of PTH and high lev- have vague complaints of depression, poor concentration, and
els of phosphate turn off the synthesis of 1,25(OH)2D3 in the personality changes. Other patients may present with neph-
kidney. PTH maintains a normal calcium level in blood by rolithiasis or peptic ulcer disease. Nephrolithiasis occurs in
Hypercalcemia
Excessive Excessive Excessive Primary increase in Hypercalcemia Other

PTH production calcium intake 1, 25(OH)2D3 bone resorption of malignancy causes
production
Primary Overproduction
hyperparathyroidism Granulomatous diseases of PTHrP
(sarcoidosis, tuberculosis, (many solid
Tertiary silicosis) tumors)
hyperparathyroidism
Lymphomas Lytic skeletal
Ectopic PTH secretion metastases
Vitamin D intoxication (breast myeloma)
Inactivating mutations
in the CaSR
Alterations in CaSR Milk-alkali Hyperthyroidism Other endocrine

function syndrome disorders (adrenal
Immobilization insufficiency,
Total parenteral pheochromocytoma,
nutrition VIPoma)
Medications
(thiazides, vitamin A,
antiestrogens)
FIGURE 13-2 Causes of hypercalcemia. CaSR, Calcium sensor receptor; PTHrP, parathormone-related peptide; VIPoma, vasoactive
intestinal polypeptide tumor (usually islet cell).
60% to 70% of patients with hyperparathyroidism. Sustained PTH. When a patient presents with an extremely high blood
hypercalcemia can result in tubular and glomerular disorders. calcium level (> 14 mg/dL), the patient likely has a distant can-
Polyuria and polydipsia are common complaints. Patients cer rather than hyperparathyroidism. Overall, about 50% of all
with calcium levels above 12 to 13 mg/dL, especially develop- cases of hypercalcemia are caused by cancer invading bone. In
ing acutely, have anorexia, nausea, vomiting, abdominal pain, these patients, prognosis is poor; more than 50% die within 6
constipation, polyuria, tachycardia, and dehydration.1,9 months. Treating hypercalcemia does not prolong survival but
Hypercalcemia can also result in significant echocardio- usually improves quality of life.13,14
graphic (ECG) changes, including bradycardia, atrioventricu- Evaluation for bony metastases includes a technetium
lar block, and short QT interval. Psychosis and obtundation diphosphonate bone scan, which is positive in a large percent-
are usually the end results of severe and prolonged hypercal- age of cancers that have metastasized. In addition to serum
cemia. Band keratopathy is a most unusual physical finding. calcium and phosphate, the bony fraction of alkaline phos-
Bone disease in hyperparathyroidism, such as subperiosteal phatase, creatinine, electrolyte, and urinary calcium levels are
resorption, can also be seen in radiographs of the teeth and obtained, as well as the appropriate skeletal radiographs and
hands in patients with prolonged hypercalcemia.10 Severe isotope bone scan (by endocrinologist) to aid diagnosis.
bone disease in hyperparathyroidism, such as osteitis fibrosa
cystica, is only rarely seen and usually in older patients with Management. Severe symptomatic hypercalcemia, espe-
long-standing disease (up to 20 years). The older patient with cially levels greater than 14 mg/dL, constitutes a medical emer-
severe osteopenia, and perhaps vertebral compression frac- gency, and often treatment must be begun before the diagnosis
tures, should prompt suspicion of hyperparathyroidism. is complete. The signs and symptoms in any one patient can-
Patients with hyperparathyroidism have elevated calcium not be related to serum calcium level. One patient with total
and low serum phosphate levels. Very mild hyperchloremic calcium of 14 mg/dL may be almost asymptomatic, whereas
acidosis may be present. The PTH level is usually elevated, another may have severe polyuria, tachycardia, dehydration,
particularly with respect to the level of calcium concentration, and even psychosis. Age seems to be a factor; that is, for any
and PTH reduction is the hallmark of successful surgery.11,12 given calcium level, the older patient is more likely to be symp-
The only two situations in which hypercalcemia would be tomatic than younger patients.
associated with a high PTH level are hyperparathyroidism The first step in the management of hypercalcemia is hydra-
and the ectopic PTH syndrome (usually secondary to a tumor tion. Infusion of 4 to 6 L of intravenous (IV) saline may be
of the lung or kidney that produces a biologically active frag- required in the first 24 hours. Loop diuretics may be required
ment of PTH).1 All other causes of hypercalcemia are associ- to enhance sodium and calcium excretion.1 Complications of
ated with either “normal” or, more appropriately, low levels of these interventions include hypomagnesemia and hypokalemia.
Extreme care must be exercised in the use of digitalis deriva- Aspiration precautions must be taken because the hypercalce-
tives for patients with hypercalcemia. Digitalis intoxication mic patient with altered mental status may have a full stomach
occurs quite readily in the presence of hypercalcemia, and dys- or may be unable to protect the airway. Radiographs of the
rhythmias from digitalis toxicity are common (Box 13-1). cervical spine should be taken to rule out lytic lesions when
If there is increased calcium mobilization from bone, as in hypercalcemia results from cancer.16 Laryngoscopy in a patient
malignancy or severe hyperparathyroidism, drugs that inhibit with an unstable cervical spine may result in quadriplegia.
bone resorption should be considered. Zoledronic acid (e.g.,
4 mg intravenously [IV] over 30 minutes), pamidronate (e.g., Intraoperative and Postoperative Considerations. There
60–90 mg IV over 2-4 hours), and etidronate (e.g., 7.5 mg/kg/ have been significant advances in parathyroid surgery. With
day for 3-7 consecutive days) can be used in the treatment newer imaging and radionuclide techniques and rapid intra-
of hypercalcemia of malignancy in adults. Onset of action operative PTH assay, it is no longer necessary to remove all
is within 1 to 3 days, with normalization of serum calcium four parathyroid glands. Unilateral removal of the glands is
levels occurring in 60% to 90% of patients. Because of their now possible with less invasive techniques.17 Surgery can be
effectiveness, bisphosphonates have replaced calcitonin and performed under general, regional, or local anesthesia based
plicamycin, which are rarely used in current practice for the on institutional approach. Although no controlled study
management of hypercalcemia.1 In rare cases, dialysis may be has demonstrated clinical advantages of one anesthetic over
necessary. Finally, although IV phosphate chelates calcium another, if rapid intraoperative PTH assessment is contem-
and decreases serum calcium levels, this therapy can be toxic plated (to determine the effectiveness of resection), propofol
because calcium-phosphate complexes may deposit in tissues use is discouraged. If propofol is used, it should be stopped at
and cause extensive organ damage. least 5 minutes before the assay is drawn.
In patients with 1,25(OH)2D3-mediated hypercalcemia, Maintenance of anesthesia usually presents little diffi-
glucocorticoids are the preferred therapy because they culty. No special intraoperative monitoring for hyperparathy-
decrease 1,25(OH)2D3 production. IV hydrocortisone (100- roid patients is required. Because of the proximity of surgical
300 mg daily) or oral prednisone (40-60 mg daily) for 3 to 7 retraction to the face, however, meticulous care is taken to
days are used most often. Other drugs, such as ketoconazole, protect the eyes. The possibility of lytic or pathologic frac-
chloroquine, and hydroxychloroquine, may also decrease tures warrants careful positioning. Response to neuromuscu-
1,25(OH)2D3 production and are used occasionally. lar blocking agents may be unpredictable when calcium levels
are elevated; reversal of the effects may be difficult.18 Failure to
Patients with Hyperparathyroidism remove all the parathyroid adenomas may necessitate single
Preoperative Considerations. Patients with moderate hyper- or multiple reoperations. Sestamibi scanning and venous sam-
calcemia who have normal renal and cardiovascular function pling of PTH levels in thyroidal venous beds may provide use-
present no special preoperative problems. ECG findings can ful information to the surgeon at reoperation.19 Unusual sites
be examined preoperatively and intraoperatively for shortened of parathyroid adenoma include areas behind the esophagus,
PR or QT interval.15 Because severe hypercalcemia can result in the mediastinum, and within the thyroid.
in hypovolemia, normal intravascular volume and electrolyte Of the many possible postoperative complications (nerve
status should be restored before anesthesia for elective surgery. injuries, bleeding, metabolic abnormalities), bilateral recur-
rent nerve trauma and hypocalcemic tetany are most seri-
ous. Bilateral recurrent laryngeal nerve injury (from trauma
BOX 13-1 n MANAGEMENT OF HYPERCALCEMIA
or edema) causes stridor and laryngeal obstruction as a result
Provide hydration: 4-6 L of IV saline in first 24 hours. of unopposed adduction of the vocal cords and closure of
Administer loop diuretics to enhance sodium excretion. the glottic aperture. Immediate endotracheal intubation is
Inhibit bone resorption by bisphosphonates (zoledronic acid, required in these patients, usually followed by tracheostomy
pamidronate, etidronate).
Rarely, plicamycin may be indicated.
to ensure an adequate airway. This rare complication of bilat-
Correct hypokalemia and hypomagnesemia that may develop with eral recurrent nerve injury occurred only once in more than
treatment of hypercalcemia. 30,000 operations at the Lahey Clinic (Tufts University School
Anesthetic Considerations of Medicine, Burlington, Mass). Unilateral recurrent laryn-
Correct hypovolemia. geal nerve injury often goes unnoticed because of compensa-
Correct electrolyte disorders. tory overadduction of the uninvolved cord. Because bilateral
Note risk of aspiration if patient has altered mental status. injury is rare and clinically obvious, laryngoscopy after thy-
Take special care in positioning (risk of pathologic fractures).
roid or parathyroid surgery need not be performed routinely;
Avoid or discontinue propofol if rapid PTH assay is going to be
conducted intraoperatively. however, the clinician can easily test vocal cord function after
Postoperatively, note risk of recurrent laryngeal nerve injury, glottic surgery by asking the patient to say “e” or “moon.” Unilateral
edema, hypocalcemia, hypophosphatemia and hypomagnesemia. nerve injury is characterized by hoarseness, and bilateral nerve
injury is characterized by aphonia. Selective injury of adduc-
IV, Intravenous; PTH, parathormone. tor fibers of both recurrent laryngeal nerves leaves the abduc-
tor muscles relatively unopposed, and pulmonary aspiration is
a risk. Selective injury of abductor fibers, on the other hand, Other complications of hypophosphatemia include hemolysis,
leaves the adductor muscles relatively unopposed, and airway platelet dysfunction, leukocyte dysfunction (depression of che-
obstruction can occur. motaxis, phagocytosis, and bactericidal activity), paresthesias,
Bullous glottic edema is edema of the glottis and phar- muscular weakness, and rhabdomyolysis.23 In patients with
ynx, which occasionally follows parathyroid surgery. This is both hypocalcemia and hypomagnesemia, correction of the
an additional cause of postoperative respiratory compromise; hypomagnesemia may cause greatly increased PTH secretion,
it has no specific origin, and there is no known preventive resulting in dramatic hypophosphatemia. Serum phosphate
measure. levels should be monitored closely in such patients.22,23
Unintended hypocalcemia during surgery for parathyroid Hypomagnesemia may occur postoperatively. Clinical
disease occurs in rare cases, usually from the lingering effect sequelae of magnesium deficiency include cardiac dysrhyth-
of vigorous preoperative treatment. This effect is especially mias (principally ventricular tachydysrhythmias), hypocal-
important for patients with advanced osteitis because of the cemic tetany, and neuromuscular irritability independent of
calcium affinity of their bones. After parathyroidectomy, mag- hypocalcemia (tremors, twitching, asterixis, seizures).21 Both
nesium or calcium ions may be redistributed internally (into hypomagnesemia and hypokalemia augment the neuromus-
“hungry bones”), thus causing hypomagnesemia, hypocalce- cular effects of hypocalcemia. Often, just restoring the magne-
mia, or both. Risk factors for the development of hypocal- sium deficit corrects the hypocalcemia. It is preferable to use
cemia (and hypocalcemic tetany) after parathydroidectomy oral calcium (1 or 2 g of calcium gluconate four times daily)
include subtotal or 3½-gland parathyroidectomy, bilateral when the patient is able to take oral fluids.
neck exploration, removal of the parathyroids together with During the first week or 10 days after surgery, vitamin D
thyroid glands, or history of previous neck dissection.17 In derivatives are avoided to allow the suppressed parathyroid tis-
high-risk situations, management after parathyroid surgery sue (if present) to function. Vitamin D derivatives are always
should include serial determinations of serum calcium, inor- started if the patient has significant hypocalcemia 2 weeks after
ganic phosphate, magnesium, and PTH levels.20-25 Serum cal- surgery. The management of hypoparathyroidism is not easy,
cium levels fall by several milligrams per deciliter in the first 24 and careful follow-up of patients is mandatory. Oral calcium
hours. The lowest level usually is reached within 4 or 5 days. In and vitamin D analogs are used for long-term management.
some patients, hypocalcemia may be a postoperative problem.
Causes include insufficient residual parathyroid tissue, surgi-
cal trauma or ischemia, postoperative hypomagnesemia, and Hypocalcemia
delayed recovery of function of normal parathyroid gland tis-
Etiology. Probably the most common cause of hypocalce-
sue. It is particularly important to correct hypomagnesemia in
mia is hypoalbuminemia, followed by surgical removal of the
patients with hypocalcemia because PTH secretion is dimin-
parathyroids. However, causes of hypocalcemia can be dif-
ished in the presence of hypomagnesemia.22,23 Potentially
ferentiated based on high or low PTH levels. Low PTH lev-
lethal complications of severe hypocalcemia include laryngeal
els (hypoparathyroidism) are associated with (1) parathyroid
spasm and hypocalcemic seizures.
agenesis (DiGeorge syndrome); (2) parathyroid gland destruc-
In addition to monitoring total serum calcium or ionized
tion from surgery, radiation, autoimmune disease, or infiltra-
calcium postoperatively, the clinician can test for Chvostek and
tion by metastatic or inflammatory diseases; and (3) reduced
Trousseau signs. Because Chvostek sign is present in 10% to
parathyroid function caused by hypomagnesemia or activat-
20% of individuals who do not have hypocalcemia, an attempt
ing calcium sensor receptor mutations (Fig. 13-3).
should be made to elicit this sign preoperatively. Chvostek sign
Hypocalcemia can lead to a compensatory increase in PTH
is a contracture of the facial muscles produced by tapping
levels (secondary hyperparathyroidism). The causes for hypo-
the ipsilateral facial nerves at the angle of the jaw. Trousseau
calcemia in patients with high PTH level include the following:
sign is elicited by application of a blood pressure (BP) cuff at
a level slightly above the systolic pressure for a few minutes. 1. Vitamin D deficiency or impaired 1,25(OH)2D3 produc-
The resulting carpopedal spasm, with contractions of the fin- tion or action, as seen in nutritional deficiency, renal
gers and inability to open the hand, stems from the increased insufficiency with impaired 1,25(OH)2D3 production, or
muscle irritability in hypocalcemic states, which is aggravated resistance to vitamin D, including receptor defects.
by ischemia produced by the inflated BP cuff. Because a post- 2. Parathyroid hormone resistance syndromes, includ-
operative hematoma can compromise the airway, the neck and ing PTH receptor mutations and G-protein mutations
wound dressings should be examined for evidence of bleeding (pseudohypoparathyroidism).
before a patient is discharged from the recovery room. 3. Drugs such as calcium chelators, inhibitors of bone resorp-
Hypophosphatemia may also occur postoperatively. It is par- tion, and agents that alter vitamin D metabolism (e.g., phe-
ticularly important to correct this deficiency in patients with nytoin, ketoconazole).
congestive heart failure (CHF). In a group of patients with 4. Acute pancreatitis, acute rhabdomyolysis, “hungry bone”
severe hypophosphatemia, correction of serum phosphate con- syndrome after parathyroidectomy, or osteoblastic metas-
centration from 1.0 to 2.9 mg/dL led to significant improve- tases with marked stimulation of the bone (prostate
ment in left ventricular contractility at the same preload.20 cancer).
Causes of hypocalcemia
Low parathyroid hormone levels High parathyroid hormone levels

(hypoparathyroidism) (secondary hyperparathyroidism)
Parathyroid Parathyroid Reduced Vitamin D PTH hormone Drugs Other

agenesis destruction parathyroid function deficiency/ resistance causes
impaired syndromes
1,25(OH)2D3
production/
action
Isolated Surgical Hypomagnesemia PTH receptor Acute
mutations pancreatitis
DiGeorge Radiation Activating
syndrome CaSR Pseudo- Acute
Infiltration mutations Nutritional hypoparathyroidism Calcium rhabdomyolysis
metastases/ vitamin D (G protein mutations) chelators
systemic deficiency Hungry bone
diseases (poor intake or Inhibitors of syndrome
absorption) bone resorption
Autoimmune (bisphosphonates, Osteoblastic
Renal insufficiency with plicamycin) metastases
impaired 1,25(OH)2D3 production (prostate
Altered vitamin D cancer)
Vitamin D resistance, metabolism
including receptor defects (phenytoin, ketoconazole)
FIGURE 13-3 Causes of hypocalcemia.
In DiGeorge syndrome, thymic hypoplasia is associated calcium. PTH inhibits renal tubular reabsorption of phosphate
with hypoparathyroidism.26 Pseudohypoparathyroidism is an and bicarbonate; thus, serum phosphate and bicarbonate lev-
unusual entity associated with short stature, round facies, and els are elevated in patients with hypoparathyroidism.
short metacarpals, as well as parathyroid hyperplasia. It rep- The manifestations of acute hypoparathyroidism are dis-
resents in part as end-organ resistance to the action of PTH cussed earlier in the context of the postoperative management
resulting from G-protein defects. 1,25(OH)2D3 levels are low in of hypercalcemia. A nerve exposed to low calcium concentra-
pseudohypoparathyroidism, and replacement of this vitamin tion has a reduced threshold of excitation, responds repeti-
D derivative can partially reverse the end-organ resistance. tively to a single stimulus, and has impaired accommodation
Hypomagnesemia impairs PTH release and thus can cause and continuous activity. Tetany usually begins with paresthe-
profound hypocalcemia. Hypomagnesemia is common in sias of the face and extremities, which increase in severity.
patients with alcoholism, malnutrition, or chronic severe Spasms of the muscles in the face and extremities follow. Pain
malabsorption states. The calcium level may be restored by in the contracting muscle may be severe. Patients often hyper-
replacing magnesium. The vitamin D deficiency of the mal- ventilate, and the resulting hypocapnia worsens the tetany.
absorption syndrome, osteomalacia (adults) and rickets Spasm of laryngeal muscles can cause the vocal cords to be
(children), is associated with a low serum phosphorus con- fixed at the midline, leading to stridor and cyanosis. Chvostek
centration. In all other causes of hypocalcemia, serum phos- and Trousseau signs are classic signals of latent tetany, and
phorus tends to be elevated. It is disproportionately elevated manifestations of spasm distal to the inflated BP cuff should
in chronic renal failure. Cataracts and basal ganglion calcifi- occur within 2 minutes (see earlier discussion).
cation are seen in both hypoparathyroidism and pseudohy- Hypocalcemia delays ventricular repolarization, thus
poparathyroidism. Subperiosteal resorption, the hallmark of increasing the QTc interval (normal, 0.35-0.44). With electri-
excessive PTH secretion, is seen mainly in chronic renal fail- cal systole thus prolonged, the ventricles may fail to respond
ure associated with secondary hyperparathyroidism and in to the next electrical impulse from the sinoatrial (SA) node,
some forms of pseudohypoparathyroidism. causing 2:1 heart block. Prolongation of the QT interval is a
moderately reliable ECG sign of hypocalcemia, not for the
Clinical Presentation. Most of the clinical manifestations population as a whole but for individual patients. Thus, follow-
of hypoparathyroidism are attributable to hypocalcemia. ing the QT interval as corrected for heart rate is a useful but
Hypocalcemia occurs because of a fall in the equilibrium level not always accurate means of monitoring hypocalcemia. CHF
of the blood-bone calcium relationship, in association with a may also occur with hypocalcemia, but this is rare. Heart fail-
reduction in renal tubular reabsorption and GI absorption of ure in patients with coexisting heart disease can be improved
when calcium and magnesium ion levels are restored to nor- Chronic hypocalcemia from hypoparathyroidism is treated
mal, and these levels should be normal before surgery. Sudden with calcium supplements (1000-1500 mg/day of elemental
decreases in blood levels of ionized calcium (as with chelation calcium in divided doses) and either vitamin D2 or vitamin
therapy) can result in severe hypotension. D3 (25,000-100,000 U daily) or calcitriol (1,25[OH]2D3, 0.25-2
Patients with hypocalcemia may have seizures. These may μg/day). Other vitamin D metabolites (dihydrotachysterol,
be focal, jacksonian, petit mal, or grand mal in appearance, alfacalcidiol) are now used less frequently. Vitamin D defi-
indistinguishable from those that occur in the absence of hypo- ciency, however, is best treated using vitamin D supplemen-
calcemia. Patients may also have a type of seizure called cere- tation, with the dose depending on the severity of the deficit
bral tetany, which consists of generalized tetany followed by and the underlying cause. Thus, nutritional vitamin D defi-
tonic spasms. Therapy with standard anticonvulsants is inef- ciency generally responds to relatively low doses of vitamin
fective. In long-standing hypoparathyroidism, calcifications D, 50,000 U two or three times per week for several months,
may appear above the sella, representing deposits of calcium whereas vitamin D deficiency caused by malabsorption may
in and around small blood vessels of the basal ganglia, and require much higher doses (≥ 100,000 U/day).1 The treatment
may be associated with various extrapyramidal syndromes. goal is to bring serum calcium into the low-normal range and
Other common clinical signs of hypocalcemia include to avoid hypercalciuria, which may lead to nephrolithiasis.
clumsiness, depression, muscle stiffness, paresthesias, dry
Perioperative Considerations
scaly skin, brittle nails, coarse hair, and soft tissue calcifica-
Patients with Hypoparathyroidism. Because treatment of
tions. Patients with long-standing hypoparathyroidism some-
hypoparathyroidism is not surgical, hypoparathyroid patients
times adapt to the condition well enough to be asymptomatic.
require surgery for an unrelated condition. Their calcium, phos-
The symptoms related to tetany seem to correlate best with
phate, and magnesium levels should be measured both pre-
the level of the ionized calcium. If alkalosis is present, the total
operatively and postoperatively. Patients with symptomatic
calcium level may be normal, but the ionized calcium may be
hypocalcemia should be treated with IV calcium gluconate before
low. This can result in symptoms of neuromuscular irritabil-
surgery, as previously detailed. Initially, 10 to 20 mL of 10% cal-
ity (i.e., hyperventilation syndrome). With slowly developing
cium gluconate may be given at a rate of 10 mL/min. The effect on
chronic hypocalcemia, the symptoms may be very mild despite
serum calcium levels is of short duration, but a continuous infu-
severe hypocalcemia, which may partly result from adaptive
sion with 10 mL of 10% calcium gluconate in 500 mL of solution
changes in the level of the ionized calcium. Even with calcium
over 6 hours may help to maintain adequate serum calcium levels.
levels of 6 to 7 mg/dL, minor muscle cramps, fatigue, and mild
The objective of therapy is to have symptoms under control
depression may be the only symptoms. Many patients with a
before surgery and anesthesia. In patients with chronic hypo-
calcium level of 6 to 6.5 mg/dL are asymptomatic aside from
parathyroidism, the objective is to maintain the serum calcium
some mild depression of intellectual function.
level in at least the lower half of the normal range. A preopera-
Management. The approach to treatment of patient with tive electrocardiogram (ECG) can be obtained and the QTc
hypocalcemia depends on the rate of decline and clinical pre- interval calculated. The QTc value may be used as a guide to
sentation. For example, seizure and laryngospasm require the serum calcium level if a rapid laboratory assessment is not
acute treatment. Acute, symptomatic hypocalcemia is initially possible. The choice of anesthetic agents or techniques does
managed with calcium gluconate, 10 mL 10% wt/vol (90 mg or not appear to influence outcome, with the exception of avoid-
2.2 mmol) IV, diluted in 50 mL of 5% dextrose or 0.9% sodium ance of respiratory alkalosis, because this tends to decrease
chloride, IV over 5 minutes. Continuing hypocalcemia often ionized calcium levels further.
requires a constant IV infusion (typically 10 ampules of cal-
Patients with DiGeorge Syndrome. These patients can
cium gluconate or 900 mg of calcium in 1 L of 5% dextrose or
have congenital thymic hypoplasia and hypoparathyroidism;
0.9% NaCl administered over 24 hours). Accompanying hypo-
associated anomalies are usually vascular, such as tetralogy
magnesemia, if present, should be treated with appropriate
of Fallot, persistent truncus arteriosus, or right aortic arch.
magnesium supplementation (Box 13-2).
Furthermore, airway abnormality and compression of the
trachea by abnormal vessels are possibilities. Thorough pre-
operative workup to rule out lower airway abnormalities and
BOX 13-2 n MANAGEMENT OF HYPOCALCEMIA cardiovascular anomalies is warranted before elective surgery.
Acute Treatment These patients are also prone to sepsis caused by depressed
10% calcium gluconate over 5 minutes, then IV calcium gluconate cellular immunity, so leukocyte-depleted, irradiated blood is
infusion of 900 mg over 24 hours indicated for such patients.26
Chronic Therapy
Calcium supplements
Vitamin D supplements in large doses
THYROID GLAND
Anesthetic Considerations Thyroidectomy is typically performed (1) to treat benign and
Correct electrolyte imbalance: calcium, phosphate, and magnesium malignant thyroid tumors or establish definitive diagnosis of a
thyroid nodule; (2) to alleviate pressure symptoms or respiratory
difficulties associated with a benign or malignant process (e.g., almost all emergency situations, and certainly in all elective
large or substernal goiters); or (3) as therapy for hyperthyroid- situations, stabilization of any endocrine abnormality affect-
ism (thyrotoxicosis) in some patients, both those with Graves' ing the patient's preoperative state may improve outcome.27-29
disease and others with hot nodules. Thyroid tumors can be
part of rare familial syndromes such as phosphatase and tensin
Physiology
homolog (PTEN) hamartoma tumor syndrome, familial ade-
nomatous polyposis syndrome, Carney's complex, Pendred's Thyroid hormone biosynthesis involves five steps30,31:
syndrome, and Werner's syndrome (Table 13-2). (1) iodide trapping, (2) oxidation of iodide and iodination of
As with other endocrinopathies, two themes guide anes- tyrosine residues, (3) hormone storage in the colloid of the
thesia for patients with thyroid disease. First, the organ system thyroid gland as part of the large thyroglobulin molecule,
that most influences the anesthetic management of patients (4) proteolysis and release of hormones, and (5) conversion
with endocrinopathy is the cardiovascular system. Second, in of less active prohormone thyroxine (T4) to the more potent
3,5,3-tri-iodothyronine (T3). The first four steps are regulated
by pituitary thyroid-stimulating hormone (TSH, thyrotropin).
TABLE 13-2 n Syndromes Associated with Thyroid Proteolysis of stored hormone in the colloid is inhibited by
Gland Tumors iodide (Fig. 13-4).
The major thyroid products are the prohormone T4, a
Syndrome Clinical Features product of the thyroid gland, and T3, a product of both the
MEN-IIB Pheochromocytoma thyroid and the extrathyroidal enzymatic deiodination of
Mucosal neuromas T4. Approximately 85% of T3 is produced outside the thy-
Ganglioneuromatosis of intestine roid gland. Production of thyroid hormones is maintained by
Marfanoid habitus
secretion of TSH by the pituitary gland, which in turn is reg-
Carney's complex Mucocutaneous pigmented lesion ulated by secretion of thyrotropin-releasing hormone (TRH)
(syndrome, triad) Myxomas in the hypothalamus. The production of thyroid hormone is
Multiple thyroid follicular adenomas
Primary pigmented nodular
adrenocortical disease
Pituitary growth hormone-producing
adenoma Hypothalamus

PTEN hamartoma tumor Multiple adenomatous nodules
syndrome Lymphocytic thyroiditis ?
Familial adenomatous Papillary thyroid carcinoma TSH (short feedback)

polyposis syndrome Adrenal adenomas
?
Colon polyps
Desmoid tumors
Osteomas TRF
Hepatoblastomas
Retinal pigmented epithelial
hypertrophy
Anterior
Pendred's syndrome Thyroid goiter
Thyrotroph pituitary
Bilateral sensorineural hearing loss
Werner's syndrome Papillary thyroid carcinoma
Follicular thyroid carcinoma
Anaplastic thyroid carcinoma T4 T3 TSH
Premature aging
Skin atrophy
Bilateral cataracts
Cowden's disease Thyroid cancer Thyroid

(multiple hamartoma Breast cancer gland
syndrome) Hamartomas
Uterine leiomyoma
Megacephaly T4, T3
Thyroid adenoma
Benign breast disease
Mucocutaneous lesions
Endometrial carcinoma
Lhermitte-Duclos disease FIGURE 13-4 Hypothalamic-pituitary-thyroid axis. TSH,
Thyroid-stimulating hormone (thyrotropin); TRF, thyrotropin-
PTEN, Phosphatase and tensin homolog gene. releasing hormone.
initiated by absorption of iodine from the GI tract, where the significant changes in TSH secretions. Most of the T4 is bound
iodine is reduced to an iodide and released into plasma. It is to the plasma protein TBG; changes in TBG can affect the
then concentrated up to 500-fold by the thyroid gland. total T4 level. Estrogens, infectious hepatitis, and genetic fac-
Once in the gland, the iodide is oxidized by a peroxidase tors can elevate TBG level and thus secondarily raise total T4.
to iodine (organification) and then bound to tyrosine, form- Androgens, nephrosis, hypoproteinemia, and genetic factors
ing either monoiodotyrosine or di-iodotyrosine. Both these can lower TBG and thus secondarily lower total T4. Thus, it is
are then coupled enzymatically to form T4 or T3. The T3 and more important to know the value of free T4 and free T3. The
T4 are bound to the protein thyroglobulin and stored as col- normal level of TSH is 0.4 to 5.0 mU/L. A TSH level of 0.1 to
loid in the gland. A proteolytic enzyme releases T3 and T4 from 0.4 with normal levels of free T3 and free T4 is diagnostic of
the thyroglobulin as the prohormones pass from the cell to the subclinical hyperthyroidism. A TSH level less than 0.03 mU/L
plasma. T3 and T4 are transported through the bloodstream on with elevated T3 and T4 is diagnostic of overt hyperthyroidism.
thyroxine-binding globulin (TBG) and thyroxine-binding pre- Overt hypothyroidism is diagnosed if TSH levels are more
albumin. The plasma normally contains 4 to 11 μg of T4 and than 20 mU/L (even as high as 200-400 mU/L) with reduced
0.1 to 0.2 μg of T3 per deciliter (dL; 100 mL). Secretion of TSH levels of T3 and T4. Subclinical hypothyroidism is defined by
and TRH appears to be regulated by T3 in a negative feedback TSH levels in the range of 5 to 10 mU/L, with normal levels of
loop. Most of the effects of thyroid hormones are mediated by free T3 and free T4.34 Ultrasound, radioactive iodine uptake,
T3; again, T4 is both less potent and more protein bound, thus magnetic resonance imaging (MRI), and thin-slice computed
having lesser biologic effect, and is considered a prohormone.26 tomography (CT) thyroid scan can be useful in the diagnosis
In peripheral tissues there exists a ubiquitous deiodinase and management of thyroid masses. Functioning thyroid nod-
that converts T4 to T3. Thus, T4 appears to be a prohormone ules are rarely malignant, whereas “cold” or hypofunctioning
for T3. Monodeiodination can remove either the iodine at the nodules have a greater probability of malignancy.
5′ position to yield T3 or the iodine at the 5 position to yield The diagnosis of pituitary or hypothalamic disease can be
reverse T3 (rT3), which is totally inactive biologically. In gen- complicated. The procedure is often aided by the use of TRH.
eral, when T3 levels are depressed, rT3 levels are elevated. In This tripeptide is the hypothalamic factor that brings about
several situations, rT3 levels are increased, such as during ges- release of TSH from the pituitary. It may also be used to con-
tation, malnutrition, chronic disease, and surgical stress.32 firm the diagnosis of hyperthyroidism. Thyroid antibodies
A feedback circuit exists between the pituitary gland and the (antithyroglobulin and antimicrosomal) are useful in arriving
circulating thyroid hormones. High levels of thyroid hor- at the diagnosis of Hashimoto's thyroiditis. Serum thyroglob-
mones reduce release of pituitary TSH, whereas low levels ulin levels tend to be elevated in patients with thyrotoxicosis.
result in more TSH release (see Fig. 13-4). Painless thyroiditis is associated with transient hyperthyroid-
Energy-dependent transport systems move T3 across the itis. Measurement of the α subunit of TSH has been helpful in
target cell membrane into the cytoplasm. It then diffuses to identifying the rare patients who have a pituitary neoplasm and
receptors in the cell nucleus, where its binding to high-affinity who usually have increased α-subunit concentrations. Some
nuclear receptors (TRα and TRβ) alters the production of spe- patients are clinically euthyroid in the presence of elevated
cific messenger ribonucleic acid (mRNA) sequences, resulting levels of total T4 in serum. Certain drugs, notably gallbladder
in physiologic effects. Thyroid hormone has anabolic effects, dyes, corticosteroids, and amiodarone, block the conversion to
promotes growth, and advances normal brain and organ T3 to T4, thus elevating T4 levels. Severe illness also slows the
development. Thyroid hormone also increases the concentra- conversion of T4 to T3. Levels of TSH are often high when the
tion of adrenergic receptors,33 which may account for many rate of this conversion is decreased. In hyperthyroidism, car-
of its cardiovascular effects. They also bind to specific target diac function and responses to stress are abnormal; the return
genes that code for structural and regulatory proteins (myosin, of normal cardiac function parallels the return of TSH levels
β-receptors, Ca++-activated adenosine triphosphatase, phos- to normal values.
pholamban) and for calcium, sodium, and potassium chan-
nels in the heart, which are important for systolic contractile
Hyperthyroidism
function and diastolic relaxation.
Before undertaking surgery on the thyroid gland, it is Hyperthyroidism is usually caused by multinodular diffuse
important to know its functional status. Hyperthyroidism and enlargement of the gland, as in Graves' disease, which is also
hypothyroidism both have significant preoperative implica- associated with disorders of the skin and eyes. Hyperthyroidism
tions. Furthermore, imaging studies are undertaken to delin- may be associated with pregnancy, thyroiditis (with or with-
eate the anatomy of the gland, determine if other structures out neck pain), thyroid adenoma, choriocarcinoma, or TSH-
are involved, and plan the best possible surgical management. secreting pituitary adenoma (Fig. 13-5).
Major manifestations of hyperthyroidism are weight loss,
Thyroid Function Tests diarrhea, warm moist skin, weakness of large muscle groups,
The current generation of the TSH assay is very sensitive and menstrual abnormalities, nervousness, intolerance of heat,
now considered the single best test of thyroid hormone action tachycardia, cardiac dysrhythmias, mitral valve prolapse, and
at the cellular level. Small changes in thyroid function cause heart failure. When the thyroid is functioning abnormally, the
Causes of thyrotoxicosis
Primary Thyrotoxicosis without Secondary

hyperthyroidism hyperthyroidism hyperthyroidism
Graves’ disease Subacute TSH-secreting

thyroiditis pituitary adenoma
Toxic multinodular
goiter Silent Thyroid hormone
thyroiditis resistance syndrome;
Toxic adenoma occasional patients may
Amiodarone, have features of
Functioning thyroid radiation, thyrotoxicosis
carcinoma metastases infarction of adenoma
Chorionic
Activating mutation Ingestion of excess gonadotropin-
of the TSH receptor thyroid hormone secreting tumors
(thyrotoxicosis factitia)
Activating mutation or thyroid tissue Gestational
of Gs (McCune-Albright thyrotoxicosis
syndrome)
Struma ovarii
Drugs: iodine excess

(Jod-Basedow phenomenon)
FIGURE 13-5 Causes of hyperthyroidism (thyrotoxicosis). Jod-Basedow, iodine-induced hyperthyroidism.
cardiovascular system is most threatened. Severe diarrhea can Preparation of Hyperthyroid Patient for Elective Surgery
lead to dehydration, which can be corrected before surgery. A number of patients refuse radioactive iodine treatment and
Mild anemia, thrombocytopenia, increased serum alkaline undergo surgery for hyperthyroidism. However, it is impor-
phosphatase, hypercalcemia, muscle wasting, and bone loss tant to make these patients euthyroid before surgery. Typical
frequently occur in patients with hyperthyroidism. treatment for hyperthyroidism includes the antithyroid drug
Muscle disease usually involves proximal muscle groups; methimazole or propylthiouracil (PTU). These drugs inhibit
hyperthyroidism has not been reported to cause respiratory both thyroid hormone synthesis and the peripheral conversion
paralysis. In the “apathetic” form of hyperthyroidism, seen of T4 to T3. A usual dose takes full effect in about 6 to 8 weeks,
most often in persons over age 60, cardiac effects dominate although it may take much longer in a patient with a large thy-
the clinical picture.35,36 The signs and symptoms include tachy- roid gland. About 10 days before surgery, the patient typically
cardia, irregular heartbeat, atrial fibrillation, heart failure, and receives a potassium iodide saturated solution (3 drops three
occasionally, papillary muscle dysfunction. Atrial fibrillation times daily) to decrease gland vascularity and block release of
of unknown origin is a special concern in patients with apa- stored hormone. A β-blocker, typically propranolol, is added
thetic hyperthyroidism because “thyroid storm” can occur to control adrenergic symptoms31 (Box 13-3).
when they have surgery for other diseases.
Although β-adrenergic receptor blockade can con- BOX 13-3 n MANAGEMENT OF HYPERTHYROIDISM
trol heart rate, its use is fraught with hazards in a patient
already experiencing CHF. However, decreasing heart rate Treat with antithyroid medication (e.g., methimazole, propylthiouracil/
PTU) for 6-8 weeks.
may improve the cardiac pump function. Thus, hyperthy- Prescribe potassium iodide, 3 drops three times daily for 10 days
roid patients who have high ventricular rates, who have CHF, before surgery.
and who require emergency surgery are given propranolol in Treat sympathetic symptoms with beta-adrenergic blockers
doses guided by changes in pulmonary artery wedge pressure (e.g., propranolol).
and the overall clinical condition. If slowing the heart rate Anesthetic Considerations
with a small dose of esmolol (50 μg/kg) does not aggravate Ensure patient is euthyroid before elective surgery.
heart failure, additional esmolol (50-500 μg/kg) is adminis- Correct hypovolemia.
Correct electrolyte abnormalities.
tered. The aim is to avoid imposing surgery on any patient
Treat sympathetic symptoms with β-blockers (e.g., propranolol,
whose thyroid function is clinically abnormal. Therefore, esmolol).
only “life or death” emergency surgery should preclude mak- Monitor for cardiac failure and cardiac arrhythmias.
ing the patient pharmacologically euthyroid, a process that Patient may require glucocorticoids and active cooling.
can take 2 to 6 weeks.
If the clinical situation demands, preoperative preparation often sufficient. Chronic use of iodide in the mother is usually
with propranolol and iodides can yield comparable results.37-39 contraindicated because fetal goiter and hypothyroidism may
This approach is less time-consuming than methimazole/PTU result. The use of propranolol during pregnancy is controver-
therapy (7-14 days vs. 6-8 weeks); it causes the thyroid gland sial, with case reports of intrauterine growth retardation and
to shrink, as does the more traditional approach; and it treats low Apgar score in infants whose mothers received proprano-
symptoms, but abnormalities in left ventricular function may lol. Bradycardia and hypoglycemia also have been described
not be corrected.38,39 Regardless of the approach used, antithy- in these infants.
roid drugs should be administered both chronically and on The thyrotoxicosis of pregnancy tends to be mild and often
the morning of surgery. improves in the second and third trimesters. Surgery is an
If emergency surgery is necessary before the euthyroid acceptable alternative to treatment, usually postponed until
state is achieved, or if the hyperthyroidism is not well con- neural development and organogenesis of the first trimester
trolled during surgery, 50 to 500 μg/kg of IV esmolol can be are complete. After pregnancy, it is impossible to predict the
titrated for restoration of a normal heart rate (assuming that thyroid status of the mother. Whereas some patients remain
CHF is absent; see previous discussion). Larger doses may hyperthyroid, some become hypothyroid after delivery.
be required, and in the absence of better data, the return of A reported 5% of women have transient thyrotoxic effects 3 to
a normal heart rate and the absence of CHF serve as guides 6 months postpartum and tend to have recurrences with sub-
to therapy. In addition, intravascular fluid volume and elec- sequent pregnancies.44
trolyte balance should be restored. Importantly, administering The status of the neonate after delivery needs attention.
propranolol may not prevent “thyroid storm.”40 Either hypothyroidism or hyperthyroidism may be present.
Neonatal hypothyroidism is characterized by a low total T4
Thyroid Storm
(< 7 μg/dL) and an elevated TSH. At times the T4 may be per-
Thyroid storm refers to the clinical diagnosis of a life-threatening
fectly normal, with only the TSH elevated. Amniotic fluid
illness in a patient whose hyperthyroidism has been severely
rT3 levels tend to be low in the hypothyroid fetus in the third
exacerbated by illness or surgery. Mortality results from car-
trimester, and likewise, serum rT3 concentration is low after
diac failure, arrhythmia, or hyperthermia and is as high as
birth if hypothyroidism exists.
30% even with treatment. Thyroid storm manifests with
Management of neonatal hypothyroidism consists of the
hyperpyrexia, tachycardia, and striking alterations in con-
immediate replacement with l-thyroxine in the range of 9 μg/
sciousness.40,41 No laboratory tests are diagnostic of thyroid
kg/day. This dose is relatively large but often required to nor-
storm, and the precipitating (nonthyroidal) cause is the major
malize the TSH level and T4 concentration. Normally, total T4
determinant of survival. Therapy usually includes blocking
level (8-15 μg/dL) tends to be high in the first year of life, then
the synthesis of thyroid hormones by administration of anti-
slowly but progressively drops until after puberty. Likewise,
thyroid drugs, blocking release of preformed hormone with
thyroid hormone replacement doses tend to be higher than in
iodine, meticulous attention to hydration and supportive
the average adult until puberty is complete.
therapy, and correction of the precipitating cause. Survival is
Neonatal hyperthyroidism is unusual and always associ-
directly related to the success of treatment of the underlying
ated with high levels of thyroid-stimulating immunoglobu-
cause. Blocking of the sympathetic nervous system with α-
lins. These immunoglobulins cross the placental barrier and
and β-receptor antagonists may be exceedingly hazardous and
are probably the cause of fetal hyperthyroidism; therefore they
requires skillful management and constant monitoring of the
are usually measured in thyrotoxic women in the third trimes-
critically ill patient. Additional therapeutic measures include
ter. Controlling maternal hyperthyroidism seems to prevent
use of glucocorticoids, treatment of the underlying precipitat-
the development of hyperthyroidism in infants.
ing event (infection), IV fluids, and active cooling.
Management of Thyrotoxicosis during Pregnancy Amiodarone and Thyroid Function
The management of the thyrotoxicosis of Graves' dis- Depending on the iodine intake, up to 13% of patients
ease during pregnancy presents some special problems.42,43 treated with the antiarrhythmic amiodarone develop thyroid
Radioactive iodine therapy is usually considered contraindi- dysfunction, either hyperthyroidism or hypothyroidism.29
cated because it crosses the placenta. The physician's choice Approximately 39% of the drug's weight is iodine, and a 200-
is between antithyroid drugs and surgery. Antithyroid drugs mg tablet releases about 20 times the optimal daily dose of
also cross the placental barrier and can cause fetal hypothy- iodine. This iodine can lead to reduced synthesis of thyrox-
roidism. This problem may theoretically be obviated by the ine or to increased synthesis. In addition, amiodarone inhib-
simultaneous administration of l-thyroxine or T3. However, its the conversion of T4 into the more potent T3. Patients
most of the evidence indicates that neither T4 nor T3 crosses receiving amiodarone may require special attention preop-
the placental barrier. The occurrence of fetal hypothyroid- eratively to ensure no perioperative dysfunction exists, or
ism when small doses of antithyroid drugs alone are used is unsuspected thyroid hyperfunction or hypofunction. Many
unusual as long as the mother remains euthyroid. It is typi- patients with amiodarone thyrotoxicosis receive corticoste-
cally better to err on the side of undertreatment than over- roids for a time, so the anesthesiologist should determine if
treatment with antithyroid drugs. Small amounts of PTU are steroids were used.
Usually, symptoms of hypothyroidism are subclinical,

Hypothyroidism
with serum concentrations of thyroid hormones in the nor-
Hypothyroidism is a common disease. The apathy and leth- mal range and only serum TSH levels elevated.30,45,46 In the
argy that often accompany hypothyroidism often delay its less frequent cases of overt hypothyroidism, the deficiency
diagnosis, so it may be detected the first time in the periop- of thyroid hormone results in slow mental functioning, slow
erative period. Usually, hypothyroidism is subclinical; serum movement, dry skin, intolerance to cold, depression of the
concentrations of thyroid hormones are in the normal range, ventilatory responses to hypoxia and hypercarbia,47 impaired
and only serum TSH levels are elevated (5-15 mU/L).45,46 In clearance of free water, slow gastric emptying, and brady-
such cases, hypothyroidism may have minimal or no periop- cardia. In extreme cases, cardiomegaly, heart failure, and
erative significance. pericardial and pleural effusions are manifested as fatigue,
Hypofunction of the thyroid gland can be caused by surgi- dyspnea, and orthopnea.48 Hypothyroidism is often associ-
cal ablation, radioactive iodine administration, irradiation to ated with amyloidosis, which may cause enlargement of the
the neck (e.g., for Hodgkin's disease), iodine deficiency or toxic- tongue, abnormalities of the cardiac conduction system, and
ity, genetic biosynthetic defects in thyroid hormone production, renal disease. The tongue may be enlarged in the hypothy-
antithyroid drugs (e.g., PTU), amiodarone pituitary tumors, roid patient even in the absence of amyloidosis, and this may
or hypothalamic disease (Fig. 13-6). The most common cause hamper intubation.49
of primary thyroid hypofunction may be a form of thyroiditis, Full-blown myxedema presents as a variety of symp-
often chronic lymphocytic thyroiditis, or Hashimoto's disease toms, including cold intolerance, apathy, hoarseness, con-
(Hashimoto's thyroiditis). The thyroid is usually enlarged, non- stipation, impaired movement, anemia, hearing loss, and
tender, and extremely firm and indurated. A variety of antithyroid bradycardia. Myxedema coma is a rare complication associ-
antibodies are found in the serum, including antithyroglobulin ated with profound hypothyroidism and extreme lethargy,
and antimicrosomal antibodies in high titer. Hypothyroidism severe hypothermia, bradycardia, and alveolar hypoventila-
seems to be the most common consequence of Hashimoto's dis- tion with hypoxia and occasionally accompanied by peri-
ease; indeed, it is the most common cause of hypothyroidism cardial effusion and CHF. Hyponatremia associated with
in adults.46 Patients with Hashimoto's thyroiditis are extremely marked decrease in free-water clearance by the kidney is
susceptible to iodides and to antithyroid drugs, and overt severe also often part of the syndrome. This is the only indication
hypothyroidism can be exacerbated by these maneuvers. for IV T4 therapy.
Causes of hypothyroidism
Primary Transient Secondary

Autoimmune hypothyroidism: Silent thyroiditis, Hypopituitarism:
Hashimoto’s thyroiditis, including postpartum Tumors, pituitary surgery, or irradiation
atrophic thyroiditis thyroiditis Infiltrative disorders
Sheehan’s syndrome
Iatrogenic: Subacute thyroiditis Trauma
131ltreatment, Genetic forms of combined
subtotal or total thyroidectomy, Withdrawal of thyroxine pituitary hormone deficiencies
external irradiation of neck treatment in individuals with
an intact thyroid after Isolated TSH deficiency
131I treatment or
Drugs: or inactivity
iodine-containing subtotal thyroidectomy
contrast media, amiodarone, for Graves’ disease Bexarotene treatment
lithium, antithyroid drugs,
p-aminosalicylic acid, Hypothalamic disease:
interferon, and other cytokines, Tumors, trauma
aminoglutethimide, sunitinib Infiltrative disorders
Idiopathic
Congenital hypothyroidism:
absent or ectopic thyroid gland,
dyshormonogenesis, TSH-R mutation
Iodine deficiency
Infiltrative disorders:
amyloidosis, sarcoidosis,
hemochromatosis, scleroderma,
cystinosis, Riedel’s thyroiditis
FIGURE 13-6 Causes of hypothyroidism.
Preparation of Hypothyroid Patient for Surgery there is a need to consider “truly” emergency coronary artery
Hypothyroidism decreases anesthetic requirements. Ideal pre- revascularization in patients who have both severe CAD and
operative management of the hypothyroid patient consists significant hypothyroidism.
of restoring euthyroid status; the normal dose of T3 or T4 is In the presence of hypothyroidism, respiratory control mech-
administered on the morning of surgery, even though these anisms do not function normally.48 However, the response to
drugs have long half-life (1.4-10 days). The usual daily replace- hypoxia and hypercarbia and the clearance of free water nor-
ment dose in adults is 0.1 to 0.2 mg of l-thyroxine (Synthroid). malize with thyroid replacement therapy. Drug metabolism was
The T4 level itself can be used as a guide to therapy. Both T4 slowed in anecdotal reports, and awakening times after admin-
and TSH serum levels are usually in the normal range in ade- istration of sedatives were prolonged during hypothyroidism.
quately treated patients. These concerns disappear when thyroid function is normalized
For patients in myxedema coma who require emergency preoperatively. Addison's disease (with its relative steroid defi-
surgery, T3 or T4 can be given IV (with the risk of precipitating ciency) is more common in hypothyroid than in euthyroid indi-
myocardial ischemia) while supportive therapy is undertaken viduals, and some endocrinologists routinely treat patients who
to restore normal intravascular fluid volume, body tempera- have noniatrogenic hypothyroidism by giving stress doses of
ture, cardiac function, respiratory function, and electrolyte corticosteroids perioperatively. This steroid deficiency should be
balance. l-Thyroxine is given in a single IV dose of 300 to 500 considered if the patient becomes hypotensive perioperatively.
μg. IV T3 liothyronine may also be given in the dose range of
25 to 50 μg every 8 hours until the blood level of T3 is nor-
mal. Intravenous T3 is probably superior to IV T4 because T3
Thyroid Nodules and Carcinoma
is the most physiologically active thyroid hormone therapy Thyroid carcinoma is the most common malignancy of the
and bypasses the normal conversion pathway, which usually endocrine system. Based on the staging, many patients would
is greatly depressed in patients with serious systemic illnesses undergo total or partial thyroidectomy. Papillary carcinoma
(Box 13-4). accounts for more than 70% of all carcinomas. Simple excision
of lymph node metastases appears to be as efficacious for patient
Hypothyroid Patients with Coronary Artery Disease survival as radical neck procedures.51 Medullary carcinoma is
Treating hypothyroid patients who have symptomatic coro- the most aggressive form of thyroid carcinoma, accounting for
nary artery disease (CAD) poses special problems and may 5% to 10% of all thyroid cancers, and is associated with a famil-
require compromises in the general practice of preoperatively ial incidence of pheochromocytoma, as are parathyroid adeno-
restoring euthyroidism with drugs. Although both T4 and mas. For this reason, a history should be obtained for patients
esmolol may be given, adequate amelioration of both ischemic who have a surgical scar in the thyroid and parathyroid region,
heart disease and hypothyroidism may be difficult to achieve. to rule out the possibility of occult pheochromocytoma.
The need for thyroid therapy must be balanced against the risk
of aggravating anginal symptoms. One review suggests early
consideration of coronary artery revascularization.50 It advo-
cates initiating thyroid replacement therapy in the intensive The major considerations regarding anesthesia for patients
care unit (ICU) soon after the patient's arrival from the operat- with thyroid disorders are (1) attainment of a euthyroid state
ing room after myocardial revascularization surgery. However, preoperatively, (2) preoperative preparation and attention to
several deaths from dysrhythmias and CHF, as well as cardio- the characteristics of the diseases mentioned previously, and
genic shock with infarction, have occurred while patients who (3) normalization of cardiovascular function and temperature
were not given thyroid therapy were awaiting surgery. Thus, perioperatively.
No controlled study has demonstrated clinical advantages
of any one anesthetic drug over another for surgical patients
BOX 13-4 n MANAGEMENT OF HYPOTHYROIDISM who are hypothyroid. Thus, no data on human subjects imply
(MYXEDEMA COMA) that the choice of anesthetic affects patient outcome in the
Treat with l-thyroxine (300-500 μg) or intravenous T3 (25-50 μg) every
presence of thyroid disease. Some recommend avoiding anti-
8 hours until T3 level is normal. cholinergic drugs (especially atropine) because they interfere
Monitor for cardiac ischemia. with the sweating mechanism and cause tachycardia.
Patient may require stress-dose steroids. A patient who has a large goiter and an obstructed air-
Anesthetic Considerations way can be treated as would any patient whose airway man-
Consider surgery only in emergency situations. agement is problematic. Preoperative medication need not
Large tongue may create difficult airway. include “deep” sedation, and an airway can be established,
Decrease dose of anesthetics, opioids, and benzodiazepines;
often with the patient awake. A firm, armored endotracheal
hypothyroid patients are sensitive to these agents.
Correct intravascular volume. tube is preferable and should be passed beyond the point of
Correct electrolyte imbalance. extrinsic compression. It is most useful to examine CT, MRI,
Correct hypothermia. or ultrasound scans of the neck preoperatively to determine
the extent of compression.
Maintenance of anesthesia usually presents little diffi- factors are synthesized in the hypothalamus, are secreted into the
culty. Body heat mechanisms are inadequate in hypothyroid portal system, and reach the anterior pituitary in extremely high
patients, and temperature can be monitored and maintained, concentrations. Functional activity in the posterior pituitary
especially in patients who require emergency surgery before depends on specialized neurons in the hypothalamus that syn-
the euthyroid state is attained. Because incidence of myasthe- thesize vasopressin (ADH) and oxytocin. These two hormones
nia gravis is increased in hyperthyroid patients, a twitch moni- are then secreted through specialized axons down the stalk of the
tor to guide muscle relaxant administration may be advisable. pituitary and are stored in the posterior pituitary gland.
Postoperatively, extubation should be performed under Each pituitary hormone has a specific releasing factor asso-
optimal circumstances for reintubation, in case the tracheal ciated with it, as well as a specific inhibitory factor in some
rings have been weakened and the trachea collapses. Possible cases. Specific hypothalamic-releasing hormones have been
postoperative complications are those for hyperparathyroid- defined for TSH, adrenocorticotropic hormone (ACTH),
ism (see earlier). and the gonadotropins (both luteinizing hormone [LH] and
follicle-stimulating hormone [FSH]). Both a releasing and
an inhibitory hypothalamic factor have been discovered for
PITUITARY GLAND
growth hormone (GH). Prolactin is primarily associated with
Tumors involving the pituitary gland are rare. The exact inci- an inhibitory hypothalamic factor, probably the neurotrans-
dence is not known, although with recent advances in brain mitter dopamine. Generally there is no overlap in function of
imaging, more asymptomatic pituitary adenomas are being the hypothalamic hormones, except for the positive effect of
discovered. By some estimates the incidence of pituitary ade- TRH on both TSH and prolactin secretion. In disease states
nomas is three to five times higher than previously reported.52 such as acromegaly, however, both somatotropin-releasing
Although most pituitary adenomas are sporadic, approximately factor and thyrotropin-releasing factor can bring about release
5% of all cases occur in a familial setting, and more than half of of GH. In the normal state, this would not occur. An addi-
these are caused by MEN-1 and Carney's complex. A non- tional factor involving hypothalamic control of the pituitary is
MEN-I/Carney's disorder called familial isolated pituitary ade- the pulsatile periodic operation of the hypothalamus. Probably
noma (FIPA) syndrome is also described52 (Table 13-3). As in the most important biologic rhythm is the sleep or light-dark
other endocrine disorders, surgical intervention is undertaken pattern; for example, GH and ACTH show specific nocturnal
to treat a hyperfunctioning gland or cancer or to alleviate mass bursts in males. Prolactin also tends to increase in concentra-
effect. Pituitary adenomas constitute 5% to 20% of the primary tion in the blood immediately after sleep begins. LH shows a
central nervous system (CNS) tumors. sleep pattern especially during puberty.
The three monoamine neurotransmitters—dopamine, nor-
epinephrine, and serotonin—can profoundly affect hypotha-
Physiology
lamic function and are found in high concentration in major
The pituitary gland is divided into anterior and posterior por- hypothalamic centers. There is essentially no blood-brain bar-
tions that have substantially different organization. The anterior rier in either the pituitary or the hypothalamus, and target
pituitary is connected to the hypothalamus through a complex organ products such as estrogen, testosterone, thyroid, and
portal vascular system. Hypothalamic releasing or inhibitory adrenal hormones can exert feedback at either the hypotha-
lamic or the pituitary level (Fig. 13-7).
TABLE 13-3 n Syndromes Associated with Pituitary

Gland Tumors Anterior Pituitary Disease: Hypopituitarism and
Hyperpituitarism
Syndrome Clinical Features
HYPOFUNCTION OF THE PITUITARY GLAND
MEN-I Primary hyperparathyroidism
Enteropancreatic tumors
All or several of the trophic hormones may be involved in
Pituitary tumors hypopituitary states. The causes of hypopituitarism can be
Thymic or bronchial endocrine tumors grouped into two broad pathophysiologic categories: those
Adrenocortical tumors that involve the pituitary gland and those caused by hypotha-
Carney's complex Mucocutaneous pigmented lesion lamic diseases (Fig. 13-8). Mass lesions that can cause hypo-
(syndrome) Myxomas pituitarism include pituitary adenomas, cysts, lymphocytic
Multiple thyroid follicular adenomas hypophysitis, metastatic cancer, and other lesions (e.g., chro-
Primary pigmented nodular mophobe adenoma, Rathke's pouch cysts, craniopharyngioma
adrenocortical disease
in children). Necrosis following circulatory collapse results
Pituitary growth hormone–producing
adenoma from hemorrhage after delivery (Sheehan's syndrome), surgi-
cal hypophysectomy, irradiation to the skull or brain, granu-
Familial isolated Early onset, aggressive tumor growth lomatous diseases, other infectious diseases, surgical or other
pituitary adenoma Prolactin-secreting tumor
(FIPA) Somatotropin tumors
trauma, and hemochromatosis.53-55 Metastatic disease (espe-
cially from breast cancer) is only rarely seen.
Input from internal Major causes of hypopituitarism

and external stimuli
Central
nervous Pituitary diseases Hypothalamic diseases
system
Biological clock
Mass lesions: Mass lesions:

Neural Hypothalamus
Pituitary adenomas Craniopharyngiomas
stimuli
Other benign tumors Metastatic
Cysts malignant tumors
Pituitary surgery Radiation:

CNS and
Pituitary radiation nasopharyngeal
Hypothalamic CRF MIF malignancies
Releasing factors LHRF Somatostatin Infiltrative lesions:
and GHRF PIF Lymphocytic Infiltrative lesions:
Inhibitory factors TRF hypophysitis Sarcoidosis
Hemochromatosis Langerhans cell
histiocytosis
Anterior Infarction
GH pituitary (Sheehan’s syndrome) Trauma:
Prolactin Fracture of the
MSH Apoplexy skull base
Genetic diseases: Infections:

Anterior pit-1 mutation Tuberculous
pituitary ACTH FSH FSH Estrogen meningitis
hormones LH
Thyroid FSH FIGURE 13-8 Major causes of hypopituitarism. CNS, Central
Cortisol hormones LH nervous system.
Destruction of the pituitary by tumor (i.e., chromophobe

Adrenals Thyroid Testis Ovary adenoma) is probably the most common cause of hypopituita-
Adrenal Testosterone rism. One third to one half of all patients with chromophobe
hormones Thyroid Estrogen adenoma secrete excessive quantities of prolactin. GH defi-
hormones Progesterone ciency in a child results in severe growth failure. Loss of TSH
Tissue metabolism or ACTH function usually occurs later in life, when variable
Other tissues and metabolic features related to thyroid deficiency or lack of cortisol inevi-
fuel (e.g., glucose)
tably manifest. If a tumor exists, it may grow above the sella
Excitatory response Inhibitory response
Known
turcica (suprasellar extension), and headaches and visual field
Suspected defects, notably bitemporal hemianopsia, will occur.
Genetic disorders of hypothalamopituitary development
Pituitary Hypothalamic
can lead to congenital hypopituitarism and single isolated defi-
hormone regulatory hormones ciencies of specific pituitary hormones (see Table 13-3). These
typically involve specific genes that are intricately involved in
Adrenocorticotropic Corticotropin-releasing factor hypothalamopituitary organogenesis. These disorders include
hormone (ACTH) (CRF)
septo-optic dysplasia, Kallmann's syndrome, Bardet-Biedl
Thyroid-stimulating Thyrotropin-releasing factor syndrome, and Prader-Willi syndrome. Septo-optic syndrome
hormone (TSH) (TRF) results from dysgenesis of septum pellucid or corpus callosum.
These children exhibit variable combinations of cleft palate,
Follicle-stimulating Gonadotropin-releasing factor
hormone (FSH) and (GHRF) syndactyly, ear deformities, hypertelorism, optic atrophy, and
luteinizing hormone anosmia. Well-known Kallmann's syndrome is associated with
(LH) gonadotropin deficiency related to loss of the sense of smell
Growth hormone Growth hormone−releasing factor (anosmia). The syndrome may also be associated with color
(GH) (GHRF), somatostatin (inhibitory) blindness, optic atrophy, nerve deafness, cleft palate, renal
abnormalities, and cryptorchidism. Bardet-Biedl (Laurence-
Prolactin Prolactin inhibitory factor Moon) syndrome is a rare genetic disorder characterized by
(PIF)
mental retardation, renal abnormalities, obesity, and hexadac-
FIGURE 13-7 Basic feedback mechanism: hypothalamic-pituitary- tyly. It is also associated with diabetes insipidus and growth
adrenal axis. hormone deficiency. Prader-Willi syndrome is associated
with hypogonadotropic hypogonadism, hyperphagia-obesity, greatly suppresses the GH level. A few patients with active acro-
chronic muscle hypotonia, mental retardation, and adult- megaly have normal levels of fasting GH that are not suppressed
onset diabetes mellitus. after glucose is administered. The drug l-dopa, which nor-
Biochemical diagnosis of pituitary insufficiency is made by mally increases GH in healthy subjects, either has no effect or
demonstrating low levels of trophic hormones in the setting of decreases GH levels in the acromegalic patient.
low target hormones. It is possible to measure virtually all the Therapy for acromegaly includes the options of pituitary
hormones of the anterior pituitary gland (GH, TSH, LH, FSH, irradiation (heavy particle or implants) and transsphenoidal
prolactin, ACTH). Low LH and FSH associated with estrogen hypophysectomy.60 If suprasellar extension exists, conventional
deficiency in a female patient or low testosterone in a male transfrontal hypophysectomy is often employed. Surgery is the
patient indicates a hypothalamic or pituitary deficiency, even preferred primary treatment. Medical treatment includes soma-
of ACTH. Low TSH with a low T4 also indicates either hypo- tostatin analogs (octreotide, lanreotide) or specific GH receptor
thalamic or pituitary deficiency. An elevated prolactin level is antagonists (e.g., pegvisomant).56 The dopaminergic agonist bro-
often associated with chromophobe adenomas. Provocative mocriptine or cabergoline can lower GH levels in some patients.
tests may be required to test pituitary reserve. Hypoglycemia
Prolactinomas
induced by insulin (0.1 unit/kg IV) can also be used to test not
Prolactin has been one of the most interesting markers for
only ACTH reserve but also GH reserve. Hypoglycemia (blood
identifying patients with pituitary tumors.54 Elevated prolac-
glucose concentration < 50 mg/dL) should result in significant
tin levels are often (but not invariably) associated with galac-
rises in both plasma cortisol and GH if the pituitary gland is
torrhea. Female patients typically have amenorrhea, and male
functioning normally. Failure of the plasma cortisol level to rise
patients have impotence. Therapy for prolactin-secreting
after IV insulin indicates that ACTH reserve is low.
tumors includes bromocriptine or cabergoline, which can be
However, evaluation of the hypothalamic-pituitary-adrenal
extremely effective in controlling prolactin level and restoring
(HPA) axis can be difficult. The metapyrone test has long been
gonadotropin function. However, in women considering preg-
a standard test for determination of the pituitary-adrenal axis.
nancy, the concern that pregnancy will cause rapid growth of
Metapyrone blocks the conversion of 11-deoxycortisol to cor-
these tumors may favor a surgical procedure.
tisol. Normally, 11-deoxycortisol is not measurable. A single
oral dose of metapyrone (3 g) is given at midnight, and plasma
cortisol and 11-deoxycortisol concentrations are measured ANESTHETIC CONSIDERATIONS
the following morning. If the 11-deoxycortisol level is greater In patients with abnormal anterior pituitary function, the basic
than 10 μg/mL, ACTH stimulation must have occurred, approach of rendering normal endocrine functions before sur-
and the patient has a normal pituitary-adrenal axis. If both gery holds for endocrine abnormalities originating in the pitu-
11-deoxycortisol and cortisol are low, this means that ACTH itary as well as in the end organ. The most common approach
was not stimulated and the patient has little or no ACTH pitu- for pituitary surgery is transsphenoidal hypophysectomy. For
itary reserve. The test can also be performed using the mea- the patient undergoing craniotomy, the appropriate concerns
surement of urinary 17-hydroxycorticoids while 750 mg of include provision of patent airway, adequate pulmonary ven-
metapyrone is given every 4 hours for six doses. tilation, control of circulating blood volume, inhibition of
increased brain size, and effective constant monitoring for
HYPERFUNCTION OF THE PITUITARY GLAND adverse complications associated with posture, anesthesia, and
There are three major hyperfunctioning pituitary gland surgery. Acromegalic patients can be difficult to intubate.60-62
tumors: (1) prolactin-secreting chromophobe adenoma, (2) an Premedication, use of anesthetic agents and techniques, and
ACTH-secreting tumor associated with Cushing's disease (see monitoring as indicated for pituitary procedures are essen-
Adrenal Cortex), and (3) acromegaly associated with exces- tially the same as for any craniotomy. The effects of anesthetic
sive GH secretion. Gonadotropin-secreting and thyrotropin- agents on secretion of pituitary hormones do not constitute
secreting pituitary tumors are extraordinarily rare. an important factor in the selection of perioperative anesthet-
Acromegaly
ics. Disorders arising from pituitary surgery include temper-
Acromegaly is a syndrome that presents as characteristic ature deregulation and abnormalities of endocrine function,
facies, weakness, enlargement of the hands (often rendering including the need for immediate treatment of steroid defi-
usual oximeter probes difficult to use) and feet, thickening of ciency, hypoglycemia, and excessive or deficient secretion of
the tongue (often making endotracheal intubation difficult), vasopressin, also called antidiuretic hormone (ADH).
and enlargement of the nose and mandible with spreading of
the teeth (often requiring larger-than-normal laryngoscope
Posterior Pituitary Disorders: Diabetes Insipidus
blades).56-59 The patient may even appear myxedematous. Other
and SIADH
findings include abnormal glucose tolerance, carpal tunnel syn-
drome, and osteoporosis. The most specific test for acromegaly DIABETES INSIPIDUS
is measurement of GH before and after glucose administration. Deficiency of arginine vasopressin (AVP) synthesis results
The typical acromegalic patient has elevated fasting levels of GH in diabetes insipidus (DI). Clinically, DI is characterized by
(usually > 10 mg/mL), and the levels do not change appreciably the excretion of a large volume of hypotonic urine, which in
after oral glucose is administered. In the normal state, glucose turn necessitates the intake of equally large amounts of fluid
or prevention of hyperosmolarity of body fluids and dehydra-

tion.63 The many causes of DI are broadly classified as central BOX 13-5 n MANAGEMENT OF DIABETES
INSIPIDUS (DI)
DI (pituitary DI, neurophyseal DI), nephrogenic DI, or primary
polydipsia. Each category is further classified into subcatego- Remove underlying cause.
ries. In central DI, AVP deficiency is caused by decreased AVP Central DI: Administer desmopressin (0.3 μg/kg) intravenously or
intranasally.
production, whereas nephrogenic resistance to AVP action is
Nephrogenic DI: Thiazide diuretic with low sodium diet.
seen in nephrogenic DI. Primary polydipsia refers to second- Primary polydipsia: Do not administer desmopressin (can cause water
ary deficiency of AVP resulting from inhibition of secretion by intoxication).
excessive fluid intake, caused by psychogenic factors or abnor-
mal thirst mechanisms. If desmopressin is administered, monitor serum osmolality.
A number of drugs have been shown to alter the release Administer isotonic fluids.
and action of ADH. The sulfonylurea agents, notably chlor-
propamide, have been shown to augment release of ADH and
are used in the treatment of patients with partial nephrogenic
DI. Likewise, clofibrate, carbamazepine (Tegretol), vincris- Nephrogenic DI is not affected by desmopressin. Thiazide
tine, and cyclophosphamide all either release ADH or potenti- diuretics in conjunction with low-sodium diet may be indi-
ate its action on the renal tubule. Ethanol as well as phenytoin cated for nephrogenic DI patients. Prostaglandin inhibitors are
(Dilantin) and chlorpromazine inhibit the action of ADH also effective in some patients. Desmopressin can be harmful
and its release. Lithium, a drug widely used to treat bipolar if used for the treatment of primary polydipsia and can pro-
(manic-depressive) disorders, can inhibit the formation of duce water intoxication within 24 to 48 hours. If DDAVP is
cyclic adenosine monophosphate (cAMP) in the renal tubule used preoperatively to treat DI, serum osmolality should be
and probably inhibits synthesis of ADH directly, thus resulting monitored (Box 13-5).
in a DI-like picture.
The classic test to distinguish patients with DI from com- HYPERSECRETION OF VASOPRESSIN (SIADH)
pulsive water drinkers and patients with nephrogenic DI is the Excessive secretion of AVP, known as the syndrome of inap-
water deprivation test.63 Following dehydration, DI patients propriate secretion of AVP (or of antidiuretic hormone,
can only minimally concentrate their urine. When the serum SIADH) is a disorder characterized by hyponatremia that
osmolarity rises to 295 mOsm/L (osmotic threshold), all nor- results from water retention, which in turn is caused by AVP
mal patients release vasopressin into the blood and concentrate release that is inappropriately high for the plasma osmolal-
their urine to conserve water. Simultaneous measurements of ity or serum sodium concentration.63 Because patients with
urine and plasma osmolarity are made as water deprivation SIADH are unable to excrete dilute urine, they retain ingested
continues. Once the urine and plasma osmolarity have stabi- fluids, and expansion of extracellular fluid volume with or
lized (usually with 3%-5% loss in body weight), the patient is without edema. The hallmark of SIADH is hyponatremia in
given an injection of vasopressin. If vasopressin is being maxi- the presence of urinary osmolality that is higher than plasma
mally secreted by the posterior pituitary, exogenous vasopres- osmolality.
sin will have no effect. The patient with vasopressin deficiency The most common cause of SIADH is production of ecto-
never quite reaches stable plasma osmolarity, and the urine pic AVP by neoplasms. The AVP produced by neoplasms is
osmolarity rarely rises much above 500 mOsm/L. Moreover, identical to the arginine vasopressin secreted by the normal
even after severe dehydration, exogenous vasopressin causes a neurohypophysis. The most common of the neoplasms pro-
significant increase in urine osmolarity only in patients with ducing AVP are small cell carcinomas of the lungs. SIADH
true DI. Thus, this sensitive test even distinguishes patients is also associated with various nonmalignant and inflam-
who have partial diabetes insipidus. matory conditions of the lungs and CNS. Any patient with
Compulsive water drinkers may at times present a diag- suspected SIADH should be screened for possible adrenal
nostic problem, because they often cannot concentrate their insufficiency or hypothyroidism. The diagnosis is essentially
urine well, and the water deprivation test must be carried out one of exclusion. A wide variety of drugs can cause hyperse-
until the osmotic threshold is reached. Tests employing hyper- cretion or augmentation of ADH and result in SIADH, most
tonic saline as a physiologic stimulus to ADH are cumbersome often chlorpropamide, clofibrate, psychotropics, thiazides,
and difficult to interpret. Adrenocortical insufficiency can and the antineoplastic agents vincristine, vinblastine, and
mask the polyuria of partial DI, because it lowers the osmotic cyclophosphamide.
threshold for vasopressin release. Institution of corticosteroid Most of the clinical features associated with SIADH are
therapy in such patients unmasks the diabetes insipidus, and related to hyponatremia and the resulting brain edema; these
severe polyuria may result. features include weight gain, weakness, lethargy, mental con-
The treatment of DI usually consists of replacement of fusion, obtundation, and disordered reflexes, which may prog-
AVP. Desmopressin (1-deamino-8-d-arginine vasopressin ress to convulsions and coma. This form of edema rarely leads
[DDAVP]) is used for the treatment of central DI. It can be to hypertension. SIADH should be suspected when any patient
administered IV, subcutaneously (SC), intranasally, or orally. with hyponatremia excretes urine that is hypertonic relative to
degree of injury to the adjacent hypothalamus. The major-

BOX 13-6 n MANAGEMENT OF EXCESS VASOPRESSIN ity of patients who develop DI after hypophysectomy recover
SECRETION*
within a few days to 6 months. Patients with DI second-
Fluid restriction: 500-1000 mL/day ary to head trauma or surgery usually recover after a short
Administer hypertonic saline (3% N/S) for severe hyponatremia. period. Those who continue to have symptoms, and patients
Correct at a rate of no more than 1 mEq/hr, with no more than 12 mEq
with a long history of DI who require surgery, present a chal-
in 24 hours.
Monitor serum sodium every 2 hours.
lenge for the anesthesiologist with regard to perioperative
management.
Perioperative management of DI patients is based on the
Correct fluid and electrolyte imbalances as possible before surgery.
Monitor fluid status (CVP, TEE); patients are at risk of developing extent of the AVP deficiency. Management of a patient with
hypervolemia. complete DI and a total lack of AVP usually does not pres-
Be alert to the possibility of delayed awakening and emergence ent any major problems as long as side effects of the drug are
delirium. avoided and as long as that status is known before surgery.
Just before surgery, such a patient is given the usual dose
*Syndrome of inappropriate antidiuretic hormone secretion (SIADH). of desmopressin intranasally. All the IV fluids given intra-
operatively should be isotonic, to reduce the risk of water
depletion and hypernatremia. Plasma osmolality should
be measured every hour, both intraoperatively and in the
plasma. The following laboratory findings further support the
immediate postoperative period. If the plasma osmolality
diagnosis:
increases above 290 mOsm/L, hypotonic fluids should be
n Urinary sodium greater than 20 mEq/L administered.
n Low blood urea nitrogen and serum levels of creatinine, uric
Excessive Antidiuretic Hormone
acid, and albumin
Patients with SIADH resulting from malignancy have the
n Serum sodium less than 130 mEq/L
usual problems present in malignancy, such as anemia and
n Plasma osmolality less than 270 mOsm/L
malnutrition, often with fluid and electrolyte imbalance as
n Hypertonic urine relative to plasma
well. Perioperatively, they usually have low urine output, high
The response to water loading is a useful means of evaluat- urine osmolality, low serum osmolality, and delayed awaken-
ing the patient with hyponatremia. Patients with SIADH are ing from anesthesia or awakening with mental confusion.
unable to excrete dilute urine, even after water loading. Assay When a patient with SIADH comes to the operating room
of ADH in blood can confirm the diagnosis. for any procedure, fluids are managed by measuring the cen-
Patients with mild to moderate symptoms of water intoxi- tral volume status using central venous pressure (CVP) or pul-
cation can be treated with restriction of fluid intake to 500 to monary artery catheter, transesophageal echocardiography
1000 mL/day. Patients with severe water intoxication and CNS (TEE), and frequent assays of urine osmolarity, plasma osmo-
symptoms may need vigorous treatment, with IV administra- larity, and serum sodium, often into the immediate postopera-
tion of 3% saline solution over several hours at a rate no more tive period (see Box 13-6). Despite the common impression
than 0.05 mL/kg/min, followed by fluid restriction. Sodium that SIADH is frequently seen in elderly patients in the post-
should be monitored every 2 hours and stopped when it operative period, the patient's age and the type of anesthetic
increases by 12 mmol or increases to 130 mmol/L (Box 13-6). have no role in the postoperative development of SIADH. It
Treatment should be directed at the underlying problem. is not unusual to see many patients in the neurosurgical ICU
If SIADH is drug induced, the agent should be withdrawn. suffering from this syndrome. The diagnosis is usually one
Inflammation should be treated with appropriate measures, of exclusion. Patients with SIADH usually require only fluid
and neoplasms should be managed with surgical resection, restriction; hypertonic saline is rarely needed.
irradiation, or chemotherapy, as indicated.
ADRENAL CORTEX
ANESTHETIC CONSIDERATIONS
The abnormalities of ADH function that affect perioperative Physiology
management involve either a relative or absolute lack of ADH
Three major classes of hormones—glucocorticoids, mineralo-
or an excess of ADH. Regardless of the cause, the perioper-
corticoids, and androgens—are secreted by the adrenal cortex.
ative management problems can be grouped into situations
An excess or a deficiency of each hormone class is associ-
with insufficient ADH and situations with excess ADH.
ated with a characteristic clinical syndrome. Glucocorticoids
Insufficient Antidiuretic Hormone are responsible for modulating metabolism and immune
Diabetes insipidus, and thus an insufficient ADH (AVP) level, responses. Blood pressure, vascular tone, fluid volume, and
is a problem in children undergoing posterior fossa craniot- electrolytes are maintained by mineralocorticoids, and andro-
omy and is the most significant complication after hypoph- gens play a role in secondary sexual characteristics and sexual
ysectomy. The severity and duration of DI depend on the function.64
GLUCOCORTICOIDS Overproduction of glucocorticoids can be caused by adre-

The principal glucocorticoid, cortisol, is an essential regulator nal tumors (primary Cushing's disease) or by overstimula-
of carbohydrate, protein, lipid, and nucleic acid metabolism. tion of normal adrenal glands by elevated levels of ACTH
Cortisol exerts its biologic effects by a sequence of steps initi- from pituitary microadenomas (secondary Cushing's disease).
ated by its binding to stereospecific intracellular cytoplasmic Inappropriately low levels of glucocorticoids may result from
receptors. This bound complex stimulates nuclear transcription destruction or atrophy of the adrenal gland itself (primary
of specific mRNA. These mRNAs are then translated to give rise adrenal insufficiency) or from diminished levels of ACTH in
to proteins that mediate the ultimate effects of these hormones.64 pituitary dysfunction (secondary adrenal insufficiency).
Most cortisol is bound to corticosteroid-binding globu- Treatment schedules for glucocorticoid replacement are
lin (CBG, transcortin). It is the relatively small amounts of therefore based not on the measured serum half-life, but on
unbound cortisol that enter cells to induce actions or to be the well-documented, prolonged end-organ effect of these ste-
metabolized. Conditions that induce changes in the amount roids. In the past, hospitalized patients who required chronic
of CBG include liver disease and nephrotic syndrome, both glucocorticoid replacement therapy were usually treated
of which result in decreased circulating levels of CBG, as well twice daily, with a slightly higher dose in the morning than
as estrogen administration and pregnancy, which result in in the evening to simulate the normal diurnal variations in
increased CBG production. Total serum cortisol levels may cortisol levels. For patients who require parenteral “steroid
become elevated or depressed under conditions that alter the coverage” during and after surgery (see later), administra-
amount of bound cortisol and yet the unbound, active form of tion of glucocorticoid every 8 to 12 hours seems appropriate.
cortisol is present in normal amounts. The most accurate mea- Cortisol is inactivated primarily in the liver and is excreted as
sure of cortisol activity is the level of urinary cortisol, that is, 17-hydroxycorticosteroid. Cortisol is also filtered and excreted
the amount of unbound, active cortisol filtered by the kidney. unchanged into the urine. Table 13-4 lists relative potencies of
The serum half-life of cortisol is 80 to 110 minutes; how- glucocorticoids.
ever, because cortisol acts through intracellular receptors, The synthetic glucocorticoids vary in their binding specific-
pharmacokinetics based on serum levels is not a good indi- ity in a dose-related manner. When given in supraphysiologic
cator of cortisol activity. After a single dose of glucocorticoid, doses (> 30 mg/day), cortisol and cortisone bind to mineralo-
the serum glucose level is elevated for 12 to 24 hours. corticoid receptor sites and cause salt and water retention and
The HPA axis is shown in Figure 13-7. Secretion of glu- loss of potassium and hydrogen ions.65,66 When these steroids
cocorticoids is regulated exclusively by pituitary ACTH.65 are administered in maintenance doses of 30 mg/day or less,
ACTH is synthesized from a precursor molecule (preopi- patients require a specific mineralocorticoid for electrolyte
omelanocortin) that breaks down to form an endorphin and volume homeostasis. Many other steroids do not bind
(β-lipoprotropin) and ACTH. ACTH secretion has a diur- to mineralocorticoid receptors, even in large doses, and have
nal rhythm; it is normally greatest during the early-morning minimal mineralocorticoid effect66 (Table 13-4).
hours in men (afternoon in women) and is regulated at least
in part by sleep-wake cycles. Its secretion is stimulated by MINERALOCORTICOIDS
release of corticotropin-releasing factor (CRF) from the Aldosterone, the major mineralocorticoid secreted in humans,
hypothalamus. Cortisol and other glucocorticoids exert neg- comes from the zona glomerulosa of the adrenal cortex,
ative feedback at both pituitary and hypothalamic levels to causes reabsorption of sodium and secretion of potassium and
inhibit secretion of ACTH and CRF. hydrogen ions, and thus contributes to electrolyte and volume
TABLE 13-4 n Cortisol and Synthetic Analogs: Relative Potency and Half-Life
ESTIMATED POTENCY
Common Name Glucocorticoid Mineralocorticoid Biologic Half-Life (hours)
Cortisol 1 1 8-12
Cortisone 0.8 0.8 8-12
Prednisone 4 0.25 12-36
Methylprednisolone 5 0.25 12-36
Triamcinolone 5 0.25 12-36
Dexamethasone 20-30 −/+ 26-54
Fluorohydrocortisone 5 200 —
Desoxycorticosterone 0 15 —
homeostasis. This action is most prominent in the distal renal Adrenal genital syndrome should be ruled out as a p ossible
tubules, but it also occurs in salivary and sweat glands. The cause of hirsutism. These patients are not surgical candidates.
main regulator of aldosterone secretion is the renin-angiotensin Generally, in addition to high 17-ketosteroid levels in the urine,
system. Juxtaglomerular cells in the cuff of the renal arterioles these patients have very high urinary pregnanetriol levels and
are sensitive to decreased renal perfusion pressure or volume elevated 17-OH progesterone blood levels. Patients with
and consequently secrete renin. Renin splits the precursor angio- adrenal genital syndrome are usually managed with mildly
tensinogen (from the liver) into angiotensin I, which is further suppressive doses of corticosteroids.
split by converting enzyme, primarily in the lung, to angiotensin
II. Mineralocorticoid secretion is increased by increased levels EXCESSIVE GLUCOCORTICOIDS
of angiotensin. Glucocorticoid excess, or Cushing's syndrome, resulting from
either endogenous oversecretion or long-term treatment
ANDROGENS with large doses of glucocorticoids, produces a characteris-
Androstenedione and dehydroepiandrosterone, which are tic appearance and a predictable complex of disease states.68
weak androgens arising from the adrenal cortex, constitute The individual appears moon faced and plethoric, having a
major sources of androgens in women. These androgens are centripetal distribution of fat and thin extremities because
converted outside the adrenal glands to testosterone, a potent of muscle wasting. The heart and diaphragm apparently are
virilizing hormone.67 Excess secretion of androgen in women spared the effects of muscle wasting. The skin is thin and eas-
causes masculinization, pseudopuberty, or female pseudo- ily bruised, and striae are often present. Hypertension (from
hermaphroditism. Some tumors convert this androgen to an increases in renin substrate and vascular reactivity caused
estrogenic substance, and feminization results. Some congen- by glucocorticoids) and fluid retention are present in 85% of
ital enzyme defects that cause abnormal levels of androgens patients. Almost two of every three patients also have hyper-
in blood also result in glucocorticoid and mineralocorticoid glycemia resulting from inhibition of peripheral glucose use,
abnormalities. with concomitant stimulation of gluconeogenesis. Patients
The altered sexual differentiation in the presence of such with Cushing's syndrome often have osteopenia as a result
defects requires no specific modification of anesthetic tech- of decreased bone matrix formation and impaired calcium
nique. All syndromes related to abnormal androgen levels absorption. One third of these patients have pathologic frac-
are associated with cortisol deficiency. In patients who have tures (Table 13-5).
associated alterations in glucocorticoid or mineralocorticoid Special preoperative considerations for patients with
activity, anesthetic plans should be modified as outlined in the Cushing's syndrome include regulating diabetes and hyperten-
following sections. sion and ensuring that intravascular fluid volume and electro-
lyte concentrations are normal.69 Ectopic ACTH production
from sites other than the pituitary may cause marked hypoka-
Excessive Adrenocortical Hormones: Hyperplasia,
lemic alkalosis. Treatment with the aldosterone antagonist spi-
Adenoma, and Carcinoma
ronolactone halts the potassium loss and helps mobilize excess
SEX HORMONE–SECRETING TUMORS OF ADRENAL GLANDS fluid. Because of the high incidence of severe osteopenia and
Hirsutism in female patients may be caused by either adrenal the risk of fractures, meticulous attention to patient position-
or ovarian tumor. Adrenal virilizing tumors are almost always ing is necessary. In addition, glucocorticoids are lympholytic
associated with elevated 17-ketosteroid urinary excretion, and immunosuppressive, perhaps increasing the patient's sus-
whereas functioning ovarian tumors tend to produce potent ceptibility to infection.70-72
androgens such as testosterone and dihydrotestosterone, Specific considerations pertain to the surgical approach for
which are not measured as part of the 17-ketosteroids. Rarely, each cause of Cushing's syndrome. For example, almost three
adrenal tumors produce only testosterone and are stimulated fourths of the cases of spontaneous Cushing's disease result
by human chorionic gonadotropin. Similarly, some androgen- from a pituitary adenoma that secretes ACTH. Perioperative
producing ovarian tumors respond to dexamethasone sup- considerations for patients with Cushing's disease caused by
pression. A common cause of hirsutism in females is polycystic pituitary microadenoma may differ from patients with other
ovarian disease, which is associated with bilaterally enlarged adenomas because they may bleed more easily and may have a
ovaries. Extreme feminization in males can occasionally result higher central venous pressure. Thus, during transsphenoidal
from an estrogen-producing tumor of the adrenal gland. tumor resection in Cushing's patients with pituitary microad-
Functioning sex hormone–producing tumors of the adrenal enoma, monitoring central venous pressure may be indicated
gland almost always tend to be unilateral. Pelvic B-mode ultra- to maintain pressure in the low-normal range. Such monitor-
sonography, CT, and MRI are useful modalities for localizing ing is needed only infrequently in other cases of transsphenoi-
lesions. Most patients do not have to be managed with gluco- dal resection of microadenoma.
corticoids during or after surgery. The only exception is the From 10% to 15% of patients with Cushing's syndrome
patient who has associated Cushing's syndrome with cortisol have adrenal overproduction of glucocorticoids (adrenal
excess, for whom management should be as outlined later for adenoma or carcinoma). Patients with Cushing's syndrome
tumors of the adrenal gland. who require bilateral adrenalectomy have a high incidence of
replacement therapy, with the goal of complete adrenal sup-

TABLE 13-5 n Clinical Features of Hyperadrenalism
(Cushing's Syndrome) and Hypoadrenalism
pression. These patients should be considered to have sup-
pressed adrenal function, and glucocorticoid replacement
Cushing's Syndrome Hypoadrenalism should be administered preoperatively.
Central obesity Weight loss
EXCESSIVE MINERALOCORTICOIDS
Proximal muscle weakness Weakness, fatigue, lethargy Excess mineralocorticoid activity leads to sodium reten-
Osteopenia at young age and Muscle and joint pain tion, potassium depletion, hypertension, and hypokalemic
back pain alkalosis. These symptoms constitute primary hyperaldoste-
ronism, or Conn's syndrome, a cause of low-renin hyperten-
Hypertension Postural hypotension and
dizziness sion because renin secretion is inhibited by the effects of the
high aldosterone levels. Primary hyperaldosteronism is pres-
Headache Headache ent in 0.5% to 1% of hypertensive patients who have no other
Psychiatric disorders Anorexia, nausea, abdominal known cause of hypertension. Primary hyperaldosteronism is
pain, constipation, diarrhea most often the result of a unilateral adenoma, although 25%
Purple stria
to 40% of patients may have bilateral adrenal hyperplasia.
Spironolactone therapy should restore intravascular fluid vol-
Spontaneous ecchymoses Hyperpigmentation ume, electrolyte concentrations, and renal function to within
Plethoric facies Hyperkalemia, hyponatremia normal limits preoperatively. The effects of spironolactone are
slow to appear over 1 to 2 weeks. In addition, patients with
Hyperpigmentation Occasional hypoglycemia
Conn's syndrome have a high incidence of ischemic heart
Hirsutism Hypercalcemia disease, and hemodynamic monitoring appropriate for their
degree of cardiovascular impairment should be undertaken.
Acne Prerenal azotemia
A retrospective study indicated that intraoperative stability,
Hypokalemic alkalosis with preoperative control of blood pressure and electrolytes,
Glucose intolerance was better with spironolactone than with other antihyperten-
sive agents.74
Kidney stones
Polyuria
Adrenocortical Hormone Deficiency
Menstrual disorders
GLUCOCORTICOID DEFICIENCY
Increased leukocyte count Withdrawal of steroids or suppression of their adrenal syn-
thesis by steroid therapy is the leading cause of underpro-
duction of corticosteroids. The management of this type of
glucocorticoid deficiency is discussed later (see Perioperative
postoperative complications. The incidence of pneumothorax Stress and Corticoid Supplementation). Other causes of adre-
approaches 20% with adrenal carcinoma resection, requiring nocortical insufficiency include destruction of the adrenal
treatment before the wound is closed. Ten percent of patients gland by cancer (including AIDS), tuberculosis, hemorrhage,
with Cushing's syndrome who undergo adrenalectomy are or an autoimmune mechanism; some forms of congenital
found to have an undiagnosed pituitary tumor. After reduc- adrenal hyperplasia; and administration of cytotoxic drugs
tion of high levels of cortisol by adrenalectomy, the pituitary (see Table 13-5).
tumor enlarges (Nelson's syndrome).73 These pituitary tumors Primary adrenal insufficiency (Addison's disease) is caused
are potentially invasive and may produce large amounts of by a local process within the adrenal gland that leads to destruc-
ACTH and melanocyte-stimulating hormone, thus increasing tion of all zones of the cortex and causes both glucocorticoid
pigmentation. and mineralocorticoid deficiency if bilateral. Autoimmune
Adrenal tumors are discovered incidentally 85% of the disease is the most common cause of primary (nonendoge-
time during screening (and largely unindicated) CT scans. nous) bilateral ACTH deficiency. Autoimmune destruction of
Nonfunctioning adrenal adenomas are found in as many as the adrenals may be associated with other autoimmune dis-
10% of autopsies. Adrenal adenomas are usually treated sur- orders, such as Hashimoto's thyroiditis. Enzymatic defects
gically, and often the contralateral gland will resume func- in cortisol synthesis also cause glucocorticoid insufficiency,
tioning after several months. Frequently, however, the effects compensatory elevations of ACTH, and congenital adrenal
of carcinomas are not cured by surgery, and such patients hyperplasia. Adrenal insufficiency usually develops slowly.
may require administration of inhibitors of steroid synthe- Patients with Addison's disease can develop marked pigmen-
sis such as mitotane (o,p′-DDD[2,2-bis-(2-chlorophenyl- tation (because excess ACTH is present to drive an unproduc-
4-chlorophenyl)-1,1-dichloroethane]). Patients given these tive adrenal gland) and cardiopenia, apparently secondary to
adrenal suppressants also receive chronic glucocorticoid chronic hypotension.
1. Perioperative stress is related to the degree of trauma and

BOX 13-7 n MANAGEMENT OF ACUTE ADRENAL the depth of anesthesia. Deep general or regional anesthe-
CRISIS (ADDISON'S DISEASE)
sia causes the usual intraoperative glucocorticoid surge to
Treat precipitating cause. be postponed until the postoperative period.
Correct hypovolemia. 2. Few patients with suppressed adrenal function have peri-
Correct hyponatremia and hyperkalemia.
operative cardiovascular problems if they do not receive
Administer 0.9% normal saline with dextrose.
Administer IV hydrocortisone, 100 mg every 8 hours, then start oral
supplemental steroids preoperatively.
prednisone or taper as dictated by clinical situation. 3. Occasionally, a patient who habitually takes steroids will
become hypotensive perioperatively, but this event has only
rarely been documented sufficiently to implicate glucocor-
ticoid or mineralocorticoid deficiency as the cause.
Secondary adrenal insufficiency occurs when ACTH secre- 4. Although it occurs rarely, acute adrenal insufficiency can
tion is deficient, often because of a pituitary or hypothalamic be life threatening.
tumor. Treatment of pituitary tumors by surgery or radiation 5. High-dose corticosteroid coverage perioperatively poses
may result in hypopituitarism and consequent adrenal failure. minimal risk to these patients.
If glucocorticoid-deficient patients are not stressed, they
usually have no perioperative problems. However, acute adre- Usually, laboratory data defining pituitary-adrenal ade-
nal (Addisonian) crisis can occur.75 In the preparation of such quacy are not available before surgery. However, rather than
a patient for anesthesia and surgery, hypovolemia, hyper- delay surgery or test most patients, it is assumed that any
kalemia, and hyponatremia should be corrected. Because patient who has taken corticosteroids at any time in the
these patients cannot respond to stressful situations, tradi- preceding year has pituitary-adrenal suppression and will
tionally they are given a maximum stress dose of glucocor- require perioperative supplementation. The current recom-
ticoids (hydrocortisone, 300 mg/70 kg/day) perioperatively. mendation is 100 mg/70 kg/24 hr until a prospective, ran-
Symreng et al.76 gave 25 mg of hydrocortisone phosphate IV domized, double-blind trial in patients receiving physiologic
to adults at the start of surgery, followed by 100 mg IV over doses of corticosteroids is performed. A smaller dose prob-
the next 24 hours. Because using the minimal drug dose that ably can be used.
will cause an appropriate effect is desirable, this latter regimen The physiology of the HPA axis is dramatically altered
seems attractive. Evidence supports that less steroid supple- during critical illnesses such as trauma, surgery, sepsis, and
mentation does not cause problems (Box 13-7). shock. Under perioperative conditions, the adrenal glands
secrete 116 to 185 mg of cortisol daily. Under maximum
MINERALOCORTICOID DEFICIENCY stress, adrenals may secrete 200 to 500 mg daily. Good cor-
Hypoaldosteronism, a condition less common than glucocorti- relation exists between the severity and duration of surgery
coid deficiency, can be congenital or can occur after unilateral and the response of the adrenal gland during major surgery
adrenalectomy or prolonged administration of heparin. It may (e.g., colectomy) and minor surgery (e.g., herniorrhaphy).
also be a consequence of long-standing diabetes and renal fail- In one study the mean maximal plasma cortisol level during
ure. Nonsteroidal inhibitors of prostaglandin synthesis may also major surgery in 20 patients was 47 μg/dL (range, 22-75 μg/dL).
inhibit renin release and exacerbate this condition in patients Values remained above 26 μg/dL for a maximum of 72 hours
with renal insufficiency. Levels of plasma renin activity are below postoperatively. The mean maximal plasma cortisol level
normal and fail to rise appropriately in response to sodium during minor surgery was 28 μg/dL (range, 10-44 μg/dL).77
restriction or diuretics. Most patients have low blood pressure; If random plasma cortisol is measured during acute stress,
rarely, however, a patient may be normotensive or even hyper- a value greater than 34 μg/dL indicates normal pituitary-
tensive. Most symptoms are caused by hyperkalemic acidosis adrenal responsiveness. A value of 15 μg/dL indicates relative
rather than hypovolemia. Patients with hypoaldosteronism can adrenal insufficiency.
have severe hyperkalemia, hyponatremia, and myocardial con- The most sensitive test of adrenal reserve is the ACTH stim-
duction disturbances. These defects can be treated successfully ulation test. To test pituitary-adrenal sufficiency, after deter-
with mineralocorticoids (9α-fluorocortisone, 0.05-0.1 mg/day) mining baseline plasma cortisol level, 250 μg of synthetic
preoperatively. Doses must be carefully titrated and monitored ACTH (cosyntropin) is given and plasma cortisol measured
so that hypertension can be avoided. 30 to 60 minutes later. An increment in plasma cortisol of 7
to 20 μg/dL or more is normal. A normal response indicates a
recovery of pituitary-adrenal axis function. A lesser response
Perioperative Stress and Corticoid
usually indicates pituitary-adrenal insufficiency, possibly
Supplementation
requiring perioperative supplementation with corticosteroids.
Many reports (mostly anecdotal) concerning normal adre- One approach to these patients is to administer 50 to 75 mg
nal responses during the perioperative period and responses of hydrocortisone every 6 hours for 1 week and then taper. In
of patients taking steroids for other diseases indicate the patients who survive their critical illness, the pituitary-adrenal
following: function can be re-evaluated after resolution.
ADRENAL MEDULLA than 0.1% of all cases of hypertension, pheochromocytomas

have important implications to the anesthesiologist. Patients
Pheochromocytomas and paragangliomas are catecholamine- with unrecognized pheochromocytomas can have high mor-
producing tumors derived from the sympathetic and para- bidity and mortality.
sympathetic nervous system. Cells of neural crest origin are In more than 85% of cases, pheochromocytomas are spo-
capable of developing into catecholamine-secreting tumors; radic tumors of unknown cause that are localized in the
indeed, catecholamine tumors have been reported in neu- medulla of one adrenal gland; however, these vascular tumors
ral crest sites ranging from the neck to the inguinal ligament. can occur anywhere. They are found in the right atrium,
About 10% of the pheochromocytomas are bilateral, 10% spleen, broad ligament of the ovary, or Zuckerkandl organs
extra-adrenal, and 10% malignant. (bodies) at the bifurcation of the aorta. Malignant spread
occurs in less than 15% of patients with pheochromocytoma,
Pheochromocytoma
usually through venous and lymphatic channels, with a predi-
Pheochromocytomas have been reported as part of the lection for the liver. Often, bilateral tumors are present in the
MEN-IIA and MEN-IIB syndromes and in association with familial form.78
neuroectodermal dysplasias, including neurofibromatosis 1 Catecholamines, are the physiologic transmitters released
(NF1), tuberous sclerosis, Sturge-Weber syndrome, and von from the terminals of the postganglionic sympathetic nervous
Hippel–Lindau disease (Table 13-6). Although causing less system. Synthesis of catecholamines begins in the postgangli-
onic nerve cell bodies when tyrosine is hydroxylated in the
rate-limiting step to DOPA; DOPA is decarboxylated to dopa-
TABLE 13-6 n Syndromes Associated with Adrenal mine, and, in most cells dopamine is hydroxylated to norepi-
Gland Tumors nephrine. In the adrenal gland, in rare parts of the CNS, and
at some ganglia, norepinephrine can be converted by phenyl-
Syndrome Clinical Features ethanolamine-N-transferase to epinephrine. The release of
Bechwith-Wiedemann Adrenocortical carcinoma dopamine, norepinephrine, and epinephrine occurs both
syndrome Omphalocele basally and in response to physiologic and pharmacologic
Macroglossia stressors such as hypotension (through baroreceptors), low tis-
Macrosomia
sue perfusion, hypoxia, hypoglycemia, anger, determination,
Hemihypertrophy
Hypoglycemia fear, and anxiety. Such release from the sympathetic nervous
Visceromegaly system can be generalized or localized. Most pheochromocy-
Renal abnormalities tomas are independent of these physiologic stressors. Some
Li-Fraumeni syndrome Adrenocortical carcinoma
pheochromocytomas are under neurogenic control, with
Breast cancer increased release of catecholamines stimulated by physiologic
Leukemia and pharmacologic stressors. However, much of the release of
Sarcoma catecholamines from pheochromocytomas is not controlled
Brain tumors by neurogenic influence. This lack of neurologic control is
Carney's complex Mucocutaneous pigmented lesion used in the clonidine suppression test for pheochromocytoma.
Myxomas Several studies found that the triad of paroxysmal sweat-
Multiple thyroid follicular ing, hypertension, and headache strongly suggests pheochro-
adenomas
mocytoma. These are the symptoms experienced when given
Primary pigmented nodular
adrenocortical disease an infusion of epinephrine. Physical examination of a patient
Pituitary growth hormone– with a pheochromocytoma is usually unrewarding unless the
producing adenoma patient is observed during an attack. Occasionally, palpation of
MEN-II Pheochromocytoma
the abdomen causes the bladder or rectum to rub against the
Mucosal neuromas tumor and stimulates release of catecholamines; however, lab-
Ganglioneuromatosis of intestine oratory measurement of catecholamines or their metabolites
Marfanoid habitus has been the standard method of diagnosis. Half of all patients
Neurofibromatosis 1 Pheochromocytoma with pheochromocytoma have continuous hypertension with
(NF1) Neurofibromas occasional paroxysms, and another 40% have paroxysmal
Café au lait spots hypertension. Labile hypertension or the triad (hypertension,
Optic gliomas headache, sweating) usually is an indication for urine testing.
Lisch nodules
Urine tests have become a mainstay of diagnosis. The usual
Short stature
Learning disabilities urine tests used measure 3-methoxy-4-hydroxymandelic acid,
Macrocephaly or metanephrines, or native catecholamines per milligram
of creatine secreted. If the results of three 24-hour collec-
von Hippel–Lindau Same as for NF1
disease
tions of urine are normal, a pheochromocytoma can usually
be ruled out. Catecholamine levels in urine and plasma are
diagnostic when elevated to three times the normal median

value. Sensitivity and specificity of biochemical tests vary BOX 13-8 n MANAGEMENT OF PHEOCHROMOCYTOMA
greatly and are important when considering borderline eleva- Treat hypertension with alpha-adrenergic blockers
tions; the results of various tests may be combined to reach a (phenoxybenzamine, prazosin, labetalol).
diagnosis.79 Add β-blockers after initiation and titration of α-blockers.
Metyrosine can be used to decrease production of catecholamines.
Once the diagnosis of pheochromocytoma is made, the
Correct hypovolemia, if indicated.
tumor must be localized and pretreated before surgical resec-
tion. The protocol for localizing these often small tumors now Anesthetic Considerations
Prepare for intraoperative hypertension and hypotension
favors MRI, which replaced CT, which in turn had replaced
(nitroprusside infusion, IV phentolamine, phenylephrine, and
urography and venous sampling. When such techniques do norepinephrine).
not yield definitive results, m-iodobenzylguanidine (ioben- Consider invasive monitoring of blood pressure (A-line).
guane) iodine 129 (129I) scanning or positron emission tomog- Consider central venous pressure monitoring and central line for
raphy (PET) is considered. delivery of vasoactive drugs.
ANESTHETIC CONSIDERATIONS
Complete tumor removal is the therapeutic goal. Perioperative Most patients require treatment for 10 to 14 days, as deter-
morbidity and mortality associated with pheochromocytoma mined by the time needed for BP stabilization and amelio-
are well reported.80-83 Mortality for patients with pheochromo- ration of symptoms. The patient who does not complain of
cytoma is usually the result of myocardial failure, myocardial nasal stuffiness is not ready for surgery. Pheochromocytomas
infarction, or hemorrhage (hypertensive) into the myocardium spread slowly, allowing the patient's preoperative condition to
or brain. Persistently elevated catecholamine levels may result be optimized with medical therapy. Painful or stressful events
in catecholamine myocarditis. This cardiomyopathy appears to such as intubation often cause an exaggerated catecholamine
pose an extra risk for patients, but it can be treated success- response in less-anesthetized patients with pheochromocy-
fully by alpha-adrenergic blockade preoperatively. Patients toma. This response is caused by release of catecholamines
with pheochromocytoma should receive α-blockers preop- from nerve endings that are “loaded” by the reuptake process.
eratively to reduce the perioperative complications of hyper- Stresses may cause catecholamine levels of 200 to 2000 pg/mL
tensive crisis, the wide fluctuations in blood pressure during in normal patients. For the patient with pheochromocytoma,
intraoperative manipulation of the tumor (especially until even simple stresses can lead to blood catecholamine levels of
venous drainage is obliterated), and perioperative myocardial 2000 to 20,000 pg/mL. Squeezing the tumor, however gently,
dysfunction. Perioperative mortality associated with the exci- or infarction of the tumor with release of products onto peri-
sion of pheochromocytoma was reduced with the introduction toneal surfaces, can result in blood levels of 200,000 to 1 mil-
of preoperative α-blocker therapy and when it was recognized lion pg/mL, a potentially disastrous situation that should be
that these patients often had hypovolemia preoperatively.84 anticipated and avoided. The physician should ask for a tem-
Preoperative therapy consisting of α-adrenergic blockade porary delay of surgery, if at all possible, during which the
with phenoxybenzamine, prazosin, or labetalol alleviates the rate of nitroprusside infusion will be increased. Although spe-
patient's symptoms, favors a successful outcome, and allows cific anesthetic drugs have been recommended for patients
re-expansion of intravascular plasma volume by eradicating with pheochromocytoma, optimal preoperative preparation,
the vasoconstrictive effects of high levels of catecholamines. careful and gradual induction of anesthesia, and good com-
This re-expansion of fluid volume is often accompanied by munication between surgeon and anesthesiologist are most
a decreased hematocrit. Because some patients are sensitive, important.
phenoxybenzamine should initially be administered at 10 to Virtually all anesthetic agents, muscle relaxants, and tech-
20 mg orally two or three times daily. Most patients require niques have been used successfully for patients with pheochro-
60 to 250 mg/day. The efficacy of the therapy is judged by the mocytoma, and all are associated with a high rate of transient
reduction of symptoms (especially sweating) and by BP sta- intraoperative dysrhythmias. The theoretic advantages or dis-
bilization. For patients with catecholamine myocarditis, as advantages of some agents have not been demonstrated clini-
evidenced by often-localized ST-segment and T-wave ECG cally. It is prudent to avoid drugs that cause histamine release,
changes, preoperative and long-term α-blockade (15 days to including morphine and droperidol (which can cause tran-
6 months) has been effective in resolving the clinical and ECG sient hypertension).
alterations80 (Box 13-8). Phenylephrine or dopamine is used for treatment of hypo-
Beta-adrenergic receptor blockade with concomitant tension, whereas nitroprusside is preferable when hypertension
administration of phenoxybenzamine is suggested for patients occurs.29 Phentolamine, previously a mainstay of intraopera-
with persistent dysrhythmias or tachycardia. The β-receptor tive therapy, has overlong onset and duration of action. After
blockade should not be started without α-blockade, because the venous supply has been secured, some patients become
unopposed β-blockade could produce dangerous vasocon- hypotensive and occasionally require a relatively large infu-
striction and hypertension; with hypertension reported only sion of catecholamines. On rare occasions, patients remain
rarely, however, perhaps no firm rules are necessary. hypertensive intraoperatively. Postoperatively, about 50% of
patients have hypertension for 1 to 3 days and have greatly ele- insulinoma tend to have high levels of proinsulin (> 20% of
vated but declining plasma catecholamine levels. After 3 to 10 total insulin) in plasma and C-peptide levels that parallel insu-
days, all but 25% become normotensive. Catecholamine levels lin levels.
do not return to normal for 10 days; therefore, early measure-
ment of urine concentrations is usually not helpful in ensuring
Hypoglycemia and Hyperinsulinism (Islet Cell
complete catecholamine removal from tissue.
Tumors of Pancreas)
Because pheochromocytomas may be hereditary, it is
important to screen other family members. They are advised Almost all the signs and symptoms in patients with insuli-
to inform the anesthesiologist about their potential for occult nomas are directly related to prolonged hypoglycemic states.
pheochromocytoma should they require surgery in the future. Hypoglycemia is a clinical syndrome with many causes that
results in plasma glucose levels sufficiently low to promote
secretion of catecholamines and to impair CNS function
PANCREAS (Fig. 13-9). The two major classifications of hypoglycemia can
be distinguished by the relationship of symptoms to meals.
Physiology
Reactive hypoglycemia occurs 2 to 4 hours after ingestion of
Pancreatic islets are composed of at least three cell types: food and is associated primarily with adrenergic symptoms.
alpha cells that secrete glucagon, beta cells that secrete insu- Fasting hypoglycemia occurs more than 6 hours after a meal,
lin, and delta cells that contain secretory granules. Insulin is is precipitated by exercise, and is often associated with CNS
first synthesized as proinsulin, converted to insulin by pro- symptoms.
teolytic cleavage, and then packaged into granules within the Insulinomas usually cause fasting hypoglycemia. Reactive
β cells. A large quantity of insulin, normally about 200 units, hypoglycemia can be caused by alimentation, impaired glu-
is stored in the pancreas, and continued synthesis is stimu- cose tolerance, or functional causes. Alimentary hypoglycemia
lated by glucose. There is basal, steady-state release of insulin is associated with low levels of plasma glucose 2 to 3 hours
from the β granules and additional release that is controlled after ingestion of food by patients who have rapid gastric
by stimuli external to the β cell. Basal insulin secretion emptying (e.g., after subtotal gastrectomy, vagotomy, or pylo-
continues in the fasted state and is key to the inhibition of roplasty). Rapid gastric emptying and rapid absorption of glu-
catabolism and ketoacidosis. Glucose and fructose are the cose may result in excessive release of insulin, falling glucose
primary regulators of insulin release. Other stimulators of levels, and reactive hypoglycemia. Impaired glucose tolerance
insulin release include amino acids, glucagon, GI hormones resulting in hypoglycemia, an early symptom of diabetes, usu-
(gastrin, secretin, cholecystokinin-pancreozymin, enteroglu- ally occurs 4 to 5 hours after ingestion of food. Because the
cagon), and acetylcholine. Epinephrine and norepinephrine brain is extremely sensitive to glucose utilization, CNS effects
inhibit insulin release by stimulating α-adrenergic receptors, often manifest with hypoglycemia. Most patients show CNS
and they stimulate its release at β-adrenergic receptors. symptoms that include visual disturbances, dizziness, confu-
A normal plasma glucose level requires adequate endog- sion, epilepsy, lethargy, transient loss of consciousness, and
enous substrate for glucose production, normal enzymatic coma. Perhaps because of the many CNS manifestations of
mechanisms capable of converting glycogen and other sub- insulinomas, many patients with these tumors have been mis-
strates to glucose, and normal hormonal modulation of glu- diagnosed as having psychiatric illness.
coneogenesis.85 The rise in glucose levels after a meal causes Less frequent but nevertheless important manifestations
release of insulin from β cells in the pancreas. The mag- of insulinomas involve the cardiovascular system. More than
nitude of the insulin response depends partly on other GI 10% of insulinoma patients have palpitations, tachycardia,
hormones secreted after food intake, the action of which or hypertension (or all three). These symptoms are probably
accounts for the greater rise in insulin levels after oral than related to catecholamine release secondary to hypoglycemia,
after parenteral administration of glucose. Release of insu- and about 9% of the patients have either severe hunger or GI
lin can also be triggered by β-adrenergic stimuli believed to upset, including cramping, nausea, and vomiting. Other inves-
act by increasing cAMP levels. Insulin release is inhibited by tigators have noted obesity or weight gain as a symptom. The
α-adrenergic stimuli. The action of insulin tends to return symptoms of hypoglycemia caused by insulinoma may occur
the levels of plasma glucose to normal within 1 to 2 hours at a particular time of day that is associated with a low blood
after completion of a meal. glucose level, especially 6 hours or more after eating, after fast-
When endogenous nutrients are not available, plasma glu- ing for a time, or in the early morning.
cose levels are maintained by hepatic glycogenolysis and then Fasting hypoglycemia results from inadequate hepatic
gluconeogenesis.86 Insulin levels are low in these patients, and glucose production or from overutilization of glucose in the
glucagon, GH, cortisol, and catecholamines play important peripheral tissues. The causes of inadequate production of
roles in gluconeogenesis. Insulin is normally secreted from glucose during the fasting state may be hormone deficiencies,
the pancreas in response to elevated levels of blood glucose as enzyme defects, inadequate substrate delivery, acquired liver
a prohormone (proinsulin). This hormone is rapidly cleaved disease, or drugs. Overutilization of glucose may occur in the
into C peptide and insulin in the portal vein. Patients with presence of either elevated or appropriate insulin levels.
Causes of hypoglycemia
Fasting (postabsorptive) Reactive (postprandial)

hypoglycemia hypoglycemia
Drugs: Alimentary (postgastrectomy)
Insulin, sulfonylureas, ethanol,
quinine, pentamidine Noninsulinoma pancreatogenous
hypoglycemia syndrome:
Critical illnesses: Following Roux-en-Y gastric bypass
Hepatic, renal, and cardiac failure,
sepsis Hereditary fructose intolerance
Hormone deficiencies: Idiopathic

Cortisol, growth hormone,
glucagon, and epinephrines
Non-beta cell tumors
Hyperinsulinism:
Insulinoma
Other beta-cell disorders
Insulin secretagogues
Autoimmune
Ectopic insulin secretion
Disorders of infancy or childhood:

Congenital hyperinsulinism
Inherited enzyme deficiencies
FIGURE 13-9 Causes of hypoglycemia.
To define the diagnosis of insulinomas, Whipple intro- ANESTHETIC CONSIDERATIONS

duced a triad of diagnostic criteria, which have been mod- Most patients who come to surgery with the diagnosis of
ified to include (1) symptoms of hypoglycemia brought reactive or fasting hypoglycemia do not require special
on by fasting and exercise; (2) blood glucose levels, while intraoperative care other than frequent assays of blood glu-
symptoms are present, of less than 40 mg/dL in females cose levels and adequate infusion of dextrose. The varia-
and less than 45 mg/dL in males; and (3) relief of these tions in plasma glucose levels are exaggerated in patients
symptoms by administration of glucose, either orally or with functional islet cell adenoma. An intraoperative rise
intravenously. If an insulinoma is suspected and Whipple's in blood glucose, sometimes quite striking, is thought
triad is confirmed, several tests may be done with which to be evidence of tumor removal.87 Therefore, two other
one can differentiate insulinoma from other causes of methods of intraoperative glucose management have been
hypoglycemia. designed not to mask this hyperglycemic rebound. In the
With the ability to determine insulin levels as well as glu- first approach, glucose infusion is stopped approximately 2
cose levels, the diagnosis is made with even more certainty. hours before surgery. Blood glucose is monitored frequently,
During a prolonged fast in patients with insulinoma, hypo- but no glucose is administered unless the level drops below
glycemia develops because of a relative underproduction a certain value.
of glucose by the liver rather than because of increased glu- Administration of insulin to hyperglycemic patients dur-
cose utilization. High levels of C peptide and proinsulin levels ing and after surgery is aimed at short-term control of glu-
greater than 20% of total insulin measured in blood are also cose levels. Intraoperatively, the aim should be to keep the
helpful. Selective celiac CT angiography or MRI of the pan- blood glucose levels above 100 mg/dL but less than 180 mg/
creatic region is often used for localization of tumors before dL, administering regular insulin intravenously. Frequent
surgical exploration. monitoring of glucose is continued and glucose infusion
Medical management of insulin-secreting tumors is often titrated to achieve the goal. The aim is to keep the blood glu-
difficult but has been simplified by somatostatin, before cose level higher than the level at which the patient becomes
and during surgery and when surgery fails to remove all the symptomatic while awake. Blood glucose also is monitored in
tumor(s). Surgical treatment of insulin-secreting islet cell the postoperative period because hyperglycemia and its com-
tumors involves their removal, usually from the pancreas, plications can occur. Muir et al.88 reviewed 39 patients who
their usual location. About 13% of patients have more than underwent surgery for insulinoma. After tumor removal, all
one adenoma. Most insulinomas are benign; approximately patients except one had an increase in plasma glucose concen-
one third of malignant tumors are found at laparotomy to have tration. All patients subsequently proved to be cured, whereas
metastasized to the liver. the patient who had a hyperglycemic response was later shown
not to be cured. In six patients whose blood glucose concen- two broad categories of DM are designated type 1 and type
tration increased after tumor resection, the rise was less sharp 2 (Fig. 13-10). Both types of diabetes are preceded by a
than that before tumor removal. phase of abnormal glucose homeostasis as the pathogenic
Perioperative control of glucose levels is aimed at euglyce- processes progress. Type 1 DM is the result of complete or
mia, with either glucose infusion or an artificial β cell. near-total insulin deficiency. Type 2 DM is a heterogeneous
group of disorders characterized by variable degrees of insu-
lin resistance, impaired insulin secretion, and increased glu-
Diabetes Mellitus
cose production. Other etiologies for DM include specific
Diabetes mellitus (DM) is a common condition with far- genetic defects in insulin secretion or action, metabolic
reaching implications. “Diabetes mellitus” refers to a group abnormalities that impair insulin secretion, mitochondrial
of common metabolic disorders that share the phenotype of abnormalities, and a host of conditions that impair glucose
hyperglycemia. Several distinct types of DM are caused by a tolerance. The fourth variety is related to glucose intoler-
complex interaction of genetics and environmental factors. ance that develops during pregnancy and is called gesta-
Depending on the etiology of the DM, factors contributing to tional diabetes. It is important to know the various types of
hyperglycemia include reduced insulin secretion, decreased diabetes because of their distinct therapeutic implications.
glucose utilization, and increased glucose production. The Furthermore, classifying patients into insulin-dependent
metabolic dysregulation associated with DM causes second- (IDDM) and non-insulin-dependent (NIDDM) groups is
ary pathophysiologic changes in multiple organ systems. In confusing and now considered obsolete.
the United States, DM is the leading cause of end-stage renal
disease (ESRD), nontraumatic lower-extremity amputations, ACUTE COMPLICATIONS
and adult blindness. It also predisposes to cardiovascular dis- Diabetic patients are subject to a series of long-term com-
eases. Surgical mortality rates for the diabetic population aver- plications resulting from cataracts, retinopathy, neuropathy,
age five times higher than for the nondiabetic population.89 nephropathy, and angiopathy and leading to considerable
Diabetes mellitus is classified on the basis of the patho- morbidity and premature mortality. Many complications
genic process that leads to hyperglycemia, in contrast to bring the diabetic patient to surgery; more than 50% of all dia-
earlier criteria such as age at onset or type of therapy. The betic patients require surgery at some time. However, acute
Etiologic classification of
diabetes mellitus
Type I Type II Specific types Gestational

diabetes diabetes of diabetes diabetes
Immune-mediated
idiopathic
Genetic defects of Genetic defects Genetic syndromes Uncommon Drug or chemical Diseases of Infections Endocrinopathies
beta-cell function in insulin action associated with forms of induced exocrine pancreas
diabetes immune-mediated
Hepatocyte nuclear diabetes Glucocorticoids Congenital rubella
transcription factor (HNF)4 Wolfram’s syndrome Pentamidine Cytomegalovirus
Glucokinase Down syndrome Nicotinic acid Coxsackievirus
HNF-1 Klinefelter’s syndrome Diazoxide
Turner’s syndrome Beta-adrenergic agonists
Insulin promoter factor-1 Friedreich’s ataxia Thiazides
Neuro01 Huntington’s chorea Hydantoins
Mitochondrial DNA Laurence-Moon-Biedl syndrome Asparaginase
Subunits of ATP-sensitive Myotonic dystrophy Alpha-interferon
potassium channel Porphyria Protease inhibitors
Proinsulin or insulin Prader-Willi syndrome Antipsychotics
Epinephrine
Type A insolin resistance “Stiff-person” syndrome, Pancreatitis Acromegaly

Leprechaunism anti-insulin receptor Pancreatectomy Cushing’s syndrome
Rabson-Mendenhall syndrome antibodies Neoplasia Glucagonoma
Lipodystrophy syndromes Cystic fibrosis Pheochromocytoma
Hemochromatosis Hyperthyroidism
Fibrocalculous pancreatopathy Somatostatinoma
Mutations in carboxyl ester lipase Aldosteronoma
FIGURE 13-10 Etiologic classification of diabetes mellitus.
complications are most life threatening and include hypogly- lactic acid in lactic acidosis, increased organic acids from renal
cemia, diabetic ketoacidosis, and hyperglycemic hyperosmo- insufficiency, or all three. In ketoacidosis the plasma levels of
lar nonketotic coma. acetoacetate, β-hydroxybutyrate, and acetone are increased.
Plasma and urinary ketones are measured semiquantitatively
Hyperglycemic Hyperosmolar State
with Ketostix and Acetest tablets. The role of bicarbonate ther-
Hyperglycemic hyperosmolar nonketotic diabetic coma is
apy in diabetic ketoacidosis is controversial. Myocardial func-
characterized by elevated serum osmolality (> 330 mOsm/L)
tion and respiration are known to be depressed at a blood pH
and elevated blood glucose level (> 600 mg/dL) with mild or no
below 7.0 to 7.10; however, rapid correction of acidosis with
acidosis. Trauma or infection in type 2 diabetic patients usually
bicarbonate therapy may result in alterations in CNS func-
leads to this state rather than to ketoacidosis. Hyperglycemia
tion and structure. The alterations may be caused by (1) para-
induces marked osmotic diuresis and dehydration, enhanc-
doxical development of cerebrospinal fluid and CNS acidosis
ing the hyperosmolar state; this can result in failure to emerge
resulting from rapid conversion of bicarbonate to carbon diox-
from anesthesia and persistent coma. Serum electrolyte values
ide and diffusion of the acid across the blood-brain barrier,
are often normal, although a widened anion gap may indicate
(2) altered CNS oxygenation with decreased cerebral blood
lactic acidosis or a uremic state.
flow, and (3) development of unfavorable osmotic gradients.
Ketoacidosis After treatment with fluids and insulin, β-hydroxybutyrate
Many diabetic patients who need emergency surgery for levels decrease rapidly, whereas acetoacetate levels may remain
trauma or infection have significant metabolic decompen- stable or even increase before declining. Plasma acetone levels
sation, including ketoacidosis. Often the time available for remain elevated for 24 to 42 hours, long after blood glucose,
patient stabilization is limited, but even a few hours may be β-hydroxybutyrate, and acetoacetate levels have returned to
sufficient to correct potentially life-threatening fluid and elec- normal; the result is continuing ketonuria. Persistent keto-
trolyte disturbances. It is futile to delay surgery in an attempt sis, with a serum bicarbonate level of less than 20 mEq/L in
to eliminate ketoacidosis completely if the underlying sur- the presence of a normal glucose level, represents a contin-
gical condition will lead to further metabolic deterioration. ued need for intracellular glucose and insulin for reversal of
Intraoperative cardiac dysrhythmias and hypotension result- lipolysis.
ing from ketoacidosis are less likely to occur if volume deple- The most important electrolyte disturbance in diabetic
tion and hypokalemia are at least partly treated. ketoacidosis is depletion of total body potassium. The defi-
Insulin therapy is initiated with an IV bolus of regular cits range from 3 mEq/kg up to 10 mEq/kg. Rapid declines in
insulin, 0.1 unit/kg, followed by continuous insulin infusion serum potassium level occur, reaching a nadir within 2 to 4
at 0.1 unit/kg/hr. Regular monitoring of glucose, potassium, hours after the start of IV insulin administration. Aggressive
and pH is recommended. Because the number of insulin- replacement therapy may be required. The potassium admin-
binding sites is limited, the maximum rate of glucose decline istered moves into the intracellular space with insulin as the
is fairly constant, averaging 75 to 100 mg/dL/hr, regardless of acidosis is corrected. Potassium is also excreted in the urine
the insulin dose. During the first 1 to 2 hours of fluid resusci- with the increased delivery of sodium to the distal renal tubules
tation, the glucose level may fall more precipitously. When the that accompanies volume expansion. Phosphorus deficiency
serum glucose concentration reaches 250 mg/dL, 5% dextrose in ketoacidosis caused by tissue catabolism, impaired cellular
should be added to the IV fluid.90 uptake, and increased urinary losses may result in significant
The volume of fluid required for therapy varies with over- muscular weakness and organ dysfunction. The average phos-
all deficits, ranging from 3 to 5 L but as high as 10 L. Despite phorus deficit is approximately 1 mmol/kg. Replacement may
losses of water in excess of losses of solute, sodium levels are be needed if the plasma concentration falls below 1.0 mg/dL.
generally normal or reduced. Factitious hyponatremia caused
by hyperglycemia or hypertriglyceridemia may result in this PREOPERATIVE MANAGEMENT OF HYPERGLYCEMIA
seeming contradiction. The plasma sodium concentration Prior to the past decade, little attention was paid to the control
decreases by about 1.6 mEq/L for every 100-mg/dL increase of hyperglycemia in the perioperative period or in the acute
in plasma glucose concentration above normal. Initially, nor- phase of critical illness managed in the ICU. “Permissive” or
mal saline is infused at 250 to 1000 mL/hr, depending on the stress-induced hyperglycemia was generally accepted as the
degree of volume depletion and the patient's cardiac status. norm, defined as a transient response to the stress of an acute
About one third of the estimated fluid deficit is corrected in injury or illness.92 Observational studies have reported sig-
the first 6 to 8 hours, with the other two thirds corrected over nificant prevalence of hyperglycemia in hospitalized patients;
the next 24 hours. It may be prudent to monitor left ventricu- 70% of diabetic patients with acute coronary syndrome and
lar volume in diabetic patients who have a history of signifi- 80% of cardiac surgery patients in the perioperative period
cant myocardial dysfunction.91 may develop hyperglycemia.93 Van den Berghe's landmark
The degree of acidosis is determined by measurement of 2001 paper94 demonstrated for the first time a mortality ben-
arterial blood gases and an increased anion gap. Acidosis efit of tight glucose control in the ICU. From this study origi-
with an increased anion gap (at least 16 mEq/L) in an acutely nated the concept of intensive insulin therapy (IIT) as a means
ill diabetic patient may be caused by ketones in ketoacidosis, of normalizing elevated glucose levels in critically ill patients.
IIT is defined by a target glucose range of 80 to 110 mg/dL, 3. Zhang Y, Nose V: Endocrine tumors as part of inherited tumor syn-
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1057, 1978.
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Diseases of The Endocrine System

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Diseases of The Endocrine System

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C H A P T E R

n If rapid parathyroid hormone assay is contemplated intra-

of underproduction of corticosteroids. If not stressed,

Neonatal severe Occurs in childhood

increasing calcium reabsorption from bone and by promot-

Excessive Excessive Excessive Primary increase in Hypercalcemia Other

Alterations in CaSR Milk-alkali Hyperthyroidism Other endocrine

Low parathyroid hormone levels High parathyroid hormone levels

Parathyroid Parathyroid Reduced Vitamin D PTH hormone Drugs Other

Familial adenomatous Papillary thyroid carcinoma TSH (short feedback)

Cowden's disease Thyroid cancer Thyroid

Primary Thyrotoxicosis without Secondary

Graves’ disease Subacute TSH-secreting

Drugs: iodine excess

Usually, symptoms of hypothyroidism are subclinical,

Primary Transient Secondary

TABLE 13-3 n Syndromes Associated with Pituitary

Input from internal Major causes of hypopituitarism

Mass lesions: Mass lesions:

Pituitary surgery Radiation:

Genetic diseases: Infections:

Destruction of the pituitary by tumor (i.e., chromophobe

or prevention of hyperosmolarity of body fluids and dehydra-

degree of injury to the adjacent hypothalamus. The major-

GLUCOCORTICOIDS Overproduction of glucocorticoids can be caused by adre-

TABLE 13-4 n Cortisol and Synthetic Analogs: Relative Potency and Half-Life

Common Name Glucocorticoid Mineralocorticoid Biologic Half-Life (hours)

Cortisone 0.8 0.8 8-12

Prednisone 4 0.25 12-36

Methylprednisolone 5 0.25 12-36

Triamcinolone 5 0.25 12-36

Dexamethasone 20-30 −/+ 26-54

replacement therapy, with the goal of complete adrenal sup-

1. Perioperative stress is related to the degree of trauma and

ADRENAL MEDULLA than 0.1% of all cases of hypertension, pheochromocytomas

diagnostic when elevated to three times the normal median

Fasting (postabsorptive) Reactive (postprandial)

Hormone deficiencies: Idiopathic

Non-beta cell tumors

Disorders of infancy or childhood:

To define the diagnosis of insulinomas, Whipple intro- ANESTHETIC CONSIDERATIONS

Type I Type II Specific types Gestational

Type A insolin resistance “Stiff-person” syndrome, Pancreatitis Acromegaly

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TABLE 13-3 n Syndromes Associated with Pituitary